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14 Rossle M, Ochs A, Gulberg V, Siegerstetter V, et al. A comparison of paracentesis and Indication and assessment for transjugular intrahepatic portosystemic shunting in patients with ascites. N Engl J Med 2000;342:1701–7. 15 Lake JR. The role of transjugular shunting in patients with ascites. N Engl J Med 2000; 342:1745–7. Paul B Southern MB ChB MRCP , used. The Child-Pugh classification 2 Transplant Fellow (Table1) allows objective assessment of a Mervyn H Davies MD FRCP, patient’s functional liver status and in the Lead Clinician in USA forms the basis for the criteria Department of Medical Hepatology, required to list patients. Those with St James’s University Hospital, Leeds Childs C grade have a 58%, 21% and 0% one-year, five-year and 10-year survival, Clin Med JRCPL 2002;2:313–6 respectively. Subjective measures of may be more difficult to assess. Tools are Liver transplantation provides effective available to document quality of life 3, therapy for most forms of acute and and a full psychosocial assessment chronic – one-year survival should be carried out. rates exceed 90% 1 – and the indications continue to expand. In general terms, the Cholestatic liver disease indications for liver transplantation are objective evidence of liver failure and Primary biliary subjective criteria such as poor quality of Primary biliary cirrhosis (PBC) is a life due to liver disease and occasionally declining indication for liver transplan- rare metabolic defects. tation, but still accounted for 7.8% of liver transplants in Europe in 1998– Chronic liver disease 20001. The disease has three stages: an initial asymptomatic stage In chronic liver disease the most impor- • tant aspect of patient selection is timing. • a symptomatic stage with worsening Transplantation should improve both and declining synthetic quality and quantity of life. The proce- function (falling and dure is optimally carried out when the increasing ) patient is well enough to withstand the • a decompensating stage with severe procedure, but ill enough to warrant it and evidence of portal (iepredicted survival is about 1–2 years hypertension. without a transplant). The natural history of PBC is well Assessment for transplantation in defined. Various prognostic models have chronic liver disease is difficult. been designed. The most commonly Objective and subjective measures are used is the Mayo Clinic model 4; this has

Key Points

There are objective and subjective criteria for transplantation

Disease-specific criteria exist for different conditions

Certain indications are common to all conditions, for example: •failing synthetic function (serum albumin <25 g/l) •complications of portal hypertension •intolerable quality of life

Discussion/referral should occur prior to end-stage disease

KEY WORDS: acute liver disease, chronic liver disease, CPD, liver transplantation

