Kenneth R. McQuaid, MD
SYMPTOMS & SIGNS OF GASTROINTESTINAL DISEASE
ESSENTIALS OF DIAGNOSIS
Epigastric pain or burning, early satiety, or postprandial fullness.
Endoscopy is warranted in patients with alarm features or in those older than 55 years.
All other patients should first undergo testing for Helicobacter pylori or a trial of empiric proton pump inhibitor.
Dyspepsia refers to acute, chronic, or recurrent pain or discomfort centered in the upper abdomen. An international committee of clinical investigators (Rome III Committee) has defined dyspepsia as epigastric pain or burning, early satiety, or postprandial fullness. Heartburn (retrosternal burning) should be distinguished from dyspepsia. When heartburn is the dominant complaint, gastroesophageal reflux is nearly always present. Dyspepsia occurs in 15% of the adult population and accounts for 3% of general medical office visits.
Acute, self-limited “indigestion” may be caused by overeating, eating too quickly, eating high-fat foods, eating during stressful situations, or drinking too much alcohol or coffee. Many medications cause dyspepsia, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics (metronidazole, macrolides), diabetes drugs (metformin, alpha-glucosidase inhibitors, amylin analogs, GLP-1 receptor antagonists), antihypertensive medications (angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers), cholesterol-lowering agents (niacin, fibrates), neuropsychiatric medications (cholinesterase inhibitors [donepezil, rivastigmine]), SSRIs (fluoxetine, sertraline), serotonin-norepinephrine-reuptake inhibitors (venlafaxine, duloxetine), Parkinson drugs (dopamine agonists, monoamine oxidase [MAO]-B inhibitors), corticosteroids, estrogens, digoxin, iron, and opioids.
This is the most common cause of chronic dyspepsia. Up to three-fourths of patients have no obvious organic cause for their symptoms after evaluation. Symptoms may arise from a complex interaction of increased visceral afferent sensitivity, gastric delayed emptying or impaired accommodation to food, or psychosocial stressors. Although benign, these symptoms may be chronic and difficult to treat.
Peptic ulcer disease is present in 5–15% of patients with dyspepsia. Gastroesophageal reflux disease (GERD) is present in up to 20% of patients with dyspepsia, even without significant heartburn. Gastric or esophageal cancer is identified in 0.25–1% but is extremely rare in persons under age 55 years with uncomplicated dyspepsia. Other causes include gastroparesis (especially in diabetes mellitus), lactose intolerance or malabsorptive conditions, and parasitic infection (Giardia, Strongyloides, Anisakis).
Although chronic gastric infection with H pylori is an important cause of peptic ulcer disease, it is an uncommon cause of dyspepsia in the absence of peptic ulcer disease. The prevalence of H pylori–associated chronic gastritis in patients with dyspepsia without peptic ulcer disease is 20–50%, the same as in the general population.
Pancreatic carcinoma and chronic pancreatitis may initially be mistaken for dyspepsia but usually are associated with more severe pain, anorexia and rapid weight loss, steatorrhea, or jaundice.
The abrupt onset of epigastric or right upper quadrant pain due to cholelithiasis or choledocholithiasis should be readily distinguished from dyspepsia.
Diabetes mellitus, thyroid disease, chronic kidney disease, myocardial ischemia, intra-abdominal malignancy, gastric volvulus or paraesophageal hernia, chronic gastric or intestinal ischemia, and pregnancy are sometimes accompanied by dyspepsia.
Given the nonspecific nature of dyspeptic symptoms, the history has limited diagnostic utility. It should clarify the chronicity, location, and quality of the discomfort, and its relationship to meals. The discomfort may be characterized by one or more upper abdominal symptoms including epigastric pain or burning, early satiety, postprandial fullness, bloating, nausea, or vomiting. Concomitant weight loss, persistent vomiting, constant or severe pain, dysphagia, hematemesis, or melena warrants endoscopy or abdominal imaging. Potentially offending medications and excessive alcohol use should be identified and discontinued if possible. The patient’s reason for seeking care should be determined. Recent changes in employment, marital discord, physical and sexual abuse, anxiety, depression, and fear of serious disease may all contribute to the development and reporting of symptoms. Patients with functional dyspepsia often are younger, report a variety of abdominal and extragastrointestinal complaints, show signs of anxiety or depression, or have a history of use of psychotropic medications.
The symptom profile alone does not differentiate between functional dyspepsia and organic gastrointestinal disorders. Based on the clinical history alone, primary care clinicians misdiagnose nearly half of patients with peptic ulcers or gastroesophageal reflux and have < 25% accuracy in diagnosing functional dyspepsia.
The physical examination is rarely helpful. Signs of serious organic disease such as weight loss, organomegaly, abdominal mass, or fecal occult blood are to be further evaluated.
In patients older than age of 55 years, initial laboratory work should include a blood count, electrolytes, liver enzymes, calcium, and thyroid function tests. In patients younger than 55 years with uncomplicated dyspepsia (in whom gastric cancer is rare), initial noninvasive strategies should be pursued (see below). The cost-effectiveness of routine laboratory studies is uncertain. In most clinical settings, a noninvasive test for H pylori (urea breath test, fecal antigen test, or IgG serology) should be performed first. Although serologic tests are inexpensive, performance characteristics are poor in low-prevalence populations, whereas breath and fecal antigen tests have 95% accuracy. If H pylori breath test or fecal antigen test results are negative in a patient not taking NSAIDs, peptic ulcer disease is virtually excluded.
Upper endoscopy is indicated to look for gastric cancer or other serious organic disease in all patients over age 55 years with new-onset dyspepsia and in all patients with “alarm” features, such as weight loss, dysphagia, recurrent vomiting, evidence of bleeding, or anemia. Upper endoscopy is the study of choice to diagnose gastroduodenal ulcers, erosive esophagitis, and upper gastrointestinal malignancy. It is also helpful for patients who are concerned about serious underlying disease. For patients born in regions in which there is a higher incidence of gastric cancer, such as Central or South America, China and Southeast Asia, or Africa, an age threshold of 45 years may be appropriate.
Endoscopic evaluation is also warranted when symptoms fail to respond to initial empiric management strategies within 4–8 weeks or when frequent symptom relapse occurs after discontinuation of antisecretory therapy.
In patients with refractory symptoms or progressive weight loss, antibodies for celiac disease or stool testing for ova and parasites or Giardia antigen, fat, or elastase may be considered. Abdominal imaging (ultrasonography or CT scanning) is performed only when pancreatic, biliary tract, vascular disease, or volvulus is suspected. Gastric emptying studies are valuable only in patients with recurrent vomiting. Ambulatory esophageal pH testing may be of value when atypical gastroesophageal reflux is suspected.
Initial empiric treatment is warranted for patients who are < 55 years and who have no alarm features (defined above). All other patients as well as patients whose symptoms fail to respond or relapse after empiric treatment should undergo upper endoscopy with subsequent treatment directed at the specific disorder (eg, peptic ulcer, gastroesophageal reflux, cancer). Most patients will have no significant findings on endoscopy and will be given a diagnosis of functional dyspepsia.
Young patients with uncomplicated dyspepsia may be treated empirically with either a proton pump inhibitor or evaluated with a noninvasive test for H pylori, followed if positive by treatment. The prevalence of H pylori in the population influences recommendations for the timing of these empiric therapies. In clinical settings in which the prevalence of H pylori infection in the population is low (< 10%), it may be more cost-effective to initially treat patients with a 4-week trial of a proton pump inhibitor. Patients who have symptom relapse after discontinuation of the proton pump inhibitor should be tested for H pylori and treated if results are positive. In clinical settings in which H pylori prevalence is >10%, it may be more cost-effective to initially test patients for H pylori infection. Hpylori–negative patients most likely have functional dyspepsia or atypical GERD and can be treated with an antisecretory agent (proton pump inhibitor) for 4 weeks. For patients who have symptom relapse after discontinuation of the proton pump inhibitor, intermittent or long-term proton pump inhibitor therapy may be considered. For patients in whom test results are positive for H pylori, antibiotic therapy proves definitive for patients with underlying peptic ulcers and may improve symptoms in a small subset (< 10%) of infected patients with functional dyspepsia. Patients with persistent dyspepsia after H pylorieradication can be given a trial of proton pump inhibitor therapy.
Ford AC et al. Dyspepsia. BMJ. 2013 Aug 29;347:f50509. [PMID: 23990632]
Mazzoleni LE et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. Arch Intern Med. 2011 Nov 28;171(21):1929–36. [PMID: 22123802]
Zhao B et al. Efficacy of Helicobacter pylori eradication therapy on functional dyspepsia: a meta-analysis of randomized controlled studies with 12-month follow-up. J Clin Gastroenterol. 2014 Mar;48(3):241–7. [PMID: 24002127]
NAUSEA & VOMITING
Nausea is a vague, intensely disagreeable sensation of sickness or “queasiness” and is distinguished from anorexia. Vomiting often follows, as does retching (spasmodic respiratory and abdominal movements). Vomiting should be distinguished from regurgitation, the effortless reflux of liquid or food stomach contents; and from rumination, the chewing and swallowing of food that is regurgitated volitionally after meals.
The brainstem vomiting center is composed of a group of neuronal areas (area postrema, nucleus tractus solitarius, and central pattern generator) within the medulla that coordinate emesis. It may be stimulated by four different sources of afferent input: (1) Afferent vagal fibers from the gastrointestinal viscera are rich in serotonin 5-HT3 receptors; these may be stimulated by biliary or gastrointestinal distention, mucosal or peritoneal irritation, or infections. (2) Fibers of the vestibular system, which have high concentrations of histamine H1 and muscarinic cholinergic receptors. (3) Higher central nervous system centers (amygdala); here, certain sights, smells, or emotional experiences may induce vomiting. For example, patients receiving chemotherapy may start vomiting in anticipation of its administration. (4) The chemoreceptor trigger zone, located outside the blood-brain barrier in the area postrema of the medulla, which is rich in opioid, serotonin 5-HT3, neurokinin 1 (NK1) and dopamine D2 receptors. This region may be stimulated by drugs and chemotherapeutic agents, toxins, hypoxia, uremia, acidosis, and radiation therapy. Although the causes of vomiting are many, a simplified list is provided inTable 15–1.
Table 15–1. Causes of nausea and vomiting.
Acute symptoms without abdominal pain are typically caused by food poisoning, infectious gastroenteritis, drugs, or systemic illness. Inquiry should be made into recent changes in medications, diet, other intestinal symptoms, or similar illnesses in family members. The acute onset of severe pain and vomiting suggests peritoneal irritation, acute gastric or intestinal obstruction, or pancreaticobiliary disease. Persistent vomiting suggests pregnancy, gastric outlet obstruction, gastroparesis, intestinal dysmotility, psychogenic disorders, and central nervous system or systemic disorders. Vomiting that occurs in the morning before breakfast is common with pregnancy, uremia, alcohol intake, and increased intracranial pressure. Vomiting immediately after meals strongly suggests bulimia or psychogenic causes. Vomiting of undigested food one to several hours after meals is characteristic of gastroparesis or a gastric outlet obstruction; physical examination may reveal a succussion splash. Patients with acute or chronic symptoms should be asked about neurologic symptoms (eg, headache, stiff neck, vertigo, and focal paresthesias or weakness) that suggest a central nervous system cause.
With vomiting that is severe or protracted, serum electrolytes should be obtained to look for hypokalemia, azotemia, or metabolic alkalosis resulting from loss of gastric contents. Flat and upright abdominal radiographs or abdominal CT are obtained in patients with severe pain or suspicion of mechanical obstruction to look for free intraperitoneal air or dilated loops of small bowel. The cause of gastric outlet obstruction is best demonstrated by upper endoscopy, and the cause of small intestinal obstruction is best demonstrated with abdominal CT imaging. Gastroparesis is confirmed by nuclear scintigraphic studies or 13C-octanoic acid breath tests, which show delayed gastric emptying and either upper endoscopy or barium upper gastrointestinal series showing no evidence of mechanical gastric outlet obstruction. Abnormal liver biochemical tests or elevated amylase or lipase suggest pancreaticobiliary disease, which may be investigated with an abdominal sonogram or CT scan. Central nervous system causes are best evaluated with either head CT or MRI.
Complications include dehydration, hypokalemia, metabolic alkalosis, aspiration, rupture of the esophagus (Boerhaave syndrome), and bleeding secondary to a mucosal tear at the gastroesophageal junction (Mallory-Weiss syndrome).
Most causes of acute vomiting are mild, self-limited, and require no specific treatment. Patients should ingest clear liquids (broths, tea, soups, carbonated beverages) and small quantities of dry foods (soda crackers). For more severe acute vomiting, hospitalization may be required. Patients unable to eat and losing gastric fluids may become dehydrated, resulting in hypokalemia with metabolic alkalosis. Intravenous 0.45% saline solution with 20 mEq/L of potassium chloride is given in most cases to maintain hydration. A nasogastric suction tube for gastric or mechanical small bowel obstruction improves patient comfort and permits monitoring of fluid loss.
Medications may be given either to prevent or to control vomiting. Combinations of drugs from different classes may provide better control of symptoms with less toxicity in some patients. Table 15–2outlines common antiemetic dosing regimens.
Table 15–2. Common antiemetic dosing regimens.
Basch E et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011 Nov 1;29(31):4189–98. [PMID: 21947834]
Janelsins MC et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother. 2013 Apr;14(6):757–66. [PMID: 23496347]
Lee NM et al. Nausea and vomiting of pregnancy. Gastroenterol Clin North Am. 2011 Jun;40(2):309–34. [PMID: 21601782]
Though usually a benign and self-limited annoyance, hiccups may be persistent and a sign of serious underlying illness. In patients on mechanical ventilation, hiccups can trigger a full respiratory cycle and result in respiratory alkalosis.
Causes of benign, self-limited hiccups include gastric distention (carbonated beverages, air swallowing, overeating), sudden temperature changes (hot then cold liquids, hot then cold shower), alcohol ingestion, and states of heightened emotion (excitement, stress, laughing). There are over 100 causes of recurrent or persistent hiccups due to gastrointestinal, central nervous system, cardiovascular, and thoracic disorders.
Evaluation of the patient with persistent hiccups should include a detailed neurologic examination, serum creatinine, liver chemistry tests, and a chest radiograph. When the cause remains unclear, CT or MRI of the head, chest, and abdomen, echocardiography, and upper endoscopy may help.
A number of simple remedies may be helpful in patients with acute benign hiccups. (1) Irritation of the nasopharynx by tongue traction, lifting the uvula with a spoon, catheter stimulation of the nasopharynx, or eating 1 teaspoon (tsp) (7 g) of dry granulated sugar. (2) Interruption of the respiratory cycle by breath holding, Valsalva maneuver, sneezing, gasping (fright stimulus), or rebreathing into a bag. (3) Stimulation of the vagus by carotid massage. (4) Irritation of the diaphragm by holding knees to chest or by continuous positive airway pressure during mechanical ventilation. (5) Relief of gastric distention by belching or insertion of a nasogastric tube.
A number of drugs have been promoted as being useful in the treatment of hiccups. Chlorpromazine, 25–50 mg orally or intramuscularly, is most commonly used. Other agents reported to be effective include anticonvulsants (phenytoin, carbamazepine), benzodiazepines (lorazepam, diazepam), metoclopramide, baclofen, gabapentin, and occasionally general anesthesia.
Bredenoord AJ. Management of belching, hiccups, and aerophagia. Clin Gastroenterol Hepatol. 2013 Jan;11(1):6–12. [PMID: 22982101]
Moretto EN et al. Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev. 2013 Jan 31;1:CD008768. [PMID: 23440833]
Constipation occurs in 10–15% of adults and is a common reason for seeking medical attention. It is more common in women. The elderly are predisposed due to comorbid medical conditions, medications, poor eating habits, decreased mobility and, in some cases, inability to sit on a toilet (bed-bound patients). The first step in evaluating the patient is to determine what is meant by “constipation.” Patients may define constipation as infrequent stools (fewer than three in a week), hard stools, excessive straining, or a sense of incomplete evacuation. Table 15–3 summarizes the many causes of constipation, which are discussed below.
Table 15–3. Causes of constipation in adults.
Most patients have constipation that cannot be attributed to any structural abnormalities or systemic disease. Some of these patients have normal colonic transit time; however, a subset have slow colonic transit or defecatory disorders. Normal colonic transit time is approximately 35 hours; more than 72 hours is significantly abnormal. Slow colonic transit is commonly idiopathic but may be part of a generalized gastrointestinal dysmotility syndrome. Patients may complain of infrequent bowel movements and abdominal bloating. Slow transit is more common in women, some of whom have a history of psychosocial problems (depression, anxiety, eating disorder, childhood trauma) or sexual abuse. Normal defecation requires coordination between relaxation of the anal sphincter and pelvic floor musculature while abdominal pressure is increased. Patients with defecatory disorders (also known as anismus or pelvic floor dyssynergia)—women more often than men—have impaired relaxation or paradoxical contraction of the anal sphincter and/or pelvic floor muscles during attempted defecation that impedes the bowel movement. This problem may be acquired during childhood or adulthood. Patients may complain of excessive straining, sense of incomplete evacuation, or need for digital manipulation. Patients with primary complaints of abdominal pain or bloating with alterations in bowel habits (constipation, or alternating constipation and diarrhea) may have irritable bowel syndrome (see below).
Constipation may be caused by systemic disorders, medications, or obstructing colonic lesions. Systemic disorders can cause constipation because of neurologic gut dysfunction, myopathies, endocrine disorders, or electrolyte abnormalities (eg, hypercalcemia or hypokalemia); medication side effects are often responsible (eg, anticholinergics or opioids). Colonic lesions that obstruct fecal passage, such as neoplasms and strictures, are an uncommon cause but important in new-onset constipation. Such lesions should be excluded in patients older than 50 years, in patients with “alarm” symptoms or signs (hematochezia, weight loss, anemia, or positive fecal occult blood tests [FOBT] or fecal immunochemical tests [FIT]), and in patients with a family history of colon cancer or inflammatory bowel disease. Defecatory difficulties also can be due to a variety of anorectal problems that impede or obstruct flow (perineal descent, rectal prolapse, rectocele), some of which may require surgery, and Hirschsprung disease (usually suggested by lifelong constipation).
All patients should undergo a history and physical examination to distinguish primary from secondary causes of constipation. Physical examination should include digital rectal examination with assessment for anatomic abnormalities, such as anal stricture, rectocele, rectal prolapse, or perineal descent during straining as well as assessment of pelvic floor motion during simulated defecation (ie, the patient’s ability to “expel the examiner’s finger”). Further diagnostic tests should be performed in patients with any of the following: age 50 years or older, severe constipation, signs of an organic disorders, alarm symptoms (hematochezia, weight loss, positive FOBT or FIT), or a family history of colon cancer or inflammatory bowel disease. These tests should include laboratory studies (complete blood count; serum electrolytes, calcium, glucose, and thyroid-stimulating hormone); and a colonoscopy or flexible sigmoidoscopy.
Patients with refractory constipation not responding to routine medical management warrant further diagnostic studies, including pelvic floor function and colonic transit studies, in order to distinguish slow colonic transit from defecatory disorders. Colon transit time is most commonly measured by performing an abdominal radiograph 120 hours after ingestion of 24 radiopaque markers. Retention of > 20% of the markers indicates prolonged transit. Defecatory disorders are assessed with balloon expulsion testing, anal manometry, and defecography.
Table 15–4. Pharmacologic management of constipation.
Severe impaction of stool in the rectal vault may result in obstruction to further fecal flow, leading to partial or complete large bowel obstruction. Predisposing factors include medications (eg, opioids), severe psychiatric disease, prolonged bed rest, neurogenic disorders of the colon, and spinal cord disorders. Clinical presentation includes decreased appetite, nausea, and vomiting, and abdominal pain and distention. There may be paradoxical “diarrhea” as liquid stool leaks around the impacted feces. Firm feces are palpable on digital examination of the rectal vault. Initial treatment is directed at relieving the impaction with enemas (saline, mineral oil, or diatrizoate) or digital disruption of the impacted fecal material. Long-term care is directed at maintaining soft stools and regular bowel movements (as above).
When to Refer
American Gastroenterological Association medical position statement on constipation. Gastroenterology. 2013 Jan;144(1):211–7. [PMID: 23261064]
Bader S et al. Methylnaltrexone for the treatment of opioid-induced constipation. Expert Rev Gastroenterol Hepatol. 2013 Jan;7(1):13–26. [PMID: 23265145]
Ford AC. Laxatives for chronic constipation in adults. BMJ. 2012 Oct 1;345:e6168. [PMID: 23028096]
Lembo AJ et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011 Aug 11;365(6):527–36. [PMID: 21830967]
Belching (eructation) is the involuntary or voluntary release of gas from the stomach or esophagus. It occurs most frequently after meals, when gastric distention results in transient lower esophageal sphincter (LES) relaxation. Belching is a normal reflex and does not itself denote gastrointestinal dysfunction. Virtually all stomach gas comes from swallowed air. With each swallow, 2–5 mL of air is ingested, and excessive amounts may result in distention, flatulence, and abdominal pain. This may occur with rapid eating, gum chewing, smoking, and the ingestion of carbonated beverages. Evaluation should be restricted to patients with other complaints such as dysphagia, heartburn, early satiety, or vomiting.
Chronic excessive belching is almost always caused by supragastric belching (voluntary diaphragmatic contraction, followed by upper esophageal relaxation with air inflow to the esophagus) or true air swallowing (aerophagia), both of which are behavioral disorders that are more common in patients with anxiety or psychiatric disorders. These patients may benefit from referral to a behavioral or speech therapist.
The rate and volume of expulsion of flatus is highly variable. Healthy adults pass flatus up to 20 times daily and excrete up to 1500 mL. Flatus is derived from two sources: swallowed air (primarily nitrogen) and bacterial fermentation of undigested carbohydrate (which produces H2, CO2, and methane). A number of short-chain carbohydrates (fermentable oligosaccharides, disaccharides, monosaccharides, and polypols or “FODMAPS”) are incompletely absorbed in the small intestine and pass into the colon. These include lactose (dairy products); fructose (fruits, corn syrups, and some sweeteners); polypols (stone-fruits, mushrooms, and some sweeteners); and fructans (legumes, cruciferous vegetables, pasta, and whole grains). Abnormal gas production may be caused by increased ingestion of these carbohydrates or, less commonly, by disorders of malabsorption. Foul odor may be caused by garlic, onion, eggplant, mushrooms, and certain herbs and spices.
Determining abnormal from normal amounts of flatus is difficult. Patients with a long-standing history of flatulence and no other symptoms or signs of malabsorption disorders can be treated conservatively. Gum chewing and carbonated beverages should be avoided to reduce air swallowing. Lactose intolerance may be assessed by a 2-week trial of a lactose-free diet or by a hydrogen breath test. A list of foods containing FODMAPS should be provided. Multiple low-FODMAP dietary guides are available; however, referral to a knowledgeable dietician may be helpful.
The nonprescription agent Beano (alpha-d-galactosidase enzyme) reduces gas caused by foods containing galacto-oligosaccharides (legumes, chickpeas, lentils) but not other FODMAPS. Activated charcoal may afford relief. Simethicone is of no proved benefit.
Complaints of chronic abdominal distention or bloating are common. Some of these patients may produce excess gas. However, many patients have impaired small bowel gas propulsion or enhanced visceral sensitivity to gas distention. Many of these patients have an underlying functional gastrointestinal disorder such as irritable bowel syndrome or functional dyspepsia. Reduction of dietary fat, which delays intestinal gas clearance, may be helpful. Rifaximin, 400 mg twice daily, a nonabsorbable oral antibiotic with high activity against enteric bacteria, has been shown to reduce abdominal bloating and flatulence in approximately 40% of treated patients compared with 20% of controls. Symptom improvement may be attributable to suppression of gas-producing colonic bacteria; however, relapse occurs within days after stopping the antibiotic. Further trials are needed to clarify the role of nonabsorbable antibiotics in symptom management. Many patients report reduced flatus production with use of probiotics, although there has been limited controlled study of these agents for this purpose. Patients interested in complementary medical therapies may be offered a trial of 4–8 ounces daily of Kefir, a commercially available fermented milk drink containing multiple probiotics.
Gibson PR et al. Food choice as a key management strategy for functional gastrointestinal symptoms. Am J Gastroenterol. 2012 May;107(5):657–66. [PMID: 22488077]
Shepherd SJ et al. Short-chain carbohydrates and functional gastrointestinal disorders. Am J Gastroenterol. 2013 May;108(5):707–17. [PMID: 23588241]
Diarrhea can range in severity from an acute self-limited episode to a severe, life-threatening illness. To properly evaluate the complaint, the clinician must determine the patient’s normal bowel pattern and the nature of the current symptoms.
Approximately 10 L of fluid enter the duodenum daily, of which all but 1.5 L are absorbed by the small intestine. The colon absorbs most of the remaining fluid, with < 200 mL lost in the stool. Although diarrhea sometimes is defined as a stool weight of more than 200–300 g/24 h, quantification of stool weight is necessary only in some patients with chronic diarrhea. In most cases, the physician’s working definition of diarrhea is increased stool frequency (more than three bowel movements per day) or liquidity of feces.
The causes of diarrhea are myriad. In clinical practice, it is helpful to distinguish acute from chronic diarrhea, as the evaluation and treatment are entirely different (Tables 15–5 and 5–6).
Table 15–5. Causes of acute infectious diarrhea.
Table 15–6. Causes of chronic diarrhea.
ESSENTIALS OF DIAGNOSIS
Diarrhea of < 2 weeks duration is most commonly caused by invasive or noninvasive pathogens and their enterotoxins.
Acute noninflammatory diarrhea
Usually mild, self-limited.
Caused by a virus or noninvasive bacteria.
Diagnostic evaluation is limited to patients with diarrhea that is severe or persists beyond 7 days.
Acute inflammatory diarrhea
Blood or pus, fever.
Usually caused by an invasive or toxin-producing bacterium.
Diagnostic evaluation requires routine stool bacterial cultures (including E coli O157:H7) in all and testing as clinically indicated for Clostridium difficile toxin, and ova and parasites.
Etiology & Clinical Findings
Diarrhea acute in onset and persisting for < 2 weeks is most commonly caused by infectious agents, bacterial toxins (either preformed or produced in the gut), or medications. Community outbreaks (including nursing homes, schools, cruise ships) suggest a viral etiology or a common food source. Similar recent illnesses in family members suggest an infectious origin. Ingestion of improperly stored or prepared food implicates food poisoning. Pregnant women have an increased risk of developing listeriosis. Day care attendance or exposure to unpurified water (camping, swimming) may result in infection with Giardia or Cryptosporidium. Large Cyclospora outbreaks have been traced to contaminated produce. Recent travel abroad suggests “traveler’s diarrhea” (see Chapter 30). Antibiotic administration within the preceding several weeks increases the likelihood of C difficile colitis. Finally, risk factors for HIV infection or sexually transmitted diseases should be determined. (AIDS-associated diarrhea is discussed in Chapter 31; infectious proctitis is discussed in this chapter under Anorectal Disorders.) Persons engaging in anal intercourse or oral-anal sexual activities are at risk for a variety of infections that cause proctitis, including gonorrhea, syphilis, lymphogranuloma venereum, and herpes simplex.
The nature of the diarrhea helps distinguish among different infectious causes (Table 15–5).
Watery, nonbloody diarrhea associated with periumbilical cramps, bloating, nausea, or vomiting suggests a small bowel source caused by either a toxin-producing bacterium (enterotoxigenic E coli [ETEC],Staphylococcus aureus, Bacillus cereus, Clostridium perfringens) or other agents (viruses, Giardia) that disrupt normal absorption and secretory process in the small intestine. Prominent vomiting suggests viral enteritis or S aureus food poisoning. Although typically mild, the diarrhea (which originates in the small intestine) can be voluminous and result in dehydration with hypokalemia and metabolic acidosis (eg, cholera). Because tissue invasion does not occur, fecal leukocytes are not present.
The presence of fever and bloody diarrhea (dysentery) indicates colonic tissue damage caused by invasion (shigellosis, salmonellosis, Campylobacter or Yersinia infection, amebiasis) or a toxin (C difficile,Shiga-toxin–producing E coli[STEC; also known as enterohemorrhagic E coli]). Because these organisms involve predominantly the colon, the diarrhea is small in volume (< 1 L/d) and associated with left lower quadrant cramps, urgency, and tenesmus. Fecal leukocytes or lactoferrin usually are present in infections with invasive organisms. E coli O157:H7 is a Shiga toxin-producing noninvasive organism most commonly acquired from contaminated meat that has resulted in several outbreaks of an acute, often severe hemorrhagic colitis. In 2011, an outbreak of severe gastroenteritis in Germany, caused by an unusual Shiga-toxin–producing strain, E coli O104:H4, was traced to contaminated sprouts. A major complication of STEC is hemolytic-uremic syndrome, which develops in 6–22% of cases. In immunocompromised and HIV-infected patients, cytomegalovirus (CMV) can cause intestinal ulceration with watery or bloody diarrhea.
Infectious dysentery must be distinguished from acute ulcerative colitis, which may also present acutely with fever, abdominal pain, and bloody diarrhea. Diarrhea that persists for more than 14 days is not attributable to bacterial pathogens (except for C difficile) and should be evaluated as chronic diarrhea.
In over 90% of patients with acute noninflammatory diarrhea, the illness is mild and self-limited, responding within 5 days to simple rehydration therapy or antidiarrheal agents; diagnostic investigation is unnecessary.
The isolation rate of bacterial pathogens from stool cultures in patients with acute noninflammatory diarrhea is under 3%. Thus, the goal of initial evaluation is to distinguish patients with mild disease from those with more serious illness. If diarrhea worsens or persists for more than 7 days, stool should be sent for fecal leukocyte or lactoferrin determination, ovum and parasite evaluation, and bacterial culture.
Prompt medical evaluation is indicated in the following situations (Figure 15–1): (1) Signs of inflammatory diarrhea manifested by any of the following: fever (> 38.5°C), bloody diarrhea, or severe abdominal pain. (2) The passage of six or more unformed stools in 24 hours. (3) Profuse watery diarrhea and dehydration. (4) Frail older patients. (5) Immunocompromised patients (AIDS, posttransplantation). (6) Hospital-acquired diarrhea (onset following at least 3 days of hospitalization). (7) Systemic illness.
Figure 15–1. Evaluation of acute diarrhea.
Physical examination pays note to the patient’s level of hydration, mental status, and the presence of abdominal tenderness or peritonitis. Peritoneal findings may be present in infection with C difficile or STEC. Hospitalization is required in patients with severe dehydration, marked abdominal pain, or altered mental status. Stool specimens should be sent for examination for routine bacterial cultures.
The rate of positive bacterial cultures in such patients is 60–75%. For bloody stools, the laboratory should be directed to perform serotyping for Shiga-toxin–producing E coli. Special culture media are required for Yersinia, Vibrio, and Aeromonas. In patients who are hospitalized or who have a history of antibiotic exposure, a stool sample should be tested for C difficile toxin.
In patients with diarrhea that persists for more than 10 days, who have a history of travel to areas where amebiasis is endemic, or who engage in oral-anal sexual practices, three stool examinations for ova and parasites should also be performed. The stool antigen detection tests for both Giardia and Entamoeba histolytica are more sensitive than stool microscopy for detection of these organisms. A serum antigen detection test for E histolytica is also available. Cyclospora and Cryptosporidium are detected by fecal acid-fast staining.
Most mild diarrhea will not lead to dehydration provided the patient takes adequate oral fluids containing carbohydrates and electrolytes. Patients find it more comfortable to rest the bowel by avoiding high-fiber foods, fats, milk products, caffeine, and alcohol. Frequent feedings of tea, “flat” carbonated beverages, and soft, easily digested foods (eg, soups, crackers, bananas, applesauce, rice, toast) are encouraged.
In more severe diarrhea, dehydration can occur quickly, especially in children, the frail, and the elderly. Oral rehydration with fluids containing glucose, Na+, K+, Cl–, and bicarbonate or citrate is preferred when feasible. A convenient mixture is ½ tsp salt (3.5 g), 1 tsp baking soda (2.5 g NaHCO3), 8 tsp sugar (40 g), and 8 oz orange juice (1.5 g KCl), diluted to 1 L with water. Alternatively, oral electrolyte solutions (eg, Pedialyte, Gatorade) are readily available. Fluids should be given at rates of 50–200 mL/kg/24 h depending on the hydration status. Intravenous fluids (lactated Ringer injection) are preferred in patients with severe dehydration.
Antidiarrheal agents may be used safely in patients with mild to moderate diarrheal illnesses to improve patient comfort. Opioid agents help decrease the stool number and liquidity and control fecal urgency. However, they should not be used in patients with bloody diarrhea, high fever, or systemic toxicity and should be discontinued in patients whose diarrhea is worsening despite therapy. With these provisos, such drugs provide excellent symptomatic relief. Loperamide is preferred, in a dosage of 4 mg orally initially, followed by 2 mg after each loose stool (maximum: 16 mg/24 h).
Bismuth subsalicylate (Pepto-Bismol), two tablets or 30 mL orally four times daily, reduces symptoms in patients with traveler’s diarrhea by virtue of its anti-inflammatory and antibacterial properties. It also reduces vomiting associated with viral enteritis. Anticholinergic agents (eg, diphenoxylate with atropine) are contraindicated in acute diarrhea because of the rare precipitation of toxic megacolon.
When to Admit
Allen SJ et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD003048. [PMID: 21069673]
Buchholz U et al. German outbreak of Escherichia coli O104:H4 associated with sprouts. N Engl J Med. 2011 Nov 10;365(19):1763–70. [PMID: 22029753]
ESSENTIALS OF DIAGNOSIS
Diarrhea present for > 4 weeks.
Before embarking on extensive work-up, common causes should be excluded, including medications, chronic infections, and irritable bowel syndrome.
The causes of chronic diarrhea may be grouped into the following major pathophysiologic categories: medications, osmotic diarrheas, secretory conditions, inflammatory conditions, malabsorptive conditions, motility disorders, chronic infections, and systemic disorders (Table 15–6).
Numerous medications can cause diarrhea. Common offenders include cholinesterase inhibitors, SSRIs, angiotensin II-receptor blockers, proton pump inhibitors, NSAIDs, metformin, allopurinol, and orlistat. All medications should be carefully reviewed, and discontinuation of potential culprits should be considered.
As stool leaves the colon, fecal osmolality is equal to the serum osmolality, ie, approximately 290 mosm/kg. Under normal circumstances, the major osmoles are Na+, K+, Cl–, and HCO3–. The stool osmolality may be estimated by multiplying the stool (Na+ + K+) × 2. The osmotic gap is the difference between the measured osmolality of the stool (or serum) and the estimated stool osmolality and is normally < 50 mosm/kg. An increased osmotic gap (> 75 mosm/kg) implies that the diarrhea is caused by ingestion or malabsorption of an osmotically active substance. The most common causes are carbohydrate malabsorption (lactose, fructose, sorbitol), laxative abuse, and malabsorption syndromes (see below). Osmotic diarrheas resolve during fasting. Those caused by malabsorbed carbohydrates are characterized by abdominal distention, bloating, and flatulence due to increased colonic gas production.
Carbohydrate malabsorption is common and should be considered in all patients with chronic, postprandial diarrhea. Patients should be asked about their intake of dairy products (lactose), fruits and artificial sweeteners (fructose and sorbitol), and alcohol. The diagnosis of carbohydrate malabsorption may be established by an elimination trial for 2–3 weeks or by hydrogen breath tests.
Ingestion of magnesium- or phosphate-containing compounds (laxatives, antacids) should be considered in enigmatic chronic diarrhea. The fat substitute olestra also causes diarrhea and cramps in occasional patients.
Increased intestinal secretion or decreased absorption results in a high-volume watery diarrhea with a normal osmotic gap. There is little change in stool output during the fasting state, and dehydration and electrolyte imbalance may develop. Causes include endocrine tumors (stimulating intestinal or pancreatic secretion) and bile salt malabsorption (stimulating colonic secretion).
Diarrhea is present in most patients with inflammatory bowel disease (ulcerative colitis, Crohn disease). A variety of other symptoms may be present, including abdominal pain, fever, weight loss, and hematochezia. Microscopic colitis is a common cause of chronic watery diarrhea in the elderly (see Inflammatory Bowel Disease, below).
The major causes of malabsorption are small mucosal intestinal diseases, intestinal resections, lymphatic obstruction, small intestinal bacterial overgrowth, and pancreatic insufficiency. Its characteristics are weight loss, osmotic diarrhea, steatorrhea, and nutritional deficiencies. Significant diarrhea in the absence of weight loss is not likely to be due to malabsorption. The physical and laboratory abnormalities related to deficiencies of vitamins or minerals are discussed in Chapter 29.
Irritable bowel syndrome is the most common cause of chronic diarrhea in young adults (see Irritable Bowel Syndrome). It should be considered in patients with lower abdominal pain and altered bowel habits who have no other evidence of serious organic disease (weight loss, nocturnal diarrhea, anemia, or gastrointestinal bleeding). Abnormal intestinal motility secondary to systemic disorders or surgery may result in diarrhea due to rapid transit or to stasis of intestinal contents with bacterial overgrowth, resulting in malabsorption.
Chronic parasitic infections may cause diarrhea through a number of mechanisms. Pathogens most commonly associated with diarrhea include the protozoans Giardia, E histolytica, and Cyclospora as well as the intestinal nematodes. Strongyloidiasis and capillariasis should be excluded in patients from endemic regions, especially in the presence of eosinophilia. Bacterial infections with C difficile and, uncommonly, Aeromonas and Plesiomonas may cause of chronic diarrhea.
Immunocompromised patients are susceptible to infectious organisms that can cause acute or chronic diarrhea (see Chapter 31), including Microsporida, Cryptosporidium, CMV, Isospora belli,Cyclospora, and Mycobacterium avium complex.
Chronic systemic conditions, such as thyroid disease, diabetes, and collagen vascular disorders, may cause diarrhea through alterations in motility or intestinal absorption.
The history and physical examination commonly suggest the underlying pathophysiology that guides the subsequent diagnostic work-up (Figure 15–2). The clinician should establish whether the diarrhea is continuous or intermittent, the relationship to meals, and whether it occurs at night or during fasting. The stool appearance may suggest a malabsorption disorder (greasy or malodorous), inflammatory disorder (containing blood or pus), or a secretory process (watery). The presence of abdominal pain suggests irritable bowel syndrome or inflammatory bowel disease. Medications, diet, and recent psychosocial stressors should be reviewed. Physical examination should assess for signs of malnutrition, dehydration, and inflammatory bowel disease.
Figure 15–2. Decision diagram for diagnosis of causes of chronic diarrhea.
Because chronic diarrhea is caused by so many conditions, the subsequent diagnostic approach is guided by the relative suspicion for the underlying cause, and no specific algorithm can be followed in all patients. Prior to embarking on an extensive evaluation, the most common causes of chronic diarrhea should be considered, including medications, irritable bowel syndrome, and lactose intolerance. The presence of nocturnal diarrhea, weight loss, anemia, or positive results on FOBT are inconsistent with these disorders and warrant further evaluation. AIDS-associated diarrhea is discussed in Chapter 31.
If the cause of diarrhea is still not apparent, further studies may be warranted.
A number of antidiarrheal agents may be used in certain patients with chronic diarrheal conditions and are listed below. Opioids are safe in most patients with chronic, stable symptoms.
Loperamide: 4 mg orally initially, then 2 mg after each loose stool (maximum: 16 mg/d).
Diphenoxylate with atropine: One tablet orally three or four times daily as needed.
Codeine and deodorized tincture of opium: Because of potential habituation, these drugs are avoided except in cases of chronic, intractable diarrhea. Codeine may be given in a dosage of 15–60 mg orally every 4 hours; tincture of opium, 0.3–1.2 mL orally every 6 hours as needed.
Clonidine: Alpha-2-adrenergic agonists inhibit intestinal electrolyte secretion. Clonidine, 0.1–0.6 mg orally twice daily, or a clonidine patch, 0.1–0.2 mg/d, may help in some patients with secretory diarrheas, diabetic diarrhea, or cryptosporidiosis.
Octreotide: This somatostatin analog stimulates intestinal fluid and electrolyte absorption and inhibits intestinal fluid secretion and the release of gastrointestinal peptides. It is given for secretory diarrheas due to neuroendocrine tumors (VIPomas, carcinoid) and in some cases of AIDS-related diarrhea. Effective doses range from 50 to 250 mcg subcutaneously three times daily.
Cholestyramine: This bile salt-binding resin may be useful in patients with bile salt-induced diarrhea, which may be idiopathic or secondary to intestinal resection or ileal disease. A dosage of 4 g orally once to three times daily is recommended.
Li Z et al. Treatment of chronic diarrhea. Best Pract Res Clin Gastroenterol. 2012 Oct;26(5):677–87. [PMID: 23384811]
Money ME et al. Review: management of postprandial diarrhea syndrome. Am J Med. 2012 Jun;125(6):538–44. [PMID: 22624684]
Schiller LR. Definitions, pathophysiology, and evaluation of chronic diarrhoea. Best Pract Res Clin Gastroenterol. 2012 Oct;26(5):551–62. [PMID: 23384801]
ESSENTIALS OF DIAGNOSIS
Hematemesis (bright red blood or “coffee grounds”).
Melena in most cases; hematochezia in massive upper gastrointestinal bleeds.
Volume status to determine severity of blood loss; hematocrit is a poor early indicator of blood loss.
Endoscopy diagnostic and may be therapeutic.
There are over 250,000 hospitalizations a year in the United States for acute upper gastrointestinal bleeding, with a mortality rate of 4–10%. Approximately half of patients are over 60 years of age, and in this age group the mortality rate is even higher. Patients seldom die of exsanguination but rather from complications of an underlying disease.
The most common presentation of upper gastrointestinal bleeding is hematemesis or melena. Hematemesis may be either bright red blood or brown “coffee grounds” material. Melena develops after as little as 50–100 mL of blood loss in the upper gastrointestinal tract, whereas hematochezia requires a loss of more than 1000 mL. Although hematochezia generally suggests a lower bleeding source (eg, colonic), severe upper gastrointestinal bleeding may present with hematochezia in 10% of cases.
Upper gastrointestinal bleeding is self-limited in 80% of patients; urgent medical therapy and endoscopic evaluation are obligatory in the rest. Patients with bleeding more than 48 hours prior to presentation have a low risk of recurrent bleeding.
Acute upper gastrointestinal bleeding may originate from a number of sources. These are listed in order of their frequency and discussed in detail below.
Peptic ulcers account for half of major upper gastrointestinal bleeding with an overall mortality rate of 6%. However, in North America the incidence of bleeding from ulcers is declining, perhaps due to eradication of H pylori and prophylaxis with proton pump inhibitors in high-risk patients.
Portal hypertension accounts for 10–20% of upper gastrointestinal bleeding. Bleeding usually arises from esophageal varices and less commonly gastric or duodenal varices or portal hypertensive gastropathy. Approximately 25% of patients with cirrhosis have medium to large esophageal varices, of whom 30% experience acute variceal bleeding within a 2-year period. Due to improved care, the hospital mortality rate has declined over the past 20 years from 40% to 15%. Nevertheless, a mortality rate of 60–80% is expected at 1–4 years due to recurrent bleeding or other complications of chronic liver disease.
Lacerations of the gastroesophageal junction cause 5–10% of cases of upper gastrointestinal bleeding. Many patients report a history of heavy alcohol use or retching. Less than 10% have continued or recurrent bleeding.
