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. Transmission of HCV is either percutaneous (blood transfusion or needle-stick injury) or no n-percutaneous (sexual contact, perinatal exposure). After the introduction of anti-HCV scr eening of blood donors in 1991, the rate of transfusion-related cases of HCV declined signi fi- cantly in the UK. Intravenous drug use is now the most common risk factor in the UK. Se xual transmission is rare, but has been reported in homosexuals. Hepatitis C is more preval ent in southern Europe and the CASE 43 293 Indian subcontinent, where inadequate cleaning of needles used for vac- cination has been a prevalent iatrogenic cause in the past. There is no effective vaccine and no effective pos t-exposure prophylaxis against HCV. Emphasis should be placed on counseling HCV-infected pa tients and those at risk of infection. The patient should be advised to avoid sharing razors or toothbrushes and to cover any open wound. Safe sexual practice, such as the use of condoms, should be encouraged in patients with multiple sexual part- ners, although this is not recommended for people involved in lo ng- term monogamous relationships. HCV-infected patients who are users of intravenous drugs should be vaccinated against HBV if not immune. 43c) What further investigations are needed and what is the best treatment? An endoscopy to screen for varices, hepatic ultrasound, and measure- ment of AFP every 6 mo nths, to screen for hepatocellular carcinoma (see Case 14), are appropriate. The viral geno type and viral load should be measured. The goal of therapy in hepatitis C infection is a sustained virological response, defined a s undetectable HCV RNA in peripheral blood 24 weeks after antiviral treatment has stopped. Standard treatment for hepatitis C consists of pegylated interferon- given once weekly, t ogether with oral ribavirin. Overall cure rates are 50%, but this depends on the viral geno type. Only 45% with genotype 1 (the most common type in the UK) are cured after a 12-month course of therapy, compared with 60 \200\22370% for genotype 3, and 90% with genotype 2. On ly 6 months \200\231 therapy is needed for genotype 2. Cure rates are lower in cirrhosis or coinfection with HIV. 43d) What are the contraindications and possible side effects of treatment? Ribavirin may cause a 3 \200\2234g/dL drop in hemoglobin. A substantial side effect of inte rferon is psychological depression, fatigue, or irritability. Relative contraindications to therapy include a myocardial infarction within 6 months or severe cardiac failure, haemogl obinopathies, renal failure (since ribavirin is excreted by the kidneys), decompensated liv er disease, immunosuppression (such as transplant patients), uncon- trolled thyroid disease , pregnancy, and male partners of pregnant women. Potential side effects of combined therapy include: Flu-like symptoms (to be expected with interferon) Diarrhea OXFORD CASE HISTORIES 294 Fatigue Skin rashes Increased susceptibility to infection Thyroid dysfunction Psychiatric disturbance Bone marrow suppression Local reactions at injection sites. Side effects frequently necessitate interruption of treatment and dose reduction. Severe or life-threatening side effects are infrequent but do occur. A good predictor of treatment r esponse is loss of detectable HCV RNA within 4 weeks of starting therapy. This patient was treated with pegylated interferon and ribavirin for 12 months. He needed a ntidepressants during therapy and had to stop work as a consequence. He returned to work a month after stop- ping therapy. His HCV RNA at 4 weeks dropped to 1540 IU/ml and was undete ctable at week 12. Six months after stopping therapy his liver function was normal and HCV PCR remained negative, consistent with cure. Further reading Bruno S, Facciotto C (2008). The natural course of HCV infection and the ne ed for treatment. Ann Hepatol; 7: 114 \200\2239. Baldo V, Baldovin T, Trivello R, Floreani A (2008). Epidemiology of HCV infection. Curr Pharmac Design; 14(17): 1646 \200\22354. Blonski W, Reddy KR (2008). Hepatitis C virus infection and hepatocellular carcinoma. Clin Liver Dis; 12: 61 \200\22374. Fabris P, Fleming VM, Giordani MT, Barnes E (2008). Acute hepatitis C: clinical aspects, di agnosis, and outcome of acute HCV infection. Curr Pharmac Design; 14: 1661 \200\2235. Santa ntonio T, Fasano M (2008). Therapy of acute hepatitis C: a review of