Examination Medicine: A Guide to Physician Training, 7th Edition

CHAPTER 7. The gastrointestinal long case

One finger in the throat and one in the rectum makes a good diagnostician.

Sir William Osler (1849–1919)

Peptic ulceration

This long case is usually a straightforward management problem. The most important causes of chronic peptic ulcer disease are Helicobacter pylori infection and traditional non-steroidal anti-inflammatory drugs (NSAIDs), including low-dose aspirin. The COX-2-specific NSAIDs have a lower incidence of peptic ulceration. Idiopathic ulcers (H. pylori negative, NSAID negative) are increasingly being reported. The Zollinger-Ellison syndrome (gastrinoma) is a very rare but important cause. Since peptic ulcer disease affects 10% of the population, a history of this condition is not uncommon in the long case. Patients are usually admitted to hospital with peptic ulcer disease because of complications – typically haemorrhage, but more rarely, perforation.

The history

1. Determine whether the patient currently has dyspepsia or a past history of dyspepsia (i.e. epigastric pain or discomfort, early satiation or postprandial fullness). Typical ulcer symptoms include burning or sharp epigastric pain related to meals that may wake the patient from sleep at night and is relieved by antacids or antisecretory drugs. However, many patients with these symptoms do not have peptic ulcer disease and ulcers are often associated with atypical symptoms. Duodenal and gastric ulcers cannot be distinguished from one another on the basis of symptoms. The differential diagnosis of dyspepsia includes gastro-oesophageal reflux disease (usually also causing heartburn or acid regurgitation), gastric cancer (especially in older patients with new onset of symptoms or with alarm features such as weight loss), biliary pain (typically severe, constant pain in the right upper quadrant or epigastrium that occurs episodically and unpredictably and lasts at least 20 minutes, but usually hours), chronic pancreatitis, pancreatic cancer or intestinal angina (chronic mesenteric ischaemia, which causes severe postprandial pain such that the patient is afraid to eat and loses weight).

2. Diabetes mellitus, thyroid dysfunction, hyperparathyroidism and connective tissue diseases can also cause dyspepsia.

3. Ask about the course of the symptoms and, if intermittent, the number of recurrences and treatments given. Ask about alarm symptoms, such as weight loss (which suggests the possibility of malignancy) or recurrent vomiting (e.g. gastric outlet obstruction). Gastroparesis is rare and usually presents with recurrent vomiting, weight loss and abdominal pain.

4. Ask about the types of investigations the patient has had undertaken in the past. If an ulcer was apparently documented, determine whether this was by endoscopy (the most sensitive and specific test) or barium meal, or just by symptoms alone (which is inadequate). Determine whether the patient knows if H. pylori status was determined from gastric biopsies or by non-invasive tests, such as serology, urea breath testing or stool antigen testing.

5. A history of past ulcer surgery is important because of the associated complications (e.g. pain or bloating owing to bile reflux gastritis or an afferent loop syndrome, recurrent ulceration, early or late dumping, post-vagotomy diarrhoea, anaemia as a result of iron, vitamin B12 or folate deficiency, and osteomalacia or osteoporosis).

6. Ask about the family history: a strong family history of peptic ulcer may reflect the multiple endocrine neoplasia (MEN) I syndrome.

7. Enquire carefully about medication use – medications (e.g. digoxin, potassium, iron, oral antibiotics) can induce dyspepsia, which can be confused with peptic ulcer. All NSAIDs are an important cause of dyspepsia with or without chronic ulceration. Alcohol can also induce acute dyspepsia (but not chronic ulcers). Patients with an ulcer history may be taking maintenance acid suppression. First-line treatment for H. pylori usually includes a proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and clarithromycin) for 7 days, but 30–40% now fail.

8. If relevant, determine why the patient is in hospital on this occasion. If the admission is because of acute gastrointestinal bleeding, then the treatment applied needs to be documented (e.g. blood transfusion, injection of a bleeding visible vessel in a peptic ulcer base with adrenaline followed by thermal coagulation or a hemoclip; those failing endoscopy need transarterial angiographic embolisation or surgery). Remember that oral or intravenous proton pump inhibitors are routinely used and transfusions are held until the haemoglobin level drops below 70g/L (unless bleeding is massive) as survival is then better.

The examination

Physical examination in patients with suspected peptic ulcer disease is usually unhelpful. Epigastric tenderness is not a specific sign. An upper abdominal scar may indicate past ulcer surgery. Look for alarm signs, including evidence of anaemia (e.g. from bleeding) or current bleeding (melaena, tachycardia, postural hypotension) or an abdominal mass (e.g. gastric or pancreatic carcinoma).


1. Endoscopy. This is the standard test for determining that an active peptic ulcer is present. It is also the key test in a patient with upper gastrointestinal bleeding to determine whether the patient is at high risk of rebleeding and also to provide endoscopic therapy where required. Patients with active bleeding or a visible vessel at endoscopy need endoscopic therapy (e.g. injection with adrenaline followed by coagulation with a heater probe). Patients with a low risk of rebleeding (i.e. a clean ulcer base) can be discharged if stable. For patients with upper gastrointestinal tract bleeding, it is also important to exclude other causes, including variceal bleeding, erosions, angiodysplasia, a Mallory-Weiss tear or a Dieulafoy’s lesion (rupture of a large submucosal artery). Where possible, biopsies should be obtained at a diagnostic endoscopy in ulcer patients to determine the H. pylori status (but false negative results can occur in the setting of upper GI bleeding).

2. Abdominal imaging. In the patient with unexplained dyspepsia where endoscopy is normal, ultrasound can be useful in certain clinical circumstances to investigate for biliary tract pathology. CT scanning is more sensitive for pancreatic disease.

3. Atypical peptic ulcer. Peptic ulceration in an unusual location, peptic ulcers resistant to therapy, an ulcer relapse after operation, or frequent or early ulcer recurrence can occur in the Zollinger-Ellison syndrome. This syndrome can also be associated with enlarged duodenal or gastric folds, or diarrhoea or steatorrhoea. The diagnosis is made by measuring the fasting serum gastrin level: >300 pg/mL is suggestive and >1000 pg/mL is almost diagnostic. Acid secretion can be confirmed by testing the pH of gastric juice obtained at endoscopy. The next diagnostic test of choice in uncertain cases is the secretin test (if available), where a paradoxical increase in gastrin of >200 pg/mL above basal levels is highly specific. Preoperative localisation of the tumour is then attempted by CT scanning and, if necessary, angiographic venous sampling. In patients with metastatic or multifocal disease, surgery is avoided, but all other cases require surgical exploration. High-dose PPIs are used to control the disease medically.

  Remember that hypergastrinaemia also occurs in hypochlorhydria (gastric pH is not acidic; e.g. in type A atrophic gastritis and pernicious anaemia, following vagotomy or in renal failure). Other causes of hypergastrinaemia with acid hypersecretion include a retained gastric antrum after peptic ulcer surgery, massive small bowel resection, gastric outlet obstruction and thyrotoxicosis. If hypercalcaemia is present in patients with ulcer disease, this may suggest MEN I (with hyperplasia, adenoma or carcinoma of the parathyroid, pituitary and pancreatic islets; hyperparathyroidism and pituitary adenoma are most often associated with the Zollinger-Ellison syndrome in MEN I). In MEN I (autosomal dominant with variable penetrance), there is often a strong family history of peptic ulcer disease.


1. There is now consensus that if peptic ulcer disease is documented and H. pylori is present, this infection should be treated. Most duodenal ulcers will be cured by this approach, as will most gastric ulcers, unless associated with NSAID use.

2. Therapy with acid suppression alone for peptic ulcer disease is now obsolete unless no cause is identified. The optimal approach for curative treatment of H. pylori is currently three drugs (e.g. PPI plus amoxycillin plus clarithromycin), which give cure rates of approximately 60% to 70% if given for 1 week. Side-effects occur with such treatment in up to 20% of cases.

3. Patients with gastric ulcers may be advised to have a repeat gastroscopy to confirm healing and exclude carcinoma. However, 98% of cancers will be detected at the initial gastroscopy and biopsy. Therefore, repeat endoscopy is usually recommended only if symptoms have not been relieved or no initial biopsies were obtained.

4. In peptic ulcer disease, confirm that H. pylori infection has been cured (e.g. by repeat endoscopic biopsy or urea breath testing at least 1 month after completing treatment).

5. NSAID ulcers should initially be treated with a PPI, which is effective even if the NSAID is continued (although this does delay healing).

6. PPIs are more effective than histamine H2-receptor antagonists in promoting ulcer healing. NSAID use is an independent risk factor for peptic ulcer and therefore eradication of Hpylori in this situation may not prevent ulcer disease if NSAIDs are continued.