Vascular anomalies are found throughout the gastrointestinal tract and may be the source of chronic or acute gastrointestinal bleeding. They account for 7% of cases of acute upper tract bleeding. The most common are angioectasias (angiodysplasias) which are 1–10 mm distorted, aberrant submucosal vessels caused by chronic, intermittent obstruction of submucosal veins. They have a bright red stellate appearance and occur throughout the gastrointestinal tract but most commonly in the right colon. Telangiectasias are small, cherry red lesions caused by dilation of venules that may be part of systemic conditions (hereditary hemorrhagic telangiectasia, CREST syndrome) or occur sporadically. The Dieulafoy lesion is an aberrant, large-caliber submucosal artery, most commonly in the proximal stomach that causes recurrent, intermittent bleeding.
Gastric neoplasms result in 1% of upper gastrointestinal hemorrhages.
Because this process is superficial, it is a relatively unusual cause of severe gastrointestinal bleeding (< 5% of cases) and more commonly results in chronic blood loss. Gastric mucosal erosions are due to NSAIDs, alcohol, or severe medical or surgical illness (stress-related mucosal disease).
Severe erosive esophagitis due to chronic gastroesophageal reflux may rarely cause significant upper gastrointestinal bleeding, especially in patients who are bed bound long-term.
An aortoenteric fistula complicates 2% of abdominal aortic grafts or, rarely, can occur as the initial presentation of a previously untreated aneurysm. Usually located between the graft or aneurysm and the third portion of the duodenum, these fistulas characteristically present with a herald nonexsanguinating initial hemorrhage, with melena and hematemesis, or with chronic intermittent bleeding. The diagnosis may be suspected by upper endoscopy or abdominal CT. Surgery is mandatory to prevent exsanguinating hemorrhage. Unusual causes of upper gastrointestinal bleeding include hemobilia (from hepatic tumor, angioma, penetrating trauma), pancreatic malignancy, and pseudoaneurysm (hemosuccus pancreaticus).
Initial Evaluation & Treatment
The initial step is assessment of the hemodynamic status. A systolic blood pressure < 100 mm Hg identifies a high-risk patient with severe acute bleeding. A heart rate over 100 beats/min with a systolic blood pressure over 100 mm Hg signifies moderate acute blood loss. A normal systolic blood pressure and heart rate suggest relatively minor hemorrhage. Postural hypotension and tachycardia are useful when present but may be due to causes other than blood loss. Because the hematocrit may take 24–72 hours to equilibrate with the extravascular fluid, it is not a reliable indicator of the severity of acute bleeding.
In patients with significant bleeding, two 18-gauge or larger intravenous lines should be started prior to further diagnostic tests. Blood is sent for complete blood count, prothrombin time with international normalized ratio (INR), serum creatinine, liver enzymes, and blood typing and screening (in anticipation of need for possible transfusion). In patients without hemodynamic compromise or overt active bleeding, aggressive fluid repletion can be delayed until the extent of the bleeding is further clarified. Patients with evidence of hemodynamic compromise are given 0.9% saline or lactated Ringer injection and cross-matched for 2–4 units of packed red blood cells. It is rarely necessary to administer type-specific or O-negative blood. Central venous pressure monitoring is desirable in some cases, but line placement should not interfere with rapid volume resuscitation.
Placement of a nasogastric tube is not routinely needed but may be helpful in the initial assessment and triage of selected patients with suspected active upper tract bleeding. The aspiration of red blood or “coffee grounds” confirms an upper gastrointestinal source of bleeding, though up to 18% of patients with confirmed upper tract sources of bleeding have nonbloody aspirates—especially when bleeding originates in the duodenum. An aspirate of bright red blood indicates active bleeding and is associated with the highest risk of further bleeding and complications, while a clear aspirate identifies patients at lower initial risk. Erythromycin (250 mg) administered intravenously 30 minutes prior to upper endoscopy promotes gastric emptying and may improve the quality of endoscopic evaluation when substantial amounts of blood or clot in the stomach is suspected. Efforts to stop or slow bleeding by gastric lavage with large volumes of fluid are of no benefit and expose the patient to an increased risk of aspiration.
The amount of fluid and blood products required is based on assessment of vital signs, evidence of active bleeding from nasogastric aspirate, and laboratory tests. Sufficient packed red blood cells should be given to maintain a hemoglobin of 7–9 g/dL, based on the patient’s hemodynamic status, comorbidities (especially cardiovascular disease), and presence of continued bleeding. In the absence of continued bleeding, the hemoglobin should rise approximately 1 g/dL for each unit of transfused packed red cells. Transfusion of blood should not be withheld from patients with massive active bleeding regardless of the hemoglobin value. It is desirable to transfuse blood in anticipation of the nadir hematocrit. In actively bleeding patients, platelets are transfused if the platelet count is under 50,000/mcL and considered if there is impaired platelet function due to aspirin or clopidogrel use (regardless of the platelet count). Uremic patients (who also have dysfunctional platelets) with active bleeding are given three doses of desmopressin (DDAVP), 0.3 mcg/kg intravenously, at 12-hour intervals. Fresh frozen plasma is administered for actively bleeding patients with a coagulopathy and an INR > 1.8; however, endoscopy may be performed safely if the INR is < 2.5. In the face of massive bleeding, 1 unit of fresh frozen plasma should be given for each 5 units of packed red blood cells transfused.
A preliminary assessment of risk based on several clinical factors aids in the resuscitation as well as the rational triage of the patient. Clinical predictors of increased risk of rebleeding and death include age > 60 years, comorbid illnesses, systolic blood pressure < 100 mm Hg, pulse > 100 beats/min, and bright red blood in the nasogastric aspirate or on rectal examination.
Subsequent Evaluation & Treatment
Specific treatment of the various causes of upper gastrointestinal bleeding is discussed elsewhere in this chapter. The following general comments apply to most patients with bleeding.
The clinician’s impression of the bleeding source is correct in only 40% of cases. Signs of chronic liver disease implicate bleeding due to portal hypertension, but a different lesion is identified in 25% of patients with cirrhosis. A history of dyspepsia, NSAID use, or peptic ulcer disease suggests peptic ulcer. Acute bleeding preceded by heavy alcohol ingestion or retching suggests a Mallory-Weiss tear, though most of these patients have neither.
Virtually all patients with upper tract bleeding should undergo upper endoscopy within 24 hours of arriving in the emergency department. The benefits of endoscopy in this setting are threefold.
Administration of continuous intravenous proton pump inhibitor before endoscopy results in a decreased number of ulcers with lesions that require endoscopic therapy. It therefore is standard clinical practice at many institutions to administer either an intravenous or a high-dose oral proton pump inhibitor prior to endoscopy in patients with significant upper gastrointestinal bleeding. Based on the findings during endoscopy, the intravenous proton pump inhibitor may be continued or discontinued.
Greenspoon J et al; International Consensus Upper Gastrointestinal Bleeding Conference Group. Management of patients with nonvariceal upper gastrointestinal bleeding. Clin Gastroenterol Hepatol. 2012 Mar;10(3):234–9. [PMID: 21820395]
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Srygley FD et al. Does this patient have a severe upper gastrointestinal bleed? JAMA. 2012 Mar 14;307(10):1072–9. [PMID: 22416103]
Villanueva C et al. Transfusion for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Apr 4;368(1):11–21. [PMID: 23550677]
ESSENTIALS OF DIAGNOSIS
Hematochezia usually present.
Ten percent of cases of hematochezia due to upper gastrointestinal source.
Evaluation with colonoscopy in stable patients.
Massive active bleeding calls for evaluation with sigmoidoscopy, upper endoscopy, angiography, or nuclear bleeding scan.
Lower gastrointestinal bleeding is defined as that arising below the ligament of Treitz, ie, the small intestine or colon; however, up to 95% of cases arise from the colon. The severity of lower gastrointestinal bleeding ranges from mild anorectal bleeding to massive, large-volume hematochezia. Bright red blood that drips into the bowl after a bowel movement or is mixed with solid brown stool signifies mild bleeding, usually from an anorectosigmoid source, and can be evaluated in the outpatient setting. In patients hospitalized with gastrointestinal bleeding, lower tract bleeding is one-third as common as upper gastrointestinal hemorrhage and tends to have a more benign course. Patients hospitalized with lower gastrointestinal tract bleeding are less likely to present with shock or orthostasis (< 20%) or to require transfusions (< 40%). Spontaneous cessation of bleeding occurs in over 75% of cases, and hospital mortality is < 4%.
The cause of these lesions depends on both the age of the patient and the severity of the bleeding. In patients under 50 years of age, the most common causes are infectious colitis, anorectal disease, and inflammatory bowel disease. In older patients, significant hematochezia is most often seen with diverticulosis, angiectasias, malignancy, or ischemia. In 20% of acute bleeding episodes, no source of bleeding can be identified.
Hemorrhage occurs in 3–5% of all patients with diverticulosis and is the most common cause of major lower tract bleeding, accounting for 50% of cases. There is 1.35- to 3.49-fold increased risk of diverticular hemorrhage among patients who use aspirin or nonsteroidal anti-inflammatory agents. Diverticular bleeding usually presents as acute, painless, large-volume maroon or bright red hematochezia in patients over age 50 years. More than 95% of cases require < 4 units of blood transfusion. Bleeding subsides spontaneously in 80% but may recur in up to 25% of patients.
Angiectasias (angiodysplasias) occur throughout the upper and lower intestinal tracts and cause painless bleeding ranging from melena or hematochezia to occult blood loss. They are responsible for 4% of cases of lower gastrointestinal bleeding, where they are most often seen in the cecum and ascending colon. They are flat, red lesions (2–10 mm) with ectatic peripheral vessels radiating from a central vessel, and are most common in patients over 70 years and in those with chronic renal failure. Bleeding in younger patients more commonly arises from the small intestine.
Ectasias can be identified in up to 6% of persons over age 60 years, so the mere presence of ectasias does not prove that the lesion is the source of bleeding, since active bleeding is seldom seen.
Benign polyps and carcinoma are associated with chronic occult blood loss or intermittent anorectal hematochezia. Furthermore, they may cause up to 7% of acute lower gastrointestinal hemorrhage. After endoscopic removal of colonic polyps, important bleeding may occur up to 2 weeks later in 0.3% of patients. In general, prompt colonoscopy is recommended to treat postpolypectomy hemorrhage and minimize the need for transfusions.
Patients with inflammatory bowel disease (especially ulcerative colitis) often have diarrhea with variable amounts of hematochezia. Bleeding varies from occult blood loss to recurrent hematochezia usually mixed with stool. Symptoms of abdominal pain, tenesmus, and urgency are often present.
Anorectal disease (hemorrhoids, fissures) usually results in small amounts of bright red blood noted on the toilet paper, streaking of the stool, or dripping into the toilet bowl; clinically significant blood loss can sometimes occur. Hemorrhoids are the source in 10% of patients admitted with lower bleeding. Rectal ulcers may account for up to 8% of lower bleeding, usually in elderly or debilitated patients with constipation.
This condition is seen commonly in older patients, most of whom have atherosclerotic disease. Most cases occur spontaneously due to transient episodes of nonocclusive ischemia. Ischemic colitis may also occur in 5% of patients after surgery for ileoaortic or abdominal aortic aneurysm. In young patients, colonic ischemia may develop due to vasculitis, coagulation disorders, estrogen therapy, and long distance running. Ischemic colitis results in hematochezia or bloody diarrhea associated with mild cramps. In most patients, the bleeding is mild and self-limited.
Radiation-induced proctitis causes anorectal bleeding that may develop months to years after pelvic radiation. Endoscopy reveals multiple rectal telangiectasias. Acute infectious colitis (see Acute Diarrhea, above) commonly causes bloody diarrhea. Rare causes of lower tract bleeding include vasculitic ischemia, solitary rectal ulcer, NSAID-induced ulcers in the small bowel or right colon, small bowel diverticula, and colonic varices.
The color of the stool helps distinguish upper from lower gastrointestinal bleeding, especially when observed by the clinician. Brown stools mixed or streaked with blood predict a source in the rectosigmoid or anus. Large volumes of bright red blood suggest a colonic source; maroon stools imply a lesion in the right colon or small intestine; and black stools (melena) predict a source proximal to the ligament of Treitz. Although 10% of patients admitted with self-reported hematochezia have an upper gastrointestinal source of bleeding (eg, peptic ulcer), this almost always occurs in the setting of massive hemorrhage with hemodynamic instability. Painless large-volume bleeding usually suggests diverticular bleeding. Bloody diarrhea associated with cramping abdominal pain, urgency, or tenesmus is characteristic of inflammatory bowel disease, infectious colitis, or ischemic colitis.
Important considerations in management include exclusion of an upper tract source, anoscopy and sigmoidoscopy, colonoscopy, nuclear bleeding scans and angiography, and small intestine push enteroscopy or capsule imaging.
In patients with massive lower gastrointestinal bleeding manifested by continued hemodynamic instability and hematochezia, urgent angiography should be performed without attempt at colonoscopy or scintigraphy.
Initial stabilization, blood replacement, and triage are managed in the same manner as described above for Acute Upper Gastrointestinal Bleeding.
High-risk lesions (eg, angioectasias or diverticulum, rectal ulcer with active bleeding, or a visible vessel) may be treated endoscopically with epinephrine injection, cautery (bipolar or heater probe), or application of metallic endoclips or bands. In diverticular hemorrhage with high-risk lesions identified at colonoscopy, rebleeding occurs in half of untreated patients compared with virtually no rebleeding in patients treated endoscopically. Radiation proctitis is effectively treated with applications of cautery therapy to the rectal telangiectasias, preferably with an argon plasma coagulator.
When a bleeding lesion is identified, angiography with selective embolization achieves immediate hemostasis in more than 95% of patients. Major complications occur in 5% (mainly ischemic colitis) and rebleeding occurs in up to 25%.
Emergency surgery is required in < 5% of patients with acute lower gastrointestinal bleeding due to the efficacy of colonoscopic and angiographic therapies. It is indicated in patients with ongoing bleeding that requires more than 6 units of blood within 24 hours or more than 10 total units in whom attempts at endoscopic or angiographic therapy failed. Most such hemorrhages are caused by a bleeding diverticulum or angioectasia.
Surgery may also be indicated in patients with two or more hospitalizations for diverticular hemorrhage depending on the severity of bleeding and the patient’s other comorbid conditions.
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Obscure gastrointestinal bleeding refers to bleeding of unknown origin that persists or recurs after initial endoscopic evaluation with upper endoscopy and colonoscopy. Obscure-overt bleeding is manifested by persistent or recurrent visible evidence of gastrointestinal bleeding (hematemesis, hematochezia, or melena). Up to 5% of patients admitted to hospitals with clinically overt gastrointestinal bleeding do not have a cause identified on upper endoscopy or colonoscopy (and therefore have obscure-overt bleeding). Obscure-occult bleeding (discussed below) refers to bleeding that is not apparent to the patient. It is manifested by recurrent positive FOBTs or FITs or recurrent iron deficiency anemia, or both in the absence of visible blood loss (as described below).
Obscure bleeding (either occult or overt) most commonly arises from lesions in the small intestine. In up to one-third of cases, however, a source of bleeding has been overlooked in the upper or lower tract on prior endoscopic studies. Hematemesis or melena suggest an overlooked source proximal to the ligament of Treitz (ie, within the esophagus, stomach, or duodenum): erosions in a hiatal hernia (“Cameron erosions”), peptic ulcer, angioectasia, Dieulafoy vascular malformation, portal hypertensive gastropathy, gastroduodenal varices, duodenal neoplasms, aortoenteric fistula, or hepatic and pancreatic lesions. In the colon, the most commonly overlooked lesions are angioectasias and neoplasms. The etiology of obscure bleeding that arises from the small intestine depends on the age of the patient. The most common causes of small intestinal bleeding in patients younger than 40 years are neoplasms (stromal tumors, lymphomas, adenocarcinomas, carcinoids), Crohn disease, celiac disease, and Meckel diverticulum. These disorders also occur in patients over age 40; however, angioectasias and NSAID-induced ulcers are far more common.
Evaluation of Obscure Bleeding
The evaluation of obscure bleeding depends on the age and overall health status of the patient, associated symptoms, and severity of the bleeding. In an older patient with significant comorbid illnesses, no gastrointestinal symptoms, and occult or obscure bleeding in whom the suspected source of bleeding is angioectasias, it may be reasonable to limit diagnostic evaluations, provided the anemia can be managed with long-term iron therapy or occasional transfusions. On the other hand, aggressive diagnostic evaluation is warranted in younger patients with obscure bleeding (in whom small bowel tumors are the most common cause) and symptomatic older patients with overt or obscure bleeding. Upper endoscopy and colonoscopy should be repeated to ascertain that a lesion in these regions has not been overlooked. If these studies are unrevealing, capsule endoscopy should be performed to evaluate the small intestine. Capsule endoscopy is superior to radiographic studies (standard small bowel follow through, enteroclysis, or CT enterography) and standard push enteroscopy for the detection of small bowel abnormalities, demonstrating possible sources of occult bleeding in 50% of patients, most commonly vascular abnormalities (25%), ulcers (10–25%), and neoplasms (< 1–10%). Further management depends on the capsule endoscopic findings. Laparotomy is warranted if a small bowel tumor is identified by capsule endoscopy or radiographic studies. Most other lesions identified by capsule imaging can be further evaluated with enteroscopes that use overtubes with balloons to advance the scope through most of the small intestine in a forward and retrograde direction. Neoplasms can be biopsied or resected, and angioectasias may be cauterized. For massive or hemodynamically significant acute bleeding, angiography may be superior to enteroscopy for localization and embolization of a bleeding vascular abnormality. Abdominal CT may be considered to exclude a hepatic or pancreatic source of bleeding. A nuclear scan for Meckel diverticulum should be obtained in patients under age 30. With the advent of capsule imaging and advanced endoscopic technologies for evaluating and treating bleeding lesions in the small intestine, intraoperative enteroscopy of the small bowel is seldom required.
Occult gastrointestinal bleeding refers to bleeding that is not apparent to the patient. Chronic gastrointestinal blood loss of < 100 mL/d may cause no appreciable change in stool appearance. Thus, occult bleeding in an adult is identified by a positive FOBT, FIT, or iron deficiency anemia in the absence of visible blood loss. FOBT or FIT may be performed in patients with gastrointestinal symptoms or as a screening test for colorectal neoplasia (see Chapter 39). From 2% to 6% of patients in screening programs have a positive FOBT or FIT.
In the United States, 2% of men and 5% of women have iron deficiency anemia (serum ferritin < 30–45 mcg/L). In premenopausal women, iron deficiency anemia is most commonly attributable to menstrual and pregnancy-associated iron loss; however, a gastrointestinal source of chronic blood loss is present in 10%. Occult blood loss may arise from anywhere in the gastrointestinal tract. Among men and postmenopausal women, a potential gastrointestinal cause of blood loss can be identified in the colon in 15–30% and in the upper gastrointestinal tract in 35–55%; a malignancy is present in 10%. Iron deficiency on rare occasions is caused by malabsorption (especially celiac disease) or malnutrition. The most common causes of occult bleeding with iron deficiency are (1) neoplasms; (2) vascular abnormalities (angioectasias); (3) acid-peptic lesions (esophagitis, peptic ulcer disease, erosions in hiatal hernia); (4) infections (nematodes, especially hookworm; tuberculosis); (5) medications (especially NSAIDs or aspirin); and (6) other causes such as inflammatory bowel disease.
Evaluation of Occult Bleeding
Asymptomatic adults with positive FOBTs or FITs that are performed for routine colorectal cancer screening should undergo colonoscopy (see Chapter 39). All symptomatic adults with positive FOBTs or FITs or iron deficiency anemia should undergo evaluation of the lower and upper gastrointestinal tract with colonoscopy and upper endoscopy, unless the anemia can be definitively ascribed to a nongastrointestinal source (eg, menstruation, blood donation, or recent surgery). Patients with iron deficiency anemia should be evaluated for possible celiac disease with either IgA anti-tissue transglutaminase or duodenal biopsy. After evaluation of the upper and lower gastrointestinal tract with upper endoscopy and colonoscopy, the origin of occult bleeding remains unexplained in 30–50% of patients.
In younger patients (age < 60) with unexplained occult bleeding or iron deficiency, it is recommended to pursue further evaluation of the small intestine for a source of obscure-occult bleeding (as described above) in order to exclude a small intestinal neoplasm or inflammatory bowel disease. Patients over age 60 with occult bleeding who have a normal initial endoscopic evaluation and no other worrisome symptoms or signs (eg, abdominal pain, weight loss) most commonly have blood loss from angioectasias, which may be clinically unimportant. Therefore, it is reasonable to give an empiric trial of iron supplementation and observe the patient for evidence of clinically significant bleeding. For anemia that responds poorly to iron supplementation or recurrent or persistent chronic occult gastrointestinal blood loss, further evaluation is pursued for a source of obscure-occult bleeding (as described above). When possible, antiplatelet agents (aspirin, NSAIDs, clopidogrel) should be discontinued.
ASGE Standards of Practice Committee; Fisher L et al. The role of endoscopy in the management of obscure GI bleeding. Gastrointest Endosc. 2010 Sep;72(3):471–9. [PMID: 20801285]
Koulaouzidis A et al. Diagnostic yield of small-bowel capsule endoscopy in patients with iron-deficiency anemia: a systematic review. Gastrointest Endosc. 2012 Nov;76(5):983–92. [PMID: 23078923]
Lepileur L et al. Factors associated with diagnosis of obscure gastrointestinal bleeding by video capsule enteroscopy. Clin Gastroenterol Hepatol. 2012 Dec;10(12):1376–80. [PMID: 22677574]
Xin L et al. Indications, detectability, positive findings, total enteroscopy, and complications of diagnostic double-balloon endoscopy: a systematic review of data over the first decade of use. Gastrointest Endosc. 2011 Sep;74(3):563–70. [PMID: 21620401]
DISEASES OF THE PERITONEUM
ASSESSMENT OF THE PATIENT WITH ASCITES
Etiology of Ascites
The term “ascites” denotes the pathologic accumulation of fluid in the peritoneal cavity. Healthy men have little or no intraperitoneal fluid, but women normally may have up to 20 mL depending on the phase of the menstrual cycle. The causes of ascites may be classified into two broad pathophysiologic categories: that which is associated with a normal peritoneum and that which occurs due to a diseased peritoneum (Table 15–7). The most common cause of ascites is portal hypertension secondary to chronic liver disease, which accounts for over 80% of patients with ascites. The management of portal hypertensive ascites is discussed in Chapter 16. The most common causes of nonportal hypertensive ascites include infections (tuberculous peritonitis), intra-abdominal malignancy, inflammatory disorders of the peritoneum, and ductal disruptions (chylous, pancreatic, biliary).
Table 15–7. Causes of ascites.
The history usually is one of increasing abdominal girth, with the presence of abdominal pain depending on the cause. Because most ascites is secondary to chronic liver disease with portal hypertension, patients should be asked about risk factors for liver disease, especially alcohol consumption, transfusions, tattoos, injection drug use, a history of viral hepatitis or jaundice, and birth in an area endemic for hepatitis. A history of cancer or marked weight loss arouses suspicion of malignant ascites. Fevers may suggest infected peritoneal fluid, including bacterial peritonitis (spontaneous or secondary). Patients with chronic liver disease and ascites are at greatest risk for developing spontaneous bacterial peritonitis. In immigrants, immunocompromised hosts, or severely malnourished alcoholics, tuberculous peritonitis should be considered.
Physical examination should emphasize signs of portal hypertension and chronic liver disease. Elevated jugular venous pressure may suggest right-sided heart failure or constrictive pericarditis. A large tender liver is characteristic of acute alcoholic hepatitis or Budd-Chiari syndrome (thrombosis of the hepatic veins). The presence of large abdominal wall veins with cephalad flow also suggests portal hypertension; inferiorly directed flow implies hepatic vein obstruction. Signs of chronic liver disease include palmar erythema, cutaneous spider angiomas, gynecomastia, and muscle wasting. Asterixis secondary to hepatic encephalopathy may be present. Anasarca results from cardiac failure or nephrotic syndrome with hypoalbuminemia. Finally, firm lymph nodes in the left supraclavicular region or umbilicus may suggest intra-abdominal malignancy.
The physical examination is relatively insensitive for detecting ascitic fluid. In general, patients must have at least 1500 mL of fluid to be detected reliably by this method. Even the experienced clinician may find it difficult to distinguish between obesity and small-volume ascites. Abdominal ultrasound establishes the presence of fluid.
(1) Cell count—A white blood cell count with differential is the most important test. Normal ascitic fluid contains < 500 leukocytes/mcL and < 250 polymorphonuclear neutrophils (PMNs)/mcL. Any inflammatory condition can cause an elevated ascitic white blood cell count. A PMN count of > 250/mcL (neutrocytic ascites) with a percentage of > 75% of all white cells is highly suggestive of bacterial peritonitis, either spontaneous primary peritonitis or secondary peritonitis (ie, caused by an intra-abdominal source of infection, such as a perforated viscus or appendicitis). An elevated white count with a predominance of lymphocytes arouses suspicion of tuberculosis or peritoneal carcinomatosis.
(2) Albumin and total protein—The serum-ascites albumin gradient (SAAG) is the best single test for the classification of ascites into portal hypertensive and nonportal hypertensive causes (Table 15–7). Calculated by subtracting the ascitic fluid albumin from the serum albumin, the gradient correlates directly with the portal pressure. An SAAG ≥ 1.1 g/dL suggests underlying portal hypertension, while gradients < 1.1 g/dL implicate nonportal hypertensive causes.
The accuracy of the SAAG exceeds 95% in classifying ascites. It should be recognized, however, that approximately 4% of patients have “mixed ascites,” ie, underlying cirrhosis with portal hypertension complicated by a second cause for ascites formation (such as malignancy or tuberculosis). Thus, a high SAAG is indicative of portal hypertension but does not exclude concomitant malignancy.
The ascitic fluid total protein provides some additional clues to the cause. An elevated SAAG and a high protein level (> 2.5 g/dL) are seen in most cases of hepatic congestion secondary to cardiac disease or Budd-Chiari syndrome. However, an increased ascitic fluid protein is also found in up to 20% of cases of uncomplicated cirrhosis. Two-thirds of patients with malignant ascites have a total protein level > 2.5 g/dL.
(3) Culture and Gram stain—The best technique consists of the inoculation of aerobic and anaerobic blood culture bottles with 5–10 mL of ascitic fluid at the patient’s bedside, which increases the sensitivity for detecting bacterial peritonitis to over 85% in patients with neutrocytic ascites (> 250 PMNs/mcL), compared with approximately 50% sensitivity by conventional agar plate or broth cultures.
Abdominal ultrasound is useful in confirming the presence of ascites and in the guidance of paracentesis. Both ultrasound and CT imaging are useful in distinguishing between causes of portal and nonportal hypertensive ascites. Doppler ultrasound and CT can detect Budd-Chiari syndrome. In patients with nonportal hypertensive ascites, these studies are useful in detecting lymphadenopathy and masses of the mesentery and of solid organs such as the liver, ovaries, and pancreas. Furthermore, they permit directed percutaneous needle biopsies of these lesions. Ultrasound and CT are poor procedures for the detection of peritoneal carcinomatosis; the role of positron emission tomography (PET) imaging is unclear.
Laparoscopy is an important test in the evaluation of some patients with nonportal hypertensive ascites (low SAAG) or mixed ascites. It permits direct visualization and biopsy of the peritoneum, liver, and some intra-abdominal lymph nodes. Cases of suspected peritoneal tuberculosis or suspected malignancy with nondiagnostic CT imaging and ascitic fluid cytology are best evaluated by this method.
Gordon FD. Ascites. Clin Liver Dis. 2012 May;16(2):285–99. [PMID: 22541699]
Rahimi RS et al. End-stage liver disease complications. Curr Opin Gastroenterol. 2013 May;29(3):257–63. [PMID: 23429468]
SPONTANEOUS BACTERIAL PERITONITIS
ESSENTIALS OF DIAGNOSIS
A history of chronic liver disease and ascites.
Fever and abdominal pain.
Peritoneal signs uncommonly encountered on examination.
Ascitic fluid neutrophil count > 250 white blood cells/mcL.
“Spontaneous” bacterial infection of ascitic fluid occurs in the absence of an apparent intra-abdominal source of infection. It is seen with few exceptions in patients with ascites caused by chronic liver disease. Translocation of enteric bacteria across the gut wall or mesenteric lymphatics leads to seeding of the ascitic fluid, as may bacteremia from other sites. Approximately 20–30% of cirrhotic patients with ascites develop spontaneous peritonitis; however, the incidence is > 40% in patients with ascitic fluid total protein < 1 g/dL, probably due to decreased ascitic fluid opsonic activity.
Virtually all cases of spontaneous bacterial peritonitis are caused by a monomicrobial infection. The most common pathogens are enteric gram-negative bacteria (E coli, Klebsiella pneumoniae) or gram-positive bacteria (Streptococcus pneumoniae, viridans streptococci, Enterococcus species). Anaerobic bacteria are not associated with spontaneous bacterial peritonitis.
Eighty to ninety percent of patients with spontaneous bacterial peritonitis are symptomatic; in many cases the presentation is subtle. Spontaneous bacterial peritonitis may be present in 10–20% of patients hospitalized with chronic liver disease, sometimes in the absence of any suggestive symptoms or signs.
The most common symptoms are fever and abdominal pain, present in two-thirds of patients. Spontaneous bacterial peritonitis may also present with a change in mental status due to exacerbation or precipitation of hepatic encephalopathy, or sudden worsening of renal function. Physical examination typically demonstrates signs of chronic liver disease with ascites. Abdominal tenderness is present in < 50% of patients, and its presence suggests other processes.
The most important diagnostic test is abdominal paracentesis. Ascitic fluid should be sent for cell count with differential, and blood culture bottles should be inoculated at the bedside; Gram stain and reagent strips are insensitive.
In the proper clinical setting, an ascitic fluid PMN count of > 250 cells/mcL (neutrocytic ascites) is presumptive evidence of bacterial peritonitis. The percentage of PMNs is > 50–70% of the ascitic fluid white blood cells and commonly approximates 100%. Patients with neutrocytic ascites are presumed to be infected and should be started—regardless of symptoms—on antibiotics. Although 10–30% of patients with neutrocytic ascites have negative ascitic bacterial cultures (“culture-negative neutrocytic ascites”), it is presumed that these patients have bacterial peritonitis and should be treated empirically. Occasionally, a positive blood culture identifies the organism when ascitic fluid is sterile.
Spontaneous bacterial peritonitis must be distinguished from secondary bacterial peritonitis, in which ascitic fluid has become secondarily infected by an intra-abdominal infection. Even in the presence of perforation, clinical symptoms and signs of peritonitis may be lacking owing to the separation of the visceral and parietal peritoneum by the ascitic fluid. Causes of secondary bacterial peritonitis include appendicitis, diverticulitis, perforated peptic ulcer, and perforated gallbladder. Secondary bacterial infection accounts for 3% of cases of infected ascitic fluid.
Ascitic fluid total protein, LD, and glucose are useful in distinguishing spontaneous bacterial peritonitis from secondary infection. Up to two-thirds of patients with secondary bacterial peritonitis have at least two of the following: decreased glucose level (< 50 mg/dL), an elevated LD level (greater than serum), and total protein > 1 g/dL. Ascitic neutrophil counts > 10,000/mcL also are suspicious; however, most patients with secondary peritonitis have neutrophil counts within the range of spontaneous peritonitis. The presence of multiple organisms on ascitic fluid Gram stain or culture is diagnostic of secondary peritonitis.
If secondary bacterial peritonitis is suspected, abdominal CT imaging of the upper and lower gastrointestinal tracts should be obtained to look for evidence of an intra-abdominal source of infection. If these studies are negative and secondary peritonitis still is suspected, repeat paracentesis should be performed after 48 hours of antibiotic therapy to confirm that the PMN count is decreasing. Secondary bacterial peritonitis should be suspected in patients in whom the PMN count is not below the pretreatment value at 48 hours.
Neutrocytic ascites may also be seen in some patients with peritoneal carcinomatosis, pancreatic ascites, or tuberculous ascites. In these circumstances, however, PMNs account for < 50% of the ascitic white blood cells.
Up to 70% of patients who survive an episode of spontaneous bacterial peritonitis will have another episode within 1 year. Oral once-daily prophylactic therapy—with norfloxacin, 400 mg, ciprofloxacin, 250–500 mg, or trimethoprim-sulfamethoxazole, one double-strength tablet—has been shown to reduce the rate of recurrent infections to < 20% and is recommended. Prophylaxis should be considered also in patients who have not had prior bacterial peritonitis but are at increased risk of infection due to low-protein ascites (total ascitic protein < 1 g/dL). Although improvement in survival in cirrhotic patients with ascites treated with prophylactic antibiotics has not been shown, decision analytic modeling suggests that in patients with prior bacterial peritonitis or low ascitic fluid protein, the use of prophylactic antibiotics is a cost-effective strategy.
Empiric therapy for spontaneous bacterial peritonitis should be initiated with a third-generation cephalosporin (such as cefotaxime, 2 g intravenously every 8–12 hours, or ceftriaxone, 1–2 g intravenously every 24 hours) or a combination beta-lactam/beta-lactamase agent (such as ampicillin/sulbactam, 2 g/1 g intravenously every 6 hours). Because of a high risk of nephrotoxicity in patients with chronic liver disease, aminoglycosides should not be used. A repeat paracentesis is recommended after 48 hours of treatment in patients without clinical improvement. If the ascitic neutrophil count has not decreased by 25%, antibiotic coverage should be adjusted (guided by culture and sensitivity results, if available) and secondary causes of peritonitis excluded. Although the optimal duration of therapy is unknown, a course of 5–10 days is sufficient in most patients, or until the ascites fluid PMN count decreases to < 250 cells/mcL.
Kidney injury develops in up to 40% of patients and is a major cause of death. Intravenous albumin increases effective arterial circulating volume and renal perfusion, decreasing the incidence of kidney injury and mortality. Intravenous albumin, 1.5 g/kg on day 1 and 1 g/kg on day 3, should be administered to patients at high risk for hepatorenal failure (ie, patients with baseline creatinine > 1 mg/dL, blood urea nitrogen (BUN) > 30 mg/dL, or bilirubin > 4 mg/dL). Patients with suspected secondary bacterial peritonitis should be given broad-spectrum coverage for enteric aerobic and anaerobic flora with a third-generation cephalosporin and metronidazole pending identification and definitive (usually surgical) treatment of the cause.
The mortality rate of spontaneous bacterial peritonitis exceeds 30%. However, if the disease is recognized and treated early, the rate is < 10%. As the majority of patients have underlying severe liver disease, many may die of liver failure, hepatorenal syndrome, or bleeding complications from portal hypertension. The most effective treatment for recurrent spontaneous bacterial peritonitis is liver transplant.
Deshpande A et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013 Feb;28(2):235–42. [PMID: 23190338]
European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397–417. [PMID: 20633946]
Salerno F et al. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol. 2013 Feb;11(2):123–30. [PMID: 23178229]
Tandon P et al. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol. 2011 Mar;9(3):260–5. [PMID: 21145427]
Two-thirds of cases of malignant ascites are caused by peritoneal carcinomatosis. The most common tumors causing carcinomatosis are primary adenocarcinomas of the ovary, uterus, pancreas, stomach, colon, lung, or breast. The remaining one-third is due to lymphatic obstruction or portal hypertension due to hepatocellular carcinoma or diffuse hepatic metastases. Patients present with nonspecific abdominal discomfort and weight loss associated with increased abdominal girth. Nausea or vomiting may be caused by partial or complete intestinal obstruction. Abdominal CT may be useful to demonstrate the primary malignancy or hepatic metastases but seldom confirms the diagnosis of peritoneal carcinomatosis. In patients with carcinomatosis, paracentesis demonstrates a low serum ascites-albumin gradient (< 1.1 mg/dL), an increased total protein (> 2.5 g/dL), and an elevated white cell count (often both neutrophils and mononuclear cells) but with a lymphocyte predominance. Cytology is positive in over 95%, but laparoscopy may be required in patients with negative cytology to confirm the diagnosis and to exclude tuberculous peritonitis, with which it may be confused. Malignant ascites attributable to portal hypertension usually is associated with an increased serum ascites-albumin gradient (> 1.1 g/dL), a variable total protein, and negative ascitic cytology. Ascites caused by peritoneal carcinomatosis does not respond to diuretics.
Patients may be treated with periodic large-volume paracentesis for symptomatic relief. Indwelling catheters can be left in place for patients approaching the end of life who require periodic paracentesis for symptomatic relief. Intraperitoneal chemotherapy is sometimes used to shrink the tumor, but the overall prognosis is extremely poor, with only 10% survival at 6 months. Ovarian cancers represent an exception to this rule. With newer treatments consisting of surgical debulking and intraperitoneal chemotherapy, long-term survival from ovarian cancer is possible.
Cavazzoni E et al. Malignant ascites: pathophysiology and treatment. Int J Clin Oncol. 2013 Feb;18(1):1–9. [PMID: 22460778]
FAMILIAL MEDITERRANEAN FEVER
This is a rare autosomal recessive disorder of unknown pathogenesis that almost exclusively affects people of Mediterranean ancestry, especially Sephardic Jews, Armenians, Turks, and Arabs. Patients lack a protease in serosal fluids that normally inactivates interleukin-8 and the chemotactic complement factor 5A. Symptoms present in most patients before the age of 20 years. It is characterized by episodic bouts of acute peritonitis that may be associated with serositis involving the joints and pleura. Peritoneal attacks are marked by the sudden onset of fever, severe abdominal pain, and abdominal tenderness with guarding or rebound tenderness. If left untreated, attacks resolve within 24–48 hours. Because symptoms resemble those of surgical peritonitis, patients may undergo unnecessary exploratory laparotomy. Colchicine, 0.6 mg orally two or three times daily, has been shown to decrease the frequency and severity of attacks.
(See Chapter 39.)
MISCELLANEOUS PERITONEAL DISEASES
Chylous ascites is the accumulation of lipid-rich lymph in the peritoneal cavity. The ascitic fluid is characterized by a milky appearance with a triglyceride level > 1000 mg/dL. The usual cause in adults is lymphatic obstruction or leakage caused by malignancy, especially lymphoma. Nonmalignant causes include postoperative trauma, cirrhosis, tuberculosis, pancreatitis, and filariasis.
Pancreatic ascites is the intraperitoneal accumulation of massive amounts of pancreatic secretions due either to disruption of the pancreatic duct or to a pancreatic pseudocyst. It is most commonly seen in patients with chronic pancreatitis and complicates up to 3% of cases of acute pancreatitis. Because the pancreatic enzymes are not activated, pain often is absent. The ascitic fluid is characterized by a high protein level (> 2.5 g/dL) but a low SAAG. Ascitic fluid amylase levels are in excess of 1000 units/L. In nonsurgical cases, initial treatment consists of bowel rest, total parenteral nutrition (TPN), and octreotide to decrease pancreatic secretion. Persistent leakage requires treatment with either endoscopic placement of stents into the pancreatic duct or surgical drainage.
Bile ascites is caused most commonly by complications of biliary tract surgery, percutaneous liver biopsy, or abdominal trauma. Unless the bile is infected, bile ascites usually does not cause abdominal pain, fever, or leukocytosis. Paracentesis reveals yellow fluid with a ratio of ascites bilirubin to serum bilirubin > 1.0. Treatment depends on the location and rate of bile leakage. Postcholecystectomy cystic duct leaks may be treated with endoscopic sphincterotomy or biliary stent placement to facilitate bile flow across the sphincter of Oddi. Other leaks may be treated with percutaneous drainage by interventional radiologists or with surgical closure.
Baiocchi G et al. Chylous ascites in gynecologic malignancies: cases report and literature review. Arch Gynecol Obstet. 2010 Apr;281(4):677–81. [PMID: 19685063]
DISEASES OF THE ESOPHAGUS
(See Chapter 39 for Esophageal Cancer.)
Heartburn, dysphagia, and odynophagia almost always indicate a primary esophageal disorder.
Heartburn (pyrosis) is the feeling of substernal burning, often radiating to the neck. Caused by the reflux of acidic (or, rarely, alkaline) material into the esophagus, it is highly specific for GERD.
Difficulties in swallowing may arise from problems in transferring the food bolus from the oropharynx to the upper esophagus (oropharyngeal dysphagia) or from impaired transport of the bolus through the body of the esophagus (esophageal dysphagia). The history usually leads to the correct diagnosis.
Table 15–8. Causes of oropharyngeal dysphagia.
Table 15–9. Causes of esophageal dysphagia.
Odynophagia is sharp substernal pain on swallowing that may limit oral intake. It usually reflects severe erosive disease. It is most commonly associated with infectious esophagitis due to Candida, herpesviruses, or CMV, especially in immunocompromised patients. It may also be caused by corrosive injury due to caustic ingestions and by pill-induced ulcers.
Endoscopy is the study of choice for evaluating persistent heartburn, dysphagia, odynophagia, and structural abnormalities detected on barium esophagography. In addition to direct visualization, it allows biopsy of mucosal abnormalities and of normal mucosa (to evaluate for eosinophilic esophagitis) as well as dilation of strictures.
Oropharyngeal dysphagia is best evaluated with rapid-sequence videoesophagography.
Patients with esophageal dysphagia often are evaluated first with a radiographic barium study to differentiate between mechanical lesions and motility disorders, providing important information about the latter in particular. In patients with esophageal dysphagia and a suspected motility disorder, barium esophagoscopy should be obtained first. In patients in whom there is a high suspicion of a mechanical lesion, many clinicians will proceed first to endoscopic evaluation because it better identifies mucosa lesions (eg, erosions) and permits mucosal biopsy and dilation. However, barium study is more sensitive for detecting subtle esophageal narrowing due to rings, achalasia, and proximal esophageal lesions.
Esophageal motility may be assessed using manometric techniques. They are indicated: (1) to determine the location of the LES to allow precise placement of a conventional electrode pH probe; (2) to establish the etiology of dysphagia in patients in whom a mechanical obstruction cannot be found, especially if a diagnosis of achalasia is suspected by endoscopy or barium study; (3) for the preoperative assessment of patients being considered for antireflux surgery to exclude an alternative diagnosis (eg, achalasia) or possibly to assess peristaltic function in the esophageal body. High-resolution manometry may be superior to conventional manometry for distinguishing motility disorders.
The pH within the esophageal lumen may be monitored continuously for 24–48 hours. There are two kinds of systems in use: catheter-based and wireless. Traditional systems use a long transnasal catheter that is connected directly to the recording device. Wireless systems are increasingly used; in these systems, a capsule is attached directly to the esophageal mucosa under endoscopic visualization and data are transmitted by radiotelemetry to the recording device. The recording provides information about the amount of esophageal acid reflux and the temporal correlations between symptoms and reflux.
Esophageal pH monitoring devices provide information about the amount of esophageal acid reflux but not nonacid reflux. Techniques using combined pH and multichannel intraluminal impedance allow assessment of acid and nonacid liquid reflux. They may be useful in evaluation of patients with atypical reflux symptoms or persistent symptoms despite therapy with proton pump inhibitors to diagnose hypersensitivity, functional symptoms, and symptoms caused by nonacid reflux.
Villa N et al. Impedance-pH testing. Gastroenterol Clin North Am. 2013 Mar;42(1):17–26. [PMID: 23452628]
GASTROESOPHAGEAL REFLUX DISEASE
ESSENTIALS OF DIAGNOSIS
Heartburn; may be exacerbated by meals, bending, or recumbency.
Typical uncomplicated cases do not require diagnostic studies.
Endoscopy demonstrates abnormalities in one-third of patients.