literature. Curr Pharmac Design; 14: 1686 \200\2239. This page intentionally left blank OXFORD CASE HISTORIES 296 Case 44 A 27-year-old Chinese woman was referred for assessment of chronic hepatitis B infection. A raised ALT 600 IU/L had been found when traveling abroad. On return to the UK, she was see n for right upper quadrant pain and found to have hepatitis B. Her main complaint at presen tation was fatigue in addition to the pain. She had never used intravenous drugs and had no history of blood transfusion, tattoos, or jaundice. She had undergone a laparoscopic chole cys- tectomy 7 years previously, but this had not relieved the pain. On examination, she ha d no evidence of chronic liver disease or portal hypertension. Investigations showed: 9/L, platelets 251 x 109/L Hb 12.5g/dL, WCC 8.7 x 10 mol/L, ALT 32 IU/L, ALP 162 IU/L, albumin 41g/L Bilirubin 13 Viral markers: HBsAg positive, HBeAg positive, anti-HBe negative, anti-HBc IgM negative, HB V DNA 67.8 million IU/mL, HCV antibody negative Liver screen (see Case 1) otherwise negative Ultrasound scan of the abdomen: increased echogenicity in the liver CT and MRI of the abdomen: cholecystectomy noted, otherwise unre- markable Liver biopsy: chronic hepatitis with minimal activity and mild fibrosis. Questions 44a) Interpret the serology. 44b) Discuss the mode of transmission. 44c) Discuss the management options. 44d) What is the long-term prognosis? 44e) What is the significance of the abdominal pain and fatigue? This page intentionally left blank OXFORD CASE HISTORIES 298 Answers 44a) Interpret the serology. Our patient has serological evidence of HBeAg-positive chronic hepati- tis B. Chronic infec tion is defined by positive HBsAg serology for >6 months. She is likely to be in the immuno tolerant phase of hepatitis B, usually seen in young people and characterized by high level s of viral replication. This is indicated by an HBV DNA >107 copies/mL (1 IU = 2.5 \200\223 5 copies) with normal liver function tests. This phase may last decades before progressing to active disease. A normal ALT on one occasion does not imply immunotolerance, since the A LT should be shown to be nor- mal over time. Progression to active disease is recognized by a rise in the ALT and may lead to loss of HB eAg and seroconversion. This in turn may lead to the expression of anti-HBe antibodies, sup pression of viral replication, and normalization of ALT with inactive liver histology and m inimal fibrosis. This is termed the inactive carrier state. Our patient has already had a s ingle flare when her ALT rose to 600 IU/mL, but this failed to clear the virus. If she has repeated flares of hepatitis, detected by an elevated ALT and this still fails to clear the virus, it is likely that she will develop fibrosis. 44b) Discuss the mode of transmission. The time of transmission in this patient is unclear, although probably occurred at birth or in childhood. Hepatitis B is parenterally transmit- ted through contact with contaminated body fluids, either sexually, intravenous drug use and sharing of needles, transfusion of c ontami- nated blood products, body piercing or tattoos, or vertically transmitted from moth er to child. Transmission of hepatitis B in Asia is often verti- cal from mother to baby in the perinatal period. Perinatal transmission leads to chronic hepatitis in 90% of affected individuals in the absence of hepatitis B immunoglobulin and vaccination at birth. Horizon tal trans- mission during childhood carries a 20 \200\22330% risk of chronic infection. In contrast, <1% of people who contract hepatitis B in adulthood develop chronic hepatitis B. Our patient had no history of any risk factors that could have lead to her contracting a bl ood-borne illness. Her husband tested negative for hepatitis B. 44c) Discuss the management options. Treatment options for chronic hepatitis B include no treatment, treatment for a finite peri od with the aim of precipitating HBeAg CASE 44 299 seroconversion and sustained post-treatment viral suppression, or long-term treatment to su ppress viral replication. Treatment aims to delay or arrest progression to cirrhosis, hepat ic decompensation, and endstage liver disease, as well as reducing the risk of hepatocellul ar carcinoma. Treatment of finite duration involves pegylated interferon- 2a, 180 g/week. This is indic ated in those with HBeAg-positive chronic hepatitis (with an elevated ALT). These regimens