Several drugs are available to treat acute variceal hemorrhage; the choice depends on local availability, bearing in mind that the only drug shown to improve survival is terlipressin . Somatostatin and octreotide have a similar effect on bleeding, but have not been shown to improve survival. Randomized controlled trials have shown that the efficacy of vasoactive therapy is significantly improved when combined with endo- scopic therapy. If vasoactive dr ugs are started as soon as possible before endoscopy, the incidence of active variceal blee ding during the endoscopy decreases from 50% (when drugs are not used), to 20 \200\22325%. Terlipressin and octreotride have fewer systemic side effects, such as angina or gut ischae mia, than vasopressin, but should still be used with caution in people with a history of co ronary artery disease. Endoscopic therapy Endoscopy should be performed as soon as possible after resuscitation, especially in patien ts with active bleeding and features suggesting cirrhosis. The aim is to stop bleeding by b anding (ligation) or sclerotherapy, and subsequently to obliterate the oesophageal varices. Variceal wall tension is the key factor that determines variceal rupture. Endoscopic thera py reduces variceal wall tension by reducing variceal size until obliteration, and by incre asing the thickness of the vascular wall. Variceal banding has proved more effective and sa fer than sclerotherapy (with eth- anolamine) and is currently the endoscopic treatment of c hoice for oesophageal varices. Nevertheless, the choice is also influenced by the availabil ity of equipment and expertise. Variceal obturation with tissue adhesives such as cyanoacry late or with thrombin are generally limited to the treatment of gastric varices. The current recommended therapy for variceal bleeding (combining vasoactive drugs, emergenc y endoscopic variceal banding and antibiotic prophylaxis), has reduced 5-day re-bleeding ra tes from 30% to 10 \200\22315%. Endotracheal intubation may be required for airway protecti on during endoscopy, particularly in patients with encephalopathy. OXFORD CASE HISTORIES 30 Treat and prevent encephalopathy Hepatic encephalopathy can be precipitated by bleeding in patients with cirrhosis. Patients who present or develop encephalopathy should be treated with lactulose. Although there are no studies to evaluate the value of lactulose for preventing hepatic encephalopathy, eithe r lactulose or phosphate enemas are usually given to prevent encephalopathy following a var iceal bleed. Following endoscopy a proton pump inhibitor should be given, because acid suppression has b een shown to reduce the risk of bleeding from oesophageal ulcers following variceal banding . Proton pump inhibitors should be continued until varices have been eradicated. A non-sele ctive beta-blocker should also be started (below). 5b) What are the predictors of failure to control variceal bleeding? Clinical factors associated with failure to control bleeding and mortal- ity are: Active bleeding at endoscopy Shock at admission Early re-bleeding (<5 days) Severity of liver disease (Child \200\223Pugh grade: mortality in patients with Class C = 7 0 \200\22380%) Raised bilirubin Prothrombin time (reflecting severity of liver disease) Thrombocytopenia (indirect measure of portal hypertension) Encephalopathy Recent use of corticosteroids for alcoholic hepatitis within 7 days of bleeding Age >60 years Complicating hepatocellular carcinoma. Portal hypertension increases with increasing severity of cirrhosis. The best predictor of re-bleeding is, however, an increased hepatic venous pressure gradient. The hepatic venous pressure gradient is a measure of the severity of portal hypertension. A hepatic venous pre ssure gradient >20mmHg has been shown to be independently associated with mortality and ear ly re-bleeding. Measurement of hepatic venous pressure gradient is performed by transjugula r venous cannulation, and requires access to skilled interventional radiology. Although acc urate and reproducible, CASE 5 31 with a low coefficient of variation in measurement and few complica- tions, it is rarely us ed outside the research setting except in one or two centers. Unfortunately, the patient did re-bleed and required another endos- copy, but the endoscopi st was unable to control the bleeding. By this stage the patient had had 10 units of packed red cells and remained tachycardic and hypotensive. 