Gastroenterology and Hepatology — Long Cases

6 Gastroenterology and Hepatology—Long Cases Man-Fung Yuen, Wai-Keung Leung, and Ching-Lung Lai 6.1 Epigastric pain (functional dyspepsia) History A 35-year-old woman complained of on and off epigastric discomfort for 5 years, with worsening symptoms in the past 2 months. The discomfort occurred intermittently throughout day and night. Tt was slightly worse after meals and associated with belching, abdominal distension, and early satiety (fullness). There was no recent weight loss or dysphagia. Her appetite was poor recently due to the epigastric distension. Because of worsening symptoms in the last 2 months, she attended her family doctor. A blood test was performed, which suggested the presence of Helicobacter pylori infection. She was given 1 week of “triple” therapy for treatment of H. pylori. A urea breath test was performed 1 week earlier (4 weeks after completing her drug therapy) and was negative. Her family doctor then arranged an upper endoscopy and an abdominal ultrasound examination and both were normal. However, she continued having epigastric pain and was referred for a second opinion. Physical examination She was a well-nourished lady with normal blood pressure and pulse. Abdominal examination revealed mild epigastric tenderness

74 Problem-Based Medical Case Management Case 6.1 without guarding or rebound tenderness. There was no organo- megaly and the bowel sounds were active. Other systems were normal. Questions 1. 2. What is the likely diagnosis? The most likely diagnosis is functional dyspepsia. Functional dyspepsia needs to be distinguished from uninvestigated dys- pepsia. Uninvestigated dyspepsia is the initial presentation to family doctors. It could be due to a wide variety of diseases like gastro-oesophageal reflux disorder, peptic ulcers/erosions, oesophageal and gastric cancer, gall-bladder and/or biliary dis- orders, pancreatic disease like pancreatic cancer and chronic pancreatitis, irritable bowel syndrome, and other rare condi- tions. Dyspepsia is a very common presentation in Chinese, with an estimated population prevalence of 10-20%. It is also one of the most common reasons for consultation to family doctors. Functional dyspepsia is diagnosed after excluding some common causes by investigations (blood tests, upper endoscopy, and ultrasonography). It is the commonest cause of epigastric discomfort. Although it is largely a diagnosis of exclusion, special caution should be given to those with persistent symp- toms despite medical treatment. How common is Helicobacter pylori infection and how should it be diagnosed? Helicobacter pylori infection affects about 50% of the popula- tion in China. In developed countries its prevalence is around 10-40% but in developing countries it is as high as 40-80%. It is believed to be transmitted by the oral-oral or faecal-oral route, mostly in childhood and is associated with low socio- economic status, overcrowding, and poor social hygiene. Diagnosis of Helicobacter pylori infection: — Non-invasive methods: C-13 urea breath test, H. pylori stool antigen test, and serological antibody test that detects IgG antibody against H. pylori. The first two methods are more

Case 6.1 Gastroenterology and Hepatology 75 accurate particularly for monitoring of treatment success, whereas serological test needs to be validated locally to ensure accuracy. - Invasive methods: these are based on gastric antral biopsy specimens obtained during upper endoscopy, which can be used for the rapid urease test, histological examination, or bacterial culture and antibiotics sensitivity testing. The rapid urease and histology tests are very accurate for diag- nostic tools. Bacterial culture is less sensitive due to techni- cal difficulties in growing the bacteria, but is the only test that allows antibiotics sensitivity testing, and is therefore useful in the event of treatment failure by providing a guide to future drug interventions. 3. What issues are pertinent to diagnosing and monitoring of treatment success? * All tests except antibody tests are affected by recent intake of proton pump inhibitors, antibiotics, and bismuth compounds: ~ which may produce false negative results due to the suppres- sion of bacterial growth to below the diagnostic thresholds. ~ H,-receptor antagonists and antacids do not affect the tests. — Post-treatment testing should be done at least 4 weeks after stopping all drugs that can affect the test results, the longer the better. - Antibody tests should not be used for post-treatment testing, as antibody titres, particularly IgG, can remain high for 6-12 months, even after successful treatment. 4. How is Helicobacter pylori infection treated? * The conventional treatment for H. pylori is triple therapy con- sisting of (i) a proton pump inhibitor (PPI) at standard dose + (ii) clarithromycin 500 mg + (iii) either amoxicillin 1 g or met- ronidazole 400 mg, all given twice daily for 7 days. The success rate varies in different countries, according to the prevailing patterns of antibiotic resistance and compliance to drug treat- ment in the respective populations. The success rate is around 90-94% among Chinese. There is however arising trend of anti- biotics resistance, particularly with resistance to clarithromycin, which limits the efficacy of conventional clarithromycin-based

76 Problem-Based Medical Case Management Case 6.1 triple therapy. Side effects are common, though usually mild and self-limiting. Skin rash and profuse diarrhoea need urgent management, including cessation of therapy. « To overcome the issue of falling eradication rate of conventional PPI-based triple therapy, there is a rising trend of inclusion of all three antibiotics (amoxicillin, clarithromycin, and metroni- dazole) given as sequential (amoxicillin given for first 5 days and followed by subsequent 5 days of the remaining two antibi- otics) or concomitant therapy regime (all three antibiotics given together). 5. Why do some patients appear not to respond after treat- ment of Helicobacter pylori? * H. pylori infection is associated with peptic ulcers, gastric cancer, and gastric lymphoma. However, it remains uncertain whether H. pylori infection causes non-ulcer dyspepsia or even functional dyspepsia. Treatment of H. pylori infection is one of the options for treatment of functional dyspepsia, but the symptom response rate is only around 20-40% (similar to other options). Hence, 60-80% of patients would have incomplete symptom relief, despite successful H. pylori eradi- cation. This must be communicated to all patients starting treat- ment. Appropriate investigation (ultrasonography or CT scan to exclude gall-stones or pancreatic disease) may be required. 6. What are the treatment options for managing functional dyspepsia? ° The initial approach is to have a constructive patient-physician relationship and provide education and reassurance about its being benign and non-life-threatening. Medical treatment includes: — Use of anti-secretory agents like antacids, H,-receptor antagonists, proton pump inhibitors, or triple therapy for Helicobacter pylori infection if positive. — Prokinetic agents like metoclopramide, domperidone, and some newer drugs under evaluation. — Anti-nociceptive agents like tricyclic antidepressants and selective serotonin reuptake inhibitors.

