Oxford Case Histories Oxford Case Histories Series Editors Sarah Pendlebury and Peter Rothwell Published: Neurological Case Histories (Sarah Pendlebury and Peter Rothwell) Upcoming: Oxford Case Histories in Cardiology (Colin Forfar, Javed Ehtisham, and Rajkumar Rajendram) Oxford Case Histories in Gastroenterology and Hepatology (Alissa Walsh, Otto Buchel, Jane C ollier, and Simon Travis) Oxford Case Histories in Nephrology (Chris Pugh, Chris O \200\231 Callaghan, Aron Chakera, Richard Cornall, and David Mole) Oxford Case Histories in Respirat ory Medicine (John Stradling, Andrew Stanton, Anabell Nickol, Helen Davies, and Najib Rahma n) Oxford Case Histories in Rheumatology (Joel David, Anne Miller, Anushka Soni, and Lyn Wi lliamson) Oxford Case Histories in Stroke and TIA (Sarah Pendlebury, Ursula Schulz, Aneil M alhotra, and Peter Rothwell) Oxford Case Histories in Gastroenterology and Hepatology Alissa J. Walsh St.Vincent \200\231s Hospital Staff Specialist Sydney, Australia Otto C. Buchel Consultant Physician and Fellow in Gastroenterology Universitas Hospital Blu emfontein, South Africa Jane Collier Consultant Hepatologist Department of Gastroenterology and Hepatology John Rad cliffe Hospital, Oxford, UK Simon P.L. Travis Consultant Gastroenterologist John Radcliffe Hospital Fellow of Linacre C ollege University of Oxford Oxford, UK 1 1 Great Clarendon Street, Oxford ox2 6dp Oxford University Press is a department of the University of Oxford. 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Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, a t the address above You must not circulate this book in any other binding or cover and you must impose this sam e condition on any acquirer British Library Cataloging in Publication Data Data available Library of Congress Cataloging in Publication Data Data available Typeset in Minion by Glyph International, Bangalore, India Printed in Great Britain on acid -free paper by The MPG Books Group, UK ISBN 978 \200\2230 \200\22319 \200\223955789 \200\2239 10 9 8 7 6 5 4 3 2 1 Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and c linical procedures with the most up-to-date published product information and data sheets p rovided by the manufacturers and the most recent codes of conduct and safety regulations. T he authors and the publishers do not accept responsibility or legal liability for any error s in the text or for the misuse or misapplication of material in this work. Except where ot herwise stated, drug dosages and recommendations are for the non-pregnant adult who is not breastfeeding. A note from the series editors Case histories have always had an important role in medical education, but most published m aterial has been directed at undergraduates or residents. The Oxford Case Histories series aims to provide more complex case-based learn- ing for clinicians in specialist training an d consultants, with a view to aiding preparation for entry and exit-level specialty examina tions or revalidation. Each case book follows the same format with approximately 50 cases, each comprising a brief clinical history and investigations, followed by questions on diffe rential diagnosis and management, and detailed answers with discussion. All cases are peer- reviewed by Oxford consultants in the relevant specialty. At the end of each book, cases ar e listed by mode of presentation, etiology and diagnosis. We are grateful to our colleagues in the various medical specialties for their enthusiasm a nd hard work in making the series possible. Sarah Pendlebury and Peter Rothwell Quotes on the first book in the series \200\223 \200\234Neurological Case Histories \200 \235 \200\234I recommend this excellent volume highly this book will enlighten and ente rtain consultants, and all readers will learn something. \200\235 Lancet Neurology 2007; 6: 951 \200\234This short and well-written text is designed to enhance the reader \200\231s diagnostic ability and clinical understanding A well documented and practical book \200\235 European Journal of Neurology 2007; 14: e19 This page intentionally left blank Preface This book contains a series of cases that we have encountered in Oxford Gastroenterology pr actice. One purpose is to assist re-validation. Another is to provide a resource of real ca ses in preparation for specialist exams. A further purpose is more general, being education al for physicians in general internal or emergency medicine, or indeed gastroenterologists, since the cases are often advanced and sometimes challenging. All 50 cases include a series of questions, to which we have given detailed, evidence-based answers, although it is the nature of evidence-based practice that clinical judgment is al so