5c) What management should be considered at this stage? This patient has uncontrolled variceal bleeding despite medical and endo- scopic therapy. S uch patients are best managed with a transjugular intra- hepatic portal systemic shunt (TIP SS) (Figs 5.1a and 5.1b). TIPSS is an interventional treatment to decompress the portal sys tem by creation of an intrahepatic shunt between the portal and hepatic veins. TIPSS is onl y indicated for \200\230salvage therapy \200\231 when first-line methods (medical and endo scopic) have failed. Studies report immediate control of bleeding in 91 \200\223100% of cas es, 30-day re-bleeding in 7 \200\22330% and a 1-month mortality of 28 \200\22355%, reflecti ng the severity of the underlying liver disease . If access to TIPSS is not immediately available, mechanical balloon tam- ponade is accepted as a temporary measure until definitive therapy can be instituted. Most commonly used is t he three-lumen, double balloon Sengstaken-Blakemore tube. Only the gastric balloon need be used (filled with about 250ml of water mixed with 50ml radiological contrast) in most cases . Insertion is best achieved using a well lubricated stiffening guidewire, and should be ca rried out by an experienced physician, because of the risk of oesophageal perforation. The oesophageal balloon is rarely necessary and should not be insufflated for more than 8 hours . Surgical shunting, (portocaval or splenorenal) does not appear to improve survival, and is associated with a substantial incidence of enceph- alopathy. Surgery should only ever be co nsidered in patients with non- severe (Child \200\223Pugh A) liver disease. Liver transplan tation is not indicated for an acute bleeding episode, but all such people should be consid ered as transplant candidates, if only to exclude this as an option if (for instance) the p erson continues to drink or has substantial comorbidity. 5d) Why did the patient became confused and disorientated several days later? The most likely explanation for the confusion in this patient is post-TIPSS hepatic encepha lopathy. Hepatic encephalopathy is the main complication that has limited the application o f TIPSS. Clinically evident hepatic encephalopathy develops in approximately 35% of patient s after TIPSS, most often within the first 7 days. It is often short lived when managed OXFORD CASE HISTORIES 32 Guidewire going via the hepatic veins through the liver Varices with collateral flow away from the portal vein Tip of self-expanding stent Fig. 5.1a This picture shows the wire through the hepatic vein into the portal vein, with m etal TIPSS stent visible. There are varices visible on the right. Expanded stent Metal coils Portal vein Fig. 5.1b This picture shows the metal TIPSS stent, which is just proximal to the opacified portal vein. The varices seen on the right have been coiled. with regular lactulose, but in severe cases the shunt has to be reduced in diameter or occl uded, with all the implications for increasing the hepatic venous pressure gradient and re- bleeding. Our patient responded well to treatment with lactulose. Interestingly, the develo pment of post-TIPSS encephalopathy is not associated with a poor prognosis, and minor degre es of hepatic encephalopathy are no more prevalent after TIPSS than expected in a general c irrhotic population. CASE 5 33 5e) What is the subsequent management plan for those patients in whom acute variceal bleeding is controlled endoscopically? The current regimen to prevent re-bleeding in those patients who have controlled acute oeso phageal variceal bleeding is: eradication of varices (repeat banding every 1 \200\2232 weeks Endoscopic until varices eradicated) Combined with oral, non-selective beta-blockers The combination is more effective than beta-blockers alone in preventing late re-bleeding. Haemodynamic responders (i.e. those with a decrease in hepatic venous pressure gradient to <12mmHg, or by >20% of baseline) have a marked reduction in the risk of hemorrhage, but thi s is not meas- ured routinely, and there is unfortunately no surrogate marker at present. Further reading Bendtsen F, Krag A, M ller S (2008). Treatment of acute variceal bleeding. Dig Liver Dis; 40: 328 \200\22336. Dell \200\231 A, deFranchis R, Iannuzzi F (2008). Acute variceal bleeding: pharmacological treatment and primary/secondary prophylaxis. Best Pract Res Clin Gastroenterol; 22: 279 \200\22394. T riantos CK, Burroughs AK (2008). Predicting failure to control bleeding in acute variceal bleeding. J Hepatology; 48: 185 \200\22388. Villanueva C, Colomo A, Aracil C, Guarner (2008). Current endoscopic therapy of variceal bleeding. Best Pract Res Clin Gastroenterol; 22: 261 \200\22378. OXFORD CASE HISTORIES 34 Case 6 A 70-year-old Irish man presented to his doctor with a skin rash on his right lower leg. Ro utine blood tests were performed and mildly disordered liver function tests were found, wit h a markedly raised serum ferritin. He was referred to the hepatology clinic for assessment . There was no history of liver disease and he was not taking any medication. He had stoppe d smoking 30 years earlier and drank heavily until 10 years before, but now only drank two units of alcohol per day. He had no other risk factors for chronic liver