Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION VIII. Disorders of the Gastrointestinal System

ANSWERS

VIII-1.  The answer is E. (Chap. 292) Endoscopy, also known as esophagogastroduodenoscopy (EGD), is the best test for the evaluation of the proximal gastrointestinal tract. Because of high-quality images, disorders of color such as Barrett’s metaplasia, and mucosal irregularities are easily demonstrated. The sensitivity of endoscopy is superior to that of barium radiography for mucosal lesions. Because the endoscope has an instrumentation channel, biopsy specimens are easily obtained and dilation of strictures can also be performed. The only advantage that barium radiography confers is the absence of the requirement for sedation, which, in some populations at risk for conscious sedation, is an important consideration.

VIII-2.  The answer is E. (Chap. 292) Intermittent solid food dysphagia is a classic symptom in Schatzki’s ring in which a distal esophageal ring occurs at the squamocolumnar mucosal junction. The origin of these rings is unknown, and smaller rings with a lumen of greater than 13 mm are common in the general population (up to 15%). When the lumen is less than 13 mm, dysphagia may occur. Schatzki’s rings typically occur in persons older than 40 years and often cause “steakhouse syndrome” from meat getting stuck at the ring. The rings are easily treated with dilation. Plummer-Vinson syndrome also includes esophageal rings, but typically the rings occur in the proximal esophagus, are associated with iron-deficiency anemia, and occur in middle-aged women. Achalasia involves both solid and liquid dysphagia often with regurgitation. Adenocarcinoma often includes solid and liquid dysphagia at later stages. Most esophageal diverticulae are asymptomatic.

VIII-3.  The answer is B. (Chap. 292) Aside from the discomfort and local complications of gastroesophageal reflux disease (GERD), a number of other non-GI–related sites may have a complication related to it. Syndromes with a well-established association with GERD include chronic cough, laryngitis, asthma, and dental erosions. Other diseases have implicated GERD as potentially contributory, but the role of GERD is less well established. These include pharyngitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias, sleep apnea, and recurrent aspiration pneumonia.

VIII-4.  The answer is A. (Chap. 292) This patient has symptoms of esophagitis. In patients with HIV, various infections can cause this disease, including herpes simplex virus (HSV), cytomegalovirus (CMV), varicella-zoster virus (VZV), Candida, and HIV itself. The lack of thrush does not rule out Candida as a cause of esophagitis, and EGD is necessary for diagnosis. CMV classically causes serpiginous ulcers in the distal esophagus that may coalesce to form giant ulcers. Brushings alone are insufficient for diagnosis, and biopsies must be performed. Biopsies reveal intranuclear and intracytoplasmic inclusions with enlarged nuclei in large fibroblasts and endothelial cells. Given her notable swallowing symptoms, IV ganciclovir is the treatment of choice. Valganciclovir is an effective oral preparation. Foscarnet is useful in treating ganciclovir-resistant CMV. Herpes simplex virus manifests as vesicles and punched-out lesions in the esophagus, with the characteristic finding on biopsy of ballooning degeneration with ground-glass changes in the nuclei. It can be treated with acyclovir or foscarnet in resistant cases. Candida esophagitis has the appearance of yellow nodular plaques with surrounding erythema. Treatment usually requires fluconazole therapy. Finally, HIV alone can cause esophagitis that can be quite resistant to therapy. On EGD these ulcers appear deep and linear. Treatment with thalidomide or oral glucocorticoids is employed, and highly active antiretroviral therapy should be considered.

VIII-5.  The answer is D. (Chap. 293) The patient has a duodenal ulcer, which is almost universally due to H. pylori infection, although in a minority of cases NSAID use may either facilitate development or be the only identified cause. The patient was taking acetaminophen and not a traditional NSAID, making H. pylori–associated peptic ulcer disease the most likely cause of the findings. H. pylori infection is closely correlated with advancing age, low socioeconomic status, and low education levels. After initial infection, antral gastritis is very common, and in a portion of cases, duodenal or gastric ulcers form. Associated with these conditions is the development of gastric cancer or MALT lymphoma. Duodenal ulcers are rarely cancerous, although this is a not an uncommon finding in gastric cancers. After discovery of the ulcer, first-line therapy is eradication of H. pylori in addition to acid suppression.

VIII-6.  The answer is D. (Chap. 293) Noninvasive testing for H. pylori infection is recommended in patients with suggestive symptoms and no other indication for endoscopy, e.g., GI bleeding, atypical symptoms. Several tests have good sensitivity and specificity, including plasma serology for H. pylori14C or 13C-urea breath test, and the fecal H. pylori antigen test. Sensitivity and specificity are greater than 80% and greater than 90%, respectively, for serology, while the urea breath test and fecal antigen testing are greater than 90% for both. Serology is not useful for early follow-up after therapy completion, as antibody titers will take several weeks to months to fall. The urea breath test, which relies on the presence of urease secreted by H. pylori to digest the swallowed radioactive urea and liberate 14C or 13C as part of ammonia, is simple and rapid. It is useful for early follow-up, as it requires living bacteria to secrete urease and produce a positive test. The limitations to the test include the requirement for ingestion of radioactive materials, albeit low dose, and false-negative results with recent use of PPI, antibiotics, or bismuth compounds. Stool antigen testing is cheap and convenient, but is not established for proof of eradication.

VIII-7.  The answer is A. (Chap. 293) H. pylori should be eradicated in patients with documented peptic ulcer disease no matter the number of episodes, severity, presence of confounding factors (e.g., NSAID ingestion), or symptomatic status. Documented eradication of H. pylori is associated with substantially lower recurrence rates and symptom improvement. Treating patients with GERD who require long-term acid reduction therapy and the role of H. pylori eradication to prevent gastric cancer are controversial. Fourteen-day regimens are most effective. Shorter duration of therapy with current agents available has high recurrence rates. Dual-therapy regimens are not recommended because of eradication rates of less than 80%. A number of combinations are available (Table VIII-7). Triple-therapy regimens (one antacid plus two antibiotics) for 14 days have an eradication rate of 85–90%. Antibiotic resistance is the most common cause of failure to eradicate in compliant patients. Unfortunately, there is no currently available test for H. pylori sensitivity to direct therapy. Quadruple therapy should be reserved for patients with failure to eradicate after an effective initial course.

TABLE VIII-7 Regimens Recommended for Eradication of H. Pylori Infection

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VIII-8.  The answer is C. (Chap. 293) Fasting gastrin levels can be elevated in a variety of conditions including atrophic gastritis with or without pernicious anemia, G-cell hyperplasia, and acid suppressive therapy (gastrin levels increase as a consequence of loss of negative feedback). The diagnostic concern in a patient with persistent ulcers following optimal therapy is Zollinger-Ellison syndrome (ZES). The result is not sufficient to make a diagnosis because gastrin levels may be elevated in a variety of conditions. Elevated basal acid secretion also is consistent with ZES, but up to 12% of patients with peptic ulcer disease may have basal acid secretion as high as 15 meq/h. Thus, additional testing is necessary. Gastrin levels may go up with a meal (>200%), but this test does not distinguish G-cell hyperfunction from ZES. The best test in this setting is the secretin stimulation test. An increase in gastrin levels greater than 200 pg within 15 minutes of administering 2 μg/kg of secretin by IV bolus has a sensitivity and specificity of greater than 90% for ZES. Endoscopic ultrasonography is useful in locating the gastrin-secreting tumor once the positive secretin test is obtained. Genetic testing for mutations in the gene that encodes the menin protein can detect the fraction of patients with gastrinomas that are a mani festation of multiple endocrine neoplasia type I (Wermer’s syndrome). Gastrinoma is the second most common tumor in this syndrome following parathyroid adenoma, but its peak incidence is generally in the third decade.

VIII-9.  The answer is B. (Chap. 294) The patient presents with nonspecific gastrointestinal symptoms, but the presence of weight loss suggests malabsorption syndrome. Patients with lactose intolerance are usually able to relate symptoms to consumption of milk-based products and also report a strong history of crampy pain and flatulence. Therefore, a lactose-free diet is unlikely to be helpful. The patient does not have nocturnal diarrhea, which is commonly a feature of steatorrhea along with floating stools. In the absence of symptoms suggesting fat malabsorption, the first test should not be fecal fat measurement. As the patient has weight loss, irritable bowel syndrome is less likely, and an increase dietary fiber is unlikely to be useful. Finally, her symptoms may be consistent with celiac disease. The widespread availability of antibodies to gliadin, endomysial, and tTG can be easily measured in peripheral blood. Antiendomysial antibody has a 90–95% sensitivity and equal specificity, making it a reasonable first test in symptomatic individuals. The presence of the antibody is not diagnostic, however, and duodenal biopsy is recommended. Duodenal biopsy will show villous atrophy, absence or reduced height of villi, cuboidal appearance of surface epithelial cells, and increased lymphocytes and plasma cells in the lamina propria. These changes regress with complete removal of gluten from the diet.

VIII-10. The answer is B. (Chap. 294) Short bowel syndrome is a descriptive term referring to the many clinical complications that may occur after resection of varying lengths of the small bowel. Rarely, these complications may be due to congenital abnormalities of the small bowel. Most commonly in adults, short bowel syndrome occurs in mesenteric vascular disease, primary mucosal or submucosal disease (Crohn’s disease), and operations without preexisting small bowel disease such as trauma. Multiple factors contribute to diarrhea and steatorrhea including gastric acid hypersecretion, increased bile acids in the colon due to absent or decreased reabsorption in the small bowel, and lactose intolerance due to increased gastric acid secretion. Nonintestinal symptoms may include renal calcium oxalate calculi due to an increase in oxalate absorption by the large intestine with subsequent hyperoxaluria. This may be due to increased fatty acids in the colon that bind calcium, and thus calcium in the gut is not free to bind oxalate and free oxalate is absorbed in the large intestine. Increased bile acid pool size results in the generation of cholesterol gallstones from supersaturating in gallbladder bile. Gastric hypersecretion of acid is well described and thought to be due to loss of inhibition of gastric acid secretion because of absent short bowel to secrete inhibitory hormones. Coronary artery disease is not described as a complication of short bowel syndrome.

