Hepatology

Genetic haemochromatosis

Genetic haemochromatosis is an autosomal recessive disorder of iron metabolism. Excessive iron is absorbed from the gut and deposited in tissues such as the liver, heart, pancreas, anterior pituitary, joints, and skin. This results in end organ damage, which may include cirrhosis and hepatocellular carcinoma. Genetic haemochromatosis is common—in the north European population, the gene carrier rate is 10%, and the disorder may affect up to 1 in 300 heterozygotes. Early detection of haemochromatosis has proved difficult until now, but a sensitive screening method has been developed. This means that liver disease in affected people can be prevented by early prophylactic treatment with repeated venesection.

For more than 20 years it has been recognised that the gene for genetic haemochromatosis was closely linked to the HLA locus on the short arm of chromosome 6. The precise location has recently been identified; the candidate gene, originally called HLA-H, has been renamed HFE.1 This work involved localisation and detailed sequencing of a large segment of DNA around the HLA locus. A single point mutation in the HFE gene was shown to encode a single amino acid substitution from cysteine to tyrosine (C282Y) and is closely linked to a β₂ microglobulin binding domain (figure). Studies from collaborating centres in the United Kingdom, United States, and Australia have shown frequencies of the mutant allele of 90%, 83%, and 100% respectively in patients with genetic haemochromatosis.2 Exactly how the C282Y mutation leads to increased absorption and iron overload is not clearly understood. However, the discovery of the gene has led to the development of a reliable, simple screening method based on polymer chain reaction techniques.

Predicted structure of the protein encoded for by the haemochromatosis gene, based on analogy with other major histocompatibility complex class I proteins, consists of three extracellular domains, a membrane spanning hydrophobic region, and a cytosolic tail. Mutations of cysteine 282 to tyrosine (C282Y) may alter disulphide bridging (-S-S-) and protein conformation, thereby disrupting the interaction with β2 microglobulin. (Adapted from Feder et al1)

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Wilson's disease

Wilson's disease is a rare, autosomal recessive, inborn error of metabolism. It is characterised by defective biliary copper excretion which leads to the accumulation of toxic amounts of copper in the liver, brain, kidney, and cornea. Thus far, treatment has been based on chelation of copper with penicillamine to prevent end organ damage or liver transplantation in patients who present with acute liver failure.

Since the discovery of the gene for Wilson's disease, designated ATP7B,3 at least 60 mutations specific to the disease have been identified. The gene is located on the long arm of chromosome 13 and comprises a region 30 kb long. In contrast to genetic haemochromatosis, there does not seem to be a single dominant mutation in the gene for Wilson's disease; most patients have at least two mutant alleles. However, analysis of microsatellite markers surrounding the ATP7B gene enables affected family members to be identified and earlier prophylactic treatment with penicillamine to be given.4

Treatments other than penicillamine have been reported recently. These include trientine, alone or combined with zinc,5 and ammonium tetrathiomolybdate, which is particularly effective for patients with neurological or psychiatric manifestations of the disorder.6 Magnetic resonance imaging of the brain shows resolution of copper deposits with ammonium tetrathiomolybdate treatment. The success of these alternative treatments suggests that with careful monitoring liver transplantation can be avoided in a selected group of patients.

Hepatitis B infection

The hepatitis B virus, discovered in 1966, has infected more than 350 million people worldwide. It is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and is an important indication for liver transplantation.7 Recent studies have focused on improved molecular understanding of the virus, in particular its mutant strains, and trials of new antiviral treatments. Interferon alfa is currently the only approved treatment for chronic hepatitis B infection, but it achieves response rates of only 30% to 40% within the first year of treatment. Interferon alfa reduces viral replication. This results in increased clearance of the hepatitis B e antigen and hepatitis B surface antigen and thereby prevents continuing liver damage.