GERD is a condition that develops when the reflux of stomach contents causes troublesome symptoms or complications. GERD affects 20% of adults, who report at least weekly episodes of heartburn, and up to 10% complain of daily symptoms. Although most patients have mild disease, esophageal mucosal damage (reflux esophagitis) develops in up to one-third and more serious complications develop in a few others. Several factors may contribute to GERD.
The antireflux barrier at the gastroesophageal junction depends on LES pressure, the intra-abdominal location of the sphincter (resulting in a “flap valve” caused by angulation of the esophageal-gastric junction), and the extrinsic compression of the sphincter by the crural diaphragm. In most patients with GERD, baseline LES pressures are normal (10–35 mm Hg). Most reflux episodes occur during transient relaxations of the LES that are triggered by gastric distention by a vagovagal reflex. A subset of patients with GERD have an incompetent (< 10 mm Hg) LES that results in increased acid reflux, especially when supine or when intra-abdominal pressures are increased by lifting or bending. A hypotensive sphincter is present in up to 50% of patients with severe erosive GERD.
Hiatal hernias are found in one-fourth of patients with nonerosive GERD, three-fourths of patients with severe erosive esophagitis, and over 90% of patients with Barrett esophagus. They are caused by movement of the LES above the diaphragm, resulting in dysfunction of the gastroesophageal junction reflux barrier. Hiatal hernias are common and may cause no symptoms; however, in patients with gastroesophageal reflux, they are associated with higher amounts of acid reflux and delayed esophageal acid clearance, leading to more severe esophagitis and Barrett esophagus. Increased reflux episodes occur during normal swallowing-induced relaxation, transient LES relaxations, and straining due to reflux of acid from the hiatal hernia sac into the esophagus.
Truncal obesity may contribute to GERD, presumably due to an increased intra-abdominal pressure, which contributes to dysfunction of the gastroesophageal junction and increased likelihood of hiatal hernia.
Esophageal mucosal damage is related to the potency of the refluxate and the amount of time it is in contact with the mucosa. Acidic gastric fluid (pH < 4.0) is extremely caustic to the esophageal mucosa and is the major injurious agent in the majority of cases. In some patients, reflux of bile or alkaline pancreatic secretions may be contributory.
Most acid reflux episodes occur after meals, despite the buffering effect of food that raises intragastric pH. In fact, meal-stimulated acid secretion from the proximal stomach mixes poorly with gastric contents, forming an unbuffered “acid pocket” that floats on top of the meal contents. In patients with GERD, this acid pocket is located near the gastroesophageal junction and may extend into the LES or hiatal hernia.
Acid refluxate normally is cleared and neutralized by esophageal peristalsis and salivary bicarbonate. One-half of patients with severe GERD have diminished clearance due to hypotensive peristaltic contractions (< 30 mm Hg) or intermittent failed peristalsis after swallowing. Certain medical conditions such as scleroderma are associated with diminished peristalsis. Sjögren syndrome, anticholinergic medications, and oral radiation therapy may exacerbate GERD due to impaired salivation.
Impaired gastric emptying due to gastroparesis or partial gastric outlet obstruction potentiates GERD.
The typical symptom is heartburn. This most often occurs 30–60 minutes after meals and upon reclining. Patients often report relief from taking antacids or baking soda. When this symptom is dominant, the diagnosis is established with a high degree of reliability. Many patients, however, have less specific dyspeptic symptoms with or without heartburn. Overall, a clinical diagnosis of gastroesophageal reflux has a sensitivity and specificity of only 65%. Severity is not correlated with the degree of tissue damage. In fact, some patients with severe esophagitis are only mildly symptomatic. Patients may complain of regurgitation—the spontaneous reflux of sour or bitter gastric contents into the mouth. Dysphagia occurs in one-third of patients and may be due to erosive esophagitis, abnormal esophageal peristalsis, or the development of an esophageal stricture.
“Atypical” or “extraesophageal” manifestations of gastroesophageal disease may occur, including asthma, chronic cough, chronic laryngitis, sore throat, and noncardiac chest pain. Gastroesophageal reflux may be either a causative or an exacerbating factor in a subset of these patients, especially those with refractory symptoms. In the absence of heartburn or regurgitation, atypical symptoms are unlikely to be related to gastroesophageal reflux.
Physical examination and laboratory data are normal in uncomplicated disease.
Initial diagnostic studies are not warranted for patients with typical GERD symptoms suggesting uncomplicated reflux disease. Patients with typical symptoms of heartburn and regurgitation should be treated empirically with a once daily proton pump inhibitor for 4–8 weeks. Symptomatic response to empiric treatment (while clinically desirable) only has a 78% sensitivity and 54% specificity for GERD. Therefore, further investigation is required in patients with symptoms that persist despite empiric proton pump inhibitor therapy to identify complications of reflux disease and to diagnose other conditions, particularly in patients with “alarm features” (troublesome dysphagia, odynophagia, weight loss, iron deficiency anemia).
Symptoms of GERD may be similar to those of other diseases such as esophageal motility disorders, peptic ulcer, angina pectoris, or functional disorders. Reflux erosive esophagitis may be confused with pill-induced damage, eosinophilic esophagitis, or infections (CMV, herpes, Candida).
This is a condition in which the squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium containing goblet and columnar cells (specialized intestinal metaplasia). Present in up to 10% of patients with chronic reflux, Barrett esophagus is believed to arise from chronic reflux-induced injury to the esophageal squamous epithelium; however, it is also increased in patients with truncal obesity independent of GERD. Barrett esophagus is suspected at endoscopy from the presence of orange, gastric type epithelium that extends upward from the stomach into the distal tubular esophagus in a tongue-like or circumferential fashion. Biopsies obtained at endoscopy confirm the diagnosis. Three types of columnar epithelium may be identified: gastric cardiac, gastric fundic, and specialized intestinal metaplasia. There is agreement that the latter carries an increased risk of dysplasia; however, some authorities believe that gastric cardiac mucosa also raises risk.
Barrett esophagus does not provoke specific symptoms but gastroesophageal reflux does. Most patients have a long history of reflux symptoms, such as heartburn and regurgitation. Barrett esophagus should be treated with long-term proton pump inhibitors once or twice daily to control reflux symptoms. Although these medications do not appear to cause regression of Barrett esophagus, they may reduce the risk of cancer. Paradoxically, one-third of patients report minimal or no symptoms of GERD, suggesting decreased acid sensitivity of Barrett epithelium. Indeed, over 90% of individuals with Barrett esophagus in the general population do not seek medical attention.
The most serious complication of Barrett esophagus is esophageal adenocarcinoma. It is believed that most adenocarcinomas of the esophagus and many such tumors of the gastric cardia arise from dysplastic epithelium in Barrett esophagus. In recent studies, the incidence of adenocarcinoma in patients with Barrett esophagus has been estimated at 0.12–0.33%/year. Although this still is an 11-fold increase risk compared with patients without Barrett esophagus, adenocarcinoma of the esophagus remains a relatively uncommon malignancy in the United States (7000 cases/year). Given the large number of adults with chronic GERD relative to the small number in whom adenocarcinoma develops, 2011 clinical guidelines recommend against endoscopic screening for Barrett esophagus in adults with GERD except in those with multiple risk factors for adenocarcinoma (chronic GERD, hiatal hernia, obesity, white race, male gender, and age 50 years of older).
In patients known to have Barrett esophagus, surveillance endoscopy every 3–5 years is recommended to look for low- or high-grade dysplasia or adenocarcinoma. The risk of progression to adenocarcinoma is a 0.8% risk per year for patients with low-grade dysplasia and a 6% risk per year for high-grade dysplasia. Patients with low-grade dysplasia require repeat endoscopic surveillance in 6 months to exclude coexisting high-grade dysplasia or cancer and, if low-grade dysplasia persists, endoscopic surveillance should be repeated yearly.
Approximately 13% of patient with high-grade dysplasia may harbor an unrecognized invasive esophageal cancer. Therefore, patients with high-grade dysplasia should undergo repeat staging endoscopy with resection of visible mucosal nodules and random mucosal biopsies in order to exclude invasive cancer (for which esophagectomy is recommended). The subsequent management of patients with intramucosal cancer or high-grade dysplasia has rapidly evolved. Until recently, esophagectomy was recommended for patients deemed to have a low operative risk; however, this procedure is associated with high morbidity and mortality rates (40% and 1–5%, respectively). Therefore, it is now recommended that endoscopic therapy be performed for most patients with high-grade dysplasia or intramucosal adenocarcinoma. Endoscopic therapies can remove or ablate dysplastic Barrett epithelium, using mucosal snare resection and radiofrequency wave ablation electrocautery. Snare resection is performed of visible neoplastic mucosal nodules to exclude submucosal invasion (which favors surgical resection). Of the patients who have cancer confined to the mucosa, < 2% have recurrence of cancer or high-grade dysplasia after snare resection. Radiofrequency wave ablation electrocautery is used to ablate Barrett epithelium with flat (non-nodular) dysplasia and to ablate Barrett epithelium that remains after snare resection of dysplastic mucosal nodules. The efficacy of endoscopic ablation therapies in patients with Barrett dysplasia is supported by several studies. When high-dose proton pump inhibitors are administered to normalize intraesophageal pH, radiofrequency wave ablation electrocautery eradication of Barrett columnar epithelium is followed by complete healing with normal squamous epithelium in > 90% of patients. In a 2011 randomized, sham-controlled trial in 127 patients with Barrett dysplasia with 3-year follow up, eradication of high-grade dysplasia occurred in 98% after radiofrequency ablation (HALO) and progression to cancer was only 0.55%/year. After initial ablation, Barrett esophagus recurs (with or without dysplasia) in up to 33% within 2 years, justifying periodic surveillance endoscopy.
Endoscopic ablation techniques have a risk of complications (bleeding, perforation, strictures). Therefore, endoscopic eradication therapy currently is not recommended for patients with nondysplastic Barrett esophagus for whom the risk of developing esophageal cancer is low and treatment does not appear to be cost-effective.
Stricture formation occurs in about 5% of patients with esophagitis. It is manifested by the gradual development of solid food dysphagia progressive over months to years. Often there is a reduction in heartburn because the stricture acts as a barrier to reflux. Most strictures are located at the gastroesophageal junction. Endoscopy with biopsy is mandatory in all cases to differentiate peptic stricture from stricture by esophageal carcinoma. Active erosive esophagitis is often present. Up to 90% of symptomatic patients are effectively treated with dilation with graduated polyvinyl catheters passed over a wire placed at the time of endoscopy or fluoroscopically, or balloons passed fluoroscopically or through an endoscope. Dilation is continued over one to several sessions. A luminal diameter of 13–17 mm is usually sufficient to relieve dysphagia. Long-term therapy with a proton pump inhibitor is required to decrease the likelihood of stricture recurrence. Some patients require intermittent dilation to maintain luminal patency, but operative management for strictures that do not respond to dilation is seldom required. Refractory strictures may benefit from endoscopic injection of triamcinolone into the stricture.
The goal of treatment is to provide symptomatic relief, to heal esophagitis (if present), and to prevent complications. In the majority of patients with uncomplicated disease, empiric treatment is initiated based on a compatible history without the need for further confirmatory studies. Patients not responding and those with suspected complications undergo further evaluation with upper endoscopy or esophageal manometry and pH recording (see above).
Patients with infrequent heartburn (less than once weekly) may be treated on demand with antacids or oral H2-receptor antagonists. Antacids provide rapid relief of heartburn; however, their duration of action is < 2 hours. Many are available over the counter. Those containing magnesium should not be used for patients with kidney disease, and patients with acute or chronic kidney disease should be cautioned appropriately.
All oral H2-receptor antagonists are available in over-the-counter formulations: cimetidine 200 mg, ranitidine and nizatidine 75 mg, famotidine 10 mg—all of which are half of the typical prescription strength. When taken for active heartburn, these agents have a delay in onset of at least 30 minutes. However, once these agents take effect, they provide heartburn relief for up to 8 hours. When taken before meals known to provoke heartburn, these agents reduce the symptom.
Side effects of proton pump inhibitors are uncommon. Headache, diarrhea, and abdominal pain may occur with any of the agents but generally resolve when another formulation is tried. Potential risks of long-term use of proton pump inhibitors include an increased risk of infectious gastroenteritis (including C difficile), iron and vitamin B12 deficiency, hypomagnesemia, pneumonia, hip fractures (possibly due to impaired calcium absorption), and fundic gland polyps (which appear to be of no clinical significance).
Surgical fundoplication affords good to excellent relief of symptoms and healing of esophagitis in over 85% of properly selected patients and can be performed laparoscopically with low complication rates in most instances. Although patient satisfaction is high, typical reflux symptoms recur in 10–30% of patients. Furthermore, new symptoms of dysphagia, bloating, increased flatulence, dyspepsia, or diarrhea develop in over 30% of patients. In 2011, results from a randomized trial comparing laparoscopic fundoplication with prolonged medical therapy (esomeprazole 40 mg/d) for chronic GERD were reported. After 5 years, adequate GERD symptom control (symptom remission) were similar, occurring in 85–92% of patients; however, patients who had undergone fundoplication had increased dysphagia, bloating, and flatulence. In 2012, the FDA approved a novel, minimally invasive magnetic artificial sphincter for the treatment of GERD. The device is made up a flexible, elastic string of titanium beads (wrapped around a magnetic core) that is placed laparoscopically below the diaphragm at the gastroesophageal junction. A 2013 prospective study of 100 patients reported that 64% of patients had significant reductions in esophageal acid reflux. Further experience with this device is needed before widespread adoption can be recommended.
Surgical treatment is not recommended for patients who are well controlled with medical therapies but should be considered for: (1) otherwise healthy, carefully selected patients with extraesophageal manifestations of reflux, as these symptoms often require high doses of proton pump inhibitors and may be more effectively controlled with antireflux surgery; (2) those with severe reflux disease who are unwilling to accept lifelong medical therapy due to its expense, inconvenience, or theoretical risks; and (3) patients with large hiatal hernias and persistent regurgitation despite proton pump inhibitor therapy. Gastric bypass (rather than fundoplication) should be considered for obese patients with GERD.
When to Refer
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Galmiche JP et al; LOTUS Trial Collaborators. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD. JAMA. 2011 May 18;305(19):1969–77. [PMID: 21586712]
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Johnson DA et al. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin Gastroenterol Hepatol. 2013 May;11(5):458–64. Erratum in: Clin Gastroenterol Hepatol. 2013 Jul;11(7):880. [PMID: 23247326]
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Katz PO et al. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013 Mar;108(3):308–28. Erratum in: Am J Gastroenterol. 2013 Oct;108(10):1672. [PMID: 23419381]
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ESSENTIALS OF DIAGNOSIS
Odynophagia, dysphagia, and chest pain.
Endoscopy with biopsy establishes diagnosis.
Infectious esophagitis occurs most commonly in immunosuppressed patients. Patients with AIDS, solid organ transplants, leukemia, lymphoma, and those receiving immunosuppressive drugs are at particular risk for opportunistic infections. Candida albicans, herpes simplex, and CMV are the most common pathogens. Candida infection may occur also in patients who have uncontrolled diabetes and those being treated with systemic corticosteroids, radiation therapy, or systemic antibiotic therapy. Herpes simplex can affect normal hosts, in which case the infection is generally self-limited.
The most common symptoms are odynophagia and dysphagia. Substernal chest pain occurs in some patients. Patients with candidal esophagitis are sometimes asymptomatic. Oral thrush is present in only 75% of patients with candidal esophagitis and 25–50% of patients with viral esophagitis and is therefore an unreliable indicator of the cause of esophageal infection. Patients with esophageal CMV infection may have infection at other sites such as the colon and retina. Oral ulcers (herpes labialis) are often associated with herpes simplex esophagitis.
Treatment may be empiric. For diagnostic certainty, endoscopy with biopsy and brushings (for microbiologic and histopathologic analysis) is preferred because of its high diagnostic accuracy. The endoscopic signs of candidal esophagitis are diffuse, linear, yellow-white plaques adherent to the mucosa. CMV esophagitis is characterized by one to several large, shallow, superficial ulcerations. Herpes esophagitis results in multiple small, deep ulcerations.
Systemic therapy is required for esophageal candidiasis. An empiric trial of antifungal therapy is often administered without performing diagnostic endoscopy. Initial therapy is generally with fluconazole, 400 mg on day 1, then 200–400 mg/d orally for 14–21 days. Patients not responding to empiric therapy within 3–5 days should undergo endoscopy with brushings, biopsy, and culture to distinguish resistant fungal infection from other infections (eg, CMV, herpes). Esophageal candidiasis not responding to fluconazole therapy may be treated with itraconazole suspension (not capsules), 200 mg/d orally, or voriconazole, 200 mg orally twice daily. Refractory infection may be treated intravenously with caspofungin, 50 mg daily.
In patients with HIV infection, immune restoration with highly active antiretroviral therapy (HAART) is the most effective means of controlling CMV disease. Initial therapy is with ganciclovir, 5 mg/kg intravenously every 12 hours for 3–6 weeks. Neutropenia is a frequent dose-limiting side effect. Once resolution of symptoms occurs, it may be possible to complete the course of therapy with oral valganciclovir, 900 mg once daily. Patients who either do not respond to or cannot tolerate ganciclovir are treated acutely with foscarnet, 90 mg/kg intravenously every 12 hours for 3–6 weeks. The principal toxicity is acute renal injury, hypocalcemia, and hypomagnesemia.
Immunocompetent patients may be treated symptomatically and generally do not require specific antiviral therapy. Immunosuppressed patients may be treated with oral acyclovir, 400 mg orally five times daily, or 250 mg/m2 intravenously every 8–12 hours, usually for 14–21 days. Oral famciclovir, 500 mg orally three times daily, or valacyclovir, 1 g twice daily, are also effective but more expensive than generic acyclovir. Nonresponders require therapy with foscarnet, 40 mg/kg intravenously every 8 hours for 21 days.
Most patients with infectious esophagitis can be effectively treated with complete symptom resolution. Depending on the patient’s underlying immunodeficiency, relapse of symptoms off therapy can raise difficulties. Long-term suppressive therapy is sometimes required.
Kim KY et al. Acid suppression therapy as a risk factor for Candida esophagitis. Dig Dis Sci. 2013 May;58(5):1282–6. [PMID: 23306845]
A number of different medications may injure the esophagus, presumably through direct, prolonged mucosal contact. The most commonly implicated are the NSAIDs, potassium chloride pills, quinidine, zalcitabine, zidovudine, alendronate and risedronate, emepronium bromide, iron, vitamin C, and antibiotics (doxycycline, tetracycline, clindamycin, trimethoprim-sulfamethoxazole). Because injury is most likely to occur if pills are swallowed without water or while supine, hospitalized or bed-bound patients are at greater risk. Symptoms include severe retrosternal chest pain, odynophagia, and dysphagia, often beginning several hours after taking a pill. These may occur suddenly and persist for days. Some patients (especially the elderly) have relatively little pain, presenting with dysphagia. Endoscopy may reveal one to several discrete ulcers that may be shallow or deep. Chronic injury may result in severe esophagitis with stricture, hemorrhage, or perforation. Healing occurs rapidly when the offending agent is eliminated. To prevent pill-induced damage, patients should take pills with 4 oz of water and remain upright for 30 minutes after ingestion. Known offending agents should not be given to patients with esophageal dysmotility, dysphagia, or strictures.
Ueda K et al. A case of esophageal ulcer caused by alendronate sodium tablets. Gastrointest Endosc. 2011 May;73(5):1037–8. [PMID: 21521571]
CAUSTIC ESOPHAGEAL INJURY
Caustic esophageal injury occurs from accidental (usually children) or deliberate (suicidal) ingestion of liquid or crystalline alkali (drain cleaners, etc) or acid. Ingestion is followed almost immediately by severe burning and varying degrees of chest pain, gagging, dysphagia, and drooling. Aspiration results in stridor and wheezing. Initial examination should be directed to circulatory status as well as assessment of airway patency and the oropharyngeal mucosa, including laryngoscopy. Patients without major symptoms (dyspnea, dysphagia, drooling, hematemesis) or oropharyngeal lesions have a very low likelihood of having severe gastroesophageal injury. All other patients initially should be hospitalized in an ICU. Chest and abdominal radiographs are obtained looking for pneumonitis or free perforation. Initial treatment is supportive, with intravenous fluids, intravenous proton pump inhibitors to prevent gastric stress ulceration (pantoprazole or esomeprazole, 40 mg twice daily) and analgesics. Nasogastric lavage and oral antidotes may be dangerous and should generally not be administered. Laryngoscopy should be performed in patients with respiratory distress to assess the need for tracheostomy. Endoscopy is usually performed within the first 12–24 hours to assess the extent of injury, especially in patients with significant symptoms or oropharyngeal lesions. Many patients are discovered to have no mucosal injury to the esophagus or stomach, allowing prompt discharge and psychiatric referral. Patients with evidence of mild damage (edema, erythema, exudates or superficial ulcers) recover quickly, have low risk of developing stricture, and may be advanced from liquids to a regular diet over 24–48 hours. Patients with signs of severe injury—deep or circumferential ulcers or necrosis (black discoloration) have a high risk (up to 65%) of acute complications, including perforation with mediastinitis or peritonitis, bleeding, stricture, or esophageal-tracheal fistulas. These patients must be kept fasting and monitored closely for signs of deterioration that warrant emergency surgery with possible esophagectomy and colonic or jejunal interposition. A nasoenteric feeding tube is placed after 24 hours. Oral feedings of liquids may be initiated after 2–3 days if the patient is able to tolerate secretions. Neither corticosteroids nor antibiotics are recommended. Esophageal strictures develop in up to 70% of patients with serious esophageal injury weeks to months after the initial injury, requiring recurrent dilations. Endoscopic injection of intralesional corticosteroids (triamcinolone 40 mg) increases the interval between dilations. The risk of esophageal squamous carcinoma is 2–3%, warranting endoscopic surveillance 15–20 years after the caustic ingestion.
Chirica M et al. Surgery for caustic injuries of the upper gastrointestinal tract. Ann Surg. 2012 Dec;256(6):994–1001. [PMID: 22824850]
Harlak A et al. Surgical treatment of caustic esophageal strictures in adults. Int J Surg. 2013;11(2):164–8. [PMID: 23267851]
BENIGN ESOPHAGEAL LESIONS
ESSENTIALS OF DIAGNOSIS
Hematemesis; usually self-limited.
Prior history of vomiting, retching in 50%.
Endoscopy establishes diagnosis.
Mallory-Weiss syndrome is characterized by a nonpenetrating mucosal tear at the gastroesophageal junction that is hypothesized to arise from events that suddenly raise transabdominal pressure, such as lifting, retching, or vomiting. Alcoholism is a strong predisposing factor. Mallory-Weiss tears are responsible for approximately 5% of cases of upper gastrointestinal bleeding.
Patients usually present with hematemesis with or without melena. A history of retching, vomiting, or straining is obtained in about 50% of cases.
As with other causes of upper gastrointestinal hemorrhage, upper endoscopy should be performed after the patient has been appropriately resuscitated. The diagnosis is established by identification of a 0.5- to 4-cm linear mucosal tear usually located either at the gastroesophageal junction or, more commonly, just below the junction in the gastric mucosa.
At endoscopy, other potential causes of upper gastrointestinal hemorrhage are found in over 35% of patients with Mallory-Weiss tears, including peptic ulcer disease, erosive gastritis, arteriovenous malformations, and esophageal varices. Patients with underlying portal hypertension are at higher risk for continued or recurrent bleeding.
Patients are initially treated as needed with fluid resuscitation and blood transfusions. Most patients stop bleeding spontaneously and require no therapy. Endoscopic hemostatic therapy is employed in patients who have continuing active bleeding. Injection with epinephrine (1:10,000), cautery with a bipolar or heater probe coagulation device, or mechanical compression of the artery by application of an endoclip or band is effective in 90–95% of cases. Angiographic arterial embolization or operative intervention is required in patients who fail endoscopic therapy.
Fujisawa N et al. Risk factors for mortality in patients with Mallory-Weiss syndrome. Hepatogastroenterology. 2011 Mar–Apr;58(106):417–20. [PMID: 21661406]
Yin A et al. Mallory-Weiss syndrome: clinical and endoscopic characteristics. Eur J Intern Med. 2012 Jun;23(4):e92–6. [PMID: 22560400]
Eosinophilia of the esophagus may be caused by several conditions, most commonly eosinophilic esophagitis; GERD; proton pump inhibitor–responsive eosinophilia; and celiac disease, Crohn disease, and pemphigus (although rarely).
Eosinophilic esophagitis is a disorder in which food or environmental antigens are thought to stimulate an inflammatory response. Initially recognized in children, it is increasingly identified in young or middle-aged adults, predominantly men (75%). A history of allergies or atopic conditions (asthma, eczema, hay fever) is present in over half of patients.
Most adults have a long history of dysphagia for solid-foods or an episode of food impaction. Heartburn may be present. Children may have abdominal pain, vomiting, chest pain, or failure to thrive. On laboratory tests, a few have eosinophilia or elevated IgE levels. Barium swallow studies may demonstrate a small-caliber esophagus; focal or long, tapered strictures; or multiple concentric rings. However, endoscopy with esophageal biopsy and histologic evaluation is required to establish the diagnosis. Endoscopic appearances include white exudates or papules, red furrows, corrugated concentric rings, and strictures; however, the esophagus is grossly normal in up to 10% of patients. Multiple biopsies (at least 2–4) from the proximal and distal esophagus should be obtained to demonstrate multiple (> 15/high-powered field) eosinophils in the mucosa. Most children have other coexisting atopic disorders. Skin testing for food allergies may be helpful to identify causative factors, especially in children.
Before making a diagnosis of eosinophilic esophagitis, all patients should be given an empiric trial of a proton pump inhibitor orally twice daily for 2 months followed by repeat endoscopy and mucosal biopsy to exclude GERD and so-called proton pump inhibitor–responsive eosinophilia, a distinct entity that is not necessarily related to GERD. Approximately 35% of symptomatic patients with increased esophageal eosinophils have clinical and histologic improvement with proton pump inhibitor treatment.
Eosinophilic esophagitis is diagnosed in patients with persistent symptoms and eosinophilia; the optimal treatment of this condition is uncertain. Referral to an allergist for evaluation of coexisting atopic disorders and for testing for food and environmental allergens may be considered. In children, food elimination or elemental diets lead to clinical and histologic improvement in 75%. The most common allergenic foods are dairy, eggs, wheat, soy, peanuts, and shellfish. In a 2012 prospective study of 50 adults who eliminated these foods for 6 weeks, dysphagia improved in 94% and esophageal eosinophils were reduced to < 10/hpf in 70%. Reintroduction of the trigger food results in prompt recurrence of symptoms. Topical corticosteroids lead to symptom resolution in 70% of adults. For example, budesonide suspension (1 mg orally) may be administered twice daily or one to two puffs of fluticasone (440 mcg/puff inhaler without a spacer twice daily after meals) may be swallowed after activation instead of inhaled. Symptomatic relapse is common after discontinuation of therapy and may require maintenance therapy. Graduated dilation of strictures should be conducted in patients with dysphagia and strictures or narrow-caliber esophagus but should be performed cautiously because there is an increased risk of perforation and postprocedural chest pain.
Chehade M et al. Causes, evaluation, and consequences of eosinophilic esophagitis. Ann N Y Acad Sci. 2013 Oct;1300:110–8. [PMID: 24117638]
Dellon ES et al. ACG Clinical Guideline: evidence based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis. Am J Gastroenterol. 2013 May;108(5):679–92. [PMID: 23567357]
Gonsalves N et al. Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology. 2012 Jun;142(7):1451–9.e1 [PMID: 22391333]
Esophageal webs are thin, diaphragm-like membranes of squamous mucosa that typically occur in the mid or upper esophagus and may be multiple. They may be congenital but also occur with eosinophilic esophagitis, graft-versus-host disease, pemphigoid, epidermolysis bullosa, pemphigus vulgaris, and, rarely, in association with iron deficiency anemia (Plummer-Vinson syndrome). Esophageal “Schatzki” rings are smooth, circumferential, thin (< 4 mm in thickness) mucosal structures located in the distal esophagus at the squamocolumnar junction. Their pathogenesis is controversial. They are associated in nearly all cases with a hiatal hernia, and reflux symptoms are common, suggesting that acid gastroesophageal reflux may be contributory in many cases. Most webs and rings are over 20 mm in diameter and are asymptomatic. Solid food dysphagia most often occurs with rings < 13 mm in diameter. Characteristically, dysphagia is intermittent and not progressive. Large poorly chewed food boluses such as beefsteak are most likely to cause symptoms. Obstructing boluses may pass by drinking extra liquids or after regurgitation. In some cases, an impacted bolus must be extracted endoscopically. Esophageal webs and rings are best visualized using a barium esophagogram with full esophageal distention. Endoscopy is less sensitive than barium esophagography.
The majority of symptomatic patients with a single ring or web can be effectively treated with the passage of bougie dilators to disrupt the lesion or endoscopic electrosurgical incision of the ring. A single dilation may suffice, but repeat dilations are required in many patients. Patients who have heartburn or who require repeated dilation should receive long-term acid suppressive therapy with a proton pump inhibitor.
Müller M et al. Is the Schatzki ring a unique esophageal entity? World J Gastroenterol. 2011 Jun 21;17(23):2838–43. [PMID: 21734791]
Zenker diverticulum is a protrusion of pharyngeal mucosa that develops at the pharyngoesophageal junction between the inferior pharyngeal constrictor and the cricopharyngeus. The cause is believed to be loss of elasticity of the upper esophageal sphincter, resulting in restricted opening during swallowing. Symptoms of dysphagia and regurgitation tend to develop insidiously over years in older patients. Initial symptoms include vague oropharyngeal dysphagia with coughing or throat discomfort. As the diverticulum enlarges and retains food, patients may note halitosis, spontaneous regurgitation of undigested food, nocturnal choking, gurgling in the throat, or a protrusion in the neck. Complications include aspiration pneumonia, bronchiectasis, and lung abscess. The diagnosis is best established by a barium esophagogram.
Symptomatic patients require upper esophageal myotomy and, in most cases, surgical diverticulectomy. An intraluminal approach has been developed in which the septum between the esophagus and diverticulum is incised using a rigid or flexible endoscope. Significant improvement occurs in over 90% of patients treated surgically. Small asymptomatic diverticula may be observed.
Prisman E et al. Zenker diverticulum. Otolaryngol Clin North Am. 2013 Dec;46(6):1101–11. [PMID: 24262962]
ESSENTIALS OF DIAGNOSIS
Develop secondary to portal hypertension.
Found in 50% of patients with cirrhosis.
One-third of patients with varices develop upper gastrointestinal bleeding.
Diagnosis established by upper endoscopy.
Esophageal varices are dilated submucosal veins that develop in patients with underlying portal hypertension and may result in serious upper gastrointestinal bleeding. The causes of portal hypertension are discussed in Chapter 16. Under normal circumstances, there is a 2–6 mm Hg pressure gradient between the portal vein and the inferior vena cava. When the gradient exceeds 10–12 mm Hg, significant portal hypertension exists. Esophageal varices are the most common cause of important gastrointestinal bleeding due to portal hypertension, though gastric varices and, rarely, intestinal varices may also bleed. Bleeding from esophageal varices most commonly occurs in the distal 5 cm of the esophagus.
The most common cause of portal hypertension is cirrhosis. Approximately 50% of patients with cirrhosis have esophageal varices. Bleeding from varices occurs in 30% of patients with esophageal varices. In the absence of any treatment, variceal bleeding spontaneously stops in about 50% of patients. Patients surviving this bleeding episode have a 60% chance of recurrent variceal bleeding, usually within the first 6 weeks. With current therapies, the in-hospital mortality rate associated with bleeding esophageal varices is 15%.
A number of factors have been identified that may portend an increased risk of bleeding from esophageal varices. The most important are: (1) the size of the varices; (2) the presence at endoscopy of red wale markings (longitudinal dilated venules on the varix surface); (3) the severity of liver disease (as assessed by Child scoring); and (4) active alcohol abuse—patients with cirrhosis who continue to drink have an extremely high risk of bleeding.
Patients with bleeding esophageal varices present with symptoms and signs of acute gastrointestinal hemorrhage. (See Acute Upper Gastrointestinal Bleeding, above.) In some cases, there may be preceding retching or dyspepsia attributable to alcoholic gastritis or withdrawal. Varices per se do not cause symptoms of dyspepsia, dysphagia, or retching. Variceal bleeding usually is severe, resulting in hypovolemia manifested by postural vital signs or shock. Twenty percent of patients with chronic liver disease in whom bleeding develops have a nonvariceal source of bleeding.
These are identical to those listed above in the section on acute upper gastrointestinal tract bleeding.
The initial management of patients with acute upper gastrointestinal bleeding is also discussed in the section on acute upper gastrointestinal bleeding (see above). Variceal hemorrhage is life-threatening; rapid assessment and resuscitation with fluids or blood products are essential. Overtransfusion should be avoided as it leads to increased central and portal venous pressures, increasing the risk of rebleeding. Many patients with bleeding esophageal varices have coagulopathy due to underlying cirrhosis; fresh frozen plasma (20 mL/kg loading dose, then 10 mg/kg every 6 hours) or platelets should be administered to patients with INRs > 1.8–2.0 or with platelet counts < 50,000/mcL in the presence of active bleeding. Recombinant factor VIIa has not demonstrated efficacy in controlled studies and is not recommended. Patients with advanced liver disease are at high risk for poor outcome regardless of the bleeding source and should be transferred to an ICU.
Terlipressin, 1–2 mg intravenous every 4 hours, (not available in the United States) is a synthetic vasopressin analog that causes a significant and sustained reduction in portal and variceal pressures while preserving renal perfusion. Where available, terlipressin may be preferred to somatostatin or octreotide. Terlipressin is contraindicated in patients with significant coronary, cerebral, or peripheral vascular disease.
Emergent endoscopy is performed after the patient’s hemodynamic status has been appropriately stabilized (usually within 2–12 hours). In patients with active bleeding, endotracheal intubation is commonly performed to protect against aspiration during endoscopy. An endoscopic examination is performed to exclude other or associated causes of upper gastrointestinal bleeding such as Mallory-Weiss tears, peptic ulcer disease, and portal hypertensive gastropathy. In many patients, variceal bleeding has stopped spontaneously by the time of endoscopy, and the diagnosis of variceal bleeding is made presumptively. Acute endoscopic treatment of the varices is performed with either banding or sclerotherapy. These techniques arrest active bleeding in 80–90% of patients and reduce the chance of in-hospital recurrent bleeding to about 20%.
If banding is chosen, repeat sessions are scheduled at intervals of 2–4 weeks until the varices are obliterated or reduced to a small size. Banding achieves lower rates of rebleeding, complications, and death than sclerotherapy and should be considered the endoscopic treatment of choice.
Sclerotherapy is still preferred by some endoscopists in the actively bleeding patient (in whom visualization for banding may be difficult). Sclerotherapy is performed by injecting the variceal trunks with a sclerosing agent (eg, ethanolamine, tetradecyl sulfate). Complications occur in 20–30% of patients and include chest pain, fever, bacteremia, esophageal ulceration, stricture, and perforation. After initial treatment, band ligation therapy should be performed.
Mechanical tamponade with specially designed nasogastric tubes containing large gastric and esophageal balloons (Minnesota or Sengstaken-Blakemore tubes) provides initial control of active variceal hemorrhage in 60–90% of patients; rebleeding occurs in 50%. The gastric balloon is inflated first, followed by the esophageal balloon if bleeding continues. After balloon inflation, tension is applied to the tube to directly tamponade the varices. Complications of prolonged balloon inflation include esophageal and oral ulcerations, perforation, aspiration, and airway obstruction (due to a misplaced balloon). Endotracheal intubation is recommended before placement. Given its high rate of complications, mechanical tamponade is used as a temporizing measure only in patients with bleeding that cannot be controlled with pharmacologic or endoscopic techniques until more definitive decompressive therapy (eg, TIPS; see below) can be provided.
In the 10–20% of patients with variceal bleeding that cannot be controlled with pharmacologic or endoscopic therapy, emergency portal decompression may be considered.
Prevention of Rebleeding
Once the initial bleeding episode has been controlled, therapy is warranted to reduce the high risk (60%) of rebleeding.
Nonselective beta-adrenergic blockers (propranolol, nadolol) reduce the risk of rebleeding from esophageal varices to about 40%. Likewise, long-term treatment with band ligation reduces the incidence of rebleeding to about 30%. In most patients, two to six treatment sessions (performed at 2- to 4-week intervals) are needed to eradicate the varices.
Meta-analyses of randomized controlled trials suggest that a combination of band ligation plus beta-blockers is superior to either variceal band ligation alone (RR 0.68) or beta-blockers alone (RR 0.71). Therefore, combination therapy is recommended for patients without contraindications to beta-blockers. Recommended starting doses of beta-blockers are propranolol (20 mg orally twice daily), long-acting propranolol (60 mg orally once daily), or nadolol (20–40 mg orally once daily), with gradual increases in the dosage every 1–2 weeks until the heart rate falls by 25% or reaches 55–60 beats/min, provided the systolic blood pressure remains above 90 mm Hg and the patient has no side effects. The average dosage of long-acting propranolol is 120 mg once daily and for nadolol, 80 mg once daily. One-third of patients with cirrhosis are intolerant of beta-blockers, experiencing fatigue or hypotension. Drug administration at bedtime may reduce the frequency and severity of side effects.
TIPS has resulted in a significant reduction in recurrent bleeding compared with endoscopic sclerotherapy or band ligation—either alone or in combination with beta-blocker therapy. At 1 year, rebleeding rates in patients treated with TIPS versus various endoscopic therapies average 20% and 40%, respectively. However, TIPS was also associated with a higher incidence of encephalopathy (35% vs 15%) and did not result in a decrease in mortality. Another limitation of TIPS is that stenosis and thrombosis of the stents occur in the majority of patients over time with a consequent risk of rebleeding. Therefore, periodic monitoring with Doppler ultrasonography or hepatic venography is required. Stent patency usually can be maintained by balloon angioplasty or additional stent placement. Given these problems, TIPS should be reserved for patients who have recurrent (two or more) episodes of variceal bleeding that have failed endoscopic or pharmacologic therapies. TIPS is also useful in patients with recurrent bleeding from gastric varices or portal hypertensive gastropathy (for which endoscopic therapies cannot be used). TIPS is likewise considered in patients who are noncompliant with other therapies or who live in remote locations (without access to emergency care).
Shunt surgery has a significantly lower rate of rebleeding compared with endoscopic therapy but also a higher incidence of encephalopathy. With the advent and widespread adoption of TIPS, surgical shunts are seldom performed.
Candidacy for orthotopic liver transplantation should be assessed in all patients with chronic liver disease and bleeding due to portal hypertension. Transplant candidates should be treated with band ligation or TIPS to control bleeding pretransplant.
Prevention of First Episodes of Variceal Bleeding
Among patients with varices that have not previously bled, bleeding occurs in 12% of patients each year, with a lifetime risk of 30%. Because of the high mortality rate associated with variceal hemorrhage, prevention of the initial bleeding episode is desirable. Therefore, patients with cirrhosis should undergo diagnostic endoscopy or capsule endoscopy to determine whether varices are present. Varices are present in 40% of patients with Child-Turcotte-Pugh class A cirrhosis and in 85% with Child-Turcotte-Pugh class C cirrhosis. In patients without varices on screening endoscopy, a repeat endoscopy is recommended in 3 years, since varices develop in 8% of patients per year. Patients with varices have a higher risk of bleeding if they have large varices (> 5 mm), varices with red wale markings, or Child-Turcotte-Pugh class B or C cirrhosis. The risk of bleeding in patients with small varices (< 5 mm) is 5% per year and with large varices is 15–20% per year. Patients with small varices without red wale marks and compensated (Child-Turcotte-Pugh class A) cirrhosis have a low-risk of bleeding; hence, prophylaxis is unnecessary, but endoscopy should be repeated in 1–2 years to reassess size.
Nonselective beta-adrenergic blockers are recommended to reduce the risk of first variceal hemorrhage in patients with medium/large varices and patients with small varices who either have variceal red wale marks or advanced cirrhosis (Child-Turcotte-Pugh class B or C). (See Combination Beta-Blockers and Variceal Band Ligation, above.) Band ligation is not recommended for small varices due to technical difficulties in band application. Prophylactic band ligation may be preferred for higher risk patients with medium/large varices (Child-Turcotte-Pugh class B or C or varices with red wale markings) as well as patients with contraindications to or intolerance of beta-blockers.
When to Refer
When to Admit
All patients with acute upper gastrointestinal bleeding and suspected cirrhosis should be admitted to an ICU.
Bhogal HK et al. Using transjugular intrahepatic portosystemic shunts for complications of cirrhosis. Clin Gastroenterol Hepatol. 2011;9(11) :936–46. [PMID: 21699820]
Rahimi RS et al. End-stage liver disease complications. Curr Opin Gastroenterol. 2013 May;29(3):257–63. [PMID: 23429468]
Huberty V et al. Endoscopic treatment for Zenker’s diverticulum: long-term results (with video). Gastrointest Endosc. 2013 May;77(5):701–7. [PMID: 23394840]
ESOPHAGEAL MOTILITY DISORDERS
ESSENTIALS OF DIAGNOSIS
Gradual, progressive dysphagia for solids and liquids.
Regurgitation of undigested food.
Barium esophagogram with “bird’s beak” distal esophagus.
Esophageal manometry confirms diagnosis.
Achalasia is an idiopathic motility disorder characterized by loss of peristalsis in the distal two-thirds (smooth muscle) of the esophagus and impaired relaxation of the LES. There appears to be denervation of the esophagus resulting primarily from loss of nitric oxide-producing inhibitory neurons in the myenteric plexus. The cause of the neuronal degeneration is unknown.
There is a steady increase in the incidence of achalasia with age; however, it can be seen in individuals as young as 25 years. Patients complain of the gradual onset of dysphagia for solid foods and, in the majority, of liquids also. Symptoms at presentation may have persisted for months to years. Substernal discomfort or fullness may be noted after eating. Many patients eat more slowly and adopt specific maneuvers such as lifting the neck or throwing the shoulders back to enhance esophageal emptying. Regurgitation of undigested food is common and may occur during meals or up to several hours later. Nocturnal regurgitation can provoke coughing or aspiration. Up to 50% of patients report substernal chest pain that is unrelated to meals or exercise and may last up to hours. Weight loss is common. Physical examination is unhelpful.
Chest radiographs may show an air-fluid level in the enlarged, fluid-filled esophagus. Barium esophagography discloses characteristic findings, including esophageal dilation, loss of esophageal peristalsis, poor esophageal emptying, and a smooth, symmetric “bird’s beak” tapering of the distal esophagus. Without treatment, the esophagus may become markedly dilated (“sigmoid esophagus”).
After esophagography, endoscopy is always performed to evaluate the distal esophagus and gastroesophageal junction to exclude a distal stricture or a submucosal infiltrating carcinoma. The diagnosis is confirmed by esophageal manometry. The manometric features are complete absence of normal peristalsis and incomplete lower esophageal sphincteric relaxation with swallowing.
Chagas disease is associated with esophageal dysfunction that is indistinguishable from idiopathic achalasia and should be considered in patients from endemic regions (Central and South America); it is becoming more common in the southern United States. Primary or metastatic tumors can invade the gastroesophageal junction, resulting in a picture resembling that of achalasia, called “pseudoachalasia.” Endoscopic ultrasonography and chest CT may be required to examine the distal esophagus in suspicious cases. Tumors such as small cell lung cancer can cause a paraneoplastic syndrome resembling achalasia due to secretion of antineuronal nuclear antibodies (ANNA-1 or Anti-Hu) that affect the myenteric plexus. Achalasia must be distinguished from other motility disorders such as diffuse esophageal spasm and scleroderma esophagus with a peptic stricture.