VIII-11. The answer is E. (Chap. 294) The patient presents with symptoms suggestive of Whipple’s disease with a chronic multisystem disease often including diarrhea/steatorrhea, migratory arthralgias, weight loss, and CNS or cardiac problems. Generally the presentation is of insidious onset, and dementia is a late finding and poor prognostic sign. The disease primarily occurs in middle-aged white males. The diagnosis requires small bowel biopsy and demonstration of PAS-positive macrophages within the small bowel. Small bacilli are often present and suggest the diagnosis of Whipple’s disease. Similar macrophages may be found in other affected organs, e.g., the CNS. Dilated lymphatics are present in patients with intestinal lymphangiectasia. Mononuclear cell infiltrate in the lamina propria is often demonstrated in patients with tropical sprue, and flat villi with crypt hyperplasia are the hallmark of celiac disease.

VIII-12. The answer is D. (Chap. 294) This patient has a stool osmolality gap (measured stool osmolality – calculated stool osmolality) of less than 50 mosmol/L, suggesting a secretory rather than an osmotic cause for diarrhea. Secretory causes of diarrhea include toxin-mediated diarrhea (cholera, enterotoxigenic Escherichia coli) and intestinal peptide–mediated diarrhea in which the major pathophysiology is a luminal or circulating secretagogue. The distinction between secretory diarrhea and osmotic diarrhea aids in forming a differential diagnosis. Secretory diarrhea will not decrease substantially during a fast and has a low osmolality gap. Osmotic diarrhea will generally decrease during a fast and has a high (>50 mosmol/L) osmolality gap. Celiac sprue, chronic pancreatitis, lactase deficiency, and Whipple’s disease all cause an osmotic diarrhea.

VIII-13. The answer is E. (Chaps. 294 and e37) Cobalamin malabsorption may occur due to disease at multiple anatomic sites extending from the stomach to the ileum. In the past, the Schilling test was utilized to assess cobalamin absorption, but this test is not currently commercially available. Cobalamin is primarily present in meat, but dietary deficiency is rare except in strict vegans. Dietary cobalamin is bound in the stomach to R-binder protein that is synthesized in salivary glands and stomach. The cobalamin–R binder complex requires an acid medium. Therefore, achlorhydria of any cause may result in the inability for splitting of cobalamin from food and binding to R-binder protein. Cobalamin absorption has an absolute requirement for intrinsic factor, which allows uptake by specific receptors in the ileum. Intrinsic factor is produced and released by gastric parietal cells. Thus pernicious anemia, the autoimmune atrophy of parietal cells, is a cause of cobalamin malabsorption. Pancreatic protease enzymes lyse the cobalamin–R binder protein complex to release cobalamin in the proximal intestine where it is bound to intrinsic factor for ileal absorption. Thus a deficiency of pancreatic enzymes, such as in chronic pancreatitis, can lead to cobalamin malabsorption. Finally, cobalamin-intrinsic factor is absorbed via an intact epithelium in the ileum. Inflammation (Crohn’s disease) or absence (surgical removal) of ileum will cause cobalamin malabsorption. The large intestine is not involved in cobalamin absorption; thus ulcerative colitis confined to the large intestine will not cause malabsorption.

VIII-14. The answer is D. (Chap. 295) The incidence of inflammatory bowel disease is highly influenced by ethnicity, location, and environmental factors. Both conditions have their highest incidence in the United Kingdom and North America, and the peak incidence has a bimodal distribution of age of presentation: 15–30 years and 60–80 years. The incidence of both ulcerative colitis and Crohn’s disease is highest among persons of the Ashkenazi Jewish population. Prevalence decreases progressively in non-Jewish white, African-American, Hispanic, and Asian populations. Cigarette smoking is associated with a decreased incidence of ulcerative colitis, but may cause Crohn’s disease. Oral contraceptive use is associated with a slightly higher incidence of Crohn’s disease, but not ulcerative colitis. Monozygotic twins are highly concordant for Crohn’s disease, but not ulcerative colitis.

VIII-15. The answer is C. (Chap. 295) Chronic bloody diarrhea associated with weight loss and systemic symptoms in a young person is highly suggestive of inflammatory bowel disease. Her surgical findings suggest discontinuous lesions, which is typical of Crohn’s disease. Ulcerative colitis, in contrast, typically affects the rectum and proceeds caudally from there without normal mucosa until the area of inflammation terminates. The presence of strictures and fissures further supports the diagnosis of Crohn’s disease, as these are not features of ulcerative colitis. Microscopically, both ulcerative colitis and Crohn’s disease may have crypt abscess and, although Crohn’s disease is more often transmural, full thickness disease may be present in ulcerative colitis. The hallmark of Crohn’s disease is granulomas that may be present throughout the bowel wall and involve the lymph nodes, mesentery, peritoneum, liver, and pancreas. Although pathognomonic for Crohn’s disease, granulomas are only found in about half of surgical resections. Flat villi are not always present in either disease and are more commonly found in isolation with celiac disease.

VIII-16. The answer is D. (Chap. 295) There are a number of dermatologic manifestations of inflammatory bowel disease (IBD), and each type of IBD has a particular predilection for different dermatologic conditions. This patient has pyoderma gangrenosum. Pyoderma gangrenosum can occur in up to 12% of patients with ulcerative colitis and is characterized by a lesion that begins as a pustule and progresses concentrically to surrounding normal skin. The lesions ulcerate with violaceous, heaped margins and surrounding erythema. They are typically found on the lower extremities. Often the lesions are difficult to treat and respond poorly to colectomy; similarly, pyoderma gangrenosum is not prevented by colectomy. Treatment commonly includes IV antibiotics, glucocorticoids, dapsone, infliximab, and other immunomodulatory agents. Erythema nodosum is more common in Crohn’s disease, and attacks correlate with bowel symptoms. The lesions are typically multiple red hot, tender nodules measuring 1–5 cm and are found on the lower legs and arms. Psoriasis is more common in ulcerative colitis. Finally, pyoderma vegetans is a rare disorder in inter-triginous areas reported to be a manifestation of inflammatory bowel disease in the skin.

VIII-17. The answer is D. [Chap. 295, Cochrane Database Syst Rev 2007 Oct 17; (4)] Despite being described as a clinical entity for over a century, the etiology of IBD remains cryptic. Current theory is related to an interplay between inflammatory stimuli in genetically predisposed individuals. Recent studies have identified a group of genes or polymorphisms that confer risk of IBD. Multiple microbiologic agents, including some that reside as “normal” flora, may initiate IBD by triggering an inflammatory response. Anaerobic organisms (e.g., Bacteroides and Clostridia spp.) may be responsible for the induction of inflammation. Other organisms, for unclear reasons, may have the opposite effect. These “probiotic” organisms include Lactobacillus spp., Bifidobacterium spp., Taenia suis, and Saccharomyces boulardiiShigellaEscherichia, and Campylobacter spp. are known to promote inflammation. Studies of probiotic therapy in adults and children with IBD have shown potential benefit for reducing disease activity.

VIII-18. The answer is D. (Chap. 295) Methotrexate, azathioprine, cyclosporine, tacrolimus, and anti-tumor necrosis factor (TNF) antibody are reasonable options for patients with CD, depending on the extent of macroscopic disease. Pneumonitis is a rare but serious complication of methotrexate therapy. Primary sclerosing cholangitis is an extraintestinal manifestation of inflammatory bowel disease (IBD). Pancreatitis is an uncommon complication of azathioprine, and IBD patients treated with azathioprine are at a fourfold increased risk of developing a lymphoma. Anti-TNF antibody therapy is associated with an increased risk of tuberculosis, disseminated histoplasmosis, and a number of other infections.

VIII-19. The answer is C (Chap. 296) Irritable bowel syndrome is characterized by the following: recurrence of lower abdominal pain with altered bowel habits over a period of time without progressive deterioration, onset of symptoms during periods of stress or emotional upset, absence of other systemic symptoms such as fever and weight loss, and small-volume stool without evidence of blood. Warning signs that the symptoms may be due to something other than irritable bowel syndrome include presentation for the first time in old age, progressive course from the time of onset, persistent diarrhea after a 48-hour fast, and presence of nocturnal diarrhea or steatorrheal stools. Each patient, except for patient C, has “warning” symptoms that should prompt further evaluation.

VIII-20. The answer is C. (Chap. 296) Although this patient has signs and symptoms consistent with IBS, the differential diagnosis is large. Few tests are required for patients who have typical IBS symptoms and no alarm features. In this patient, alarm features include anemia, an elevated ESR, and evidence of WBCs in the stool. Alarm features warrant further investigation to rule out other gastrointestinal disorders such as colonic pathology including diverticular disease or inflammatory bowel disease. In this case, colonoscopy to evaluate for luminal lesions and mucosal characteristics would be the logical first step. At this point, with the warning signs, empiric therapy for IBS is premature. Reassurance, stool bulking agents, and antidepressants are all therapies to consider if a patient does indeed have IBS.

VIII-21. The answer is D. (Chap. 296) Up to 80% of patients with irritable bowel syndrome (IBS) also have abnormal psychiatric features; however, no single psychiatric diagnosis predominates. The mechanism is not well understood but may involve altered pain thresholds. Although these patients are hypersensitive to colonic stimuli, this does not carry over to the peripheral nervous system. Functional brain imaging shows disparate activation in, for example, the mid-cingulate cortex, but brain anatomy does not discriminate IBS patients from those without IBS. An association between a history of sexual abuse and IBS has been reported. There is no reported association with sexually transmitted diseases. Patients with IBS do not have an increased risk of autoimmunity.

