Article Text

Developments in liver transplantation
1. J Neuberger
1. Correspondence to:
Professor J M Neuberger
The Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK; James.Neubergeruhb.nhs.uk

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In the last few years, there have developments in many aspects of liver transplantation. This review will focus on those areas where adult clinical practice has developed1–3; the topics selected are those which, it is hoped, will be of interest and relevance to those health care professionals who refer patients to transplant centres and share in their follow up. In such a review, it is not possible to be comprehensive.

## CHANGING INDICATIONS (TABLE 1)

Table 1

Transplant activity and indications in Europe (data from the European Liver Transplant Registry, kindly provided by Dr Vincent Karam)

Indications for transplantation are evolving: liver failure from hepatitis C virus (HCV) infection and alcohol now represent the commonest indications for liver transplantation both in Europe and North America (table 1).

### Alcoholic liver disease (ALD)

ALD remains a controversial indication for liver transplantation and adverse publicity surrounding selected high profile cases can impact on organ donation. None the less, both short and long term outcomes in those transplanted for ALD are similar to those seen in patients transplanted for other causes of cirrhosis, with respect to survival and quality of life. However, this simplistic analysis takes no account of case mix (see box 1).

### Box 1 Alcoholic liver disease

• Alcoholic liver disease remains a good indications for liver transplantation with survival similar to those for other indications.

• Indications for transplantation need refining as estimated short term gain is small.

• The role of transplantation for alcoholic hepatitis is uncertain.

• Transplantation is not indicated in those who are likely to return to a pattern of drinking that will either result in graft damage or lead to non-compliance.

• The number of reported cases of graft damage or loss associated with a return to alcohol is small.

• Potential candidates need to be assessed by a multidisciplinary team.

• A fixed period of abstinence is not indicated but there should be a period of stable abstinence.

• Extrahepatic alcohol induced organ damage may preclude liver transplantation.

• Abstinence should be recommended after transplantation.

The major issues with respect to alcohol centre on whether the patient will return to a pattern of drinking after transplantation that will lead to graft damage and/or to non-compliance. Available data suggest that while many patients grafted for ALD do return to some pattern of alcohol consumption, less than 5% damage their graft.4,5

There remains controversy about the need for and duration of abstinence pre-transplant. There is no good evidence suggesting that a fixed period of abstinence (such as six months) will help identify those at risk of subsequent relapse. However, a period of abstinence allows time

• to identify those patients whose liver function will improve to an extent transplantation is no longer indicated (about 10% referrals in our centre);

• to identify reasons for excess alcohol consumptions and put in place measures to ensure abstinence post-transplantation.

Most centres advise strict abstinence post-transplant as it is difficult to identify in advance those who can effectively return to a pattern of controlled drinking. Monitoring of patients, pre and post liver transplantation for alcohol consumption, is difficult: measurements of blood, urine, or breath alcohol will identify those who have drunk recently; the value of carbohydrate deficient transferrin in identifying those who continue to drink alcohol remains uncertain.

#### Alcoholic hepatitis

It still remains uncertain whether liver transplantation is an appropriate therapy for those who present with alcoholic hepatitis: such patients are often very sick with renal failure and malnutrition. There is rarely time to assess fully the likelihood for further abstinence. Initial studies showed a poor outcome after transplantation but some more recent studies suggested that good survival can be achieved. Since indications and contraindications are not well defined in this group, a prospective trial has been advocated but may prove difficult to set up.6

### Viral hepatitis

#### Hepatitis B viral infection (HBV)

Historically, those with evidence of active viral replication were not considered as liver transplant candidates because of the high risk of viral damage to the graft; those with no replication could be successfully grafted with the risk of graft infection greatly reduced by the use of hepatitis B immunoglobulin (HBIg). Introduction of effective antiviral treatments has allowed successful transplantation of HBV infected patients. Currently there are three approaches to prevention of graft infection.7

1. Lamuvidine monotherapy: given before and after transplantation is associated with inhibition of viral replication and prevention of graft damage and loss, but viral breakthrough may occur; this is more likely when the pretreatment viral load is high.

2. HBIg monotherapy: for those with HBV infection but without replication, post-transplant treatment has been with immunoglobulin, given to maintain antibody levels above 100–500 IU/l. The duration of treatment and level of antibody required to maintain freedom from recurrence is uncertain. At present, many centres use immunoglobulin long term, others for just one year or until viral breakthrough develops.

3. Combination therapy: a combination of HBIg and lamivudine increases the freedom from recurrence and is currently the management of choice, but even in those without evidence of recurrent disease HBV DNA may persist.8 However, because of the expense of HBIg, many centres are evaluating the effectiveness of discontinuation of HBIg after a few months and maintaining the patient on lamivudine monotherapy.

