On examination, her pulse rate was 76 and irregular, consistent with atrial fibrillation, b lood pressure 125/86mmHg, and she was afebrile. No abdominal masses were palpable. Investigations showed: 9/L, platelets 165 x 109/L mol/L Hb 11.5g/dL, WCC 5.6 x 10 Na 130mmol/L, K 4.1mmol/L, creatinine 85 mol/L, AST 25 IU/L, ALT 35 IU/L, ALP 60 IU/L, GGT Bilirubin 20 70 IU/L. In view of the anemia and symptoms, she had a gastroscopy. This did not reveal any mucosal lesions, and the stomach inflated well, but there was an impression of extrinsic compressio n of the stomach. A CT of the abdomen was carried out (Figs 39.1 and 39.2). Questions 39a) Explain the CT appearance and the differential diagnosis. 39b) Explain the management options for this patient and the pros and cons of each option. 39c) What are the complications of the above management strategies? OXFORD CASE HISTORIES 266 Fig. 39.1 CT scan. Fig. 39.2 CT scan. This page intentionally left blank OXFORD CASE HISTORIES 268 Answers 39a) Explain the CT appearance and the differential diagnosis The CT shows a pancreatic pseudocyst. There is a low attenuation, unilocular cyst, with acc ompanying signs of an atrophic pancreas. If this were a complex pseudocyst, the density of the fluid would be higher than in an uncomplicated pseudocyst, owing to the presence of hem orrhage or gas that develops because of bacterial infection. The precise relation- ship to the stomach can be seen. There is no associated calcification or pancreatic duct dilatation . Pancreatic pseudocysts need to be distinguished from pancreatic cystic neoplasms (see Case 29), acute fluid collections, organized pancreatic necrosis, pancreatic abscess, pseudoaneu ryms, and duplication cysts. Pseudocysts result from pancreatic inflammation or trauma leading to pancreatic duct disrup tion and the accumulation of fluid in the lesser sac. They are usually anechoic on ultrasou nd and unilocular. They generally contain thin brown fluid, rich in amylase and inflam- mat ory cells, but no mucin (see Table 29.1). They are not lined by a true epithelium (hence th e term pseudo-) and therefore have no malig- nant potential. Instead, they have a thick wal l of granulation tissue that takes approximately 4 \200\2236 weeks to develop after an epis ode of acute pancreatitis. The incidence is 10 \200\22320% after acute pancreatitis and 20 \200\22340% in chronic pancreatitis. Most pseudocysts regress within 6 weeks Fig. 39.1 CT scan showing a low attenuation, unilocular cyst (long arrow), with accompanyin g signs of an atrophic pancreas (short arrow), in the lesser sac (stomach shown by medium a rrow). CASE 39 269 of diagnosis, and an expectant management is appropriate in the first instance. Chronic pse udocysts are more commonly associated with chronic pancreatitis. 39b) Explain the main management decisions for this patient and the pros and cons of each option. The main management decision is whether to be conservative (no drain- age) or interventiona l (drainage). The size of pseudocyst is not itself an indication for drainage. Patients wit h a stable pseudocyst do not require therapy unless they have symptoms. Pseudocyst drainage should be con- sidered in the following circumstances: Abdominal pain Gastric outlet obstruction Early satiety Weight loss Jaundice Suspected infection of the cyst Increasing size of the cyst. The patient had abdominal discomfort, early satiety, and weight loss. There was no evidence of gastric outlet obstruction or jaundice. In view of the history of pancreatic surgery an d the atrophic pancreas, it was assumed to be a chronic pseudocyst. Comorbidity had to be c onsidered in the management. The patient was on warfarin for atrial fibrillation, which wou ld need to be stopped before drainage. Drainage can be achieved by: Surgery (cystogastrostomy) Percutaneous insertion of catheter under radiological guidance Endoscopic drainage guided by endoscopic ultrasound. This is possi- ble in 90% of cases, ei ther through the wall of the stomach or duode- num, with the insertion of a flanged stent. There are no prospective studies that compare endoscopic drainage to conservative managemen t, percutaneous or surgical drainage. Nevertheless, endoscopic drainage is probably the tre atment of choice since it is less interventional than surgery and does not involve an exter - nal drain that is prone to infection. It may not be possible if the cyst contents are thi ck, or the cyst is multilocular. OXFORD CASE HISTORIES 270 39c) What are the complications of the above management strategies? The complications of conservative management are that the patient \200\231s symptoms are un likely to resolve and may deteriorate. Surgical management carries appreciable morbidity (6 \200\22337%) and mor- tality (1 \200 \22316%), with a cyst recurrence rate of up to 20%. Percutaneous drainage has a high recurr ence rate (up to 70%). Although continuous percutaneous drainage with an indwelling cathete r decreases recurrence, the complication rate is 5 \200\22360%, including infection, bleedi ng, and fistula formation. Endoscopic drainage has a morbidity of 9 \200\22325%, resulting from complications such as bleeding from penetration of adjacent vessels or varices, perfor ation, infection, pancreatitis, stent migration or occlusion, and pancreatic duct damage. I nfection of a pseudocyst usually indicates inadequate drainage of fluid. The mortality is 0 \200\2231%. Definitive treatment is possible in up to 75%, and recurrence rates as low as 5% have been reported. However, endoscopic drainage of pseudocysts should be carried out on ly with interventional radiology support and surgical back up. Our patient underwent endoscopic drainage under endoscopic ultra- sound guidance and had tw o transmural stents inserted. Her symptoms resolved. After stenting, it was decided to disc ontinue her warfarin, since it had only been given for atrial fibrillation and there was no evidence of mural thrombus or history of a cerebrovascular event. Further reading AGSE guideline (2005). The role of endoscopy in the diagnosis and the management of cystic lesions and inflammatory fluid collections of the pancreas. Gastrointest Endosc; 61: 363 \200\22370. Brugge WR, Lauwers GY, Sahani D, Fernandez-del Castillo C, Warshaw AL (2004). Cystic neoplasms of the pancreas. N Engl J Med; 351: 1218 \200\22326. Vignesh S, Brugge WR (2008). Endoscopic diagnosis and treatment of pancreatic cysts. J Clin Gastroenterology; 42: 493 \200\223506. CASE 40 271 Case 40 A 42-year-old shop assistant with hypertension and obesity had a routine blood test, which showed a raised ALP. She was asymptomatic. She was on ramipril 5mg/day and a combined oral contraceptive pill. She had lost 10kg in 5 months, but attributed this to a diet. She did n ot smoke or drink. Examination, including breast and rectal examinations, was normal. Investigations showed: 9/L, platelets 405 x 109/L, MCV 86fL Hb 12.3g/dL, WCC 10.19 x10 Electrolytes and renal function normal mol/L, ALT 16 IU/L, ALP 527 IU/L, albumin 48g/L g/L, CA125 7 IU/L, CA 19-9 <1 IU/L Bilirubin 5 AFP 3.0 IU/mL, CEA 0.5 Ultrasound scan: multiple liver lesions, consistent with metastases MRI: multiple large, irregular, enhancing lesions occupying about a third of the liver. Nor mal spleen, kidneys, adrenals, pancreas (Fig. 40.1) Questions 40a) Discuss the clinical dilemma and differential diagnosis in this patient. 40b) How would you investigate the problem? 40c) Discuss the diagnosis. 40d) How should the condition be managed? 40e) What other advice might you offer? Fig. 40.1 Multiple focal liver lesions with irregular enhancement. OXFORD CASE HISTORIES 272 Answers 40a) Discuss the clinical dilemma and differential diagnosis in this patient. The dilemma is that the patient is young, asymptomatic, and has multi- ple focal hepatic le sions suggestive of metastasis. There is a disparity between the lack of symptoms and the e xtent of liver involvement. Since there is no evidence of a primary tumor, it is tempting t o take the ima- ging report at face value and diagnose a carcinoma of unknown primary. Her weight loss, which she had attributed to a diet, might conceivably have had a more sinister cause. A diagnosis of malignancy, however, should not be assumed without confirmatory hist opathology. It is possible that these are multiple benign lesions. Benign lesions of the li ver in a young woman include hepatic haemangiomas, focal nodular hyperplasia, and hepatic a denomas, in decreasing order of prevalence. Hepatic haemanigiomas are the most common benign solid lesions of the liver, found in up to 20% of the population. They are three times more common and often larger or multiple in wo men than in men, typi- cally presenting in the 4th and 5th decades of life. Size may vary f rom a few millimeters to more than 20cm. Most haemangiomas are asympto- matic and discovere d incidentally. Large lesions may cause symptoms because of a mass effect, with pain result ing from distension of the hepatic (Glissen s) capsule, or a feeling of fullness, early sat iety, nausea and vomiting because of compression of adjacent vicera. Both dynamic contrast- enhanced CT and MRI are used to diagnose haemangiomas when lesions have been detected by u ltrasound. They rarely require resection. Focal nodular hyperplasia is the second most common solid lesion of the liver, with a preva lence of up to 8%. They are eight times more com- mon in women than in men and may be multi ple in 20% of cases. The lesions are rarely symptomatic and are usually identified incident ally during ultrasound examination of non-specific symptoms in 75% of cases. Abdominal pain is unusual. Infarction, hemorrhage and necrosis are rare in these lesions. Malignant trans formation is not known to occur. A characteristic central scar is typically seen on radiolo gical imaging (CT or MRI). Hepatic adenomas are usually found in women in their reproductive years and are clearly ass ociated with oral contraceptive drugs. They exhibit some radiographic features (well circum scribed hyperintense lesions in T1 weighted MRI, or isointense on CT with peripheral enhanc ement), but are often difficult to characterize by imaging alone. CASE 40 273 They can increase in size and number in pregnancy or if the oral contra- ceptive pill is co ntinued. 