VIII-22. The answer is B. (Chap. 297) The patient presents with classic signs of diverticulitis with fever, abdominal pain that is usually left lower quadrant, anorexia or obstipation, and leukocytosis. This most commonly occurs in older individuals. Patients may present with acute abdomen due to perforation, though this occurs in less than 25% of cases. Plain radiographs of the abdomen are seldom helpful, but may rarely show the presence of an air–fluid level in the left lower quadrant indicating a giant diverticulum with impending perforation. CT with oral contrast is the diagnostic modality of choice with the following findings: sigmoid diverticula, thickened colonic wall greater than 4 mm, and inflammation within the pericolic space with or without the collection of contrast material or fluid. Abscesses, if present, will also be demonstrated on CT. Barium enema and colonoscopy should be avoided in acute diverticulitis because the insufflation of air or contrast material may lead to perforation. Although diverticular disease may result in hematochezia, these are generally not temporally linked to diverticulitis.

VIII-23. The answer is B. (Chap. 297) Medical management is appropriate for many patients with uncomplicated diverticular disease. Uncomplicated disease has fever, abdominal pain, leukocytosis, and anorexia/obstipation, while complicated disease includes that with abscess formation, perforation, strictures, or fistulae. Uncomplicated disease accounts for at least 75% of cases. Medical therapy generally involves bowel rest and antibiotics, usually trimethoprim/sulfamethoxazole or ciprofloxacin and metronidazole targeting aerobic gram-negative rods and anaerobic bacteria. Patients with more than two attacks of diverticulitis were previously thought to require surgical therapy, but newer data suggest that these patients do not have an increased risk of perforation and can continue medical management. Patients with immunosuppressive therapy, chronic renal failure, or collagen vascular disease have a fivefold higher risk of perforation during recurrent attacks. Surgical therapy is indicated for surgical low-risk patients with complicated disease.

VIII-24. The answer is B. (Chap. 297) Hemorrhoids can be internal or external; however, they are normally internal and may prolapse to the external position. Hemorrhoids are staged in the following manner: stage I, enlargement with bleeding; stage II, protrusion with spontaneous reduction; stage III, protrusion requiring manual reduction; stage IV, irreducible protrusion. Stage I, which this patient has, is treated with fiber supplementation, cortisone suppositories, and/or sclerotherapy. Stage II is treated with fiber and cortisone suppositories. Stage III patients are offered the prior three therapies and banding or operative hemorrhoidectomy. Stage IV patients benefit from fiber and cortisone therapy as well as operative hemorrhoidectomy. While substantial upper GI bleeding may result in hematochezia, the absence of suggestive signs/symptoms and the consistent findings of hemorrhoids do not indicate the need for upper endoscopy.

VIII-25. The answer is A. (Chap. 297) An anorectal abscess is an abnormal fluid-containing cavity in the anorectal region. Anorectal abscess results from an infection involving the glands surrounding the anorectal canal. The disease is more common in males with a peak incidence in the third to fifth decades. Patients with diabetes, inflammatory bowel disease, or who are immunocompromised are at increased risk for this condition. Perianal pain with defecation and fever are common presenting symptoms.

VIII-26. The answer is C. (Chap. 297) This patient has symptoms (social isolation), signs (foul odor), and risk factors (multiparity) for procidentia (rectal prolapse) and fecal incontinence. Procidentia is far more common in women than men and is often associated with pelvic floor disorders. It is not uncommon for these patients to become socially withdrawn and suffer from depression because of the associated fecal incontinence. The foul odor is a result of poor perianal hygiene due to the prolapsed rectum. Although depression in the elderly is an important medical problem, it is too premature in the evaluation of this patient to initiate medical therapy for depression. Occult malignancy and thyroid abnormalities may cause fecal incontinence and depression, but a physical examination would be diagnostic and avoid costly tests. Often patients are concerned that they have a rectal mass or carcinoma. Examination after an enema often makes the prolapse apparent. Medical therapy is limited to stool bulking agents or fiber. Surgical correction is the mainstay of therapy.

VIII-27. The answer is E. (Chap. 297) Surgical therapy is indicated in all low-risk surgical patients with complicated diverticular disease. Patients with at least two episodes of diverticulitis requiring hospitalization, with disease that does not respond to medical therapy, or who develop intra-abdominal complications are considered to have complicated disease. Complicating this patient’s relapse of diverticulitis is probably an enterovesicular fistula causing pneumaturia. Studies indicate that younger patients (<50 years) may experience a more aggressive form of the disease than older patients, and therefore waiting for more than two attacks before considering surgery is not recommended. Rifaximin is a poorly absorbed broad-spectrum antibiotic that, when combined with a fiber-rich diet, is associated with less frequent symptoms in patients with uncomplicated diverticular disease. Pneumaturia represents a potential surgical urgency and should not be confused with proteinuria.

VIII-28. The answer is A. (Chap. 298) Mesenteric ischemia is a relatively uncommon and highly morbid illness. Acute mesenteric ischemia is usually due to arterial embolus (usually from the heart) or from thrombosis in a diseased vascular bed. Major risk factors include age, atrial fibrillation, valvular disease, recent arterial catheterization, and recent myocardial infarction. Ischemia occurs when the intestines are inadequately perfused by the splanchnic circulation. This blood supply has extensive collateralization and can receive up to 30% of the cardiac output, making poor perfusion an uncommon event. Patients with acute mesenteric ischemia will frequently present with pain out of proportion to their initial physical examination. As ischemia persists, peritoneal signs and cardiovascular collapse will follow. Mortality is greater than 50%. While radiographic imaging can suggest ischemia, the gold standard for diagnosis is laparotomy.

VIII-29. The answer is C. (Chap. 300) Obstruction of the appendiceal lumen is believed to typically result in appendicitis. Although obstruction is most commonly caused by fecalith, which results from accumulation and inspissation of fecal matter around vegetable fibers, other causes have been described. These other potential causes include enlarged lymphoid follicles associated with viral infection (e.g., measles), inspissated barium, worms (e.g., pinworms, Ascaris and Taenia), and tumors such as carcinoma or carcinoid. Cholelithiasis is a common cause of acute pancreatitis.

VIII-30. The answer is E. (Chap. 300) Infection with Yersinia organisms may potentially cause acute appendicitis after obstruction occurs. High complement fixation antibody titers have been found in up to 30% of proven cases of acute appendicitis. Chronic appendicitis is quite rare, but may occur due to tuberculosis, amebiasis, and actinomycosis.

VIII-31. The answer is A. (Chap. 300) The patient presents with classic findings for acute appendicitis with anorexia, progressing to vague periumbilical pain, followed by localization to the right lower quadrant. Low-grade fever and leukocytosis are frequently present. Although acute appendicitis is primarily a clinical diagnosis, imaging modalities are frequently employed as the symptoms are not always classic. Plain radiographs are rarely helpful except when an opaque fecalith is found in the right lower quadrant (<5% of cases). Ultrasound may demonstrate an enlarged appendix with a thick wall, but is most useful to rule out ovarian pathology, tuboovarian abscess, or ectopic pregnancy. Recently both nonenhanced and contrasted CT have been shown be superior to ultrasound or plain radiograph in the diagnosis of acute appendicitis, with a positive predictive value of 95–97% and overall accuracy of 90–97%. Findings often include a thickened appendix with periappendiceal stranding and often the presence of a fecalith. Free air is uncommon, even in the case of a perforated appendix. Nonvisualization of the appendix on CT is associated with surgical findings of a normal appendix 98% of the time. Colonoscopy has no role in the diagnosis of acute appendicitis.

VIII-32 and VIII-33. The answers are C and D, respectively. (Chap. 300) The patient presents with several months of epigastric abdominal pain that is worse after eating. His symptoms are highly suggestive of peptic ulcer disease, with the worsening pain after eating suggesting a duodenal ulcer. The current presentation with acute abdomen and free air under the diaphragm diagnoses perforated viscus. Perforated gallbladder is less likely in light of the duration of symptoms and the absence of the significant systemic symptoms that often accompany this condition. As the patient is relatively young with no risk factors for mesenteric ischemia, necrotic bowel from an infarction is highly unlikely. Pancreatitis can have a similar presentation, but a pancreas cannot perforate and liberate free air. Peritonitis is most commonly associated with bacterial infection, but it can be caused by the abnormal presence of physiologic fluids, for example, gastric contents, bile, pancreatic enzymes, blood, or urine, or by foreign bodies. In this case peritonitis most likely is due to the presence of gastric juice in the peritoneal cavity after perforation of a duodenal ulcer has allowed these juices to leave the gut lumen.

VIII-34. The answer is A. (Chap. 301) The most common and most characteristic symptom of liver disease is fatigue. Unfortunately, it is also very nonspecific with little specific diagnostic utility. The fatigue in liver disease seems to improve in the morning and worsen throughout the day, but it can be intermittent. Jaundice is the hallmark of liver disease and is much more specific. Jaundice, however, is typically a sign of more advanced disease. Itching is also typically a symptom of more advanced disease and is more common in cholestatic causes of liver disease. Nausea often occurs in severe disease and can be accompanied by vomiting. Right upper quadrant pain is a less common symptom and indicates stretching of the liver capsule.

VIII-35. The answer is B. (Chap. 301) Women are more susceptible to the effects of alcohol on the liver. On average, drinking about two drinks daily can lead to chronic liver disease in women, whereas in men it is about three drinks daily. In individuals with alcoholic cirrhosis, the average daily alcohol intake is usually much higher, however, and heavy drinking for more than 10 years is typical before the onset of liver disease.