Case 6.2 Gastroenterology and Hepatology 77 _ Other modalities: psychological therapy; “alternative” thera- pies (acupuncture, herbal medicine, probiotics) have been tried with limited success. 6.2 Heartburns (gastro-oesophageal reflux disease) History A 50-year-old man complained of retrosternal chest discomfort in the past 6 months. The discomfort was compressing in nature, without radiation to the throat. It occurs more often after meals; sometimes waking him in the middle of the night and relieved by drinking water. He had regular jogging exercise and there was no discomfort walking up stairs or during exercise. Nor was there any history of recent trauma, falls, significant Joss of weight or appe- tite. His past medical history was unremarkable. He was a heavy smoker and a social drinker. His father had coronary heart disease diagnosed at the age of 55. Physical examination The cardiovascular system was normal; his blood pressure was 140/90 mmHg and he was in sinus rhythm (heart rate 80/min). Examination of the chest wall revealed no scarring, deformity, or local tenderness. Other systems were normal. Questions 1. What is the likely diagnosis and how common is it? s Gastro-oesophageal reflux disease is the likely diagnosis. It is more common in developed countries; 30-40% of the general population having symptoms at least monthly. The figure is around 10% in Chinese. Characteristic features in the history include heartburn and acid regurgitation. Heartburn represents

78 Problem-Based Medical Case Management Case 6.2 a burning sensation behind the sternum that may or may not include radiation to the throat. Acid regurgitation includes a feeling of acidity in the stomach that flows up the chest to the throat. Heartburn is ill-defined in non-English-speaking (includ- ing most Asian) populations. Therefore, patients presenting with chest pain should have their history carefully evaluated, in order to exclude gastro-oesophageal reflux disease. 2. What is gastro-oesophageal reflux disease? « In simple terms it refers to reflux of gastric contents into the oesophagus or other proximal organs, leading to either symp- toms or mucosal damage. According to the consensus report of a workshop held at Genval the term should be used to include all individuals experiencing physical complications or clinically significant impairment of health-related well-being (quality of life) due to gastro-oesophageal reflux or reflux- related symptoms. ¢ QGastro-oesophageal reflux disease is a spectrum of disorders that can be broadly classified into three categories: — Non-erosive reflux disease (the main group), which includes patients with typical symptoms of reflux but normal oesoph- ageal mucosa as documented by upper endoscopy. — Erosive oesophagitis (mucosal lesions documented by upper endoscopy) with or without local complications (stricture, Barrett’s oesophagus, adenocarcinoma). — Extra-oesophageal disease (asthma, chronic cough, globus sensation, posterior laryngitis, sleep disorders, non-cardiac chest pain), where symptoms may or may not be due to reflux. . Depending on their respective symptoms, patients in the latter category may initially present to and be investigated by respira- tory physicians, ear, nose and throat surgeons or cardiologists. The diagnosis of such patients is relatively difficult, and the response to treatment is not as satisfactory as in those with typical symptoms. 3. What are the risk factors for gastro-oesophageal reflux? * Exogenous risk factors include: obesity, high body mass index, smoking, alcohol, and family history of reflux disease.

Case 6.2 Gastroenterology and Hepatology 79 » Endogenous risk factors entail: genetically predetermined vari- ations in upper gastrointestinal physiology; occurrence of other comorbid diseases that disrupt normal oesophageal physiology and promote reflux. 4. How is gastro-oesophageal reflux disease diagnosed? o There is no gold standard, but the following four main methods are available and can be used alone or in combination: Symptom questionnaires: different versions are available and their accuracy is around 80-90%. Upper endoscopy: detects erosive oesophagitis and other macroscopic complications, but these account for only 20-40% of symptomatic patients; presence of such lesions supports the diagnosis but their absence is unhelpful. Ambulatory 24-hour oesophageal pH monitoring: accuracy of 80-90%, but is inconvenient, uncomfortable, and seldom used as a first line diagnostic tool, as it is not widely available. Proton pump inhibitor testing: constitutes a therapeutic trial and is conducted over 1-4 weeks; patients responding favourably are likely to have a reflux component to their symptoms. 5. How is gastro-oesphageal reflux disease treated? ¢ Three types of treatment options are available as follows: Dietary and lifestyle modifications: These include low-fat diet, maintenance of ideal body weight, smoking cessation, avoidance of tight belts, corsets, alcohol, chocolate, spicy foods, and coffee, and regular exercise. Nocturnal symptoms may benefit from elevating the head of the bed and avoid- ance of eating 2-3 hours before bedtime. Such measures can only improve symptoms to a modest extent. Medical therapy: A range of drugs may be useful, includ- ing: (i) antacids, (ii) H,-receptor antagonists, and (iii) proton pump inhibitors (omeprazole, esomeprazole, lansopra- zole, pantoprazole, rabeprazole). For patients with erosive oesophagitis, proton pump inhibitors provide optimal initial healing as well as long-term maintenance therapy. Patients with more advanced erosive oesophagitis (Los Angeles classification grades C and D) need long-term maintenance

