Liver transplantation: current status, complications and prevention

Transcription

1 Journal of Antimicrobial Chemotherapy (1995) 36, Suppl. B, Liver transplantation: current status, complications and prevention John A. C. Buckels Liver Unit, Queen Elizabeth Hospital, Birmingham B152TH, UK The results of liver transplantation have improved dramatically over the past 15 years and this has produced a marked increase in demand for the procedure. Perioperative problems due to haemorrhage have been largely solved by surgical experience, the use of veno-venous bypass and careful control of coagulation parameters. Developments in graft preservation with the introduction of University of Wisconsin Solution led to improved early graft function as well as allowing day-time surgery. The number of technical failures and subsequent need for retransplantation have been markedly reduced: many units have almost eradicated failure due to hepatic artery thrombosis, although biliary complications still occur, which can often be managed non-operatively with the help of skilled radiologists using percutaneous techniques. Despite advances in immunosuppression, rejection remains a significant problem with many patients requiring additional high dose therapy with inherent risks of infective complications. In addition to conventional bacterial infections, opportunistic organisms including Pneumocystis carinii, cytomegalovirus and fungi pose a particular problem. Specific protocols for prophylaxis against opportunistic infection have been developed which have significantly reduced morbidity and mortality. Current survival after liver replacement is 80 90% at 12 months and, apart from patients grafted for malignancy, the survival curves are relatively flat. The next decade is likely to see refinements in selection and timing to reduce morbidity and costs of liver transplantation. Future developments include the use of xenografts which could provide a limitless number of donor livers and allow liver replacement to be performed as an elective service. Introduction There are few areas in surgery which can match the major advances in outcome after liver transplantation seen over the past 15 years. After the early pioneering efforts of the 1960s, little progress was made during the next decade, with only 20-25% of patients surviving in a small handful of active centres. Liver transplantation was regarded as a dangerous procedure and patients were usually referred only when they had reached a terminal phase. The early 1980s saw a dramatic improvement in outcome which coincided with the introduction of a new immunosuppressive agent, cyclosporin with centres reporting survival rates of over 80%. Moreover there has been an almost exponential increase in transplant activity. In 1980 less than 50 grafts were performed in Europe whereas, by 1990, over 2000 liver grafts were undertaken by more than 60 separate clinical teams. This rise in activity has come from an increasing demand once the procedure was shown to be successful. The improvements in outcome are multifactorial but include identification of the patients who are likeiy to benefit from liver /95/36B $12.00/ The British Society for Antimicrobial Chemotherapy

2 40 J. A. C. Buckels transplantation, earlier referral of such patients, improved surgical technique and better immunosuppressive regimens. This paper is concerned with the current practice of liver transplantation with specific reference to the likely complications and ways in which these can be either prevented or effectively treated. Current status The results of liver transplantation today are sufficiently good that no patient should be allowed to die of primary liver disease without prior consideration of a liver graft. There are many reasons why a patient might not be suitable e.g. continuing alcohol abuse, advanced age, other medical problems, yet despite the recent increase in transplant activity there is evidence that many potential recipients are dying without transplantation being considered (Davies et al., 1992). Advancing liver disease leads to progressive disability, with muscle loss, ascites and risks of catastrophic variceal haemorrhage. Delaying referral for transplantation until the terminal stage reduces the chances of survival and patients should therefore be considered for liver grafting once the anticipated survival is less than 12 months. The indications for liver transplantation can be broadly classified into chronic liver failure, acute fulminant hepatic failure, primary liver tumours which cannot be resected by conventional surgical techniques and certain inborn errors of metabolism; these will be dealt with in turn. Chronic liver failure Indications for transplantation Chronic liver failure is the commonest indication for liver transplantation (Table I) and the diseases which most frequently predispose to this condition are described below. The autoimmune disease, primary biliary cirrhosis (PBC) is the commonest indication Table I. Commoner indications for liver transplantation Chronic liver failure Primary biliary cirrhosis Primary sclerosing cholangitis Chronic active hepatitis Cryptogenic cirrhosis Alcoholic liver disease Biliary atresia i\ antitrypsin deficiency Cirrhosis caused by HBV or HCV Acute fulminant hepatic failure Viral hepatitis Drugs e.g. paracetamol, halothane, antituberculous therapy Toxins and solvents Primary hepatic malignancy Unresectable primary tumours Hepatocellular carcinoma developing in a cirrhotic liver Inborn errors of metabolism