VIII-36. The answer is D. (Chap. 302) It is important to understand the patterns of laboratory abnormalities that indicate liver disease is present. One way to consider laboratory evaluation of liver disease is to consider three general categories of tests: tests based on excretory function of the liver, tests of biosynthetic activity of the liver, and coagulation factors. The most common tests of liver function fall under the category of tests based on the detoxification and excretory function of the liver. These include serum bilirubin, urine bilirubin, ammonia, and enzyme levels. Bilirubin can exist as a conjugated and an unconjugated form. The unconjugated form is often referred to as the indirect fraction. Elevations in the unconjugated form of bilirubin are not related to liver disease, but are most commonly seen in hemolysis and a number of benign genetic conditions such as Gilbert’s syndrome. In contrast, conjugated hyperbilirubinemia almost always indicates disease of the liver or biliary tract. Conjugated bilirubin is water soluble and is excreted in the urine, but unconjugated bilirubin is not. Rather, it binds to albumin in the blood. Therefore, bilirubinuria implies liver disease as well. Among the serum enzymes, it is useful to consider those that are associated with hepatocellular injury or those that reflect cholestasis. Alanine and aspartate aminotransferases are the primary enzymes that indicate hepatocyte injury. Alkaline phosphatase is the most common enzyme elevated in cholestasis, but bone disease also causes increased alkaline phosphatase. In some cases, one needs additional information to determine if the alkaline phosphatase is liver or bone in origin. Other tests that would be elevated in cholestatic liver disease are 5′-nucleotidase and γ-glutamyl transferase. The primary test of synthetic function is measurement of serum albumin. Coagulation factors can be directly measured, but impaired production of coagulation factors in liver disease is primarily inferred from elevations in prothrombin time.

VIII-37. The answer is A. (Chaps. 43 and 302) Diagnostic paracentesis is part of the routine evaluation in a patient with ascites. Fluid should be examined for its gross appearance, protein content, cell count and differential, and albumin. Cytologic and culture studies should be performed when one suspects infection or malignancy. The serum-ascites albumin gradient (SAG) offers the best correlation with portal pressure. A high gradient (>1.1 g/dL) is characteristic of uncomplicated cirrhotic ascites and differentiates ascites caused by portal hypertension from ascites not caused by portal hypertension in more than 95% of cases. Conditions that cause a low gradient include more “exudative” processes such as infection, malignancy, and inflammatory processes. Similarly, congestive heart failure and nephrotic syndrome cause high gradients. In this patient the SAG is 1.5 g/dL, indicating a high gradient. The low number of leukocytes and polymorphonuclear cells makes bacterial or tubercular infection unlikely. Chylous ascites often is characterized by an opaque milky fluid with a triglyceride level greater than 1000 mg/dL in addition to a low SAG.

VIII-38 and VIII-39. The answers are E and D, respectively. (Chap. 303) This patient is presenting with an asymptomatic and mild elevation in unconjugated hyperbilirubinemia that has occurred during a time of increased stress, fatigue, and likely decreased caloric intake. This presentation is characteristic of Gilbert’s syndrome (option E), an inherited disorder of bilirubin conjugation. In Gilbert’s syndrome, there is a mutation of the UGT1A1 gene that encodes bilirubin UDP-glucuronosyltransferase that leads to a reduction in activity on the enzyme to 10–35% of normal. This enzyme is of critical importance in the conjugation of bilirubin. Most of the time, there is no apparent jaundice, as the reduced ability to conjugate bilirubin is not reduced to a degree that leads to an elevation of bilirubin. However, during times of stress, fatigue, alcohol use, decreased caloric intake, or intercurrent illness, the enzyme can become overwhelmed, leading to a mild hyperbilirubinemia. Typical bilirubin levels are less than 4.0 mg/dL unless the individual is ill or fasting. Diagnosis usually occurs during young adulthood, and episodes are self-limited and benign. If a liver biopsy were to be performed, hepatic histology would be normal. No treatment is necessary as there are no long-term consequences of Gilbert’s syndrome, and patient reassurance is recommended. Other inherited disorders of bilirubin conjugation are Crigler-Najjar syndrome types I and II. Crigler-Najjar syndrome type I is a congenital disease characterized by more dramatic elevations in bilirubin as high as 20–45 mg/dL that is first diagnosed in the neonatal period and is present throughout life. This rare disorder was once fatal in early childhood due to the development of kernicterus. However, with phototherapy, individuals are now able to survive into adulthood, although neurologic deficits are common. Crigler-Najjar syndrome type II is similar to type I, but the elevations in bilirubin are less. Kernicterus is rare. This is due to the fact that there is some residual function of the bilirubin UDP-glucoronosyltransferase enzyme (<10%), which is totally absent in type I disease. Hemolysis is another frequent cause of elevated unconjugated bilirubin. Hemolysis can be caused by many factors including medications, autoimmune disorders, and inherited disorders, among others. However, the normal hematocrit, LDH, and haptoglobin eliminate hemolysis as a possibility. Dubin-Johnson syndrome is another congenital hyperbilirubinemia. However, it is a predominantly conjugated hyperbilirubinemia caused by a defect in biliary excretion from hepatocytes. Obstructive choledocholithiasis is characterized by right upper quadrant pain that is often exacerbated by fatty meals. The absence of symptoms or elevation in other liver function tests, especially alkaline phosphatase, also makes this diagnosis unlikely.

VIII-40. The answer is B. (Chap. 304) This patient presents with acute hepatitis, which has numerous etiologies. These include viruses, toxins/drugs, autoimmune diseases, metabolic disease, alcohol, ischemia, pregnancy, and other infectious etiologies including rickettsial diseases and leptospirosis. In this clinical scenario, the patient has risk factors for hepatitis A, B, and C infection, including having had sex with men and a prior history of injection drug use. All acute viral hepatitis presents with a similar clinical pattern, although incubation periods vary after exposure. The most common initial symptoms are fatigue, anorexia, nausea, vomiting, myalgias, and headache. These symptoms precede the onset of jaundice by about 1–2 weeks. Once jaundice develops, the prodromal symptoms regress. On physical examination, there is usually obvious icterus with an enlarged and tender liver. Splenomegaly can occur. AST and ALT are elevated with peak levels that are quite variable between 400–4000 U/L, and alkaline phosphatase levels are increased to a much lesser degree. Hyperbilirubinemia (levels from 5 to 20 mg/dL) occurs with primarily increased levels of conjugated bilirubin. Thus, it is important to recognize the patterns of antibody production in the viral hepatidities. Hepatitis A is an RNA virus that presents with acute hepatitis and is transmitted by the fecal-oral route. In the acute state, the IgM would be elevated, which is not seen in this scenario. Hepatitis B virus is a DNA virus with three common antigens that are tested serologically to determine the time course of the illness. These antigens are the surface antigen, the core antigen, and the e antigen, which is a nucleocapsid protein produced from the same gene as the core antigen but is immunologically distinct. Several distinct patterns can be observed. In acute hepatitis B, the core IgM, surface antigen, and e antigens are all positive, which is what is seen in this case. At this point, the patient is highly infectious with viral shedding in body fluids, including saliva. In a late acute infection, core IgG may be positive at the same time as surface and e-antigen positivity. In chronic hepatitis B, this same pattern of serologies is seen. If a patient has a prior infection without development of chronic hepatitis, the core IgG and surface antibody is positive. However, when immunity is obtained via vaccination, only the surface antibody (SAb) is positive; the e antigen and surface antigen will be negative since the patient was never infected. The variety of antigen-antibody positivities that can result are outlined in Table VIII-40. Acute hepatitis C often is detectable with contemporary immunoassays early in the disease when the aminotransferases are positive. Thus, a positive HCV antibody could indicate acute hepatitis C in this individual. However, given his clinical history of prior injection drug use and inability to donate blood, this likely indicates chronic hepatitis C infection. In some instances, ecstasy has been reported to cause drug-induced hepatitis, but given the viral serologies in this patient, this would be unlikely.

TABLE VIII-40 Commonly Encountered Serologic Patterns of Hepatitis B Infection

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VIII-41. The answer is E. (Chap. 304) No treatment is recommended for acute hepatitis B in most individuals because 99% of infected individual recover without assistance. Therefore, it would not be expected that an individual would derive any particular benefit from treatment. In severe acute hepatitis B, nucleoside analogues, including lamivudine, have been used successfully, although there are no clinical trial data to support such an approach. For acute hepatitis C, however, there is a growing body of literature to support the use of interferon α therapy to prevent the development of chronic hepatitis C. In a study of 44 patients, 98% had a sustained virologic response after 3 months, and therapy was continued for a total of 24 weeks. Many experts are now recommending that pegylated interferon α plus ribavirin be used as an alternative treatment for acute hepatitis C, although clinical trial data to support this approach is also lacking. Hepatitis A is an acute and self-limited illness that does not progress to chronic liver disease. Thus, no treatment is required. Anti–hepatitis A virus immunoglobulin can be given prophylactically following a known exposure to prevent the development of disease, but it is not helpful in established disease. There is no role for oral or IV corticosteroids in the treatment of acute viral hepatitis of any etiology. It has demonstrated no clinical benefit and may increase the risk of developing chronic disease.

VIII-42. The answer is E. (Chap. 304) In most instances, patients with any form of acute viral hepatitis do not succumb to fulminant liver failure. However, pregnant women are highly susceptible to fulminant hepatic failure in the setting of acute hepatitis E infection. This RNA virus is an enteric virus that is endemic in India, Asia, Africa, the Middle East, and Central America, and is spread via contaminated water supplies. Person-to-person spread is rare. Generally, the clinical course of hepatitis E infection is mild, and the rate of fulminant hepatitis is only 1–2%. However, in pregnant women, this is as high as 10–20%. For hepatitis A and C, the rate of fulminant hepatic failure is about 0.1% or less. It is slightly higher for hepatitis B at around 0.1–1%. Hepatitis D occurs as a coinfection with hepatitis B virus. When the two viruses are acquired simultaneously, the rate of fulminant hepatitis is about 5% or less. When hepatitis D is acquired in the setting of chronic hepatitis B infection, this number rises to 20%.

VIII-43. The answer is E. (Chap. 304) Hepatitis A is an acute, self-limited virus that is acquired almost exclusively via the fecal-oral route. It is classically a disease of poor hygiene and overcrowding. Outbreaks have been traced to contaminated water, milk, frozen raspberries and strawberries, green onions, and shellfish. Infection occurs mostly in children and young adults. It almost invariably resolves spontaneously and results in lifelong immunity. Fulminant disease occurs in 0.1% or less of cases, and there is no chronic form (in contrast to hepatitis B and C). Diagnosis is made by demonstrating a positive IgM antibody to HAV, as described in the case for this question. An IgG antibody to HAV indicates immunity that has been obtained by previous infection or vaccination. A small proportion of patients will experience relapsing hepatitis weeks to months after a full recovery from HAV infection. This too is self-limited. There is no approved antiviral therapy for hepatitis A disease. An inactivated vaccine has decreased the incidence of the disease, and it is recommended for all U.S. children, high-risk adults, and travelers to endemic areas. Passive immunization with immune globulin is also available, and it is effective in preventing clinical disease before exposure or during the early incubation period.