80 Problem-Based Medical Case Management Case 6.3 therapy to avoid recurrences and complications. Patients with non-erosive reflux (Los Angeles classification grades A and B) that respond to initial treatment with proton pump inhibitors may be considered for on-demand symptomatic treatment. — Surgical treatment: Anti-reflux surgery (various types of fundoplications) helps to restore the anti-reflux mechanism and improve reflux. It may be considered for patients who do not want to receive long-term maintenance therapy for gastro-oesophageal reflux. Pitfalls and tips » A thorough cardiovascular evaluation, including ECG and Treadmill examination, should be performed in this middle- aged man with known risk factors of coronary artery disease including smoking and family history. 6.3 Chronic diarrhoea (ulcerative colitis) History A 21-year-old male medical student presented with diarrhoea and rectal bleeding for 3 months. Bowel motions were up to 6 times per day and were getting worse recently. There was also mucus in stool and mild abdominal pain. There was no fever and signifi- cant weight loss. There were however some painful nodules in his lower limb for a few weeks. He enjoyed good past health and there was no recent travel history. He was given some antibiotics by the university clinic with no improvement. His father had a history of ulcerative colitis and was stable on treatment. Physical examination General examination revealed some erythematous and painful nodules over his shin, which was compatible with erythema

Case 6.3 Gastroenterology and Hepatology 81 nodosum. Abdominal examination was unremarkable and rectal examination showed no abnormality. Questions 1. What is the most likely diagnosis? The most likely diagnosis for this patient is inflammatory bowel disease, more likely to be ulcerative colitis. Although this disease is relatively uncommon in the past, the incidences of inflammatory bowel disease including both Crohn’s disease and ulcerative colitis are rising rapidly in Asia. . What is inflammatory bowel disease? Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory condition of the gastrointestinal tract. Ulcerative colitis typically affects the rectum and colon only, with rectal involvement in virtually all patients. Crohn’s disease could affect any part of the gastrointestinal tract starting from the mouth with recurrent aphthous ulcers to the anus with peri-anal fistula and abscess. Crohn’s disease tends to have transmural involvement, resulting in ulceration, perforation, and even stricture. In contrast, ulcerative colitis involves the mucosa layer only. . What are the differential diagnoses? Infective causes of colitis should be considered including bacterial gastroenteritis, amoebic colitis, and tuberculosis infection of intestinal tract. In patients with recent antibiotics exposure, Clostridium difficile infection should be ruled out by stool culture and endotoxin assay. In immunocompromised hosts, opportunistic infection such as CMV infection should be considered. . How to diagnose ulcerative colitis? After ruling out infection by various stool examinations, colo- noscopy and biopsy would be useful in assessing the colonic mucosal conditions such as the extent and degree of inflamma- tion, and the presence of ulcerations etc. Colonic biopsy typi- cally shows the presence of chronic inflammatory infiltrates and

82 Problem-Based Medical Case Management Case 6.3 the absence of CMV inclusion or parasites. Granuloma is more often seen in patients with Crohn’s disease. 5. Are there any risk factors for IBD? e Although the exact etiological agent for IBD remains to be determined, approximately 10% of Western patients with IBD have family histories of IBD. Smoking is found to be associated with fistulizing Crohn’s disease but appears to be protective against development of ulcerative colitis. Appendicectomy in childhood is also found to be a protective factor for ulcerative colitis. 6. What are the extra-intestinal manifestations of IBD? * Apart from intestinal manifestations, patients with IBD could have many extra-intestinal manifestations, particularly those affecting the eyes, skin, joints, and hepatobiliary system. Ocular manifestations include uveitis, episcleritis, corneal ulcers, and retinal vascular disease. Dermatological manifestations could lead to erythema nodosum (as in this patient) and pyoderma gangrenosum, which correlate with disease activity. Joint involvement could present with oligoarthritis or seronegative ankylosing spondylitis-like features. Primary sclerosing chol- angitis and gall-stones are also associated with IBD. 7. How do you treat ulcerative colitis? * *Mild to moderate disease can be treated with oral or topical sulphasalazine or 5-aminosalicylic acid. Sulphasalazine is associated with some adverse effects like skin rash and azoo- ‘spermia. Topical treatment including suppository or enema is more effective for rectal disease. Severe disease should be © treated with short-term corticosteroids. Immunomodulators like azathioprine or 6-mercaptopurine could be used in patients ~ who are steroid-dependent or with frequent relapse of disease. Biologics, mainly anti-tumour necrosis factor (TNF), are »ihcreasingly used in patients with severe disease. 8. What are the potential complications of ulcerative colitis? - Longstanding extensive colitis is associated with higher risk - of colorectal cancer. Surveillance colonoscopy is therefore - indicated in patients with extensive colitis of more than 8- -year duration. Severe exacerbation of ulcerative colitis could present