Interferon alfa treatment is generally given subcutaneously for up to 12 months as either 5 MU daily or 10 MU three times weekly. Unfortunately, despite the development of criteria that help to predict a good outcome (box), response rates are still lower than 50%. The need for alternative antiviral agents has led to the use of nucleoside analogues in clinical trials. The most promising at present is lamivudine (3'-thiacytidine). This is now being used before and after liver transplantation to prevent recurrent infection in the liver graft. Lamivudine is given alone or with hepatitis B virus immunoglobulin.

Mutant viruses

A small but important group of patients have no detectable hepatitis B e antigen in their serum, yet continue to show active viral replication because of a viral mutation. This underlines the importance of testing for hepatitis B e antigen and hepatitis B virus DNA to assess viral replication and infectivity. Infection with mutant viruses may result in a more aggressive chronic hepatitis, an increased risk of developing liver failure, and more rapid graft loss after transplantation.

Hepatitis C infection

Hepatitis C virus is an RNA virus. It is predominantly transmitted parenterally, but in up to 40% of cases no identifiable risk factor is found. Since the discovery of hepatitis C virus, screening of blood and blood products has had a substantial impact on limiting the incidence of post-transfusion hepatitis. Unfortunately, almost all patients with haemophilia in the United Kingdom who received pooled clotting factor concentrates before 1987 became infected with hepatitis C virus. In the past five years some have presented with end stage liver disease and often need consideration for liver transplantation.8

Recent studies of large cohorts of patients with chronic hepatitis C infection have identified factors that promote more rapid progression of liver fibrosis.9 These factors are age at the onset of infection, concomitant alcohol consumption, and male sex. No association between the genotype and the development of fibrosis has been found, suggesting that host factors are more important overall than virological factors.

At present, interferon alfa is the only approved treatment for chronic hepatitis C infection. Up to 50% of patients respond to interferon alfa treatment initially, but in only 25% is a sustained response achieved. Long term responses are even less likely in patients with cirrhosis. 10 11 However, two recent studies have confirmed that interferon alfa may still have a considerable role in reducing the risk of hepatocellular carcinoma in these patients, and suggest that there is a long term benefit overall, despite the presence of cirrhosis.12 The recent National Institutes of Health consensus conference on treating hepatitis C infection decided that initial treatment should be 3 MU of interferon alfa, given subcutaneously three times a week for 12 months. Patients should be reviewed at three months. If they are still positive for hepatitis C virus RNA, treatment with interferon alfa alone should be stopped and they should be considered for combination therapy with interferon alfa and ribavirin in a trial setting.13

After transplantation, almost all liver grafts become reinfected. In a recent long term follow up study of 149 patients, survival five years after transplantation in those who had had hepatitis C infection was similar to survival in patients with other disease aetiologies. However, liver biopsy five years after transplantation showed that 20% of the patients who had had hepatitis C infection developed cirrhosis. This suggests that the virus infection and subsequent liver damage may be accelerated in these patients, perhaps by immunosuppressive treatment.14 Trials to assess whether single treatment with ribavirin helps to prevent reinfection and progression to liver disease are currently underway.

Auxiliary liver transplantation

In auxiliary transplantation, the left or right lobe of the donor liver is transplanted, while all or part of the native liver is left in situ. When the native liver has recovered from its initial insult and has regenerated completely, the graft can then be removed or immunosuppressive treatment can be stopped and the graft allowed to atrophy. The latter approach is advantageous in that it avoids the need for lifelong immunosuppression and potential drug toxicity.

The largest study to date reports experience with 30 patients who underwent auxiliary liver transplantation for acute liver failure.15 It found complete regeneration of the native liver with complete withdrawal, or at least a considerable reduction, of immunosuppression in 50% of patients.