VIII-44. The answer is C. (Chap. 304) The current hepatitis B vaccine is a recombinant vaccine consisting of yeast-derived hepatitis B surface antigen particles. A strategy of vaccinating only high-risk individuals in the United States has been shown to be ineffective, and universal vaccination against hepatitis B is now recommended. Pregnancy is not a contraindication to vaccination. Vaccination should ideally be performed in infancy. Routine evaluation of hepatitis serologies is not cost-effective and is not recommended. The vaccine is given in three divided IM doses at 0, 1, and 6 months.

VIII-45. The answer is A. (Chap. 304) A clear distinction between viral etiologies of acute hepatitis cannot be made on clinical or epidemiologic features alone. This patient is at risk for many forms of hepatitis due to his lifestyle. Given his occupation in food services, from a public health perspective it is important to make an accurate diagnosis. Serologies must be obtained to make a diagnosis. While hepatitis C virus typically does not present as an acute hepatitis, this is not absolute. Hepatitis E virus infects men and women equally and resembles hepatitis A virus in clinical presentation. This patient should be questioned regarding IV drug use, and in addition to hepatitis serologies, an HIV test should be performed.

VIII-46. The answer is C. (Chaps. 302 and 304) Causes of extreme elevations in serum transaminases generally fall into a few major categories, including viral infections, toxic ingestions, and vascular/hemodynamic causes. Both acute hepatitis A and hepatitis B infections may be characterized by high transaminases. Fulminant hepatic failure may occur, particularly in situations in which acute hepatitis A occurs on top of chronic hepatitis C infection, or if hepatitis B and hepatitis D are cotransmitted. Most cases of acute hepatitis A or B infection in adults are self-limited. Hepatitis C is an RNA virus that does not typically cause acute hepatitis. However, it is associated with a high probability of chronic infection. Therefore, progression to cirrhosis and hepatoma is increased in patients with chronic hepatitis C infection. Extreme transaminitis is highly unlikely with acute hepatitis C infection. Acetaminophen remains one of the major causes of fulminant hepatic failure and is managed by prompt administration of N-acetylcysteine. Budd-Chiari syndrome is characterized by posthepatic thrombus formation. It often presents with jaundice, painful hepatomegaly, ascites, and elevated transaminases.

VIII-47. The answer is A. (Chap. 305) The liver is the primary site for the metabolism of many drugs and as such is susceptible to injury related to drugs and toxins. Indeed, the most common cause of acute hepatic failure is drug-induced liver injury. In general, it is useful to think of chemical hepatotoxicity within two broad categories: direct toxic effects and idiosyncratic reactions. Drugs or toxins that cause a direct toxic effect on the liver are either poisons themselves or are metabolized to toxic substances. With agents that cause a direct toxic effect on hepatocytes, there is a predictable, dose-related pattern of injury, and the time to effect is relatively short. The most common drug or toxin causing direct hepatocyte toxicity is acetaminophen. In therapeutic doses, acetaminophen does not cause liver injury. However, in higher doses, one of the metabolites of acetaminophen, N-acetyl-p-benzoquinone-imine (NAPQI), can overwhelm the glutathione stores of the liver that are necessary to convert NAPQI to a nontoxic metabolite and lead to hepatocyte necrosis. Other medications or toxins that cause direct hepatocyte injury are carbon tetrachloride, trichloroethylene, tetracycline, and the Amanita phalloides mushroom. More commonly known as the deathcap mushroom, ingestion of a single mushroom can contain enough hepatotoxin to be lethal. Idiosyncratic reactions are infrequent and unpredictable. There is no dose dependency, and the timing of hepatic injury has little association with the duration of drug treatment. Many drugs produce idiosyncratic reactions, and often it is difficult to known when an idiosyncratic reaction will lead to more serious liver failure. Often, mild increases in transaminase levels will occur, but over time adaptation leads to a return of liver enzymes to normal levels. In other instances, idiosyncratic reactions can lead to fulminant hepatic failure. Although rare, serious hepatic reactions can lead to medications being removed from the market. It is now recognized that many idiosyncratic reactions are related to metabolites leading to liver injury. However, it is likely that individual genetic variations in liver metabolism are the primary cause, and these are not predictable effects of the drug given our current state of knowledge. Common medications that can lead to idiosyncratic drug reactions include halothane, isothane, isoniazid, HMG-CoA reductase inhibitors, and chlorpromazine.

VIII-48. The answer is B. (Chap. 305) Acetaminophen overdose is the most common cause of acute liver failure and drug-induced liver failure that leads to transplantation. Acetaminophen is metabolized in the liver through two pathways. The primary pathway is a phase II reaction that produces nontoxic sulfate and glucuronide metabolites. The minor pathway occurs through a phase I reaction leading to the production of N-acetyl-p-benzoquinone-imine (NAPQI). This metabolite is directly toxic to liver cells and can lead to hepatocyte necrosis. With therapeutic use of acetaminophen, glutathione in the liver rapidly converts NAPQI to a nontoxic metabolite that is excreted in the urine. However, glutathione stores can become depleted in the setting of a large acute ingestion, chronic alcoholism, or the chronic ingestion of increased acetaminophen. In addition, because alcohol upregulates the first enzyme in the metabolic pathway, NAPQI accumulates more quickly in alcoholics. Given the known hepatotoxicity of acetaminophen, the U.S. Food and Drug Administration has recommended a maximum daily dose of no more than 3.25 g, with lower doses in individuals who use alcohol chronically. Acute ingestions of 10–15 g of acetaminophen is sufficient to cause clinical evidence of liver injury, and doses higher than 25 g can lead to fatal hepatic necrosis. The course of illness with acute acetaminophen ingestion follows a predictable pattern. Nausea, vomiting, abdominal pain, and shock occur within 4–12 hours after ingestion. Liver enzymes and synthetic function are normal during this time. Within 24–48 hours, these symptoms subside and are followed by evidence of hepatic injury. Maximal levels of aminotransferases can reach more than 10,000 U/L and may not occur until 4–6 days after ingestion. These patients must be followed carefully for fulminant hepatic failure with serious complications including encephalopathy, cerebral edema, marked coagulopathy, renal failure, metabolic acidosis, electrolyte abnormalities, and refractory shock. Levels of acetaminophen are predictive of the development of hepatotoxicity. The first level should be measured no sooner than 4 hours after a known ingestion. Levels should be plotted on a nomogram that relates acetaminophen levels to the time after ingestion. If at 4 hours the acetaminophen level is greater than 300 μg/mL, significant hepatotoxicity is likely. In the setting of overdose, it may be difficult to know the exact quantity and timing of the ingestion. For the patient presenting in the clinical scenario in this question, her acetaminophen level of greater than 300 μg/mL is quite concerning for a large ingestion, and treatment should be initiated immediately. The primary treatment for acetaminophen overdose is N-acetylcysteine. N-acetylcysteine acts to replete glutathione levels in the liver and also provides a reservoir of sulfhydryl groups to bind to the toxic metabolites. The typical dose of N-acetylcysteine is 140 mg/kg given as a loading dose, followed by 70 mg/kg every 4 hours for a total of 15–20 doses. This drug can also be given by continuous infusion. Activated charcoal or cholestyramine should only be given if the patient presents within 30 minutes after ingestion. Hemodialysis will not accelerate clearance of acetaminophen and will not protect the liver. Most patients with fulminant hepatic failure develop acute renal failure, often requiring hemodialysis. If a patient survives an acetaminophen overdose, there is usually no chronic liver injury.

VIII-49. The answer is E. (Chap. 306) The patient in this scenario has evidence of chronic active hepatitis B virus (HBV) infection. The presence of hepatitis B e–antigen (HBeAg) is indicative of ongoing viral replication, and individuals with HBeAg positivity typically have high levels of HBV DNA on testing. The spectrum of clinical infection in chronic hepatitis B is quite variable, and often individuals are asymptomatic with elevated liver enzymes identified on testing for other reasons. Thus, the decision to treat chronic HBV infection should not be based on clinical features. Most experts recommend treatment of HBeAg-positive chronic HBV infection with HBV DNA levels above 2 × 104 IU/mL if the ALT is elevated greater than twice the upper limit of normal. At present, many treatment options are available for the treatment of HBV infection and fall broadly into two categories: nucleoside analogues and interferons. While lamivudine and interferon were the first drugs used for the treatment of chronic HBV infection, these drugs have largely been supplanted by entecavir, tenofovir, and pegylated interferon as first-line therapy. When choosing among these agents, treatment can be tailored to specific patient preferences. Pegylated interferon achieves more rapid clearance of HBeAg and does not contribute to viral mutations. However, it is associated with systemic side effects that many find intolerable and requires weekly SC injections. In contrast, the oral agents often require a longer duration of therapy, are very well tolerated, and yield a more profound suppression of HBV DNA. However, mutations can occur with the use of these medications. Combination therapy does not appear to be more effective than single-drug therapy. The patient’s husband should also be screened for hepatitis B given the continued viremia.