Viral breakthrough may occur in approximately 20% of patients taking lamivudine therapy, with resulting graft damage9; in such patients newer antiviral agents such as adefovir and entecavir are effective in inhibiting viral replication.10

Other approaches to prevent infection of the graft include the use of vaccination and adoptive transfer of immunity. The latter has been reported to occur when the donor is immune to the virus.11 While this may offer an effective therapy, especially in living donors who can be pretreated, more work is required to confirm the clinical significance of this observation.

#### Hepatitis C viral infection (HCV)

Recurrence of HCV after liver transplantation is almost universal but the natural history of recurrent disease is highly variable and accelerated compared with HCV in the native liver; indeed, cirrhosis may develop within one year of transplantation. Characteristics of recurrent HCV infection of the graft are shown in box 2. The rate of development of graft damage is greater in those grafted more recently; the reasons for this phenomenon are not clear but may relate in part to increasing donor age and greater use of split livers. Identification of those factors associated with recurrence may lead to development of strategies to reduce the impact of recurrence: avoidance of rejection is important as treatment of rejection is associated with an increased level of viral RNA, although more potent immunosuppressive agents (such as mycophenolate) are associated with an increased rate of fibrosis.12 Antiviral treatment pre-transplant to reduce the viral load is of some benefit.

### Box 2 Characteristics of HCV reinfection

• Average time to graft cirrhosis 9–12 years.

• Decompensation occurs in up to 50% within one year of onset of cirrhosis.

• Levels of HCV RNA rise after transplantation.

• Risk factors for HCV recurrence:

• HCV RNA levels pre-transplant;

• episodes of acute rejection;

• donor age;

• use of more potent immunosuppressive drugs;

• use of corticosteroids and OKT3;

• year of transplant.

• Factors possibly associated with recurrence:

• genotype 1b;

• split or living donor grafts.

• Treatment: pre-emptive or as required.

### Recurrent non-viral disease (table 4)

Table 4

Some recurrent diseases after transplantation

Recognising recurrent disease in the allograft may be difficult because conventional diagnostic criteria may not apply; and the clinical, serological, and histological features and the natural history may be modified by concurrent immunosuppression and by the mismatched host/graft immune environment. Recognition and early intervention for reduction in risk factors for vascular disease may help reduce this risk.

#### Autoimmune hepatitis

Recurrent AIH may develop in up to 30% of patients grafted for AIH: treatment with increased corticosteroids is usually but not invariably effective in treating the hepatic inflammation75 Of note, evidence of recurrence may be first detected more than 10 years after transplantation and histological changes may precede the biochemical abnormalities, suggesting that protocol liver biopsies should be done regardless of biochemistry.76 Because of the consequences of recurrent AIH, many centres now use corticosteroids for at least the first year.

#### De novo autoimmune hepatitis

Graft hepatitis with features of autoimmune processes (such as raised serum transaminases, elevated immunoglobulins, and autoantibodies) may develop in allograft recipients transplanted for non-autoimmune indications. This syndrome develops in approximately 1% adults and 4% children. There is usually, but not always, a good response to steroids. A recent report77 of de novo autoimmune hepatitis affecting an auxiliary partial graft and not the native liver adds additional support to the concept that de novo hepatitis is a variant of rejection.

#### Primary biliary cirrhosis

Evidence of histological recurrence of PBC is found in approximately 35% of patients at 10 years.78 It is rare that cirrhosis develops and the effect on graft survival is small. Whether ursodeoxycholic acid affects rates of progression is not known. We have found that immunosuppression with tacrolimus compared with cyclosporin is associated with more rapid progression.

#### Primary sclerosing cholangitis

The diagnosis of recurrent PSC is difficult to make as it can be difficult to distinguish recurrent PSC from secondary sclerosing cholangitis. Secondary sclerosing cholangitis which is associated with:

• prolonged ischaemic times,

• ABO incompatibility,

• bacterial or viral cholangitis,

• hepatic artery thrombosis

• rejection.

The diagnosis is made on imaging the biliary tree or finding characteristic histological features of PSC (such as fibro-obliterative lesions) on histology, in the absence of other causes of sclerosing cholangitis. Recurrent PSC is thought to occur in approximately 50% of patients at five years after transplant and leads to graft loss in 10%.79 The only risk factor identified to date is colectomy (before or during transplantation appears to protect against recurrence).80

## FUTURE DEVELOPMENTS

Ideally, medical treatments will become effective and so liver transplantation will become redundant. New strategies to replace organ transplantation are being developed but remain some years away from introduction into clinical practice.

Xenotransplantation is still banned in humans; while the introduction of genetically modified pigs has overcome some of the problems of hyperacute rejection, there are many problems to be overcome before this technology can be transferred into the clinical arena.81 Baboon to human liver transplantation has been done with initial success.82

Stem cell technology in time may provide an alternative to organ transplantation.83

Isolated hepatocytes transplantation has been used to treat metabolic defects such as urea cycle disorders. Cells can be isolated readily from donor livers considered unsuitable for organ transplantation, and can be infused repeatedly.84,85 Such an approach can also be used for gene therapy.86

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