disease and had un dergone a hip replacement for arthritis 7 years previously. Examination revealed a pulse rate of 80 beats/minute and blood pressure 115/65mmHg. His ski n appeared pigmented. Examination of cardiac and res- piratory systems was normal. He had n o clinical evidence of chronic liver dis- ease or portal hypertension, although the liver w as palpable 4cm below the costal margin. Investigations showed: 9/L, platelets 155 x 109/L Hb 13.5g/dL, WCC 5.6 x 10 mol/L, ALT 56 IU/L, ALP 536 IU/L, albumin 41g/L Bilirubin 15 Fasting glucose 8.2mmol/L g/L Ferritin 4838 Prothrombin time 12.4 sec Autoimmune and viral markers were negative Ultrasound of the abdomen: normal liver echogenicity and no lesions, no ascites, normal spl een. Questions 6a) Discuss the most likely diagnosis and how you would confirm it. 6b) What are the disease manifestations? 6c) Discuss the types of genetic iron overload. 6d) Discuss the pathophysiology of haemochromatosis. 6e) Discuss the management and aspects of screening for this disease. This page intentionally left blank OXFORD CASE HISTORIES 36 Answers 6a) Discuss the most likely diagnosis and how you would confirm it. The most likely diagnosis is hereditary haemochromatosis. The combi- nation of hepatomegaly , skin pigmentation, arthritis, abnormal liver function tests, and a markedly raised serum ferritin is highly suggestive of hereditary haemochromatosis. The arthritis in this case, h owever, is of the hip joint, which is atypical and may simply represent degenerative joint disease in a 70-year-old man, unrelated to iron overload. The raised ferritin is a measure of body iron stores and is consistent with (but not diagnostic of) iron overload. Other cau ses of a raised ferritin include inflammatory conditions, obesity, and excess alcohol intak e, although it would be exceptional for any of these to cause a ferritin >1500 g/L. Confirmation of the diagnosis involves a liver biopsy when the ferritin is >1000 g/L. Stai ning with Prussian blue (Perl \200\231s) confirms iron overload in the hepatocytes and is u sed for staging of the degree of fibrosis, since cirrhosis may be present in asymptomatic i ndividuals. Cirrhosis can be predicted, however, in 80% of people homozygous for C282Y with a ferritin >1000 g/L, AST >40 and a platelet count of <200 x 109/L, without liver biopsy. Genotyping for the common HFE gene mutations (C282Y and H63D, below) is sugges- tive, but not necessarily diagnostic. Liver fibrosis is unusual in patients who are homozygous for th e C282Y mutation with a ferritin <1000 g/L, so a liver biopsy is not indicated unless ther e is diagnostic doubt. Our patient was found to be homozygous for C282Y, and a liver biopsy was performed. The bio psy showed a severely fibrotic liver, bordering on cirrhosis with grade 4 haemosiderosis (F ig. 6.1 in central colored section). This was compatible with the diagnosis of haemochromat osis. Liver syn- thetic function was still normal, and on ultrasound of the abdomen there w as no evidence of focal liver lesions (hepatocellular carcinoma) or portal hypertension (no rmal spleen and portal vein). 6b) What are the disease manifestations? Manifestations include liver disease, arthropathy, hyperpigmentation, dia- betes, cardiac d isease and hypogonadism. Pituitary failure is a feature of the rare juvenile form of haemoc hromatosis. Liver disease is the most promi- nent manifestation, being found in 95% of pati ents who have clinical dis- ease. It ranges from abnormal liver function tests to hepatomeg aly, liver fibrosis, and overt cirrhosis. Patients with cirrhosis are at increased risk of developing hepatocellular carcinoma. The arthropathy of haemochroma- tosis typically affect s the second and third metacarpophalangeal joints. CASE 6 37 Fig. 6.1 (see color plate 3) Photomicrograph of a liver biopsy stained with Prussian blue ( Perl \200\231s stain) showing features of parenchymal iron deposition (small arrow) and adv anced fibrosis (large arrow). Diabetes is typically associated with haemochromatosis, along with skin pigmentation ( \200 \230bronze diabetes \200\231). Diabetes may be due to hypoinsulinae- mia, but insulin resis tance is also a feature. Interestingly, the prevalence of diabetes in patients with haemoch romatosis is no different from the gen- eral population. A useful clinical tip is to consid er haemochromatosis should a patient have liver disease and disease in one other organ (dia betes, cardiac failure etc). Cardiac involvement is much less common and usu- ally manifest s as congestive cardiac failure, although arrhythmias may occur. Like pituitary failure, it is more common in the juvenile forms of the disease. 