VIII-50. The answer is E. (Chap. 306) Much information has been gained in recent decades about the progression and treatment of chronic hepatitis C virus (HCV) infection. Chronic hepatitis develops in about 85% of all individuals affected with HCV, and 20–25% of these individuals will progress to cirrhosis over about 20 years. Among those infected with HCV, about one-third of individuals will have normal or near-normal levels of aminotransferases, although liver biopsy demonstrates active hepatitis in as much as one-half of patients. Moreover, about 25% of individuals with normal aminotransferase levels at one point in time will develop elevations in these enzymes later, which can lead to progressive liver disease. Thus, normal aminotransferase levels at a single point in time do not definitively rule out the possibility that cirrhosis can develop. Progression to end-stage liver disease in individuals with chronic HCV hepatitis is more likely in older individuals and in those with a longer duration of infection, advanced histologic stage and grade, genotype 1 infection, more complex quasi-species diversity, concomitant other liver disease, HIV infection, and obesity. Among these factors, the best prognostic indicator for the development of progressive liver disease is liver histology. Specifically, patients who have moderate to severe inflammation or necrosis including septal or bridging fibrosis have the greatest risk of developing cirrhosis over the course of 10–20 years. Indications for therapy in those with HCV include detectable levels of HCV RNA, portal or bridging fibrosis on liver biopsy, or moderate to severe hepatitis on liver biopsy. Contraindications to treatment are age greater than 60 years, mild hepatitis on liver biopsy, and severe renal insufficiency. Standard therapy for HCV infection is pegylated interferon plus ribavirin. While genotypes 1 and 4 are less responsive to therapy than genotypes 2 and 3, the current research demonstrates a response rate of at least 40% for genotypes 1 and 4. Interestingly, even in individuals who fail to show a virologic or biochemical response, 75% will have histologic improvement on liver biopsy. The treatment course for genotypes 1 and 4 is a minimum of 48 weeks, whereas genotypes 2 and 3 can be treated for as little as 24 weeks. Once treatment has been started, a repeat HCV viral load should be assessed at 12 weeks. At this point, a 2-log drop in viral load is expected. Failure to achieve this level of response suggests that a sustained virologic response is unlikely to occur. With a drop of this magnitude, however, the likelihood of a sustained virologic response is about 66% at the end of therapy, and if the viral load is undetectable at 12 weeks, the chances of a sustained virologic response is more than 80%.

VIII-51. The answer is C. (Chap. 306) Three types of autoimmune hepatitis have been identified based on clinical and laboratory characteristics. Type I autoimmune hepatitis is a disorder typically seen in young women. The clinical characteristics can be variable from those of chronic hepatitis to fulminant hepatic failure, and many of the features are difficult to distinguish from other causes of chronic hepatitis. In some individuals, extrahepatic manifestations including fatigue, malaise, weight loss, anorexia, and arthralgias can be quite prominent. Liver enzymes are elevated but may not correlate with the clinical severity of disease. In more severe cases, elevations in serum bilirubin between 3 and 10 mg/dL can be seen. Hypoalbuminemia occurs in advanced disease, and hypergammaglobulinemia (>2.5 g/dL) is very common. The circulating antibody profile in autoimmune hepatitis depends to some extent on the type of hepatitis. Antinuclear antibodies are positive in a homogeneous staining pattern almost invariably in the disease, and rheumatoid factor is also common. Perinuclear antineutrophilic cytoplasmic antibody may be positive, but in an atypical fashion. Anti–smooth muscle antibodies and anti–liver/kidney microsomal antibodies are frequently seen, but these are nonspecific as other causes of chronic hepatitis can lead to positivity of these enzymes. Because of the lack of a specific autoimmune profile, the diagnostic criteria for autoimmune hepatitis incorporate a variety of clinical and laboratory features. Specific features that argue against this diagnosis include prominent alkaline phosphatase elevation, presence of mitochondrial antibodies, markers of viral hepatitis, history of hepatotoxic drugs or excess alcohol intake, and histologic evidence of bile duct injury or atypical biopsy features including excess hepatic iron, fatty infiltration, and viral inclusions. Antimitochondrial antibodies are typically seen in primary biliary cirrhosis.

VIII-52. The answer is D. (Chap. 306) In the course of acute hepatitis B, HBeAg positivity is common and usually transient. Persistence of HBeAg in the serum for 3 months or longer indicates an increased likelihood of development of chronic hepatitis B. In chronic hepatitis B, the presence of HBeAg in the serum indicates ongoing viral replication and increased infectivity. It is also a surrogate for inflammatory liver injury but not fibrosis. The development of antibody to HBeAg (anti-HBe) is indicative of the nonreplicative phase of HBV infection. During this phase, intact virions do not circulate and infectivity is less. Currently, quantification of HBV DNA with polymerase chain reaction allows risk stratification as fewer than 103 virions/μL is the approximate threshold for liver injury and infectivity.

VIII-53. The answer is C. (Chap. 307) This patient presents with severe acute alcoholic hepatitis. In its earliest form, alcoholic liver disease is marked by fatty infiltration of the liver. In more acute alcoholic hepatitis, there is hepatocyte injury with balloon degeneration and necrosis. Many cases of alcoholic hepatitis are asymptomatic. However, as in this case, the severe manifestations can include fever, jaundice, spider nevi, and abdominal pain that can mimic an acute abdomen in its severity. On laboratory examination, the AST is typically elevated more than the ALT, although the total transaminase levels are rarely greater than 400 U/L. Hyperbilirubinemia can be quite marked, with lesser elevation in alkaline phosphatase. Hypoalbuminemia and coagulopathy are poor prognostic indicators. A discriminate function (DF) can be calculated as (4.6 × the prolongation of prothrombin time above control) + serum bilirubin. A DF greater than 32 is associated with a poor prognosis and is an indication for the treatment of acute alcoholic hepatitis. The Model for End-Stage Liver Disease (MELD) score can also be used for prognostication in acute alcoholic hepatitis, with a score greater than 21 being an indication for treatment as well. This patient has a discriminate function of 73, indicating very severe disease and a poor prognosis. Complete abstinence from alcohol is imperative. Treatment with prednisone 40 mg daily (or prednisolone 32 mg daily) for 4 weeks should be initiated. Following the initial period, a taper should be achieved over a period of 4 weeks. Alternatively, pentoxifylline 400 mg three times daily for 4 weeks can also be used.

VIII-54. The answer is C. (Chap. 308) The clinical presentation is consistent with a cholestatic picture, which can present with painless jaundice and pruritus. The pruritus can be prominent and is present in 50% of individuals at the time of diagnosis. The pruritus is typically intermittent and worse in the evening. There is no other prominent association such as following hot baths or showers, which occurs in polycythemia vera. Other causes of pruritus outside of cholestasis include lymphoma and uncontrolled hypo-or hyperthyroidism. However, the laboratory studies in this patient clearly represent cholestasis with an elevation in alkaline phosphatase and bilirubin. The clinical characteristics are more commonly seen in primary biliary cirrhosis compared to primary sclerosis cholangitis, as the patient is a middle-aged female with positive antimitochondrial antibodies. In contrast, primary sclerosing cholangitis is associated with positive perinuclear antineutrophil cytoplasmic antibodies in 65% of patients, and 50% of individuals with primary sclerosing cholangitis have a history of ulcerative colitis.

VIII-55. The answer is B. (Chap. 308) Esophageal varices develop in the setting of portal hypertension associated most commonly with cirrhotic liver disease. In recent years, patients with cirrhosis have been commonly screened for varices by endoscopy, as about 33% will have varices on examination. Moreover, it is estimated that one-third of individuals with varices will develop bleeding. As this patient does not have medical care, it is unknown whether he has varices, but with the large volume of bleeding the patient has experienced, the treating physician should assume that the patient has variceal bleeding and act accordingly. The first step in the treatment of any individual with acute gastrointestinal bleeding is to ensure appropriate large-bore IV access, preferably in a large central vein or the antecubital fossae, and begin volume resuscitation. Volume resuscitation should be initiated with normal saline, and blood products should be administered when available. Once volume resuscitation has been initiated, emergent consultation with GI for endoscopic evaluation should be obtained. Endoscopic treatment should include esophageal band ligation, but in the acute setting, sclerotherapy may be used to control local bleeding with band ligation occurring at a future point in time. If emergent endoscopy is not an option, placement of a Sengstaken-Blakemore or Minnesota tube to tamponade bleeding should be employed. In addition, vasoconstricting agents are used to decrease splanchnic blood flow. While vasopressin was initially the agent of choice, cardiovascular ischemia can occur with the high doses used in GI bleeding. The currently preferred agents are octreotide or somatostatin by continuous infusion. Nonspecific beta blockers such as propranolol or nadolol are used for the primary or secondary prevention of variceal bleeding, but are not prescribed in the acute setting as these agents could worsen hypotension.

VIII-56. The answer is A. (Chap. 308) The cornerstone of the management of ascites is sodium restriction to less than 2 g daily. A common misconception is to institute a fluid restriction as well. However, this is neither effective nor necessary. With a sodium restriction to 2 g daily, most mild ascites can be managed quite well. If sodium restriction alone fails to correct ascites, then initiation of diuretics is required. Spironolactone at a dose of 100–200 mg daily is the initial diuretic used for ascites and can be titrated as high as 400–600 mg daily if tolerated. Loop diuretics can be added to spironolactone. The typical agent is furosemide beginning at 40–80 mg daily with the maximum doses being about 120–160 mg daily. Care must be taken to avoid renal dysfunction with loop diuretics, and higher doses may not be tolerated. If ascites is refractory to these treatments, transjugular intrahepatic portosystemic shunts (TIPS) can be considered. This procedure creates a portocaval shunt be introducing an expandable metal stent from the hepatic veins through the substance of the liver into the portal veins, creating a direct portocaval shunt. Thus, TIPS decreases portal pressures to decrease ascites and the risk of variceal bleeding. However, hepatic encephalopathy typically worsens following TIPS.