necessary. We have expressed our views, and hope that you generally agree! We have speci fically chosen cases to cover dif- ferent areas within gastroenterology and hepatology. Inc luded in this selection are acute cases where rapid diagnosis and treatment are crucial, as well as chronic disorders that require strategic thinking, and of course, the manage- ment dilemmas of daily practice. We have used the format of case reports with detailed discussions of differ- ential diagnos is and management, for three reasons. First, we believe that one of the best ways to learn advanced clinical medicine is through the analysis of individual cases. In almost all areas of medicine, it is extremely difficult to illustrate the practical process of diagnosis wi thin the format of a traditional textbook. Second, we strongly believe that it is simply mo re interesting to con- sider real cases than to read a text. This allows a clinician to ref lect on their own differential diagnosis and treatment. Finally, there is a lack of case se ries that stretch the abilities of experienced clinicians and specialists: most are aimed a t medical students or young doctors doing early postgraduate exams. It is for this reason t hat the cases and questions are sometimes challenging, although many are simple, since the aim is to educate. We would like to thank the many colleagues from many disciplines, includ- ing those allied to medicine for contributing cases, providing illustrations, or administrative support, and always for making helpful comments on the man- uscript as it developed: these include (in alphabetical order and without titles!) Adam Bailey, June Beharry, Helen Bungay, Roger Chap man, Rowan Collinson, Godman Greywoode, Hennie Grundling, Tim James, Christiaan Jansen, Sat ish Keshav, Siraj Misbah, Juan Piris, Andrew Slater, Helen Small, Alina Stoita, Jan van Zyl , Bryan Warren, and David Williams. Cases 16, 26 and 42 were seen and PREFACE viii cared for at the Gastroenterology unit, Universitas Hospital, Bloemfontein, South Africa, w hich we gratefully acknowledge. We would also like to thank our families for their toleranc e, patience, and support for work that occupies evenings, early mornings, and weekends! Alissa Walsh, Otto Buchel, Jane Collier, Simon Travis Oxford, August 2009 Contents Abbreviations xi Normal ranges xiii Cases 1 \200\22350 1 List of cases by diagnosis 341 List of cases by principal clinical features at diagnosis 343 List of cases by aetiological mechanisms 345 Index 347 This page intentionally left blank Abbreviations 5FU 5HT AGA 5-fluorouracil 5-hydroxytryptamine American Gastroenterology Association -fetoprotein ami nolaevulinic acid acute liver failure alkaline phosphatase alanine transaminase antimitocho ndrial antibodies antinuclear antigen antineutrophil cytoplasmic antibody activated partial thromboplastin time acute respiratory distress syndrome anti-smooth muscle antibody aspart ate transaminase Bacille Calmette-Gu rin beats per minute body mass index British Society of Gastroenterology carbon-14 cancer antigen common bile duct Clostridium difficile-associa ted diarrhea Clostridium difficile toxin carcinoembryonic antigen cystic fibrosis transmemb rane regulator Cytomegalovirus C reactive protein computerized tomography Epstein \200\223B arr virus ECF epirubicin, cisplatin and 5-fluorouracil combination chemotherapy electrocardiogram enzyme- linked immunosorbent assay endomysial antibody (for coeliac disease) endoscopic retrograde cholangiopancreatography erythrocyte sedimentation rate oxaliplatin and capcytabine combina tion chemotherapy Food and Drug Administration (USA) fluorescent in situ hybridization fami lial Mediterranean fever gamma-aminobutyric acid gastrointestinal gamma glutamyl transpepti dase gastrointestinal stromal tumor highly active antiretroviral therapy hepatitis A virus antibody to the hepatitis B core antigen hepatitis B e antigen antibody to the hepatitis B surface antigen hepatitis B surface antigen hepatitis B virus hepatitis C virus haemolysis, elevated liver enzymes, low platelet count syndrome ECG ELISA AFP ALA ALF ALP ALT AMA ANA ANCA EMA ERCP ESR EOX FDA APTT FISH ARDS FMF GABA GI GGT ASmAb AST BCG bpm BMI BSG GIST HAART C14 Ca CBD CDAD HAV HBcAb HBeAg HBsAb CDT CEA CFTR HBsAg HBV HCV HELLP CMV CRP CT EBV ABBREVIATIONS xii HFE High iron FE (haemochromatomosis gene) human immunodeficiency virus hydroximethylbilane syn thesase human herpesvirus 8 inflammatory bowel disease irritable bowel syndrome irinotecan with 5-fluorouracil combination chemotherapy interferon interleukin international normalize d ratio intraductal papillary mucinous neoplasm immunoproliferative small intestinal diseas e in vitro fertilization potassium