Drug-induced liver injury (DILI) accounts for 9.5% of all suspected adverse drug reactions (ADRs) and for a significant proportion of fatal ADRs. DILI may be a direct toxic effect or an immunological reaction to either the drug or an active metabolite. Drugs can cause a diverse array of liver injury, which may be acute or chronic. Adaptation to injurious effects, with only a transient increase in liver function, can occur. Inherited or acquired factors affect the risk of DILI. There is marked geographic variation in responsible agents; in the West antibiotics, anticonvulsants, psychotropic and recreational drugs are the most common offending agents, whereas in Asia, herbal and dietary supplements are more common. This contribution focuses on the pathogenesis and consequences of DILI, their investigation and management. Information on specific ADRs can be obtained from the British National Formulary, drug data sheets and other web-based databases (WHO Adverse Drug Reactions Monitoring; AERS and DIOGENES®: Adverse Drug Events Database – FDA sites; Canada Vigilance Adverse Reaction Online Database; Drug Adverse Reaction Target Database (DART)).

The incidence of hepatitis E in the UK is increasing. We recommend measuring hepatitis E serology in those with an acute hepatitis.

Drugs that damage the liver account for 9.5% of all suspected adverse drug reactions (ADRs), are the main cause of fatal ADRs and are the most common reason for withdrawal of drugs from the market. Pre-market surveillance detects common ADRs, but those seen in clinical practice are rare (1 in 10,000–100,000). Their recognition depends on individual reports and post market surveillance. In the UK, the yellow card scheme is used to report all suspected ADRs with new drugs and serious ADRs with established drugs. Both under-reporting and over-reporting occur. Information on hepatotoxicity, therefore, is neither systematic or comprehensive. The liver is particularly affected as it is the central metabolizing organ through which all foreign compounds pass. Injury may be a direct toxic effect or immunological reaction to either the drug or an active metabolite formed by bio-activation (it was reported that for 62% of withdrawn drugs it is the metabolite that is toxic). Any type of liver injury can be reproduced by drugs and any drug can produce different types of liver injury. Injury may be acute or chronic and there can be adaptation to injurious effects with a transient increase in liver function in patients that have significant ongoing injury. Many factors interact to lead to injury and there is considerable variation in susceptibility which may be inherited and acquired. This contribution focuses on general principles of drug-induced liver disease. Information on specific ADRs can be obtained from the British National Formulary, drug datasheets and databases.

AIMS AND METHODS Oxidant stress is proposed to be an important pathogenic factor in liver damage related to alcohol. The glutathione S-transferases (GSTs) are a group of polymorphic enzymes that are important in protection against oxidant stress. As there is evidence for genetic susceptibility to alcohol-related liver disease we have compared the frequency of polymorphisms of GSTM1, M3, P1, T1 and A1 by polymerase chain reaction (PCR) on leucocyte DNA in patients from North Staffordshire, Birmingham and Liverpool with alcohol-related chronic liver disease heavy drinking and normal local controls. RESULTS There were no significant differences in GSTM1, GSTM3 or GSTP1 genotype frequencies among patients, drinking and non-drinking controls from the three centres. There was a significant increase in the GSTT1 null Liverpool alcoholic liver disease (ALD) patients compared with corresponding non-drinking controls (26.3 and 14.6%, respectively; P = 0.044, odds ratio (OR) = 2.1, 95% CI = 1.1-4.7) though this was not repeated in the Birmingham and North Staffordshire cohorts. For GSTA1, the -69 CC genotype was associated with increased risk of ALD in the Liverpool group, but a reduced risk in the North Staffordshire group. CONCLUSIONS We have failed to demonstrate within the limitation of a case-control study a reproducible significant association of GST polymorphisms with susceptibility to ALD but there are suggestions that GSTA1 and GSTT1 warrant further study.