6c) Discuss the types of genetic iron overload. Genetic forms of iron overload may be divided into haemochromatosis and other forms. Haemoc hromatosis refers to a particular phenotype of hereditary iron overload, characterized by n ormal erythropoiesis, increased transferrin saturation, and parenchymal iron deposition bec ause of reduced activity of hepcidin. Haemochromatosis consists of five different genetic d isorders, of which by far the most common form (90%) is type 1 haemochromatosis or \200 \230HFE \200\231 haemochromatosis. The genetic defect in the HFE gene is a mutation on chro mosome 6p21.3, resulting in substitution of tyrosine for cysteine at position 282 (C282Y). The condition is auto- somal recessive and homozygotes with the C282Y mutation are at risk of developing iron overload. In the European population homozygocity is OXFORD CASE HISTORIES 38 found in around 1:250 people, but only a tiny proportion of homozygotes (perhaps 1%) develo p clinical haemochromatosis, for reasons unknown. A second mutation (H63D) has also been identified, but homozygocity for this mutation or co mpound heterozygosity with C282Y, rarely leads to iron overload. It was initially thought t hat C282Y homozygotes would invariably lead to progressive iron overload and resulting dise ase manifes- tations. High penetrance was assumed based on studies performed in patients wi th symptomatic disease. It is now known that penetrance is variable and that environmental or genetic factors influ ence the development of manifestations. The incom- plete penetrance of haemochromatosis in patients who are homozygous for C282Y is illustrated by a 50 \200\22375% prevalence of bioc hemical expression (increased ferritin and transferrin saturation), a 25% prevalence of non - specific asthenia or arthropathy, and <10% prevalence of severe organ damage with cirrhos is, hepatocellular carcinoma, diabetes, or cardiomy- opathy. From another perspective, appr oximately 20% of men and 40% of women who are homozygous for C282Y have a normal serum ferr itin. One clear influence on clinical expression of the disease is that of female gender. L ower disease penetrance in woman may be due to physiological blood loss, but this may not b e the only factor. Coinheritance of other gene mutations (for hepcidin or haemojuvelin for example, see below) are associated with earlier clinical disease and a greater iron burden. An important environmental factor influencing clinical expression of haemochromatosis is al cohol consumption, since alcohol increases the iron burden and has independent toxic effect s on end-organs affected by haemochromatosis. Other mutations associated with clinical expression of iron overload are much less common. Type 2 haemochromatosis (juvenile haemochroma- tosis) is caused by mutations in the gene fo r haemojuvelin or hepcidin. It is autosomal recessive and results in early onset severe dis ease presenting with cardiac or endocrine manifestations (hypopituitarism). A mutation in t he transferrin receptor 2 (TFR2) gene causes type 3 haemochromatosis, which is similar to H FE haemochromatosis and autosomal recessive. The only dominant mutation (SLC40A1) causing t ypical haemochroma- tosis is ferroportin disease type B and is rare. Other genetic causes of iron overload include ferroportin disease type A, which is autosoma l dominant and causes mesenchymal iron overload. It is rare. Two recessive conditions are h ereditary acaeruloplasminaemia, which causes neurological, hematological, or endocrine dise ase, and hereditary hypotransferrinaemia, which causes microcytic anemia with CASE 6 39 parenchymal iron overload. Both are the stuff of case reports, because of insights they giv e into physiological iron transportation. 6d) Discuss the pathophysiology of haemochromatosis. Iron balance is regulated solely by variation in intestinal absorption. Hepcidin is the cen tral player, promoting iron export from enterocytes, macrophages, or placental cells. Hepci din deficiency is to haemochromato- sis what insulin is to diabetes. It works by modulating the delivery of iron to the plasma and consequently controls intestinal iron absorption. H epcidin is a 25 amino acid polypeptide hormone that induces the degradation of the cellular iron exporter, ferroportin. Hepcidin concentrations are influenced by serum iron concentra tions, hypoxia, anemia, and inflammation, but the precise interaction of HFE gene expressio n with hepcidin remains unclear. 