Endoscopically guided injection of botulinum toxin directly into the LES results in a marked reduction in LES pressure with initial improvement in symptoms in 65–85% of patients. However, symptom relapse occurs in over 50% of patients within 6–9 months and in all patients within 2 years. Three-fourths of initial responders who relapse have improvement with repeated injections. Because it is inferior to pneumatic dilation therapy and surgery in producing sustained symptomatic relief, this therapy is most appropriate for patients with comorbidities who are poor candidates for more invasive procedures.
Up to 90% of patients derive good to excellent relief of dysphagia after one to three sessions of pneumatic dilation of the LES. Dilation is less effective in patients who are younger than age 50 or have a dilated esophagus. Symptoms recur following pneumatic dilation in up to 35% within 10 years but usually respond to repeated dilation. Perforations occur in < 3% of dilations and may require operative repair. The success of laparoscopic myotomy is not compromised by prior pneumatic dilation.
A modified Heller cardiomyotomy of the LES and cardia results in good to excellent symptomatic improvement in over 90% of patients. Because gastroesophageal reflux develops in up to 20% of patients after myotomy, most surgeons also perform an antireflux procedure (fundoplication), and all patients are prescribed a once-daily proton pump inhibitor. Myotomy is performed with a laparoscopic approach and is preferred to the open surgical approach. Symptoms recur following cardiomyotomy in > 25% of cases within 10 years but usually respond to pneumatic dilation. Pneumatic dilation may be less effective in young males (age < 45 years) so surgical myotomy may be preferred for them. In 2011, results from a large randomized, multicenter trial comparing laparoscopic myotomy to pneumatic dilation were reported. After 2 years of follow-up, adequate symptom control was achieved in 86% of the dilation group and 90% of the surgery group. Thus, in experienced hands, the initial efficacies of pneumatic dilation and laparoscopic myotomy are nearly equivalent. Since 2011, selected, highly experienced centers in Southeast Asia and, more recently, in the United States, have reported excellent results with a less invasive, incisionless, per-oral endoscopic myotomy (POEM). Complete esophagectomy may be required in patients with megaesophagus, in whom dilation and myotomy are less effective.
Boeckxstaens GE et al; European Achalasia Trial Investigators. Pneumatic dilation versus laparoscopic Heller’s myotomy for idiopathic achalasia. N Engl J Med. 2011 May 12;364(19):1807–12. [PMID: 21561346]
Pandolfino JE et al. Presentation, diagnosis, and management of achalasia. Clin Gastroenterol Hepatol. 2013 Aug;11(8):887–97. [PMID: 23395699]
Swanstrom LL et al. Long-term outcomes of an endoscopic myotomy for achalasia: the POEM procedure. Ann Surg. 2012 Oct;256(4):659–67. [PMID: 22982946]
Vaezi MF et al. ACG Clinical Guideline: diagnosis and management of achalasia. Am J Gastroenterol. 2013 Aug;108(8):1238–49. [PMID: 23877351]
Abnormalities in esophageal motility may cause dysphagia or chest pain. Dysphagia for liquids as well as solids tends to be intermittent and nonprogressive. Periods of normal swallowing may alternate with periods of dysphagia, which usually is mild though bothersome—rarely severe enough to result in significant alterations in lifestyle or weight loss. Dysphagia may be provoked by stress, large boluses of food, or hot or cold liquids. Some patients may experience anterior chest pain that may be confused with angina pectoris but usually is nonexertional. The pain generally is unrelated to eating. (See Chest Pain of Undetermined Origin, below.)
The evaluation of suspected esophageal motility disorders includes barium esophagography, upper endoscopy, and, in some cases, esophageal manometry. Barium esophagography is useful to exclude mechanical obstruction and to evaluate esophageal motility. The presence of simultaneous contractions (spasm), disordered peristalsis, or failed peristalsis supports a diagnosis of esophageal dysmotility. Upper endoscopy also is performed to exclude a mechanical obstruction (as a cause of dysphagia) and to look for evidence of erosive reflux esophagitis (a common cause of chest pain) or eosinophilic esophagitis (confirmed by esophageal biopsy). Manometry is not routinely used for mild to moderate symptoms because the findings seldom influence further medical management, but it may be useful in patients with persistent, disabling dysphagia to exclude achalasia and to look for other disorders of esophageal motility. These include spastic disorders (diffuse esophageal spasm, hypercontractile esophagus, hypertensive peristalsis, and esophagogastric junction outflow obstruction) and findings of ineffective esophageal peristalsis (failed or weak esophageal peristalsis). The further evaluation of noncardiac chest pain is discussed in a subsequent section.
For patients with mild symptoms of dysphagia, therapy is directed at symptom reduction and reassurance. Patients should be instructed to eat more slowly and take smaller bites of food. In some cases, a warm liquid at the start of a meal may facilitate swallowing. Because unrecognized gastroesophageal reflux may cause dysphagia, a trial of a proton pump inhibitor (esomeprazole 40 mg, lansoprazole 30 mg) orally twice daily should be administered for 4–8 weeks. Treatment of patients with severe dysphagia is empiric. Suspected spastic disorders may be treated with isosorbide (10–20 mg four times daily) or nitroglycerin (0.4 mg sublingually as needed) and nifedipine (10 mg) or diltiazem (60–90 mg) 30–45 minutes before meals may be tried; their efficacy is unproved. Phosphodiesterase type 5 inhibitors (eg, sildenafil) promote smooth muscle relaxation and improve esophageal motility in small numbers of patients with spastic disorders but require further clinical study before they can be recommended. Injection of botulinum toxin into the lower esophagus may improve chest pain and dysphagia in some patients for a limited time. For unclear reasons, esophageal dilation provides symptomatic relief in some cases.
Roman S et al. Distal esophageal spasm. Dysphagia. 2012 Mar;27(1):115–23. [PMID: 22215281]
Roman S et al. Management of spastic disorders of the esophagus. Gastroenterol Clin North Am. 2013 Mar;42(1):27–43. [PMID: 23452629]
CHEST PAIN OF UNDETERMINED ORIGIN
One-third of patients with chest pain undergo negative cardiac evaluation. Patients with recurrent noncardiac chest pain thus pose a difficult clinical problem. Because coronary artery disease is common and can present atypically, it must be excluded prior to evaluation for other causes.
Causes of noncardiac chest pain may include the following.
These are easily diagnosed by history and physical examination.
Up to 50% of patients have increased amounts of gastroesophageal acid reflux or a correlation between acid reflux episodes and chest pain demonstrated on esophageal pH testing. An empiric 4-week trial of acid-suppressive therapy with a high-dose proton pump inhibitor is recommended (eg, omeprazole or rabeprazole, 40 mg orally twice daily; lansoprazole, 30–60 mg orally twice daily; or esomeprazole or pantoprazole, 40 mg orally twice daily), especially in patients with reflux symptoms. In patients with persistent symptoms, ambulatory esophageal pH or impedance and pH study may be useful to exclude definitively a relationship between acid and nonacid reflux episodes and chest pain events.
Esophageal motility abnormalities such as diffuse esophageal spasm or hypertensive peristalsis (nutcracker esophagus) are uncommon causes of noncardiac chest pain. In patients with chest pain and dysphagia, a barium swallow radiograph should be obtained to look for evidence of achalasia or diffuse esophageal spasm. Esophageal manometry is not routinely performed because of low specificity and the unlikelihood of finding a clinically significant disorder, but it may be recommended in patients with frequent symptoms.
Some patients with noncardiac chest pain report pain in response to a variety of minor noxious stimuli such as physiologically normal amounts of acid reflux, inflation of balloons within the esophageal lumen, injection of intravenous edrophonium (a cholinergic stimulus), or intracardiac catheter manipulation. Low doses of oral antidepressants such as trazodone 50 mg or imipramine 10–50 mg reduce chest pain symptoms and are thought to reduce visceral afferent awareness. In a 2010 controlled crossover trial, over 50% of patients treated with venlafaxine, 75 mg once daily at bedtime, achieved symptomatic improvement compared with only 4% treated with placebo.
A significant number of patients have underlying depression, anxiety, and panic disorder. Patients reporting dyspnea, sweating, tachycardia, suffocation, or fear of dying should be evaluated for panic disorder.
Arora AS et al. How do I handle the patient with noncardiac chest pain? Clin Gastroenterol Hepatol. 2011 Apr;9(4): 295–304. [PMID: 21056690]
Flook NW et al. Acid-suppressive therapy with esomeprazole for relief of unexplained chest pain in primary care: a randomized, double-blind, placebo-controlled trial. Am J Gastroenterol. 2013 Jan;108(1):56–64. [PMID: 23147520]
Hershcovici T et al. Systematic review: the treatment of noncardiac chest pain. Aliment Pharmacol Ther. 2012 Jan;35(1):5–14. [PMID: 22077344]
DISEASES OF THE STOMACH & DUODENUM
(See Chapter 39 for Gastric Cancers.)
GASTRITIS & GASTROPATHY
The term “gastropathy” should be used to denote conditions in which there is epithelial or endothelial damage without inflammation, and “gastritis” should be used to denote conditions in which there is histologic evidence of inflammation. In clinical practice, the term “gastritis” is commonly applied to three categories: (1) erosive and hemorrhagic “gastritis” (gastropathy); (2) nonerosive, nonspecific (histologic) gastritis; and (3) specific types of gastritis, characterized by distinctive histologic and endoscopic features diagnostic of specific disorders.
ESSENTIALS OF DIAGNOSIS
Most commonly seen in alcoholic or critically ill patients, or patients taking NSAIDs.
Often asymptomatic; may cause epigastric pain, nausea, and vomiting.
May cause hematemesis; usually not significant bleeding.
The most common causes of erosive gastropathy are medications (especially NSAIDs), alcohol, stress due to severe medical or surgical illness, and portal hypertension (“portal gastropathy”). Major risk factors for stress gastritis include mechanical ventilation, coagulopathy, trauma, burns, shock, sepsis, central nervous system injury, liver failure, kidney disease, and multiorgan failure. The use of enteral nutrition reduces the risk of stress-related bleeding. Uncommon causes of erosive gastropathy include caustic ingestion and radiation. Erosive and hemorrhagic gastropathy typically are diagnosed at endoscopy, often being performed because of dyspepsia or upper gastrointestinal bleeding. Endoscopic findings include subepithelial hemorrhages, petechiae, and erosions. These lesions are superficial, vary in size and number, and may be focal or diffuse. There usually is no significant inflammation on histologic examination.
Erosive gastropathy is usually asymptomatic. Symptoms, when they occur, include anorexia, epigastric pain, nausea, and vomiting. There is poor correlation between symptoms and the number or severity of endoscopic abnormalities. The most common clinical manifestation of erosive gastritis is upper gastrointestinal bleeding, which presents as hematemesis, “coffee grounds” emesis, or bloody aspirate in a patient receiving nasogastric suction, or as melena. Because erosive gastritis is superficial, hemodynamically significant bleeding is rare.
The laboratory findings are nonspecific. The hematocrit is low if significant bleeding has occurred; iron deficiency may be found.
Upper endoscopy is the most sensitive method of diagnosis. Although bleeding from gastritis is usually insignificant, it cannot be distinguished on clinical grounds from more serious lesions such as peptic ulcers or esophageal varices. Hence, endoscopy is generally performed within 24 hours in patients with upper gastrointestinal bleeding to identify the source. An upper gastrointestinal series is sometimes obtained in lieu of endoscopy in patients with hemodynamically insignificant upper gastrointestinal bleeds to exclude serious lesions but is insensitive for the detection of gastritis.
Epigastric pain may be due to peptic ulcer, gastroesophageal reflux, gastric cancer, biliary tract disease, food poisoning, viral gastroenteritis, and functional dyspepsia. With severe pain, one should consider a perforated or penetrating ulcer, pancreatic disease, esophageal rupture, ruptured aortic aneurysm, gastric volvulus, and myocardial colic. Causes of upper gastrointestinal bleeding include peptic ulcer disease, esophageal varices, Mallory-Weiss tear, and angiodysplasias.
Specific Causes & Treatment
Prophylaxis should be routinely administered to critically ill patients with risk factors for significant bleeding upon admission. Prophylactic suppression of gastric acid with intravenous H2-receptor antagonists or proton pump inhibitors (oral or intravenous) has been shown to reduce the incidence of clinically overt and significant bleeding but may increase the risk of nosocomial pneumonia. A 2012 meta-analysis of 13 randomized trials found that oral and intravenous proton pump inhibitors significantly decreased the incidence of clinically significant bleeding compared with intravenous H2-receptor antagonists (1.3% vs 6.6%, OR 0.30).
The optimal, cost-effective prophylactic regimen remains uncertain, hence clinical practices vary. For patients with nasoenteric tubes, immediate-release omeprazole (40 mg at 1 and 6 hours on day 1; then 40 mg once daily beginning on day 2) may be preferred because of lower cost and ease of administration. For patients requiring intravenous administration, continuous intravenous infusions of H2-receptor antagonists provide adequate control of intragastric pH in most patients in the following doses over 24 hours: cimetidine (900–1200 mg), ranitidine (150 mg), or famotidine (20 mg). Alternatively, intravenous proton pump inhibitors, although more expensive, may be preferred due to superior efficacy. The optimal dosing of intravenous proton pump inhibitors is uncertain; however, in clinical trials pantoprazole doses ranging from 40 mg to 80 mg and administered every 8–24 hours appear equally effective.
Of patients receiving NSAIDs in clinical trials, 25–50% have gastritis and 10–20% have ulcers at endoscopy; however, symptoms of significant dyspepsia develop in about 5%. NSAIDs that are more selective for the cyclooxygenase (COX)-2 enzyme (“coxibs”), such as celecoxib, etodolac, and meloxicam, decrease the incidence of endoscopically visible ulcers by approximately 75% and significant ulcer complications by up to 50% compared with nonselective NSAIDs (nsNSAIDs) (see below). However, a twofold increase in the incidence in cardiovascular complications (myocardial infarction, cerebrovascular infarction, and death) in patients taking coxibs compared with placebo led to the withdrawal of two highly selective coxibs (rofecoxib and valdecoxib) from the market by the manufacturers. Celecoxib and all currently available nsNSAIDS (with notable exception of aspirin and possibly naproxen) are associated with increased risk of cardiovascular complications and therefore should be used with caution in patients with cardiovascular risk factors.
In population surveys, the rate of dyspepsia is increased 1.5- to 2-fold with nsNSAID and coxib use. However, dyspeptic symptoms correlate poorly with significant mucosal abnormalities or the development of adverse clinical events (ulcer bleeding or perforation). Given the frequency of dyspeptic symptoms in patients taking NSAIDs, it is neither feasible nor desirable to investigate all such cases. Patients with alarm symptoms or signs, such as severe pain, weight loss, vomiting, gastrointestinal bleeding, or anemia, should undergo diagnostic upper endoscopy. For other patients, symptoms may improve with discontinuation of the agent, reduction to the lowest effective dose, or administration with meals. Proton pump inhibitors have demonstrated efficacy in controlled trials for the treatment of NSAID-related dyspepsia and superiority to H2-receptor antagonists for healing of NSAID-related ulcers even in the setting of continued NSAID use. Therefore, an empiric 2–4 week trial of an oral proton pump inhibitor (omeprazole, rabeprazole, or esomeprazole 20–40 mg/d; lansoprazole or dexlansoprazole, 30 mg/d; pantoprazole, 40 mg/d) is recommended for patients with NSAID-related dyspepsia, especially those in whom continued NSAID treatment is required. If symptoms do not improve, diagnostic upper endoscopy should be conducted.
Excessive alcohol consumption may lead to dyspepsia, nausea, emesis, and minor hematemesis—a condition sometimes labeled “alcoholic gastritis.” However, it is not proven that alcohol alone actually causes significant erosive gastritis. Therapy with H2-receptor antagonists, proton pump inhibitors, or sucralfate for 2–4 weeks often is empirically prescribed.
Portal hypertension commonly results in gastric mucosal and submucosal congestion of capillaries and venules, which is correlated with the severity of the portal hypertension and underlying liver disease. Usually asymptomatic, it may cause chronic gastrointestinal bleeding in 10% of patients and, less commonly, clinically significant bleeding with hematemesis. Treatment with propranolol or nadolol reduces the incidence of recurrent acute bleeding by lowering portal pressures. Patients who fail propranolol therapy may be successfully treated with portal decompressive procedures (see section above on treatment of esophageal varices).
Barkun AN et al. Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012 Apr;107(4):507–20. [PMID: 22290403]
den Hollander WJ et al. Current pharmacotherapy options for gastritis. Expert Opin Pharmacother. 2012 Dec;13(18):2625–36. [PMID: 23167300]
Ripoll C et al. The management of portal hypertensive gastropathy and gastric antral vascular ectasia. Dig Liver Dis. 2011 May;43(5):345–51. [PMID: 21095166]
The diagnosis of nonerosive gastritis is based on histologic assessment of mucosal biopsies. Endoscopic findings are normal in many cases and do not reliably predict the presence of histologic inflammation. The main types of nonerosive gastritis are those due to H pylori infection, those associated with pernicious anemia, and eosinophilic gastritis. (See Specific Types of Gastritis below.)
Helicobacter pylori Gastritis
H pylori is a spiral gram-negative rod that resides beneath the gastric mucous layer adjacent to gastric epithelial cells. Although not invasive, it causes gastric mucosal inflammation with PMNs and lymphocytes. The mechanisms of injury and inflammation may in part be related to the products of two genes, vacA and cagA.
In developed countries the prevalence of H pylori is rapidly declining. In the United States, the prevalence rises from < 10% in non-immigrants under age 30 years to over 50% in those over age 60 years. The prevalence is higher in non-whites and immigrants from developing countries and is correlated inversely with socioeconomic status. Transmission is from person to person, mainly during infancy and childhood; however, the mode of transmission is unknown.
Acute infection with H pylori may cause a transient clinical illness characterized by nausea and abdominal pain that may last for several days and is associated with acute histologic gastritis with PMNs. After these symptoms resolve, the majority progress to chronic infection with chronic, diffuse mucosal inflammation (gastritis) characterized by PMNs and lymphocytes. Although chronic H pylori infection with gastritis is present in 30–50% of the population, most persons are asymptomatic and suffer no sequelae. Three gastritis phenotypes occur which determine clinical outcomes. Most infected people have a mild, diffuse gastritis that does not disrupt acid secretion and seldom causes clinically important outcomes. About 15% of infected people have inflammation that predominates in the gastric antrum but spares the gastric body (where acid is secreted). People with this phenotype tend to have increased gastrin; increased acid production; and increased risk of developing peptic ulcers, especially duodenal ulcers. An even smaller subset of infected adults have inflammation that predominates in the gastric body. Over time, this may lead to destruction of acid-secreting glands with resultant mucosal atrophy, decreased acid secretion, and intestinal metaplasia. This phenotype is associated with an increased risk of gastric ulcers and gastric cancer. Long-term treatment with proton pump inhibitors can potentiate the development of H pylori–associated atrophic gastritis. Chronic H pylori gastritis leads to the development of duodenal or gastric ulcers up to 10%, gastric cancer in 0.1–3%, and low-grade B cell gastric lymphoma (mucosa-associated lymphoid tissue lymphoma; MALToma) in < 0.01%.
Eradication of H pylori may be achieved with antibiotics in over 85% of patients and leads to resolution of the chronic gastritis (see section on Peptic Ulcer Disease). Testing for H pylori is indicated for patients with either active or a past history of documented peptic ulcer disease or gastric MALToma and for patients with a family history of gastric carcinoma. Testing and empiric treatment is cost-effective in young patients (< 55 years of age) with uncomplicated dyspepsia prior to further medical evaluation. The role of testing and treating H pylori in patients with functional dyspepsia remains controversial but is generally recommended (see Dyspepsia, above). H pylori eradication decreases the risk of gastric cancer in patients with peptic ulcer disease. Some groups recommend population-based screening of all asymptomatic persons in regions in which there is a high prevalence of H pylori and gastric cancer (such as Japan, Korea, and China) to reduce the incidence of gastric cancer. Population-based screening of asymptomatic individuals is not recommended in western countries, in which the incidence of gastric cancer is low, but should be considered in immigrants from high-prevalence regions.
Recent proton pump inhibitors or antibiotics significantly reduce the sensitivity of urea breath tests and fecal antigen assays (but not serologic tests). Prior to testing, proton pump inhibitors should be discontinued 7–14 days and antibiotics for at least 28 days.
Malfertheiner P et al; European Helicobacter Study Group. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut. 2012 May;61(5):646–64. [PMID: 22491499]
McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med. 2010 Apr 29;362(17):1597–1604. [PMID: 20427808]
Pernicious Anemia Gastritis
Pernicious anemia gastritis is an autoimmune disorder involving the fundic glands with resultant achlorhydria, decreased intrinsic factor secretion, and vitamin B12 malabsorption. Of patients with B12deficiency, less than half have pernicious anemia. Most patients have malabsorption secondary to aging or chronic H pylori infection that results in atrophic gastritis, hypochlorhydria, and impaired release of B12 from food. Fundic histology in pernicious anemia is characterized by severe gland atrophy and intestinal metaplasia caused by autoimmune destruction of the gastric fundic mucosa. Anti-intrinsic factor antibodies are present in 70% of patients. Achlorhydria leads to pronounced hypergastrinemia (> 1000 pg/mL) due to loss of acid inhibition of gastrin G cells. Hypergastrinemia may induce hyperplasia of gastric enterochromaffin-like cells that may lead to the development of small, multicentric carcinoid tumors in 5% of patients. Metastatic spread is uncommon in lesions smaller than 2 cm. The risk of gastric adenocarcinoma is increased threefold, with a prevalence of 1–3%. Endoscopy with biopsy is indicated in patients with pernicious anemia at the time of diagnosis. Patients with dysplasia or small carcinoids require periodic endoscopic surveillance. Pernicious anemia is discussed in detail in Chapter 13.
Annibale B et al. Diagnosis and management of pernicious anemia. Curr Gastroenterol Rep. 2011 Dec;13(6):518–24. [PMID: 21947876]
A number of disorders are associated with specific mucosal histologic features.
Acute bacterial infection of the gastric submucosa and muscularis with a variety of aerobic or anaerobic organisms produces a rare, rapidly progressive, life-threatening condition known as phlegmonous or necrotizing gastritis, which requires broad-spectrum antibiotic therapy and, in many cases, emergency gastric resection. Viral infection with CMV is seen in patients with AIDS and after bone marrow or solid organ transplantation. Endoscopic findings include thickened gastric folds and ulcerations. Fungal infection with mucormycosis and Candida may occur in immunocompromised and diabetic patients. Larvae of Anisakis marina ingested in raw fish or sushi may become embedded in the gastric mucosa, producing severe abdominal pain. Pain persists for several days until the larvae die. Endoscopic removal of the larvae provides rapid symptomatic relief.
Okano K et al. Acute abdomen with epigastric pain and vomiting in an adult healthy patient. Gastroenterology. 2010 Nov;139(5):1465. [PMID: 20875783]
PEPTIC ULCER DISEASE
ESSENTIALS OF DIAGNOSIS
History of dyspepsia present in 80–90% of patients with variable relationship to meals.
Ulcer symptoms characterized by rhythmicity and periodicity.
Ten to 20 percent of patients present with ulcer complications without antecedent symptoms.
Most NSAID-induced ulcers are asymptomatic.
Upper endoscopy with gastric biopsy for H pylori is the diagnostic procedure of choice in most patients.
Gastric ulcer biopsy or documentation of complete healing necessary to exclude gastric malignancy.
Peptic ulcer is a break in the gastric or duodenal mucosa that arises when the normal mucosal defensive factors are impaired or are overwhelmed by aggressive luminal factors such as acid and pepsin. By definition, ulcers extend through the muscularis mucosae and are usually over 5 mm in diameter. In the United States, there are about 500,000 new cases per year of peptic ulcer and 4 million ulcer recurrences; the lifetime prevalence of ulcers in the adult population is approximately 10%. Ulcers occur five times more commonly in the duodenum, where over 95% are in the bulb or pyloric channel. In the stomach, benign ulcers are located most commonly in the antrum (60%) and at the junction of the antrum and body on the lesser curvature (25%).
Ulcers occur slightly more commonly in men than in women (1.3:1). Although ulcers can occur in any age group, duodenal ulcers most commonly occur in patients between the ages of 30 and 55 years, whereas gastric ulcers are more common in patients between the ages of 55 and 70 years. Ulcers are more common in smokers and in patients taking NSAIDs on a long-term basis (see below). Alcohol, dietary factors, and stress do not appear to cause ulcer disease. The incidence of duodenal ulcer disease has been declining dramatically for the past 30 years, but the incidence of gastric ulcers appears to be increasing as a result of the widespread use of NSAIDs and low-dose aspirin.
There are two major causes of peptic ulcer disease: NSAIDs and chronic H pylori infection. Evidence of H pylori infection or NSAID ingestion should be sought in all patients with peptic ulcer. Less than 5–10% of ulcers are caused by other conditions, including acid hypersecretory states (such as Zollinger-Ellison syndrome or systemic mastocytosis), CMV (especially in transplant recipients), Crohn disease, lymphoma, medications (eg, alendronate), chronic medical illness (cirrhosis or chronic kidney disease), or are idiopathic. NSAID and H pylori-associated ulcers will be presented in this section; Zollinger-Ellison syndrome will be discussed subsequently.
H pylori infection with associated gastritis and, in some cases, duodenitis appears to be a necessary cofactor for the majority of duodenal and gastric ulcers not associated with NSAIDs. Ulcer disease will develop in an estimated 10% of infected patients. The prevalence of H pylori infection in duodenal ulcer patients is 75–90%. The association with gastric ulcers is lower, but H pylori is found in most patients in whom NSAIDs cannot be implicated.
The natural history of H pylori–associated peptic ulcer disease is well defined. In the absence of specific antibiotic treatment to eradicate the organism, 85% of patients will have an endoscopically visible recurrence within 1 year. Half of these will be symptomatic. After successful eradication of H pylori with antibiotics, ulcer recurrence rates are reduced dramatically to 5–20% at 1 year. Most of these ulcer recurrences are due to NSAID use or, rarely, reinfection with H pylori.
There is a 10–20% prevalence of gastric ulcers and a 2–5% prevalence of duodenal ulcers in long-term NSAID users. Approximately 2–5%/year of long-term NSAID users will have an ulcer that causes clinically significant dyspepsia or a serious complication. The incidence of serious gastrointestinal complications (hospitalization, bleeding, perforation) is 0.2–1.9%/year. The risk of NSAID complications is greater within the first 3 months of therapy and in patients who are older than 60 years; who have a prior history of ulcer disease; or who take NSAIDs in combination with aspirin, corticosteroids, or anticoagulants.
Traditional nsNSAIDs inhibit prostaglandins through reversible inhibition of both COX-1 and COX-2 enzymes. Aspirin causes irreversible inhibition of COX-1 and COX-2 as well as of platelet aggregation. Coxibs (or selective NSAIDs) preferentially inhibit COX-2—the principal enzyme involved in prostaglandin production at sites of inflammation—while providing relative sparing of COX-1, the principal enzyme involved with mucosal cytoprotection in the stomach and duodenum. Celecoxib is the only coxib currently available in the United States, although other older NSAIDs (etodolac, meloxicam) may have similar COX-2/COX-1 selectivity.
Coxibs decrease the incidence of endoscopically visible ulcers by approximately 75% compared with nsNSAIDs. Of greater clinical importance, the risk of significant clinical events (obstruction, perforation, bleeding) is reduced by up to 50% in patients taking coxibs versus nsNSAIDs. However, a twofold increase in the incidence in cardiovascular complications (myocardial infarction, cerebrovascular infarction, and death) has been detected in patients taking coxibs compared with placebo, prompting the voluntary withdrawal of two coxibs (rofecoxib and valdecoxib) from the market by the manufacturers. In two large, prospective, randomized controlled trials testing the efficacy of coxibs on polyp prevention, celecoxib was associated with a 1.3- to 3.4-fold increased risk of cardiovascular complications versus placebo; the risk was greatest in patients taking higher doses of celecoxib. A review by an FDA panel suggested that all NSAIDs (other than aspirin and, possibly, naproxen) may be associated with an increased risk of cardiovascular complications, but concluded that celecoxib, which has less COX-2 selectivity than rofecoxib and valdecoxib, does not have higher risk than other nsNSAIDs when used in currently recommended doses (200 mg/d).
Use of even low-dose aspirin (81–325 mg/d) leads to a twofold increased risk of gastrointestinal bleeding complications. In randomized controlled trials, the absolute annual increase of gastrointestinal bleeding attributable to low-dose aspirin is only 0.12% higher than with placebo therapy. However, in population studies, gastrointestinal bleeding occurs in 1.2% of patients each year. Patients with a prior history of peptic ulcers or gastrointestinal bleeding have a markedly increased risk of complications on low-dose aspirin. It should be noted that low-dose aspirin in combination with NSAIDs or coxibs increases the risk of ulcer complications by up to tenfold compared with NSAIDs or low-dose aspirin alone.
H pylori infection increases the risk of ulcer disease and complications over threefold in patients taking NSAIDs or low-dose aspirin. It is hypothesized that NSAID initiation may potentiate or aggravate ulcer disease in susceptible infected individuals.
Epigastric pain (dyspepsia), the hallmark of peptic ulcer disease, is present in 80–90% of patients. However, this complaint is not sensitive or specific enough to serve as a reliable diagnostic criterion for peptic ulcer disease. The clinical history cannot accurately distinguish duodenal from gastric ulcers. Less than 25% of patients with dyspepsia have ulcer disease at endoscopy. Twenty percent of patients with ulcer complications such as bleeding have no antecedent symptoms (“silent ulcers”). Nearly 60% of patients with NSAID-related ulcer complications do not have prior symptoms.
Pain is typically well localized to the epigastrium and not severe. It is described as gnawing, dull, aching, or “hunger-like.” Approximately 50% of patients report relief of pain with food or antacids (especially duodenal ulcers) and a recurrence of pain 2–4 hours later. However, many patients deny any relationship to meals or report worsening of pain. Two-thirds of duodenal ulcers and one-third of gastric ulcers cause nocturnal pain that awakens the patient. A change from a patient’s typical rhythmic discomfort to constant or radiating pain may reflect ulcer penetration or perforation. Most patients have symptomatic periods lasting up to several weeks with intervals of months to years in which they are pain free (periodicity).
Nausea and anorexia may occur with gastric ulcers. Significant vomiting and weight loss are unusual with uncomplicated ulcer disease and suggest gastric outlet obstruction or gastric malignancy.
The physical examination is often normal in uncomplicated peptic ulcer disease. Mild, localized epigastric tenderness to deep palpation may be present. FOBT or FIT is positive in one-third of patients.
Laboratory tests are normal in uncomplicated peptic ulcer disease but are ordered to exclude ulcer complications or confounding disease entities. Anemia may occur with acute blood loss from a bleeding ulcer or less commonly from chronic blood loss. Leukocytosis suggests ulcer penetration or perforation. An elevated serum amylase in a patient with severe epigastric pain suggests ulcer penetration into the pancreas. A fasting serum gastrin level to screen for Zollinger-Ellison syndrome is obtained in some patients (see below).
Upper endoscopy is the procedure of choice for the diagnosis of duodenal and gastric ulcers. Duodenal ulcers are virtually never malignant and do not require biopsy. Three to 5 percent of benign-appearing gastric ulcers prove to be malignant. Hence, biopsies of the ulcer margin are almost always performed. Provided that the gastric ulcer appears benign to the endoscopist and adequate biopsy specimens reveal no evidence of cancer, dysplasia, or atypia, the patient may be monitored without further endoscopy. If these conditions are not fulfilled, follow-up endoscopy should be performed 12 weeks after the start of therapy to document complete healing; nonhealing ulcers are suspicious for malignancy.
Because barium upper gastrointestinal series is less sensitive for detection of ulcers and less accurate for distinguishing benign from malignant ulcers, it has been supplanted by upper endoscopy in most settings. Abdominal CT imaging is obtained in patients with suspected complications of peptic ulcer disease (perforation, penetration, or obstruction).
In patients in whom an ulcer is diagnosed by endoscopy, gastric mucosal biopsies should be obtained both for a rapid urease test and for histologic examination. The specimens for histology are discarded if the urease test is positive.
In patients with a history of peptic ulcer or when an ulcer is diagnosed by upper gastrointestinal series, noninvasive assessment for H pylori with fecal antigen assay or urea breath testing should be done, which both have a sensitivity and specificity of 95%. Proton pump inhibitors may cause false-negative urea breath tests and fecal antigen tests and should be withheld for at least 14 days before testing. Because of its lower sensitivity (85%) and specificity (79%), serologic testing should not be performed unless fecal antigen testing or urea breath testing is unavailable.
Peptic ulcer disease must be distinguished from other causes of epigastric distress (dyspepsia). Over 50% of patients with dyspepsia have no obvious organic explanation for their symptoms and are classified as having functional dyspepsia (see sections above on Dyspepsia and Functional Dyspepsia). Atypical gastroesophageal reflux may be manifested by epigastric symptoms. Biliary tract disease is characterized by discrete, intermittent episodes of pain that should not be confused with other causes of dyspepsia. Severe epigastric pain is atypical for peptic ulcer disease unless complicated by a perforation or penetration. Other causes include acute pancreatitis, acute cholecystitis or choledocholithiasis, esophageal rupture, gastric volvulus, and ruptured aortic aneurysm.
The pharmacology and use of several agents that enhance the healing of peptic ulcers is briefly discussed here. They may be divided into three categories: (1) acid-antisecretory agents, (2) mucosal protective agents, and (3) agents that promote healing through eradication of H pylori.
There are six oral proton pump inhibitors currently available: omeprazole, rabeprazole, esomeprazole, lansoprazole, dexlansoprazole, and pantoprazole. The available oral agents inhibit over 90% of 24-hour acid secretion, compared with under 65% for H2-receptor antagonists in standard dosages. Despite minor differences in their pharmacology, they are equally efficacious in the treatment of peptic ulcer disease. Treatment with oral proton pump inhibitors results in over 90% healing of duodenal ulcers after 4 weeks and 90% of gastric ulcers after 8 weeks when given once daily (30 minutes before breakfast) at the following recommended doses: omeprazole, 20–40 mg; esomeprazole, 40 mg; rabeprazole, 20 mg; lansoprazole, 30 mg; dexlansoprazole, 30–60 mg; pantoprazole, 40 mg. Compared with H2-receptor antagonists, proton pump inhibitors provide faster pain relief and more rapid ulcer healing.
The proton pump inhibitors are remarkably safe for short-term therapy. Long-term use may lead to mild decreases in vitamin B12, iron, and calcium absorption. Observational studies suggest an increased risk of enteric infections, including C difficile and bacterial gastroenteritis, a modest (1.4-fold) increased risk of hip fracture, and pneumonia. Serum gastrin levels rise significantly in 3% of patients receiving long-term therapy but return to normal limits within 2 weeks after discontinuation.
Bismuth, misoprostol, and antacids all have been shown to promote ulcer healing through the enhancement of mucosal defensive mechanisms. Given the greater efficacy and safety of antisecretory agents and better compliance of patients, these other agents are no longer used as first-line therapy for active ulcers in most clinical settings.
Eradication of H pylori has proved difficult. Combination regimens that use two or three antibiotics with a proton pump inhibitor or bismuth are required to achieve adequate rates of eradication and to reduce the number of failures due to antibiotic resistance. In the United States, up to 50% of strains are resistant to metronidazole and 13% are resistant to clarithromycin. Recommended regimens are listed in Table 15–10. At present, experts disagree on the optimal regimen; however, updated Maastricht consensus guidelines were published in 2012. In areas of low clarithromycin resistance, including the United States, a 14-day course of “triple therapy,” with an oral proton pump inhibitor, clarithromycin 500 mg, and amoxicillin 1 g (or, if penicillin allergic, metronidazole 500 mg), all given twice daily for 14 days, is still recommended for first-line therapy. Unfortunately, this regimen only achieves rates of eradication > 75%. “Quadruple therapy,” with a proton pump inhibitor, bismuth, tetracycline, and metronidazole or tinidazole for 14 days (Table 15–10) is a more complicated but also more effective regimen. In a 2011 randomized, controlled trial, the per protocol eradication rates were 93% with quadruple therapy and 70% with triple therapy. Bismuth-based quadruple therapy is recommended as first-line therapy for patients in areas with high clarithromycin resistance (> 20%), in patients who have previously been treated with a macrolide antibiotic, or as second-line therapy for patients whose infection persists after an initial course of triple therapy. Several studies reported eradication rates of > 90% using a 10-day sequential regimen consisting of four drugs: a proton pump inhibitor and amoxicillin for 5 days, followed by a proton pump inhibitor, clarithromycin, and tinidazole for 5 days. However, subsequent studies confirmed equivalent or superior efficacy when all four drugs were given concomitantly for 10 days (non-bismuth quadruple therapy). Unfortunately, recent studies have reported lower eradication rates with sequential therapy, and a 2013 meta-analysis did not detect superiority compared with 14-day triple therapy or bismuth-based therapy, except in patients with organisms exhibiting clarithromycin resistance. Most recently, a 2013 large multicenter European controlled trial conducted in regions of high clarithromycin resistance reported 92% eradication with a 14-day quadruple therapy consisting of a proton pump inhibitor, amoxicillin, clarithromycin, and nitroimidazole (the latter not available in the United States).
Table 15–10. Treatment options for peptic ulcer disease.
Patients should be encouraged to eat balanced meals at regular intervals. There is no justification for bland or restrictive diets. Moderate alcohol intake is not harmful. Smoking retards the rate of ulcer healing and increases the frequency of recurrences and should be prohibited.
For patients with an increased risk of cardiovascular complications, it is preferable to avoid NSAIDs, if possible. If an NSAID is required, naproxen is preferred because it appears to have reduced risk of cardiovascular complications compared with other nsNSAIDs. Coxibs should not be prescribed in patients with increased cardiovascular risk. Almost all patients with increased cardiovascular risk also will be taking antiplatelet therapy with low-dose aspirin or clopidogrel, or both. Because combination therapy with an nsNSAID and antiplatelet therapy increases the risks of gastrointestinal complications, these patients should all receive cotherapy with a proton pump inhibitor once daily or misoprostol.
At the present time, the optimal management of patients who require dual antiplatelet therapy with clopidogrel and aspirin is uncertain. Clopidogrel is a prodrug that is activated by the cytochrome P450 CYP2C19 enzyme. All proton pump inhibitors inhibit CYP2C19 to varying degrees, with omeprazole having the highest and pantoprazole the least level of inhibition. In vitro and in vivo platelet aggregation studies demonstrate that proton pump inhibitors (especially omeprazole) may attenuate the antiplatelet effects of clopidogrel, although the clinical importance of this interaction is uncertain. Some large retrospective cohort studies reported a higher incidence (hazard ratio or odds ratio < 2) of myocardial infarction in patients taking clopidogrel and a proton pump inhibitor (especially omeprazole) than in patients taking clopidogrel alone, although the majority of observational studies have shown no association. By contrast, subgroup analysis from three prospective, randomized controlled trials (CREDO, TRITON, PRINCIPLE) have not found an increase in clinically important cardiac events in patients taking a combination of clopidogrel with proton pump inhibitors, including omeprazole. Furthermore, in 2010 a prospective, randomized controlled trial (COGENT) comparing a combination of clopidogrel with omeprazole versus placebo found no difference in adverse events. Notwithstanding, the FDA issued a warning in 2009 that patients should avoid using clopidogrel with omeprazole, stating further that the safety of other proton pump inhibitors also was uncertain. Faced with this warning, the optimal strategy to reduce the risk of gastrointestinal bleeding in patients taking clopidogrel (with or without aspirin) is uncertain. A 2010 expert consensus panel concluded that once daily treatment with an oral proton pump inhibitor (pantoprazole 40 mg; rabeprazole 20 mg; lansoprazole or dexlansoprazole 30 mg) may still be recommended for patients who have an increased risk of gastrointestinal bleeding (prior history of peptic ulcer disease or gastrointestinal bleeding; concomitant NSAIDs). In keeping with the FDA warning and product labeling, omeprazole and esomeprazole should not be used. For patients with a lower risk of gastrointestinal bleeding, the risks and benefits of proton pump inhibitors must be weighed. Pending further recommendations, an acceptable alternative is to treat with an oral H2-receptor antagonist (famotidine 20 mg, ranitidine 150 mg, nizatidine 150 mg) twice daily. Cimetidine is a CYP2C19 inhibitor and should not be used. In 2011, the FDA approved ticagrelor, an antiplatelet agent, for use with low-dose aspirin in the treatment of acute coronary syndrome. Like clopidogrel, ticagrelor blocks the platelet ADP p2y12 receptor; however, it does not require hepatic activation, it does not interact with the CYP2C19 enzyme, and its efficacy is not diminished by proton pump inhibitors.
Ulcers that are truly refractory to medical therapy are now uncommon. Less than 5% of ulcers are unhealed after 8 weeks of once daily therapy with proton pump inhibitors, and almost all benign ulcers heal with twice daily therapy. Thus, noncompliance is the most common cause of ulcer nonhealing. NSAID and aspirin use, sometimes surreptitious, are commonly implicated in refractory ulcers and must be stopped. H pylori infection should be sought and the infection treated, if present, in all refractory ulcer patients. Single or multiple linear gastric ulcers may occur in large hiatal hernias where the stomach slides back and forth through the diaphragmatic hiatus (“Cameron lesions”), which may be a cause of iron deficiency anemia. Other causes of nonhealing ulcers include acid hypersecretion (Zollinger-Ellison syndrome), unrecognized malignancy (adenocarcinoma or lymphoma), medications causing gastrointestinal ulceration (eg, iron or bisphosphonates), Crohn disease, and unusual infections (H heilmanii, CMV, mucormycosis). Fasting serum gastrin levels should be obtained to exclude gastrinoma with acid hypersecretion (Zollinger-Ellison syndrome). Repeat ulcer biopsies are mandatory after 2–3 months of therapy in all nonhealed ulcers to look for malignancy or infection. Patients with persistent nonhealing ulcers are referred for surgical therapy after exclusion of NSAID use and persistent H pylori infection.
Abraham NS et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ASSG/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010 Dec;105(12):2533–49. [PMID: 21131924]
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Lanas A et al. Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis. Clin Gastroenterol Hepatol. 2011 Sep;9(9):762–8. [PMID: 21699808]
Lin KJ et al. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology. 2011 Jul;141(1):71–9. [PMID: 21458456]
Malfertheiner P et al; European Helicobacter Study Group. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut. 2012 May;61(5):646–64. [PMID: 22491499]
Molina-Infante J et al. Optimized nonbismuth quadruple therapies cure most patients with Helicobacter pylori infection in populations with high rates of antibiotic resistance. Gastroenterology. 2013 Jul;145(1):121–8. [PMID: 23562754]
COMPLICATIONS OF PEPTIC ULCER DISEASE
ESSENTIALS OF DIAGNOSIS
“Coffee grounds” emesis, hematemesis, melena, or hematochezia.
Emergent upper endoscopy is diagnostic and therapeutic.