40b) How would you investigate the problem? The most common malignancies that spread to the liver in women are primary tumors of the br east, lung, and colon. These three sites repre- sent >50% of primary tumors in women. A his tory should identify whether a young woman is at risk of a cancer family syndrome (see Case 17). Our patient had no significant family history and had never smoked. Apart from a thorough clinical examination including examination of the breasts and a digit al rectal examination, imaging should include a chest radiograph. Cross-sectional imaging o f the abdomen and pelvis (CT and MRI) is appropriate if not already performed. In our patie nt, no primary tumor had been found. Tumor markers are of limited value as diagnostic tests , with the exception of -fetoprotein (AFP). The role of CA 19-9, CEA, or CA 125 is in the follow-up of proven malignancy of the pancreas, colon and ovaries respectively, after diag nosis. They per- form poorly as diagnostic tests, because they are non-specific, with a hig h false-positive rate that is misleading and distressing for the patient. A liver biopsy is appropriate when there is diagnostic doubt about a liver lesion, but the risk of tumor tra cking along the biopsy site and the option of surgical resection if the lesion is isolated, should be considered (see Case 14). The liver biopsy was consistent with a hepatic adenoma . There was no evidence of malignancy. 40c) Discuss the diagnosis. Hepatic adenomas are uncommon in woman who do not take oral contraceptive drugs, with an in cidence of 1/million in this group. Among women taking contraceptives the incidence is esti mated at 40/million. The incidence has consequently risen since the 1960s, when oral contra ceptives became available. Adenomas of the liver are common in glycogen storage disease typ es I and III, when they occur in young males (< 20 years of age). The diagnosis is usually coincidental, since pain occurs in only a fourth of individuals. S evere pain may follow necrosis of the adenoma, haemorrage into the lesion or rupture with h emorrhage into the perito- neum. All these consequences are exceptional, but the risk is in creased when there are multiple or large lesions, subcapsular location, continued use of or al contraceptives, and in pregnancy. Liver function tests are OXFORD CASE HISTORIES 274 usually normal, but may be abnormal after hemorrhage or with multi- ple lesions. Malignant transformation to hepatocellular carcinoma is reported to occur in cross-sectional studies in 10% of cases but there are no prospective studies. Liver biopsy is unnecessary when an a denoma can be diagnosed on radiological grounds in the appropriate clinical setting. Molecular studies have attempted to classify hepatic adenomas in an attempt to identify sub types that may be at risk of malignant transforma- tion, but have been inconclusive. Asympt omatic hepatic adenomas do not need resection. 40d) How should the condition be managed? The oral contraceptive should be stopped. Repeat imaging after an interval of 6 \200\22312 months is often appropriate to reassure both patient and physi- cian. Shrinkage usually occ urs when oral contraceptives have been stopped, but this is not universal. Surgery should b e considered for symptomatic, large (>5cm), single lesions. Resection of an uncomplica- ted adenoma has a mortality of <1%, but up to 8% if emergency resec- tion is required for hemo rrhage. Hemorrhage into the peritoneal cavity has a mortality of 7% and may be managed by s elective emboliza- tion of the hepatic artery. Orthotopic liver transplantation has been ca rried out in patients with multiple adenomas or those associated with glycogen storage dise ase. Since our patient had no symptoms, she was followed up with repeat imaging after stopping o ral contraceptives. The largest lesion (7cm) had shrunk to 5cm 10 months later. 40e) What other advice might you offer this patient? The patient should be advised that lesions may enlarge if she became pregnant. She should a lso be aware of the uncertain risk of malignant transformation. This patient subsequently had an uncomplicated pregnancy. Further reading Bahirwani R, Reddy KR (2008). Review article: the evaluation of solitary liver masses. Aliment Pharmacol Ther; 28: 953 \200\22365. Lim KH, Ward SC, Roayaie S et al. (2008). Multiple inflammatory and serum amyloid A positiv e telangiectatic hepatic adenomas with glycogenated nuclei arising in a background of nonal coholic steatohepatitis. Semin Liver Dis; 28: 434 \200\2239. Rebouissou S, Bioulac-Sage P, Zucman-Rossi J (2008). Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol; 48: 163 \200\22370. CASE 40 275 Vetel inen R, Erdogan D, de Graaf W et al. (2008) Liver adenomatosis: re-evaluation of etiology and management. Liver Int; 28: 499 \200\223508. Viale G, Mastropasqua MG (2006). Diagnostic and therapeutic management of carcinoma of unkn own primary: histopathological and molecular diagnosis. Ann Oncol; 17(Suppl 10): x163 \200 \223x167. OXFORD CASE HISTORIES 276 Case 41 A 23-year-old female architecture student presented to the emergency depart- ment with a 2- week history of bloody diarrhea and abdominal discomfort, but no pain. She had returned fro m a field trip with colleagues in India a month previously, but her colleagues had remained well. She reported passing up to 10 loose bowel motions per day with bleeding, and had sev eral episodes of nocturnal diarrhea. She was a vegetarian and her only medical history was presumed infectious diarrhea 3 years previously. Her cousin had Crohn \200\231s disease, bu t there was no illness in immediate family members. On examination, she appeared dehydrated and had a temperature of 38.2oC, with a tachycardia (pulse 104bpm) and blood pressure 90/50mmHg. There was no abdominal distension, but there was mild generalized tenderness. Investigations showed: 9/L, platelets 600 x 109/L Hb 12.5g/L, WCC 14.5 x 10 mol/L, urea 15mmol/L Na 130mmol/L, K 3.2mmol/L, creatinine 75 ESR 65mm/hour CRP 87mg/L Plain abdominal radiograph as shown in Fig. 41.1. Questions 41a) What is the differential diagnosis? 41b) What treatment should be instituted? 41c) What investigations should be carried out? 41d) There was a limited response to treatment after 3 days; the patient still had eight bl oody bowel motions per day and a CRP of 50mg/L, although she was apyrexial and had a pulse rate of 72bpm. How does this change management? 41e) What is the natural history of this condition? CASE 41 277 Fig. 41.1 OXFORD CASE HISTORIES 278 Answers 41a) What is the differential diagnosis? Given the acute history, the major differential diagnosis is between infec- tive colitis an d acute severe ulcerative colitis. Crohn \200\231s colitis is unlikely, since it usually ca uses diarrhea, severe abdominal pain, and weight loss, but not bloody diarrhea. The most co mmon organisms causing infec- tive colitis with bloody diarrhea are Shigella spp, Campyloba cter spp, Entamoeba histolytica, Escherichia coli 0157 H7, Clostridium difficile, and Yersi nia spp. Salmonella spp and Giardia lamblia do not cause bloody diarrhea. Clinical clues fo r an infective cause are the recent onset and travel to India. None of her contacts, howeve r, had diarrhea, and she had little abdominal pain, which characterizes Campylobacter and S higella spp. Amoebiasis is certainly possible. A history of travel to an endemic area and f ever should raise suspicion. E. coli and C. difficile are much less likely in the absence o f a recent history of eating meat from a questionable source, or antibiotic therapy. This p atient also fits the crite- ria for acute severe ulcerative colitis, which is defined by th e Truelove and Witts \200\231 criteria of \211 6 bloody bowel motions per day plus one or more of the following: pulse >90bpm, temperature >37.8oC, Hb<10.5g/dL, or ESR >30mm/hour. 41b) What treatment should be instituted? Treatment must cover BOTH infective colitis and acute severe colitis. It is better to treat both rather than either alone, and it is potentially dangerous to treat for infection alon e while awaiting other investiga- tions. Intravenous corticosteroids will not put the patie nt at risk if the diagnosis turns out to be infection. An appropriate treatment regimen wou ld be: Intravenous hydrocortisone 100mg four times/day Rectal hydrocortisone 100mg in 100ml 0.9% saline twice daily Subcutaneous heparin developing a deep venous thrombosis once daily to reduce the chance of the patient 3L of fluid/day KCl/day. Such patients always become hypokalaemic (2L 0.9% saline and 1L 5% dextrose), with 60 \200\22380mmol Antibiotics to cover the possibility of infective colitis, because this is the first attack and there has been recent overseas travel: intravenous metronidazole 500mg three times/day and oral ciprofloxacin 500mg twice daily are appropriate, although antibiotics do not alte r the out- come of acute severe inflammatory colitis CASE 41 279 Ask the nurses to temperature four times/day. This helps objective decision-making monitor stool frequency and the pulse and If pain relief is needed in acute colitis, it may indicate impending per- foration. It is b est to avoid opioids