6e) Discuss the management and aspects of screening for this disease. The mainstay of therapy is the depletion of iron stores by phlebotomy. Phlebotomy, with the removal of 500mL of whole blood each week until the serum ferritin is <50 g/L, is standar d practice. The aim is to deplete iron stores to an extent that iron leaches from the tissu es. This is subject to tolerance and patients who become anemic naturally have a less inten se regimen of bloodletting. Once the target ferritin has been reached, the frequency of mai ntenance phlebotomy is judged by ferritin measurements every 4 \200\2236 months. The rate o f reaccumulation of iron is highly variable, since maintenance phlebotomy increases the rat e of intestinal iron absorp- tion. Effective phlebotomy has been shown to reverse fibrosis in the liver and reduce the risk of hepatocellular carcinoma in the presence of cirrhosis b y reversing parenchymal iron deposition. Hepatocellular carcinoma remains a leading cause of death and is more common than liver fai lure in patients with haemochromatosis and cirrhosis (see Case 14). Screening cirrhotic pat ients for a carcinoma every 6 months, with ultrasound of the liver and -fetoprotein deter mination, is recommended. Orthotopic liver transplantation is uncommonly carried out for un controlled haemochromatosis, since the mortality from sepsis or cardiac decompensation is h igh. Population screening for a condition that is common, may have serious and preventable conse quences, is easily treatable, and readily diagnosed by a blood test, may seem appropriate. However, biochemical measures of iron overload (such as serum transferrin saturation) have a low positive predictive value for C282Y homozygocity. Since the genetic defect also has v ariable penetrance, this decreases the population benefit of screening, so it is not curren tly indicated. OXFORD CASE HISTORIES 40 Further reading Adams PC, Barton JC (2007). Haemochromatosis. Lancet; 370: 1855 \200\22360. Deugnier Y, Bri ssot P, Loreal O (2008). Iron and the liver. J Hepatol; 48 (Suppl.): S113 \200\223S123. Bacon BR, Britton RS (2008). Clinical penetrance of hereditary hemochromatosis. (Editorial). N Engl J Med; 358: 291 \200\2232. CASE 7 41 Case 7 A 40-year-old HIV-positive male theater critic presented to the outpatient department with a 10-week history of watery diarrhea associated with a 7kg loss of weight. He had been diag nosed with HIV 2 years earlier after he developed two AIDS-defining illnesses (Pneumocystis jiroveci pneumonia and cytomegalovirus retinitis). His current medications were zidovudine , lamivu- dine, and saquinavir. There had been no changes to the prescribed regimen for ove r 6 months. On examination he was cachetic, afebrile, had a pulse rate of 96 beats per minute and blood pressure 125/78mmHg. There was no abdominal tenderness or distension. Investigations showed: 9/L, platelets 215 x109/L mol/L Hb 11.2g/dL, WCC 3.4 x 10 Na 130mmol/L, K 3.1mmol/L, creatinine 85 CRP 25mg/L CD4 lymphocyte count 100 cells/ L. Questions 7a) What is the differential diagnosis? 7b) What should be the sequence of evaluation? 7c) What is the role of endoscopy? 7d) What does \200\230HIV enteropathy \200\231 mean? OXFORD CASE HISTORIES 42 Answers 7a) What is the differential diagnosis? The differential diagnosis includes: Infection: protozoal, bacterial, mycobacterial, viral, and fungal Drug-induced diarrhea: protease inhibitors, other medications Gut neoplasms: lymphoma, Kaposi \200\231s sarcoma Idiopathic: HIV enteropathy Pancreatic insufficiency Unrelated to HIV (microscopic colitis, coincidental coeliac disease). The CD4+ count of 100 cells/mm means that infection is highly likely. Poor compliance wit h medication is probable. The most common cause of infectious diarrhea in the HIV populatio n is protozoal infection (Ciclospora spp., Isospora belli, Microsporidium sp. or Cryptospor idium sp.). Diarrhea is generally self limited if the CD4+ count is normal. A CD4+ count <1 00 cells/mm means that severe disease is likely. Bacterial diarrhea also occurs more freq uently in patients with low CD4 counts, with more virulence. Shigella sp. and Campylobacter sp. generally present with severe abdominal pain and bloody diarrhea. Clostridium difficil e diarrhea is common, because antibiotic use is commonplace and hospi- talization is freque nt. Intestinal tuberculosis caused by Mycobacterium avium complex (MAC) or drug-resistant Mycob acterium tuberculosis needs to be consid- ered, especially if the CD4+ count is <50 cells/m m . Viral colitis may also cause diarrhea in HIV-positive patients. Cytomegalovirus (CMV) is the most common cause of diarrhea in patients with multiple negative stool tests, especi ally if the CD4+ count is <100 cells/mm . Other viruses (herpes simplex, adenovirus, norov irus, or rotavirus) are occasional causes. HIV itself has also been implicated (see below). Fungal infections of the gut include Histoplasma capsulatum, coccidioidomycosis, and crypt ococcosis, but generally occur in the context of systemic infection. Diarrhea in the era of highly active antiretroviral therapy (HAART) is very often drug indu ced (antiretroviral therapy), but in this case is unlikely in view of the very low CD4+ cou nt, profound weight loss, and stable medication. Diarrhea due to HAART is generally not ass ociated with weight loss and the mechanism is not understood. The incidence of diar- rhoea associated with protease inhibitors (most commonly with saquina- vir and nelfinavir when th erapy is initiated) ranges between 5% and 50%, CASE 7 43 and usually resolves even if the medication is continued. The temporal relationship of the diarrhea to any medication change is relevant. Intestinal lymphoma associated with HIV is usually rapidly progressive and associated with \200\230B \200\231 symptoms. Kaposi \200\231s sarcoma is possible, but tends to cause blee ding. Irritable bowel syndrome can be excluded given the marked weight loss, but microscopi c colitis or coeliac disease is possible. 