Split liver transplantation

Increased expertise in liver reduction techniques has led to the development of split liver transplantation, where one graft can often be used for an adult recipient and a child. The procedure involves splitting the liver along the principal planes into the anatomical left and right lobes. Considerable surgical precision is then needed to dissect out and divide the arterial, venous, and biliary connections to allow reanastomosis into two different patients. Initial reports of this technique, published in 1988-9, showed poor results at one year—only 50% of patients and grafts survived. More recently, a multicentre European study has shown a much better outcome.16

Live related donor transplantation

Paediatric liver transplantation has expanded rapidly in the past five years. Around 90-100 transplantations are carried out in the United Kingdom each year. Demand for donor organs which are suitably matched in size exceeds supply, and the development of live related donor transplantation is one way of correcting the imbalance. With this procedure, a parent donates either the left lobe or left lateral segment of their liver to their child. The procedure allows transplantation to be performed more quickly (almost electively), as there is no need to await a suitable donor organ, and a good quality graft, which has already been screened for disease or transmissible viruses, is ensured. Early graft function is reported to be as high as 94%.17 Furthermore, the risks of acute and chronic rejection should be reduced in theory because the parent and child have a similar tissue type. If the procedure is carried out by an experienced operator, the potential risks to the donor parent are very low, and postoperative liver function should remain normal as the volume of liver removed seldom exceeds 30%-40% of the total. More than 200 of these procedures have now been performed worldwide.17

N-acetylcysteine infusion

N-acetylcysteine infusion, a well established treatment in toxicity induced by paracetomol, is now used selectively to treat other forms of acute liver failure. The considerable experience of King's College Hospital in treating patients with paracetamol toxicity and liver failure between 1987 and 1993 was reported recently.18 Survival improved from 50% to 75% as the frequency of N-acetylcysteine administration increased from 40% to 83%. Survival in patients with acute liver failure was correlated significantly with the use of N-acetylcysteine infusion and the speed with which this treatment was given after the paracetomol had been ingested.18 Survival was better even in patients treated more than 24 hours after the overdose.

New technologies

Without liver transplantation, the survival of patients with acute liver failure is 60% at best. Other forms of artificial liver support are therefore needed to allow spontaneous recovery or to sustain the patient awaiting transplantation. Current work has centered on bioartificial liver devices, two of which have recently undergone clinical trials. Both the Extracorporeal Liver Assist device and the Bioartificial Liver device use hepatocytes and have the potential to provide artificial metabolic and synthetic liver function in acute liver failure. Experimental and early clinical data suggest that transplantation of hepatocytes may be of benefit in acute liver failure.

Herbal remedies

Herbal remedies have become increasingly popular, and reports of hepatotoxicity induced by these have increased. The spectrum of liver injury ranges from mild hepatic inflammation to extensive necrosis, persistent cholestasis, veno-occlusive disease, chronic hepatitis, and even cirrhosis. Chinese herbal teas, popular for treating dermatitis, are now well recognised as potentially hepatotoxic. Two recent case reports described jaundice and hepatitis after drinking these teas. The ingredients common to the teas were isolated and analysed. Those found to be hepatotoxic were plant extracts from Dictamnus dasycarpus and Paeonia sp.19 It is now clear that remedies previously thought to be innocuous are potentially hepatotoxic. Great care should be taken to assess the ingredients before recommending any herbal remedies to patients.

Ecstasy

Ecstasy (3,4-methylenedioxymethamphetamine) has now been reported as the sole culprit in several cases of acute liver failure; liver transplantation is often required.20 Jaundice, encephalopathy, coagulopathy, persistent hyperthermia (as high as 40°C), and rhabdomyolysis are often the presenting features that give a clue to the possible aetiology. In several young adolescents, cases of idiopathic liver failure that were previously attributed to a non-A-E hepatitis may have been caused by ecstasy.

Vanishing bile duct syndrome

Vanishing bile duct syndrome describes the progressive destruction of segments of the intrahepatic biliary tree that is caused by a number of agents. It results in the disappearance of intrahepatic bile ductules and the development of long lasting cholestasis. At least 30 drugs have now been reported as causes of this phenomenon (box).21 Even though the offending agent is stopped, there is usually chronic cholestasis, often with jaundice, and high alkaline phosphatase and γ glutamyltranspeptidase activities for more than one year.