l-ornithine l-aspartate liver function test liver kidney microsomal antibody type 1 lumbar puncture Mycobacterium avium complex mucosa-associated l ymphoid tissue molecular absorbent re-circulating system mucinous cystic neoplasm mean cell volume multi-drug resistant Model for Endstage Liver Disease magnesium mismatch repair mag netic resonance cholangiopancreatography magnetic resonance imaging methicillin resistant s taphylococcus aureus microsatellite instability Na NAFLD sodium non-alcoholic fatty liver disease non-alcoholic steatohepatitis N-acetyltransferase 2 non-steroidal anti- inflammatory drugs orthotopic liver transplantation antineutrophil cy toplasmic antibodies reacting with myeloperoxidase primary biliary cirrhosis polymerase cha in reaction positron emission tomography peripherally inserted central catheter peroxisome proliferator- activated receptor gamma proton pump inhibitor primary sclerosing cholangitis peptic ulcer disease polyvinyl chloride right upper quadrant serous cystadenoma systemic i nflammatory response syndrome soluble liver antigen systemic lupus erythematosus spinal mus cular atrophy Selective serotonin reuptake inhibitor tuberculosis transferrin receptor 2 tr ansjugular intrahepatic portal systemic shunt tumor necrosis factor thyroid stimulating hor mone urea and electrolytes white cell count extensively drug resistant Zollinger \200\223El lison syndrome HIV NASH NAT2 NSAIDs HMB HHV 8 IBD IBS IFL OLT pANCA IFN IL INR IPMN PBC PCR PET PICC IPSID PPAR IVF K LOLA LFT LKM1 PPI PSC PUD PVC RUQ SCA SIRS LP MAC MALT SLA SLE SMA SSRI MARS MCN MCV MDR MELD TB TFR2 TIPSS Mg MMR MRCP TNF TSH U&E WCC XDR ZES MRI MRSA MSI Normal ranges Normal ranges in the laboratories of the John Radcliffe Hospital, Oxford Hb 13 \200\22317g1dL (men) 12 \200\22315g/dL (women) 83 \200\223101fL (men) 76 \200\22396fL (w omen) 4 \200\22311 x 109/L 150 \200\223400 x 109/L GGT Albumin Amylase AFP CEA Ca125 Ca19 \200\2239 Ferritin 15 \200\22340 IU/L 35 \200\22350 g/L 25 \200\223125 IU/L 0 \200\2237 IU/mL 0 \200\2233 g/ L 0 \200\22330 IU/L 0 \200\22331 U/mL 20 \200\223300 g/L (Men) 10 \200\223200 g/L (Wome n) 4 \200\22324 g/L 180 \200\223900 ng/L 11 \200\22320 mol/L 16 \200\22360 mg/dL MCV WCC Platelets Prothrombin time 12 \200\22315 secs INR APTT Haptoglobin Na K Urea Creatinine 0.7 \200\2231.1 24 \200\22334 secs 0.5 \200\2232.65 g/L 135 \200\223145 mmol/L 3.5 \200\223 5.0 mmol/L 2.5 \200\2236.7 mmol/L 54 \200\223145 umol/L (range usually corrected for age or weight) 2.12 \200\2232.65 mmol/L 0.75 \200\223 1.05 mmol/L 0.80 \200\2231.45 mmol/L 0 \200\2238 mg/L need range 3.0 \200\2235.5 mmol/L 3 \200\22317 mol/L 15 \200\22342 IU/L 10 \200\22345 IU/L 95 \200\223320 IU/L (notably different between laboratories, depending on the analytical technique) Folate Vitamin Bl2 Copper Caeruloplasmin CD4 lymphocyte count TSH Free T4 Fecal elastase 0.6 \200\2231.5 x109/L 0.35 \200\2235.5 mU/L 10.5 \200\22320 pmol/L >200 g elastase/g of stool 0.8 \200\2233.0 g/L 6 \200\22313 g/L Calcium Magnesium Phosphate CRP ESR Glucose (fasting) Bilirubin AST ALT ALP IgA IgG Ascitic fluid WCC none This page intentionally left blank Case 1 A 22-year-old male porter from South Africa was admitted to hospital after being found by h is landlord with confusion. On arrival at the hospital his Glasgow Coma Score was 13. He wa s apyrexial, with a blood glucose of 5.4mmol/L, pulse rate 60 beats/min and regular, and bl ood pressure 114/58mmHg. Heart sounds were normal and his chest was clear. He was noted to be jaundiced. Asterixis was present. There were no focal neurological signs. There were no spider naevi, muscle wasting, or gynaecomastia. His only medical history was pulmonary tuberculosis 6 months earlier, diag- nosed by pleura l biopsy and pleural fluid analysis. He had last been followed up 2 months previously and w as well at that time. He had completed 2 months of rifampicin, isoniazid, pyrazinamide and ethambutol, followed by rifampicin and isoniazid alone. There was no record of any other me dications or over the counter preparations. There was no known alcohol or drug history. HIV testing had been negative. Investigations showed: 9/L, platelets 173 x 109/L Hb 15.2g/dL, WCC 9.1 x 10 mol/L mol/L, ALT 1307 IU/L, ALP 436 IU/L, albumin 32g/L Na 135mmol/L, K 3.7mmol/L, urea 2.8mmol/L, creatinine 78 Bilirubin 357 Prothrombin time 53.8 sec. Questions 1a) What is the clinical syndrome illustrated by this case? 1b) Give a differential diagnosis for the cause of (a). 1c) What blood tests would you request? 1d) What radiological tests would you request? 1e) What is the management? 1f) What is the most likely cause in this patient and why? What is the mechanism of injury? 