Case 6.4 Gastroenterology and Hepatology 83 as toxic megacolon with fever, abdominal pain and distension, diarrhoea, and rectal bleeding. Prompt medical therapies with supportive treatment and intravenous corticosteroid are indi- cated. If patient fails to respond to corticosteroid, treatment with intravenous ciclosporin or anti-TNF should be used. Surgeon should be consulted early for the possibility of protocolectomy if all medical therapies fail. 6.4 Progressive abdominal distension (hepatitis B cirrhosis with ascites) History A 50-year-old postman presented with gradual abdominal disten- sion for 2 months. He first knew he had chronic hepatitis B when he tried to donate blood 30 years ago. Twenty years ago he was admitted to hospital because of severe anorexia, nausea, darkened urine, and jaundice lasting for about 4 weeks. He was treated with intravenous fluid and diagnosed to have an acute exacerbation of his chronic hepatitis. Since then he remained well until 2 months ago when he noted gradual onset of abdominal and ankle swelling, especially prominent in the evenings. His appetite remained good. His mother was known to carry the hepatitis B virus, two of his four siblings also had chronic hepatitis B and his maternal uncle died of liver cancer at the age of 55 years. The patient was an occasional beer drinker (mainly on weekends). He had multiple sexual partners 30 years ago. Physical examination He had at least 3 spiders in his upper chest, palmar erythema, and early clubbing (loss of angle between nail and nail bed together with floating sensation), but he was not jaundiced. He had ankle oedema up to his knees as well as bilateral shin pigmentation. He had a distended abdomen with a flattened umbilicus. The liver was not palpable and liver dullness was actually decreased to

84 Problem-Based Medical Case Management Case 6.4 about a 5 cm span at the right mid-clavicular line. The spleen was enlarged to 5 cm below the costal margin, firm and non-tender. Shifting dullness was evident, but there was no fluid thrill. Questions 1. 3. What is the diagnosis and on what is it based? Ascites, secondary to cirrhosis of the liver due to chronic hepa- titis B infection. The diagnosis of post-hepatitis cirrhosis of the liver is based on: — History of chronic hepatitis B. Stigmata of chronic liver disease. Shrunken liver. Splenomegaly. Presence of ascites. The latter two signs are indicative of portal hypertension. 1 . How did the patient acquire the hepatitis B infection? Probably from his mother (at birth or through close post-natal contact). The maternal uncle’s death due to hepatocellular carcinoma further confirms that his mother’s family had the infection. - Typically not all siblings are infected; theoretically the younger children are less likely to be infected, as the mother might have undergone HBeAg seroconversion, resulting in a lower viral load as she grows older. Though he could have come into contact with the hepatitis B virus through his multiple sexual partners, infection in adult- hood is unlikely to give rise to chronic infection. What evidence is there that his abdominal distension is not due to obesity and why are cirrhotic patients more prone to develop ascites at an early stage of the disease? . The concomitant ankle swelling is indicative of fluid retention in the patient, making ascites a likely cause of his simultaneous abdominal swelling. Cirrhosis patients are prone to ascites early because of portal hypertension, which localizes the retained fluid in the peritoneum.

Case 6.4 Gastroenterology and Hepatology 85 4. Ts occasional beer drinking dangerous in this patient? « Alcohol and hepatitis B have synergistic effects on liver damage. However, small amounts of alcohol appear acceptable, in contrast to hepatitis C patients in whom even a very small amount of alcohol is dangerous. (For safe levels and dangerous levels of drinking, see p. 98.) S. What are the relevant investigations for this patient? o Liver functions tests: Serum albumin level; when reduced, this is a good indica- tor of subacute and chronic liver diseases (its half-life being around 25 days). Globulin tends to be increased in cirrhosis of the liver due to increased antigenic stimulation of the B cells. This may be due to gut antigens being shunted directly to the systemic circulation through porto-systemic shunts; the failing liver not being able to eliminate such antigens; as well as the pro- duction of abnormal antigens by the cirrhotic liver. Bilirubin level is usually normal until a relatively late stage of cirrhosis. Serum transaminases (ALT and AST) levels do not reflect the severity of the cirrhosis, rather, the degree of hepatitic activity. Alkaline phosphatase and gamma glutamyl transpeptidase are raised only in space-occupying diseases of the liver or cholestasis. They are normal or only marginally raised in parenchymal liver disease. Prothrombin time prolongation is an indication of clinically significant liver dysfunction. Alpha-fetoprotein levels should be routinely measured to screen for early hepatoma; raised levels may be encoun- tered due to liver regeneration (after an acute exacerbation). Moreover, it is not a sensitive test. * Hepatitis B serology: HBsAg: should be tested annually since there is a 0.1-1% annual rate of spontaneous HBsAg seroclearance. HBeAg/anti-HBe: the majority of cirrhosis complications including hepatoma occur when the patients are anti-HBe positive.

86 Problem-Based Medical Case Management Case 6.4 — HBV DNA: this needs checking to determine whether patient requires treatment. * Complete blood count: yields important information about the degree of hypersplenism as well as possible blood loss through varices or portal hypertensive gastropathy. « Diagnostic paracentesis of ascitic fluid (for in-patients): — White cell count and differentials to exclude spontaneous bacterial peritonitis. — Protein level (tend to be low in cirrhosis of the liver. In spon- taneous bacterial peritonitis, the protein level is typically < 10 g/L, indicative of low opsonic activity). — Malignant cytology (often useless since sensitivity is < 10%). ¢ Renal function tests and electrolytes; mainly as a baseline before diuretics therapy. » Ultrasonography of the liver; should be performed every 6 months in order to detect early hepatoma. Unlike alpha fetoprotein, this is a generally accepted screening procedure; six monthly testing is recommended for detecting small hepato- mas (< 3 cm in diameter). e Ultrasound can also support the diagnosis of cirrhosis if the liver is small. Cirrhosis may also be suspected if the spleen is enlarged and/or there are ascites. 6. How would you treat this patient? Ascites is treated as follows: — Adpvise a low-salt diet and restrict fluid intake (~1 L per day). — Commence potassium-sparing diuretics; spironolactone is especially effective for fluid control because in cirrhosis hyperaldosteronism is especially severe (aldosterone being normally metabolized by the liver). However, due to the fre- quent side effect of painful gynaecomastia in male patients, amiloride is often used as a first line agent in males. — Addition of loop diuretics if necessary; bumetamide may be more reliably absorbed from the gut than frusemide, when there is portal hypertension. — Therapeutic paracentesis can be used as the first treatment for in-patients. It is relatively safe and free of side effects, °