lead to HBeAg sero- conversion to HBeAb-positive (the primary endpoint of clinical trials a nd treatment) in about a third of patients. The response is durable in up to 90% of respond ers followed for 7 years. Interferon therapy usually has side effects: flu-like symptoms, f atigue, weight loss, alopecia, bone mar- row suppression, and alterations of mood with depr ession (see Case 43). Treatment is contraindicated in decompensated liver disease, and used with caution in cirrhosis. Long-term therapy is required for patients with HBeAg-positive chronic hepatitis B who do n ot seroconvert with interferon, or those with HBeAg-negative chronic hepatitis B (Table 44. 1). In some chronic hepatitis B carriers (HBsAg-positive, HBeAb-positive with a normal ALT) the virus mutates, leading to a rise in viral load, abnormal liver blood tests, and liver damage known as HBeAg-negative chronic hepa- titis B. Several nucleoside or nucleotide anal ogs suppress HBV. They are given as monotherapy, unlike treatment of HIV or HCV. Drugs incl ude lamivudine, adefovir, tenofovir, and entecavir. The latter two are particularly resista nt to viral mutation even after continuous monotherapy for 3 years. Life-long treatment is likely to be necessary. Since our patient had normal ALT she was unlikely to benefit from interferon therapy. She o nly had mild fibrosis and minimal activity on liver histology. Long-term viral suppression was unlikely to be benefi- cial and risks provoking viral resistance, making subsequent the rapy more difficult. We therefore followed her up with ALT measurements every 3 months. The plan was to identify a two-fold increase in ALT, which would prompt a finite course of int erferon therapy, hoping to provoke seroconversion. Loss of HBsAg and viral eradication is u ncom- mon. The patient \200\231s husband and children tested negative for HBsAg, and immuni zation to hepatitis B was recommended. During follow up, she had a flare of ALT to 102 IU/L . She was given a course of therapy with pegylated interferon- 2a, although unfortunately this did not lead to seroconversion on this occasion. OXFORD CASE HISTORIES 300 Table 44.1 The natural history of hepatitis B Phase Serum ALT HBe Ag Anti-HBe HBV-DNA Level Copies/mL IU/mL 108 \200\2231012 Immune tolerance Normal or minimally elevated Positive Negative Very high 20m \200\22320bn 106 \200\2231010 200k \200\2232bn HBeAg-positive chronic hepatitis Persistently elevated Positive Negative High 104 \200\223108 2k \200\22320m HBeAg-negative chronic hepatitis Elevated and often fluctuating Negative Positive Moderate, fluctuating <104 Inactive carrier Normal Negative Positive Low or not detectable <2k 44d) What is the long-term outlook? The natural history of chronic hepatitis B infection is variable. Adverse outcomes include liver cirrhosis, hepatic decompensation, endstage liver disease, and the development of hep atocellular carcinoma. Risk factors for cirrhosis in chronic hepatitis B are similar to tho se for HCV (see Case 43), and include age >40 years at diagnosis, male gender, severe fibro sis at presentation, recurrent flares of hepatitis, high levels of HBV replication, HBV gen otype C, mutant strains of virus, coinfection with HDV, HIV or HCV, and heavy alcohol consu mption. Once cirrhosis is established the risk of hepatocellular carcinoma increases. Older age is probably a surrogate marker of longer duration of infection, as is Asian ethnicity, since infection is usually acquired early in life. Of particular relevance to our patient is that repeated flares without viral clearance, increases the risk of progression to cirrh osis. The risk of developing cir- rhosis over a 5-year period in a patient of East Asian or igin, with HBeAg- positive chronic hepatitis B is 8%. The risk of hepatocellular carcinoma is 0.01 \200\2230.1%/year in patients with chronic hepatitis B without cirrhosis, and 1 \200\2233%/year in the presence of cirrhosis. 