7b) What should be the sequence of evaluation? Evaluation of this patient should include: : drug history, symptoms such as weight loss, nocturnal or History bloody diarrhea, abdomin al pain, and symptoms of systemic infec- tion. Chronic diarrhea with profound weight loss i s strongly sugges- tive of an underlying opportunistic infection. Examination : fever, cachexia, abdominal tenderness or mass, and signs of opportunistic inf ection (oral candidiasis) or malabsorption (glossitis). Stool tests bacterial pathogens and should be sent for: : three stool samples will identify about 80% of identifiable microscopy, culture, and sensitivity ova, cysts, and parasites Clostridium difficile toxin assay If the CD4+ count is <200 cells/ L, specific stool tests for cryptosporidia and microspori dia should be carried out. If the CD4+ count is <100 cells/ L, mycobacterial culture of stool and colonic mucosal bio psy should be carried out. 7c) What is the role of endoscopy? Upper gastrointestinal endoscopy and colonoscopy increase the diagnos- tic yield if the sto ol tests are negative. The endoscopist should be alerted to the need for biopsies for micro scopy and culture. If the CD4+ count is <100/mm , the patient is at risk of CMV, for which mucosal biopsy is needed for diagnosis. Although there is some controversy about whether t o do a sigmoidoscopy (involving a simple phosphate enema preparation, usually available the same day, without sedation) or a full colonoscopy (needing full bowel preparation and less readily available), the most appropriate test is usually indicated by the clinical feature s. If the patient is unwell with metabolic disturbance (as in this case), colonoscopy is be st avoided unless the diagnosis is not detected by flexible sigmoidoscopy. OXFORD CASE HISTORIES 44 Some studies report that CMV is missed in 40% of cases if right-sided colonic biopsies are not taken, but this seems an over estimate. Upper gastrointestinal endoscopy with duodenal biopsy for microscopy and, very importantly, for culture is required to diagnose MAC (consider if CD4+ <100/mm ), Microsporidium spp., or Cryptosporidium sp. infec- tion. Endoscopic procedures are less helpful if there is no weight loss. 7d) What does \200\230HIV enteropathy \200\231 mean? The role of HIV as a diarrhoeal pathogen remains controversial. HIV enteropathy is a term u sed to account for diarrhea in AIDS patients who lack an identifiable cause. Although the p recise features are not agreed, the term implies a chronic diarrhoeal illness in patients w ith AIDS where no cause can be found despite extensive evaluation. With improvement in diag nostic techniques, greater awareness of the spectrum of diarrhoeal pathogens, and endoscopy with small intestinal biopsies in patients with negative stool tests, a diminishing propor tion have \200\230idiopathic diarrhea \200\231. In this case, the patient had cryptosporidiosis, diagnosed by an acid-fast stain of the sto ol, (organisms appear as bright red spherules). He was encouraged to comply with HAART, whi ch cleared the infection. This is the most effective therapy for treatment of cryptosporidi osis. Further reading Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK (2007). Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev; 1 : CD004932. Cello JP, Day LW (2009). Idiopathic AIDS enteropathy and treatment of gastrointestinal opportunistic pathogens. Gastroenterology; 136: 1952 \200\22365. Nemechek PM, Polsky B, Gottlieb MS (2000). Treatment guidelines for HIV-associated wasting. Mayo Clin Proc; 75: 386 \200\22394. Wilcox CM, Saag MS (2008). Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut; 57: 861 \200\22370. CASE 8 45 Case 8 A 39-year-old restaurant owner was seen in the hepatology clinic with abdom- inal distensio n. Wilson \200\231s disease had been diagnosed 25 years before. One of his siblings also ha d Wilson \200\231s disease. He had been prescribed penicillamine, but had taken it erratica lly over the years: generally for just 3 weeks before each clinic appointment. His weight had increased by 6kg and he had ankle oedema in addition to abdominal distension , which had improved on spironolactone 100mg/day. He had restarted penicillamine 1g/day. He had traveled to Africa 5 months before. He drank eight units of alcohol per week. He had n ever had a blood transfu- sion and had no tattoos. On examination his pulse was 72bpm and blood pressure 140/80mmHg. He was apyrexial, with no rmal cardiorespiratory examination. He had spider naevi, but was not jaundiced. He had 4cm hepatomegaly, shifting dullness and a brownish discoloration around the periphery of the ir is, in keeping with Kayser \200\223Fleischer rings. Neurological examination was normal. Investigations in clinic showed: 9/L, platelets 96 x109/L Hb 13.3g/dL, WCC 5.8 x10 Prothrombin time 20.5 sec, INR 1.5 mol/L Na 137mmol/L, K 3.8mmol/L, creatinine 83 mol/L, ALT 126 IU/L, ALP 275 IU/L, albumin 28g/L Bilirubin 46 IgG 21.9g/L Caeruloplasmin <9.7mg/dL mol/L. Copper 11.4 He was strongly advised to take regular penicillamine, and was then seen again 5 weeks late r in clinic. He was now jaundiced and had tense ascites. There was no evidence of encephalo pathy. He was admitted to hospital from clinic and on admission he had a temperature of 38 C. Investigations on admission showed: 9/L, platelets 76 x109/L Hb 12.5g/dL, WCC 16.6 x10 Prothrombin time 28.1 sec mol/L Na 126mmol/L, K 3.6mmol/L, creatinine 80 mol/L, ALT 114 IU/L, ALP 318 IU/L, albumin 22g/L Bilirubin 125 OXFORD CASE HISTORIES 46 Ascitic fluid: macroscopically clear, yellow fluid, protein <10g/L, albumin<5g/L 3, polymorphonuclear leucocytes 254/mm3, Gram stain WCC 460/mm negative, culture negative. Questions 8a) Define the clinical problem at presentation to the clinic. How would you assess the sev erity and what would be your initial management? 8b) What precipitated the deterioration that lead to the hospital admission? 8c) What treatment would you give? 8d) Describe whether and how you would perform a therapeutic paracentesis? 8e) How should this patient be managed in the future? This page intentionally left blank OXFORD CASE HISTORIES 48 Answers 8a) Describe the clinical problem at presentation to the clinic. How would you assess the s everity and what would be your initial management? This patient presents with decompensated chronic liver disease. There is likely to be cirrh osis, owing to stigmata of chronic liver disease, a low platelet count, and a long history of inadequately treated Wilson s disease. Ascites indicates portal hypertension complicatin g chronic liver disease, but does not always indicate cirrhosis. The absence of a clear pre cipitant (e.g. gastrointestinal bleed, infection, or acute toxic liver insult), suggests th at the decompensation results from progression of the underlying liver disease alone. Assessment of severity The degree of liver dysfunction in cirrhosis is graded using the Child \200\223 Pugh classi fication. This classification scores the serum levels of bilirubin, albumin, and prothrombi n time, and the presence/severity of ascites and encephalopathy. The total score ranges fro m 5 to 15 and places a patient in one of three groups that reflect increasing severity of d isease (Table 8.1). The groups (and corresponding scores) are: Child \200\223Pugh A (5 \200\2236), B (7 \200 \2239) and C (10 \200\22315). There are several limitations to the score. The five variable s were selected empirically and not based on statistical regression; cut-off values are arb itrary; and each variable is given the same weight. Renal function, which is an important p rognostic variable, is not taken into account. However, it is user friendly and has stood t he test of time, because it relates to outcome. Survival at 5 years and 10 years in cirrhot ic patients are 95% and 90%, respectively in Child A, 75% and 60% in Child B, and 55% and 3 0% in Child C. Another score, the Model for Endstage Liver Disease (MELD), was initially devised to predic t prognosis in patients being considered for Table 8.1 Child \200\223Pugh Score Measure 1 point 2 points 3 points units Bilirubin <34 (<2) 34 \200\22350(2 \200\2233) >50 (>3) mol/L (mg/dL) Albumin >35 28 \200\22335 <28 g/L INR <1.7 1.71 \200\2232.20 >2.20 N/A Ascites None Diuretic responsive Refractory N/A Encephalopathy None Gr I-II Gr III-IV N/A CASE 8 49 transjugular intrahepatic portal systemic shunts (TIPSS). It is derived from statistical re gression analysis, with each variable given the appropri- ate weight, and it includes renal function. It requires a calculator, is not user friendly at the bedside, but is used in th e USA for patients being considered for transplantation. Model for Endstage Liver Disease: 9.6 loge(creatinine in mg/dL) + 3.8 loge (bilirubin in mg/dL) + 11.2 loge (INR) + 6.4 Calcu lator: www.unos.org/resources/meldpeldcalculator.asp Interpretation of score (predicted 3-m onth mortality): 40 or more: 100% mortality 30 \200\22339: 83% mortality 20 \200\22329: 76% mortality 10 \200\22319: 27% mortality <10: 4% mortality. This patient was Child \200\223Pugh