1g) How might this problem have been prevented? OXFORD CASE HISTORIES 2 Answers 1a) What is the clinical syndrome illustrated by this case? This is acute liver failure (ALF), which is defined by three criteria: Rapid development of hepatocellular dysfunction (e.g. jaundice, coagulopathy) Encephalopathy Absence of a prior history of liver disease. 1b) Give a differential diagnosis for the cause of (a) The differential diagnosis for ALF in this patient includes: Drugs (paracetamol, antituberculosis medications, propylthioracyl) Hepatotropic viruses (hepatitis B, hepatitis A, hepatitis E, with hepatitis B being the mos t common) Acute cryptogenic (non-A, non-B, non-C) hepatitis Autoimmune hepatitis Ischaemia Metabolic disorders such as Wilson \200\231s disease Malignant infiltration. A careful history of past and present medications needs to be taken, together with a travel history and assessment of risk factors to determine the likelihood of acute viral hepatiti s. Routine viral testing should be done for all patients (see below). In the presence of te nse ascites Budd Chiari syndrome (hepatic venous outflow obstruction) should be considered, because ascites is unusual in early acute liver failure from other causes. Wilson \200\231 s disease may present with acute liver failure and should always be considered in patients presenting at a young age, but usually there is accompanying haemolysis or renal failure, w hich were absent in the present case. Furthermore, the alkaline phosphatase is usually norm al in Wilson \200\231s disease, whereas in this case it was elevated. Fulminant hepatic fai lure is an unusual presentation of hepatic neoplasms, whether primary or metastatic. Although this patient had ALF, it may be difficult to distinguish this from acute decompens ation of chronic liver disease in patients in whom the past medical history is unknown. For example, exacerbation of chronic viral hepatitis (B and C) may produce a similar picture t o ALF. Patients with chronic liver disease, however, usually show stigmata, including spide r naevi, muscle wasting, testicular strophy, or gynaecomastia, none CASE 1 3 of which were present in this patient. Furthermore, in chronic liver disease it would be ra re for the prothrombin time to be over 40 sec (usually it would be about 25 sec). In this p atient it was 53.8 sec. In alcoholic hepatitis, the alanine transaminase (ALT) rarely excee ds 300 IU/L, (see box 2) whereas in this case it was 1370 IU/L. 1c) What blood tests would you request? A \200\230liver screen \200\231 should be performed to look for the cause of ALF including : Paracetamol concentration (although N-acetyl cysteine should be started before the result i s known, to cover the possibility of toxicity). Note that paracetamol may be undetectable i f the overdose was over 72 hours before blood testing Hepatitis A IgM Hepatitis B core IgM Autoimmune markers: antinuclear antigen (ANA), anti-smooth muscle antibody (ASmAb), liver k idney microsomal antibody type 1 (LKM1), and immunoglobulins Copper and caeruloplasmin to screen for Wilson \200\231s disease. 1d) What radiological tests would you request? An ultrasound of the abdomen should be performed, since this will help distinguish between acute and chronic liver disease (splenomegaly is more common in chronic liver disease). Thi s is particularly helpful in the context of a less severe coagulopathy, where it may be unc lear whether this represents ALF or an acute exacerbation of chronic disease. Ultrasound wi ll not help to differentiate between different causes of ALF. 1e) What is the management? The management of ALF includes: Intravenous rehydration : most patients require liberal volume expan- sion, since such pati ents are often vasodilated, volume depleted and acidotic. The choice of fluid is not crucia l and is usually a mixture of crystalloid and colloid. Fluid resuscitation can often revers e the acidosis. The blood glucose should be measured hourly and replaced: with intra- venous glucose (10 \200\22350%) as necessary, since there is a high risk of hypoglycaemia. Glucose concentrati ons need to be maintained to prevent the cerebral and systemic effects of hypoglycaemia. OXFORD CASE HISTORIES 4 to monitor acidosis: correction of lactic acidosis is Arterial blood gas important, because it can affect circulatory function and aggravate cerebral hyperaemia. should be given to cover the possibility of paracetamol N-acetyl cysteine overdose. Antibiotics : prophylaxis with an intravenous cephalosporin is recom- mended. Patients with ALF have a high risk of infection and sepsis from bacterial and/or fungal infection. The u se of prophylactic antibiotics is associated with lower rates of infection complicating ALF . Without