Approximately 50% of all episodes of upper gastrointestinal bleeding are due to peptic ulcer. Clinically significant bleeding occurs in 10% of ulcer patients. About 80% of patients stop bleeding spontaneously and generally have an uneventful recovery; the remaining 20% have more severe bleeding. The overall mortality rate for ulcer bleeding is 7%, but it is higher in the elderly, in patients with comorbid medical problems, and in patients with hospital-associated bleeding. Mortality is also higher in patients who present with persistent hypotension or shock, bright red blood in the vomitus or nasogastric lavage fluid, or severe coagulopathy.
Up to 20% of patients have no antecedent symptoms of pain; this is particularly true of patients receiving NSAIDs. Common presenting signs include melena and hematemesis. Massive upper gastrointestinal bleeding or rapid gastrointestinal transit may result in hematochezia rather than melena; this may be misinterpreted as signifying a lower tract bleeding source. Nasogastric lavage that demonstrates “coffee grounds” or bright red blood confirms an upper tract source. Recovered nasogastric lavage fluid that is negative for blood does not exclude active bleeding from a duodenal ulcer.
The hematocrit may fall as a result of bleeding or expansion of the intravascular volume with intravenous fluids. The BUN may rise as a result of absorption of blood nitrogen from the small intestine and prerenal azotemia.
The assessment and initial management of upper gastrointestinal tract bleeding are discussed above. Specific issues pertaining to peptic ulcer bleeding are described below.
High-dose oral proton pump inhibitors (omeprazole 40 mg twice daily) also appear to be effective in reducing rebleeding but have not been compared with the intravenous regimen. Intravenous H2-receptor antagonists have not been demonstrated to be of any benefit in the treatment of acute ulcer bleeding.
Endoscopy is the preferred diagnostic procedure in almost all cases of upper gastrointestinal bleeding because of its high diagnostic accuracy, its ability to predict the likelihood of recurrent bleeding, and its availability for therapeutic intervention in high-risk lesions. Endoscopy should be performed within 24 hours in most cases. In cases of severe active bleeding, endoscopy is performed as soon as patients have been appropriately resuscitated and are hemodynamically stable.
On the basis of clinical and endoscopic criteria, it is possible to predict which patients are at a higher risk of rebleeding and therefore to make more rational use of hospital resources. Nonbleeding ulcers under 2 cm in size with a base that is clean have a < 5% chance of rebleeding. Most young (under age 60 years), otherwise healthy patients with clean-based ulcers may be safely discharged from the emergency department or hospital after endoscopy. Ulcers that have a flat red or black spot have a < 10% chance of significant rebleeding. Patients who are hemodynamically stable with these findings should be admitted to a hospital ward for 24–72 hours and may begin immediate oral feedings and antiulcer (or anti-H pylori) medication.
By contrast, the risk of rebleeding or continued bleeding in ulcers with a nonbleeding visible vessel is 50%, and with active bleeding it is 80–90%. Endoscopic therapy with thermocoagulation (bipolar or heater probes) or application of endoscopic clips (akin to a staple) is the standard of care for such lesions because it reduces the risk of rebleeding, the number of transfusions, and the need for subsequent surgery. The optimal treatment of ulcers with a dense clot that adheres despite vigorous washing is controversial; removal of the clot followed by endoscopic treatment of an underlying vessel may be considered in selected high-risk patients. For actively bleeding ulcers, a combination of epinephrine injection followed by thermocoagulation or clip application commonly is used. These techniques achieve successful hemostasis of actively bleeding lesions in 90% of patients. After endoscopic therapy followed by an intravenous proton pump inhibitor, significant rebleeding occurs in < 10%, of which over 70% can be managed successfully with repeat endoscopic treatment. After endoscopic treatment, patients should remain hospitalized for at least 72 hours, when the risk of rebleeding falls to below 3%.
Patients with recurrent bleeding or bleeding that cannot be controlled by endoscopic techniques should be evaluated by a surgeon. However, < 5% of patients treated with hemostatic therapy require surgery for continued or recurrent bleeding. Overall surgical mortality for emergency ulcer bleeding is < 6%. The prognosis is poorer for patients over age 60 years, those with serious underlying medical illnesses or chronic kidney disease, and those who require more than 10 units of blood transfusion. Percutaneous arterial embolization is an alternative to surgery for patients in whom endoscopic therapy has failed.
Perforations develop in < 5% of ulcer patients, usually from ulcers on the anterior wall of the stomach or duodenum. Perforation results in a chemical peritonitis that causes sudden, severe generalized abdominal pain that prompts most patients to seek immediate attention. Elderly or debilitated patients and those receiving long-term corticosteroid therapy may experience minimal initial symptoms, presenting late with bacterial peritonitis, sepsis, and shock. On physical examination, patients appear ill, with a rigid, quiet abdomen and rebound tenderness. Hypotension develops later after bacterial peritonitis has developed. If hypotension is present early with the onset of pain, other abdominal emergencies should be considered such as a ruptured aortic aneurysm, mesenteric infarction, or acute pancreatitis. Leukocytosis is almost always present. A mildly elevated serum amylase (less than twice normal) is sometimes seen. Abdominal CT usually establishes the diagnosis without need for further studies. The absence of free air may lead to a misdiagnosis of pancreatitis, cholecystitis, or appendicitis.
Laparoscopic perforation closure can be performed in many centers, significantly reducing operative morbidity compared with open laparotomy.
Gastric outlet obstruction occurs in < 2% of patients with ulcer disease and is due to edema or cicatricial narrowing of the pylorus or duodenal bulb. With the advent of potent antisecretory therapy with proton pump inhibitors and the eradication of H pylori, obstruction now is less commonly caused by peptic ulcers than by gastric neoplasms or extrinsic duodenal obstruction by intra-abdominal neoplasms. The most common symptoms are early satiety, vomiting, and weight loss. Later, vomiting may develop that typically occurs one to several hours after eating and consists of partially digested food contents. Patients may develop dehydration, metabolic alkalosis, and hypokalemia. On physical examination, a succussion splash may be heard in the epigastrium. In most cases, nasogastric aspiration will result in evacuation of a large amount (> 200 mL) of foul-smelling fluid, which establishes the diagnosis. Patients are treated initially with intravenous isotonic saline and KCl to correct fluid and electrolyte disorders, an intravenous proton pump inhibitor, and nasogastric decompression of the stomach. Upper endoscopy is performed after 24–72 hours to define the nature of the obstruction and to exclude gastric neoplasm.
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Wong TC et al. A comparison of angiographic embolization with surgery after failed endoscopic hemostasis to bleeding peptic ulcers. Gastrointest Endosc. 2011 May;73(5):900–8. [PMID: 21288512]
ZOLLINGER-ELLISON SYNDROME (Gastrinoma)
ESSENTIALS OF DIAGNOSIS
Peptic ulcer disease; may be severe and atypical.
Gastric acid hypersecretion.
Diarrhea common, relieved by nasogastric suction.
Most cases are sporadic; 25% with multiple endocrine neoplasia type 1 (MEN 1).
Zollinger-Ellison syndrome is caused by gastrin-secreting gut neuroendocrine tumors (gastrinomas), which result in hypergastrinemia and acid hypersecretion. Less than 1% of peptic ulcer disease is caused by gastrinomas. Primary gastrinomas may arise in the pancreas (25%), duodenal wall (45%), or lymph nodes (5–15%), and in other locations or of unknown primary in 20%. Approximately 80% arise within the “gastrinoma triangle” bounded by the porta hepatis, the neck of the pancreas, and the third portion of the duodenum. Most gastrinomas are solitary or multifocal nodules that are potentially resectable. Over two-thirds of gastrinomas are malignant, and one-third have already metastasized to the liver at initial presentation. Approximately 25% of patients have small multicentric gastrinomas associated with MEN 1 that are more difficult to resect.
Over 90% of patients with Zollinger-Ellison syndrome develop peptic ulcers. In most cases, the symptoms are indistinguishable from other causes of peptic ulcer disease and therefore the syndrome may go undetected for years. Ulcers usually are solitary and located in the duodenal bulb, but they may be multiple or occur more distally in the duodenum. Isolated gastric ulcers do not occur. Gastroesophageal reflux symptoms occur often. Diarrhea occurs in one-third of patients, in some cases in the absence of peptic symptoms. Gastric acid hypersecretion can cause direct intestinal mucosal injury and pancreatic enzyme inactivation, resulting in diarrhea, steatorrhea, and weight loss; nasogastric aspiration of stomach acid stops the diarrhea. Screening for Zollinger-Ellison syndrome with fasting gastrin levels should be obtained in patients with ulcers that are refractory to standard therapies, giant ulcers (> 2 cm), ulcers located distal to the duodenal bulb, multiple duodenal ulcers, frequent ulcer recurrences, ulcers associated with diarrhea, ulcers occurring after ulcer surgery, and patients with ulcer complications. Ulcer patients with hypercalcemia or family histories of ulcers (suggesting MEN 1) should also be screened. Finally, patients with peptic ulcers who are H pylori negative and who are not taking NSAIDs should be screened.
The most sensitive and specific method for identifying Zollinger-Ellison syndrome is demonstration of an increased fasting serum gastrin concentration (> 150 pg/mL [> 150 ng/L]). Levels should be obtained with patients not taking H2-receptor antagonists for 24 hours or proton pump inhibitors for 6 days. Withdrawal of the proton pump inhibitor may be accompanied by massive gastric hypersecretion with serious consequences and should be closely monitored. The median gastrin level is 500–700 pg/mL (500–700 ng/L), and 60% of patients have levels < 1000 pg/mL (< 1000 ng/L). Hypochlorhydria with increased gastric pH is a much more common cause of hypergastrinemia than is gastrinoma. Therefore, a measurement of gastric pH (and, where available, gastric secretory studies) is performed in patients with fasting hypergastrinemia. Most patients have a basal acid output of over 15 mEq/h. A gastric pH of > 3.0 implies hypochlorhydria and excludes gastrinoma. In a patient with a serum gastrin level of > 1000 pg/mL (> 1000 ng/L) and acid hypersecretion, the diagnosis of Zollinger-Ellison syndrome is established. With lower gastrin levels (150–1000 pg/mL [150–1000 ng/L]) and acid secretion, a secretin stimulation test may be performed to distinguish Zollinger-Ellison syndrome from other causes of hypergastrinemia. Intravenous secretin (2 units/kg) produces a rise in serum gastrin of over 200 pg/mL (200 ng/L) within 2–30 minutes in 85% of patients with gastrinoma. An elevated serum calcium suggests hyperparathyroidism and MEN 1 syndrome. In all patients with Zollinger-Ellison syndrome, a serum parathyroid hormone (PTH), prolactin, luteinizing hormone-follicle-stimulating hormone (LH-FSH), and growth hormone (GH) level should be obtained to exclude MEN 1.
Imaging studies are obtained in an attempt to determine whether there is metastatic disease and, if not, to identify the site of the primary tumor. CT and MRI scans are commonly obtained first to look for large hepatic metastases and primary lesions, but they have low sensitivity for small lesions. Gastrinomas express somatostatin receptors that bind radiolabeled octreotide. Somatostatin receptor scintigraphy (SRS) with single photon emission computed tomography (SPECT) allows total body imaging for detection of primary gastrinomas in the pancreas and lymph nodes, primary gastrinomas in unusual locations, and metastatic gastrinomas (liver and bone). The 80% sensitivity for tumor detection of SRS exceeds all other imaging studies combined. If SRS is positive for tumor localization, further imaging studies are not necessary. In patients with negative SRS, endoscopic ultrasonography (EUS) may be useful to detect small gastrinomas in the duodenal wall, pancreas, or peripancreatic lymph nodes. With a combination of SRS and EUS, more than 90% of primary gastrinomas can be localized preoperatively.
Gastrinomas are one of several gut neuroendocrine tumors that have similar histopathologic features and arise either from the gut or pancreas. These include carcinoid, insulinoma, VIPoma, glucagonoma, and somatostatinoma. These tumors usually are differentiated by the gut peptides that they secrete; however, poorly differentiated neuroendocrine tumors may not secrete any hormones. Patients may present with symptoms caused by tumor metastases (jaundice, hepatomegaly) rather than functional symptoms. Once a diagnosis of a neuroendocrine tumor is established from the liver biopsy, the specific type of tumor can subsequently be determined. Both carcinoid and gastrinoma tumors may be detected incidentally during endoscopy after biopsy of a submucosal nodule and must be distinguished by subsequent studies.
Hypergastrinemia due to gastrinoma must be distinguished from other causes of hypergastrinemia. Atrophic gastritis with decreased acid secretion is detected by gastric secretory analysis. Other conditions associated with hypergastrinemia (eg, gastric outlet obstruction, vagotomy, chronic kidney disease) are associated with a negative secretin stimulation test.
The most important predictor of survival is the presence of hepatic metastases. In patients with multiple hepatic metastases, initial therapy should be directed at controlling hypersecretion. Oral proton pump inhibitors (omeprazole, esomeprazole, rabeprazole, pantoprazole, or lansoprazole) are given at a dose of 40–120 mg/d, titrated to achieve a basal acid output of < 10 mEq/h. At this level, there is complete symptomatic relief and ulcer healing. Owing to the slow growth of these tumors, 30% of patients with hepatic metastases have a survival of 10 years.
Cure can be achieved only if the gastrinoma can be resected before hepatic metastatic spread has occurred. Lymph node metastases do not adversely affect prognosis. Laparotomy should be considered in all patients in whom preoperative studies fail to demonstrate hepatic or other distant metastases. A combination of preoperative studies, duodenotomy with careful duodenal inspection, and intraoperative palpation and sonography allows successful localization and resection in the majority of cases. The 15-year survival of patients who do not have liver metastases at initial presentation is over 95%. Surgery usually is not recommended in patients with MEN 1 due to the presence of multifocal tumors and long-term survival in the absence of surgery in most patients.
Ito T et al. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012 Dec;26(6):737–53. [PMID: 23582916]
Poitras P et al. The Zollinger-Ellison syndrome: dangers and consequences of interrupting antisecretory treatment. Clin Gastroenterol Hepatol. 2012 Feb;10(2):199–202. [PMID: 21871248]
Pritchard DM. Zollinger-Ellison syndrome: still a diagnostic challenge in the 21st century? Gastroenterology. 2011 May;140(5):1380–83. [PMID: 21443889]
DISEASES OF THE SMALL INTESTINE
The term “malabsorption” denotes disorders in which there is a disruption of digestion and nutrient absorption. The clinical and laboratory manifestations of malabsorption are summarized in Table 15–11.
Table 15–11. Clinical manifestations and laboratory findings in malabsorption of various nutrients.
ESSENTIALS OF DIAGNOSIS
Typical symptoms: weight loss, chronic diarrhea, abdominal distention, growth retardation.
Atypical symptoms: dermatitis herpetiformis, iron deficiency anemia, osteoporosis.
Abnormal serologic test results.
Abnormal small bowel biopsy.
Clinical improvement on gluten-free diet.
Celiac disease (also called sprue, celiac sprue, and gluten enteropathy) is a permanent dietary disorder caused by an immunologic response to gluten, a storage protein found in certain grains, that results in diffuse damage to the proximal small intestinal mucosa with malabsorption of nutrients. Although symptoms may manifest between 6 months and 24 months of age after the introduction of weaning foods, the majority of cases present in childhood or adulthood. Population screening with serologic tests suggests that the disease is present in 1:100 whites of Northern European ancestry, in whom a clinical diagnosis of celiac disease is made in only 10%, suggesting that most cases are undiagnosed or asymptomatic. Celiac disease only develops in people with the HLA-DQ2 (95%) or -DQ8 (5%) class II molecules, which are present in 40% of the population. Although the precise pathogenesis is unclear, celiac disease arises in a small subset of genetically susceptible (-DQ2 or -DQ8) individuals when dietary gluten stimulates an inappropriate immunologic response.
The most important step in diagnosing celiac disease is to consider the diagnosis. Symptoms are present for more than 10 years in most adults before the correct diagnosis is established. Because of its protean manifestations, celiac disease is grossly underdiagnosed in the adult population.
The gastrointestinal symptoms and signs of celiac disease depend on the length of small intestine involved and the patient’s age when the disease presents. “Classic” symptoms of malabsorption, including diarrhea, steatorrhea, weight loss, abdominal distention, weakness, muscle wasting, or growth retardation, more commonly present in infants (< 2 years). Older children and adults are less likely to manifest signs of serious malabsorption. They may report chronic diarrhea, dyspepsia, or flatulence due to colonic bacterial digestion of malabsorbed nutrients, but the severity of weight loss is variable. Many adults have minimal or no gastrointestinal symptoms but present with extraintestinal “atypical” manifestations, including fatigue, depression, iron deficiency anemia, osteoporosis, short stature, delayed puberty, amenorrhea, or reduced fertility. Approximately 40% of patients with positive serologic tests consistent with sprue have no symptoms of disease; the natural history of these patients with “silent” sprue is unclear.
Physical examination may be normal in mild cases or may reveal signs of malabsorption such as loss of muscle mass or subcutaneous fat, pallor due to anemia, easy bruising due to vitamin K deficiency, hyperkeratosis due to vitamin A deficiency, bone pain due to osteomalacia, or neurologic signs (peripheral neuropathy, ataxia) due to vitamin B12 or vitamin E deficiency (Table 15–11). Abdominal examination may reveal distention with hyperactive bowel sounds.
Dermatitis herpetiformis is regarded as a cutaneous variant of celiac disease. It is a characteristic skin rash consisting of pruritic papulovesicles over the extensor surfaces of the extremities and over the trunk, scalp, and neck. Dermatitis herpetiformis occurs in < 10% of patients with celiac disease; however, almost all patients who present with dermatitis herpetiformis have evidence of celiac disease on intestinal mucosal biopsy, though it may not be clinically evident.
Endoscopic mucosal biopsy of the proximal duodenum (bulb) and distal duodenum is the standard method for confirmation of the diagnosis in patients with a positive serologic test for celiac disease. Mucosal biopsy should also be pursued in patients with negative serologies when symptoms and laboratory studies are strongly suggestive of celiac disease. At endoscopy, atrophy or scalloping of the duodenal folds may be observed. Histology reveals abnormalities ranging from intraepithelial lymphocytosis alone to extensive infiltration of the lamina propria with lymphocytes and plasma cells with hypertrophy of the intestinal crypts and blunting or complete loss of intestinal villi. An adequate normal biopsy excludes the diagnosis. Partial or complete reversion of these abnormalities occurs within 3–24 months after a patient is placed on a gluten-free diet, but symptom resolution remains incomplete in 50% of patients. If a patient with a compatible biopsy demonstrates prompt clinical improvement on a gluten-free diet and a decrease in antigliadin antibodies, a repeat biopsy is unnecessary.
Many patients with chronic diarrhea or flatulence are erroneously diagnosed as having irritable bowel syndrome. Celiac sprue must be distinguished from other causes of malabsorption, as outlined above. Severe panmalabsorption of multiple nutrients is almost always caused by mucosal disease. The histologic appearance of celiac sprue may resemble other mucosal diseases such as tropical sprue, bacterial overgrowth, cow’s milk intolerance, viral gastroenteritis, eosinophilic gastroenteritis, and mucosal damage caused by acid hypersecretion associated with gastrinoma. Documentation of clinical response to gluten withdrawal therefore is essential to the diagnosis.
Some patients complain of symptoms after gluten ingestion but do not have serologic or histologic evidence of celiac disease. The frequency and cause of this entity is debated. A large 2013 study found that symptoms improved in gluten-sensitive patients when placed on a FODMAP-restricted diet and worsened to similar degrees when challenged in a double-blind crossover trial with gluten or whey proteins. These data suggest that nonceliac gluten sensitivity may not be a true entity and that the symptom improvement reported by patients with gluten restriction may be due to broader FODMAP elimination.
Removal of all gluten from the diet is essential to therapy—all wheat, rye, and barley must be eliminated. Although oats appear to be safe for many patients, commercial products may be contaminated with wheat or barley during processing. Because of the pervasive use of gluten products in manufactured foods and additives, in medications, and by restaurants, it is imperative that patients and their families confer with a knowledgeable dietitian to comply satisfactorily with this lifelong diet. Several excellent dietary guides and patient support groups are available. Most patients with celiac disease also have lactose intolerance either temporarily or permanently and should avoid dairy products until the intestinal symptoms have improved on the gluten-free diet. Dietary supplements (folate, iron, calcium, and vitamins A, B12, D, and E) should be provided in the initial stages of therapy but usually are not required long-term with a gluten-free diet. Patients with confirmed osteoporosis may require long-term calcium, vitamin D, and bisphosphonate therapy.
Improvement in symptoms should be evident within a few weeks on the gluten-free diet. The most common reason for treatment failure is incomplete removal of gluten. Intentional or unintentional rechallenge with gluten may trigger acute severe diarrhea with dehydration, electrolyte imbalance, and may require TPN and intravenous or oral corticosteroids (prednisone 40 mg or budesonide 9 mg) for 2 or more weeks as a gluten-free diet is re-initiated.
Prognosis & Complications
If appropriately diagnosed and treated, patients with celiac disease have an excellent prognosis. Celiac disease may be associated with other autoimmune disorders, including Addison disease, Graves disease, type 1 diabetes mellitus, myasthenia gravis, scleroderma, Sjögren syndrome, atrophic gastritis, and pancreatic insufficiency. In some patients, celiac disease may evolve and become refractory to the gluten-free diet. The most common cause is intentional or unintentional dietary noncompliance, which may be suggested by positive serologic tests. Celiac disease that is truly refractory to gluten withdrawal occurs in < 5% and generally carries a poor prognosis. There are two types of refractory disease, which are distinguished by their intraepithelial lymphocyte phenotype. This diagnosis should be considered in patients previously responsive to the gluten-free diet in whom new weight loss, abdominal pain, and malabsorption develop.
Biesiekierski JR et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013 Aug;145(2):320–8. [PMID: 23648697]
Celiac Disease Foundation, 13251 Ventura Blvd, Suite #1, Studio City, CA 91604-1838. http://www.celiac.org
Fasano A et al. Clinical practice. Celiac disease. N Engl J Med. 2012 Dec 20;367(25):2419–26. [PMID: 23252527]
Harris LA et al. Celiac disease: clinical, endoscopic, and histopathologic review. Gastrointest Endosc. 2012 Sep;76(3):625–40. [PMID: 22898420]
Rubio-Tapia A et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013 May;108(5):656–76. [PMID: 23609613]
ESSENTIALS OF DIAGNOSIS
Fever, lymphadenopathy, arthralgias.
Weight loss, malabsorption, chronic diarrhea.
Duodenal biopsy with periodic acid-Schiff (PAS)-positive macrophages with characteristic bacillus.
Whipple disease is a rare multisystem illness caused by infection with the bacillus Tropheryma whippelii. It may occur at any age but most commonly affects white men in the fourth to sixth decades. The source of infection is unknown, but no cases of human-to-human spread have been documented.
The clinical manifestations are protean; however, the most common are arthralgias, diarrhea, abdominal pain, and weight loss. Arthralgias or a migratory, nondeforming arthritis occurs in 80% and is typically the first symptom experienced. Gastrointestinal symptoms occur in approximately 75% of cases. They include abdominal pain, diarrhea, and some degree of malabsorption with distention, flatulence, and steatorrhea. Weight loss is the most common presenting symptom—seen in almost all patients. Loss of protein due to intestinal or lymphatic involvement may result in protein-losing enteropathy with hypoalbuminemia and edema. In the absence of gastrointestinal symptoms, the diagnosis often is delayed for several years. Intermittent low-grade fever occurs in over 50% of cases.
Physical examination may reveal hypotension (a late finding), low-grade fever, and evidence of malabsorption (see Table 15–11). Lymphadenopathy is present in 50%. Heart murmurs due to valvular involvement may be evident. Peripheral joints may be enlarged or warm, and peripheral edema may be present. Neurologic findings are cited above. Hyperpigmentation on sun-exposed areas is evident in up to 40%.
If significant malabsorption is present, patients may have laboratory abnormalities as outlined in Table 15–11. There may be steatorrhea.
In most cases, the diagnosis of Whipple disease is established by endoscopic biopsy of the duodenum with histologic evaluation, which demonstrates infiltration of the lamina propria with PAS-positive macrophages that contain gram-positive bacilli (which are not acid-fast) and dilation of the lacteals. Because the PAS stain is less sensitive and specific for extraintestinal Whipple disease, polymerase chain reaction (PCR) is used to confirm the diagnosis. Because asymptomatic central nervous system infection occurs in 40% of patients, examination of the cerebrospinal fluid by PCR for T whippelii should be performed routinely. The sensitivity of PCR is 97% and the specificity 100%.
Whipple disease should be considered in patients who present with signs of malabsorption, fever of unknown origin, lymphadenopathy, seronegative arthritis, culture-negative endocarditis, or multisystem disease. Small bowel biopsy readily distinguishes Whipple disease from other mucosal malabsorptive disorders, such as celiac sprue.
Antibiotic therapy results in a dramatic clinical improvement within several weeks, even in some patients with neurologic involvement. The optimal regimen is unknown. Complete clinical response usually is evident within 1–3 months; however, relapse may occur in up to one-third of patients after discontinuation of treatment. Therefore, prolonged treatment for at least 1 year is required. Drugs that cross the blood-brain barrier are preferred. A randomized controlled trial in 40 patients with 3–10 years follow-up demonstrated 100% remission with either ceftriaxone 1 g intravenously twice daily or meropenem 1 g intravenously three times daily for 2 weeks, followed by trimethoprim-sulfamethoxazole 160/800 mg twice daily for 12 months. After treatment, repeat duodenal biopsies for histologic analysis and cerebrospinal fluid PCR should be obtained every 6 months for at least 1year. The absence of PAS-positive material predicts a low likelihood of clinical relapse.
If untreated, the disease is fatal. Because some neurologic signs may be permanent, the goal of treatment is to prevent this progression. Patients must be followed closely after treatment for signs of symptom recurrence.
Puéchal X. Whipple’s disease. Postgrad Med J. 2013 Nov;89(1057):659–65. [PMID: 24129033]
Schwartzman S et al. Whipple’s disease. Rheum Dis Clin North Am. 2013 May;39(2):313–21. [PMID: 23597966]
ESSENTIALS OF DIAGNOSIS
Symptoms of distention, flatulence, diarrhea, and weight loss.
Increased qualitative or quantitative fecal fat.
Advanced cases associated with deficiencies of iron or vitamins A, D, and B12.
Diagnosis suggested by breath tests using glucose, lactulose, or 14 C-xylose as substrates.
Diagnosis confirmed by jejunal aspiration with quantitative bacterial cultures.
The small intestine normally contains a small number of bacteria. Bacterial overgrowth in the small intestine of whatever cause may result in malabsorption via a number of mechanisms. Bacterial deconjugation of bile salts may lead to inadequate micelle formation, resulting in decreased fat absorption with steatorrhea and malabsorption of fat-soluble vitamins (A, D). Microbial uptake of specific nutrients reduces absorption of vitamin B12 and carbohydrates. Bacterial proliferation also causes direct damage to intestinal epithelial cells and the brush border, further impairing absorption of proteins, carbohydrates, and minerals. Passage of the malabsorbed bile acids and carbohydrates into the colon leads to an osmotic and secretory diarrhea and increased flatulence.
Causes of bacterial overgrowth include: (1) gastric achlorhydria (including proton pump inhibitor therapy); (2) anatomic abnormalities of the small intestine with stagnation (afferent limb of Billroth II gastrojejunostomy, resection of ileocecal valve, small intestine diverticula, obstruction, blind loop); (3) small intestine motility disorders (vagotomy, scleroderma, diabetic enteropathy, chronic intestinal pseudo-obstruction); (4) gastrocolic or coloenteric fistula (Crohn disease, malignancy, surgical resection); and (5) miscellaneous disorders. Bacterial overgrowth is an important cause of malabsorption in the elderly, perhaps because of decreased gastric acidity or impaired intestinal motility. It may also be present in a subset of patients with irritable bowel syndrome.
Many patients with bacterial overgrowth are asymptomatic. Symptoms are nonspecific and include flatulence, weight loss, abdominal pain, diarrhea, and sometimes steatorrhea. Severe cases may result in clinically significant vitamin and mineral deficiencies, including fat-soluble vitamins A or D, vitamin B12, and iron (Table 15–11). Qualitative or quantitative fecal fat assessment typically is abnormal. Bacterial overgrowth should be considered in any patient with diarrhea, flatulence, weight loss, or macrocytic anemia, especially if the patient has a predisposing cause (such as prior gastrointestinal surgery). A stool collection should be obtained to corroborate the presence of steatorrhea. Vitamins A, D, B12, and serum iron should be measured. A specific diagnosis can be established firmly only by an aspirate and culture of proximal jejunal secretion that demonstrates over 105 organisms/mL. However, this is an invasive and laborious test that requires careful collection and culturing techniques and therefore is not available in many clinical settings. Noninvasive breath tests are easier to perform and have a sensitivity of 60–90% and specificity of 85% compared with jejunal cultures. Breath hydrogen and methane tests with glucose or lactulose as substrates are commonly done because of their ease of use. A small bowel barium radiography or CT enterography study should be obtained to look for mechanical factors predisposing to intestinal stasis.
Owing to the lack of an optimal test for bacterial overgrowth, many clinicians use an empiric antibiotic trial as a diagnostic and therapeutic maneuver in patients with predisposing conditions for bacterial overgrowth in whom unexplained diarrhea or steatorrhea develops.
Where possible, the anatomic defect that has potentiated bacterial overgrowth should be corrected. Otherwise, treatment as follows for 1–2 weeks with oral broad-spectrum antibiotics effective against enteric aerobes and anaerobes usually leads to dramatic improvement: twice daily ciprofloxacin 500 mg, norfloxacin 400 mg, or amoxicillin clavulanate 875 mg, or a combination of metronidazole 250 mg three times daily plus either trimethoprim-sulfamethoxazole (one double-strength tablet) twice daily or cephalexin 250 mg four times daily. Rifaximin 400 mg three times daily is a nonabsorbable antibiotic that also appears to be effective but has fewer side effects than the other systemically absorbed antibiotics.
In patients in whom symptoms recur off antibiotics, cyclic therapy (eg, 1 week out of 4) may be sufficient. Continuous antibiotics should be avoided, if possible, to avoid development of bacterial antibiotic resistance.
In patients with severe intestinal dysmotility, treatment with small doses of octreotide may prove to be of benefit.
Bohm M et al. Diagnosis and management of small intestinal bacterial overgrowth. Nutr Clin Pract. 2013 Jun;28(3):289–99. [PMID: 23614961]
Grace E et al. Review article: small intestinal bacterial overgrowth—prevalence, clinical features, current and developing diagnostic tests, and treatment. Aliment Pharmacol Ther. 2013 Oct;38(7):674–88. [PMID: 23957651]
Short bowel syndrome is the malabsorptive condition that arises secondary to removal of significant segments of the small intestine. The most common causes in adults are Crohn disease, mesenteric infarction, radiation enteritis, volvulus, tumor resection, and trauma. The type and degree of malabsorption depend on the length and site of the resection and the degree of adaptation of the remaining bowel.
Terminal Ileal Resection
Resection of the terminal ileum results in malabsorption of bile salts and vitamin B12, which are normally absorbed in this region. Patients with low serum vitamin B12 levels or resection of over 50 cm of ileum require monthly subcutaneous or intramuscular vitamin B12 injections. In patients with < 100 cm of ileal resection, bile salt malabsorption stimulates fluid secretion from the colon, resulting in watery diarrhea. This may be treated with bile salt binding resins (cholestyramine, 2–4 g orally three times daily with meals or colesevelam, 625 mg, 1–3 tablets twice daily). Resection of over 100 cm of ileum leads to a reduction in the bile salt pool that results in steatorrhea and malabsorption of fat-soluble vitamins. Treatment is with a low-fat diet and vitamins supplemented with medium-chain triglycerides, which do not require micellar solubilization. Unabsorbed fatty acids bind with calcium, reducing its absorption and enhancing the absorption of oxalate. Oxalate kidney stones may develop. Calcium supplements should be administered to bind oxalate and increase serum calcium. Cholesterol gallstones due to decreased bile salts are common also. In patients with resection of the ileocolonic valve, bacterial overgrowth may occur in the small intestine, further complicating malabsorption (as outlined above).
Extensive Small Bowel Resection
Resection of up to 40–50% of the total length of small intestine usually is well tolerated. A more massive resection may result in “short-bowel syndrome,” characterized by weight loss and diarrhea due to nutrient, water, and electrolyte malabsorption. If the colon is preserved, 100 cm of proximal jejunum may be sufficient to maintain adequate oral nutrition with a low-fat, high complex-carbohydrate diet, though fluid and electrolyte losses may still be significant. In patients in whom the colon has been removed, at least 200 cm of proximal jejunum is typically required to maintain oral nutrition. Antidiarrheal agents (loperamide, 2–4 mg orally three times daily) slow transit and reduce diarrheal volume. Octreotide reduces intestinal transit time and fluid and electrolyte secretion. Gastric hypersecretion initially complicates intestinal resection and should be treated with proton pump inhibitors.
Patients with < 100–200 cm of proximal jejunum remaining almost always require parenteral nutrition. Teduglutide is a glucagon-like peptide-2 analogue that stimulates small bowel growth and absorption and was approved in 2012 for the treatment of short-bowel syndrome. In clinical trials, it resulted in a reduced need for parenteral nutrition. Small intestine transplantation is now being performed with reported 5-year graft survival rates of 40%. Currently, it is performed chiefly in patients in whom serious problems develop due to parenteral nutrition.
Jeppesen PB et al. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012 Dec;143(6):1473–1481.e3. [PMID: 22982184]
ESSENTIALS OF DIAGNOSIS
Diarrhea, bloating, flatulence, and abdominal pain after ingestion of milk-containing products.
Diagnosis supported by symptomatic improvement on lactose-free diet.
Diagnosis confirmed by hydrogen breath test.
Lactase is a brush border enzyme that hydrolyzes the disaccharide lactose into glucose and galactose. The concentration of lactase enzyme levels is high at birth but declines steadily in most people of non-European ancestry during childhood and adolescence and into adulthood. Thus, approximately 50 million people in the United States have partial to complete lactose intolerance. As many as 90% of Asian Americans, 70% of African Americans, 95% of Native Americans, 50% of Mexican Americans, and 60% of Jewish Americans are lactose intolerant compared with < 25% of white adults. Lactase deficiency may also arise secondary to other gastrointestinal disorders that affect the proximal small intestinal mucosa. These include Crohn disease, sprue, viral gastroenteritis, giardiasis, short bowel syndrome, and malnutrition. Malabsorbed lactose is fermented by intestinal bacteria, producing gas and organic acids. The nonmetabolized lactose and organic acids result in an increased stool osmotic load with an obligatory fluid loss.
Patients have great variability in clinical symptoms, depending both on the severity of lactase deficiency and the amount of lactose ingested. Because of the nonspecific nature of these symptoms, there is a tendency for both lactose-intolerant and lactose-tolerant individuals to mistakenly attribute a variety of abdominal symptoms to lactose intolerance. Most patients with lactose intolerance can drink one or two 8 oz glasses of milk daily without symptoms if taken with food at wide intervals, though rare patients have almost complete intolerance. With mild to moderate amounts of lactose malabsorption, patients may experience bloating, abdominal cramps, and flatulence. With higher lactose ingestions, an osmotic diarrhea will result. Isolated lactase deficiency does not result in other signs of malabsorption or weight loss. If these findings are present, other gastrointestinal disorders should be pursued. Diarrheal specimens reveal an increased osmotic gap and a pH of < 6.0.
The most widely available test for the diagnosis of lactase deficiency is the hydrogen breath test. After ingestion of 50 g of lactose, a rise in breath hydrogen of > 20 ppm within 90 minutes is a positive test, indicative of bacterial carbohydrate metabolism. In clinical practice, many clinicians prescribe an empiric trial of a lactose-free diet for 2 weeks. Resolution of symptoms (bloating, flatulence, diarrhea) is suggestive of lactase deficiency (though a placebo response cannot be excluded) and may be confirmed, if necessary, with a breath hydrogen study.
The symptoms of late-onset lactose intolerance are nonspecific and may mimic a number of gastrointestinal disorders, such as inflammatory bowel disease, mucosal malabsorptive disorders, irritable bowel syndrome, and pancreatic insufficiency. Furthermore, lactase deficiency frequently develops secondary to other gastrointestinal disorders (as listed above). Concomitant lactase deficiency should always be considered in these gastrointestinal disorders.
The goal of treatment in patients with isolated lactase deficiency is achieving patient comfort. Patients usually find their “threshold” of intake at which symptoms will occur. Foods that are high in lactose include milk (12 g/cup), ice cream (9 g/cup), and cottage cheese (8 g/cup). Aged cheeses have a lower lactose content (0.5 g/oz). Unpasteurized yogurt contains bacteria that produce lactase and is generally well tolerated.
By spreading dairy product intake throughout the day in quantities of < 12 g of lactose (one cup of milk), most patients can take dairy products without symptoms and do not require lactase supplements. Most food markets provide milk that has been pretreated with lactase, rendering it 70–100% lactose free. Lactase enzyme replacement is commercially available as nonprescription formulations (Lactaid, Lactrase, Dairy Ease). Caplets or drops of lactase may be taken with milk products, improving lactose absorption and eliminating symptoms. The number of caplets ingested depends on the degree of lactose intolerance. Patients who choose to restrict or eliminate milk products may have increased risk of osteoporosis. Calcium supplementation (calcium carbonate 500 mg orally two to three times daily) is recommended for susceptible patients.
Carter SL et al. The diagnosis and management of patients with lactose intolerance. Nurse Pract. 2013 Jul 10;38(7):23–8. [PMID: 23778177]
Suchy FJ et al. National Institutes of Health Consensus Development Conference: lactose intolerance and health. Ann Intern Med. 2010 Jun 15;152(12):792–6. [PMID: 20404261]
INTESTINAL MOTILITY DISORDERS
ESSENTIALS OF DIAGNOSIS
Precipitating factors: surgery, peritonitis, electrolyte abnormalities, medications, severe medical illness.
Nausea, vomiting, obstipation, distention.
Minimal abdominal tenderness; decreased bowel sounds.
Plain abdominal radiography with gas and fluid distention in small and large bowel.
Ileus is a condition in which there is neurogenic failure or loss of peristalsis in the intestine in the absence of any mechanical obstruction. It is commonly seen in hospitalized patients as a result of: (1) intra-abdominal processes such as recent gastrointestinal or abdominal surgery or peritoneal irritation (peritonitis, pancreatitis, ruptured viscus, hemorrhage); (2) severe medical illness such as pneumonia, respiratory failure requiring intubation, sepsis or severe infections, uremia, diabetic ketoacidosis, and electrolyte abnormalities (hypokalemia, hypercalcemia, hypomagnesemia, hypophosphatemia); and (3) medications that affect intestinal motility (opioids, anticholinergics, phenothiazines). Following surgery, small intestinal motility usually normalizes first (often within hours), followed by the stomach (24–48 hours), and the colon (48–72 hours). Postoperative ileus is reduced by the use of patient-controlled or epidural analgesia and avoidance of intravenous opioids as well as early ambulation, gum chewing, and initiation of a clear liquid diet.
Patients who are conscious report mild diffuse, continuous abdominal discomfort with nausea and vomiting. Generalized abdominal distention is present with minimal abdominal tenderness but no signs of peritoneal irritation (unless due to the primary disease). Bowel sounds are diminished to absent.
The laboratory abnormalities are attributable to the underlying condition. Serum electrolytes, including potassium, magnesium, phosphorus, and calcium, should be obtained to exclude abnormalities as contributing factors.
Plain film radiography of the abdomen demonstrates distended gas-filled loops of small and large intestine. Air-fluid levels may be seen. Under some circumstances, it may be difficult to distinguish ileus from partial small bowel obstruction. A CT scan may be useful in such instances to exclude mechanical obstruction, especially in postoperative patients.
Ileus must be distinguished from mechanical obstruction of the small bowel or proximal colon. Pain from small bowel mechanical obstruction is usually intermittent, cramping, and associated initially with profuse vomiting. Acute gastroenteritis, acute appendicitis, and acute pancreatitis may all present with ileus.
The primary medical or surgical illness that has precipitated adynamic ileus should be treated. Most cases of ileus respond to restriction of oral intake with gradual liberalization of diet as bowel function returns. Severe or prolonged ileus requires nasogastric suction and parenteral administration of fluids and electrolytes. Alvimopan is a peripherally acting mu-opioid receptor antagonist with limited absorption or systemic activity that reverses opioid-induced inhibition of intestinal motility. In five randomized controlled trials, it reduced the time to first flatus, bowel movement, solid meal, and hospital discharge compared with placebo in postoperative patients. Alvimopan may be considered in patients undergoing partial large or small bowel resection when postoperative opioid therapy is anticipated.
Delaney CP et al. Evaluation of clinical outcomes with alvimopan in clinical practice: a national matched-cohort study in patients undergoing bowel resection. Ann Surg. 2012 Apr;255(4):731–8. [PMID: 22388106]
Doorly MG et al. Pathogenesis and clinical and economic consequences of paralytic ileus. Surg Clin North Am. 2012 Apr;92(2):259–72. [PMID: 22414412]
Gaines SL et al. Real world efficacy of alvimopan on elective bowel resection patients: an analysis of statistical versus clinical significance. Am J Surg. 2012 Mar;203(3):308–11. [PMID: 22178482]
ESSENTIALS OF DIAGNOSIS
Severe abdominal distention.
Arises in postoperative state or with severe medical illness.
May be precipitated by electrolyte imbalances, medications.
Absent to mild abdominal pain; minimal tenderness.
Massive dilation of cecum or right colon.
Spontaneous massive dilation of the cecum and proximal colon may occur in a number of different settings in hospitalized patients. Progressive cecal dilation may lead to spontaneous perforation with dire consequences. The risk of perforation correlates poorly with absolute cecal size and duration of colonic distention. Early detection and management are important to reduce morbidity and mortality. Colonic pseudo-obstruction is most commonly detected in postsurgical patients (mean 3–5 days), after trauma, and in medical patients with respiratory failure, metabolic imbalance, malignancy, myocardial infarction, heart failure, pancreatitis, or a recent neurologic event (stroke, subarachnoid hemorrhage, trauma). Liberal use of opioids or anticholinergic agents may precipitate colonic pseudo-obstruction in susceptible patients. It may also occur as a manifestation of colonic ischemia. The etiology of colonic pseudo-obstruction is unknown, but either an increase in gut sympathetic activity or a decrease in sacral parasympathetic activity of the distal colon, or both, is hypothesized to impair colonic motility.
Many patients are on ventilatory support or are unable to report symptoms due to altered mental status. Abdominal distention is frequently noted by the clinician as the first sign, often leading to a plain film radiograph that demonstrates colonic dilation. Some patients are asymptomatic, although most report constant but mild abdominal pain. Nausea and vomiting may be present. Bowel movements may be absent, but up to 40% of patients continue to pass flatus or stool. Abdominal tenderness with some degree of guarding or rebound tenderness may be detected; however, signs of peritonitis are absent unless perforation has occurred. Bowel sounds may be normal or decreased.
Laboratory findings reflect the underlying medical or surgical problems. Serum sodium, potassium, magnesium, phosphorus, and calcium should be obtained. Significant fever or leukocytosis raises concern for colonic ischemia or perforation.
Radiographs demonstrate colonic dilation, usually confined to the cecum and proximal colon. The upper limit of normal for cecal size is 9 cm. A cecal diameter > 10–12 cm is associated with an increased risk of colonic perforation. Varying amounts of small intestinal dilation and air-fluid levels due to adynamic ileus may be seen. Because the dilated appearance of the colon may raise concern that there is a distal colonic mechanical obstruction due to malignancy, volvulus, or fecal impaction, a CT scan or water-soluble (diatrizoate meglumine) enema may sometimes be performed.