7. Certain patients taking traditional NSAIDs have a higher risk of ulcer complications. These include elderly patients, those having their first 3 months of treatment, those on higher doses, those with a past history of peptic ulcer, those taking concomitant corticosteroid therapy or anticoagulants, and those with other serious medical illnesses. NSAID ulcers often present with complications without a history of dyspepsia because these drugs are analgesic agents that may mask symptoms. The prostaglandin E1 analogue misoprostol and PPIs both substantially reduce the risk of NSAID-induced gastric and duodenal ulcers; histamine H2-receptor antagonists in standard doses do not prevent NSAID-induced gastric ulcers. H. pylori eradication before treatment reduces, but does not eliminate, the risk of aspirin-induced ulcer development. H. pylori eradication alone provides insufficient protection from gastroduodenal complications arising from non-selective NSAID use in high-risk patients, who will still require a PPI.

Malabsorption and chronic diarrhoea

This can be a difficult long case. It is usually a diagnostic problem. Coeliac disease (Table 7.1), chronic pancreatitis and previous gastric surgery account for 60% of cases of malabsorption.

Table 7.1

Coeliac disease


The history

1. Ask about presenting symptoms:

a. pale, bulky, offensive stools (steatorrhoea)

b. weight loss

c. weakness (e.g. from potassium deficiency)

d. anaemia (megaloblastic, iron deficiency, etc.)

e. bone pain (osteomalacia)

f. glossitis and angular stomatitis (vitamin B group deficiency)

g. bruising (vitamin K deficiency)

h. oedema (as a result of protein deficiency)

i. peripheral neuropathy (owing to vitamin B12 or B1 deficiency)

j. skin rash (eczema, dermatitis herpetiformis) (Fig 7.1)


FIGURE 7.1 Dermatitis herpetiformis – the most typical manifestation is polymorphic eruption above the elbows. S Kárpáti. Dermatitis herpetiformis. Clinics in Dermatology, 2012. 30(1):56–59, with permission.

k. amenorrhoea (owing to protein depletion).

2. Ask about the time of onset of symptoms and their duration.

3. Ask aetiological questions concerning:

a. gastrectomy, other bowel surgery

b. history of liver or pancreatic disease

c. drugs (e.g. alcohol, neomycin, cholestyramine)

d. history of Crohn’s disease

e. previous radiotherapy

f. gluten-free diet treatment at any stage

g. history of diabetes mellitus

h. risk factors for HIV infection.

4. Ask about current treatment (e.g. diet, pancreatic supplements, vitamin supplements, cholestyramine, antibiotics).

5. Enquire about family history (e.g. coeliac disease, inflammatory bowel disease).

6. Ask about social problems related to the chronic illness.

The examination

Pay particular attention to the current weight and nutritional status (e.g. BMI), the presence of abdominal scars, skin lesions (e.g. bruising, dermatitis herpetiformis (Fig 7.1), pigmentation (Fig. 7.2), erythema nodosum (Fig 7.5), pyoderma gangrenosum (Fig 7.4), stomatitis, perianal lesions), signs of anaemia, signs of chronic liver disease, signs of peripheral neuropathy and lymphadenopathy.


FIGURE 7.2 Whipple’s disease and skin pigmentation. Erythema nodosum-like subcutaneous, slightly erythematous nodules affected (a) the lower legs and (b) the abdomen. J Schaller. Erythema nodosum-like lesions in treated Whipple’s disease: Signs of immune reconstitution inflammatory syndrome. Journal of the American Academy of Dermatology, 2008. 60(2):277–288, with permission.


FIGURE 7.3 Aphthous ulcers. S O Akintoye, M S Greenberg. Oral soft tissue lesions: Recurrent aphthous stomatitis. Dental clinics of North America. 2005. 49(1):31–47, Fig 2, 2005.


FIGURE 7.4 Pyoderma gangrenosum. E Wierzbicka-Hainaut et al. Pyoderma gangrenosum récidivant lors des grossesses. Recurring pyoderma gangrenosum in pregnancy. Anales de dermatologie et de venereologie. 2010. 137(3):225–9, Fig 1.


FIGURE 7.5 Erythema nodosum. J Mana, J Marcoval. Erythema nodosum. Clinics in dermatology. 2007. 25(3):288–94. Elsevier, with permission.

Investigations (see Table 7.2)

Table 7.2

Typical results of investigations in malabsorption


*This is a test of proximal small bowel function. Falsely low values occur in patients with chronic kidney disease, dehydration, ascites or hyperthyroidism and in the elderly. PAS = periodic acid-Schiff technique.

1. Demonstrate malabsorption:

a. the ‘big six’ laboratory screen tests – look for a low serum iron, prolonged prothrombin time, low calcium, low cholesterol, low carotene and a positive Sudan stain of the stool for fat (which is a good screening test for steatorrhoea)

b. faecal fat estimation over 3 days – more than 7 g per day is abnormal; note that patients with severe small bowel diarrhoea of any cause without fat malabsorption may lose up to 14 g per day; this gold standard test is very useful if you strongly suspect fat malabsorption based on the screening evaluation, but is not widely used or available

c. glucose or lactulose breath hydrogen test for bacterial overgrowth (think about this possibility in the setting of macrocytosis with a high folate and low B12 level, or in patients with structural, motility or immunoglobulin deficiency disorders that predispose to bacterial overgrowth)

d. Schilling test for ileal disease causing vitamin B12 deficiency (rarely ordered)

e. SeHCAT test for bile salt malabsorption that can occur with ileal rejection or terminal ileal disease (e.g. Crohn’s disease).

2. Evaluate the consequences:

a. blood count with particular attention to red cell indices

b. serum iron and ferritin, serum and red cell folate, and vitamin B12 studies

c. serum albumin estimation

d. vitamin D level (25-OH vitamin D), serum calcium, phosphate and alkaline phosphatase estimations

e. clotting profile – international normalised ratio (INR)

f. cholesterol and carotene.

3. Find the cause.

a. Check small bowel X-ray films for localised disease (e.g. Crohn’s disease or anatomical causes of bacterial overgrowth such as diverticula or blind loops).

b. Check gastroscopy and small bowel biopsy (the optimal number for diagnosis of coeliac disease is four duodenal biopsies, as disease can be patchy) and duodenal aspirate for histology, parasites and bacterial overgrowth; look for multiple duodenal ulcers (e.g. as a result of Zollinger-Ellison syndrome, lymphoma, jejunoileitis).

  Subtotal villous atrophy may be present histologically in:

• coeliac disease

• tropical sprue

• giardiasis

• lymphoma

• hypogammaglobulinaemia

• Whipple’s disease.

  Note that tissue transglutaminase (or anti-endomysial antibody) is the most useful screening test for sprue. Remember that 2% of the population is IgA deficient and will have negative serology, so check IgA levels if testing is negative and your suspicion is high. Do not rely on antigliadin antibodies. Serology is not a substitute for small bowel biopsy, which remains the gold standard test if coeliac disease is suspected.

c. Vitamin B12 absorption may be abnormal in ileal disease, bacterial overgrowth, pernicious anaemia and pancreatic disease.

d. Greatly raised faecal fat levels (>40 g per day) strongly suggest pancreatic disease, but this test is now uncommonly available. An alternative is faecal elastase testing. Suspected pancreatic disease is investigated by plain abdominal X-ray films (for calcification), CT scan, magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound; pancreatic function testing is not performed routinely.


Treatment depends on the cause and also involves the replacement of essential nutrients (see Table 7.3).

Table 7.3

Causes and treatment of malabsorption


Management of coeliac disease

Coeliac disease is a commonly missed diagnosis! Have a low threshold for ordering serology; patients may present with no gastrointestinal symptoms. Remember to consider the possibility of coeliac disease in a patient with osteoporosis or osteomalacia, abnormal transaminases, new neuropsychiatric symptoms or unexplained iron deficiency.

1. The management of coeliac disease includes a gluten-free diet (exclusion of wheat, rye and barley; there is controversy about oats). Symptoms usually improve in weeks and the histology in months; tissue transglutaminase antibody also normalises in 3 to 6 months.

2. A strict diet may reduce complications. It is reasonable to re-biopsy the duodenum in 3 months to confirm histological healing.

3. Lack of response to a gluten-free diet may be caused by inadvertent gluten exposure, the presence of another problem (e.g. lactose intolerance, pancreatic insufficiency, bacterial overgrowth), refractory sprue (which may respond to corticosteroids) or lymphoma (T cell enteropathy: unresponsive to steroids).

4. Pneumococcal vaccine is recommended because of the hyposplenism of coeliac disease.

5. Osteoporosis must be looked for and managed.

6. Latent coeliac disease can be diagnosed if the small bowel biopsy appears normal but there is a positive serology. For these patients, a gluten-free diet is not usually recommended, but follow-up with repeat biopsy is indicated if the symptoms recur.

Inflammatory bowel disease

Both ulcerative colitis and Crohn’s disease are common conditions in hospitals and outpatient clinics. They present both diagnostic and treatment problems. Mutations in the NOD2 gene (also called CARD 15) increase the risk of Crohn’s disease (ileal and fibrostenosing). The patient will usually know the diagnosis, but you may have to decide which type of inflammatory bowel disease (IBD) is present.