3 Liver transplantation 41 for liver transplantation in adults in the UK. Numerous clinical trials have failed to identify any effective medical therapy but have led to the development of a prognostic index of survival which has been helpful in planning the timing of liver replacement (Hughes, Rasthinol & Pocock, 1992). Thus appropriate referral and grafting for PBC produces in excess of 90% survival at many centres. Primary sclerosing cholangitis (PSC) is a condition closely associated with inflammatory bowel disease. Though progression of PSC is less predictable than PBC, a prognostic index has also been developed which may allow improved results with transplantation (Dickson et al., 1992). PSC is complicated by the development of cholangiocarcinoma in approximately 20% of cases and these are usually incurable at diagnosis. Early referral to a specialist centre is recommended and patients with biliary dilatation should be screened for the possible development of malignancy. Cryptogenic cirrhosis and chronic active hepatitis are less frequent indications and may pose problems in optimizing the timing of transplantation. In both conditions the patients may survive for some time despite small cirrhotic livers before late rapid decompensation. Earlier stages of chronic active hepatitis may improve with corticosteroid therapy although the dosages of these agents should be reduced or treatment stopped altogether once the decision has been made to transplant. Chronic viral hepatitis caused by hepatitis B virus (HBV) is the commonest global cause of serious liver disease. HBV related cirrhosis in the UK is uncommon but represents a major challenge because of the risks of recurrent disease in the grafted liver. Recognition that patients who are HBV-DNA positive will almost always develop early recurrent disease after grafting has led to most centres excluding them from their programmes. Current trials are underway to find suitable antiviral therapies which will allow such patients to be grafted in the future. Hepatitis C virus (HCV) is a recently identified virus which causes infection following transfusion which can progress to cirrhosis. Recurrent HCV infection in the grafted liver occurs but has not yet been a clinical problem. Although alcohol is the commonest cause of chronic liver failure in the UK, few patients with alcoholic liver disease have undergone liver transplantation. Many patients with alcohol-related liver damage will improve if they abstain, and continued drinking, despite medical advice, would be regarded as a contraindication to transplantation. Nevertheless, there are increasing pressures to accept reformed drinkers for liver grafting and the proportion of recipients with alcoholic liver disease is rising. The commonest cause of chronic liver failure in children is biliary atresia. This can often be palliated by a portoenterostomy (Kasai operation) if performed within the first 8 weeks of life. Sadly, many children are not referred in time and others develop early cirrhosis and die within the first few years of life if not transplanted. In addition to the obvious signs of liver disease seen in adults, such as ascites and muscle wasting, in children failure to thrive is a common finding and should be considered an indication for liver transplantation. Acute fulminant hepatic failure Acute fulminant hepatic failure (AFHF) has been defined as the development of hepatic encephalopathy within 8 weeks of the onset of symptoms in a patient without previous liver disease (Trey & Davidson, 1970). A more slowly developing form, subacute or late onset hepatic failure, is the development of hepatic encephalopathy between 8 weeks

4 42 J. A. C. Buckels and 6 months of the onset of symptoms. The commonest causes of AFHF in the UK include drugs and toxins (e.g. paracetamol overdose, halothane, antituberculous drugs, solvents), viral hepatitis (A, B and non-a, non-b) and miscellaneous causes including Wilson's disease, Budd-Chiari syndrome and fatty liver of pregnancy. The progression of AFHF leads to cerebral oedema with risks of coning, as well as hepatorenal failure. Though specialist medical support may allow some patients to recover spontaneously, it is important to recognize those patients with little chance of recovery. For instance, patients with paracetamol poisoning who present with acidosis do not respond well to medical management and should be considered for early transplantation. Those with hepatic failure caused by viruses and grade III or IV encephalopathy with worsening coagulopathy should also be considered for liver grafting. Specific factors which are associated with a poor prognosis following medical management, and are therefore indications for liver grafting, have been described previously (O'Grady el al., 1989). Primary hepatic