BACKGROUND:A review of biliary tract complications was performed in 32 patients who underwent liver transplantation by the Western Australian Liver Transplantation Service during a 2-year period.METHODS:A review was made of patient data collected prospectively, and confirmed by retrospective casenote review.RESULTS:A total of 30 patients (31 grafts) survived more than 2 days after transplantation, and of these 28 had an end-to-end biliary anastomosis. Analysis of these 28 patients found that eight of 17 patients with T-tubes had complications: three leaks at T-tube removal; two strictures and leaks; and three strictures. Six of 11 patients without a T-tube had complications: one leak; three strictures and leaks; and two strictures. Predisposing factors were present in eight of the 14 patients with biliary tract complications: hepatic artery stenosis in three; and one each with hepatic artery thrombosis; biliary calculi; donor-recipient bile duct mismatch; severe cellular rejection: and prolonged postoperative hypotension. Acute rejection, steroid-resistant rejection and cytomegalovirus infection were all significantly more common in those patients with biliary tract complications compared with those without. There was no difference in cold ischaemic time or donor age. Twelve of the 14 patients with biliary complications required endoscopic stenting with or without balloon dilation, and eight patients required radiological percutaneous drainage of bile collections. Only one patient required biliary reconstruction and two patients required re-transplantation. One patient died of uncontrolled infection. Of three patients who underwent choledochojejunostomy, biliary leak developed in two patients, both of whom required operative biliary and hepatic repair. One of the three patients died from disseminated Aspergillus infection. The median total hospital stay of patients with biliary complications was 61 days (range: 30-180 days) compared with 33.5 days (range: 22-70 days) for patients without. Of patients with end-to-end biliary anastomosis, 50% had biliary tract complications and more than half of these had predisposing factors. The majority of biliary complications were managed without the need for surgery.CONCLUSION:A total of 50% of patients with end-to-end biliary anastomosis had biliary tract complications. Biliary strictures presented later than leaks, and the majority of these complications were managed without the need for surgery.

ABSTRACT— A 45‐year‐old HBsAg carrier (HBeAb positive with normal liver function tests) underwent renal transplantation for mesangioproliferative glomerulonephritis. Sixteen months later he developed jaundice. Investigations showed he remained HBeAb positive, but HBV‐DNA levels were 99 pg/ml, indicating active replication of a HBV pre‐core mutant. He was commenced on lamivudine therapy with a subsequent rapid fall in HBV‐DNA levels to 2.8 pg/ml, but liver function tests continued to deteriorate and he developed hepatorenal failure. Liver biopsy showed fibrosing cholestatic hepatitis. He underwent liver transplantation, which was complicated by lactic acidosis. Lamivudine was withdrawn and HBV prophylaxis with HB immunoglobulin was commenced. Unfortunately he died 38 days post‐transplant of surgical complications with no evidence of HBV recurrence. We discuss the use of nucleoside analogues in fibrosing cholestatic hepatitis and review the literature.

The aim of this study was to determine the prevalence of infection with the newly described hepatitis G virus (HGV) in a liver transplant cohort, and to establish the frequency and nature of hepatitis in those with and without HGV infection. A reverse transcriptase-polymerase chain reaction technique was employed to determine viraemia in the patients, and liver biopsies taken at different times after transplantation were assessed histologically, Hepatitis G virus RNA was detected in 47% of the liver transplant recipients investigated. Those positive for HGV had received significantly more blood or blood products than the HGV-negative patients. The frequency of abnormal liver function tests was similar in HGV-positive and HGV-negative recipients. Bile duct epithelial cell damage was more frequently seen in those with HGV viraemia. This study indicates that almost half of the liver transplant recipients in Northern England are positive for HGV, and that infection is associated with exposure to blood and blood products. It appears that, in the immunosuppressed patient, HGV does not cause clinically significant liver disease, at least up to 2 years after transplantation. If HGV infection is associated with hepatitis outside this clinical setting, it is likely that the liver damage is immunopathologically mediated rather than as a result of direct viral cytotoxicity.