The history

1. Find out about symptoms at presentation and, if relevant, the current reason for admission. Ulcerative colitis (UC) typically presents in young adults with relapsing bloody diarrhoea, malaise, fever and weight loss. Crohn’s disease can present like UC or can have a variable presentation, including an insidious onset of pain, diarrhoea, weight loss, malabsorption, intestinal obstruction or symptoms suggestive of ‘appendicitis’.

2. Ask about local complications and extracolonic manifestations of the disease (Table 7.4).

Table 7.4

Complications of inflammatory bowel disease



3. Enquire about sexual orientation if relevant (infective proctitis in men who have sex with men must be considered in the differential diagnosis).

4. Ask about medications – NSAIDs, retinoic acid and possibly oral contraceptives can cause a similar picture.

5. Determine the investigations at the time of presentation and subsequently (and particularly whether infectious causes were considered).

6. Ask about the number of hospital admissions.

7. Ask whether regular follow-up colonoscopy has been performed in patients with longstanding colitis.

8. Find out about treatment, including medications – such as sulfasalazine, 5-aminosalicylic acid preparations (mesalazine, olsalazine), local or systemic steroids, budesonide, metronidazole, immunosuppressants (e.g. azathioprine), other antibiotics (consider pseudomembranous colitis), infliximab or adalimumab (tumour necrosis factor antibody) – and a detailed surgical history.

9. Enquire about family history of inflammatory bowel disease or bowel carcinoma.

10. Ask about smoking – a greater proportion than average of Crohn’s disease patients are smokers and the risk of developing ulcerative colitis rises when people give up smoking.

11. Enquire about the patient’s domestic arrangements and employment.

The examination

A thorough gastrointestinal system examination is important. Evaluate the general state of nutrition and hydration. Feel for any tenderness or abdominal masses and look for anal lesions externally. Always ask for the results of a rectal examination. Look for the signs of Cushing’s syndrome if the patient is taking steroids. Search for the other extracolonic manifestations, being guided by the history (e.g. arthropathy, skin lesions, uveitis, anaemia, liver disease).


It is important to exclude other causes of colitis (Table 7.5). For the investigation of inflammatory bowel disease, the following should be considered.

Table 7.5

Causes of colitis

1. Inflammatory bowel disease

2. Infections, including pseudomembranous colitis

3. Radiation

4. Ischaemic colitis

5. Diversion colitis (colonic loops excluded from the faecal stream)

6. Toxic exposure (e.g. peroxide or soapsud enemas, gold-induced colitis)

7. Microscopic or collagenous colitis

8. Lymphocytic colitis

1. Infection must be excluded. The causes include amoebiasis (diagnosed by rectal mucosal scraping or warm stool examination), ShigellaSalmonellaYersiniaCampylobacterEscherichia coli 0157:H7 and pseudomembranous colitis (Clostridium difficile toxin). Lymphogranuloma venereum (a chlamydial disease that is sexually transmitted), gonorrhoea and syphilis (particularly in men who have sex with men), and other infections in immunocompromised hosts (e.g. herpes, cytomegalovirus, cryptosporidium, Isospora belli) should be considered in patients at risk.

  Remember that TB can, uncommonly, mimic Crohn’s disease. Also, reactivation of TB is a major risk with anti-tumour necrosis factor therapy: a chest X-ray and tuberculin skin test are mandatory before starting this therapy.

2. Plain abdominal X-ray film. It is important to look for bowel wall thickening (oedema), gaseous distension and evidence of toxic megacolon in ulcerative colitis. In Crohn’s disease also look for loops of matted bowel and small bowel obstruction.

3. Blood count. Check for anaemia (caused by chronic disease, blood loss, macrocytic anaemia in ileal disease, or haemolytic anaemia from an autoimmune process, microangiopathic disease or sulfasalazine). Check the white cell count (e.g. leucopenia from azathioprine). Look at the ESR (or CRP) for evidence of active disease.

4. Liver function tests and blood levels of electrolytes, urea and creatinine. These patients may develop liver disease. Crohn’s disease may lead to renal stones, pyelonephritis, hydronephrosis or amyloidosis. Remember that hypoalbuminaemia is a sign of severe disease.

5. Barium enema. This is only rarely used to make a diagnosis. It is contraindicated in very active colitis and with toxic megacolon because of the risk of perforation. This investigation will help distinguish ulcerative colitis from Crohn’s disease – in ulcerative colitis the rectum is nearly always involved and there are no skip lesions. Look for loss of haustrations, mucosal irregularity and ulceration, spasm, pseudopolyps and bowel shortening. Also look for evidence of strictures and carcinoma. In Crohn’s colitis, look for thickening, ‘cobblestoning’, luminal narrowing, skip lesions, fistulas and transverse fissures (sinus tracts).

6. Colonoscopy. This is a very useful investigation to assess whether disease is patchy or not and to assess its extent; the test is more sensitive than a barium enema. Note decreased mucosal translucency, loss of vascular pattern, granular and friable mucosa, hyperaemia, ulceration and pseudopolyps in the report. Mucosal biopsies may not differentiate ulcerative colitis from Crohn’s disease. Mucus depletion and prominent crypt abscess formation are more suggestive of ulcerative colitis. Granulomas (in 25%) or focal inflammation are found in Crohn’s colitis (but, note, granulomas also occur in biopsies from Chlamydia trachomatis and syphilitic proctitis or in cases of tuberculosis). Patients with ulcerative or Crohn’s colitis who have had pancolitis for more than 7 years or left-sided colitis for 15 years or more should have colonoscopic screening with biopsy offered every 1 or 2 years to look for high-grade dysplasia and carcinoma. If high-grade dysplasia is confirmed in the absence of severe inflammation, colectomy is indicated. If severe inflammation is present, assessment for dysplasia may be misleading.

7. Antibody testing. The presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) does not make the diagnosis, but p-ANCA-negative and ASCA-positive patients are more likely to have Crohn’s disease than ulcerative colitis (the test is specific but not sensitive).



In ulcerative colitis, grade the severity of the disease:

• mild – fewer than four bowel motions per day, minimal bleeding, normal temperature and pulse

• acute severe – more than six motions per day, profuse bleeding, temperature >37.5°C, pulse >90 beats/min, abdominal tenderness

• fulminant – more than 10 motions per day, continuous bleeding, fever and tachycardia as above, abdominal tenderness and distension.

Other useful indices of severity are anaemia, hypoalbuminaemia and acute phase reactants (e.g. ESR, CRP).

1. In an acute attack, remember to correct hypokalaemia and avoid barium enema to prevent toxic megacolon or perforation. Do not prescribe opiates or anticholinergic agents for the same reason. In severe colitis, intravenous broad-spectrum antibiotics (including metronidazole) are usually given. Intravenous steroids are the mainstay of treatment in patients with moderate-to-severe disease. Cyclosporin may be given intravenously as a short-term alternative to colectomy for patients who do not respond to steroid treatment. Infliximab is an alternative. Close cooperation with a surgeon who is interested in this field and with stoma therapist is important early on in severe disease; these consultations provide information and psychological support.

2. In mild-to-moderate disease, sulfasalazine is useful; mesalazine is the active agent, while sulfapyridine is the cause of most intolerance (allergic reactions such as skin rash – including Stevens-Johnson syndrome – and Heinz body haemolytic anaemia; and side-effects such as nausea, headache, folate deficiency and reversible male infertility). The minimum dose is 4 g per day. Sulfasalazine decreases the relapse rate and administration should be continued indefinitely.

  Mesalazine is as effective as sulfasalazine but has fewer side-effects and higher doses may be given. Mesalazine is useful for patients with sulfasalazine intolerance. Note that the alternative, olsalazine, may cause diarrhoea in patients with active ulcerative colitis (because of ileal secretion) – as a result, it is normally used as maintenance treatment. Chronic steroid use does not reduce relapse rates. Remember to correct iron and folate deficiency if necessary.

3. If proctitis is the problem, first-line treatment is topical (steroid or mesalazine enemas twice daily) plus sulfasalazine or mesalazine orally for more active disease.

4. Azathioprine or 6-mercaptopurine is useful if there are repeated episodes of ulcerative colitis. Side-effects include pancreatitis in 3% of patients and reversible bone marrow suppression in <10% of patients. The use of methotrexate is controversial.

5. It is important to try to differentiate ulcerative colitis from Crohn’s disease using the clinical presentation, X-ray, endoscopic and histological findings. This is because ulcerative colitis that does not respond to medical management can be cured by colectomy; patients with extensive ulcerative colitis are at an increased risk of developing colorectal cancer. In up to 10% of patients, a specific distinction cannot be made.

  Colectomy in ulcerative colitis is curative. Indications for surgery include chronic ill-health and severe disease, complications (e.g. perforation, massive bleeding) and severe disease not responding to optimal medical treatment in 7–10 days.