Colonic pseudo-obstruction should be distinguished from distal colonic mechanical obstruction (as above) and toxic megacolon, which is acute dilation of the colon due to inflammation (inflammatory bowel disease) or infection (C difficile–associated colitis, CMV). Patients with toxic megacolon manifest fever; dehydration; significant abdominal pain; leukocytosis; and diarrhea, which is often bloody.
Conservative treatment is the appropriate first step for patients with no or minimal abdominal tenderness, no fever, no leukocytosis, and a cecal diameter < 12 cm. The underlying illness is treated appropriately. A nasogastric tube and a rectal tube should be placed. Patients should be ambulated or periodically rolled from side to side and to the knee-chest position in an effort to promote expulsion of colonic gas. All drugs that reduce intestinal motility, such as opioids, anticholinergics, and calcium channel blockers, are discontinued if possible. Enemas may be administered judiciously if large amounts of stool are evident on radiography. Oral laxatives are not helpful and may cause perforation, pain, or electrolyte abnormalities.
Conservative treatment is successful in over 80% of cases within 1–2 days. Patients must be watched for signs of worsening distention or abdominal tenderness. Cecal size should be assessed by abdominal radiographs every 12 hours. Intervention should be considered in patients with any of the following: (1) no improvement or clinical deterioration after 24–48 hours of conservative therapy; (2) cecal dilation > 10 cm for a prolonged period (> 3–4 days); (3) patients with cecal dilation > 12 cm. Neostigmine injection should be given unless contraindicated. A single dose (2 mg intravenously) results in rapid (within 30 minutes) colonic decompression in 75–90% of patients. Cardiac monitoring during neostigmine infusion is indicated for possible bradycardia that may require atropine administration. Colonoscopic decompression is indicated in patients who fail to respond to neostigmine. Colonic decompression with aspiration of air or placement of a decompression tube is successful in 70% of patients. However, the procedure is technically difficult in an unprepared bowel and has been associated with perforations in the distended colon. Dilation recurs in up to 50% of patients. In patients in whom colonoscopy is unsuccessful, a tube cecostomy can be created through a small laparotomy or with percutaneous radiologically guided placement.
In most cases, the prognosis is related to the underlying illness. The risk of perforation or ischemia is increased with cecal diameter > 12 cm and when distention has been present for more than 6 days. With aggressive therapy, the development of perforation is unusual.
Elsner JL et al. Intravenous neostigmine for postoperative acute colonic pseudo-obstruction. Ann Pharmacother. 2012 Mar;46(3):430–5. [PMID: 22388328]
Harrison ME et al; ASGE Standards of Practice Committee. The role of endoscopy in the management of patients with known and suspected colonic obstruction and pseudo-obstruction. Gastrointest Endosc. 2010 Apr;71(4):669–79. [PMID: 20363408]
Gastroparesis and chronic intestinal pseudo-obstruction are chronic conditions characterized by intermittent, waxing and waning symptoms and signs of gastric or intestinal obstruction in the absence of any mechanical lesions to account for the findings. They are caused by a heterogeneous group of endocrine disorders (diabetes mellitus, hypothyroidism, cortisol deficiency), postsurgical conditions (vagotomy, partial gastric resection, fundoplication, gastric bypass, Whipple procedure), neurologic conditions (Parkinson disease, muscular and myotonic dystrophy, autonomic dysfunction, multiple sclerosis, postpolio syndrome, porphyria), rheumatologic syndromes (progressive systemic sclerosis), infections (postviral, Chagas disease), amyloidosis, paraneoplastic syndromes, medications, and eating disorders (anorexia); a cause may not always be identified.
Gastric involvement leads to chronic or intermittent symptoms of gastroparesis with postprandial fullness (early satiety), nausea, and vomiting (1–3 hours after meals). Patients with predominantly small bowel involvement may have abdominal distention, vomiting, diarrhea, and varying degrees of malnutrition. Abdominal pain is not common and should prompt investigation for structural causes of obstruction. Bacterial overgrowth in the stagnant intestine may result in malabsorption. Colonic involvement may result in constipation or alternating diarrhea and constipation.
Plain film radiography may demonstrate dilation of the esophagus, stomach, small intestine, or colon resembling ileus or mechanical obstruction. Mechanical obstruction of the stomach, small intestine, or colon is much more common than gastroparesis or intestinal pseudo-obstruction and must be excluded with endoscopy or CT or barium enterography, especially in patients with prior surgery, recent onset of symptoms, or abdominal pain. In cases of unclear origin, studies based on the clinical picture are obtained to exclude underlying systemic disease. Gastric scintigraphy with a low-fat solid meal is the optimal means for assessing gastric emptying. Gastric retention of 60% after 2 hours or more than 10% after 4 hours is abnormal. Small bowel manometry is useful for distinguishing visceral from myopathic disorders and for excluding cases of mechanical obstruction that are otherwise difficult to diagnose by endoscopy or radiographic studies.
There is no specific therapy for gastroparesis or pseudo-obstruction. Acute exacerbations are treated with nasogastric suction and intravenous fluids. Long-term treatment is directed at maintaining nutrition. Patients should eat small, frequent meals that are low in fiber, milk, gas-forming foods, and fat. Some patients may require liquid enteral supplements. Agents that reduce gastrointestinal motility (opioids, anticholinergics) should be avoided. In diabetic patients, glucose levels should be maintained below 200 mg/dL, as hyperglycemia may slow gastric emptying even in the absence of diabetic neuropathy, and amylin and GLP-1 analogs (exenatide or pramlintide) should be discontinued. Metoclopramide (5–20 mg orally or 5–10 mg intravenously or subcutaneously four times daily) and erythromycin (50–125 mg orally three times daily) before meals are each of benefit in treatment of gastroparesis but not small bowel dysmotility. Since the use of metoclopramide for more than 3 months is associated with a < 1% risk of tardive dyskinesia, patients are advised to discontinue the medication if neuromuscular side effects, particularly involuntary movements, develop. The elderly are at greatest risk. Gastric electrical stimulation with internally implanted neurostimulators has shown reduction in nausea and vomiting in small studies and one controlled trial in some patients with severe gastroparesis (especially those with diabetes mellitus); however, the mechanism of action is uncertain as improvement is not correlated with changes in gastric emptying. Bacterial overgrowth should be treated with intermittent antibiotics (see above). Patients with predominant small bowel distention may require a venting gastrostomy to relieve distress. Some patients may require placement of a jejunostomy for long-term enteral nutrition. Patients unable to maintain adequate enteral nutrition require TPN or small bowel transplantation. Difficult cases should be referred to centers with expertise in this area.
Camilleri M et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013 Jan;108(1):18–37. [PMID: 23147521]
De Giorgio R et al. Chronic intestinal pseudo-obstruction: clinical features, diagnosis, and therapy. Gastroenterol Clin North Am. 2011 Dec;40(4):787–807. [PMID: 22100118]
ESSENTIALS OF DIAGNOSIS
Early: periumbilical pain; later: right lower quadrant pain and tenderness.
Anorexia, nausea and vomiting, obstipation.
Tenderness or localized rigidity at McBurney point.
Low-grade fever and leukocytosis.
Appendicitis is the most common abdominal surgical emergency, affecting approximately 10% of the population. It occurs most commonly between the ages of 10 and 30 years. It is initiated by obstruction of the appendix by a fecalith, inflammation, foreign body, or neoplasm. Obstruction leads to increased intraluminal pressure, venous congestion, infection, and thrombosis of intramural vessels. If untreated, gangrene and perforation develop within 36 hours.
Appendicitis usually begins with vague, often colicky periumbilical or epigastric pain. Within 12 hours the pain shifts to the right lower quadrant, manifested as a steady ache that is worsened by walking or coughing. Almost all patients have nausea with one or two episodes of vomiting. Protracted vomiting or vomiting that begins before the onset of pain suggests another diagnosis. A sense of constipation is typical, and some patients administer cathartics in an effort to relieve their symptoms—though some report diarrhea. Low-grade fever (< 38°C) is typical; high fever or rigors suggest another diagnosis or appendiceal perforation.
On physical examination, localized tenderness with guarding in the right lower quadrant can be elicited with gentle palpation with one finger. When asked to cough, patients may be able to precisely localize the painful area, a sign of peritoneal irritation. Light percussion may also elicit pain. Although rebound tenderness is also present, it is unnecessary to elicit this finding if the above signs are present. The psoas sign (pain on passive extension of the right hip) and the obturator sign (pain with passive flexion and internal rotation of the right hip) are indicative of adjacent inflammation and strongly suggestive of appendicitis.
Owing to the variable location of the appendix, there are a number of “atypical” presentations. Because the retrocecal appendix does not touch the anterior abdominal wall, the pain remains less intense and poorly localized; abdominal tenderness is minimal and may be elicited in the right flank. The psoas sign may be positive. With pelvic appendicitis, there is pain in the lower abdomen, often on the left, with an urge to urinate or defecate. Abdominal tenderness is absent, but tenderness is evident on pelvic or rectal examination; the obturator sign may be present. In the elderly, the diagnosis of appendicitis is often delayed because patients present with minimal, vague symptoms and mild abdominal tenderness. Appendicitis in pregnancy may present with pain in the right lower quadrant, periumbilical area, or right subcostal area owing to displacement of the appendix by the uterus.
Moderate leukocytosis (10,000–20,000/mcL) with neutrophilia is common. Microscopic hematuria and pyuria are present in 25% of patients.
Both abdominal ultrasound and CT scanning are useful in diagnosing appendicitis as well as excluding other diseases presenting with similar symptoms, including adnexal disease in younger women. However, CT scanning appears to be more accurate (sensitivity 94%, specificity 95%, positive likelihood ratio 13.3, negative likelihood ratio 0.09). Abdominal CT scanning is also useful in cases of suspected appendiceal perforation to diagnose a periappendiceal abscess. In patients in whom there is a clinically high suspicion of appendicitis, some surgeons feel that preoperative diagnostic imaging is unnecessary. However, studies suggest that even in this group, imaging studies suggest an alternative diagnosis in up to 15%.
Given its frequency and myriad presentations, appendicitis should be considered in the differential diagnosis of all patients with abdominal pain. It is difficult to reliably diagnose the disease in some cases. A several-hour period of close observation with reassessment usually clarifies the diagnosis. Absence of the classic migration of pain (from the epigastrium to the right lower abdomen), right lower quadrant pain, fever, or guarding makes appendicitis less likely. Ten to twenty percent of patients with suspected appendicitis have either a negative examination at laparotomy or an alternative surgical diagnosis. The widespread use of ultrasonography and CT has reduced the number of incorrect diagnoses to < 2%. Still, in some cases diagnostic laparotomy or laparoscopy is required. The most common causes of diagnostic confusion are gastroenteritis and gynecologic disorders. Viral gastroenteritis presents with nausea, vomiting, low-grade fever, and diarrhea and can be difficult to distinguish from appendicitis. The onset of vomiting before pain makes appendicitis less likely. As a rule, the pain of gastroenteritis is more generalized and the tenderness less well localized. Acute salpingitis or tubo-ovarian abscess should be considered in young, sexually active women with fever and bilateral abdominal or pelvic tenderness. A twisted ovarian cyst may also cause sudden severe pain. The sudden onset of lower abdominal pain in the middle of the menstrual cycle suggests mittelschmerz. Sudden severe abdominal pain with diffuse pelvic tenderness and shock suggests a ruptured ectopic pregnancy. A positive pregnancy test and pelvic ultrasonography are diagnostic. Retrocecal or retroileal appendicitis (often associated with pyuria or hematuria) may be confused with ureteral colic or pyelonephritis. Other conditions that may resemble appendicitis are diverticulitis, Meckel diverticulitis, carcinoid of the appendix, perforated colonic cancer, Crohn ileitis, perforated peptic ulcer, cholecystitis, and mesenteric adenitis. It is virtually impossible to distinguish appendicitis from Meckel diverticulitis, but both require surgical treatment.
Perforation occurs in 20% of patients and should be suspected in patients with pain persisting for over 36 hours, high fever, diffuse abdominal tenderness or peritoneal findings, a palpable abdominal mass, or marked leukocytosis. Localized perforation results in a contained abscess, usually in the pelvis. A free perforation leads to suppurative peritonitis with toxicity. Septic thrombophlebitis (pylephlebitis) of the portal venous system is rare and suggested by high fever, chills, bacteremia, and jaundice.
The treatment of early, uncomplicated appendicitis is surgical appendectomy in most patients. When possible, a laparoscopic approach is preferred to open laparotomy. Access via a single incision through the umbilicus (single-incision laparoscopic appendectomy) is increasingly utilized. Prior to surgery, patients should be given broad-spectrum antibiotics with gram-negative and anaerobic coverage to reduce the incidence of postoperative infections. Recommended preoperative intravenous regimens include cefoxitin or cefotetan 1–2 g every 8 hours; ampicillin-sulfabactam 3 g every 6 hours; or ertapenem 1 g as a single dose. Up to 80% of patients treated with antibiotics alone have resolution of symptoms and signs of uncomplicated appendicitis. Although conservative management may be considered, appendectomy generally is recommended to prevent recurrent appendicitis (20% within 1 year).
Emergency appendectomy is required in patients with perforated appendicitis with generalized peritonitis. Likewise, the optimal treatment of stable patients with perforated appendicitis and a contained abscess is controversial. Surgery in this setting can be difficult. Many recommend percutaneous CT-guided drainage of the abscess with intravenous fluids and antibiotics to allow the inflammation to subside. An interval appendectomy may be performed after 6 weeks to prevent recurrent appendicitis.
The mortality rate from uncomplicated appendicitis is extremely low. Even with perforated appendicitis, the mortality rate in most groups is only 0.2%, though it approaches 15% in the elderly.
Gill RS et al. Single-incision appendectomy is comparable to conventional laparoscopic appendectomy: a systematic review and pooled analysis. Surg Laparosc Endosc Percutan Tech. 2012 Aug;22(4):319–27. [PMID: 22874680]
Markar SR et al. Systematic review and meta-analysis of single-incision versus conventional multiport appendectomy. Br J Surg. 2013 Dec;100(13):1709–18. [PMID: 24227355]
Varadhan KK et al. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ. 2012 Apr 5;344:e2156. [PMID: 22491789]
Intestinal tuberculosis is common in underdeveloped countries. Previously rare in the United States, its incidence has been rising in immigrant groups and patients with AIDS. It is caused by bothMycobacterium tuberculosis and M bovis. Active pulmonary disease is present in < 50% of patients. The most frequent site of involvement is the ileocecal region; however, any region of the gastrointestinal tract may be involved. Intestinal tuberculosis may cause mucosal ulcerations or scarring and fibrosis with narrowing of the lumen. Patients may be without symptoms or complain of chronic abdominal pain, obstructive symptoms, weight loss, and diarrhea. An abdominal mass may be palpable. Complications include intestinal obstruction, hemorrhage, and fistula formation. The purified protein derivative (PPD) skin test may be negative, especially in patients with weight loss or AIDS. Barium radiography may demonstrate mucosal ulcerations, thickening, or stricture formation. Abdominal CT may show thickening of the cecum and ileocecal valve and massive lymphadenopathy. Colonoscopy may demonstrate an ulcerated mass, multiple ulcers with steep edges and adjacent small sessile polyps, small ulcers or erosions, or small diverticula, most commonly in the ileocecal region. The differential diagnosis includes Crohn disease, carcinoma, and intestinal amebiasis. The diagnosis is established by either endoscopic or surgical biopsy revealing acid-fast bacilli, caseating granuloma, or positive cultures from the organism. Detection of tubercle bacilli in biopsy specimens by PCR is now the most sensitive means of diagnosis.
Treatment with standard antituberculous regimens is effective.
Yu H et al. Clinical, endoscopic and histological differentiations between Crohn’s disease and intestinal tuberculosis. Digestion. 2012;85(3):202–9. [PMID: 22354097]
Protein-losing enteropathy comprises a number of conditions that result in excessive loss of serum proteins into the gastrointestinal tract. The essential diagnostic features are hypoalbuminemia and an elevated fecal alpha-1-antitrypsin level.
The normal intact gut epithelium prevents the loss of serum proteins. Proteins may be lost through one of three mechanisms: (1) mucosal disease with ulceration, resulting in the loss of proteins across the disrupted mucosal surface, such as in chronic gastric ulcer, gastric carcinoma, or inflammatory bowel disease; (2) lymphatic obstruction, resulting in the loss of protein-rich chylous fluid from mucosal lacteals, such as in primary intestinal lymphangiectasia, constrictive pericarditis or heart failure, Whipple disease or tuberculosis, Kaposi sarcoma or lymphoma, retroperitoneal fibrosis, or sarcoidosis; and (3) idiopathic change in permeability of mucosal capillaries and conductance of interstitium, resulting in “weeping” of protein-rich fluid from the mucosal surface, such as in Ménétrier disease, Zollinger-Ellison syndrome, viral or eosinophilic gastroenteritis, celiac disease, giardiasis or hookworm, common variable immunodeficiency, systemic lupus erythematosus, amyloidosis, or allergic protein-losing enteropathy.
Hypoalbuminemia is the sine qua non of protein-losing enteropathy. However, a number of other serum proteins such as alpha-1-antitrypsin also are lost from the gut epithelium. In protein-losing enteropathy caused by lymphatic obstruction, loss of lymphatic fluid commonly results in lymphocytopenia (< 1000/mcL), hypoglobulinemia, and hypocholesterolemia.
In most cases, protein-losing enteropathy is recognized as a sequela of a known gastrointestinal disorder. In patients in whom the cause is unclear, evaluation is indicated and is guided by the clinical suspicion. Protein-losing enteropathy must be distinguished from other causes of hypoalbuminemia, which include liver disease and nephrotic syndrome; and from heart failure. Protein-losing enteropathy is confirmed by determining the gut alpha-1-antitrypsin clearance (24-hour volume of feces × stool concentration of alpha-1-antitrypsin ÷ serum alpha-1-antitrypsin concentration). A clearance of more than 27 mL/24 h is abnormal.
Laboratory evaluation of protein-losing enteropathy includes serum protein electrophoresis, lymphocyte count, and serum cholesterol to look for evidence of lymphatic obstruction. Serum ANA and C3 levels are useful to screen for autoimmune disorders. Stool samples should be examined for ova and parasites. Evidence of malabsorption is evaluated by means of a stool qualitative fecal fat determination. Intestinal imaging is performed with small bowel enteroscopy biopsy, CT enterography, or wireless capsule endoscopy of the small intestine. Colonic diseases are excluded with colonoscopy. A CT scan of the abdomen is performed to look for evidence of neoplasms or lymphatic obstruction. Rarely, lymphangiography is helpful. In some situations, laparotomy with full-thickness intestinal biopsy is required to establish a diagnosis.
Treatment is directed at the underlying cause. Patients with lymphatic obstruction benefit from low-fat diets supplemented with medium-chain triglycerides. Case reports suggest that octreotide may lead to symptomatic and nutritional improvement in some patients.
DISEASES OF THE COLON & RECTUM
(See Chapter 39 for Colorectal Cancer.)
IRRITABLE BOWEL SYNDROME
ESSENTIALS OF DIAGNOSIS
Chronic functional disorder characterized by abdominal pain or discomfort with alterations in bowel habits.
Symptoms usually begin in late teens to early twenties.
Limited evaluation to exclude organic causes of symptoms.
The functional gastrointestinal disorders are characterized by a variable combination of chronic or recurrent gastrointestinal symptoms not explicable by the presence of structural or biochemical abnormalities. Several clinical entities are included under this broad rubric, including chest pain of unclear origin (noncardiac chest pain), functional dyspepsia, and biliary dyskinesia (sphincter of Oddi dysfunction). There is a large overlap among these entities. For example, over 50% of patients with noncardiac chest pain and over one-third with functional dyspepsia also have symptoms compatible with irritable bowel syndrome. In none of these disorders is there a definitive diagnostic study. Rather, the diagnosis is a subjective one based on the presence of a compatible profile and the exclusion of similar disorders.
Irritable bowel syndrome can be defined, therefore, as an idiopathic clinical entity characterized by chronic (more than 6 months) abdominal pain or discomfort that occurs in association with altered bowel habits. These symptoms may be continuous or intermittent. Consensus definition of irritable bowel syndrome is abdominal discomfort or pain that has two of the following three features: (1) relieved with defecation, (2) onset associated with a change in frequency of stool, or (3) onset associated with a change in form (appearance) of stool. Other symptoms supporting the diagnosis include abnormal stool frequency; abnormal stool form (lumpy or hard; loose or watery); abnormal stool passage (straining, urgency, or feeling of incomplete evacuation); passage of mucus; and bloating or a feeling of abdominal distention.
Patients may have other somatic or psychological complaints such as dyspepsia, heartburn, chest pain, headaches, fatigue, myalgias, urologic dysfunction, gynecologic symptoms, anxiety, or depression.
The disorder is a common problem presenting to both gastroenterologists and primary care physicians. Up to 10% of the adult population have symptoms compatible with the diagnosis, but most never seek medical attention. Approximately two-thirds of patients with irritable bowel syndrome are women.
A number of pathophysiologic mechanisms have been identified and may have varying importance in different individuals.
A variety of abnormal myoelectrical and motor abnormalities have been identified in the colon and small intestine. In some cases, these are temporally correlated with episodes of abdominal pain or emotional stress. Whether they represent a primary motility disorder or are secondary to psychosocial stress is debated. Differences between patients with constipation-predominant and diarrhea-predominant syndromes are reported.
Patients often have a lower visceral pain threshold, reporting abdominal pain at lower volumes of colonic gas insufflation or colonic balloon inflation than controls. Many patients complain of bloating and distention, which may be due to a number of different factors including increased visceral sensitivity, increased gas production (due to small bowel bacterial overgrowth or carbohydrate malabsorption), impaired gas transit through the intestine, or impaired rectal expulsion. Many patients report rectal urgency despite small rectal volumes of stool.
Symptoms compatible with irritable bowel syndrome develop within 1 year in up to 10% of patients after an episode of bacterial gastroenteritis compared with < 2% of controls. Women and patients with increased life stressors at the onset of gastroenteritis appear to be at increased risk for developing “postinfectious” irritable bowel syndrome. Increased inflammatory cells have been found in the mucosa, submucosa, and muscularis of some patients with irritable bowel syndrome, but their importance is unclear. Chronic inflammation is postulated by some investigators to contribute to alterations in motility or visceral hypersensitivity.
Some investigators suggest that alterations in the numbers and distribution of bacterial species (estimated 30,000 different species) may affect bowel transit time, gas production, and sensitivity. An increase in breath hydrogen or methane excretion after lactulose ingestion in 65% of patients with irritable bowel syndrome has been reported, believed by some investigators to indicate small intestinal bacterial overgrowth. However, many investigators dispute these findings because overgrowth was confirmed in only 4% of patients using jejunal aspiration and bacterial culture. Small bowel bacterial overgrowth may be more likely in patients with bloating, postprandial discomfort, and loose stools. It is hypothesized that bacterial overgrowth may lead to alterations in immune alterations that affect motility or visceral sensitivity or to degradation of carbohydrates in the small intestine that may cause increased postprandial gas, bloating, and distention.
More than 50% of patients with irritable bowel who seek medical attention have underlying depression, anxiety, or somatization. By contrast, those who do not seek medical attention are similar psychologically to normal individuals. Psychological abnormalities may influence how the patient perceives or reacts to illness and minor visceral sensations. Chronic stress may alter intestinal motility or modulate pathways that affect central and spinal processing of visceral afferent sensation.
Irritable bowel is a chronic condition. Symptoms usually begin in the late teens to twenties. Symptoms should be present for at least 3 months before the diagnosis can be considered. The diagnosis is established in the presence of compatible symptoms and the judicious use of tests to exclude organic disease.
Abdominal pain usually is intermittent, crampy, and in the lower abdominal region. As previously stated, the onset of pain typically is associated with a change in stool frequency or form and commonly is relieved by defecation. It does not usually occur at night or interfere with sleep. Patients with irritable bowel syndrome may be classified into one of three categories based on the predominant bowel habit: irritable bowel syndrome with diarrhea; irritable bowel syndrome with constipation; or irritable bowel syndrome with mixed constipation and diarrhea. It is important to clarify what the patient means by these complaints. Patients with irritable bowel and constipation report infrequent bowel movements (less than three per week), hard or lumpy stools, or straining. Patients with irritable bowel syndrome with diarrhea refer to loose or watery stools, frequent stools (more than three per day), urgency, or fecal incontinence. Many patients report that they have a firm stool in the morning followed by progressively looser movements. Complaints of visible distention and bloating are common, though these are not always clinically evident.
The patient should be asked about “alarm symptoms” that suggest a diagnosis other than irritable bowel syndrome and warrant further investigation. The acute onset of symptoms raises the likelihood of organic disease, especially in patients aged > 40–50 years. Nocturnal diarrhea, severe constipation or diarrhea, hematochezia, weight loss, and fever are incompatible with a diagnosis of irritable bowel syndrome and warrant investigation for underlying disease. Patients who have a family history of cancer, inflammatory bowel disease, or celiac disease should undergo additional evaluation.
A physical examination should be performed to look for evidence of organic disease and to allay the patient’s anxieties. The physical examination usually is normal. Abdominal tenderness, especially in the lower abdomen, is common but not pronounced. A new onset of symptoms in a patient over age 40 years warrants further examination.
In patients whose symptoms fulfill the diagnostic criteria for irritable bowel syndrome and who have no other alarm symptoms, evidence-based consensus guidelines do not support further diagnostic testing, as the likelihood of serious organic diseases does not appear to be increased. Although the vague nature of symptoms and patient anxiety may prompt clinicians to consider a variety of diagnostic studies, overtesting should be avoided. A 2013 study of primary care patients aged 30–50 years with suspected irritable bowel found that patients randomized to a strategy of extensive testing prior to diagnosis had higher health care costs but similar symptoms and satisfaction at 1 year as patients randomized to a strategy of minimal testing but a positive clinical diagnosis. The use of routine blood tests (complete blood count, chemistry panel, serum albumin, thyroid function tests, erythrocyte sedimentation rate) is unnecessary in most patients. Stool specimen examinations for ova and parasites should be obtained only in patients with increased likelihood of infection (eg, day care workers, campers, foreign travelers). Routine sigmoidoscopy or colonoscopy is not recommended in young patients with symptoms of irritable bowel syndrome without alarm symptoms but should be considered in patients who do not improve with conservative management. In all patients age 50 years or older who have not had a previous evaluation, colonoscopy should be obtained to exclude malignancy. When colonoscopy is performed, random mucosal biopsies should be obtained to look for evidence of microscopic colitis (which may have similar symptoms). In patients with irritable bowel syndrome with diarrhea, serologic tests for celiac disease should be performed. Routine testing for bacterial overgrowth with hydrogen breath tests are not recommended.
A number of disorders may present with similar symptoms. Examples include colonic neoplasia, inflammatory bowel disease (ulcerative colitis, Crohn disease, microscopic colitis), hyperthyroidism or hypothyroidism, parasites, malabsorption (especially celiac disease, bacterial overgrowth, lactase deficiency), causes of chronic secretory diarrhea (carcinoid), and endometriosis. Psychiatric disorders such as depression, panic disorder, and anxiety must be considered as well. Women with refractory symptoms have an increased incidence of prior sexual and physical abuse. These diagnoses should be excluded in patients with presumed irritable bowel syndrome who do not improve within 2–4 weeks of empiric treatment or in whom subsequent alarm symptoms develop.
As with other functional disorders, the most important interventions the clinician can offer are reassurance, education, and support. This includes identifying and responding to the patient’s concerns, careful explanation of the pathophysiology and natural history of the disorder, setting realistic treatment goals, and involving the patient in the treatment process. Because irritable bowel symptoms are chronic, the patient’s reasons for seeking consultation at this time should be determined. These may include major life events or recent psychosocial stressors, dietary or medication changes, concerns about serious underlying disease, or reduced quality of life and impairment of daily activities. In discussing with the patient the importance of the mind-gut interaction, it may be helpful to explain that alterations in visceral motility and sensitivity may be exacerbated by environmental, social, or psychological factors such as foods, medications, hormones, and stress. Symptoms such as pain, bloating, and altered bowel habits may lead to anxiety and distress, which in turn may further exacerbate bowel disturbances due to disordered communication between the gut and the central nervous system. Fears that the symptoms will progress, require surgery, or degenerate into serious illness should be allayed. The patient should understand that irritable bowel syndrome is a chronic disorder characterized by periods of exacerbation and quiescence. The emphasis should be shifted from finding the cause of the symptoms to finding a way to cope with them. Moderate exercise is beneficial. Clinicians must resist the temptation to chase chronic complaints with new or repeated diagnostic studies.
Patients commonly report dietary intolerances. Proposed mechanisms for dietary intolerance include food allergy, hypersensitivity, effects of gut hormones, changes in bacterial flora, increased bacterial gas production (arising in the small or large intestine), and direct chemical irritation. Fatty foods and caffeine are poorly tolerated by many patients with irritable bowel syndrome. In patients with diarrhea, bloating, and flatulence, lactose intolerance should be excluded with a hydrogen breath test or a trial of a lactose-free diet. A host of poorly absorbed, fermentable, monosaccharides and short-chain carbohydrates (“FODMAPS”) may exacerbate bloating, flatulence, and diarrhea in some patients. These include fructose (corn syrups, apples, pears, watermelon, raisins), fructans (onions, leeks, asparagus, artichokes), wheat-based products (breads, pasta, cereals, cakes), sorbitol (stone fruits), and raffinose (legumes, lentils, brussel sprouts, cabbage). Dietary restriction of these fermentable carbohydrates may improve symptoms.
A high-fiber diet and fiber supplements appears to be of little value in patients with irritable bowel syndrome. Many patients report little change in bowel frequency but increased gas and distention.
More than two-thirds of patients with irritable bowel syndrome have mild symptoms that respond readily to education, reassurance, and dietary interventions. Drug therapy should be reserved for patients with moderate to severe symptoms that do not respond to conservative measures. These agents should be viewed as being adjunctive rather than curative. Given the wide spectrum of symptoms, no single agent is expected to provide relief in all or even most patients. Nevertheless, therapy targeted at the specific dominant symptom (pain, constipation, or diarrhea) may be beneficial.
Cognitive-behavioral therapies, relaxation techniques, and hypnotherapy appear to be beneficial in some patients. Patients with underlying psychological abnormalities may benefit from evaluation by a psychiatrist or psychologist. Patients with severe disability should be referred to a pain treatment center.
The majority of patients with irritable bowel syndrome learn to cope with their symptoms and lead productive lives.
Begtrup LM et al. A positive diagnostic strategy is noninferior to a strategy of exclusion for patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013 Aug;11(8):956–62. [PMID: 23357491]
Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med. 2012 Oct 25;367(17):1626–35. [PMID: 23094724]
Chapman RW et al. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol. 2013 Sep;108(9):1508–15. [PMID: 23835436]
Johannesson E et al. Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2011 May;106(5):915–22. [PMID: 21206488]
Khan S et al. Diagnosis and management of IBS. Nat Rev Gastroenterol Hepatol. 2010 Oct;7(10):565–81. [PMID: 20890316]
Menees SB et al. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012 Jan;107(1):28–35. [PMID: 22045120]
Videlock EJ et al. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a meta-analysis. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1084–92. [PMID: 23644388]
ESSENTIALS OF DIAGNOSIS
Most cases of antibiotic-associated diarrhea are not attributable to C difficile and are usually mild and self-limited.
Symptoms of antibiotic-associated colitis vary from mild to fulminant; almost all colitis is attributable to C difficile.
Diagnosis in most cases established by stool assay.
Antibiotic-associated diarrhea is a common clinical occurrence. Characteristically, the diarrhea occurs during the period of antibiotic exposure, is dose related, and resolves spontaneously after discontinuation of the antibiotic. In most cases, this diarrhea is mild, self-limited, and does not require any specific laboratory evaluation or treatment. Stool examination usually reveals no fecal leukocytes, and stool cultures reveal no pathogens. Although C difficile is identified in the stool of 15–25% of cases of antibiotic-associated diarrhea, it is also identified in 5–10% of patients treated with antibiotics who do not have diarrhea. Most cases of antibiotic-associated diarrhea are due to changes in colonic bacterial fermentation of carbohydrates and are not due to C difficile.
Antibiotic-associated colitis is a significant clinical problem almost always caused by C difficile infection. Hospitalized patients are most susceptible. C difficile colitis is the major cause of diarrhea in patients hospitalized for more than 3 days, affecting 22 patients of every 1000. This anaerobic bacterium colonizes the colon of 3% of healthy adults. It is acquired by fecal-oral transmission. Found throughout hospitals in patient rooms and bathrooms, it is readily transmitted from patient to patient by hospital personnel. Fastidious hand washing and use of disposable gloves are helpful in minimizing transmission. C difficile is acquired in approximately 20% of hospitalized patients, most of whom have received antibiotics that disrupt the normal bowel flora and thus allow the bacterium to flourish. Although almost all antibiotics have been implicated, colitis most commonly develops after use of ampicillin, clindamycin, third-generation cephalosporins, and fluoroquinolones. C difficile colitis will develop in approximately one-third of infected patients. In clinical trials, prophylactic administration of the probiotics “DanActiv” and “Bio-K+,” containing Lactobacillus casei, Lactobacillus bulgaricus, and Streptococcus thermophilus, to hospitalized patients who are receiving antibiotics reduced the incidence of C difficile–associated diarrhea. Symptoms usually begin during or shortly after antibiotic therapy but may be delayed for up to 8 weeks. All patients with acute diarrhea should be asked about recent antibiotic exposure. Patients who are elderly; debilitated; immunocompromised; receiving multiple antibiotics or prolonged (> 10 days) antibiotic therapy; receiving enteral tube feedings, proton pump inhibitors, or chemotherapy; or who have inflammatory bowel disease have a higher risk of acquiring C difficile and developing C difficile–associated diarrhea.
The incidence and severity of C difficile colitis in hospitalized patients appear to be increasing, which is attributable to the emergence of a more virulent strain of C difficile (NAP1) that contains an 18-base pair deletion of the tcdC inhibitory gene, resulting in higher toxin A and B production. This hypervirulent strain has been associated with several hospital outbreaks of severe disease with up to 7% mortality.
Most patients report mild to moderate greenish, foul-smelling watery diarrhea 5–15 times per day with lower abdominal cramps. Physical examination is normal or reveals mild left lower quadrant tenderness. The stools may have mucus but seldom gross blood. In most patients, colitis is most severe in the distal colon and rectum. Over half of hospitalized patients diagnosed with C difficile colitis have a white blood count > 15,000/mcL, and C difficile should be considered in all hospitalized patients with unexplained leukocytosis.
Severe or fulminant disease occurs in 10–15% of patients. It is characterized by fever; hemodynamic instability; and abdominal distention, pain, and tenderness. Most patients have profuse diarrhea (up to 30 stools/day); however, diarrhea may be absent or appear to be improving in patients with fulminant disease or ileus. Laboratory data suggestive of severe disease include a white blood count > 30,000/mcL, albumin < 2.5 g/dL (due to protein-losing enteropathy), elevated serum lactate, or rising creatinine.
In the hospitalized patient in whom acute diarrhea develops after admission, the differential diagnosis includes simple antibiotic-associated diarrhea (not related to C difficile), enteral feedings, medications, and ischemic colitis. Other infectious causes are unusual in hospitalized patients in whom diarrhea develops more than 72 hours after admission, and it is not cost-effective to obtain stool cultures unless tests for C difficile are negative. Rarely, other organisms (staphylococci, Clostridium perfringens) have been associated with pseudomembranous colitis. Klebsiella oxytoca may cause a distinct form of antibiotic-associated hemorrhagic colitis that is segmental (usually in the right or transverse colon); spares the rectum; and is more common in younger, healthier outpatients.
Severe colitis may progress quickly to fulminant disease, resulting in hemodynamic instability, respiratory failure, metabolic acidosis, megacolon (> 7 cm diameter), perforation, and death. Chronic untreated colitis may result in weight loss and protein-losing enteropathy.
If possible, antibiotic therapy should be discontinued and therapy with metronidazole, vancomycin, or fidaxomicin (a poorly absorbable macrolide antibiotic) should be initiated. For patients with mild disease, oral metronidazole (500 mg orally three times daily), vancomycin (125 mg orally four times daily), or fidaxomicin, (200 mg orally two times daily) are equally effective for initial treatment. Vancomycin and fidaxomicin are significantly more expensive than metronidazole. Therefore, metronidazole remains the preferred first-line therapy in patients with mild disease, except in patients who are intolerant of metronidazole, pregnant women, and children. The duration of initial therapy is usually 10–14 days. Symptomatic improvement occurs in most patients within 72 hours.
For patients with severe disease, characterized by a white blood cell count > 15,000/mcL, serum albumin < 3 g/dL, or a rise in serum creatinine to > 1.5 times baseline, vancomycin, 125 mg orally four times daily, is the preferred agent because it achieves significantly higher response rates (97%) than metronidazole (76%). In patients with severe, complicated disease, characterized by fever > 38.5oC, hypotension, mental status changes, ileus, megacolon, or WBC > 30,000/mcL, intravenous metronidazole, 500 mg every 6 hours, should be given—supplemented by vancomycin (500 mg four times daily administered by nasoenteric tube) and, in some cases, vancomycin enemas (500 mg in 100 mL every 6 hours). Intravenous vancomycin does not penetrate the bowel and should not be used. The efficacy of fidaxomicin for severe or fulminant disease requires further investigation. Early surgical consultation is recommended for all patients with severe or fulminant disease. Total abdominal colectomy or loop ileostomy with colonic lavage may be required in patients with toxic megacolon, perforation, sepsis, or hemorrhage.
Up to 25% of patients have a relapse of diarrhea from C difficile within 1 or 2 weeks after stopping initial therapy. This may be due to reinfection or failure to eradicate the organism. In a 2011 multicenter, randomized controlled trial, patients treated with fidaxomicin had significantly lower recurrence rates (7.8%) of non-NAP1 C difficile strains than patients treated with vancomycin (23.6%). The recurrence rates were not different among patients with the NAP1 strain. Fidaxomicin may be appropriate for patients with C difficile infection or as initial therapy in patients believed to be at higher risk for recurrent disease. Controlled trials show that oral administration of a live yeast, Saccharomyces boulardii, 500 mg twice daily, reduces the incidence of relapse by 50%. The optimal treatment regimen for recurrent relapses is evolving. Most relapses respond promptly to a second course of the same regimen used for the initial episode. Some patients, however, have recurrent relapses that can be difficult to treat. For patients with two relapses, a 7-week tapering regimen of vancomycin is recommended: 125 mg orally four times daily for 14 days; twice daily for 7 days; once daily for 7 days; every other day for 7 days; and every third day for 2–8 weeks. Probiotic therapy is recommended as adjunctive therapy in patients with relapsing disease. For patients with three or more relapses, updated 2013 guidelines recommend consideration of an installation of a suspension of fecal bacteria from a healthy donor (“fecal microbiota transplant”). In uncontrolled case reports and case series involving several hundred patients, such “fecal transplantation” into the terminal ileum or proximal colon (by colonoscopy) or into the duodenum and jejunum (by nasoenteric tube) results in disease remission after a single treatment in over 90% of patients with recurrent C difficile infection. In a 2013 randomized study, duodenal infusion of donor feces led to resolution of C difficile diarrhea in 94%, which was dramatically higher than vancomycin treatment (31%), prompting early study termination. Despite uncertainties, fecal transplantation should be considered in patients with refractory infection.
Brandt LJ. American Journal of Gastroenterology Lecture: intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol. 2013 Feb;108(2):177–85. [PMID: 23318479]
Brandt LJ et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012 Jul;107(7):1079–87. [PMID: 22450732]
McCollum DL et al. Detection, treatment, and prevention of Clostridium difficile infection. Clin Gastroenterol Hepatol. 2012 Jun;10(6):581–92. [PMID: 22433924]
Surawicz CM et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013 Apr;108(4):478–98. [PMID: 23439232]
van Nood E et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407–15. [PMID: 23323867]
INFLAMMATORY BOWEL DISEASE
The term “inflammatory bowel disease” includes ulcerative colitis and Crohn disease. Ulcerative colitis is a chronic, recurrent disease characterized by diffuse mucosal inflammation involving only the colon. Ulcerative colitis invariably involves the rectum and may extend proximally in a continuous fashion to involve part or all of the colon. Crohn disease is a chronic, recurrent disease characterized by patchy transmural inflammation involving any segment of the gastrointestinal tract from the mouth to the anus.
Crohn disease and ulcerative colitis may be associated in 50% of patients with a number of extraintestinal manifestations, including oral ulcers, oligoarticular or polyarticular nondeforming peripheral arthritis, spondylitis or sacroiliitis, episcleritis or uveitis, erythema nodosum, pyoderma gangrenosum, hepatitis and sclerosing cholangitis, and thromboembolic events.
Although ulcerative colitis and Crohn disease appear to be distinct entities, the same pharmacologic agents are used to treat both. Despite extensive research, there are still no specific therapies for these diseases. The mainstays of therapy are 5-aminosalicylic acid derivatives, corticosteroids, immunomodulating agents (such as mercaptopurine or azathioprine and methotrexate), and biologic agents.
5-ASA is a topically active agent that has a variety of anti-inflammatory effects. It is used in the active treatment of ulcerative colitis and Crohn disease and during disease inactivity to maintain remission. It is readily absorbed from the small intestine but demonstrates minimal colonic absorption. A number of oral and topical compounds have been designed to target delivery of 5-ASA to the colon or small intestine while minimizing absorption. Commonly used formulations of 5-ASA are sulfasalazine, mesalamine, and azo compounds. Side effects of these compounds are uncommon but include nausea, rash, diarrhea, pancreatitis, and acute interstitial nephritis.
Sulfasalazine contains 5-ASA linked to a sulfapyridine moiety. It is unclear whether the sulfapyridine group has any anti-inflammatory effects. One gram of sulfasalazine contains 400 mg of 5-ASA. The sulfapyridine group, however, is absorbed and may cause side effects in 15–30% of patients—much higher than with other 5-ASA compounds. Dose-related side effects include nausea, headaches, leukopenia, oligospermia, and impaired folate metabolism. Allergic and idiosyncratic side effects are fever, rash, hemolytic anemia, neutropenia, worsened colitis, hepatitis, pancreatitis, and pneumonitis. Because of its side effects, sulfasalazine is less frequently used than other 5-ASA agents. It should always be administered in conjunction with folate. Eighty percent of patients intolerant of sulfasalazine can tolerate mesalamine.
A variety of intravenous, oral, and topical corticosteroid formulations have been used in inflammatory bowel disease. They have utility in the short-term treatment of moderate to severe disease. However, long-term use is associated with serious, potentially irreversible side effects and is to be avoided. The agents, route of administration, duration of use, and tapering regimens used are based more on personal bias and experience than on data from rigorous clinical trials. The most commonly used intravenous formulations have been hydrocortisone or methylprednisolone, which are given by continuous infusion or every 6 hours. Oral formulations are prednisone or methylprednisolone. Adverse events commonly occur during short-term systemic corticosteroid therapy, including mood changes, insomnia, dyspepsia, weight gain, edema, elevated serum glucose levels, acne, and moon facies. Side effects of long-term use include osteoporosis, osteonecrosis of the femoral head, myopathy, cataracts, and susceptibility to infections. Calcium and vitamin D supplementation should be administered to all patients receiving long-term corticosteroid therapy. Bone densitometry should be considered in patients with inflammatory bowel disease with other risk factors for osteoporosis and in all patients with a lifetime use of corticosteroids for 3 months or more. Topical preparations are provided as hydrocortisone suppositories (100 mg), foam (90 mg), and enemas (100 mg). Budesonide is an oral corticosteroid with high topical anti-inflammatory activity but low systemic activity due to high first-pass hepatic metabolism. A controlled-release formulation is available (Entocort) that targets delivery to the terminal ileum and proximal colon. An enteric coated, delayed-release formulation is available (Uceris) that is released at a pH > 7, targeting delivery to the colon. Budesonide produces less suppression of the hypothalamic-pituitary-adrenal axis and fewer steroid-related side effects than hydrocortisone or prednisone.