44e) What is the significance of the abdominal pain and fatigue? Neither abdominal pain nor fatigue is attributable to chronic hepatitis B infection. The pa tient had had right upper quadrant pain for at least 7 years. Biliary type pain, in the abs ence of gallstones often results from sphincter of Oddi dysfunction (often known as SOD, by name and nature!). CASE 44 301 In sphincter of Oddi dysfunction, biliary-type pain recurs or persists after cholecystectom y. It is sometimes referred to as post-cholecystectomy syn- drome. Residual gallstones, tum ors, or common bile duct strictures should first be excluded. Sphincter of Oddi dysfunction presents as pain, commonly with fatigue, sometimes with abnor mal liver function tests, and occasionally a dilated common bile duct or pancreatic duct. S phincter of Oddi dys- function is classified on the basis of whether or not there is a dila ted common bile duct or raised alkaline phosphatase during pain attacks. Type 1 is defined as a dilated common bile duct and a two-fold elevation in ALP on two occa sions, which responds best to treatment with endoscopic sphincterotomy. Type 2 is defined a s an elevated ALP or dilated CBD and responds to sphincterotomy in less than two-thirds of cases. Type 3 is characterized by biliary type pain with a normal CBD and without a rise in ALP. Type 3 is most difficult to treat and the risks (pan- creatitis and mortality) associ ated with intervention by sphincterotomy cannot be justified. Patients should be treated me dically, often with a low dose of a tricyclic as in irritable bowel syndrome (see Case 32). Our patient had type 3 sphincter of Oddi dysfunction unrelated to her liver disease and sh e responded to amitriptyline 10 \200\22325mg at night. Further reading Corazziari E (2003). Sphincter of Oddi dysfunction. Dig Liver Dis; 35(Suppl. 3): S26 \200 \223S29. Dusheiko G, Antonakopoulos N (2008). Current treatment of hepatitis B. Gut; 57: 10 5 \200\22324. Fattovich G, Bortolotti F, Donato F (2008). Natural history of chronic hepati tis B: Special emphasis on disease progression and prognostic factors. J Hepatol; 48: 335 \200\22352. Papa theodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ (2008). Therapeutic strategies in the management of patients with chronic hepatitis B virus infecti on. Lancet Infect Dis; 8: 167 \200\22378. OXFORD CASE HISTORIES 302 Case 45 A 47-year-old woman presented with a 2-week history of abdominal distension. She had an 18- year history of type 2 diabetes, now controlled with insulin. She also had peripheral vascu lar disease with a left, below-knee amputation. There was no history of myocardial infarcti on, neuropathy, or retinal disease. Current medications were enalapril, atenolol, aspirin, amlodipine, and insulin. She drank <10 units/week of alcohol and denied ever having been a heavy drinker. On examination, her pulse was 80bpm, blood pressure 150/80mmHg, and she was apyrexial. There were no stigmata of chronic liver disease. Ascites was present and there w as pitting oedema to the sacrum. Her BMI prior to the ascites was 31kg/m2. Investigations showed: 9/L, platelets 100 x 109/L Hb 12.5g/dL, WCC 10.1 x 10 mol/L Na 132mmol/L, K 3.5mmol/L, urea 6.3mmol/L, creatinine 87 Random blood glucose 8.7mmol/L mol/L, AST 95 IU/L, ALT 70 IU/L, ALP 434 IU/L, GGT 40 Bilirubin 4 IU/L, albumin 26g/L g/L Prothrombin time 14.0 sec Ferritin 440 Abdominal ultrasound: coarse liver texture, ascites, normal sized spleen Ascitic fluid analysis: albumin 4g/L, WCC <250 cells/mL, no malignant cells CA125 1052 IU/ml (normal range 0 \200\22330) CT of the abdomen: enlarged irregular liver, splenomegaly, patent portal vein. Questions 45a) What is the differential diagnosis and what other serological blood tests are appropriate? 45b) What should be the next investigation? 45c) What is the natural history of this condition? 45d) Which patients should have a liver biopsy? 45e) How could the patient \200\231s liver disease have been prevented? This page intentionally left blank OXFORD CASE HISTORIES 304 Answers 45a) What is the differential diagnosis and what other serological blood tests are appropriate? The differential diagnosis of ascites in this patient includes: \200 Cirrhosis Non-alcoholic fatty liver disease (NAFLD) Alcoholic liver disease Haemochromatosis Autoimmune liver disease Chronic viral hepatitis (B or C, see Cases 43 and 44) Cryptogenic cirrhosis Right heart failure Ovarian cancer with peritoneal metastases. This patient is likely to have cirrhosis, because there is thrombocytopae- nia, hypoalbumin aemia, an elevated prothrombin time, and an abnormal appearance of the liver on both ultras ound and CT scan. The sensitivity and specificity, however, of ultrasound or CT for the dia gnosis of cirrhosis is low. The patient is at particular risk of NAFLD because she has type 2 diabetes, obesity, and hyperlipidaemia. NAFLD is, however, a clinico- pathological diagn osis