and hyoscine butyl bromide (Buscopan) because these can promote dilata tion, and avoid NSAIDS since these can exacerbate colitis. Paracetamol is safe. If pain per sists, the plain abdominal radiograph should be repeated that day. 41c) What investigations should be carried out? The following investigations should be carried out on admission. Abdominal radiograph is re quired in any patient with diarrhea severe enough to need admission. The mucosal appearance of the colon looks oedematous in acute colitis (unlike the crisp outline to the haustral f olds in a normal colon), the wall is thickened, and mucosal islands may be present, which i ndicate residual rests of mucosa surrounded by ulcera- tion. The colon may also be dilated (>5.5cm), which then represents toxic megacolon that needs urgent specialist gastroenterolo gy and surgi- cal opinions (see Case 22). Three stool cultures for C. difficile toxin assay, microscopy culture and sensitivity, and ova cysts and parasites are required. With the current history of travel to India, it is ad visable to send a hot stool to the labora- tory for immediate microscopy to exclude amoebic colitis. Monitor blood tests: FBC, U&E daily and a CRP on days 3 and 5 are required. Repeat the abdo minal radiograph after 24hr if there is estab- lished or incipient colonic dilatation (diam eter >5.5cm). 41d) There was a limited response to treatment after 3 days. The patient still had eight bl oody bowel motions per day and a CRP of 50mg/L, although she was apyrexial and had a pulse rate of 72bpm. How does this change management? The patient has had a poor response to intensive treatment. This is defined on day 3 of int ensive treatment as a stool frequency >8/day, or a CRP>45mg/L, and frequency 3 \200\2238/da y. This is associated with a high risk (85%) of colectomy on that admission. Treatment need s to be changed as a consequence and specialist advice sought urgently. Options for med- ic al rescue therapy include intravenous ciclosporin 2mg/kg once daily (if serum cholesterol > 3mmol/L and magnesium >0.5mmol/L) OR inflix- imab 5mg/kg infusion. This is a specialist dec ision, but should not be delayed: if local advice is unavailable, a regional specialist sho uld be con- tacted. Contingency plans in case surgery is necessary should also be started: better to introduce a surgeon (as \200\230probably unnecessary \200\231) at this OXFORD CASE HISTORIES 280 Fig. 41.1 Abdominal radiograph in acute severe colitis showing oedematous colonic mucosa wi thout visible haustra and a thickened wall (arrow). The absence of any fecal residue is con sistent with a pancolitis. The colonic diameter is 4.5cm. stage, than a day or two later (as \200\230unfortunately essential \200\231). This is one of the reasons for specialist input. This patient was given infliximab (5mg/kg infusion) an d responded well. 41e) What is the natural history of this condition? Improvement in the management of acute severe ulcerative colitis has improved mortality fro m severe attacks of ulcerative colitis from 75% in 1933, 24% in 1955 to <1% in specialist c enters today. This can be attrib- uted to intravenous corticosteroids and early surgery for lack of response. Nevertheless, the colectomy rate for acute severe colitis (29%) has rema ined stable over the past 30 years. Ciclosporin or infliximab appear to defer, rather than prevent colectomy, although further trials are in progress. Further reading Brown S, George B, Blakeborough A, Haboubi N, Travis SPL (2008). ACPGBI Position statement on the management of acute severe colitis. Colorectal Dis; 10(Suppl 3): 8 \200 \22329. Stange EF, Travis SPL, Vermeire S et al. for the European Crohn \200\231s and Colit is Organization (ECCO) (2008). European Consensus on the diagnosis and management of ulcera tive colitis: definitions and diagnosis. J Crohn \200\231s & Colitis; 2: 1 \200\2234. Jacobovits S, Travis SPL (2006). The management of acute severe colitis. Br Med Bull; 75 \200\22376: 131 \200\22344. This page intentionally left blank OXFORD CASE HISTORIES 282 Case 42 A 35-year-old single mother from a remote part of South Africa was referred from the neurol ogy unit for evaluation of abnormal liver enzymes. She had presented initially with transve rse myelitis. She was on antihypertensive medi- cation and had had a Caesarian section 6 ye ars before. Apart from the weak- ness in her lower limbs and dysuria, she volunteered no ot her symptoms. On clinical examination, her pulse rate was 84bpm, and blood pressure 130/80mmHg. She was p ale, but anicteric. There was no palpable lymphaden- opathy, finger clubbing, or oedema. Sh e had oral thrush. The cardiorespira- tory examination was unremarkable. Abdominal examinat ion was normal, without organomegaly. She had no signs of chronic liver disease. Investigations showed: 9/L, platelets 200 x 109/L Hb 11.4g/dL, WCC 3.3 x 10 ESR >90mm/hour INR 1.0 mol/L, ALT 76 IU/L, ALP 632 IU/L, GGT 682 IU/L, Bilirubin 13 albumin 36g/L HbsAg negative, anti-HCV negative HIV positive CD4 count 7 cells/ uL. Questions 42a) Discuss the clinical problem and differential diagnosis. 