  Patients with a very high risk of carcinoma (confirmed high-grade dysplasia on biopsy or dysplasia in a lesion or mass) should be advised to undergo a colectomy. All manifestations of the disease are cured by colectomy, but ankylosing spondylitis, liver disease and occasionally pyoderma gangrenosum do not respond.

  While the standard Brooke ileostomy is the simplest procedure, the ileal pouch anal anastomosis is increasingly being used as it maintains intestinal continuity, although it does leave the patient with four to eight bowel movements daily and sometimes with minor incontinence (20%), and is often complicated by pouchitis (in up to 50% of patients). The latter usually responds to treatment with metronidazole or probiotics.


You are more likely to encounter Crohn’s disease in the clinic and exam than UC. A rectal exam for fistula is routine (the results will be provided for you). Small bowel imaging nodalities include CT enteroclysis or MR enteroclysis. Capsule endoscopy is widely available, but remember the capsule may obstruct the small intestine in Crohn’s disease. Fistula can be evaluated by radiology (e.g. CT, MR and fistulography) and examination under anaesthesia. For active colonic disease, treatment is similar to ulcerative colitis. Always advise the patient to stop smoking! Always try to taper off and stop steroids once the patient is in remission. A multi-disciplinary team approach is needed to manage what can be a devastating disease long term.

1. Sulfasalazine or mesalazine is more effective in colonic disease, whereas steroids are more effective in small bowel disease.

2. Budenoside (a steroid derivative that acts locally and is 90% inactivated by the liver) is useful in ileocolonic disease.

3. In quiescent disease, mesalazine only very modestly reduces the frequency of relapse in the postoperative setting.

4. Azathioprine (or 6-mercaptopurine) is useful for those who cannot cease steroids and to reduce relapse (including post-resection surgery). Methotrexate is an alternative if azathioprine fails.

5. Oral cyclosporin is largely ineffective.

6. With extensive ileal disease, diarrhoea may respond to a bile-salt-sequestering drug (cholestyramine or colestipol).

7. Metronidazole or ciprofloxacin is modestly useful for severe perianal disease and fistulae, which tend to recur once treatment is stopped; azathioprine may be tried in difficult severe cases.

8. Tumour necrosis factor (TNF) alpha monoclonal antibody-infliximab and adalimumab heal fistulae and suppress underlying inflammatory disease, but relapse is common and therefore maintenance treatment is required. A positive antinuclear antibody occurs in half the patients. Infusion reactions, infection (including miliary tuberculosis), lymphoproliferative diseases and demyelination can occur. These drugs are very expensive, but TNF antibody therapy is becoming the standard of care for fistulas and refractory disease.

9. Surgery is reserved for the complications of Crohn’s disease (e.g. internal fistula with abscess, intestinal obstruction not responding to medical management). The best operation is resection. Strictureplasty may allow relief of localised obstruction without the deleterious effects of multiple resections.

10. When a total colectomy is needed, a standard ileostomy is the procedure of choice. The recurrence rate of the disease is unchanged by surgery.

Colon cancer

This is a particularly common tumour that usually develops in those 50 years of age or older, although patients at risk with hereditary syndromes will present at a younger age. Because early disease is curable, there has been increased interest recently in colon cancer screening. Hence, a history of polyps or colon cancer is increasingly likely to be encountered in the examination.

Table 7.6

Immunosuppression in inflammatory bowel disease


FBC = full blood count; LFTs = liver function tests; 6MP = 6 mercaptopurine; TPMT = thiopurine methyltransferase

The history

1. The patient may have been diagnosed recently as having a colon cancer. In this case, ascertain the reasons for diagnostic testing. A recent change in bowel habit or bright red blood per rectum (from a rectal or left-sided colon cancer), symptoms of anaemia, new-onset abdominal pain or symptoms suggestive of small bowel obstruction (with a slow-growing caecal cancer) may have been the presenting complaint. There may have been symptoms from involvement of the bladder or female genital tract owing to local invasion. Sacral plexus pain is a very late manifestation.

2. If colon cancer was identified, determine the staging tests and treatment undertaken. If radiotherapy was given to the pelvis, enquire about any ongoing proctitis or cystitis.

3. Determine whether the patient understands the prognosis and ascertain the social support network. Ask whether stoma therapy has been discussed.

4. If the patient has a history of polyps, try to determine from the patient whether these were adenomatous polyps, their approximate size and number. Patients are often rather unclear about these matters and when discussing with the examiners you may need to request information from the medical record. Adenomatous polyps may be tubular or villous (or tubulovillous); invasive cancer is more likely in larger polyps (10% of those >2.5 cm are malignant). If polyps were detected, ask the patient whether surveillance colonoscopy has been conducted in the past, when this began and how often. A repeat colonoscopy after 3 years in those patients without previously documented colonic cancer who have a documented large (>1 cm) adenomatous polyp or multiple (3–10) polyps is generally recommended (Table 7.7), although surveillance needs to be tailored to other risk factors, including the family history. A serrated polyp is usually flat and can lead to colon cancer through a different pathway (hypermethylation of genes).

Table 7.7

Current recommended follow-up colonoscopy intervals in patients otherwise at average risk based on findings at initial colonoscopy (American Gastroenterology Association, 2012)



No polyps or small (<10 mm) hyperplastic polyps in rectum or sigmoid


1–2 small (<10 mm) tubular adenomas


3–10 tubular adenomas or one or more tubular adenomas ≥10 mm


10 adenomas


One or more villous adenomas or sessile serrated polyp ≥ 10mm


5. The family history needs to be carefully obtained for any patient with a history of polyps or colon cancer in the past. If the patient describes having had thousands of adenomatous polyps throughout the large bowel, then familial adenomatous polyposis (FAP) is the diagnosis (until proven otherwise). These polyps usually occur after puberty and most individuals are affected by the age of 25 years. If the colon is not removed, almost all will have colon cancer before the age of 40. In this type of clinical case, ask about the presence of any soft-tissue or bony tumours (Gardiner’s syndrome) or tumours in the central nervous system (Turkot’s syndrome), which are variants of FAP.

  Most patients with FAP will have undergone a total colectomy with ileoanal anastomosis. Ask about continence and stool frequency if this operation has been performed. Screening for duodenal and periampullary cancers every 1 to 3 years by endoscopy is generally recommended.

  Ask whether any offspring of a patient with this condition have been screened. Flexible sigmoidoscopy on an annual basis is recommended. DNA testing of peripheral blood mononuclear cells for the presence of the mutated APC gene at puberty is also useful (after first testing affected relatives to validate the APC mutation presence) in screening offspring.

  The MuTYH-associated polyposis (MAP) syndrome (autosomal recessive) can present just like FAP.

  If there is a strong family history of colon cancer, consider the possibility of Lynch syndrome (see below). There is a 70% lifetime risk of colon cancer in this autosomal dominant disease. There is often also a family history of either ovarian or endometrial carcinoma. Members of such families are typically screened by colonoscopy biennially beginning at the age of 25 years, as well as undergoing pelvic ultrasonography and endometrial biopsies.

6. Enquire about any history of documented inflammatory bowel disease. The risk of colorectal cancer in a patient with ulcerative colitis is small during the initial 7–10 years after pancolonic disease development, but then increases approximately 1% per year. Ask whether colonoscopic surveillance has been undertaken or not. Patients with Crohn’s colitis should now also be offered similar surveillance.

7. Ask whether there has been any history of possible septicaemia. Streptococcus bovis or Clostridium septicus bacteraemia indicates an underlying high risk of occult colon cancer and requires aggressive investigation.

8. Haematomas of the gastrointestinal tract with mucocutaneous pigmentation (Peutz-Jeghers syndrome) increase the risk of both large and small bowel cancer, as well as breast, uterine and ovarian cancers. Affected patients should undergo surveillance by colonoscopy and gastroscopy every 3 years from 18 years of age.

9. Determine whether there is any history of a ureterosigmoidostomy for correction of congenital exstrophy of the bladder, which increases the risk of colon cancer 15–30 years later.

10. Diabetes mellitus, renal transplant and acromegaly may be associated with an increased risk; regular full-dose aspirin use may reduce the risk of colon cancer.

The examination

1. Look for evidence of jaundice or anaemia.

2. If the patient is currently undergoing 5-fluorouracil-derived chemotherapy, look at the palms and soles for evidence of hand–foot syndrome (very tender, symmetrical erythema) (Fig 7.6).


FIGURE 7.6 Hand, foot and mouth syndrome. Skin reaction to docetaxel. Note erythema and edema of the palms in this patient.A T Skarin. Atlas of diagnostic oncology. 4th edn, Fig 21.4F. Mosby, Elsevier, 2010, with permission.

3. Carefully examine the abdomen, in particular looking for any evidence of malignant deposits in the liver or other intraperitoneal masses or skin changes that are consistent with radiotherapy. Record any scars on the abdomen.