malignancy Primary bile duct carcinoma (cholangiocarcinoma) invariably recurrs after transplantation and is no longer considered an indication for transplantation. Hepatocellular carcinoma (HCC) is the commonest primary liver malignancy. It is rare in the UK but worldwide is one of the commonest cancers. It can occur in the non-cirrhotic liver but most cases are diagnosed in the presence of cirrhosis which is a risk factor for the development of HCC. There is evidence that HBV and HCV are independent risk factors for development of HCC. Unfortunately most patients with primary hepatic malignancy occurring in a non-cirrhotic liver present with advanced disease. Conventional resection, if possible, is the treatment of choice but if this is not possible, transplantation is appropriate. Recurrence occurs in the majority of patients and, given the shortage of donor organs, perhaps should only be considered for younger patients. If malignancy is detected at an early stage in a cirrhotic liver the prospects of cure by liver transplantation are reasonably good. Thus patients with cirrhosis should be screened for malignancy with serial ultrasound scans and a-fetoprotein estimations. Inborn errors of metabolism Liver transplantation may be indicated in children with inherited disorders particularly those whose livers are functionally normal but are deficient in an hepatic enzyme which causes severe extrahepatic disease. These conditions are generally rare and will not be considered further. Preoperative assessment Surgical aspects Ideally patients should be placed on the transplantation waiting list before they enter the terminal stages of liver failure. An in-depth anaesthetic assessment is made to ensure they are fit to withstand the surgical procedure. Pretransplant counselling is important in allowing the patients and their families to become aware of what is involved and this is facilitated if patients can meet previously grafted recipients. Psychological evaluation

5 Liver transplantation 43 is not usually necessary but should be undertaken in patients with alcohol-related liver diseases. Specific investigations include assessment of patency of the portal vein which is needed to allow perfusion of the new liver, although vein grafts are possible if the portal vein is thrombosed. In these patients preoperative angiography should be performed to identify suitable alternative vessels. Patients transplanted for AFHF need careful monitoring of cerebral perfusion and this may require cerebral pressure monitoring. Sustained elevation of intracerebral pressure is a contraindication to transplantation because of the production of cerebral damage, although early detection of high pressures often allows therapeutic intervention and improvement of cerebral blood flow. Liver procurement and preservation Livers are taken from beating-heart donors, usually as part of a multiorgan procurement which includes kidneys and intrathoracic organs. Initially livers had to be used within 8 h which meant that the majority of transplantations were performed at night. The development of an improved preservation fluid, University of Wisconsin Solution, allows storage for up to 20 h, thereby allowing grafting to be performed during daylight hours. This has undoubtably contributed to the improved outcome of liver grafting. Liver transplant surgery Details of the transplant operation are beyond the scope of this paper but brief general principles will be given. Successful outcome demands the presence of skilled surgical and anaesthetic teams. The combination of cirrhosis with portal hypertension and poor coagulation can make the surgery difficult and bloody, particularly if there has been previous surgery around the liver. The use of veno-venous bypass reduces this risk and is used by most centres. The operation is in two stages removal of the diseased liver, followed by implantation of the new organ. Bypass is introduced during the hepatectomy and carries blood from the lower half of the body via the inferior vena cava and portal vein, usually into the axillary vein. This decompresses the blood vessels during clamping and maintains venous return and cardiac output. Implantation of the donor liver commences with the upper caval anastomosis, then the lower caval anastomosis, followed by the portal anastomosis at which time the new liver is perfused with blood. Once haemostasis has been secured, the hepatic arterial and biliary anastomoses are performed. Biliary drainage is established by means of a duct-to-duct anastomosis usually over a latex rubber T-tube or internal stent but those with abnormal biliary trees (e.g. in biliary atresia or primary sclerosing cholangitis) require a Roux-en-Y jejunal loop. During surgery the anaesthetist administers clotting factors in order to maintain clotting parameters which will help to reduce overall blood loss. After reperfusion the new liver must function immediately or the patient will develop worsening acidosis and coagulopathy leading to early death. Indications of prompt graft function include a reversal of the acidosis which develops during the anhepatic phase, as well as early production of bile.