42b) How would you proceed with investigation? 42c) How would you manage this patient? 42d) Discuss liver involvement in HIV in the context of highly active antiretroviral therapy (HAART). This page intentionally left blank OXFORD CASE HISTORIES 284 Answers 42a) Discuss the clinical problem and differential diagnosis. The two considerations in our patients are: The level of immune deficiency The pattern of liver function tests derangement. Apart from transverse myelitis, this young woman presents with abnor- mal liver function te sts (LFTs) and evidence of impaired cell mediated immunity. Serology for HIV was positive a nd a CD4 cell count of 7 cells/ l confirmed advanced immune deficiency. Her HIV infection was newly diagnosed and she had never received any antiretroviral medication. The pattern of LFT derangement is predominantly that of cholestasis (ALP three times the up per limit, with a raised GGT). This indicates either diffuse infiltration of the liver (see Case 48), space-occupying lesions, or biliary tract disease. Infiltration or space-occupyi ng lesions of the liver result from: Malignancy Disseminated infection involving the liver. Malignancies involving the liver in HIV may occur at any level of immune deficiency, but be come more common as immune deficiency progresses. In HIV, non-Hodgkin \200\231s lymphoma us ually presents in extranodal sites, with up to 16% of cases involving the liver. Imaging of the liver usually reveals mass lesions. Kaposi s sarcoma of the liver is usually not clin ically evident, but has been found in up to 50% of autopsies, in series from the pre-HAART era. It has been more commonly found in homosexual men and is caused by infection with huma n herpesvirus 8 (HHV 8). Opportunistic infections are much more likely in the absence of HAART with a CD4 cell count <200 cells/ l and often involve the liver. Tuberculosis is the most common concern. At CD 4 counts >200 cells/ l, tuberculosis is usually confined to the lungs, presenting with cli nical and radiological characteristics similar to those in the immune competent host. Once the CD4 count drops to <200 cells/ l, atypical presentations are more frequent. The typica l apical distribution reactivated (second- ary) tuberculosis (see chest radiograph, Case 26 ) is not seen in advanced immune deficiency. Appearances on the chest radiograph resemble t hose seen in primary tuberculosis, with alveolar infiltrates, air-bronchograms, CASE 42 285 basal infiltrates, mediastinal lymphadenopathy, and miliary shadowing. Dissemination with i nvolvement of multiple organs is frequent. In contrast to Mycobacterium tuberculosis, Mycobacterium avium com- plex infection occurs i n advanced HIV and is purely opportunistic. It is more frequently documented in cohorts fro m developed countries. Mycobacterium avium complex infection rarely occurs at CD4 counts >5 0 cells/ l. Liver infection is usually clinically silent, with systemic symp- toms of feve r, night sweats and weight loss. Systemic cytomegalovirus infection may involve the liver a nd occurs in advanced immune defi- ciency. Again symptoms are predominantly systemic. Funga l infections also occur late. Hepatomegaly is common in systemic histoplasmosis, which usua lly occurs in endemic areas such as the mid-West of the USA. Apart from Histoplasma capsula tum, other opportunistic fungal infections include Cryptococcus neoformans, coccidioidomyco sis, and blastomycosis, all of which may involve the liver in disseminated disease. Pneumoc ystis jiroveci has also been reported to involve the liver. Biliary tract involvement infection in HIV is well recognized: cryp- tosporidia leads to an AIDS cholangiopathy. It is characterized by irreg- ular intrahepatic and extrahepatic bile ducts resembling primary sclerosing cholangitis (see Case 50), but the associated papillar y stenosis is considered specific. Large duct biliary obstruction unrelated to HIV, includi ng gallstone disease, may occur in patients with HIV, so com- monplace disorders should not be overlooked! 