VIII-57. The answer is A. (Chap. 308) Severe right-sided heart failure may lead to chronic liver injury and cardiac cirrhosis. Elevated venous pressure leads to congestion of the hepatic sinusoids and of the central vein and centrilobular hepatocytes. Centrilobular fibrosis develops, and fibrosis extends outward from the central vein, not the portal triads. Gross examination of the liver shows a pattern of “nutmeg liver.” Although transaminases are typically mildly elevated, severe congestion, particularly associated with hypotension, may result in dramatic elevation of AST and ALT 50- to 100-fold above normal. Budd-Chiari syndrome, or occlusion of the hepatic veins or inferior vena cava, may be confused with congestive hepatopathy. However, the signs and symptoms of congestive heart failure are absent in patients with Budd-Chiari syndrome, and these patients can be easily distinguished clinically from those with heart failure. Venoocclusive disease may result from hepatic irradiation and high-dose chemotherapy in preparation for hematopoietic stem cell transplantation. It is not a typical complication of liver transplantation. Although echocardiography is a useful tool for assessing left and right ventricular function, findings may be unimpressive in patients with constrictive pericarditis. A high index of suspicion for constrictive pericarditis (e.g., prior episodes of pericarditis, mediastinal irradiation) should lead to a right-sided heart catheterization with demonstration of “square root sign,” which is the limitation of right heart filling pressure in diastole that is suggestive of restrictive cardiomyopathy. Cardiac magnetic resonance imaging may also be helpful in determining which patients should proceed to cardiac surgery.

VIII-58. The answer is B. (Chap. 308) The presence of cirrhosis in an elderly woman with no prior risk factors for viral or alcoholic cirrhosis should raise the possibility of primary biliary cirrhosis (PBC). It is characterized by chronic inflammation and fibrous obliteration of intrahepatic ductules. The cause is unknown, but autoimmunity is assumed, as there is an association with other autoimmune disorders, such as autoimmune thyroiditis, CREST syndrome, and the sicca syndrome. The vast majority of patients with symptomatic disease are women. The antimitochondrial antibody test (AMA) is positive in over 90% of patients with PBC and only rarely is positive in other conditions. This makes it the most useful initial test in the diagnosis of PBC. Since there are false positives, if AMA is positive a liver biopsy is performed to confirm the diagnosis. The 24-hour urine copper collection is useful in the diagnosis of Wilson’s disease. Hepatic failure from Wilson’s disease typically occurs before age 50. Hemochromatosis may result in cirrhosis. It is associated with lethargy, fatigue, loss of libido, discoloration of the skin, arthralgias, diabetes, and cardiomyopathy. Ferritin levels are usually increased, and the most suggestive laboratory abnormality is an elevated transferrin saturation percentage. Although hemochromatosis is a possible diagnosis in this case, PBC is more likely in light of the clinical scenario. Although chronic hepatitis B and hepatitis C are certainly in the differential diagnosis and must be ruled out, they are unlikely because of the patient’s history and lack of risk factors.

VIII-59. The answer is D. (Chap. 309) This patient presents with nonalcoholic fatty liver disease (NAFLD) that has progressed to cirrhosis. It is now commonly thought that many individuals previously identified as having cryptogenic cirrhosis had NAFLD as a cause of end-stage liver disease. With the rising prevalence of obesity in the United States and Europe, NAFLD is expected to continue to rise. At present, the prevalence of NAFLD is estimated between to be 14–20%. Of these individuals, 30–40% with nonalcoholic steato-hepatitis will develop advanced fibrosis and 10–15% will develop outright cirrhosis. Most patients diagnosed with NAFLD are asymptomatic with incident note of elevated liver enzymes found on testing for other reasons. The ALT is typically slightly higher than the AST, and both enzymes are only mildly elevated. In most instances the ALT and AST are only 1.5–2 times the upper limit of normal. NAFLD often accompanies other components of the metabolic syndrome, with insulin resistance being a common link between these disorders. The diagnosis of NAFLD requires a careful history and examination to rule out other disorders. Alcohol intake should be less than 20 g/d. Comprehensive testing should include serologies for viral hepatitis, iron studies, ceruloplasmin, α1 antitrypsin levels, and autoimmune serologies. Liver biopsy most commonly shows macrovesicular steatosis with a mixed inflammatory infiltrate in a lobular distribution. The fibrosis that occurs has a characteristic perivenular and perisinusoidal distribution. In cirrhotic patients, steatosis may not be seen, but can recur following transplant. The only known effective treatment for NAFLD is weight loss and exercise. Thiazolidinediones are currently being studied given their effects on insulin resistance. In addition, ongoing research into statins and ursodeoxycholic acid is being undertaken, but no specific medication can be recommended at this point for patients with NAFLD.

VIII-60. The answer is C. (Chap. 310) In the United States, over 6000 individuals undergo liver transplants yearly. However, the demand for organs far outpaces the supply with a waiting list of over 16,000 individuals. The most common reasons for liver transplant are alcoholic cirrhosis and chronic hepatitis C infection. When evaluating someone for liver transplantation, it is important to ensure that the patient is an appropriate candidate. For individuals with alcoholic cirrhosis, sustained abstinence and recovery need to be demonstrated, although the recidivism rate is as high as 25% after transplantation. Absolute contraindications to liver transplant include uncontrolled infection, active substance or alcohol abuse, extrahepatobiliary malignancy (excluding nonmelanoma skin cancer), metastatic malignancy to the liver, AIDS, or life-threatening or advance systemic disease. Cholangiocarcinoma almost invariably recurs following liver transplantation. Thus, it is now considered a contraindication to transplant. While primarily performed in children, living donor transplantation is increasingly being considered in adults given the poor availability of cadaveric organs. In living donor transplantation, typically the right lobe of the liver is taken from a suitable healthy donor. Currently, living donor transplantation accounts for 4% of all liver transplants. It is certainly not without risk. The average healthy donor will be medically disabled for at least 10 weeks, and the risk of death for the donor is 0.2–0.4%. Individuals receiving all forms of liver transplant have demonstrated increasing survival over the past decades. The current 5-year survival rate is more than 60%. Following transplantation, however, rejection, infection, and recurrence of primary disease can occur. For chronic hepatitis B infection, reinfection of the transplant frequently occurs, but this may be reduced to as little as 35% with post-transplantation treatment with hepatitis B immunoglobulin. For hepatitis C, reinfection is universal and is associated with the development of allograft cirrhosis in 20–30% of patients within 5 years. Autoimmune diseases can also recur in the transplanted liver, although it can be difficult to differentiate between the autoimmune disease and rejection. Wilson’s disease and α1antitrypsin deficiency, however, do not recur following transplantation.

VIII-61. The answer is E. (Chap. 310) The patient has advanced cirrhosis with a high risk of mortality, as evidenced by his episode of spontaneous bacterial peritonitis. His diabetes and remote skin cancer (since it was a basal cell carcinoma, not melanoma) are not absolute contraindications for liver transplantation, but active alcohol abuse is. The other absolute contraindications to transplantation are life-threatening systemic disease, uncontrolled infections, preexisting advanced cardiac or pulmonary disease, metastatic malignancy, and life-threatening congenital malignancies. Ongoing drug or alcohol abuse is an absolute contraindication, and patients who would otherwise be suitable candidates should immediately be referred to appropriate counseling centers to achieve abstinence. Once that is achieved for an acceptable period of time, transplantation can be considered. Indeed, alcoholic cirrhosis accounts for a substantial proportion of the patients who undergo liver transplantation.

VIII-62. The answer is B. (Chap. 311) In the National Health and Nutrition Examination Survey, the prevalence of gallstone disease in the United States was 7.9% in men and 16.6% in women. While the disease is quite prevalent, not all patients with gallstone disease require cholecystectomy. It is estimated that 1–2% of patients with asymptomatic gallstone disease will develop complications that will require surgery yearly. Therefore, it is important to know which patients with asymptomatic gallstones require referral for surgery. The first factor to consider is whether the patient has symptoms that are caused by gallstones and whether they are frequent enough and severe enough to necessitate surgery. Commonly called biliary colic, the classic symptoms of gallstone disease are right upper quadrant pain and fullness that begins suddenly and can last as long as 5 hours. Nausea and vomiting can accompany the episode. Vague symptoms of epigastric fullness, dyspepsia, and bloating following meals should not be considered biliary colic. A second factor that would be considered in recommending a patient for cholecystectomy is whether the patient has a prior history of complications of gallstone disease such as pancreatitis or acute cholecystitis. A final factor that would lead to the recommendation for cholecystectomy is the presence of anatomical factors that would increase the likelihood of complications such as a porcelain gallbladder or congenital abnormalities of the biliary tract. Individuals with very large stones (>3 cm) would also need to be considered carefully for cholecystectomy. Ursodeoxycholic acid can be used in some instances to dissolve gallstones. It acts to decrease the cholesterol saturation of bile and also allows the dispersion of cholesterol from stones by producing a lamellar crystalline phase. It is only effective, however, in individuals with radiolucent stones measuring less than 10 mm.

VIII-63. The answer is D. (Chap. 311) A practitioner needs to have a high index of suspicion for acalculous cholecystitis in critically ill patients who develop decompensation during the course of treatment for the underlying disease and have no other apparent source of infection. Some predisposing conditions for the development of acalculous cholecystitis include serious trauma or burns, postpartum following prolonged labor, prolonged parenteral hyperalimentation, and the postoperative period following orthopedic and other major surgical procedures. The clinical manifestations of acalculous cholecystitis are identical to calculous disease, but the disease is more difficult to diagnose. Ultrasonography and CT scanning typically only show biliary sludge, but they may demonstrate large and tense gallbladders. Hepatobiliary scintigraphy often shows delayed or absent gallbladder emptying. Successful management relies on accurate and early diagnosis. In critically ill patients, a percutaneous cholecystostomy may be the safest immediate procedure to decompress an infected gallbladder. Once the patient is stabilized, early elective cholecystectomy should be considered. Metronidazole to provide anaerobic coverage should be added, but this would not elucidate or adequately treat the underlying condition.

VIII-64. The answer is C. (Chap. 311) Gallstones are very common, particularly in Western countries. Cholesterol stones are responsible for 80% of cases of cholelithiasis; pigment stones account for the remaining 20%. Cholesterol is essentially water insoluble. Stone formation occurs in the setting of factors that upset cholesterol balance. Obesity, cholesterol-rich diets, high-calorie diets, and certain medications affect the biliary secretion of cholesterol. Intrinsic genetic mutations in certain populations may affect the processing and secretion of cholesterol in the liver. Pregnancy results in both an increase in cholesterol saturation during the third trimester and changes in gallbladder contractility. Pigment stones are increased in patients with chronic hemolysis, cirrhosis, Gilbert’s syndrome, and disruptions in the enterohepatic circulation. Although rapid weight loss and low-calorie diets are associated with gallstones, there is no evidence that a high-protein diet confers an added risk of cholelithiasis.