6 44 J. A. C. Buckels Table II. Complications of liver transplantation Immediate Haemorrhage Primary non-function Acute renal failure Early Primary poor function Acute rejection Chronic rejection Hepatic artery thrombosis Portal vein thrombosis Cholangitis Bile leakage Biliary obstruction Graft-versus-host disease Bacterial infection Opportunistic infection (viral, fungal) Postoperative course Following surgery, patients are ventilated on the intensive care unit. They can usually be extubated within 24 h provided they are haemodynamically stable with satisfactory liver function, urine output and blood gases. Patients with AFHF are often slow to reverse their encephalopathy and may need ventilation for several days. An ultrasound of the graft is performed in all patients on the first postoperative day to demonstrate patency of the vessels and this is repeated whenever clinically indicated. Immunosuppressive therapy is started on the day of surgery and this is discussed further below. Daily tests of liver function, including serum aspartate transaminase, prothrombin time, bilirubin and alkaline phosphatase, are performed during the early postoperative period. Initially the transaminases are significantly elevated (between 500 and 2000 international units), although these fall rapidly, usually halving each day until they return to normal. Patients with cholestatic diseases soon become less jaundiced whereas patients with non-cholestatic diseases who are not icteric before transplantation paradoxically often become jaundiced in the early postoperative period, probably due to the preservation process; this soon settles with adequate graft function. The prothrombin time often stays elevated (INR up to two to three times normal) for the first few days after grafting. Spontaneous resolution implies improving liver function. Many patients are sufficiently well to be mobilized within the first few days and are able to spend time out of hospital within 2-3 weeks. However recovery in some patients can be prolonged, especially if acute renal failure requiring prolonged dialysis develops, as well as in those grafted for fulminant liver failure. Complications The complications affecting liver transplant recipients prior to discharge (or death) can be classified as immediate (intensive care phase) or early (Table II).

7 Liver transplantation 45 Immediate complications after surgery The immediate complications following liver transplantation include haemorrhage, primary non-function and acute renal failure. The incidence of these is greatly influenced by the transplant operation itself and the quality of the newly inserted liver. Haemorrhage. Although the recipient hepatectomy can be difficult in patients with severe portal hypertension, especially if there has been previous liver surgery, haemostasis is usually possible with a variety of approaches, including correction of clotting abnormalities, warming of blood and blood products, veno-venous bypass for decompression during the anhepatic phase and the control of bleeding points with suture ligation, fibrin glue or diathermy. The use of the thromboelastograph (TEG), which measures the quality of blood clot, allows a dynamic evaluation of the coagulation status of the patient in the operating room and enables the selection of appropriate factors, whether platelets, fresh frozen plasma or cryoprecipitate. The TEG detects fibrinolysis which can be corrected or prevented by an infusion of aprotinin which is used by many centres (Mallett et ah, 1991). Primary non-function. Primary non-function is the failure of the new liver to work. This may be due to pre-existing factors in the donor, poor preservation or injury caused by reperfusion at implantation. At surgery the patient develops a progressive acidosis, renal failure and all of the other features of fulminant hepatic failure. Haemodynamic instability and death ensues unless retransplantation is urgently undertaken. Fortunately, primary non-function is rare, although poor function occurs in 5-10% of cases. These patients display some of the features of acute liver failure and the liver biopsy taken at implantation may show excess fat or centrolobular necrosis (so-called preservation injury); these grafts usually improve within 2 weeks. Whilst the fitter recipients may cope well with a liver which is slow to work, such dysfunction can be life-threatening in the most ill recipients when regrafting might be the only chance for recovery. Renal failure. Mild renal impairment is observed in many liver transplant recipients and is characterized by a period of oliguria and a rise in creatinine for several days after surgery which will usually respond to correction of any fluid deficit and an infusion of dopamine. Acute renal failure requiring dialysis or haemofiltration is uncommon in stable patients transplanted for chronic liver disease, whereas patients with AFHF are often dialysis-dependent before grafting. This is best performed as continuous arterio-venous haemodialysis and most patients will produce a diuresis within 2 weeks. Early complications after surgery Complications developing after liver grafting are common and varied, producing a lengthy learning curve for the liver transplant team. However, with experience, problems can often be preempted by the early recognition of clinical patterns and potential disasters can be averted. The commonest problems encountered are rejection, infection, graft ischaemia and biliary tract obstruction or leakage and these will be discussed below. Rejection. Despite early reports based on animal studies that the liver is an immunologically privileged organ, rejection is a major problem after liver grafting in man. High-dosage immunosuppression will reduce the incidence of rejection but may lead to unacceptable risks from infection.