42b) How would you proceed with investigation? An opportunistic infection was the most likely cause, and since these are usually dissemina ted in advanced HIV, they may be diagnosed in any accessible organ. The patient \200\231s c hest radiograph showed basal infiltrates, giving a differential diagnosis of Pneumocystis j iroveci (formerly carinii) pneumonia,tuberculosis, Mycobacterium avium complex infection, h is- toplasmosis, or malignancy. Tuberculosis, was by far the most likely diagnosis, but dif ficult to confirm in the absence of sputum production. Mycobacterium avium complex and diss eminated fungal infection remained possible. Our patient had no respiratory symptoms so Pne umocystis jiroveci pneumonia was unlikely. Histopathology is often the simplest (and quicke st) way to diagnose infection and exclude malignancy; bronchoscopy would be reasonable, but depends on local expertise and liver biopsy is often more accessible (See Figs 42.1a and 4 2.1b). OXFORD CASE HISTORIES 286 Further investigation showed: Ultrasound of the liver showed no evidence of biliary duct dilation or gallstones. Normal a ppearances of liver parynchyma. MRCP: normal appearances of the intrahepatic and extrahepatic biliary tree. This effectively excluded biliary tract disease, and the normal scan indi- cates that diffu se hepatic infiltration is the cause of the liver dysfunction. Liver biopsy showed multiple non-caseating granulomas (Figs 42.1a and 42.1b in the central color section). The differential diagnosis of granulomatous hepatitis in HIV-postive patients includes: Tuberculosis Mycobacterium avium complex infection Histoplasmosis. Disseminated tuberculosis is still by far the most likely cause, despite the lack of caseat ion or organisms on Ziehl \200\223Neilsen staining. In series from developing countries tub erculosis causes most cases of granulomatous hepatitis in patients with HIV. A microbiologi cal diagnosis is often difficult, because these patients are usually sputum negative, and t reat- ment has to be based on the clinical picture in an area of high prevalence. Fig. 42.1a (see color plate 20) A needle biopsy of the liver (haematoxylin and eosin stain) showing a granuloma (arrow). CASE 42 287 Fig. 42.1b (see color plate 21) The same biopsy using a Periodic Acid Schiff stain. The gra nuloma does not contain stored glycogen, so is PAS-negative. 42c) How would you manage this patient? Treatment of the presumed tuberculosis Institution of HAART. The treatment of tuberculosis in a patient with HIV is generally the same as for HIV-negati ve patients (see Case 26). Medication should, however, always be given daily (not twice wee kly as in some regimens) and in cases of poor response, therapy may be prolonged by 3 month s (i.e. extension of the continuation phase from 4 months to 7 months). Treatment of tuberc ulosis always precedes the institution of HAART. This is to ensure that antituberculous dru gs are tolerated and to reduce the possibility of immune reconstitution syndrome. 42d) Discuss liver involvement in HIV disease in the context of highly active antiretroviral therapy (HAART) In the pre-HAART era, liver involvement in patients with HIV was mainly because of opportun istic infection. Although coinfection with HBV and HCV was well recognized in view of simil ar modes of trans- mission, coinfections had little impact on outcomes. The outcome was det ermined by the natural history of the underlying HIV disease. With the institution of HAART , the natural history of HIV infection was altered dramatically. As a consequence, coinfect ion with hepatotropic viruses has become significant, because patients survive long enough to develop endstage liver disease. In the past decade liver disease has become an important cause of death in HIV-positive patients, accounting for OXFORD CASE HISTORIES 288 15% of deaths. For this reason HIV-positive patients in developed countries may now be cons idered for liver transplantation in the same way as HIV-negative patients with endstage liv er disease. Active HBV infection occurs in up to 10% of HIV-positive patients. The course of HBV infect ion in HIV is more rapid. With the institution of HAART in a patient with HBV coinfection, recovery of the immune system may lead to a flare of the hepatitis with fulminant liver fai lure. For this reason the HAART regimen needs to contain antiretroviral agents with efficac y against both HIV and HBV. Lamivudine is effective, but when used as the sole agent, rapid ly results in HBV resistance. Tenofovir or entecovir are also effective against both viral infections when used in combination with lamivudine. For a three-drug HAART regimen, two of the three drugs should be active against HBV for patients with HIV-HBV coinfection. Coinfection with HCV occurs in 13 \200\22380% of HIV-positive patients, being most common i n intravenous drug users. HCV infection in the context of HIV is associated with higher vir al loads, the rapid develop- ment of fibrosis, and rapid progression to cirrhosis (which ma y develop within 10 years in these patients). Toxicity from HAART is also higher in patient s with HCV coinfection. Despite this, HAART probably reduces liver-related mortality in the se patients. Pegylated interferon and ribavi- rin remain the therapy of choice for HCV-HIV infection. Unfortunately a sustained virological response is less common for all HCV genoty pes in patients who also have HIV. Therapy for HCV is best delayed until immune