that is made after the exclusion of other liver disorders. The following aetiologies need to be excluded: Significant alcohol consumption (>20g/day ethanol) g/L, Haemochromatosis (although an elevated ferritin, usually <1000 is common in NAFLD) Chronic viral hepatitis Alpha-1 antitrypsin deficiency Autoimmune liver disease. In NAFLD, it is the ALT and GT that are commonly abnormal, although a third of patients hav e cholestatic liver function tests with an elevated ALP and GT. The ALT is characteristical ly higher than the AST, in con- trast to alcoholic liver disease. A high ALT/AST ratio reve rses in the pres- ence of cirrhosis. A low platelet count is common in cirrhosis. It is important to exclude right heart failure as a cause of ascites, by examination (eleva ted jugular venous pressure, pulsatile liver), and by CASE 45 305 echocardiogram. Our patient had no clinical signs of right heart failure and the echocardio gram was normal. It is also prudent to check that the hypoalbuminaemia is not caused by nep hrotic syndrome. The patient \200\231s 24-hour urinary protein was <1g. An elevated CA125 can occur in cirrhosis, although it is important to exclude ovarian cance r. No malignant cells were seen in the ascitic fluid (sensitivity 60 \200\22370%). The coar se liver texture on ultrasound and CT, the splenomegaly and low protein ascites with a seru m ascites albumin gradient >11g/L, is characteristic of cirrhosis. 45b) What should be the next investigation? This patient needs a liver biopsy (Figs 45.1 and 45.2 in the central color section). Since the patient had ascites and a BMI >30kg/m2, this was car- ried out via the transjugular rou te. Transjugular liver biopsy is appropri- ate in the presence of ascites, coagulopathy (PT prolonged >5 sec above the normal upper range) or platelets <60 x 109/L. Liver biopsy help s con- firm the stage of cirrhosis and establishes the etiology. The histological features of NAFLD associated with cirrhosis are those of non-alcoholic steatohepatitis (NASH). These include Mallory \200\231s hyaline, macrovesicular fat, and a chronic inflammatory portal i nfiltrate with interface hepatitis and a varying degree of fibrosis. The amount of fat in h epatocytes often declines as cirrhosis develops. The histopathological features are indis- tinguishable from alcoholic liver disease, so a clinical history is needed to differentiate the two conditions. Many cases of cryptogenic cirrhosis (i.e. unknown cause) are attributa ble to non-alcoholic fatty liver disease. Fig. 45.1 (see color plate 22) Liver biopsy in non-alcoholic fatty liver disease (low power ) showing steatosis (large arrow) and interface hepatitis (small arrow). OXFORD CASE HISTORIES 306 Fig. 45.2 (see color plate 23) Liver biopsy in non-alcoholic fatty liver disease (high powe r) showing Mallory \200\231s hyaline (arrow). 45c) What is the natural history of this condition? NAFLD can be separated on histopathology into simple steatosis and non-alcoholic steatohepa titis (NASH). Only NASH is associated with fibrosis and progression to cirrhosis. It typica lly presents with asymptomatic abnormal liver function tests. The prevalence of NAFLD is 3 \200\2237%. About a third of those with NASH will develop cirrhosis, although this may take several decades. NASH is associated with increased liver-related mortality. Factors associated with more severe disease include: Obesity Type 2 diabetes Age >45 years Hypertriglyceridaemia The role of gender is contentious. Some studies suggest that female gender is an independen t risk factor for more severe disease. 45d) Which patients should have a liver biopsy? Patients who present with cirrhosis of unknown cause should have a liver biopsy. When a pat ient presents with abnormal liver function tests and NAFLD is suspected, a period of lifest yle modification is generally appropriate before biopsy. This means weight reduction for 3 \200\2236 months. Biopsy is required for patients: in whom liver tests fail to correct after lifestyle modification >45 years of age CASE 45 307 2 with a BMI >30kg/m with type 2 diabetes with features suggestive of cirrhosis if ALT levels remain persistently above twice the upper level of normal. 