8 46 J. A. C. Buckets The introduction of cyclosporin in the early 1980s coincided with a significant improvement in the results of liver grafting. Nevertheless, a continuing high incidence of rejection episodes led several centres to give 'triple therapy' with a combination of low-dosage cyclosporin, azathioprine and steroids. Episodes of acute rejection are treated with high-dosage prednisolone. One problem with oral cyclosporin is that it requires bile for absorption which can be reduced if liver function is deteriorating. Thus rejection may cause a further reduction in cyclosporin concentrations due to poor absorption, thereby exacerbating the situation. A new drug, FK 506, is not dependent on bile for absorption and the results of controlled trials comparing FK 506 with conventional immunosuppression are awaited. Other immunosuppressive regimens include the use of monoclonal or polyclonal antibodies. The most widely used agent is the monoclonal antibody OTK.3. In North America this is often given to induce immunosuppression immediately after surgery, followed several days later by conventional immunosuppression although this has not produced a clear survival advantage (McDairmid et al., 1991). There is evidence that OKT3 may be useful in patients with steroid-resistant acute rejection. However, this may be achieved at the expense of an increased incidence of infection, caused particularly by viruses such as cytomegalovirus (CMV) (Cosimi et al., 1987). Early acute rejection, which occurs in 80% of patients receiving liver grafts (Kirby et al., 1987), is usually associated with deteriorating graft function (rising bilirubin, liver enzymes and prothrombin time). Other common causes of dysfunction, including bacterial infection (e.g. cholangitis), viral infection (e.g. CMV hepatitis), ischaemia, and biliary obstruction should also be excluded. Histological confirmation of rejection should be obtained before additional immunosuppression is given. Late acute rejection is uncommon and dosages of immunosuppressive drugs are progressively reduced, with a corresponding reduction in the risks of infection. Steroids can usually be discontinued after 3 months, and long-term maintenance comprising azathioprine and cyclosporin (Padbury et al., 1992). Late acute rejection suggests other factors such as poor absorption due to gastroenteritis or poor compliance. Chronic rejection of the liver is a biliary rather than a vascular phenomenon which is seen in other transplanted organs. The small bile radicles are destroyed (vanishing bile duct syndrome, VBDS) and the process is usually irreversible (Hubscher et al., 1991). This occurs in less than 10% of grafted livers, which is in contrast to the chronic vascular rejection which eventually produces graft failure in the majority of kidneys and hearts; the dual blood supply of the liver may account for some of this difference. Regrafting is the only definitive option, although VBDS recurs in some cases. One other immunological event of note is the occurrence of massive haemolysis if ABO-blood-group-compatible but not ABO-identical grafts are used e.g. O blood group liver into Group A or B recipients. The liver can produce antibody to the recipient's red blood cells, causing haemolysis around the seventh to tenth postoperative day. A blood film will show fragmented red cells and the direct Coomb's test is positive. To prevent the dangers of ongoing haemolysis, any anaemia should be corrected by the administration of donor-group blood only. Infection. All patients receive prophylactic broad-spectrum antibiotics for 48 h following surgery and this period is extended in patients requiring prolonged ventilation. Despite this, bacterial infections are common and most frequently involve the respiratory and biliary tracts. The combination of postoperative ventilation, a painful upper abdominal wound and a high incidence of pleural effusions contributes to

9 Liver transplantation 47 impaired respiratory function. Adequate analgesia and frequent physiotherapy are necessary to prevent underventilation and secondary pulmonary infection. Larger pleural effusions should be tapped, particularly if symptomatic. Bile rapidly becomes colonized with bacteria and cholangitis as a cause of fever or liver dysfunction is often difficult to diagnose. A combination of fever, bactobilia and impaired liver function in the presence of a normal liver biopsy would support a diagnosis of cholangitis and indicate the need for antibiotic therapy. Attempts to sterilize the bile by repeated administration of antibiotics is likely to lead to superinfection caused by resistant bacteria or fungi. Early biliary obstruction or leakage as a cause of cholangitis can be detected by cholangiography through a T-tube and this is considered below. All immunosuppressed