Case 6.5 Gastroenterology and Hepatology 87 provided adequate amounts of albumin are infused to main- tain intravascular volume. Possible complications include: (i) renal impairment (which may in turn precipitate hepatic encephalopathy) (ii) infection (iii) intraperitoneal bleeding (prevented by fresh frozen plasma and/or platelet transfusion) o Treatment directed at the hepatitis B virus infection, which is indicated if the viral DNA load is high and the ALT level is > the upper limit of normal (< 30 w/L for male, < 19 w/L for female). _ Interferon is contra-indicated in cirrhosis, since it may cause further liver decompensation in patients with borderline liver function. _ Nucleoside analogues can be used. Lamivudine was shown to reduce the development of cirrhosis complications includ- ing hepatoma in a double-blind placebo-controlled trial and is almost without side effects. However, it is associated with progressive increase in viral resistance (> 65% after 4 years of therapy). At present, the first line agents are entecavir and tenofovir. Both agents have the highest antiviral potency and low rate of drug resistance (1.2% for entecavir, 0% for tenofovir). 6.5 Abdominal distension in a previous intravenous drug abuser (hepatitis C-related hepatocellular carcinoma) History A 55-year-old male church helper was admitted with abdominal distension. He was an intravenous drug abuser when he was about 20 years old, but subsequently converted to Christianity, stopped drug abuse and for over 30 years had been working tirelessly for the church.

88 Problem-Based Medical Case Management Case 6.5 Ten years ago, he was found to have abnormal liver function tests and investigations revealed he had chronic hepatitis C, for which he was treated with interferon and ribavirin for 1 year. However, he was told that the treatment was not effective. Five years ago, he developed mild abdominal swelling and was diag- nosed to have “fluid” in his abdomen. He was advised to limit his fluid intake to around 1 L per day and prescribed some diuretics, whereupon his abdominal distension regressed. During routine follow-up 10 months ago, he was told that his alpha-fetoprotein level was raised and he noticed recurrence of abdominal distension. An ultrasonogram of the liver performed 2 weeks later was reported to show some suspicious masses, but was inconclusive about their exact nature. Further investigation involving injection of dye into his blood vessel confirmed that he had a malignant tumour in the liver. He was told that surgery was not possible, and was started on injections of chemotherapeutic agents into his thigh artery. These were repeated every 8 weeks and the present admission was for the 4th such course of treatment. After each course he only had mild fever for 1-2 days and was told that the response to the treatment was good, and that his alpha- fetoprotein level had returned to normal. On the advice of his doctor he had abstained from alcohol, ever since he was diagnosed to have hepatitis C, but he continued to smoke (1 pack of 20 cigarettes per day for over the last 30 years). Physical examination He was not jaundiced but had palmar erythema. There was no abdominal distension; the liver was marginally reduced in size (span of 8 cm at the right mid-clavicular line) and the spleen was palpable 4 cm below the costal margin. Questions 1. How would you establish the diagnosis of hepatocellular carcinoma? * The diagnostic level of alpha-fetoprotein for hepatocellular carcinoma is 500 ng/mL. Based on this moderately high cut-off

Case 6.5 Gastroenterology and Hepatology 89 level, the sensitivity of this test is still low (< 70%). Moreover, acute exacerbations of chronic hepatitis B and C can also give rise to similar alpha-fetoprotein levels. In a patient with chronic hepatitis and raised alpha-fetoprotein levels, one should undertake: _ ALT and AST levels measurements; these are usually raised during acute exacerbations but within normal limits in the presence of small hepatocellular carcinomas; in large cancers, AST levels are typically = 2 fold the ALT levels. _ Ultrasonography of the liver; this is a more sensitive test for diagnosing early hepatocellular carcinoma, which can detect Jesions 1-2 cm in diameter. _ Serial alpha-fetoprotein measurements after 2-4 weeks; levels decrease after acute exacerbation of hepatitis, but not if due to hepatocellular carcinoma. « CT or magnetic resonance imaging (MRI) of the liver, which can detect even smaller lesions than by ultrasonography and is essential for the assessment of tumour operability. o Hepatic arteriogram with post-lipiodal CT scan can be per- formed if CT/MRI images results are conclusive. Hepatic arte- riography may show: — Neovascularization. _ Tumour staining, i.e., dense staining due to neovascularization. — Arterio-venous shunting. _ Portal vein thrombosis, which can also be detected by ultra- sound, CT, and magnetic resonance imaging of the liver. Lipiodal (a lipid iodine oil) is injected together with contrast during angiography and is retained in tumour tissue (which lack lymphatics that can clear the dye). An interval CT scan (performed about 2 weeks after the initial angiography) enables even smaller hepatoceliular carcinoma lesions to be visualized as dense white areas. 2. What other investigations would you like to perform for this patient? « Liver function tests, including prothrombin time to monitor for any hepatic decompensation, especially after each course of treatment.