4. Results of a rectal examination need to be obtained.

5. Other lymph node groups should be examined and evidence of metastatic malignancy elsewhere (e.g. the lungs, bones or brain) should be sought.

6. Look for the pigmentation of Peutz-Jeghers syndrome (see Fig 7.7).


FIGURE 7.7 Pigmentation of Peutz-Jeghers syndrome. (a) Buccal mucus in the mouth (b) Discreet brown-black lesion of lips.(a) F S McDonald (ed.). Mayo Clinic images in internal medicine. With permission.©Mayo Clinic Scientific Press and CRC Press. (b) D V Jones et al., in M Feldman et al., Sleisenger and Fordtran’s gastrointestinal disease, 6th edn, Ch 112. Saunders, Elsevier, 1998, with permission.

7. Multiple skin lesions (e.g. sebaceous adenomas and carcinomas, basal cell and squamous cell carcinomas, keratoacanthomas) occur in a variant of hereditary non-polyposis colorectal cancer (Torres syndrome).


1. Screening. The possibility of hereditary non-polyposis colon cancer (HNPCC, or Lynch syndrome) should be considered for certain patients. This includes the ‘3–2–1’ rule (Amsterdam II Criteria): patients who have three or more relatives with a history of colon cancer where one of these is a first-degree relative of the other two; those who have colorectal cancer diagnosed in at least two generations of the family and those who have one or more cases of colorectal cancer in family members younger than 50. Screening starts at age 25 in affected families. In most kindreds with HNPCC, germ-line mutations have occurred in one of six DNA mismatch repair genes. Commercial testing is available for hMSH2 and hMLH1 mutations and these have a high sensitivity. ‘Microsatellite instability’ (MSI) is the expansion or contraction of short repeated DNA sequences. MSI has been observed in more than 90% of samples of tumour tissue from patients with HNPCC who fulfil the clinical (Amsterdam) criteria for this disease and also in up to 15% of tumours from patients with sporadic colorectal cancer. The presence of MSI may indicate a better prognosis and better response to adjuvant chemotherapy. Testing for the presence of MSI in a tumour or adenoma should be an initial screening test for patients suspected of having HNPCC, and positive cases should undergo genetic screening.

2. Symptomatic patients. Most will have had the cancer identified by colonoscopy. With the increasing introduction of screening measures in asymptomatic patients (e.g. faecal occult blood testing), earlier stage colon cancers will be detected in average-risk patients. The prognosis depends on the stage of disease. Survival is decreased if the bowel wall is penetrated (Dukes’ B2 stage) or with lymph node involvement (Dukes’ C stage).


1. For colon cancer, total tumour resection in local disease is the treatment of choice undertaken either endoscopically or surgically. Before surgery, patients should be evaluated for the possibility of metastatic disease, including a careful physical examination. Many physicians would also order a chest X-ray and liver function tests and measure the baseline carcinoembryonic antigen (CEA) level. If possible, a complete colonoscopy should be undertaken to look for evidence of synchronous cancers or polyps. If colonoscopy was not performed before the operation, it should be carried out as soon as practicable after the operation.

2. Following a resection, patients are often followed up for 5 years with annual physical examinations and surveillance colonoscopy every 3 years. Measuring CEA levels every 3 months for 2 years after surgery for Dukes’ B or C stage disease, as a test for tumour recurrence, is often recommended but remains controversial.

3. If metastatic disease is present, resection of the primary colorectal tumour does not change prognosis and should be done only for symptomatic reasons. The exception is limited metastases to the liver only, where 25% may be cured by resection.

4. Determine whether the patient has had radiation therapy to the pelvis, which may have been offered with a rectal cancer. Some patients may have received chemotherapy; in particular, patients with Dukes’ C stage often have had adjuvant leucovorin modulated 5-fluorouracil for 6 months. Oxaliplatin may be added.

Chronic liver disease

Cirrhosis alone or in combination with other disease will often crop up, particularly in repatriation hospitals. (Warning: You may be exposed to prolonged war stories and discussions about shrapnel.) It is a pathological diagnosis. This discussion will be limited to aspects of cirrhosis and chronic hepatitis, which tend to be most frequent in the examination.

The history

Cirrhosis can present with ascites (Fig 7.9), jaundice (Fig 7.10), abdominal pain, acute bleeding or encephalopathy. Occasionally patients present with only weakness, lassitude or loss of libido. There may be no symptoms (incidental cirrhosis).


FIGURE 7.9 Stretch marks. Ascites in a patient with alcoholic cirrhosis showing distended abdomen; dilated superficial collateral veins; hemorrhagic scratch marks due to pruritus and coagulopathy; umbilical varices; plaster in left iliac fossa indicating diagnostic paracentesis. A Forbes, J J Misiewicz, C C Crompton, M Levine et al. (eds). Atlas of clinical gastroenterology, 3rd edn. 2005, in F Ferri. Ferri’s clinical advisor 2012. Fig 1-300, Mosby, Elsevier, 2012, with permission.


FIGURE 7.10 Jaundice. Tropical dermatology, 2006, Fig 12.15.

1. Ask about length of history of liver disease:

a. past history of hepatitis or jaundice, including contacts

b. alcohol intake (in men, 80 g per day for more than 10 years is usually necessary; women need less exposure)

c. history of drug addiction (intravenous), sexual orientation, transfusions, tattoos, etc.

d. drug history (e.g. for chronic hepatitis: methyldopa, isoniazid, nitrofurantoin)

e. history of diabetes mellitus, cardiac failure or arthropathy (haemochromatosis)

f. overseas travel (e.g. acute hepatitis).

2. Ask about treatment (e.g. protein restriction, fluid restriction, alcohol abstinence, steroids, lactulose, neomycin).

3. Ask about complications, such as any history of encephalopathy. An early sign of this is reversal of the sleep cycle. Is there any history of portal hypertension (ascites or bleeding from varices), recent abdominal pain (gallstones – usually pigment stones, acute alcoholic hepatitis etc.).

4. Ask about recent fever, abdominal pain or tenderness, or evidence of altered mental status – in the setting of ascites this suggests spontaneous bacterial peritonitis (SBP) and it is important to start antibiotic treatment as soon as ascitic fluid, blood, and urine have been obtained for culture and analysis. Determine if there have been one or more previous episodes of SBP, an indication for long-term prophylactic antibiotic therapy. In the setting of cirrhosis, an admission for GI bleeding is an indication for short-term antibiotic cover as mortality is reduced.

5. Ask about investigations (e.g. liver biopsy, endoscopy for varices).

6. Ask about operations (e.g. transjugular intrahepatic portosystemic shunt – TIPS).

7. Enquire about erectile dysfunction, loss of libido.

8. Enquire about social problems (e.g. employment, family).

The examination

1. Note the patient’s racial origin. Hepatitis B and C viruses are endemic in Southeast Asia, Italy and Egypt. Look for tattoos – tattoo needles are a source of infection. Examine carefully for the signs of chronic liver disease (Figs Also note any hepatic encephalopathy, signs of portal hypertension, including splenomegaly, ascites, oedema and signs of bleeding (e.g. melaena).


FIGURE 7.8 Palmar erythema. A Nautiyal, K B Chopra. Liver palms – palmar erythema. The American Journal of Medicine, 2010. 123(7): 596–597 Fig 1.

2. Consider hepatocellular carcinoma (particularly in haemochromatosis, and cirrhosis as a result of hepatitis B or C virus infection). In patients with decompensated cirrhosis, examine for a hard mass and liver bruit (hepatoma).

3. Look for the signs of haemochromatosis. In young patients, consider Wilson’s disease and look carefully for Kayser-Fleischer rings (Fig 7.11). If there is deep jaundice with scratch marks and xanthelasma, particularly in a woman, consider end-stage primary biliary cirrhosis.


FIGURE 7.11 Kayser-Fleischer ring. M M Deguti, J F Uwe Tietge, E R Barbosa, E L R Cancado. The eye in Wilson’s disease: sunflower cataract associated with Kayser-Fleischer ring. Journal of Hepatology, 2002. 7(5).

4. Exclude severe right heart failure, tricuspid regurgitation or constrictive pericarditis clinically in all patients. Search for other causes and sequelae (see Tables 7.8 and 7.9).

Table 7.8

Causes of cirrhosis in adults


Table 7.9

Sequelae of cirrhosis



Management of cirrhosis depends on the aetiology, morphology and hepatic function. It is important to make a diagnosis and exclude potentially reversible causes of further liver deterioration.

1. Liver function tests. These should be used to confirm abnormalities, follow progress and give an idea of prognosis (particularly a low albumin level and prolonged INR). An aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio of >2.0 suggests alcoholic liver disease.

2. Full blood count. This is helpful because anaemia may be caused by chronic disease, blood loss, folate deficiency, bone marrow depression, hypersplenism, haemolysis or sideroblastic anaemia. Round macrocytes are common in alcoholics. Remember that leucopenia and thrombocytopenia occur in hypersplenism. A low platelet count in the setting of chronic liver disease suggests cirrhosis.