patients are at risk of developing opportunistic infections and after liver replacement CMV and fungal infection are common. Pneumocystis carinii pneumonia was seen in early series but has been virtually eliminated by the prophylactic use of co-trimoxazole, one tablet taken on alternate days. Severe CMV infections are usually primary rather than reactivation infections and should be avoidable if CMV-matched donors are used. However, many units are unable to obtain adequate supplies of CMV-free blood and blood products, for administration during surgery in CMV-negative recipients, making CMV liver matching superfluous. CMV infection usually presents with fever, malaise and leucopaenia. Severe infections cause gastrointestinal disturbance, pneumonia, encephalopathy and hepatitis. Prompt diagnosis is imperative and although serological confirmation takes time, recent tests such as PCR can give earlier results. Tissue diagnosis (liver biopsy or rectal or gastric biopsies in patients with gastrointestinal symptoms) can be the most rapid means of reaching a diagnosis. Clinical infections are treated by reducing baseline immunosuppression, together with the administration of ganciclovir which is supplemented with hyperimmune globulin in severe cases. The use of acyclovir as prophylaxis against CMV in patients given CMV-positive grafts has been partially successful in reducing the incidence and severity of infection. Fungal colonization is common in patients with advanced liver disease and prophylaxis with oral nystatin and amphotericin B can reduce oral and oesophageal infection. Because invasive fungal infections are difficult to diagnose, often becoming only apparent at post mortem, they should be treated on suspicion with antifungal therapy together with a reduction in baseline immunosuppression. Risk factors for fungal infection include AFHF, prolonged ventilation and repeat high-dosages immunosuppression for rejection. It is our current practice to use systemic antifungals prophylactically in patients transplanted for AFHF. Finally, tuberculosis is a risk in patients from the Asian sub-continent undergoing transplantation. This reactivation of primary infection carries a grave prognosis even with adequate therapy and cessation of immunosuppresive agents. Patients with evidence of previous infection should receive prophylaxis with isoniazid for 6 months which is effective. Graft ischaemia. Hepatic artery thrombosis causing graft ischaemia can be a devastating complication. This usually occurs in the early postoperative period and may lead to graft necrosis, intrahepatic abscess or infarction of the bile ducts with bile leakage. The incidence is higher in children (up to 20%) than adults (up to 10%). Infarction is often heralded by massive rises in the liver enzymes but should be suspected in cases of acute graft failure, biliary problems or Gram-negative septicaemia. An urgent

10 48 J. A. C. Buckels Table III. Indications for early retransplantation Primary non-function Early arterial thrombosis Acute drug-resistant rejection Established chronic rejection Major non-anastomotic biliary stricture ultrasound may suggest thrombosis which should be confirmed by arteriography. Early thrombosis is an indication for urgent regrafting, although patients with late thrombosis may survive with satisfactory graft function. Thrombosis of the portal vein is rare and usually presents with variceal bleeding in the early postoperative period which should be urgently investigated by ultrasound and angiography. Emergency thrombectomy is usually effective and graft loss is uncommon. Biliary obstruction and leakage. The biliary anastomosis has aptly been called the 'Achilles heel' of liver transplantation. Biliary complications can be classified into four groups: leakage from the anastomosis or T-tube insertion site; anastomotic stricture; non-anastomotic strictures of the donor bile duct; and biliary sludge. In all biliary problems an ultrasound is indicated to confirm patency of the artery. This might also detect intraabdominal bile collections or intrahepatic duct dilatation. For patients with a T-tube, cholangiography is the most useful test. In the absence of a T-tube, imaging of the biliary tree requires transhepatic cholangiography. Minor leakage often resolves by leaving the T-tube on open drainage but major leaks require formal reconstruction. Although late obstruction of the biliary anastomosis can be dilated at ERCP or by the transhepatic route, early obstruction also requires surgical correction which is best performed as a Roux-en-Y choledocho-jejunostomy. Non-anastomotic strictures of the donor ducts are rare and usually occur at the junction of the right and left hepatic ducts. Prolonged preservation times have been suggested as a cause but this has not been