90 Problem-Based Medical Case Management Case 6.5 * Serial alpha-fetoprotein monitoring, to follow tumour progression/regression. ¢ Periodic (usually every 12-24 weeks) ultrasonography/CT examinations of the liver to assess tumour size regression/ progression. « Complete blood picture, especially after each course of treat- ment; pancytopoenia is rare if the chemotherapy is intra-arterial. * Hepatitis C virus RNA levels, to monitor for continuing viraemia. 3. What are the routes for hepatitis C virus transmission? » In Hong Kong, ~50% of patients acquire hepatitis C through previous blood or blood product transfusion and a further 25% through sharing of needles. The remainder have “sporadic” hepatitis C virus infection; sexual transmission though possible - is rare, mainly due to its low infectivity. 4. In what ways is the patient’s clinical course typical? * He acquired hepatitis C virus (presumably via the parenteral route) and without a symptomatic illness; his cirrhosis mani- fested > 15 years later and hepatocellular carcinoma > 20 years later. . — Individuals responding to interferon and ribavirin are at much lower risk of future complications, but this patient was a non-responder. Though his ascites was well-controlled, he probably had cirrhosis at least 5 years earlier. — Hepatocellular carcinoma that complicates chronic hepati- tis C typically presents on top of a cirrhotic liver, whereas in chronic hepatitis B, ~20% of hepatocellular carcinomas occur in a non-cirrhotic liver. Unlike hepatitis C virus, the B virus has direct oncogenic effects. — Another typical feature is its asymptomatic course, until it is relatively large. Hepatocellular carcinoma usually only causes symptoms (abdominal pain/distension) when its size exceeds 8 cm in diameter. 5. Which patients with chronic hepatitis C infection need treatment and what should they receive? * Patients with elevated ALT levels (indicating active liver destruction) who are hepatitis C virus RNA positive (indicating

Case 6.5 Gastroenterology and Hepatology 91 continuing viraemia) should be treated. There are two types of standard treatment. First, all oral direct acting antiviral agents. Second, a combination of pegylated interferon and ribavirin is given once weekly. Recommended treatment dura- tions and response rates differ according to the C virus geno- type. Responders have markedly reduced liability to disease progression. 6. Why is the prognosis so often very poor in hepatocellular carcinoma and what clinical/biochemical parameters can indi- cate the likely prognosis? o Hepatocellular carcinoma is one of the most malignant cancers affecting humans and carries a poor prognosis for the following reasons: — A majority of patients (about 80% for hepatitis B and 100% for C virus) have underlying cirrhosis, which limits the scope for resection or other interventions, and predisposes patients to post-treatment liver failure. — Early or pre-malignant lesions are present in other parts of the liver, so that there is a high chance of a second primary ensuing. This phenomenon may be termed “field canceriza- tion™; the whole liver having been exposed to oncogenic influence of the hepatitis B virus infection and/or cirrhosis. _ Patients do not have symptoms till late (tumour usually > 8 cm in diameter). — Early intravenous spread leads to carly mefastases and/or portal vein thrombosis. 7. What are the treatment options for hepatocellular carcinoma? * Liver transplantation is probably the only “curative” treatment, which can also treat any underlying cirrhosis. It is only possible for single tumours of < 5 cm in diameter or three tumours each of < 3 cm in diameter. Availability of liver transplant facilities and/or of suitable donors is a further limitation. Donor short- age may be partly overcome by resorting to living related liver donors. * Surgical resection is only possible for < 30% of cases, because of the four aforementioned poor prognostic factors, despite

92 Problem-Based Medical Case Management Case 6.5 screening programmes for early detection. Moreover, recurrence rates are also high due to the effect of “field cancerization”. * Radiofrequency ablation is useful for lesions < 5 cm in diam- eter, but tumours close to the portal venous system pose a special risk. » Percutaneous ethanol injection can also be used for lesions < 5 cm in diameter. ¢ Transcatheter arterial chemoembolization (TACE) is often used when other options are not feasible; the chemotherapeu- tic agent (e.g., cisplatin, doxorubicin) mixed with lipiodal by emulsification is infused into hepatic artery branches supply- ing the tumour(s). This is followed by partial embolization of the artery with gelfoam. Intra-arterial injection enables tar- geting of the chemotherapeutic agent to the cancerous tissue and minimizes systemic drug adverse/side effects, as they are subject to first pass metabolism. Moreover, lipoidal-associated chemotherapeutic agents are retained in the cancerous tissue for prolonged periods. Finally, the post-drug injection, partial gelfoam embolization, prevents rapid clearance of the agent and promotes tumour necrosis. Common side effects include: acute hepatic decompensation (20-30%), fever (due to tumour necro- sis and/or transient bacteremia). In rare instances, an abscess may develop in the necrotic tumour. Patients may also have nausea and vomiting, abdominal pain or ischaemic ulceration/ gastritis (from disturbed gastrointestinal blood supply) and “injection site haematomas or infection. 8. What are the contra-indications to TACE? ¢ They include: — Distant metastases. — Moderate/severe liver function impairment. — Arterio-venous shunting around the tumour. — Portal vein thrombosis (non-tumorous liver may be com- pletely dependent on hepatic arterial blood supply). — Diffuse hepatocellular carcinoma (as response is highly unlikely).

Case 6.6 Gastroenterology and Hepatology 93 6.6 Patient with primary biliary cirrhosis and hepatic encephalopathy for assessment of hepatic transplantation History A 50-year-old female secretary was admitted for consideration of liver transplantation. She was first found to have abnormal liver enzymes 10 years ago and 2 years later developed pruritus. She was referred to a specialist clinic where a liver biopsy was per- formed. She was told she had a relatively rare kind of liver cirrhosis involving the bile duct, and was started on daily oral medication, which was followed by some improvement of her liver function and pruritis. Five years ago, she started noticing progressive abdominal swelling, which was only partially controlled with diuretics. Her abdominal swelling became more severe over the last 2 years and required repeated hospital admission for paracentesis and increas- ing doses of diuretics. Six months ago, she became drowsy after celebrating her daughter’s marriage; she was admitted to hospital and diagnosed to have “liver coma”. Subsequently she was discharged home on a low-protein diet as well as laxatives. At an outpatient follow- up 2 months ago, the doctor told her that her “liver function” had deteriorated over the years and she would greatly benefit from a liver transplantation. After discussing this option with her family, the current admission was arranged to assess her for possible liver transplantation. . Physical examination revealed a moderately jaundiced lady, with liver palm and spider angioma. The liver was palpable 6 cm below the right costal margin, with upper border at the fifth inter- costals space (span of 16 cm at the right mid-clavicular line), and was firm, non-tender. It had a smooth surface and edge. The spleen was palpable 5 cm along its longest axis and there was a moderate amount of ascites.