45e) How could the patient \200\231s liver disease have been prevented? This patient was always at high risk of NAFLD, because she had type 2 diabetes, obesity, an d hypercholesterolaemia. She now presents with evidence of decompensated cirrhosis. If NASH had been diagnosed at an earlier stage, progression to cirrhosis would probably have been delayed by: : she is already on insulin and her control Improved diabetic control should be optimized. Although there is no evidence of a beneficial effect of metformin on hepatic fibrosis, it c an be given in the presence of cirrhosis. The thiazolidinediones (such as pioglitazone) act on per- oxisome proliferator-activated receptor gamma (PPAR ) to increase insulin recepto r expression in adipocytes and hepatocytes. This can improve LFTs but can also increase bod y weight. Weight loss , which improves liver fibrosis even when severe. Exercise (difficult in this particular case because of below-knee amputation and peripheral vascular disease) Gastric banding has been shown to improve liver disease. Abstinence contributes to cellular damage. from alcohol, because alcohol aggravates steatosis and Further reading Ali R, Cusi K (2009). New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD). Ann Med; 41: 265 \200\22378. Dixon JB, Bhathal PS, Hughes NR, O \200\231 PE (2004). Non alcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology; 39: 1647 \200\2235 4. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H (2009). Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol; 15: 280 \200\2238. OXFORD CASE HISTORIES 308 Case 46 A 68-year-old woman presented with a 10-day history of a flu-like illness fol- lowed by a w eek of jaundice. She complained of lethargy, myalgia, and nausea, but no vomiting. She had lost no weight. She lived on a small holding with her husband and kept livestock, including sheep and goats. She had epilepsy for which she was taking carbamazepine. On examination, she looked ill. Her Glasgow Coma Score was 15, but she was dehydrated and j aundiced. Her pulse was 110bpm and blood pressure 90/60mmHg. Her temperature was 38 C. Exa mination of the abdomen was unremarkable. Investigations showed: 9/L, neutrophils 10 x 109/L, platelets 27 x Hb 10.6g/dL, WCC 12 x 10 109/L Blood movie: left shift of myeloid cells, peripheral plasma cells Prothrombin time 18 sec Haptoglobin 1.9g/L mol/L Na 123mmol/L, K 3.0mmol/L, urea 31mmol/L, creatinine 280 mol/L, ALT 24 IU/L, ALP 279 IU/L, albumin 32g/L Bilirubin 208 CRP 133g/L Abdominal ultrasound showed a large stone in the gallbladder, with prominent intrahepatic b ile ducts, but normal extrahepatic ducts. Normal spleen and kidneys. Questions 46a) Describe how you would establish a diagnosis. 46b) What is particularly notable in the history? 46c) How do we treat this condition? 46d) What are the complications and outcomes of this condition? This page intentionally left blank OXFORD CASE HISTORIES 310 Answers 46a) Describe how you would establish a diagnosis. Presentation with flu-like symptoms, fever, and jaundice suggests an infectious cause. This is supported by the markedly elevated CRP and leucocytosis with prominent neutrophilia and left shift. Bacterial infections with septicaemia should first be considered, including as cending cholangitis, pneumonia, or urinary tract infections. A raised ALP is common with sy stemic bacterial infection, but cholangitis can also occur with only mildly elevated ALP. B lood cultures are manda- tory and should be followed by empiric therapy with broad-spectrum antibiotics. Acute viral hepatitis may present with a similar syndrome, but the ALT was normal in this c ase. Hepatitis A (see Case 16), hepatitis B, and hepatitis E commonly present with acute he patitis. Epstein \200\223Barr virus infection may cause jaundice in 10% of cases but is usu ally contracted in childhood or early adulthood. There were no risk factors for parenterall y or enterically transmitted hepatitis. There is also a marked disparity between the renal impairment and severity of liver dysfunction, since the prothrombin time was only mildly pr olonged. Renal impairment is only associated with severe hepatitis. A travel history is important, because other infections should be con- sidered, including m alaria and rickettsial infection. Our patient had not recently traveled, but she had been i n contact with animals. 