prophylaxis, infection develops in up to 80% of patients with ALF, and bacteraemi a occurs in 20 \200\22325% (usually gram-negative organisms). If definite infection is prov en, this should be treated aggressively (e.g. vancomycin and a third-generation cephalospor in). Vitamin K is not indicated: bleeding is unusual in ALF despite the increased prothrombin ti me. Fresh frozen plasma is not advocated, because the risks (fluid overload, normalization of the prothrombin time artificially) outweigh the benefits. Plasma product should be used only if the patient is bleeding or an invasive procedure is being performed. The prothrombi n time is also a good prognostic indicator. Lactulose is of no proven benefit in ALF. Intensive care management : if the patient is not protecting their airway (grade 3 or 4 enc ephalopathy), intubation and ventilation is indicated. This applies especially during trans fer to a transplant unit, because grade 4 encephalopathy can develop rapidly. Liver transplant : In patients with acute liver failure, liver transplanta- tion should be considered at an early stage and the regional liver transplant unit contacted for advice. I n paracetamol-induced ALF, referral to a transplant unit should be made if the prothrombin time is >60 sec. For non-paracetamol acute liver failure, the criteria are listed below. The King \200\231s College Hospital criteria for liver transplantation in non- paracetamol ALF are: INR >6.5 or prothrombin time >100 sec OR three of the following: patient age <11 years old or >40 years old mol/L serum bilirubin >300 time from onset of jaundice to development of coma >7 days CASE 1 5 INR >3.5 or prothrombin time >50 sec etiology: non-A, non-B, or drug toxicity (not paracetamol). It should be noted that patients should be transferred well before the development of these criteria. The patient in this case met the criteria on admission, since he had a prothromb in time of 53.8 sec, bilirubin of 357 mol/L, and drug toxicity as the etiology (below). 1f) What is the most likely cause of ALF in this patient and why? What is the mechanism of injury? The most likely cause of ALF in this patient is isoniazid toxicity. One to two percent of p atients receiving isoniazid develop severe liver injury, defined as an ALT being at least 3 times the upper limit of normal. Fulminant hepatotoxicity is well described and has 10 \200\22320% mortality if the isoniazid is continued. The mechanism of injury is the product ion of toxic metabolites through isoniazid oxidation in the cytochrome p450 pathway. These metabolites accumulate in people who are slow acetylators and in those on concurrent enzyme -inducing medication such as rifampicin or alcohol. Although it remains controversial, cert ain polymorphisms of N-acetyltransferase 2 (NAT2) and glutathione-S-transferase genes are a lso thought to be risk factors. Other risk factors for hepatotoxicity include underlying li ver disease (especially coexistent hepatitis B or hepatitis C), other hepatotoxic medicatio ns (such as protease inhibitors for treatment of HIV), excessive alcohol consumption, age > 35 years, and female gender. It is unclear whether race or malnutrition contributes to the risk of toxicity. 1g) How might this problem have been prevented? Before starting antituberculous treatment the patient requires education regarding the medi cation. Detection of risk factors for toxicity (1f, above) is important and every patient s hould have baseline LFTs. Individual patients need to be aware that they should see a docto r if non-specific symptoms occur. If the ALT is >5 times normal, or if symptoms arise, then antituberculous medications need to be stopped. If the ALT is 2 \200\2234 times normal, th en liver function tests should be checked weekly for 2 weeks and then fortnightly until the y have improved. If treatment needs to be continued, alternative agents such as ethambutol or fluoroquinolo- nes should be considered, since these are the least hepatotoxic. Once the LFTs have normalized, antituberculous drugs should be reintroduced one by one. Rifampicin is usually introduced first and then isoniazid. Pyrazinamide should be omitted if possible. These drugs are often tolerated on reintroduction. OXFORD CASE HISTORIES 6 Further reading Devlin J, O \200\230Grady J (1999). Indications for referral and assessment in adult liver transplantation: a clinical guideline. Gut; 45(Suppl. 