reconstitut ion has occurred on HAART. Drug-related liver toxicity on HAART occurs in about 10%. In patients with hepatotoxicity t he mortality is 3%. Risk factors for hepato- toxicity include The use of ritonavir Baseline elevated transaminases HCV coinfection Underlying liver disease with advanced fibrosis. A lactic acidosis syndrome with progressive microvesicular steatosis of the liver is specif ically associated with nucleoside reverse transcriptase inhibitors, including zidovudine, d idanosine, and stavudine. This syn- drome may be fatal if not recognized. Hepatotoxicity fr om antitubercu- lous therapy has been discussed (see Case 1). CASE 42 289 Further reading Ocama P, Katwere M, Piloya T et al. (2008). The spectrum of liver diseases in HIV infected individuals at an HIV treatment clinic in Kampala, Uganda. Afr Health Sci; 8: 8 \200\22312. Sharma SK, Mohan A, Kadhiravan T (2005). HIV-TB co-infection: Epidemiology, diagnosis & management. Indian J Med Res; 121: 550 \200\22367. Terzic D, Brambolic B, Singer D et al. (2008). Liver enlargement associated with opportunistic infections in patients with human immunodeficiency virus infection. J Gastroi ntest Liver Dis; 17: 401 \200\2234. Wilcox CM, Saag MS (2008). Gastrointestinal complications of HIV infection: changing priorities in the HAART era. Gut; 57: 861 \200\22370. OXFORD CASE HISTORIES 290 Case 43 A 42-year-old male caretaker had abnormal liver function tests when he went to see his fami ly practitioner about back pain and fatigue. He remembered being jaundiced for 2 weeks when he was 18 years of age, but this was never investigated. He drank 2 \200\2233 cans of beer each week. He had not been tested for hepatitis C, but he had used intravenous drugs from 17 years of age until he was 24 years. There was no family history of liver disease or auto immune dis- ease. He was a non-smoker and not on any regular medication. He had been diagno sed with depression in the past and had taken fluoxetine 2 years ago. On examination, there were multiple spider naevi, but no evidence of hepatosplenomegaly, ascites, or encephalopathy. Investigations showed: 9/L; platelets 126 x 109/L Hb 15.2g/dL; WCC 5.6 x 10 Prothrombin time 13.2 sec mol/L; ALT 122 IU; ALP 205 IU; albumin 43g/L Bilirubin 30 AFP 5 IU/mL HCV antibody positive HCV RNA 2,016,074 IU/mL HBsAb positive and HBcAb positive Ultrasound abdomen revealed a coarse liver texture, and an enlarged spleen (15cm) Questions 43a) What is the most likely reason for jaundice when the patient was 18 years old? 43b) How severe is the patient \200\231s liver disease and what is his prognosis? 43c) Outline the advice that should be given to the patient regarding transmission. 43d) What further investigations are needed and what is the best treatment? 43e) What are the contraindications and possible complications of treatment? This page intentionally left blank OXFORD CASE HISTORIES 292 Answers 43a) What is the most likely reason for jaundice when the patient was 18 years old? Acute presentation of hepatitis C with jaundice is very rare and most individuals present i n the chronic phase with abnormal liver function tests. About 20 \200\22330% will spontaneo usly clear hepatitis C infection, which probably occurs within 6 months of acute infection. This cohort will have hepatitis C antibodies, but undetectable HCV RNA in the serum. Such people do not need follow-up and should be considered as uninfected. HCV RNA is therefore a n important confirmatory test for hepatitis C infection, since treatment cannot be based on the detection of antibodies alone. In this man, jaundice almost certainly resulted from ac ute hepatitis B infection, which is cleared in 90% of adults who become infected. This is c onsistent with the detection of hepatitis B core and surface antibodies. 43b) How severe is the patient \200\231s liver disease and what is his prognosis? The presence of thrombocytopenia and splenomegaly in a patient with chronic liver disease i s highly suggestive of cirrhosis, which was subsequently confirmed by liver biopsy. About 1 0% of people with hepatitis C will progress to cirrhosis within 20 years. Risk factors for progression are coexistent heavy alcohol intake, immunosuppression such as HIV, or organ tr ansplantation, age >40 years at infection, and male gender. Once cirrhosis develops, 25% wi ll develop complications (such as ascites) by 10 years. There is a 1% per year risk of prim ary liver cell cancer once cirrhosis develops. The degree of elevation of ALT is unrelated to the extent of liver fibrosis although those with persistently normal liver function test s tend to have less fibrosis and progress more slowly. In contrast to HIV, HCV viral load i s not a prognostic indicator and is mainly used to evaluate the response to therapy. 43c) Outline the advice that should be given to the patient regarding transmission.