B (score 9) at presentation, with a MELD score of 15. Management Management at this stage would be aimed at control of fluid retention, which is the main re ason that the patient was referred. His ascites had already improved on spironolactone, whi ch had been prescribed by the family practitioner. Therapeutic drainage of the ascites was not indicated at this stage. Spironolactone has a long half-life and should be given at a o nce daily dose of 100 \200\223400mg/day. It is an aldosterone antagonist, which promotes re nal sodium loss and conserves potassium. Dose adjustments should consider the serum potassi um, because hyperkalaemia is a major adverse effect. It is antiandrogenic and may lead to g ynaecomastia. Fluid restriction is not required at this stage, but salt (NaCl) restriction is advis- able. Sodium intake should be restricted to 90mmol/day (5.2g of salt/day), which can be achieved by a \200\230no-added-salt \200\231 dictum and avoiding pre-pre- pared or canned food. The patient does not yet have neurological signs of Wilson s disease, so penicillamine shou ld initially be continued at a dose of 500mg twice a day, in the hope that liver function w ill improve. Adherence to therapy is a complex topic and should be addressed empathetically , with appropriate support to ensure that medication is taken. OXFORD CASE HISTORIES 50 Complete abstinence from alcohol is also advisable, even though his previous intake was low . Percutaneous liver biopsy is too risky at this stage, in view of the pressure of ascites and the prothrombin time which is already prolonged and would not alter management. It is i mportant, nev- ertheless, to exclude concomitant liver disease, and a full liver screen sho uld be performed (see Case 1), to exclude viral hepatitis in view of the travel history. An ultrasound scan of the abdomen should be requested to document liver size, exclude hepatoc ellular carcinoma (which is rare in Wilson \200\231s disease) or portal vein thrombosis, an d to document spleen size. An endoscopy would be appropriate to look for varices. 8b) What precipitated the deterioration that led to the hospital admission? The acute deterioration resulted from spontaneous bacterial peritonitis. Five weeks after h is initial clinic appointment the patient presented with marked deterioration of his condit ion, with tense ascites, rising bilirubin, further prolongation of prothrombin time and a d ecline in serum albu- min. He had a systemic inflammatory response (tachycardia, fever, and elevated WCC), but no encephalopathy or evidence of gastrointestinal hemorrhage. Bacterial infection is by far the most likely cause. The following should be carried out: blood cultures diagnostic paracentesis, with ascitic fluid analysis for albumin, cell count, and culture. Spontaneous bacterial peritonitis is diagnosed when the ascitic fluid polymorphonuclear leu cocyte count exceeds 250/mm3 of fluid. In this patient the cell count was marginal (254/mm3 of fluid), but diagnostic in the circumstances. The Gram stain was negative, which is typi cal in spon- taneous bacterial peritonitis, because there is a low bacterial load. Fluid cu lture was also negative, which is also typical, because it depends on the method used. Cult ures are positive in 40% (fluid sent in a sterile container for inoculation onto culture me dium) to 80% (inoculation into blood culture medium at the bedside). An obsolete term \200 \230culture-negative neu- trocytic ascites \200\231 is now thought to represent the 20 \200 \22360% of patients who have spontaneous bacterial peritonitis and a false-negative ascitic fluid culture. The very low ascitic fluid albumin concentration, resulting in a high serum -ascites albumin gradient (>11g/L), indicates portal hyper- tension as the cause of the asc ites. Low protein concentration in the ascitic fluid is a risk factor for spontaneous bacte rial peritonitis. Secondary bacte- rial peritonitis should be suspected if a polymicrobial infection is detected on culture. CASE 8 51 8c) What treatment would you give? Intravenous third generation cephalosporin antibiotics or oral quinolones are the mainstay of therapy. The most common bacterial isolates are Escherichia coli, Klebsiella sp., entero cocci, and streptococci. Antibiotics given for 5 days seem to be as effective as 10 days, s o the shorter course should be given. Oral fluoroquinolones are an alternative to intraveno us cefotaxime in patients who are not encephalopathic or vomiting. Aminoglycoside antibioti cs are best avoided in patients with decompen- sated liver disease, because of an unpredict able volume of distribution (ascites) and the risk of precipitating renal failure. Antibiot ic therapy should be started as soon as the ascitic polymorphonuclear leucocyte count confi rms the diagnosis, so an urgent request for analysis is appropriate.