Mercaptopurine and azathioprine are thiopurine drugs that are used in many patients with moderate to severe Crohn disease and ulcerative colitis either in combination with anti-TNF agents or in patients who are corticosteroid-dependent in an attempt to reduce or withdraw the corticosteroids and to maintain patients in remission. Azathioprine is converted in vivo to mercaptopurine. It is believed that the active metabolite of mercaptopurine is 6-thioguanine. Monitoring of 6-thioguanine levels is performed in some clinical settings but is of unproven value in the management of most patients. Side effects of mercaptopurine and azathioprine, including allergic reactions (fever, rash, or arthralgias) and nonallergic reactions (nausea, vomiting, pancreatitis, hepatotoxicity, bone marrow suppression, infections), occur in 15% of patients. Thiopurines are associated with an up to a fivefold increased risk of non-Hodgkin lymphomas (1/1000 patient-years), increasing with age and length of drug exposure; with an increased risk of human papillomavirus (HPV)–related cervical dysplasia; and with an increased risk of non-melanoma skin cancer. Younger patients also are at risk for severe primary Epstein Barr virus (EBV) infection, if not previously exposed.
Three competing enzymes are involved in the metabolism of mercaptopurine to its active (6-thioguanine) and inactive metabolites. About 1 person in 300 has a homozygous mutation of one of the enzymes that metabolizes thiopurine methyltransferase (TPMT), placing them at risk for profound immunosuppression; 1 person in 9 is heterozygous for TPMT, resulting in intermediate enzyme activity. Measurement of TPMT functional activity is recommended prior to initiation of therapy. Treatment should be withheld in patients with absent TPMT activity. The most effective dose of mercaptopurine is 1–1.5 mg/kg. For azathioprine, it is 2–3 mg/kg daily. For patients with normal TPMT activity, both drugs may be initiated at the weight-calculated dose. A complete blood count should be obtained weekly for 4 weeks, biweekly for 4 weeks, and then every 1–3 months for the duration of therapy. Liver biochemical tests should be measured periodically. Some clinicians prefer gradual dose-escalation, especially for patients with intermediate TPMT activity or in whom TPMT measurement is not available; both drugs may be started at 25 mg/d and increased by 25 mg every 1–2 weeks while monitoring for myelosuppression until the target dose is reached. If the white blood count falls below 3000–4000/mcL or the platelet count falls below 100,000/mcL, the medication should be held for at least 1 week before reducing the daily dose by 25–50 mg.
Methotrexate is used in the treatment of patients with inflammatory bowel disease, especially patients with Crohn disease who are intolerant of mercaptopurine. Methotrexate is an analog of dihydrofolic acid. Although at high doses it interferes with cell proliferation through inhibition of nucleic acid metabolism, at low doses it has anti-inflammatory properties, including inhibition of expression of tumor necrosis factor (TNF) in monocytes and macrophages. Methotrexate may be given intramuscularly, subcutaneously, or orally. Side effects of methotrexate include nausea, vomiting, stomatitis, infections, bone marrow suppression, hepatic fibrosis, and life-threatening pneumonitis. A complete blood count and liver function tests should be monitored every 1–3 months. Folate supplementation (1 mg/d) should be administered.
Although the etiology of inflammatory bowel disorders is uncertain, it appears that an abnormal response of the mucosal innate immune system to luminal bacteria may trigger inflammation, which is perpetuated by dysregulation of cellular immunity. A number of biologic therapies are available or in clinical testing that more narrowly target various components of the immune system. Biologic agents are highly effective for patients with corticosteroid-dependent or refractory disease and potentially may improve the natural history of disease. The potential benefits of these agents, however, must be carefully weighed with their high cost and risk of serious and potentially life-threatening side effects.
Infliximab is a chimeric (75% human/25% mouse) IgG1 antibody that is administered by intravenous infusion. A three-dose regimen of 5 mg/kg administered at 0, 2, and 6 weeks is recommended for acute induction, followed by infusions every 8 weeks for maintenance therapy. Acute infusion reactions occur in 5–10% of infusions but occur less commonly in patients receiving regularly scheduled infusions or concomitant immunomodulators (ie, azathioprine or methotrexate). Most reactions are mild or moderate (nausea; headache; dizziness; urticaria; diaphoresis; or mild cardiopulmonary symptoms that include chest tightness, dyspnea, or palpitations) and can be treated by slowing the infusion rate and administering acetaminophen and diphenhydramine. Severe reactions (hypotension, severe shortness of breath, rigors, severe chest discomfort) occur in < 1% and may require oxygen, diphenhydramine, hydrocortisone, and epinephrine. Delayed serum sickness-like reactions occur in 1%. With repeated, intermittent intravenous injections, antibodies to infliximab develop in up to 40% of patients, which are associated with a shortened duration or loss of response and increased risk of acute or delayed infusion reactions. Giving infliximab in a regularly scheduled maintenance therapy (eg, every 8 weeks), concomitant use of infliximab with other immunomodulating agents (azathioprine, mercaptopurine, or methotrexate), or preinfusion treatment with corticosteroids (intravenous hydrocortisone 200 mg) significantly reduces the development of antibodies to approximately 10%.
Adalimumab and golimumab are fully human IgG1 antibodies that are administered by subcutaneous injection. For adalimumab, a dose of 160 mg at week 0 and 80 mg at week 2 is recommended for acute induction, followed by maintenance therapy with 40 mg subcutaneously every other week. For golimumab, a dose of 200 mg at week 0 and 100 mg at week 2 is recommended for acute induction, followed by maintenance therapy with 100 mg subcutaneously every 4 weeks.
Certolizumab is a fusion compound in which the Fab1 portion of a chimeric (95% human/5% mouse) TNF-antibody is bound to polyethylene glycol in order to prolong the drug half-life. A dose of 400 mg at weeks 0, 2, and 4 is recommended for acute induction, followed by maintenance therapy with 400 mg subcutaneously every 4 weeks. Injection site reactions (burning, pain, redness, itching) are relatively common but are usually minor and self-limited. Because of their subcutaneous route of injection, acute and delayed hypersensitivity reactions are rare. Antibodies to adalimumab develop in 5% of patients and to certolizumab in 10%, which may lead to shortened duration or loss of response to the drug.
Serious infections with anti-TNF therapies may occur in 2–5% of patients, including sepsis, pneumonia, abscess, and cellulitis; however, controlled studies suggest the increased risk may be attributable to increased severity of disease and concomitant use of corticosteroids. Patients treated with anti-TNF therapies are at increased risk for the development of opportunistic infections with intracellular bacterial pathogens including tuberculosis, mycoses (candidiasis, histoplasmosis, coccidioidomycosis, nocardiosis), and listeriosis, and with reactivation of viral infections, including hepatitis B, herpes simplex, varicella zoster, and EBV. Prior to use of these agents, patients should be screened for latent tuberculosis with PPD testing and a chest radiograph. Antinuclear and anti-DNA antibodies occur in a large percentage of patients; however, the development of drug-induced lupus is rare. All agents may cause severe hepatic reactions leading to acute hepatic failure; liver biochemical tests should be monitored routinely during therapy. Anti-TNF therapies increase the risk of non-melanoma skin cancer and, possibly, non-Hodgkin lymphoma. Most lymphomas, however, are associated with a combination of an anti-TNF agent and a thiopurine, and it appears that the risk of anti-TNF monotherapy is very low. Rare cases of optic neuritis and demyelinating diseases, including multiple sclerosis have been reported. Anti-TNF therapies may worsen heart failure in patients with cardiac disease.
Vedolizumab (approved by the FDA in May 2014) is a new anti-integrin that blocks the alpha4beta7 heterodimer, selectively blocking gut, but not brain, lymphocyte trafficking. It is believed that greater selectivity may prevent JC virus reactivation.
Beaugerie L. Lymphoma: the bête noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterology. 2013 Nov;145(5):927–30. [PMID: 24070724]
Bloomgren G et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870–80. [PMID: 22591293]
Coskun M et al. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med. 2013 Dec 26;369(26):2561–2. [PMID: 24369082]
Ford AC et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):590–9. [PMID: 21407179]
Targownik LE et al. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol. 2013 Dec;108(12):1835–42. [PMID: 24042192]
Social Support for Patients
Inflammatory bowel disease is a lifelong illness that can have profound emotional and social impacts on the individual. Patients should be encouraged to become involved in the Crohn’s and Colitis Foundation of America (CCFA). National headquarters may be contacted at 444 Park Avenue South, 11th Floor, New York, NY 10016-7374; phone 212-685-3440. Internet address: http://www.ccfa.org.
ESSENTIALS OF DIAGNOSIS
Intermittent bouts of low-grade fever, diarrhea, and right lower quadrant pain.
Right lower quadrant mass and tenderness.
Perianal disease with abscess, fistulas.
Radiographic or endoscopic evidence of ulceration, stricturing, or fistulas of the small intestine or colon.
One-third of cases of Crohn disease involve the small bowel only, most commonly the terminal ileum (ileitis). Half of all cases involve the small bowel and colon, most often the terminal ileum and adjacent proximal ascending colon (ileocolitis). In 20% of cases, the colon alone is affected. One-third of patients have associated perianal disease (fistulas, fissures, abscesses). Less than 5% patients have symptomatic involvement of the upper intestinal tract. Unlike ulcerative colitis, Crohn disease is a transmural process that can result in mucosal inflammation and ulceration, stricturing, fistula development, and abscess formation. Cigarette smoking is strongly associated with the development of Crohn disease, resistance to medical therapy, and early disease relapse.
Because of the variable location of involvement and severity of inflammation, Crohn disease may present with a variety of symptoms and signs. In eliciting the history, the clinician should take particular note of fevers, the patient’s general sense of well-being, weight loss, the presence of abdominal pain, the number of liquid bowel movements per day, and prior surgical resections. Physical examination should focus on the patient’s temperature, weight, and nutritional status, the presence of abdominal tenderness or an abdominal mass, rectal examination, and extraintestinal manifestations (described below). Most commonly, there is one or a combination of the following clinical constellations.
There is a poor correlation between laboratory studies and the patient’s clinical picture. Laboratory values may reflect inflammatory activity or nutritional complications of disease. A complete blood count and serum albumin should be obtained in all patients. Anemia may reflect chronic inflammation, mucosal blood loss, iron deficiency, or vitamin B12 malabsorption secondary to terminal ileal inflammation or resection. Leukocytosis may reflect inflammation or abscess formation or may be secondary to corticosteroid therapy. Hypoalbuminemia may be due to intestinal protein loss (protein-losing enteropathy), malabsorption, bacterial overgrowth, or chronic inflammation. The sedimentation rate or C-reactive protein level is elevated in many patients during active inflammation. Fecal lactoferrin or calprotectin levels also are increased in patients with intestinal inflammation. Stool specimens are sent for examination for routine pathogens, ova and parasites, leukocytes, fat, and C difficile toxin.
In most patients, the initial diagnosis of Crohn disease is based on a compatible clinical picture with supporting endoscopic, pathologic, and radiographic findings. Colonoscopy usually is performed first to evaluate the colon and terminal ileum and to obtain mucosal biopsies. Typical endoscopic findings include aphthoid, linear or stellate ulcers, strictures, and segmental involvement with areas of normal-appearing mucosa adjacent to inflamed mucosa. In 10% of cases, it may be difficult to distinguish ulcerative colitis from Crohn disease. Granulomas on biopsy are present in < 25% of patients but are highly suggestive of Crohn disease. CT or MR enterography or a barium upper gastrointestinal series with small bowel follow-through often is obtained in patients with suspected small bowel involvement. Suggestive findings include ulcerations, strictures, and fistulas; in addition, CT or MR enterography may identify bowel wall thickening and vascularity, mucosal enhancement, and fat stranding. Capsule imaging may help establish a diagnosis when clinical suspicion for small bowel involvement is high but radiographs are normal or nondiagnostic.
The presence of a tender abdominal mass with fever and leukocytosis suggests an abscess. Emergent CT of the abdomen is necessary to confirm the diagnosis. Patients should be given broad-spectrum antibiotics. Percutaneous drainage or surgery is usually required.
Small bowel obstruction may develop secondary to active inflammation or chronic fibrotic stricturing and is often acutely precipitated by dietary indiscretion. Patients should be given intravenous fluids with nasogastric suction. Systemic corticosteroids are indicated in patients with symptoms or signs of active inflammation but are unhelpful in patients with inactive, fixed disease. Patients unimproved on medical management require surgical resection of the stenotic area or stricturoplasty.
Many fistulas are asymptomatic and require no specific therapy. Most symptomatic fistulas eventually require surgical therapy; however, medical therapy is effective in a subset of patients and is usually tried first in outpatients who otherwise are stable. Large abscesses associated with fistulas require percutaneous or surgical drainage. After percutaneous drainage, long-term antibiotics are administered in order to reduce recurrent infections until the fistula is closed or surgically resected. Fistulas may close temporarily in response to TPN or oral elemental diets but recur when oral feedings are resumed. Anti-TNF agents may promote closure in up to 60% within 10 weeks; however, relapse occurs in over one-half of patients within 1 year despite continued therapy. Surgical therapy is required for symptomatic fistulas that do not respond to medical therapy. Fistulas that arise above (proximal to) areas of intestinal stricturing commonly require surgical treatment.
Patients with fissures, fistulas, and skin tags commonly have perianal discomfort. Successful treatment of active intestinal disease also may improve perianal disease. Specific treatment of perianal disease can be difficult and is best approached jointly with a surgeon with an expertise in colorectal disorders. Pelvic MRI and endoscopic ultrasonography are the best noninvasive studies for evaluating perianal fistulas. Patients should be instructed on proper perianal skin care, including gentle wiping with a premoistened pad (baby wipes) followed by drying with a cool hair dryer, daily cleansing with sitz baths or a water wash, and use of perianal cotton balls or pads to absorb drainage. Oral antibiotics (metronidazole, 250 mg three times daily, or ciprofloxacin, 500 mg twice daily) may promote symptom improvement or healing in patients with fissures or uncomplicated fistulas; however, recurrent symptoms are common. Refractory fissures may benefit from mesalamine suppositories or topical 0.1% tacrolimus ointment. Immunomodulators or anti-TNF agents or both promote short-term symptomatic improvement from anal fistulas in two-thirds of patients and complete closure in up to one-half of patients; however, less than one-third maintain symptomatic remission during long-term maintenance treatment.
Anorectal abscesses should be suspected in patients with severe, constant perianal pain, or perianal pain in association with fever. Superficial abscesses are evident on perianal examination, but deep perirectal abscesses may be detected by digital examination or pelvic CT scan. Depending on the abscess location, surgical drainage may be achieved by incision, or catheter or seton placement. Surgery should be considered for patients with severe, refractory symptoms but is best approached after medical therapy of the Crohn disease has been optimized.
Patients with colonic Crohn disease are at increased risk for developing colon carcinoma; hence, annual screening colonoscopy to detect dysplasia or cancer is recommended for patients with a history of 8 or more years of Crohn colitis. Patients with Crohn disease have an increased risk of lymphoma and of small bowel adenocarcinoma; however, both are rare.
Unlike ulcerative colitis, severe hemorrhage is unusual in Crohn disease.
Malabsorption may arise after extensive surgical resections of the small intestine and from bacterial overgrowth in patients with enterocolonic fistulas, strictures, and stasis resulting in bacterial overgrowth.
Chronic cramping abdominal pain and diarrhea are typical of both irritable bowel syndrome and Crohn disease, but radiographic examinations are normal in the former. Celiac disease may cause diarrhea with malabsorption. Acute fever and right lower quadrant pain may resemble appendicitis or Yersinia enterocolitica enteritis. Intestinal lymphoma causes fever, pain, weight loss, and abnormal small bowel radiographs that may mimic Crohn disease. Patients with undiagnosed AIDS may present with fever and diarrhea. Segmental colitis may be caused by tuberculosis, E histolytica, Chlamydia, or ischemic colitis. C difficile or CMV infection may develop in patients with inflammatory bowel disease, mimicking disease recurrence. Diverticulitis with abscess formation may be difficult to distinguish acutely from Crohn disease. NSAIDs may exacerbate inflammatory bowel disease and may also cause NSAID-induced colitis characterized by small bowel or colonic ulcers, erosion, or strictures that tend to be most severe in the terminal ileum and right colon.
Treatment of Active Disease
Crohn disease is a chronic lifelong illness characterized by exacerbations and periods of remission. As no specific therapy exists, current treatment is directed toward symptomatic improvement and control of the disease process, in order to improve quality of life and reduce disease progression and complications. Although sustained clinical remission should be the therapeutic goal, this is achieved in less than one-third of patients. Choice of therapies depends on the disease location and severity, patient age and comorbidities, and patient preference. Early introduction of biologic therapy should be considered strongly in patients with risk factors for aggressive disease, including young age, perianal disease, structuring disease, or need for corticosteroids. All patients with Crohn disease should be counseled to discontinue cigarettes.
There are several potential mechanisms by which diarrhea may occur in Crohn disease in addition to active Crohn disease. A rational empiric treatment approach often yields therapeutic improvement that may obviate the need for corticosteroids or immunosuppressive agents. Involvement of the terminal ileum with Crohn disease or prior ileal resection may lead to reduced absorption of bile acids that may induce secretory diarrhea from the colon. This diarrhea commonly responds to cholestyramine 2–4 g, colestipol 5 g, or colesevelam 625 mg one to two times daily before meals to bind the malabsorbed bile salts. Patients with extensive ileal disease (requiring more than 100 cm of ileal resection) have such severe bile salt malabsorption that steatorrhea may arise. Such patients may benefit from a low-fat diet; bile salt-binding agents will exacerbate the diarrhea and should not be given. Patients with Crohn disease are at risk for the development of small intestinal bacterial overgrowth due to enteral fistulas, ileal resection, and impaired motility and may benefit from a course of broad-spectrum antibiotics (see Bacterial Overgrowth, above). Other causes of diarrhea include lactase deficiency and short bowel syndrome (described in other sections). Use of oral antidiarrheal agents may provide benefit in some patients. Loperamide (2–4 mg), diphenoxylate with atropine (one tablet), or tincture of opium (5–15 drops) may be given as needed up to four times daily. Because of the risk of toxic megacolon, these drugs should not be used in patients with active severe colitis.
Prednisone or methylprednisolone, 40–60 mg/d, is generally administered to patients with Crohn disease that is severe, that involves the distal colon or proximal small intestine, or that has failed treatment with budesonide. Remission or significant improvement occurs in > 80% of patients after 8–16 weeks of therapy. After improvement at 2 weeks, tapering proceeds at 5 mg/wk until a dosage of 20 mg/d is being given. Thereafter, slow tapering by 2.5 mg/wk is recommended. Approximately 20% of patients cannot be completely withdrawn from corticosteroids without experiencing a symptomatic flare-up. Furthermore, more than 50% of patients who achieve initial remission on corticosteroids will experience a relapse within 1 year. Use of long-term low corticosteroid doses (2.5–10 mg/d) should be avoided, because of associated complications (see above). Patients requiring long-term corticosteroid treatment should be given immunomodulatory drugs (as described below) in an effort to wean them from corticosteroids.
Patients with persisting symptoms despite oral corticosteroids or those with high fever, persistent vomiting, evidence of intestinal obstruction, severe weight loss, severe abdominal tenderness, or suspicion of an abscess should be hospitalized. In patients with a tender, palpable inflammatory abdominal mass, CT scan of the abdomen should be obtained prior to administering corticosteroids to rule out an abscess. If no abscess is identified, parenteral corticosteroids should be administered (as described for ulcerative colitis below).
The doses for acute induction therapy are described above. Up to two-thirds of patients have significant clinical improvement during acute induction therapy.
Indications for Surgery
Over 50% of patients will require at least one surgical procedure. The main indications for surgery are intractability to medical therapy, intra-abdominal abscess, massive bleeding, symptomatic refractory internal or perianal fistulas, and intestinal obstruction. Patients with chronic obstructive symptoms due to a short segment of ileal stenosis are best treated with resection or stricturoplasty (rather than long-term medical therapy), which promotes rapid return of well-being and elimination of corticosteroids. After surgery, endoscopic evidence of recurrence occurs in 60% within 1 year. Endoscopic recurrence precedes clinical recurrence by months to years; clinical recurrence occurs in 20% of patients within 1 year and 80% within 10–15 years. Therapy with metronidazole, 250 mg three times daily for 3 months, or long-term therapy with immunomodulators (mercaptopurine or azathioprine) have only been modestly effective in preventing clinical and endoscopic recurrence after ileocolic resection; however, small uncontrolled studies suggest that anti-TNF therapies may prevent endoscopic recurrence in up to 90% of patients. Clinicians may choose to perform endoscopy in high-risk patients 6–12 months after surgery in order to identify patients with early endoscopic recurrence who may benefit from anti-TNF therapy.
With proper medical and surgical treatment, the majority of patients are able to cope with this chronic disease and its complications and lead productive lives. Few patients die as a direct consequence of the disease.
When to Refer
When to Admit
Colombel JF et al; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010 Apr 15;362(15):1383–95. [PMID: 20393175]
Cosnes J et al; Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Early administration of azathioprine vs conventional management of Crohn’s Disease: a randomized controlled trial. Gastroenterology. 2013 Oct;145(4):758–65.e2. [PMID: 23644079]
D’Haens GR et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011 Feb;106(2):199–212. [PMID: 21045814]
Ford AC et al. Efficacy of 5-aminosalicylates in Crohn’s disease: systematic review and meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):617–29. [PMID: 21407190]
Ford AC et al. Efficacy of biologic therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. Apr; 2011;106(4):644–59. [PMID: 21407183]
Panés J et al; AZTEC Study Group. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology. 2013 Oct;145(4):766–74.e1. [PMID: 23770132]
Savarino E et al. Adalimumab is more effective than azathioprine and mesalamine at preventing postoperative recurrence of Crohn’s disease: a randomized controlled trial. Am J Gastroenterol. 2013 Nov;108(11):1731–42. [PMID: 24019080]
Terdiman JP et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013 Dec;145(6):1459–63. [PMID: 24267474]
ESSENTIALS OF DIAGNOSIS
Lower abdominal cramps and fecal urgency.
Anemia, low serum albumin.
Negative stool cultures.
Sigmoidoscopy is the key to diagnosis.
Ulcerative colitis is an idiopathic inflammatory condition that involves the mucosal surface of the colon, resulting in diffuse friability and erosions with bleeding. Approximately one-third of patients have disease confined to the rectosigmoid region (proctosigmoiditis); one-third have disease that extends to the splenic flexure (left-sided colitis); and one-third have disease that extends more proximally (extensive colitis). In patients with distal colitis, the disease progresses with time to more extensive involvement in 25–50%. There is some correlation between disease extent and symptom severity. In most patients, the disease is characterized by periods of symptomatic flare-ups and remissions. Ulcerative colitis is more common in nonsmokers and former smokers. Disease severity may be lower in active smokers and may worsen in patients who stop smoking. Appendectomy before the age of 20 years for acute appendicitis is associated with a reduced risk of developing ulcerative colitis.
The clinical profile in ulcerative colitis is highly variable. Bloody diarrhea is the hallmark. On the basis of several clinical and laboratory parameters, it is clinically useful to classify patients as having mild, moderate, or severe disease (Table 15–12). Patients should be asked about stool frequency, the presence and amount of rectal bleeding, cramps, abdominal pain, fecal urgency, and tenesmus. Physical examination should focus on the patient’s volume status as determined by orthostatic blood pressure and pulse measurements and by nutritional status. On abdominal examination, the clinician should look for tenderness and evidence of peritoneal inflammation. Red blood may be present on digital rectal examination.
Table 15–12. Ulcerative colitis: Assessment of disease activity.
The degree of abnormality of the hematocrit, sedimentation rate, and serum albumin reflects disease severity.
In acute colitis, the diagnosis is readily established by sigmoidoscopy. The mucosal appearance is characterized by edema, friability, mucopus, and erosions. Colonoscopy should not be performed in patients with fulminant disease because of the risk of perforation. After patients have demonstrated improvement on therapy, colonoscopy is performed to determine the extent of disease.
Plain abdominal radiographs are obtained in patients with severe colitis to look for significant colonic dilation. Barium enemas are of little utility in the evaluation of acute ulcerative colitis and may precipitate toxic megacolon in patients with severe disease.
The initial presentation of ulcerative colitis is indistinguishable from other causes of colitis, clinically as well as endoscopically. Thus, the diagnosis of idiopathic ulcerative colitis is reached after excluding other known causes of colitis. Infectious colitis should be excluded by sending stool specimens for routine bacterial cultures (to exclude Salmonella, Shigella, and Campylobacter, as well as specific assays for E coli O157), ova and parasites (to exclude amebiasis), and stool toxin assay for C difficile. Mucosal biopsy can distinguish amebic colitis from ulcerative colitis. CMV colitis occurs in immunocompromised patients, including patients receiving prolonged corticosteroid therapy, and is diagnosed on mucosal biopsy. Gonorrhea, chlamydial infection, herpes, and syphilis are considerations in sexually active patients with proctitis. In elderly patients with cardiovascular disease, ischemic colitis may involve the rectosigmoid. A history of radiation to the pelvic region can result in proctitis months to years later. Crohn disease involving the colon but not the small intestine may be confused with ulcerative colitis. In 10% of patients, a distinction between Crohn disease and ulcerative colitis may not be possible.
There are two main treatment objectives: (1) to terminate the acute, symptomatic attack and (2) to prevent recurrence of attacks. The treatment of acute ulcerative colitis depends on the extent of colonic involvement and the severity of illness.
Patients with mild to moderate disease should eat a regular diet but limit their intake of caffeine and gas-producing vegetables. Antidiarrheal agents should not be given in the acute phase of illness but are safe and helpful in patients with mild chronic symptoms. Oral loperamide (2 mg) or diphenoxylate with atropine (one tablet) may be given up to four times daily. Such remedies are particularly useful at nighttime and when taken prophylactically for occasions when patients may not have reliable access to toilet facilities.
Patients with disease confined to the rectum or rectosigmoid region generally have mild to moderate but distressing symptoms. Patients may be treated with topical mesalamine, topical corticosteroids, or oral aminosalicylates (5-ASA) according to patient preference and cost considerations. Topical mesalamine is the drug of choice and is superior to topical corticosteroids and 5-ASA. Mesalamine is administered as a suppository, 1000 mg once daily at bedtime for proctitis, and as an enema, 4 g at bedtime for proctosigmoiditis, for 4–12 weeks, with 75% of patients improving. Patients who either decline or are unable to manage topical therapy may be treated with oral 5-ASA, as discussed below. Topical corticosteroids are a less expensive alternative to mesalamine but are also less effective. Hydrocortisone suppository or foam is prescribed for proctitis and hydrocortisone enema (80–100 mg) for proctosigmoiditis. Systemic effects from short-term use are very slight. For patients with distal disease who do not improve with topical or oral mesalamine therapy, the following options may be considered: (1) a combination of a topical agent with an oral 5-ASA agent is more effective than either drug alone; (2) combination topical therapy with a 5-ASA suppository or enema at bedtime and a corticosteroid enema or foam in the morning; or (3) a combination of oral 5-ASA agent, topical 5-ASA agent, and a topical corticosteroid. Patients with distal colitis who are refractory to all of these therapies or who have severe disease may require treatment with oral prednisone 40–60 mg/d or infliximab, as described below.
Patients whose acute symptoms resolve rapidly with immediate therapy may have prolonged periods of remission that are treated successfully with intermittent courses of therapy. Patients with early or frequent relapse should be treated with maintenance therapy with mesalamine suppositories (1000 mg) or enemas (4 g) nightly or every other night. For patients who have difficulty complying with topical therapies, oral 5-ASA agents are an acceptable, though possibly less effective, alternative (see below). Topical corticosteroids are ineffective for maintaining remission of distal colitis.
The anti-TNF agents infliximab, adalimumab, and golimumab are approved in the United States for the treatment of patients with moderate to severe ulcerative colitis who have had an inadequate response to conventional therapies (oral corticosteroids, mercaptopurine or azathioprine, and mesalamine). Following a three-dose induction regimen of infliximab 5 mg/kg administered at 0, 2, and 6 weeks, clinical response occurs in 65% and clinical remission in 35%. By comparison, phase III trials of adalimumab and golimumab reported clinical response rates of 50–59% and remission rates of 16–21% after 8 weeks. Although the response and remission rates appear lower with adalimumab and golimumab than infliximab, differences in study design and patient populations limit comparisons. Importantly, 40% of patients in the adalimumab trials were previously treated with other anti-TNF agents, in whom lower response rates were noted.
About 15% of patients with ulcerative colitis have a more severe course. Because they may progress to fulminant colitis or toxic megacolon, hospitalization is generally required.
A subset of patients with severe disease has a more fulminant course with rapid progression of symptoms over 1–2 weeks and signs of severe toxicity. These patients appear quite ill, with fever, prominent hypovolemia, hemorrhage requiring transfusion, and abdominal distention with tenderness. They are at a higher risk of perforation or development of toxic megacolon and must be followed closely. Broad-spectrum antibiotics should be administered to cover anaerobes and gram-negative bacteria.
Toxic megacolon develops in < 2% of cases of ulcerative colitis. It is characterized by colonic dilation of more than 6 cm on plain films with signs of toxicity. In addition to the therapies outlined above, nasogastric suction should be initiated. Patients should be instructed to roll from side to side and onto the abdomen in an effort to decompress the distended colon. Serial abdominal plain films should be obtained to look for worsening dilation or ischemia. Patients with fulminant disease or toxic megacolon who worsen or fail to improve within 48–72 hours should undergo surgery to prevent perforation. If the operation is performed before perforation, the mortality rate should be low.
Maintenance of Remission
Without long-term therapy, 75% of patients who initially go into remission on medical therapy will experience a symptomatic relapse within 1 year. Long-term oral maintenance therapy with sulfasalazine, 1–1.5 g twice daily, or mesalamine, 1.6–2.4 g once daily, have been shown to reduce relapse rates to < 35%. Mercaptopurine and azathioprine are useful in patients with frequent disease relapses (more than two per year) or corticosteroid-dependent disease to maintain remission. The role of long-term infliximab therapy in the maintenance of remission is evolving. In two, large, controlled studies of patients with active moderate to severe colitis, initial induction therapy was followed by infliximab maintenance infusions (5 mg/kg) administered every 8 weeks for 30–54 weeks. At the end of the study (30 or 54 weeks), 35% were in clinical remission, (21% in corticosteroid-free remission), a modest but impressive response in patients with more refractory disease. In considering long-term infliximab therapy, patients and clinicians need to weigh the long-term risks of immunosuppression against colectomy.
Risk of Colon Cancer
In patients with ulcerative colitis with disease proximal to the rectum and in patients with Crohn colitis, there is a markedly increased risk of developing colon carcinoma. A large meta-analysis of observational studies reported a cumulative incidence of 2% at 10 years, 8% at 20 years, and 18% after 30 years of disease. Retrospective studies suggest that the risk of colon cancer may be reduced in patients treated with long-term 5-ASA therapy. Ingestion of folic acid, 1 mg/d, also is associated with a decreased risk of cancer development. Colonoscopies are recommended every 1–2 years in patients with colitis, beginning 8 years after diagnosis. At colonoscopy, all adenoma-like polyps should be resected, when possible, and biopsies obtained of non-endoscopically resectable mass lesions. In addition, multiple (at least 32) random mucosal biopsies are taken throughout the colon at 10-cm intervals to look for evidence of dysplasia in flat mucosa. Because of the relatively high incidence of concomitant carcinoma in patients with dysplasia (either low or high grade) in flat mucosa or non-endoscopically resectable mass lesions, colectomy is recommended. Several prospective studies demonstrate that dye spraying with methylene blue or indigo carmine (“chromoendoscopy”) enhances the detection of subtle mucosal lesions, thereby significantly increasing the detection of dysplasia compared with standard colonoscopy. Although surveillance colonoscopy appears to be effective in reducing the incidence of colon cancer, patients must understand that approximately one-third of detected cancers are advanced, despite compliance with routine colonoscopy surveillance.
Surgery in Ulcerative Colitis
Surgery is required in 25% of patients. Severe hemorrhage, perforation, and documented carcinoma are absolute indications for surgery. Surgery is indicated also in patients with fulminant colitis or toxic megacolon that does not improve within 48–72 hours, in patients with flat dysplasia or non-endoscopically resectable dysplastic lesions on surveillance colonoscopy, and in patients with refractory disease requiring long-term corticosteroids to control symptoms.
Although total proctocolectomy (with placement of an ileostomy) provides complete cure of the disease, most patients seek to avoid it out of concern for the impact it may have on their bowel function, their self-image, and their social interactions. After complete colectomy, patients may have a standard ileostomy with an external appliance, a continent ileostomy, or an internal ileal pouch that is anastomosed to the anal canal (ileal pouch-anal anastomosis). The latter maintains intestinal continuity, thereby obviating an ostomy. Under optimal circumstances, patients have five to seven loose bowel movements per day without incontinence. Endoscopic or histologic inflammation in the ileal pouch (“pouchitis”) develops in over 40% of patients, resulting in increased stool frequency, fecal urgency, cramping, and bleeding, but usually resolves with a 2-week course of oral metronidazole (250–500 mg three times daily) or ciprofloxacin (500 mg twice daily). Patients with frequently relapsing pouchitis may need continuous antibiotics. Probiotics containing nonpathogenic strains of lactobacilli, bifidobacteria, and streptococci (VSL#3) are effective in the maintenance of remission in patients with recurrent pouchitis. Bismuth subsalicylate (Pepto Bismol, 262 mg, two tablets four times daily) has demonstrated benefit in some series. Some clinicians report that topical corticosteroids or oral budesonide 9 mg/d are of benefit. Refractory cases of pouchitis can be disabling and may require conversion to a standard ileostomy.
Ulcerative colitis is a lifelong disease characterized by exacerbations and remissions. For most patients, the disease is readily controlled by medical therapy without need for surgery. The majority never require hospitalization. A subset of patients with more severe disease will require surgery, which results in complete cure of the disease. Properly managed, most patients with ulcerative colitis lead close to normal productive lives.
When to Refer
When to Admit
Autenrieth DM et al. Toxic megacolon. Inflamm Bowel Dis. 2012 Mar;18(3):584–91. [PMID: 22009735]
Bessissow T et al. Advanced endoscopic imaging for dysplasia surveillance in ulcerative colitis. Expert Rev Gastroenterol Hepatol. 2013 Jan;7(1):57–67. [PMID: 23265150]
Bitton A et al; Canadian Association of Gastroenterology Severe Ulcerative Colitis Consensus Group. Treatment of hospitalized adult patients with severe ulcerative colitis: Toronto consensus statements. Am J Gastroenterol. 2012 Feb;107(2):179–94. [PMID: 22108451]
Collins PD. Strategies for detecting colon cancer and dysplasia in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013 Mar–Apr;19(4):860–3. [PMID: 23446340]
Danese S et al. Ulcerative colitis. N Engl J Med. 2011 Nov 3;365(18):1713–25. [PMID: 22047562]
Danese S et al. Review article: the role of anti-TNF in the management of ulcerative colitis—past, present and future. Aliment Pharmacol Ther. 2013 May;37(9):855–66. [PMID: 23489068]
Marshall JK et al. Rectal 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012 Nov 14;11:CD004118. [PMID: 23152224]
Ord´s I et al. Ulcerative colitis. Lancet. 2012 Nov 3;380(9853):1606–19. [PMID: 22914296]
Sandborn WJ et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2011 2012 Feb;142(2):257–65. [PMID: 22062358]
Sandborn WJ et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014 Jan;146(1):85–95. [PMID: 23735746]
Microscopic colitis is an idiopathic condition that is found in up to 15% of patients who have chronic or intermittent watery diarrhea with normal-appearing mucosa at endoscopy. There are two major subtypes—lymphocytic colitis and collagenous colitis. In both, histologic evaluation of mucosal biopsies reveals chronic inflammation (lymphocytes, plasma cells) in the lamina propria and increased intraepithelial lymphocytes. Collagenous colitis is further characterized by the presence of a thickened band (> 10 mcm) of subepithelial collagen. Both forms occur more commonly in women, especially in the fifth to sixth decades. Symptoms tend to be chronic or recurrent but may remit in most patients after several years. A more severe illness characterized by abdominal pain, fatigue, dehydration, and weight loss may develop in a subset of patients. The cause of microscopic colitis usually is unknown. Several medications have been implicated as etiologic agents, including NSAIDs, sertraline, paroxetine, lansoprazole, lisinopril, and simvastatin. Diarrhea usually abates within 30 days of stopping the offending medication. Celiac sprue may be present in up to 20% of patients and should be excluded with serologic testing (antitissue transglutaminase or antiendomysial antibody). Treatment is largely empiric since there are few well-designed, controlled treatment trials. Antidiarrheal therapy with loperamide is the first-line treatment, providing symptom improvement in up to 70%. For patients who do not respond to loperamide, the next option is budesonide (which is efficacious but expensive) versus other agents (which have limited data supporting efficacy but are less expensive). In uncontrolled studies, treatment with 5-ASAs (sulfasalazine, mesalamine) or bile-salt binding agents (cholestyramine, colestipol) is reported to be effective in many patients. A small unpublished controlled trial demonstrated efficacy for bismuth subsalicylate (two tablets three times daily) for 2 months; however, clinical experience has yielded only modest benefit. Delayed release budesonide (Entocort) 9 mg/d for 6–8 weeks has been shown in three prospective controlled studies to induce clinical remission in > 80% of patients; however, relapse occurs in most patients after stopping therapy. In two prospective studies, remission was maintained in 75% of patients treated with budesonide 6 mg/d compared with 25% of persons given placebo. In clinical practice, budesonide is tapered to the lowest effective dose for maintaining symptoms. Less than 3% of patients have refractory or severe symptoms, which may be treated with immunosuppressive agents (azathioprine or methotrexate).
Ianiro G. Microscopic colitis. World J Gastroenterol. 2012 Nov 21;18(43):6206–15. [PMID: 23180940]
Pardi DS et al. Microscopic colitis. Gastroenterology. 2011 Apr;140(4):1155–65. [PMID: 21303675]
Yen EF et al. Non-IBD colitides (eosinophilic, microscopic). Best Pract Res Clin Gastroenterol. 2012 Oct;26(5):611–22. [PMID: 23384806]
DIVERTICULAR DISEASE OF THE COLON
Colonic diverticulosis increases with age, ranging from 5% in those under age 40, to 30% at age 60, to more than 50% over age 80 years in Western societies. Most are asymptomatic, discovered incidentally at endoscopy or on barium enema. Complications occur in < 5%, including gastrointestinal bleeding and diverticulitis.
Colonic diverticula may vary in size from a few millimeters to several centimeters and in number from one to several dozen. Almost all patients with diverticulosis have involvement in the sigmoid and descending colon; however, only 15% have proximal colonic disease.
For over 40 years, it has been believed that diverticulosis arises after many years of a diet deficient in fiber. It is hypothesized that undistended, contracted segments of colon have higher intraluminal pressures. Over time, the contracted colonic musculature, working against greater pressures to move small, hard stools, develops hypertrophy, thickening, rigidity, and fibrosis. Diverticula may develop more commonly in the sigmoid because intraluminal pressures are highest in this region. Recent epidemiologic studies challenge this theory, finding no association between the prevalence of asymptomatic diverticulosis and low dietary fiber intake or constipation. Thus, the etiology of diverticulosis is uncertain. The extent to which abnormal motility and hereditary factors contribute to diverticular disease is unknown. Patients with diffuse diverticulosis may have an inherent weakness in the colonic wall. Patients with abnormal connective tissue are also disposed to development of diverticulosis, including Ehlers-Danlos syndrome, Marfan syndrome, and scleroderma.
More than 90% of patients with diverticulosis have uncomplicated disease and no specific symptoms. In most, diverticulosis is an incidental finding detected during colonoscopic examination or barium enema examination. Some patients have nonspecific complaints of chronic constipation, abdominal pain, or fluctuating bowel habits. It is unclear whether these symptoms are due to alterations in the colonic motility, visceral hypersensitivity, gut microbiota, or in low-grade inflammation. Physical examination is usually normal but may reveal mild left lower quadrant tenderness with a thickened, palpable sigmoid and descending colon. Screening laboratory studies should be normal in uncomplicated diverticulosis.
There is no reason to perform imaging studies for the purpose of diagnosing asymptomatic, uncomplicated disease. Diverticula are well seen on barium enema, colonoscopy and CT imaging. Involved segments of colon may also be narrowed and deformed.
Patients in whom diverticulosis is discovered, especially patients with symptoms or a history of complicated disease (see below) should be treated with a high-fiber diet or fiber supplements (bran powder, 1–2 tbsp twice daily; psyllium or methylcellulose) (see section on constipation). Retrospective studies suggest that such treatment may decrease the likelihood of subsequent complications.
Maconi G et al. Treatment of diverticular disease of the colon and prevention of acute diverticulitis: a systematic review. Dis Colon Rectum. 2011 Oct;54(10):1326–38. [PMID: 21904150]
Peery AF et al. Constipation and a low-fiber diet are not associated with diverticulosis. Clin Gastroenterol Hepatol. 2013 Dec;11(12):1622–7. [PMID: 23891924]
Strate LL et al. Diverticular disease as a chronic illness: evolving epidemiologic and clinical insights. Am J Gastroenterol. 2012 Oct;107(10):1486–93. [PMID: 22777341]
ESSENTIALS OF DIAGNOSIS
Acute abdominal pain and fever.
Left lower abdominal tenderness and mass.
Perforation of a colonic diverticulum results in an intra-abdominal infection that may vary from microperforation (most common) with localized paracolic inflammation to macroperforation with either abscess or generalized peritonitis. Thus, there is a range from mild to severe disease. Most patients with localized inflammation or infection report mild to moderate aching abdominal pain, usually in the left lower quadrant. Constipation or loose stools may be present. Nausea and vomiting are frequent. In many cases, symptoms are so mild that the patient may not seek medical attention until several days after onset. Physical findings include a low-grade fever, left lower quadrant tenderness, and a palpable mass. Stool occult blood is common, but hematochezia is rare. Leukocytosis is mild to moderate. Patients with free perforation present with a more dramatic picture of generalized abdominal pain and peritoneal signs.
In patients with mild symptoms and a presumptive diagnosis of diverticulitis, empiric medical therapy is started without further imaging in the acute phase. Patients who respond to acute medical management should undergo complete colonic evaluation with colonoscopy or radiologic imaging (CT colonography or barium enema) after resolution of clinical symptoms to corroborate the diagnosis or exclude other disorders such as colonic neoplasms. In patients who do not improve rapidly after 2–4 days of empiric therapy and in those with severe disease, CT scan of the abdomen is obtained to look for evidence of diverticulitis and determine its severity, and to exclude other disorders that may cause lower abdominal pain. The presence of colonic diverticula and wall thickening, pericolic fat infiltration, abscess formation, or extraluminal air or contrast suggest diverticulitis. Endoscopy and colonography are contraindicated during the initial stages of an acute attack because of the risk of free perforation.