6): V11 \200\223V121. Jalan R (2005). Acute liver failure: current management and future prospects. J Hepatol; 42 : S115 \200\223S123. Sass DA, Obaid Shakil A (2005). Fulminant hepatic failure. Liv Trans; 11: 594 \200\223605. CASE 2 7 Case 2 A 24-year-old female hairdresser presented with a 5-day history of jaundice, right upper qu adrant discomfort, and general malaise. Her stool was of normal color and not pale, nor did she have dark urine. She admitted to recent alcohol excess while on holiday in Ibiza, from where she had returned 10 days before. Her usual alcohol intake was 24 units/week, with bi nges during social events. She had no past medical history and used no prescription drugs, over-the-counter medications or NSAIDs, no nutritional supplements or herbal remedies, and no illicit drugs. She had not recently had a course of antibiotics. There was no history of previous blood transfusion, contact with hepatitis, or previous jaundice, and she had no t attoos. She had last had unpro- tected sex 8 months previously. There was no significant fa mily history. On examination she was clinically well, haemodynamically stable, and apy- rexial. She was j aundiced, without lymphadenopathy, peripheral oedema, or finger clubbing. There were no sig ns of chronic liver disease or portal hyper- tension. She had a liver edge, palpable 3 cm b elow the costal margin, which was firm, smooth and non-tender. Cardiac and respiratory exam ination was unremarkable. Investigations showed: 9/L, platelets 182 x 109/L Hb 13.4g/dL, WCC 4.22 x 10 Prothrombin time 13.2 sec, APTT 36.1 sec mol/L, ALT 2858 IU/L, ALP 626 IU/L, albumin 40g/L Bilirubin 56 Ultrasound scan of the abdomen: mild splenomegaly with a span of 13.5cm. No gallstones, but there was slight thickening of the gallbladder wall. The liver was homogeneous and of norm al size. The pancreas, bile duct, kidneys, and spleen appeared sonographically normal. OXFORD CASE HISTORIES 8 Questions 2a) What is the clinical problem and the differential diagnosis in this case? 2b) What is the significance of the ultrasound findings? Further investigation revealed: hepatitis A IgM negative, hepatitis B surface Ag negative, cytomegalovirus IgM negative, EBV IgG positive, ANA positive 1/640, smooth muscle antibody negative, antimitochondrial antibody negative, IgG 35.6g/L, IgM 1.76g/L, IgA 2.81g/L. 2c) What is the most likely diagnosis given these investigation results? 2d) What would be your next investigation? 2e) How would you treat this patient? This page intentionally left blank OXFORD CASE HISTORIES 10 Answers 2a) What is the clinical problem and the differential diagnosis in this case? The clinical features of this case are consistent with acute hepatitis. Acute hepatitis is characterized by mild jaundice, lethargy, and markedly elevated transaminases. The sudden o nset of symptoms in the presence of a normal albumin suggests acute liver injury. There is no evidence of acute liver failure, because the prothrombin time is normal (see Case 1, acu te liver failure). The differential diagnosis in this case includes: Viral hepatitis Toxins Autoimmune disease. Viral, toxic (drug), and autoimmune causes may be responsible for mark- edly elevated trans aminases. Recent travel to a coastal resort raises the possibility of shellfish consumption , which increases the risk of hepatitis A virus infection. The return from Ibiza 10 days pr ior to presentation is compatible with the incubation period for hepatitis A virus infectio n (see Case 16). There is no history of high-risk sexual behavior within the past 90 days, and no contact with blood or blood products, so acute hepatitis B virus infection is unlike ly. Hepatitis A (see Case 16), hepatitis B (see Case 44), cytomegalovirus and Epstein \200 \223Barr virus infections should, never- theless, be excluded by appropriate serology. If o ther investigations are negative, Hepatitis E virus infection should be considered. Acute p resen- tation of hepatitis C virus infection (see Case 43) is rare, but should be considere d once other aetiologies have been excluded, especially if risk factors such as intravenous drug abuse are present. Drug-induced hepati- tis in our patient is effectively excluded by the history, but checking a paracetamol concentration on admission would be a sensible pre caution. Even though she has a history of binge drinking, the markedly elevated ALT is agai nst an acute alcoholic hepatitis, in which transaminases rarely exceed 300 IU/L (see Case 1 ). In our patient, hepatomegaly was not marked and the leucocyte count was normal, which ma kes alcoholic hepa- titis less likely, since it is associated with peripheral leucocytosis. Excess alcohol consumption may lead to fatty liver with hepatomegaly (see Case 45). Autoim mune hepatitis should be excluded, and investigation should include autoantibodies and immu noglobulin fractions. CASE 2 11 2b) What is the significance of the ultrasound findings? The ultrasound features of note are splenomegaly and gall bladder wall thickening. Splenomegaly may occur in acute viral hepatitis. Alternatively, autoimmune hepatitis may pr esent acutely, superimposed on chronic autoimmune liver disease, in which case splenomegaly could represent underlying portal hypertension. Thickening of the wall of the gall bladder has been well described in acute hepatitis and is thought to be proportional to the degree of liver cell necrosis, illustrated by the transaminitis. 