94 Problem-Based Medical Case Management Case 6.6 Questions 1. What is the basis for diagnosing primary biliary cirrhosis (PBC)? Though pruritus is often present, there may be no symptoms. The diagnosis of PBC is suspected when liver biochemistry shows a cholestatic pattern, i.e., high alkaline phosphatase and gamma glutamyl transpeptidase, and ultrasonography shows no evidence of biliary disease or a space-occupying lesion. Over 90% of the patients test positive for anti-mitochondrial antibody (AMA); AMA M2 is especially diagnostic. Liver biopsy may clinch the diagnosis; characteristically there is destruction of bile ducts by inflammatory cells and granuloma formation (stage I), ductular proliferation (stage II), septal fibrosis (stage III), and cirrhosis (stage IV). However, due to sampling error with a small biopsy, it may be difficult to deter- mine in the later stages the actual cause of the fibrosis/cirrhosis. . What are the possible complications of PBC? There may be: — The usual complications of cirrhosis: portal hypertension; ascites; hepatic encephalopathy; and variceal bleeding. — Complications specific for PBC, including: pruritus; steatorrhoea (due to decreased bile production); decreased absorption of fat-soluble vitamins A, D, and K; and hepatic osteodystrophy. — Association with other autoimmune disorders (e.g., Sjogren syndrome, thyroiditis) 3. Is there any specific drug treatment for PBC and how effec- tive is it? Ursodeoxycholic acid, which affects biliary composition and flow by an unknown mechanism, decreases pruritus and improves liver function, but its effect on liver histology is uncertain. The only trial suggesting that it may improve sur- vival and delay liver transplantation had some methodological shortcomings.

Case 6.6 Gastroenterology and Hepatology 95 6. . What other agents may be used to treat PBC? Cholestyramine, by chelating bile salts, may improve pruritus (if ursodeoxycholic acid alone is ineffective). Medium chain triglycerides (MCT) can be used for cooking to minimize steatorrhoea; MCTs are absorbed by diffusion and do not require micellar formation. Vitamin A can be given orally as a supplement to compensate for any deficiency (N.B. Vitamin A may be teratogenic). Vitamin D or 1,25 dihydroxy cholecalciferol may be prescribed to treat the hepatic osteodystrophy. . How would you diagnose hepatic encephalopathy? Clinically the patient may be drowsy to comatose. The patient may have flapping tremor and fetor hepaticus. The arterial ammonia should also be raised. What are the precipitating factors responsible for hepatic encephalopathy? Hepatic encephalopathy may occur “spontaneously” but may also be provoked by the following: — Increased protein intake. — Gastrointestinal bleeding (high protein content of the blood in the gut and decreased blood supply to an already cirrhotic liver). — Over-diuresis (with dehydration and electrolyte disturbances). — Constipation. — Inappropriate paracentesis (without adequate albumin infusion). — Infection, especially spontaneous bacterial peritonitis. ~ Hypnotics. - Alcohol. ~ Shunting procedures, including TIPS. . How would you manage hepatic encephalopathy? Any treatable precipitating factor should be identified and treated. Patient should be put on a no-protein diet, intravenous 10% dextrose drip to provide adequate calorie intake (to prevent

96 Problem-Based Medical Case Management Case 6.6 protein breakdown) and lactulose as an enema and orally (with the aim of inducing bowel movements 2—4 times per day). 8. What are the mechanisms of action and side effects of lactulose? » Being a non-absorbable disaccharide, it acts as an osmotic diar- rhoeal agent (30 mL of lactulose is equivalent to 840 mL of normal saline). » In the colon it is acted upon by lactobacilli to form carbon dioxide and hydrogen. The acidic pH buffers NH; from gut- derived bacteria and in the blood to form NH,". « The acidic pH also inhibits growth of NH;-forming bacteria. e Side effects include: flatulence, dehydration (from excessive diarrhoea), aversion to sweet taste, and very rarely, pneumatosis coli. 9. What issues need consideration when contemplating liver transplantation? * Prioritization of patients for liver transplantation is usually based on the Model for End-Stage Liver Disease (MELD) score. This is a formula that takes account of the patient’s bili- rubin and creatinine levels as well as the INR. For patients with non-biliary and non-alcoholic liver diseases, an extra mark is added to the score. « Other clinical features (including development of encephalopa- thy, uncontrollable ascites, spontaneous bacterial peritonitis, and variceal bleeding) also need to be considered. « The patient should be younger than the accepted age of trans- plantation; an age limit that varies in different countries (usually 60-65 years old). + There should be no serious comorbidity and the patient should also be psychologically prepared to accept the transplant operation. 10. In what way is the MELD score superior to the Childs- Pugh score? » The MELD score is superior because:

Case 6.7 Gastroenterology and Hepatology 97 — It has a continuous scale for all three parameters in the formula (the Childs score is “discontinuous”). — It eliminates subjective elements (presence and degree of encephalopathy/ascites) and parameters that are often vari- able in different laboratories (e.g., serum albumin, prothrom- bin time). 6.7 A woman with haematemesis (variceal bleeding complizating alcoholic cirrhosis) History A 54-year-old woman presented with sudden onset of haem- etemesis with dizziness on the day of admission. She had started working as a barmaid when she was 19 years old and continued in that line of work for about 20 years. At that time she drank approximately 6 cans of beer every day and intermittently binged on whisky and wine. She now worked as a shop assistant in a boutique shop. However, she continued to drink 6-8 cans of beer daily. She noticed bilateral ankle swelling for the past 2 years but did not seek any medical advice. She also experienced generalized weakness, palpitations, and mild shortness of breath during the recent 3 months. There was no past history of hepatitis, vomiting, or passing of black stool. Physical examination There was a strong smell of alcohol around the patient. She was pale, jaundiced, and had palmar erythema, Dupuytren’s contrac- tures and bilateral ankle oedema. Abdominal examination revealed hepatomegaly (liver span 13 cm) with mild splenomegaly (3 cm below costal margin). Shifting dullness was elicited, indicating the presence of ascites. Per rectal examination revealed fresh melaena.