Diverticulitis must be distinguished from other causes of lower abdominal pain, including perforated colonic carcinoma, Crohn disease, appendicitis, ischemic colitis, C difficile–associated colitis, and gynecologic disorders (ectopic pregnancy, ovarian cyst or torsion) by abdominal CT scan, pelvic ultrasonography, or radiographic studies of the distal colon that use water-soluble contrast enemas.
Fistula formation may involve the bladder, ureter, vagina, uterus, bowel, and abdominal wall. Diverticulitis may result in stricturing of the colon with partial or complete obstruction.
Most patients can be managed with conservative measures. Patients with mild symptoms and no peritoneal signs may be managed initially as outpatients on a clear liquid diet. Although broad-spectrum oral antibiotics with anaerobic activity commonly are prescribed, large clinical trials confirm that antibiotics are not beneficial in uncomplicated disease. Reasonable regimens include amoxicillin and clavulanate potassium (875 mg/125 mg) twice daily; or metronidazole, 500 mg three times daily; plus either ciprofloxacin, 500 mg twice daily, or trimethoprim-sulfamethoxazole, 160/800 mg twice daily orally, for 7–10 days or until the patient is afebrile for 3–5 days. Symptomatic improvement usually occurs within 3 days, at which time the diet may be advanced. Once the acute episode has resolved, a high fiber diet is often recommended. Patients with increasing pain, fever, or inability to tolerate oral fluids require hospitalization. Patients with severe diverticulitis (high fevers, leukocytosis, or peritoneal signs) and patients who are elderly or immunosuppressed or who have serious comorbid disease require hospitalization acutely. Patients should be given nothing by mouth and should receive intravenous fluids. If ileus is present, a nasogastric tube should be placed. Intravenous antibiotics should be given to cover anaerobic and gram-negative bacteria. Single-agent therapy with either a second-generation cephalosporin (eg, cefoxitin), piperacillin-tazobactam, or ticarcillin clavulanate appears to be as effective as combination therapy (eg, metronidazole or clindamycin plus an aminoglycoside or third-generation cephalosporin [eg, ceftazidime, cefotaxime]). Symptomatic improvement should be evident within 2–3 days. Intravenous antibiotics should be continued for 5–7 days, before changing to oral antibiotics.
Surgical consultation and repeat abdominal CT imaging should be obtained on all patients with severe disease or those who do not improve after 72 hours of medical management. Patients with a localized abdominal abscess ≥ 4 cm in size are usually treated urgently with a percutaneous catheter drain placed by an interventional radiologist. This permits control of the infection and resolution of the immediate infectious inflammatory process. In this manner, a subsequent elective one-stage surgical operation can be performed (if deemed necessary) in which the diseased segment of colon is removed and primary colonic anastomosis performed. After recovery, the decision to perform elective surgery depends on the patient’s age, comorbid disease, and frequency and severity of attacks. Patients with chronic disease resulting in fistulas or colonic obstruction will require elective surgical resection.
Indications for emergent surgical management include generalized peritonitis, large undrainable abscesses, and clinical deterioration despite medical management and percutaneous drainage. Surgery may be performed in one- or two-stage operations depending on the patient’s nutritional status, severity of illness, and extent of intra-abdominal peritonitis and abscess formation. In a two-stage operation, the diseased colon is resected and the proximal colon brought out to form a temporary colostomy. The distal colonic stump is either closed (forming a Hartmann pouch) or exteriorized as a mucous fistula. Weeks later, after inflammation and infection have completely subsided, the colon can be reconnected electively.
Diverticulitis recurs in 10–30% of patients treated with medical management over 10–20 years, However, < 5% have more than two recurrences. Recurrent attacks warrant elective surgical resection, which carries a lower morbidity and mortality risk than emergency surgery.
Biondo S et al. Current status of the treatment of acute colonic diverticulitis: a systematic review. Colorectal Dis. 2012 Jan;14(1):e1–e11. [PMID: 21848896]
Peery AF et al. Diverticular disease: reconsidering conventional wisdom. Clin Gastroenterol Hepatol. 2013 Dec;11(12):1532–7. [PMID: 23669306]
Shahedi K et al. Long-term risk of acute diverticulitis among patients with incidental diverticulosis found during colonoscopy. Clin Gastroenterol Hepatol. 2013 Dec;11(12):1609–13. [PMID: 23856358]
Half of all cases of acute lower gastrointestinal bleeding are attributable to diverticulosis. For a full discussion, see the section on Acute Lower Gastrointestinal Bleeding, above.
Polyps are discrete mass lesions that protrude into the intestinal lumen. Although most commonly sporadic, they may be inherited as part of a familial polyposis syndrome. Polyps may be divided into four major pathologic groups: mucosal adenomatous polyps (tubular, tubulovillous, and villous), mucosal serrated polyps (hyperplastic, sessile serrated polyp, and traditional serrated adenoma), mucosal nonneoplastic polyps (juvenile polyps, hamartomas, inflammatory polyps), and submucosal lesions (lipomas, lymphoid aggregates, carcinoids, pneumatosis cystoides intestinalis). Of polyps removed at colonoscopy, over 70% are adenomatous; most of the remainder are serrated polyps. Adenomatous polyps and serrated polyps have significant clinical implications and will be considered further below.
Adenomas and serrated polyps may be flat, sessile, or pedunculated (containing a stalk). They are present in 30% of adults over 50 years of age. Their significance is that over 95% of cases of adenocarcinoma of the colon are believed to arise from these lesions. It is proposed that there is a polyp → carcinoma sequence whereby nonfamilial colorectal cancer develops through a continuous process from normal mucosa to adenoma or serrated polyps to carcinoma. The majority of cancers arise in adenomas after inactivation of the APC gene leads to chromosomal instability and inactivation or loss of other tumor suppressor genes. By contrast, cancers arising in the serrated pathway appear to have either Kras (traditional serrated adenomas) mutations or BRAF oncogene activation (sessile serrated adenomas) with methylation of CpG-rich promoter regions that leads to inactivation of tumor suppressor genes or mismatch repair genes (MLH1) with microsatellite instability.
Most adenomas are small (< 1 cm) and have a low risk of becoming malignant; < 5% of these enlarge with time. Adenomas and serrated polyps are classified as “advanced” if they are ≥ 1 cm, or contain villous features or high-grade dysplasia. Advanced lesions are believed to have a higher risk of harboring or progressing to malignancy. It has been estimated from longitudinal studies that it takes an average of 5 years for a medium-sized polyp to develop from normal-appearing mucosa and 10 years for a gross cancer to arise. The prevalence of advanced adenomas is 6% and colorectal cancer 0.3%. The role of aspirin and NSAIDs for the chemoprevention of adenomatous polyps is discussed in Chapter 39, in the section on Colorectal Cancer.
Most sessile serrated polyps and traditional serrated adenomas are believed to arise from hyperplastic polyps. It is believed that sessile serrated polyps and traditional serrated adenomas harbor an increased risk of colorectal cancer similar or greater to that of adenomas. Many pathologists cannot reliably distinguish between hyperplastic polyps and sessile serrated polyps. Small hyperplastic polyps (< 5 mm) located in the rectosigmoid region are of no consequence, except that they cannot reliably be distinguished from adenomatous lesions other than by biopsy. Hyperplastic polyps located in the proximal colon (ie, proximal to the splenic flexure) may be associated with an increased prevalence of advanced neoplasia, particularly those larger than 1 cm.
Most patients with adenomatous and serrated polyps are completely asymptomatic. Chronic occult blood loss may lead to iron deficiency anemia. Large polyps may ulcerate, resulting in intermittent hematochezia.
FOBT, FIT, and fecal DNA tests are available as part of colorectal cancer screening programs (see Chapter 39). FIT is a fecal blood immunochemical test for hemoglobin that is more sensitive than guaiac-based tests for the detection of colorectal cancer and advanced adenomas. In prospective studies, the FIT test detected 15–35% of advanced noncancerous adenomas.
Polyps are identified by means of barium enema examinations or CT colonography. Both studies require bowel cleansing with laxatives before the study and insertion of a rectal catheter for air insufflation during the study. CT colonography (“virtual colonoscopy”) uses data from helical CT imaging with computer-enabled luminal image reconstruction to generate two-dimensional and three-dimensional images of the colon. Using optimal imaging software with multidetector helical CT scanners, several studies report a sensitivity of ≥ 90% for the detection of polyps > 10 mm in size. However, the accuracy for detection of polyps 5–9 mm in size is significantly lower (sensitivity 50%). A small proportion of these small polyps harbor advanced histology or carcinoma (up to 1.2%) or carcinoma (< 1%). Abdominal CT imaging results in a radiation exposure that may lead to a small risk of cancer. CT colonography is endorsed by US Multisociety Task Force as an acceptable option for screening for colorectal adenomatous polyps and cancer in average risk asymptomatic adults. Barium enema is no longer recommended due to its poor diagnostic accuracy.
Colonoscopy allows evaluation of the entire colon and is the best means of detecting and removing adenomatous and serrated polyps. It should be performed in all patients who have positive FOBT, FIT, fecal, or DNA tests or iron deficiency anemia (see Occult Gastrointestinal Bleeding and Obscure Gastrointestinal Bleeding, above), as the prevalence of colonic neoplasms is increased in these patients. Colonoscopy should also be performed in patients with polyps detected on radiologic imaging studies (barium enema or CT colonography) or adenomas detected on flexible sigmoidoscopy to remove these polyps and to fully evaluate the entire colon. Capsule endoscopy of the colon has a 73% sensitivity and 79% specificity for detection of adenomas with advanced histology or cancer compared with colonoscopy and cannot be recommended at this time to screen for colorectal neoplasia.
Most adenomatous and serrated polyps are amenable to colonoscopic removal with biopsy forceps or snare cautery. Large sessile polyps (> 2–3 cm) may be removed by snare cautery using a variety of techniques (eg, piecemeal or saline-lift assisted mucosal resection) or may require surgical resection. Patients with large sessile polyps removed in piecemeal fashion should undergo repeated colonoscopy in 2–6 months to verify complete polyp removal. Complications after colonoscopic polypectomy include perforation in 0.2% and clinically significant bleeding in 0.3–1% of patients.
Adenomas and serrated polyps can be found in 30–40% of patients when another colonoscopy is performed within 3–5 years after the initial examination and polyp removal. Periodic colonoscopic surveillance is therefore recommended to detect these “metachronous” lesions, which either may be new or may have been overlooked during the initial examination. Most of these polyps are small, without high-risk features and of little immediate clinical significance. The probability of detecting advanced neoplasms at surveillance colonoscopy depends on the number, size, and histologic features of the polyps removed on initial (index) colonoscopy. Patients with 1–2 small (< 1 cm) tubular adenomas (without villous features or high-grade dysplasia) should have their next colonoscopy in 5–10 years. Patients with 3–10 adenomas, an adenoma >1 cm, or an adenoma with villous features or high-grade dysplasia should have their next colonoscopy at 3 years. Patients with more than 10 adenomas should have a repeat colonoscopy at 1–2 years and may be considered for evaluation for a familial polyposis syndrome (see below). Surveillance colonoscopy at 5 years is appropriate for patients with small (<1 cm) serrated polyps without cytologic dysplasia; surveillance colonoscopy at 3 years should be considered for serrated polyps >1 cm and those with cytologic atypia. No surveillance is recommended for patients with small, typical hyperplastic polyps located in the distal colon and rectum.
Lieberman DA et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012 Sep;143(3):844–57. [PMID: 22763141]
Naini BV et al. Advanced precancerous lesions (APL) in the colonic mucosa. Best Pract Res Clin Gastroenterol. 2013 Apr;27(2):235–56. [PMID: 23809243]
Rosty C et al. Serrated polyps of the large intestine: current understanding of diagnosis, pathogenesis, and clinical management. J Gastroenterol. 2013 Mar;48(3):287–302. [PMID: 23208018]
Zauber AG et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012 Feb 23;366(8):687–96. [PMID: 22356322]
Up to 4% of all colorectal cancers are caused by germline genetic mutations that impose on carriers a high lifetime risk of developing colorectal cancer (see Chapter 39). Because the diagnosis of these disorders has important implications for treatment of affected members and for screening of family members, it is important to consider these disorders in patients with a family history of colorectal cancer that has affected more than one family member, those with a personal or family history of colorectal cancer developing at an early age (≤ 50 years), those with a personal or family history of multiple polyps (>20), and those with a personal or family history of multiple extracolonic malignancies.
Patel SG et al. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. 2012 Oct;14(5):428–38. [PMID: 22864806]
ESSENTIALS OF DIAGNOSIS
Inherited condition characterized by early development of hundreds to thousands of colonic adenomatous polyps and adenocarcinoma.
Variety of extracolonic manifestations, including duodenal adenomas, desmoid tumors, and osteomas.
Attenuated variant with < 500 (average 25) colonic adenomas.
Genetic testing confirms mutation of APC gene (90%) or MYH gene (8%).
Prophylactic colectomy recommended to prevent otherwise inevitable colon cancer.
Familial adenomatous polyposis (FAP) is a syndrome affecting 1:10,000 people and accounts for approximately 0.5% of colorectal cancer. The classic form of FAP is characterized by the development of hundreds to thousands of colonic adenomatous polyps and a variety of extracolonic manifestations. An attenuated variant of FAP also has been recognized in which an average of only 25 polyps (range of 1–500) develop. FAP is most commonly caused by autosomally dominant inherited mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21. FAP arises de novo in 15% of patients in the absence of genetic mutations in the parents. Mutations in the MYH gene, a gene involved with base excision repair, are present in patients with the classic and attenuated forms of FAP who do not have mutations of the APC gene. FAP due to MYH mutation is inherited in an autosomal recessive fashion, hence a family history of colorectal cancer may not be evident. Of patients with classic FAP, approximately 90% have a mutation in the APC gene and 8% in the MYH gene. In contrast, among patients with 10–100 adenomatous polyps and suspected attenuated FAP, APC mutations are identified in 15% but MYH mutations in 25%.
Colorectal polyps develop by a mean age of 15 years and cancer at 40 years. Unless prophylactic colectomy is performed, colorectal cancer is inevitable by age 50 years. In attenuated FAP, the mean age for development of cancer is about 56 years.
Adenomatous polyps of the duodenum and periampullary area develop in over 90% of patients, resulting in a 5–8% lifetime risk of adenocarcinoma. Adenomas occur less frequently in the gastric antrum and small bowel and in those locations have a lower risk of malignant transformation. Gastric fundus gland polyps occur in over 50% but have an extremely low (0.6%) malignant potential.
A variety of other benign extraintestinal manifestations, including soft tissue tumors of the skin, desmoid tumors, osteomas, and congenital hypertrophy of the retinal pigment, develop in some patients with FAP. These extraintestinal manifestations vary among families, depending in part on the type or site of mutation in the APC gene. Desmoid tumors are locally invasive fibromas, most commonly intra-abdominal, that may cause bowel obstruction, ischemia, or hemorrhage. They occur in 15% of patients and are the second leading cause of death in FAP. Malignancies of the central nervous system (Turcot syndrome) and tumors of the thyroid and liver (hepatoblastomas) may also develop in patients with FAP.
Genetic counseling and testing should be offered to patients with a diagnosis of FAP established by endoscopy and to first-degree family members of patients with the disease; testing should be done also to confirm a diagnosis of attenuated disease in patients with 20 or more adenomas. Genetic testing is best performed by sequencing the APC gene to identify disease-associated mutations, which are identified in approximately 90% of cases of typical FAP. Mutational assessment of MYH should be considered in patients with negative test results and in patients with suspected attenuated FAP. First-degree relatives of patients with FAP should undergo genetic screening after age 10 years. If the assay cannot be done or is not informative, family members at risk should undergo yearly sigmoidoscopy beginning at 12 years of age.
Once the diagnosis has been established, complete proctocolectomy with ileoanal anastomosis or colectomy with ileorectal anastomosis is recommended, usually before age 20 years. Ileorectal anastomosis affords superior bowel function but has a 5% risk of development of rectal cancer, and for that reason frequent sigmoidoscopy with fulguration of polyps is required. Upper endoscopic evaluation of the stomach, duodenum, and periampullary area should be performed every 1–3 years to look for adenomas or carcinoma. Large (> 2 cm) periampullary adenomas require surgical resection. Sulindac and COX-2 selective agents (celecoxib) have been shown to decrease the number and size of polyps in the rectal stump but not the duodenum.
Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31–43. [PMID: 23159591]
Voorham QJ et al. Tracking the molecular features of nonpolypoid colorectal neoplasms: a systematic review and meta-analysis. Am J Gastroenterol. 2013 Jul;108(7):1042–56. [PMID: 23649184]
Hamartomatous polyposis syndromes are rare and account for < 0.1% of colorectal cancers.
Peutz-Jeghers syndrome is an autosomal dominant condition characterized by hamartomatous polyps throughout the gastrointestinal tract (most notably in the small intestine) as well as mucocutaneous pigmented macules on the lips, buccal mucosa, and skin. The hamartomas may become large, leading to bleeding, intussusception, or obstruction. Although hamartomas are not malignant, gastrointestinal malignancies (stomach, small bowel, and colon) develop in 40–60%, breast cancer in 30–50%, as well as a host of other malignancies of nonintestinal organs (gonads, pancreas). The defect has been localized to the serine threonine kinase 11 gene, and genetic testing is available.
Familial juvenile polyposis is also autosomal dominant and is characterized by several (more than ten) juvenile hamartomatous polyps located most commonly in the colon. There is an increased risk (up to 50%) of adenocarcinoma due to synchronous adenomatous polyps or mixed hamartomatous-adenomatous polyps. Genetic defects have been identified to loci on 18q and 10q (MADH4 and BMPR1A). Genetic testing is available.
PTEN multiple hamartoma syndrome (Cowden disease) is characterized by hamartomatous polyps and lipomas throughout the gastrointestinal tract, trichilemmomas, and cerebellar lesions. An increased rate of malignancy is demonstrated in the thyroid, breast, and urogenital tract.
Beggs AD et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010 Jul;59(7):975–86. [PMID: 20581245]
Latchford AR et al. Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects. Fam Cancer. 2011 Sep;10(3):455–61. [PMID: 21503746]
ESSENTIALS OF DIAGNOSIS
Autosomally dominant inherited condition.
Caused by mutations in a gene that detects and repairs DNA base-pair mismatches, resulting in DNA microsatellite instability and inactivation of tumor suppressor genes.
Increased lifetime risk of colorectal cancer (50–80%), endometrial cancer (30–60%), and other cancers that may develop at young age.
Evaluation warranted in patients with personal history of early-onset colorectal cancer or family history of colorectal, endometrial, or other Lynch syndrome–related cancers at young age or in multiple members.
Diagnosis suspected by tumor tissue immunohistochemical staining for mismatch repair proteins or testing for microsatellite instability.
Diagnosis confirmed by genetic testing.
Lynch syndrome (also known as hereditary nonpolyposis colon cancer [HNPCC]) is an autosomal dominant condition in which there is a markedly increased risk of developing colorectal cancer as well as a host of other cancers, including endometrial, ovarian, renal or vesical, hepatobiliary, gastric, and small intestinal cancers. It is estimated to account for up to 3% of all colorectal cancers. Affected individuals have a 50–80% lifetime risk of developing colorectal carcinoma and a 30–60% lifetime risk of endometrial cancer. Unlike individuals with familial adenomatous polyposis, patients with HNPCC develop only a few adenomas, which may be flat and more often contain villous features or high-grade dysplasia. In contrast to the traditional polyp → cancer progression (which may take over 10 years), these polyps are believed to undergo rapid transformation over 1–2 years from normal tissue → adenoma → cancer. HNPCC and endometrial cancer tend to develop at an earlier age than sporadic, nonhereditary cancers (mean age 45–50 years). Compared with patients with sporadic tumors of similar pathologic stage, those with HNPCC tumors have improved survival. Synchronous or metachronous cancers occur within 10 years in up to 45% of patients.
HNPCC is caused by a defect in one of several genes that are important in the detection and repair of DNA base-pair mismatches: MLH1, MSH2, MSH6, and PMS2. Germline mutations in MLH1 andMSH2 account for almost 90% of the known mutations in families with HNPCC. Mutations in any of these mismatch repair genes result in a characteristic phenotypic DNA abnormality known as microsatellite instability.
A thorough family cancer history is essential to identify families that may be affected with HNPCC so that appropriate genetic and colonoscopic screening can be offered. Owing to the limitations of genetic testing for HNPCC and the medical, psychological, and social implications that such testing may have, families with suspected HNPCC should be evaluated first by a genetic counselor and should give informed consent in writing before genetic testing is performed. Patients whose families meet any of the revised “Bethesda criteria” have an increased likelihood of harboring a germline mutation in one of the mismatch repair genes and should be considered for genetic testing. The “Bethesda criteria” are (1) colorectal cancer under age 50; (2) synchronous or metachronous colorectal or HNPCC-associated tumor regardless of age (endometrial, stomach, ovary, pancreas, ureter and renal pelvis, biliary tract, brain); (3) colorectal cancer with one or more first-degree relatives with colorectal or HNPCC-related cancer, with one of the cancers occurring before age 50; (4) colorectal cancer with two or more second-degree relatives with colorectal or HNPCC cancer, regardless of age; (5) tumors with infiltrating lymphocytes, mucinous/signet ring differentiation, or medullary growth pattern in patients younger than 60 years. The Bethesda criteria identify approximately 70% of mutation-positive HNPCC families but overlook 30%. For this reason, expert guidelines have recommended that all colorectal cancers should undergo testing for Lynch syndrome with either immunohistochemistry or microsatellite instability and BRAF testing. Patients whose tumors test positive using one of these tests should be given genetic counseling before undergoing germline testing for gene mutations.
If genetic testing documents an HNPCC gene mutation, affected relatives should be screened with colonoscopy every year beginning at age 25 (or at age 5 years younger than the age at diagnosis of the youngest affected family member). If cancer is found, subtotal colectomy with ileorectal anastomosis (followed by annual surveillance of the rectal stump) should be performed. Women should undergo screening for endometrial and ovarian cancer beginning at age 25–35 years with pelvic examination, CA-125 assay, endometrial aspiration, and transvaginal ultrasound. Prophylactic hysterectomy and oophorectomy may be considered, especially in women of postchildbearing age. Similarly, consideration should be given for increased cancer surveillance in family members in proven or suspected HNPCC families who do not wish to undergo germline testing. (See Chapter 39 for Colorectal Cancer.)
Goodenberger M et al. Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 2011 Jul;45(6):488–500. [PMID: 21325953]
Limburg PJ et al. Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer. Clin Gastroenterol Hepatol. 2011 Jun;9(6):497–502. [PMID: 21056691]
Llor X. When should we suspect hereditary colorectal cancer syndrome? Clin Gastroenterol Hepatol. 2012 Apr;10(4):363–7. [PMID: 22178459]
(See Chapter 39 for Carcinoma of the Anus.)
ESSENTIALS OF DIAGNOSIS
Bright red blood per rectum.
Characteristic findings on external anal inspection and anoscopic examination.
Internal hemorrhoids are subepithelial vascular cushions consisting of connective tissue, smooth muscle fibers, and arteriovenous communications between terminal branches of the superior rectal artery and rectal veins. They are a normal anatomic entity, occurring in all adults, that contribute to normal anal pressures and ensure a water-tight closure of the anal canal. They commonly occur in three primary locations—right anterior, right posterior, and left lateral. External hemorrhoids arise from the inferior hemorrhoidal veins located below the dentate line and are covered with squamous epithelium of the anal canal or perianal region.
Hemorrhoids may become symptomatic as a result of activities that increase venous pressure, resulting in distention and engorgement. Straining at stool, constipation, prolonged sitting, pregnancy, obesity, and low-fiber diets all may contribute. With time, redundancy and enlargement of the venous cushions may develop and result in bleeding or protrusion.
Patients often attribute a variety of perianal complaints to “hemorrhoids.” However, the principal problems attributable to internal hemorrhoids are bleeding, prolapse, and mucoid discharge. Bleeding is manifested by bright red blood that may range from streaks of blood visible on toilet paper or stool to bright red blood that drips into the toilet bowl after a bowel movement. Uncommonly, bleeding is severe and prolonged enough to result in anemia. Initially, internal hemorrhoids are confined to the anal canal (stage I). Over time, the internal hemorrhoids may gradually enlarge and protrude from the anal opening. At first, this mucosal prolapse occurs during straining and reduces spontaneously (stage II). With progression over time, the prolapsed hemorrhoids may require manual reduction after bowel movements (stage III) or may remain chronically protruding (stage IV). Chronically prolapsed hemorrhoids may result in a sense of fullness or discomfort and mucoid perianal discharge, resulting in irritation and soiling of underclothes. Pain is unusual with internal hemorrhoids, occurring only when there is extensive inflammation and thrombosis of irreducible tissue or with thrombosis of an external hemorrhoid (see below).
External hemorrhoids are readily visible on perianal inspection. Nonprolapsed internal hemorrhoids are not visible but may protrude through the anus with gentle straining while the clinician spreads the buttocks. Prolapsed hemorrhoids are visible as protuberant purple nodules covered by mucosa. The perianal region should also be examined for other signs of disease such as fistulas, fissures, skin tags, condyloma, anal cancer, or dermatitis. On digital examination, uncomplicated internal hemorrhoids are neither palpable nor painful. Anoscopic evaluation, best performed in the prone jackknife position, provides optimal visualization of internal hemorrhoids.
Small volume rectal bleeding may be caused by anal fissure or fistula, neoplasms of the distal colon or rectum, ulcerative colitis or Crohn colitis, infectious proctitis, or rectal ulcers. Rectal prolapse, in which a full thickness of rectum protrudes concentrically from the anus, is readily distinguished from mucosal hemorrhoidal prolapse. Proctosigmoidoscopy or colonoscopy should be performed in allpatients with hematochezia to exclude disease in the rectum or sigmoid colon that could be misinterpreted in the presence of hemorrhoidal bleeding.
Most patients with early (stage I and stage II) disease can be managed with conservative treatment. To decrease straining with defecation, patients should be given instructions for a high-fiber diet and told to increase fluid intake with meals. Dietary fiber may be supplemented with bran powder (1–2 tbsp twice daily added to food or in 8 oz of liquid) or with commercial bulk laxatives (eg, Benefiber, Metamucil, Citrucel). Suppositories and rectal ointments have no demonstrated utility in the management of mild disease. Mucoid discharge may be treated effectively by the local application of a cotton ball tucked next to the anal opening after bowel movements.
Patients with stage I, stage II, and stage III hemorrhoids and recurrent bleeding despite conservative measures may be treated without anesthesia with injection sclerotherapy, rubber band ligation, or application of electrocoagulation (bipolar cautery or infrared photocoagulation). The choice of therapy is dictated by operator preference, but rubber band ligation is preferred due to its ease of use and high rate of efficacy. Major complications occur in < 2%, including pelvic sepsis, pelvic abscess, urinary retention, and bleeding. Recurrence is common unless patients alter their dietary habits. Edematous, prolapsed (stage IV) internal hemorrhoids, may be treated acutely with topical creams, foams, or suppositories containing various combinations of emollients, topical anesthetics, (eg, pramoxine, dibucaine), vasoconstrictors (eg, phenylephrine), astringents (witch hazel) and corticosteroids. Common preparations include Preparation H (several formulations), Anusol HC, Proctofoam, Nupercainal, Tucks, and Doloproct (not available in the United States).
Surgical excision (hemorrhoidectomy) is reserved for < 5–10% of patients with chronic severe bleeding due to stage III or stage IV hemorrhoids or patients with acute thrombosed stage IV hemorrhoids with necrosis. Complications of surgical hemorrhoidectomy include postoperative pain (which may persist for 2–4 weeks) and impaired continence.
Thrombosis of the external hemorrhoidal plexus results in a perianal hematoma. It most commonly occurs in otherwise healthy young adults and may be precipitated by coughing, heavy lifting, or straining at stool. The condition is characterized by the relatively acute onset of an exquisitely painful, tense and bluish perianal nodule covered with skin that may be up to several centimeters in size. Pain is most severe within the first few hours but gradually eases over 2–3 days as edema subsides. Symptoms may be relieved with warm sitz baths, analgesics, and ointments. If the patient is evaluated in the first 24–48 hours, removal of the clot may hasten symptomatic relief. With the patient in the lateral position, the skin around and over the lump is injected subcutaneously with 1% lidocaine using a tuberculin syringe with a 30-gauge needle. An ellipse of skin is then excised and the clot evacuated. A dry gauze dressing is applied for 12–24 hours, and daily sitz baths are then begun.
Lohsiriwat V. Hemorrhoids: from basic pathophysiology to clinical management. World J Gastroenterol. 2012 May 7;18(17):2009–17. [PMID: 22563187]
A number of organisms can cause inflammation of the anal and rectal mucosa. Proctitis is characterized by anorectal discomfort, tenesmus, constipation, and mucus or bloody discharge. Most cases of proctitis are sexually transmitted, especially by anal-receptive intercourse. Infectious proctitis must be distinguished from noninfectious causes of anorectal symptoms, including anal fissures or fistulae, perirectal abscesses, anorectal carcinomas, and inflammatory bowel disease (ulcerative colitis or Crohn disease).
Several organisms may cause infectious proctitis.
Gonorrhea may cause itching, burning, tenesmus, and a mucopurulent discharge, although many anorectal infections are asymptomatic. Rectal swab specimens should be taken during anoscopy for culture; Gram staining is unreliable. Cultures should also be taken from the pharynx and urethra in men and from the pharynx and cervix in women. Complications of untreated infections include strictures, fissures, fistulas, and perirectal abscesses. (For treatment, see Chapter 33.)
Anal syphilis may be asymptomatic or may lead to perianal pain and discharge. With primary syphilis, the chancre may be at the anal margin or within the anal canal and may mimic a fissure, fistula, or ulcer. Proctitis or inguinal lymphadenopathy may be present. With secondary syphilis, condylomata lata (pale-brown, flat verrucous lesions) may be seen, with secretion of foul-smelling mucus. Although the diagnosis may be established with dark-field microscopy or fluorescent antibody testing of scrapings from the chancre or condylomas, this requires proper equipment and trained personnel. The VDRL or RPR test is positive in 75% of primary cases and in 99% of secondary cases. (For treatment, see Chapter 34.)
Chlamydial infection may cause proctitis similar to gonorrheal proctitis; however, some infections are asymptomatic. It also may cause lymphogranuloma venereum, characterized by proctocolitis with fever and bloody diarrhea, painful perianal ulcerations, anorectal strictures and fistulas, and inguinal adenopathy (buboes). Previously rare in developed countries, an increasing number of cases have been identified among men who have sex with men. The diagnosis is established by serology, culture, or PCR-based testing of rectal discharge or rectal biopsy. Recommended treatment is doxycycline 100 mg orally twice daily for 21 days.
Herpes simplex virus is a common cause of anorectal infection. Symptoms occur 4–21 days after exposure and include severe pain, itching, constipation, tenesmus, urinary retention, and radicular pain from involvement of lumbar or sacral nerve roots. Small vesicles or ulcers may be seen in the perianal area or anal canal. Sigmoidoscopy is not usually necessary but may reveal vesicular or ulcerative lesions in the distal rectum. Diagnosis is established by viral culture, PCR, or antigen detection assays of vesicular fluid. Symptoms resolve within 2 weeks, but viral shedding may continue for several weeks. Patients may remain asymptomatic with or without viral shedding or may have recurrent mild relapses. Treatment of acute infection for 7–10 days with acyclovir, 400 mg, or famciclovir, 250 mg orally three times daily, or valacyclovir, 1 g twice daily, has been shown to reduce the duration of symptoms and viral shedding. Patients with AIDS and recurrent relapses may benefit from long-term suppressive therapy (seeChapter 31).
Condylomata acuminata (warts) are a significant cause of anorectal symptoms. Caused by the HPV, they may occur in the perianal area, the anal canal, or the genitals. Perianal or anal warts are seen in up to 25% of men who have sex with men. HIV-positive individuals with condylomas have a higher relapse rate after therapy and a higher rate of progression to high-grade dysplasia or anal cancer. The warts are located on the perianal skin and extend within the anal canal up to 2 cm above the dentate line (see Figure 6–31). Patients may have no symptoms or may report itching, bleeding, and pain. The warts may be small and flat or verrucous, or may form a confluent mass that may obscure the anal opening. Warts must be distinguished from condyloma lata (secondary syphilis) or anal cancer. Biopsies should be obtained from large or suspicious lesions. Treatment can be difficult. Sexual partners should also be examined and treated. The treatment of anogenital warts is discussed in Chapter 30. HPV vaccines have demonstrated efficacy in preventing anogenital warts and routine vaccination is now recommended for all children and adults 9–26 years old (see Chapters 1 and 30). Vaccination also should be considered in men who have sex with men. HIV-positive individuals with condylomas who have detectable serum HIV RNA levels should have anoscopic surveillance every 3–6 months.
Hoentjen F et al. Infectious proctitis: when to suspect it is not inflammatory bowel disease. Dig Dis Sci. 2012 Feb;57(2):269–73. [PMID: 21994137]
Palefsky JM et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011 Oct 27;365(17):1576–85. [PMID: 22029979]
Workowski KA et al; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010 Dec 17;59(RR-12):1–110. [PMID: 21160459]
There are five general requirements for bowel continence: (1) solid or semisolid stool (even healthy young adults have difficulty maintaining continence with liquid rectal contents); (2) a distensible rectal reservoir (as sigmoid contents empty into the rectum, the vault must expand to accommodate); (3) a sensation of rectal fullness (if the patient cannot sense this, overflow may occur before the patient can take appropriate action); (4) intact pelvic nerves and muscles; and (5) the ability to reach a toilet in a timely fashion.
Many patients complain of inability to control flatus or slight soilage of undergarments that tends to occur after bowel movements or with straining or coughing. This may be due to local anal problems such as prolapsed hemorrhoids that make it difficult to form a tight anal seal or isolated weakness of the internal anal sphincter, especially if stools are somewhat loose. Patients should be treated with fiber supplements to provide greater stool bulk. Coffee and other caffeinated beverages should be eliminated. The perianal skin should be cleansed with moist, lanolin-coated tissue (baby wipes) to reduce excoriation and infection. After wiping, loose application of a cotton ball near the anal opening may absorb small amounts of fecal leakage. Prolapsing hemorrhoids may be treated with band ligation or surgical hemorrhoidectomy. Control of flatus and seepage may be improved by Kegel perineal exercises. Conditions such as ulcerative proctitis that cause tenesmus and urgency, chronic diarrheal conditions, and irritable bowel syndrome may result in difficulty in maintaining complete continence, especially if a toilet is not readily available. Loperamide may be helpful to reduce urge incontinence in patients with loose stools and may be taken in anticipation of situations in which a toilet may not be readily available. The elderly may require more time or assistance to reach a toilet, which may lead to incontinence. Scheduled toileting and the availability of a bedside commode are helpful. Elderly patients with chronic constipation may develop stool impaction leading to “overflow” incontinence.
Complete uncontrolled loss of stool reflects a significant problem with central perception or neuromuscular function. Incontinence that occurs without awareness suggests a loss of central awareness (eg, dementia, cerebrovascular accident, multiple sclerosis) or peripheral nerve injury (eg, spinal cord injury, cauda equina syndrome, pudendal nerve damage due to obstetric trauma or pelvic floor prolapse, aging, or diabetes mellitus). Incontinence that occurs despite awareness and active efforts to retain stool suggests sphincteric damage, which may be caused by traumatic childbirth (especially forceps delivery), episiotomy, prolapse, prior anal surgery, and physical trauma.
Physical examination should include careful inspection of the perianal area for hemorrhoids, rectal prolapse, fissures, fistulas, and either gaping or a keyhole defect of the anal sphincter (indicating severe sphincteric injury or neurologic disorder). The perianal skin should be stimulated to confirm an intact anocutaneous reflex. Digital examination during relaxation gives valuable information about resting tone (due mainly to the internal sphincter) and contraction of the external sphincter and pelvic floor during squeezing. It also excludes fecal impaction. Anoscopy is required to evaluate for hemorrhoids, fissures, and fistulas. Proctosigmoidoscopy is useful to exclude rectal carcinoma or proctitis. Anal ultrasonography or pelvic MRI is the most reliable test for definition of anatomic defects in the external and internal anal sphincters. Anal manometry may also be useful to define the severity of weakness, to assess sensation, and to predict response to biofeedback training. In special circumstances, surface electromyography is useful to document sphincteric denervation and proctography to document perineal descent or rectal intussusception.
Patients who are incontinent only of loose or liquid stools are treated with bulking agents and antidiarrheal drugs (eg, loperamide, 2 mg before meals and prophylactically before social engagements, shopping trips, etc). Patients with incontinence of solid stool benefit from scheduled toilet use after glycerin suppositories or tap water enemas. Biofeedback training with anal sphincteric strengthening (Kegel) exercises (alternating 5-second squeeze and 10-second rest for 10 minutes twice daily) may be helpful in motivated patients to lower the threshold for awareness of rectal filling—or to improve anal sphincter squeeze function—or both. In 2012, the FDA approved a sterile gel (containing dextranomer and sodium hyaluronate) for submucosal injection into the proximal anal canal for the treatment of anal incontinence for patients who have not responded to conservative therapies, such as fiber supplements and antidiarrheal agents. This treatment is hypothesized to reduce incontinence episodes by bulking and narrowing the anal canal. In clinical trials, more than one-half of treated patients reported a > 50% reduction in the number of fecal incontinence episodes. The acceptance of this novel therapy in clinical practice is not yet clear. Operative management is seldom needed but should be considered in patients with major incontinence due to prior injury to the anal sphincter who have not responded to medical therapy.
Brown SR et al. Surgery for faecal incontinence in adults. Cochrane Database Syst Rev. 2013 Jul 2;7:CD001757. [PMID: 23821339]
Omar MI et al. Drug treatment for faecal incontinence in adults. Cochrane Database Syst Rev. 2013 Jun 11;6:CD002116. [PMID: 23757096]
Thin NN et al. Systematic review of the clinical effectiveness of neuromodulation in the treatment of faecal incontinence. Br J Surg. 2013 Oct;100(11):1430–47. [PMID: 24037562]
Anal fissures are linear or rocket-shaped ulcers that are usually < 5 mm in length. Most fissures are believed to arise from trauma to the anal canal during defecation, perhaps caused by straining, constipation, or high internal sphincter tone. They occur most commonly in the posterior midline, but 10% occur anteriorly. Fissures that occur off the midline should raise suspicion for Crohn disease, HIV/AIDS, tuberculosis, syphilis, or anal carcinoma. Patients complain of severe, tearing pain during defecation followed by throbbing discomfort that may lead to constipation due to fear of recurrent pain. There may be mild associated hematochezia, with blood on the stool or toilet paper. Anal fissures are confirmed by visual inspection of the anal verge while gently separating the buttocks. Acute fissures look like cracks in the epithelium. Chronic fissures result in fibrosis and the development of a skin tag at the outermost edge (sentinel pile). Digital and anoscopic examinations may cause severe pain and may not be possible. Medical management is directed at promoting effortless, painless bowel movements. Fiber supplements and sitz baths should be prescribed. Topical anesthetics (5% lidocaine; 2.5% lidocaine plus 2.5% prilocaine) may provide temporary relief. Healing occurs within 2 months in up to 45% of patients with conservative management. Chronic fissures may be treated with topical 0.2–0.4% nitroglycerin or diltiazem 2% ointment (1 cm of ointment) applied twice daily just inside the anus with the tip of a finger for 4–8 weeks or injection of botulinum toxin (20 units) into the internal anal sphincter. All of these treatments result in healing in 50–80% of patients with chronic anal fissure, but headaches occur in up to 40% of patients treated with nitroglycerin. Fissures recur in up to 40% of patients after treatment. Chronic or recurrent fissures benefit from lateral internal sphincterotomy; however, minor incontinence may complicate this procedure.
Nelson RL et al. Non surgical therapy for anal fissure. Cochrane Database Syst Rev. 2012 Feb 15;2:CD003431. [PMID: 22336789]
Nelson RL et al. Operative procedures for fissure in ano. Cochrane Database Syst Rev. 2011 Nov 9;(11):CD002199. [PMID: 22071803]
Sajid MS et al. Systematic review of the use of topical diltiazem compared with glyceryltrinitrate for the nonoperative management of chronic anal fissure. Colorectal Dis. 2013 Jan;15(1):19–26. [PMID: 22487078]
Yiannakopoulou E. Botulinum toxin and anal fissure: efficacy and safety systematic review. Int J Colorectal Dis. 2012 Jan;27(1):1–9. [PMID: 21822595]
The anal glands located at the base of the anal crypts at the dentate line may become infected, leading to abscess formation. Other causes of abscess include anal fissure and Crohn disease. Abscesses may extend upward or downward through the intersphincteric plane. Symptoms of perianal abscess are throbbing, continuous perianal pain. Erythema, fluctuance, and swelling may be found in the perianal region on external examination or in the ischiorectal fossa on digital rectal examination. Perianal abscesses are treated with local incision and drainage, while ischiorectal abscesses require drainage in the operating room. After drainage of an abscess, most patients are found to have a fistula in ano.
Fistula in ano most often arises in an anal crypt and is usually preceded by an anal abscess. In patients with fistulas that connect to the rectum, other disorders such as Crohn disease, lymphogranuloma venereum, rectal tuberculosis, and cancer should be considered. Fistulas are associated with purulent discharge that may lead to itching, tenderness, and pain. The treatment of Crohn-related fistula is discussed elsewhere in this chapter. Treatment of simple idiopathic fistula in ano is by surgical incision or excision under anesthesia. Care must be taken to preserve the anal sphincters. Surgical fistulotomy for treatment of complex (high, transphincteric) anal fissures carries a high risk of incontinence. Techniques for healing the fistula while preserving the sphincter include an endoanal advancement flap over the internal opening and insertion of a bioprosthetic plug into the fistula opening.
Abcarian H. Anorectal infection: abscess-fistula. Clin Colon Rectal Surg. 2011 Mar;24(1):14–21. [PMID: 22379401]
Shawki S et al. Idiopathic fistula-in-ano. World J Gastroenterol. 2011 Jul 28;17(28):3277–85. [PMID: 21876614]
Perianal pruritus is characterized by perianal itching and discomfort. It may be caused by poor anal hygiene associated with fistulas, fissures, prolapsed hemorrhoids, skin tags, and minor incontinence. Conversely, overzealous cleansing with soaps may contribute to local irritation or contact dermatitis. Contact dermatitis, atopic dermatitis, bacterial infections (Staphylococcus or Streptococcus), parasites (pinworms, scabies), candidal infection (especially in diabetics), sexually transmitted disease (condylomata acuminata, herpes, syphilis, molluscum contagiosum), and other skin conditions (psoriasis, Paget, lichen sclerosis) must be excluded. In patients with idiopathic perianal pruritus, examination may reveal erythema, excoriations, or lichenified, eczematous skin. Education is vital to successful therapy. Spicy foods, coffee, chocolate, and tomatoes may cause irritation and should be eliminated. After bowel movements, the perianal area should be cleansed with nonscented wipes premoistened with lanolin followed by gentle drying. A piece of cotton ball should be tucked next to the anal opening to absorb perspiration or fecal seepage. Anal ointments and lotions may exacerbate the condition and should be avoided. A short course of high-potency topical corticosteroid may be tried, although efficacy has not been demonstrated. Diluted capsaicin cream (0.006%) led to symptomatic relief in 75% of patients in a double-blind crossover study. (See Chapter 39 for Carcinoma of the Anus.)
Markell KW et al. Pruritus ani: etiology and management. Surg Clin North Am. 2010 Feb;90(1):125–35. [PMID: 20109637]