2c) What is the most likely diagnosis, given these investigation results? The most likely diagnosis is autoimmune hepatitis. A strongly positive ANA and serum IgG el evation more than twice the upper limit of normal, are highly suggestive of autoimmune hepa titis. This, together with the fact that viral serology was negative with no suggestion of biliary disease and no history of exposure to hepatotoxic drugs, makes autoimmune hepatitis the likely underlying cause. The fact that the patient is female also strength- ens the li kelihood. 2d) What would be your next investigation? A liver biopsy should be performed. A needle biopsy of the liver is essen- tial for confirm ing the diagnosis of autoimmune hepatitis, grading disease activity, and staging the fibros is. Histopathological features of autoim- mune hepatitis include portal inflammation with a mononuclear cellular infiltrate including plasma cells, extending beyond the limiting plat e of hepatocytes into the lobule (interface hepatitis). If severe, confluent areas of necro sis may isolate groups of liver cells and form rosettes. Varying degrees of fibrosis may be present. Fatty change, iron excess, and biliary pathology are not features. Although a pro minent plasma cell infiltrate is highly suggestive of autoimmune hepatitis, the biopsy feat ures are not entirely specific. In our patient interface hepatitis and plasma cells were seen in the mononuclear portal cel lular infiltrate (see Figs 2.1 and 2.2 in the central color section). An international scoring system to aid in the diagnosis of autoimmune hepatitis has been de veloped as a research tool (Czaja 2006). This scoring system (Table 2.1) accommodates the d iverse manifestations of the disease and produces an aggregate score, reflecting the probab ility of the diagnosis. It may be used when the diagnosis of autoimmune hepatitis is in dou bt. OXFORD CASE HISTORIES 12 Fig. 2.1 (see color plate 1) A low-power magnification image of a liver biopsy, showing a s evere inflammatory infiltrate at the interface between the portal triad and lobule (arrow). Fig. 2.2 (see color plate 2) A higher magnification showing distinct plasma cells (arrow). Using the scoring system, this patient \200\231s aggregate score was 17 prior to ther- apy (female gender, ALP:ALT ratio <1.5, IgG >twice upper limit, antinuclear antigen >1/80, nega tive viral serology, interface hepatitis, and plasma cell infiltrate on liver histology). A pre-treatment score of >15 gives a definite diagnosis. 2e) How would you treat this patient? Treatment is with immunosuppression. The mainstay of treatment is corticosteroids. Azathiop rine may be added once liver function tests have normalized, often allowing the prednisolon e dose to be reduced to 5 \200\2237.5mg/day, or stopped completely. In our patient there wa s no CASE 2 13 Table 2.1 International scoring system for autoimmune hepatitis Criterion Component Score Criterion Component Score Sex Female +2 HLA DR3 or DR4 +1 AP:AST (or ALT) ratio > 3.0 \210\2222 Immune disease Thyroiditis, colitis, +2 others < 1.5 +2 Gamma-globulin or IgG level above normal > 2.0 +3 Other markers Anti-SLA/LP, actin, LC1, pANCA +2 1.5 \200\2232.0 +2 1.0 \200\2231.5 +1 < 1.0 0 ANA, SMA, or anti-LKM1 titres > 1:80 +3 Histological features Interface hepatitis +3 1:80 +2 Plasmacytic +1 1:40 +1 Rosettes +1 < 1:40 0 None of above \210\2225 Biliary changes \210\2223 Other features \210\2223 AMA Positive \210\2224 Treatment response Complete +2 Relapse +3 Viral markers Positive \210\2223 Negative +3 Drugs Yes \210\2224 Pre-treatment score No +1 Definite diagnosis: > 15 Probable diagnosis: 10 \200\22315 Alcohol < 25g/day +2 Post-treatment score > 60g/day \210\2222 Definite diagnosis: > 17 Probable diagnosis: 12 \200\22317 contraindication to azathioprine, so this was given in combination with prednisolone. Remis sion is defined as transaminases less than twice the upper limit of normal. Immunosuppressi on is usually required long term, but patients do not routinely require repeat liver biopsy . After withdrawal of therapy, only around 20% of patients have a sustained remission. Most relapses occur within 12 weeks of cessation of therapy and can be severe. However, relapse may occur months or years later, so there is a need for continued follow-up. Life