3. Renal function tests. These are important to exclude the hepatorenal syndrome. Hyponatraemia is common in cirrhosis.

4. Ascitic tap (see Tables 7.10 and 7.11). Rule out spontaneous bacterial peritonitis if ascites is present (>250/mm3 polymorphs).

Table 7.10

Causes of ascites and interpretation of ascitic fluid studies


Table 7.11

Budd-Chiari syndrome


5. Ultrasound or abdominal CT scan (see Fig 7.12). This may help exclude biliary obstruction and infiltration. The texture of the liver may suggest infiltration (e.g. fat) or nodularity (cirrhosis).


FIGURE 7.12 CT scan of abdomen showing a hepatocellular carcinoma (arrow), confirmed on biopsy. Figure reproduced courtesy of The Canberra Hospital.

6. Fibro-scanning. This can be used in place of biopsy to help diagnose cirrhosis.

7. In the setting of dyspnoea, consider hepatopulmonary syndrome. Platypnoea (dyspnoea that is worse when the patient sits up and is relieved by lying down) and orthodexia (arterial desaturation when upright) are strongly suggestive; a diagnosis of intrapulmonary vascular dilatation may be possible by contrast echocardiography.

8. Always assess for possible causative factors (see Table 7.8).

• Obtain hepatitis B and C serologies.

• Screen for antimitochondrial antibody (AMA) if primary biliary cirrhosis is suspected. In suspected chronic hepatitis (e.g. young woman with raised globulins) test for antinuclear antibody (ANA), smooth muscle antibody, and anti-liver and kidney microsomes type 1 (anti-LKM1) antibody. In type I autoimmune chronic hepatitis there is marked hyperglobulinaemia, and ANA and anti-smooth muscle antibody (ASMA) are present. In type II, ANA is negative, but anti-LKM1 is present in high titre and liver cytosol antigen may be present (this antibody also occurs in low titre in hepatitis C). In the rare overlap syndromes, the only serological abnormality may be AMA, but the histology shows autoimmune hepatitis or the patient is ANA or ASMA (but not AMA) positive and has primary biliary cirrhosis (autoimmune cholangiopathy) on histology.

• Order iron studies and, in a young patient, caeruloplasmin levels. Alpha1- antitrypsin deficiency should be considered; absence of the alpha1 fraction on a protein electrophoresis is a useful clue.

• Evaluate for evidence of inflammatory bowel disease if there are colonic symptoms. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) occur in up to 80% of patients with ulcerative colitis and are a marker for primary sclerosing cholangitis (60% of cases).

• Screening for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis secondary to hepatitis B or C. Screening is now by 6-monthly liver ultrasound.

• Assess the hepatic functional reserve of patients with known or suspected cirrhosis (Table 7.12).

Table 7.12

Child’s classification of patients with cirrhosis in terms of hepatic functional reserve


8. Liver biopsy. This is a definitive test and probably should be done if the diagnosis is uncertain, unless there are specific contraindications (e.g. coagulopathy).


The Child Pugh score can be used as an aide-memoire for the complications of CLD viz. jaundice, coagulopathy, poor nutrition, ascites, encephalopathy.


Decide whether the patient has acute or acute-on-chronic disease and decide whether the disease is compensated or decompensated. Management includes treating hepatocellular failure (synthetic function) and portal hypertension (plumbing). Cirrhosis is irreversible. However, removing causative factors, such as alcohol, iron overload and drugs, or treating viral infection is of value.


Acute hepatic encephalopathy is precipitated by bleeding into the gastrointestinal tract or electrolyte disturbances (alkalosis increases the ammonia crossing the blood–brain barrier, whereas hypokalaemia increases renal ammonia production). Hypokalaemia may be caused by recent diuretic use. Infection (e.g. spontaneous bacterial peritonitis), drugs (e.g. sedatives), a high-protein diet, constipation, deteriorating liver function (e.g. alcoholic binge, hepatocellular carcinoma) and rarely metabolic disturbances (e.g. hypoglycaemia, hypoxia) may also precipitate encephalopathy.


1. Management consists of removing the precipitating factors. This means removing blood from the gut (e.g. enemas), giving a low-protein diet, treating infection, correcting electrolyte disturbances, avoiding sedatives and attacking the urea-splitting organisms with lactulose (or lactitol; these decrease the pH inhibiting the flora) or antibiotics (e.g. neomycin, metronidazole or rifaximin), or both.

2. Chronic hepatocellular failure should be managed by treating the cause where possible and manipulating the protein diet as required.

3. Control encephalopathy and ascites.

4. Watch for gastrointestinal bleeding and renal failure.

5. In cases of autoimmune chronic hepatitis, steroids are helpful in patients without viral markers.


Clinical features include splenomegaly, the presence of collaterals, ascites and fetor hepaticus. Investigations include endoscopy for oesophageal varices, ascitic tap and abdominal ultrasound with Doppler arterial and venous flow studies.


1. An attempt should be made to assess the bleeding risk for a patient with varices. High-risk patients (75% risk of haemorrhage over 1 year) are those with Child’s class C cirrhosis, gross ascites and large varices. All patients with large varices should be recommended prophylactic treatment – usually with beta-blockers or, if contraindicated, variceal band ligation.

2. Bleeding varices should be managed acutely by replacing intravascular volume (transfuse only if the haemoblobin is less than 70 or bleeding is massive) and correcting coagulation abnormalities. Intravenous octreotide or terlipressin (triglycyl lysine vasopressin) or alternatively vasopressin combined with glyceryl trinitrate is first-line therapy but only a temporary measure. Also give antibiotic cover for a maximum of 7 days (e.g. IV ciprofloxacin or oral norfloxacin). Oesophageal variceal banding therapy is effective (and superior to sclerotherapy) in stopping acute bleeding. Balloon tamponade at the gastro-oesophageal junction with the gastric balloon is now rarely required; oesophageal balloon tamponade may worsen the prognosis. To prevent recurrent variceal bleeding, elective endoscopic banding to obliterate varices may be effective. Beta-blockers (e.g. propranolol) can reduce portal pressure and may be useful in patients with good liver function. TIPS is preferable to shunt surgery. Mortality is high for ‘crash’ shunts.

3. Treatment of ascites consists of gentle diuresis (maximum weight loss of 500 g per day). Begin with bed rest, salt restriction and spironolactone but increase the dose slowly. If the urinary sodium to potassium ratio is >1, a dose of 150 mg/day is usually adequate; if the ratio is less than 1, higher doses are needed. Frusemide is given if necessary. A combination of frusemide 40 mg daily and spironolactone 25 to 100 mg daily may be the most helpful, although there is evidence that spironolactone alone may be as effective. Therapeutic paracentesis is a safe alternative in patients with tense ascites, especially when there is also peripheral oedema. Intravenous salt-poor albumin is given to replace the protein lost in ascitic fluid and 5–10 L can be removed; the procedure can be repeated as necessary. Therapeutic paracentesis is contraindicated in renal failure or severe coagulopathy. These patients are at risk of spontaneous bacterial peritonitis. Antibiotic treatment (e.g. cefotaxime) is indicated if SBP is suspected (advanced cirrhotic patient presenting with fever, abdominal tenderness or encephalopathy) or the ascitic fluid has a polymorph cell count >250/mm3. Usually there is a dramatic clinical response (within 5 days); otherwise repeat the paracentesis. SBP is associated with a poor 6 months survival. Antibiotic prophylaxis is also indicated in an upper GI bleeder with cirrhosis.

4. In resistant ascites, an alternative is TIPS. Remember though that this is contraindicated in encephalopathic patients.

5. Nutrition is important for these decompensated patients. Naso-gastric feeding has been shown to be helpful.

6. Liver transplantation is the definitive treatment in suitable patients (in the absence of hepatorenal syndrome).


Renal impairment in cirrhosis is not always due to hepatorenal syndrome (HRS), and first you must look for and cease any nephrotoxic drugs if possible (especially NSAIDs and diuretics), exclude infection (e.g. spontaneous bacterial peritonitis), ensure hypovolaemia is identified and corrected, and consider other causes of renal disease (e.g. hepatitis C or B glomerulonephritis – look for proteinuria, casts etc). Hepatorenal syndrome occurs in those with advanced chronic liver disease or liver failure and can be acute and rapidly progressive (type I) or subacute with a better prognosis (type II). The diagnosis of HRS is based on excluding the risk factors above and lack of improvement over 48 hours during volume expansion with albumin. Diuretics should have been stopped. If the diagnosis of HRS is made, a vasoconstrictor is added (a vasopressin analogue or alpha-adrenergic agonist), and listing for transplant should be considered.


Hepatitis B virus (HBV) may be transmitted parenterally (intravenous drug users, infected blood products etc.) or sexually. Infection is common among New Zealand Maoris and people from Southeast Asia. Most infected individuals seroconvert and develop immunity; however, a small proportion become chronic carriers or progress to chronic hepatitis and ultimately cirrhosis. The risk of developing HCC in the latter group is high.