46b) What in the history is specifically significant? The close contact with farm animals is relevant. Brucellosis has to be considered since the patient kept sheep and goats. Brucella melitensis is associated with goats and B. ovis wit h sheep. Either is acquired from contact, including unpasteurized milk, and present with an acute febrile illness (B. melitensis is named after David Bruce, who identified this organ ism as the cause of Malta Fever). When severe the illness may be associated with jaundice, but the ALP is usually raised since brucellosis causes granulomatous hepatitis (see Case 42 ). The most likely diagnosis was leptospirosis. This characteristically causes a disproportion ately high bilirubin compared with the ALT and ALP. Where there are farms there are rats an d the ubiquitous spirochete, Leptospira interrogans, is specifically associated with rats. A wide range of mammals may harbor the organism in the renal tubules, including cattle, dog s (which become severely ill), pigs, and all kinds of rodents. CASE 46 311 Rodents are the most important vector. The organism is transmitted through direct contact w ith infected urine, or indirectly through contact with contaminated water or soil. Leptospi ra survive in the environment for long periods if conditions are wet. Occupational exposure occurs in vets, farmers, rat catchers, sewage or slaughterhouse workers, and recreational exposure occurs during immersion in contaminated rivers or lakes. The diagnosis is made through dark field microscopy or culture of urine. In the first (lept ospiraemic) phase of the illness, blood cultures may be positive and in the second (immune) phase urine culture may be positive. The diagnosis is frequently considered late in the il lness. A sero- logical agglutination test is the reference method, but requires a 4-fold ri se in titres to be diagnostic, so two samples separated by an interval of 10 days are neede d. Recent seroconversion may be demonstrated by ELISA methods that detect IgM antibodies. Investigations showed: Leptospira ELISA IgM positive 1:2560 Leptospira microscopic agglutination test positive at 1:2560 Blood cultures were negative, probably because they were taken in the second phase of the i llness. 46c) How do we treat this condition? Leptospira spp. are sensitive to most antibiotics, with the exception of chloramphenicol. M ild illness may be treated with oral doxycycline. Severe illness should be treated intraven ously with either penicillin G 1.5 million units 6-hourly, or ampicillin 1g 6-hourly if the diagnosis is established. In the absence of an established diagnosis, a broad-spectrum ant ibiotic should be used. A third-generation cephalosporin was a rea- sonable choice in our p atient. This patient was started on intravenous fluids and cefotaxime 1g 3 times a day IVI on admis sion, following appropriate procurement of blood cultures and before serology results were known. Improvement in all respects occurred over the following 3 days, and she survived the ill- ness without permanent sequelae. 46d) What are the complications and outcomes of this condition? Leptospirosis classically has two phases. The leptospiraemic phase fol- lows direct exposur e, commonly through intact skin, after a 7 \200\22314-day incubation period. Blood cultures may be positive, and it characteristi- cally causes a flu-like illness, with fever, intens e myalgia, headache, OXFORD CASE HISTORIES 312 anorexia, nausea, vomiting, lymphadenopathy and conjunctival injec- tion. Conjunctival inje ction is an important clue, as it is particularly characteristic. Myalgia is frequently sev ere, especially with L. hajji caught from cattle, particularly affecting the calves, back a nd abdominal mus- cles. This is followed by a period of up to 3 days when the fever subside s, before the onset of the immune phase. Organisms may then be present in the urine, but le ptospiraemia is over. A second clinical phase does not occur in mild cases, but when it doe s there is hepatorenal and pulmo- nary symptoms. Weil \200\231s disease is the combination of jaundice, spleno- megaly, and renal failure in a patient with leptospirosis (classically L. icterohaemorrhagiae). Pulmonary involvement is indicated by a non- specific cough and d yspnoea, but severe pulmonary hemorrhage can occur that may be fatal. Leptospirosis needs to be differentiated from viral haemorrhagic fever (Lassa, Marburg, and Ebola) when the illness presents with petichiae, purpura and epistaxis, but the travel his tory is usually then the clue to diagnosis. Severe gastrointestinal and intracranial hemorr hage, haemo- lysis, cardiac involvement, ARDS, rhabdomyolysis, and pancreatitis have been d escribed but are rare.