expectan cy of treated patients exceeds 85% at 10 years and 74% at 20 years. In around 10% of patien ts, therapy fails to prevent progression of liver disease, with eventual hepatic decom- pen sation, leading to liver transplantation. OXFORD CASE HISTORIES 14 This patient responded well to treatment with corticosteroids and aza- thioprine, with norm alization of liver biochemistry, so she was maintained on immunosuppression. Alternatives e xist for those patients who do not tolerate first-line drugs. Mycophenolate mofetil and tac rolimus have both been used, although there are no controlled data. Further reading Czaja AJ (2007). Corticosteroids or not in severe acute or fulminant autoimmune hepatitis: therapeutic brinksmanship and the point beyond salvation. Liver Transpl; 13: 953 \200\2235. Czaja AJ (2006). Autoimmune hepatitis \200\223 approach to diagnosis. Med Gen Med; 8: 55. Juttner H-U, Ralls PW, Quint MF, Jenney JM (1982). Thickening of the gallbladder wall in acute hepatitis: Ultrasound presentation. Radiology; 142: 465 \200\2236. Montano Loza AJ, Czaja AJ (2007). Current therapy for autoimmune hepatitis. Nat Clin Pract Gastroenterol Hepatol; 4: 202 \200\22314. Heathcote J (2006). Treatment strategies for autoimmune hepatitis. Am J Gastroenterol; 101(Suppl. 12): S630 \200\2232. CASE 3 15 Case 3 A 35-year-old florist, 26 weeks pregnant, was referred to the outpatient department because of mild jaundice, a 1-month history of intense pruritus and fatigue. Her first pregnancy, 3 years previously, was complicated by hypertension, but was otherwise uneventful and the child remained healthy. The current pregnancy followed three miscarriag es. During this period, she was diagnosed with systemic lupus erythematosus (SLE) and antip hospholipid syndrome. There were no cerebral or renal manifestations of SLE. Current medica tions included azathioprine 200mg/day, prednisolone 5mg/day, low-dose aspirin, and low mole cular weight heparin. She had been on azathioprine for 2 years. On examination, she was fully orientated. Her pulse rate was 72bpm, and blood pressure 130/ 80mmHg. There was mild icterus, no spider naevi, no abdominal tenderness, and no hyper-refl exia. Investigations showed: 9/L, platelets 312 x 109/L Hb 12.5g/L, WCC 10 x 10 mol/L Na 135mmol/L, K 4.2mmol/L, urea 4.3mmol/L, creatinine 82 mol/L, AST 475 IU/L, ALT 157 IU/L, ALP 350 IU/L, Bilirubin 102 GGT 52 IU mol/L(normal 0 \200\22310) Serum bile acids 192 Urine dipstix \200\223 negative for protein. Questions 3a) What is the differential diagnosis? 3b) Is a liver biopsy necessary? 3c) What treatment should be instituted? 3d) What are the maternal and fetal prognoses? OXFORD CASE HISTORIES 16 Answers 3a What is the differential diagnosis? The differential diagnosis includes pregnancy-related liver disease and non-pregnancy relat ed liver disease, including complications of SLE. Pregnancy-related liver disease: Intrahepatic cholestasis of pregnancy Pre-eclampsia and eclampsia HELLP syndrome (Haemolysis (H), elevated liver enzymes (EL), low platelet count (LP) Acute fatty liver of pregnancy. Non-pregnancy related liver disease: Autoimmune hepatitis (see Case 2) Viral hepatitis (see Cases 16, 43, 44) Drug-induced hepatitis (see Case 1) Biliary obstruction (see Case 9) Primary biliary cirrhosis (see Case 4) Primary sclerosing cholangitis (see Case 50). The most likely pregnancy-related diagnosis is intrahepatic cholestasis of pregnancy. Pruri tus is the primary clinical symptom of intrahepatic cholestasis of pregnancy. The pruritus can range from mild and tolerable to severe and disabling. Pruritus is typically worse in t he evening, with a predilection for the palms or soles of the feet, and is not associated w ith any specific skin lesions. Mild jaundice occurs in 10 \200\22315% of cases, usually occ urring 1 \200\2234 weeks after the onset of the pruritus. The main biochemical alterations are elevations of serum bile acids, and transaminase concentra- tions. The serum concentrat ion of GGT may be modestly elevated. ALP is difficult to interpret during pregnancy, due to elevation of the placental isoenzyme. Diagnosis of intrahepatic cholestasis of pregnancy is one of exclusion. It is important to exclude other causes of liver disease and cholestasis. This case does not fit with the rare HELLP syndrome, because there is no evi- dence of haemolysis or thrombocytopenia, and the patient is relatively well. Patients with SLE are, however, at increased risk of pre-eclamp sia. Although there is hypertension, which raises the suspicion of pre-eclampsia, there is no proteinuria (making either pre-eclampsia or lupus nephritis most unlikely) or hyper-refl exia. Acute fatty liver of pregnancy is a CASE 3 17