VIII-65. The answer is B. (Chaps. 42 and 311) The clinical presentation is consistent with a cholestatic picture. Painless jaundice always requires an extensive workup, as many of the underlying pathologies are ominous and early detection and intervention often offers the only hope for a good outcome. The gallbladder showed no evidence of stones and the patient shows no evidence of clinical cholecystitis, and so a hepatobiliary iminodiacetic acid (HIDA) scan is not indicated. Similarly, antibiotics are not necessary at this point. The cholestatic picture without significant elevation of the transaminases on the liver function tests makes acute hepatitis unlikely. Antimitochondrial antibodies are elevated in cases of primary biliary cirrhosis (PBC), which may present in a similar fashion. However, PBC is far more common in women than in men, and the average age of onset is the fifth or sixth decade. The lack of an obvious lesion on CT scan does not rule out a source of the cholestasis in the biliary tree. Malignant causes such as cholangiocarcinoma and tumor of the ampulla of Vater, and nonmalignant causes such as sclerosing cholangitis and Caroli’s disease may be detected only by direct visualization with endoscopic retrograde cholangiopancreatography (ERCP). ERCP is useful both diagnostically and therapeutically, as stenting procedures may be done to alleviate the obstruction.

VIII-66. The answer is A. (Chap. 313) The most common cause of acute pancreatitis in the United States is gallstones causing common bile duct obstruction. Although bile duct obstruction may be demonstrated on technetium HIDA scan, right upper quadrant ultrasound is preferred for ease, demonstration of gallstones in the gallbladder, and demonstration of obstructed bile duct. Alcohol is the second most common cause, followed by complications of endoscopic retrograde cholangiopancreatography (ERCP). Hypertriglyceridemia accounts for 1–4% of cases with triglyceride levels usually greater than 1000 mg/dL. Other potential causes of pancreatitis include trauma, postoperative states, drugs such as valproic acid, anti-HIV medications, estrogens, and sphincter of Oddi dysfunction. Additionally, there are a number of rare causes that have been described. The most judicious first step in evaluation is to test for gallstones and pursue more rare causes after the most common cause has been ruled out.

VIII-67. The answer is A. (Chap. 313) Physical examination in acute pancreatitis commonly shows an uncomfortable patient often with low-grade fever, tachycardia, and hypotension. Abdominal tenderness and muscle rigidity are often present to varying degrees. Cullen’s sign is a faint blue discoloration around the umbilicus that may occur as the result of hemoperitoneum. Turner’s sign is blue-red-purple or green-brown discoloration of the flanks from tissue catabolism of hemoglobin. Both of these signs indicate the presence of severe necrotizing pancreatitis.

VIII-68. The answer is E. (Chap. 313) The BISAP (Bedside Index of Severity in Acute Pancreatitis) score has recently replaced Ranson’s criteria and APACHE II severity scores as the recommended modality to assess the severity of pancreatitis due to the cumbersome nature of the prior scores and the requirement of prior scores to collect large amounts of clinical and laboratory data over time. Furthermore, the APACHE II and Ranson’s scoring mechanisms did not have acceptable positive and negative predictive values in predicting severe acute pancreatitis. The BISAP score incorporates five variables in determining severity: BUN greater than 35 mg/dL, impaired mental status, presence of SIRS, age above 60 years, and pleural effusion on radiography. The presence of three or more of these factors is associated with substantially increased risk for in-hospital mortality. Additional risk factors initially predicting severity include BMI of 30 or above and comorbid disease.

VIII-69. The answer is E. (Chap. 313) Several trials over the last several decades have demonstrated that there is no role for prophylactic antibiotics in the management of either interstitial or necrotizing pancreatitis. Antibiotics are recommended for only patients who appear septic at presentation while awaiting the results of culture data. If cultures are negative, antibiotics should be discontinued to decrease the risk of the development of fungal superinfection. Similarly, several drugs have been evaluated in the treatment of acute pancreatitis and found to be of no benefit. These drugs include H2 blockers, glucagon, protease inhibitors such as aprotinin, glucocorticoids, calcitonin, nonsteroidal anti-inflammatory drugs, and lexipafant, a platelet-activating factor inhibitor. A recent meta-analysis of somatostatin, octreotide, and the antiprotease gabexate mesylate in the therapy of acute pancreatitis suggested a reduced mortality rate but no change in complications with octreotide, and no effect on mortality but reduced pancreatic damage with gabexate.

VIII-70. The answer is C. (Chap. 313) Persistent inflammatory changes in the pancreas may remain for weeks to months after an episode of acute pancreatitis. Similarly, there may be prolonged elevation of amylase and lipase. In this regard, persistent changes on CT or persistent pancreatic enzyme elevation should not discourage clinicians from feeding hungry patients with acute pancreatitis. Although there had been prior concern that feeding patients with pancreatitis may exacerbate pancreatic inflammation, this has not been borne out. Similarly, enteral feeding with a nasojejunal tube in patients with acute pancreatitis has been demonstrated to have fewer infectious complications than feeding with total parenteral nutrition. Because of this, nasogastric feeding is the preferred method of nutritional support in acute pancreatitis. Enteral feeding also helps to maintain the integrity of the intestinal tract in acute pancreatitis.

VIII-71. The answer is D. (Chap. 313) The pathophysiology of acute pancreatitis evolves in three phases. During the initial phase, pancreatic injury leads to intrapancreatic activation of digestive enzymes with subsequent autodigestion and acinar cell injury. Acinar injury is primarily attributed to activation of zymogens (proenzymes), particularly trypsinogen, by lysosomal hydrolases. Once trypsinogen is converted to trypsin, the activated trypsin further perpetuates the process by activating other zymogens to further autodigestion. The inflammation initiated by intrapancreatic activation of zymogens leads to the second phase of acute pancreatitis, with local production of chemokines that causes activation and sequestration of neutrophils in the pancreas. Experimental evidence suggests that neutrophilic inflammation can also cause further activation of trypsinogen, leading to a cascade of increasing acinar injury. The third phase of acute pancreatitis reflects the systemic processes that are caused by release of inflammatory cytokines and activated proenzymes into the systemic circulation. This process can lead to the systemic inflammatory response syndrome with acute respiratory distress syndrome, extensive third-spacing of fluids, and multiorgan failure.

VIII-72. The answer is D. (Chap. 313) Chronic pancreatitis is a common disorder in any patient population with relapsing acute pancreatitis, especially patients with alcohol dependence, pancreas divisum, and cystic fibrosis. The disorder is notable for both endocrine and exocrine dysfunction of the pancreas. Often diabetes ensues as a result of loss of islet cell function; though insulin-dependent, it is generally not as prone to diabetic ketoacidosis or coma as are other forms of diabetes mellitus. As pancreatic enzymes are essential to fat digestion, their absence leads to fat malabsorption and steatorrhea. In addition, the fat-soluble vitamins, A, D, E, and K, are not absorbed. Vitamin A deficiency can lead to neuropathy. Vitamin B12, or cobalamin, is often deficient. This deficiency is hypothesized to be due to excessive binding of cobalamin by cobalamin-binding proteins other than intrinsic factor that are normally digested by pancreatic enzymes. Replacement of pancreatic enzymes orally with meals will correct the vitamin deficiencies and steatorrhea. The incidence of pancreatic adenocarcinoma is increased in patients with chronic pancreatitis, with a 20-year cumulative incidence of 4%. Chronic abdominal pain is nearly ubiquitous in this disorder, and narcotic dependence is common. Niacin is a water-soluble vitamin, and absorption is not affected by pancreatic exocrine dysfunction.

VIII-73. The answer is A. (Chap. 313) This patient likely has chronic pancreatitis related to longstanding alcohol use, which is the most common cause of chronic pancreatitis in adults in the United States. Chronic pancreatitis can develop in individuals who consume as little as 50 g of alcohol daily (equivalent to ~30–40 ounces of beer). The patient’s description of his loose stools is consistent with steatorrhea, and the recurrent bouts of abdominal pain are likely related to his pancreatitis. In most patients, abdominal pain is the most prominent symptom. However, up to 20% of individuals with chronic pancreatitis present with symptoms of maldigestion alone. The evaluation for chronic pancreatitis should allow one to characterize the pancreatitis as large- vs. small-duct disease. Large-duct disease is more common in men and is more likely to be associated with steatorrhea. In addition, large-duct disease is associated with the appearance of pancreatic calcifications and abnormal tests of pancreatic exocrine function. Women are more likely to have small-duct disease, with normal tests of pancreatic exocrine function and normal abdominal radiography. In small-duct disease, the progression to steatorrhea is rare, and the pain is responsive to treatment with pancreatic enzymes. The characteristic findings on CT and abdominal radiograph of this patient are characteristic of chronic pancreatitis, and no further workup should delay treatment with pancreatic enzymes. Treatment with pancreatic enzymes orally will improve maldigestion and lead to weight gain, but they are unlikely to fully resolve maldigestive symptoms. Narcotic dependence can frequently develop in individuals with chronic pancreatitis due to recurrent and severe bouts of pain. However, as this individual’s pain is mild, it is not necessary to prescribe narcotics at this point in time. An ERCP or magnetic resonance cholangiopancreatography (MRCP) may be considered to evaluate for a possible stricture that is amenable to therapy. However, sphincterotomy is a procedure performed via ERCP that may be useful in treating pain related to chronic pancreatitis and is not indicated in the patient. Angiography to assess for ischemic bowel disease is not indicated as the patient’s symptoms are not consistent with intestinal angina. Certainly, weight loss can occur in this setting, but the patient usually presents with complaints of abdominal pain after eating and pain that is out of proportion with the clinical examination. Prokinetic agents would likely only worsen the patient’s malabsorptive symptoms and are not indicated.