The diagnosis of hepatitis B is made by positive serology (HBsAg-positive) and active disease is usually associated with the HBeAg-positive state, as well as elevated serum transaminase levels, particularly the serum ALT level (Table 7.13).

Table 7.13

Interpreting hepatitis (hep) B serological testing


*High ALT and AST indicates infection (versus carrier); HBC = hepatitis B core antibody; HBS = hepatitis B surface antibody

Measuring for HBV-DNA provides a more accurate assessment of viral load. Precore mutants of HBV are usually diagnosed in patients who are HBeAg-negative and HBeAb-positive, but have elevated transaminase and HBV-DNA levels.

The most accurate method of staging the disease is by means of a liver biopsy. The liver biopsy is important to assess the extent of the inflammation and fibrosis in those with chronic hepatitis.


1. The aim of antiviral therapy is to stop viral replication (i.e. seroconversion from positive HBeAg to negative HBeAg and HBV-DNA levels), as well as normalising ALT levels and histology. ‘Inactive carriers’ (normal transaminases, HBV-DNA <105 copies/mL and normal biopsy) do not need antiviral therapy.

2. Treatment is with subcutaneous peg-interferon, most commonly 5 million units thrice weekly for 2 to 6 months, or entecavir (or lamivudine) for as long as necessary. Interferon produces a response rate of approximately 30% with loss of HBeAg status and no resistance. Younger patients and women contemplating pregnancy are usually offered interferon. Nevertheless, the drug has many debilitating side-effects and is contraindicated in decompensated liver disease. Lamivudine has minimal side-effects, with a seroconversion rate after 2 years of about 30%. Lamivudine is an orally active nucleoside analogue that interferes with HBV replication, but is prescribed less often now. Long-term use of lamivudine may be associated with the development of a YMDD mutant form of HBV. To date these variants have not been shown to cause any additional liver damage. Patients should be maintained on lamivudine, despite the presence of the variant, because re-emergence of wild-type virus may have a worse outcome. Drug resistance to entecavir is low. Adefovir is active against lamivudine-resistant HBV.

3. Liver transplantation can be considered in patients with decompensated HBV liver disease, but without proper preparation HBV infection recurs in the transplanted liver and may cause very aggressive liver disease. Fortunately, strategies are available to overcome this problem. Currently, antiviral drugs are used prior to transplantation to lower HBV-DNA levels and then large doses of hepatitis B immunoglobulin are used in the peritransplantation period. This strategy is extremely effective in preventing recurrence after liver transplantation.


Hepatitis C virus (HCV) is predominantly parenterally transmitted and is particularly common in intravenous drug users. The virus is also commonly found in migrants from endemic regions, including Southeast Asia, Egypt and Italy. The majority of patients are incidentally found to be infected and are usually asymptomatic, although fatigue is a common symptom. If HCV antibody positive, confirm the diagnosis with HCV RNA.

Extrahepatic manifestations are listed in Table 7.14. The disease process is insidious in onset.

Table 7.14

Extrahepatic manifestations of hepatitis C


Approximately 80% of infected individuals go on to develop chronic hepatitis over a 20-year period. It is estimated that 20–30% of patients with chronic hepatitis C develop cirrhosis, but the process is generally slow and insidious. Once cirrhosis develops, symptoms are more common and the signs of end-stage liver disease can appear with jaundice, weakness, wasting and gastrointestinal bleeding. After 25 years of infection about 4% of patients with cirrhosis develop HCC.

Diagnosis is based on a positive HCV antibody ELISA test and then the active virus is checked with HCV-polymerase chain reaction (PCR) testing. Quantitative HCV-PCR is useful in monitoring the response to treatment. A liver biopsy is helpful to stage the disease and estimate the extent of fibrosis, although the non-invasive fibroscan is replacing liver biopsy in practice. Patients with cirrhosis respond poorly to antiviral therapy and are also at risk of developing HCC.


1. Currently, therapy is prescribed for chronic hepatitis C patients with abnormal transaminases and no contraindications (e.g. uncontrolled depression). Treatment in cirrhosis is generally reserved for those who are well compensated (no ascites or encephalopathy, INR<1.5, albumin > 34 g/L, bilirubin < 26 mmol/L, platelets >75 000).

2. Antiviral treatment is based on a combination of oral ribavirin and weekly injections of pegylated interferon and a protease inhibitor (boceprivir or telaprevir) (if genotype 1), or ribavirin and interferon (if genotype 2 or 3). Sustained response rates can be achieved in approximately 70% of patients with genotype I and 80% in the remainder with current regimens. Watch for depression (interferon) and haemolytic anaemia (ribavirin). Ribovarin is contraindicated in pregnancy. Do not treat with interferon if there is cirrhosis. There is a higher response to interferon in those with the CC variant of the IL28B gene.

3. Vaccination against hepatitis A and B is recommended for patients who are not already immune.

4. Patients who develop end-stage liver disease may be transplant candidates. Hepatitis C-related liver disease is the most common reason for liver transplantation today.

5. Surveillance for hepatocellular carcinoma (hepatoma) is recommended if there is cirrhosis from any cause and especially hepatitis C or B. Ultrasound every 6 months is recommended; alpha fetoprotein is no longer routinely measured. Small tumours can be resected if the patient is not cirrhotic (with the best outcomes if solitary with no vascular invasion). Otherwise transplant is sometimes possible (if advanced liver disease with a solitary tumour ≤5 cm or up to three tumours all ≤3 cm) and can be curative. Palliative approaches (or as a bridge to transplant) include radiofrequency ablation (RFA) or transarterial chemoembolisation (TACE). For advanced hepatoma, sorafenib (a multitargeted tyrosine kinase inhibitor) improves survival.


This is an autosomal recessive disease marked by progressive iron loading of parenchymal cells of the liver, pancreas, heart and other organs. The diagnosis is now most often made before any symptoms develop (the result of routine iron studies) and is much more common in men (menses protect women).

Symptomatic patients usually present with hepatomegaly and abdominal pain. HCC occurs in up to 30% of patients with cirrhosis. Diabetes mellitus is a classical presentation, as is grey skin pigmentation (‘bronzed diabetes’), dilated cardiomyopathy, arthropathy (second and third metacarpophalangeal (MCP) joints) and impotence (owing to iron pigmentation in the pituitary gland).

Hereditary haemochromatosis is a common genetic disorder in Caucasians, with a prevalence of at least 1 in 250. Diagnosis is suggested by an increased transferrin saturation (>62% men, >50% women) and a raised ferritin level (>300 μg/L in men and >200 μg/L in women is suggestive). The serum ferritin level is an acute-phase reactant and may be elevated in other chronic inflammatory conditions, notably those involving the liver, including non-alcoholic steatohepatitis (NASH), alcoholic liver disease and chronic viral hepatitis.

Diagnosis is made by looking for the genetic defects. In difficult cases, liver biopsy is useful to measure the amount of iron overload and the extent of liver disease (fibrosis, cirrhosis etc.). There are specific features on biopsy; a Perl’s Prussian blue stain visually demonstrates the extent of iron overload. It is important to determine the hepatic iron concentration and index (usually >1.9) on liver biopsy specimens.

The genetic defect has been localised to the short arm of chromosome 6. The gene has been termed HFE. Two mutations have been described: C282Y and H63D. Patients with phenotypic haemochromatosis are usually homozygous for the C282Y mutation; a few are compound heterozygotes (C282Y and H63D mutation). Homozygotes for H63D may not be at risk; 5% of those with haemochromatosis have none of these mutations. Genetic testing is recommended for all first-degree relatives of the proband. In those cases homozygous for C282Y, there is a one in four chance of the siblings being homozygous. The children’s chance of developing haemochromatosis depends on the other parent (homozygous normal indicates no risk).


1. Treatment is through regular venesection (weekly) for approximately 2 years and then once every 3 months. The optimal regimen is not established, but the aim is to reduce iron stores as quickly as possible: 50 units of blood removed per year equals about 12.5 g of iron withdrawn. Patients with iron overload as a result of mutations of the iron export protein ferroportin may not tolerate this rate of removal.

2. The avoidance of alcohol is important.

3. Arthropathy and endocrine changes do not respond to treatment.

4. Hepatocellular carcinoma is not prevented by venesection in patients with established cirrhosis, but life expectancy is normal in those without end-organ damage whose iron stores are reduced.


Non-alcoholic steatohepatitis is defined by histological features, resembling those of alcoholic hepatitis, which are present in patients who have not consumed excessive quantities of alcohol. The majority of patients present because they are inadvertently found to have abnormal liver function tests or steatosis detected on imaging. Even though clinical findings are uncommon, hepatomegaly is the most frequent sign detected. The typical liver function abnormalities are a two- to threefold elevation of the serum aminotransferase levels, with the serum ALT greater than the serum AST level (the opposite of alcoholic liver disease). The serum gamma-glutamyl transferase (GGT) levels are also similarly elevated. Viral markers are absent.