Of 1728 patients attending a regional drug and alcohol clinic, 202 were considered at risk of hepatitis C virus (HCV). Forty-nine per cent (99/202) agreed to testing-67% (67) were HCV antibody positive. Age and a history of needle sharing was the significant factor associated with positive HCV status. Patients on methadone maintenance medication were more-likely to have been HCV positive, but significantly (p = 0.005) less likely to have shared needles in the previous year. Seventy-three per cent (49/67) attended for follow-up at a "liver clinic". Fifty per cent were infected with genotype 1a. Eighteen patients were biopsied and all were abnormal, ranging from mild hepatitis to severe fibrotic hepatitis. Attendance for medical follow-up was poor, which emphasizes the importance of preventative measures such as methadone maintenance programmes for reducing the spread of HCV.

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.

The epidemiology of hepatitis C virus (HCV) infection was studied in an English teaching hospital over an 18 month period. A total of 104 HCV antibody positive patients were referred for further investigation. They were divided into those diagnosed through screening (blood donors and intravenous drug abusers) and those diagnosed for other reasons, and their mean ages, known risk factors for HCV transmission, genotypes, and liver biopsy histology were analysed. Screened patients were significantly younger than the others. No significant difference in age was found between genotypes. Most patients genotyped (69%) were genotype 1. Intravenous drug abusers had a higher proportion of subtype 1a, and patients who acquired HCV through blood transfusion had a higher proportion of subtype 1b. Liver biopsy specimens were scored using a histological activity index for liver inflammation and fibrosis. Patients with subtype 1b had significantly more severe liver disease than other genotypes when the histological activity index scores for fibrosis were analysed (p < 0.05). Liver disease worsened significantly with age according to all three histological activity index scores (portal activity: p < 0.01, acinar activity: p < 0.001, fibrosis: p < 0.0001). Liver disease worsened with increased duration of infection (p < 0.002), and patients who also abused alcohol presented at a significantly younger age (cirrhosis, p < 0.05, hepatocellular carcinoma, p < 0.02).

We studied hepatitis C virus (HCV)-related disease in older people because the treatment rationale for younger asymptomatic patients is based on the long-term prognosis of infection. Of the HCV-antibody-positive patients seen at Freeman Hospital 1990-1994, 25 were > 65 years old; 24 were Caucasian and one was Afro-Caribbean. Median age at presentation was 67 years, and five were female. Nine were asymptomatic at presentation, six presented with varices, five with malaise, three with abdominal pain, one with pruritus and one with oedema. Risk factors identified were: transfusion (7), haemodialysis (1), health care worker (dentist) (1), and tattoos (2). There was no recognized risk factor for infection in 14, but five of these had done military service in areas of high HCV prevalence. Liver biopsy in 20 showed chronic hepatitis in two, cirrhosis in 12, and cirrhosis and hepatocellular carcinoma in six. Three additional patients also developed hepatocellular carcinoma. HCV genotyping was done in 19 and all were type 1 (1a, 4; 1b, 14; 1 untypable, 1). Eleven died, at median age 71 years (range 65-94 years), five of HCV liver-related deaths and two from HCV-associated non-hepatic disorders (non-Hodgkin's lymphoma and fibrosing alveolitis).

The genetic locus for α-1-antitrypsin (α-AT) is highly polymorphic, but all protein variants are encoded by a single locus on chromosome 14. Periportal hepatocyte granules are described in association with chronic liver disease and the Z variant. A Z-specific point mutation in exon V of the α-AT gene, converting amino acid 342 from Glu to Lys, is thought to be responsible for the hepatocyte accumulation. We describe the use of the polymerase chain reaction (PCR) to amplify exon V of the α-AT gene and subsequent detection of the wild-type M- and Z-specific sequences by hybridisation to 32P-labelled-allele-specific oligonucleotides. We applied this technique to leucocyte DNA from 37 patients with suspected chronic liver disease, 25 of whom had hepaiocyte α-AT inclusion granules on liver biopsy. All 25 were homozygous or heterozygous for the Z allele. One patient, phetotyped as PiS, was found to be PiSZ and another phenotyped as PiZ (presumed homozygous), was found to be a Z heterozygote. No Z aliele was detected in any of the twelve patients without α-AT inclusion granules. This sensitive PCR technique could be used to assess the relative risk of chronic liver disease in PiZ heterozygotes and to determine whether individuals without the Z amino acid 342 substitution can develop periportal α-AT granules.