98 Problem-Based Medical Case Management Case 6.7 Questions 1. What is the likely diagnosis for the current problem? e The diagnosis is variceal bleeding secondary to alcoholic cir- rhosis and is based on: - Her longstanding history of significant alcohol intake, far exceeding what are referred to as “accepted” safety limits for daily intake (40 g/day for men and 20 g/day for women). In general, a 1/2 pint (~250 mL) of beer, 1 ounce of whisky or 1 glass of wine contains 10 g of ethanol. The level of dangerous drinking is 60-80 g/day for men and 40 g/day for women for 10-20 years. About 10-20% of subjects drinking these amounts or more will develop alcoholic hepatitis and/ or alcoholic cirrhosis. — Evidence of established cirrhosis: the presence of ankle oedema; hepatomegaly (compatible with alcohol rather than virus as the cause); splenomegaly (consistent with portal hypertension) and ascites. — The gastrointestinal bleeding is likely to be due to variceal bleeding and not Mallory Weiss syndrome (absence of any episode of severe vomiting). N.B. variceal bleeding may be from either gastric or oesophageal varices. 2. What typical abnormalities may laboratory investigations reveal? ¢ Complete blood picture: pancytopenia due to hypersplenism; low haemoglobin due to acute gradual bleeding or haemolytic anaemia (Zieve’s syndrome—characterized by hypertriglyc- eridemia and hypercholesterolemia in alcoholic liver disease); alcohol-related macrocytosis; reticulocytosis (after active bleeding). e Liver biochemistry: low albumin level due to cirrhosis and/ or malnutrition; high bilirubin level due to end-stage cirrhosis and possible Zieve’s syndrome (predominantly unconjugated bilirubin); mild elevations of ALT and AST levels (AST levels usually = x 2 the ALT levels); marked elevation of GGT and minimal elevation of alkaline phosphates levels.

Case 6.7 Gastroenterology and Hepatology 99 o Clotting profile: prolonged prothrombin time (end-stage cirrhosis). 3. Besides cirrhosis, what other liver disease entities may result from abusing alcohol? e Fatty liver: May ensue after taking moderate amounts of alcohol over short periods. May be detectable by ultrasonogram, though liver biopsy showing macrovesicular fat droplets in the centrilobular zones is the gold standard. Is reversible, if the patient abstains from alcohol. The risk of development of cirthosis is increased, espe- cially if liver biopsy shows high degrees of fatty infiltration, presence of Mallory bodies and pericellular or perivenular fibrosis. e Alcoholic hepatitis: Like alcoholic liver cirrhosis, it only develops in 10-20% of heavy drinkers. It indicates presence of hepatocellular necrosis and inflam- mation and is a precursor for cirrhosis. AST & ALT level elevations are usually less < x 10 the upper limit of normal, with AST = 2 x the ALT level. The short-term prognosis can be estimated by Maddrey’s discriminant function: 4.6 x (prothrombin time—control time in seconds + bilirubin in mg/dL); scores > 32 signify poor short-term survival. Treatment includes: management of alcohol withdrawal; nutritional support; corticosteroids (for those with very high score of Maddrey’s discriminant function or hepatic encephalopathy). 4. What is the management of variceal bleeding? * Correction of thrombocytopenia by platelet concentrates and deranged clotting profile by fresh frozen plasma. These blood products should be administered cautiously, with adequate assessment of the patient’s fluid status.

100 Problem-Based Medical Case Management Case 6.7 « Urgent upper endoscopy to confirm the bleeding site is from varices. Therapeutic haemostasis can be achieved by endo- scopic banding or injection sclerotherapy (the former is more commonly adopted because it is easier to perform and asso- ciated with lower complication rates). At intervals, the endo- scopic procedure needs to be repeated, till the size of varices is satisfactorily controlled. If adequate hemostasis is not achieved, intravenous terlipressin and/or somatostatin infusion and/or Sengstaken-Blakemore tube insertion may be required. » Drug treatment to reduce portal hypertension (to reduce bleed- ing during the acute episode and the risk of future rebleeding): e.g., propanolol » Surveillance endoscopy can be performed at 6-monthly inter- vals; banding can obliterate new varices whenever they are detected. e For patients with recurrent and/or severe variceal bleed- ing, transjugular intrahepatic portosystemic shunting can be an effective means of preventing rebleeding, but a history of hepatic encephalopathy and right heart failure constitute major contraindications. » Measures to prevent aspiration, infection and hepatic encephalopathy 5. What long-term strategy is needed to manage this patient? ¢ Advice on total abstinence of alcohol (consider referring to psychiatrist if necessary). = Consider the possibility of liver transplantation if there is a good evidence of abstinence from alcohol (at least 6 months of total abstinence is considered imperative). For such patients, transplantation is mainly indicated for poor liver synthetic func- tion, ascites and variceal bleeding (see p. 93).