NASH is more common in women and the most frequently associated underlying clinical conditions are obesity, type 2 diabetes mellitus and hyperlipidaemia, particularly hypertriglyceridaemia. Look for evidence of the metabolic syndrome (including hypertension, increased waist circumference and high lipids). Nevertheless, studies have documented lean men with NASH. Although the peak age of presentation is the fifth and sixth decades of life, NASH is now the most common cause of liver disease in adolescents.

Exclude drug causes such as steroid use and amiodarone. The definitive diagnostic test is a liver biopsy but is not usually required. Other liver disease must be excluded (e.g. haemochromatosis, chronic viral hepatitis) (Table 7.15). The typical histological features are macrovesicular steatosis with an associated necroinflammatory infiltrate (usually mononuclear) and a variable degree of fibrosis.

Table 7.15

Causes of hepatic steatosis





Diabetes mellitus



Organic solvents

Jejunoileal bypass


Total parenteral nutrition


Another group of patients has fatty liver disease without inflammation and with normal transaminase levels – non-alcoholic fatty liver disease (NAFLD).

A proportion of patients will progress to more chronic liver disease with fibrosis and ultimately cirrhosis. NASH may explain many cases previously labelled as cryptogenic. Studies have documented elevations in both cardiovascular and hepatic mortality.


Management options are limited to treating the underlying clinical condition, with slow weight loss and exercise recommended for obese patients and strict control of hyperlipidaemia and hyperglycaemia. Statin therapy is safe for patients with hypercholesterolaemia. Alcohol should be avoided. Vitamin E supplementation is recommended in the absence of diabetes and if there is fibrosis.

Liver transplantation

Liver transplantation is now an important therapeutic option in patients with irreversible, progressive liver disease for which there is no acceptable alternative therapy and no absolute contraindication. The 1-year survival rate overall is 75%. In the examination setting, a patient will either have chronic liver disease and be a candidate for transplantation or be a transplant recipient who has a problem.

The history

1. Obtain details of the patient’s liver disease, including diagnosis and duration. Candidates for liver transplantation include patients with cirrhosis, primary sclerosing cholangitis, autoimmune chronic hepatitis, chronic portal-systemic encephalopathy, Budd-Chiari syndrome, inherited metabolic diseases (e.g. Wilson’s disease, alpha1-antitrypsin deficiency) and acute or subacute hepatic failure.

2. The timing of the transplantation is crucial. This should be considered when the patient is end-stage but before complications have occurred that may preclude proceeding (e.g. preterminal variceal bleeding, irreversible hepatorenal syndrome, development of a catabolic state, irreversible coagulopathy, vascular instability with ascites or incapacitating osteopenic bone disease). Those with end-stage liver disease who have had a life-threatening episode of decompensation or whose quality of life has become unbearably reduced are potential candidates. Accepted criteria include a Child-Pugh score >6, an episode of variceal bleeding or spontaneous bacterial peritonitis, or stage II encephalopathy in acute liver failure. A model for end-stage liver disease (MELD), which has been developed at the Mayo Clinic and is based on three parameters (serum bilirubin, INR and creatinine), helps predict survival and is widely used (transplant candidates have a score >10).

3. If the patient may be a candidate for liver transplantation, enquire about potential contraindications. Relative contraindications include active sepsis outside the liver, metastatic malignancy, cholangiocarcinoma, continuing alcohol consumption, HIV, diffuse portal vein thrombosis and advanced cardiopulmonary or renal disease, a prior portacaval shunt (TIPS is not a contraindication), intrahepatic or biliary infection, localised portal vein thrombosis, renal failure, and prior complex hepatobiliary surgery. Severe hypoxaemia as a result of intrapulmonary shunting is another potential contraindication (patients with the hepatopulmonary syndrome and hypoxia can benefit, but a PaO2 of <50 mmHg is a relative contraindication; severe portopulmonary hypertension is a contraindication).

4. Ask about tests that have been done in preparation for transplant. These typically include cardiac and pulmonary tests (electrocardiogram, echocardiogram, stress test, chest X-ray, pulmonary function tests), renal tests (urine protein and creatine, and glomerular filtration rate estimation) and liver tests (imaging to exclude a hepatoma and to define the vascular anatomy).

5. Enquire about complications of the patient’s liver disease (e.g. previous variceal haemorrhages, ascites, pre-coma, hypoxaemia caused by hepatopulmonary syndrome etc.).

6. If the patient has had a transplant, enquire about the postoperative course, including whether further surgery was carried out (e.g. drainage of abscesses, reconstruction of the biliary tract for control of bleeding, retransplantation for graft failure and for hepatic arterial thrombosis). Also ask about postoperative infections.

7. Ask about complications of liver transplantation. Early on (in the first 5 days), primary graft failure, technical problems (e.g. bleeding, hepatic arterial thrombosis, bile leaks, portal vein thrombosis), renal failure and pulmonary complications (atelectasis, pleural effusion, infection) may occur. Major problems after discharge from hospital include rejection, infection, biliary complications, hypotension, recurrent disease, bone disease, nutrition and de-novo cancer. Infections occur in most patients, largely related to immunosuppression; chronic opportunistic infections usually occur from 4 weeks after transplantation. Biliary strictures may also occur from 4 weeks after transplantation. Acute liver rejection is rarely seen after the initial 6 months. Chronic rejection usually occurs 6 weeks to 9 months after transplantation; there is progressive cholestasis and diagnosis is best made by liver biopsy. Bone disease and ectopic calcification may occur some months after transplantation.

8. Ask about current medications and related complications with their use. Cyclosporin may induce cholestasis (dose-dependent), hypertension, nephrotoxicity, gum hypertrophy, seizures (controlled by phenytoin, which itself induces cyclosporin metabolism) and central nervous system effects, including tremor and central pontine myelinolysis. Patients with a low serum cholesterol level are at increased risk of central nervous system toxicity. Steroids in high doses may induce a number of problems, including aseptic necrosis of long bones, cataracts and psychosis. Enquire about drug compliance.

9. Ask about the specific complications of immunosuppression. Systemic and local infections are frequent problems and can be rapidly fatal if not treated aggressively. Opportunistic infections include Pneumocystis jirovecii and Candida albicans. Ask about prophylactic antibiotic therapy. Cytomegalovirus infection remains a major problem. Try to find out tactfully whether there has been any problem with malignancy. The incidence of skin cancers and lymphomas (especially in the central nervous system) is increased with immunosuppression.

The examination

1. The pre-transplant patient should be examined for signs of chronic liver disease and complications of liver disease. Note clubbing (which occurs in cirrhosis and might indicate hepatopulmonary syndrome is this setting).

2. The post-transplant patient should be examined for liver tenderness (e.g. acute rejection) and jaundice (e.g. vanishing bile ducts in chronic rejection, biliary stricture). Examine the chest for infection and the mouth for candidiasis. The temperature must be taken (Table 7.16). Examine the central nervous system (e.g. cyclosporin toxicity or cerebral infarction from perioperative hypotension or air embolism). Tap the spine for tenderness (e.g. vertebral collapse). Take the blood pressure (hypertension may occur at any time after transplantation; it is often caused by cyclosporin).

Table 7.16

Causes of fever in the outpatient with a liver transplant


FIGURE 7.13 Mixed cryoglobulinaemia in a patient with hepatitis C. Purpura of the legs. M Ramos-Casals. The cryoglobulinaemias. The Lancet. 2012. 379(9813):348–360. Elsevier, with permission.


FIGURE 7.14 Lichen planus on the dorsal surface of the hand. Wickham’s striae can be easily identified in the upper right lesion. Note the flat-topped nature of the lesions. J L Bolognia, J L Jorizzo, J V Schaffer. Dermatology. 3rd edn. Elsevier, 2012, with permission.

Biliary tract (stricture and cholangitis)

Pneumonia (e.g. Pneumocystis, bacterial, fungal)

Urinary tract sepsis

Hepatitis (acute or recurrent)

Central nervous system infection (especially fungal)

Viral infection (e.g. cytomegalovirus, herpes, varicella-zoster)


Pre-transplant patients need tests to confirm the diagnosis, determine current liver synthetic function (e.g. serum albumin, INR) and rule out contraindications. Ultrasound and CT scanning are routine. In patients with possible or definite malignancy, metastases must be sought. Assess bone density; osteopenia is common in liver disease and increases following transplant. Cardiopulmonary and psychiatric evaluation are important.


Routine outpatient monitoring after transplantation should include a full blood count, electrolyte levels, renal and liver profile, and trough cyclosporin levels. Remember drug interactions with cyclosporin. Diabetes mellitus may supervene as a result of treatment with tacrolimus or steroids. Hypertension should be treated. Diseases that can recur in the graft include hepatitis B and C, Budd-Chiari syndrome and primary biliary cirrhosis.