confirmed. Surgical correction can be successful although some patients require retransplantation. Biliary sludge is a common problem and probably represents a degree of ischaemic injury to the biliary tree at time of implantation. The sludge often settles after T-tube removal and this might be facilitated by the oral administration of ursodeoxycholic acid. Retransplantation Approximately 15% of patients will suffer graft loss and need retransplantation, the incidence being higher in children than in adults. Indications for retransplantation are given in Table III. Early retransplantation is usually technically straightforward and long-term survival is over 50%. An aggressive approach to retransplantation pioneered by the Pittsburgh group, was a significant factor in the improvement in survival rates (Shaw et al., 1985). Chronic rejection is the usual indication for late regrafting which can be difficult due to dense adhesions around the liver. Survival, quality of life and future developments Current survival rates after liver replacement are between 80 and 90% at 12 months. The selection and timing of transplantation are critical, and by avoiding high-risk cases

11 Liver transplantation 49 even greater survival rates might be possible. However, this does not address the problem that many patients have some risk factors and should still be considered as candidates. Apart from patients grafted for malignancy, the survival curves are relatively flat. Currently 5-year survival rates of 70% are seen and the expected median survival of a liver graft is likely to far exceed that of a heart or kidney grafts, which both approximate 10 years, because chronic rejection is less common. In patients transplanted for malignancy recurrence is the commonest cause of death with 5-year survival rates of about 25%. Basic survival data are important but quality of life is perhaps a more important goal. In the early days of liver transplantation when the majority of patients died, the excellent quality of life and rehabilitation seen in the survivors were the major incentives for the pioneers to continue their efforts. Nowadays, with the majority of centres reporting survival rates in excess of 80%, the earlier goals have been realized. The next decade is likely to see refinements in selection and timing to reduce morbidity and costs of liver transplantation. Future attention will also be directed at the possibility of using xenografts which could provide a limitless number of donor livers. In this way liver replacement could be performed mainly as an elective service with both the highest degrees of success and cost-effectiveness. References Cosimi, A. B., Cho, S. I., Delmonico, F. L., Kaplan, M. M., Rohrer, R. J. & Jenkins, R. L. (1987). A randomised clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection. Transplantation 43, Davies, M. H., Langman, M. J. S., Elias, E. & Neuberger, J. (1992). Liver disease in a district general hospital remote from a transplant centre: a study of admissions and deaths. Gut 33, Dickson, E. R., Murtaugh, P. A., Wiesner, R. H., Grambsch, P. A., Fleming, T. R., Ludwig, J. el al. (1992). Primary sclerosing cholangitis: refinement and validation of survival models. Gastroenterologv 103, Huibscher, S. G., Buckels, J. A. C, Elias, E., McMaster, P. & Neuberger, J. (1991). Vanishing bile-duct syndrome following liver transplantation is it reversible? Transplantation 51, Hughes, M. D., Rasthino, C. & Pocock, S. (1992). Predictor for short term survivors with an application in PBC. Statistics in Medicine 11, Kirby, R. M., McMaster, P., Clements, D., Hubscher, S. G., Angrisani, L., Sealey, M. et al. (1987). Orthotopic liver transplantation: postoperative complications and their outcome. British Journal of Surgery 74, McDiarmid, S. V., Busittil, R. W., Levy, P., Millis, M. J., Terasaki, P. I. & Ament, M. E. (1991). The long-term outcome of OK.T3 compared with cyclosporin prophylaxis after liver transplantation. Transplantation 52, Mallett, S., Rolles, K., Cox, D., Burroughs, A. & Hunt, B. (1991). Intraoperative use of aprotinin (Trasylol) in orthotopic liver transplantation. Transplantation Proceedings 23, O'Grady, J. G., Alexander, G. J. M., Hayllar, K. M. & Williams, R. (1989). Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 97, Padbury, R. T. A., Gunson, B. K.., Dousset, B., Hubscher, S. G., Mayer, A. D., Buckels, J. A. C. et al. (1992). Long-term immunosuppression after liver transplantation: are steroids necessary? Transplant International 5, Suppl. 1, Shaw, B. W., Gordon, R. D., Iwatsuki, S. & Starzl, T. E. (1985). Retransplantation of the liver. Seminars in Liver Disease 5, Trey, C. & Davison, C. S. (1970). The management of fulminant hepatic failure. In Progress in Liver Disease, (Popper, H. & Schaffner, F., Eds), pp Grune & Stratton, New York.