Clinical Vol 2No 4 July/August 2002 313 CME Liver disease

allowed prediction of estimated survival Table 1. Childs grading of severity in chronic liver disease with Pugh’s 1973 of PBC patients with and without trans- modifications. plantation. Criteria assessed Points scored for increasing abnormality may be used as an indicator 1 2 3 for transplantation. Serum bilirubin levels of 100 µmol/l and 150 µmol/l give grade None I–II III–IV median survivals of 24 months and Ascites Absent Slight Moderate 17 months, respectively. Treatment with ursodeoxycholic acid has meant that Serum bilirubin (µmol/ l): <35 35–50 >50 patients are less likely to be transplanted In PBC <70 70–170 >170 as a result of their serum bilirubin, but Serum albumin (g/l) >35 35–28 <28 more because of resistant ascites, other complications of Prothrombin time (prolongation in sec): 1–4 4–10 >10 (egvariceal bleed) or declining synthetic function. Occasionally, patients with Total score <6 A 7–9 B >10 C PBC are transplante d because of PBC = primary biliary cirrhosis. intractable pruritus or severe lethargy. Survival for PBC after transplantation is 80– 90% at 10 years, with a low risk (<10%) of symptomatic PBC recurrence. Autoimmune alcohol contract’ prior to listing. The Patients should be referred for transplan- six-month period of abstinence is impor- tation if their expected survival is less (AIH) usually tant since some patients may recover than two years, but before carries a good prognosis, with 93% during the time, thus negating the need they begin to decompensate rapidly or five-year survival. Several features sug- for a transplant. subjective features such as lethargy gest a bad prognosis, such as onset in Assessment of patients with alcoholic or pruritus make their quality of life childhood, typeII disease (liver-kidney liver disease includes investigations to intolerable. microsomal (LKM)-positive) rule out any comorbid alcohol-related and failure to respond to immunosup- illnesses such as cardiomyopathy, nutri- pressive treatment (associated with a tional failure or nephropathy. In patients Primary sclerosing cholangitis 6 69% mortality at four years) . with , cirrhosis is Models exist for the prognosis of primary Patients with AIH may present with often a late development. The onset of sclerosing cholangitis (PSC) and actuarial acute liver failure. It may be possible to ascites reduces median survival to survival post transplant, using these induce remission with appropriate 12 months, and the development of models is 89% at five years, compared immunosuppression, but this should be spontaneous bacterial sug- with 31% in medically managed performed in a transplant centre so that, gests a median survival of six months. patients5. The variables used to predict should treatment fail, emergency trans- (HCC) will be survival are serum bilirubin, haemo- plantation can be provided. developed by 20% of patients with alco- globin, histological state on , Transplantation for AIH has a good holic cirrhosis, and 75% of patients will age and presence of inflammatory bowel prognosis (80% five-year survival). Graft die from their liver disease. disease. failure due to disease recurrence is rare. The indications for liver transplanta- Referral for transplantation is usually for tion in patients with PSC include: chronic liver failure when predicted survival is less than 1–2 years. • severe jaundice (bilirubin >100 µmol/l) Hepatitis B is a common cause of complications arising from portal Alcoholic cirrhosis • cirrhosis worldwide, but less so in the hypertension, and Alcoholic cirrhosis is the second com- UK. The outcome of transplantation for • poor quality of life. monest indication for liver transplanta- hepatitis B was universally poor in the There is a high rate of cholangiocarci- tion, accounting for 20% of European early days of transplantation due to graft noma, with some studies suggesting a liver transplants. reinfection and the rapid onset of liver prevalence of 30% at 10 years. Un- When assessing a patient, non-depen- failure. It is mandatory that patients with diagnosed cholangiocarcinoma is found dent should be differenti- end-stage hepatitisB virus (HBV) infec- in 8– 18% of explanted , although ated from alcoholism. Most transplant tion are rendered HBV DNA negative incidental cholangioca rcinoma, either programmes in the UK insist on a with antiviral agents such as lamivudine microscopic or smaller than 1cm, does six-month abstinence period prior to prior to transplantation. Recurrence of not necessarily affect prognosis. transplantation and the signing of a ‘no hepatitis B after transplantation is pre-

314 Clinical Medicine Vol 2No 4 July/August 2002 CME Liver disease vented by administration of hepatitis B has been achieved by tightening the successful, but the outlook is not so good immunoglobulin. criteria for transplantation: a single once cirrhosis has developed. Patients Five-year survival for patients with lesion of less than 5 cm or less than may decompensate or develop HCC, compensated HBV cirrhosis (ie Childs A fivelesions in total and no evidence especially if alcohol misuse is a cofactor. disease) is 85%, and for decompensated of vascular or capsular invasion. Alpha-1-antitrypsin is another inherited disease (Childs C) is between 14 and Transplantation outside these guidelines disorder for which transplantation is 35%7. Indications for transplantation in should occur only as part of a clinical indicated when a patient has decompen- HBV are objective criteria of liver failure, trial. sated cirrhosis. In this situation, the with declining serum albumin usually outlook is excellent and soon after the best early indicator. Concerns over Metabolic indications transplant the patient expresses the graft reinfection mean that patients with alpha-1-antitrypsin phenotype of the subjective symptoms are managed There are several metabolic indications donor organ. medically. for liver transplant ation ( Table2). Wilson’s disease can present both as Other indications chronic liver disease and as acute liver failure. In the acute situation, patients Many other indications exist for trans- Hepatitis C is the commonest indication invariably die without liver transplanta- plantation. Transplantation may be used for transplantation worldwide. Of those tion. Genetic haemachromatosis is the as a rescue therapy in Budd-Chiari infected with hepatitis C, 80–90% of commonest inherited genetic disorder in syndrome, but it is often technically patients will become chronic carriers and Northern Europe. If patients are diag- challenging. T ransplantation also has a 20% will later develop hepatitisC virus nosed before cirrhosis has developed, role in structura l disorders such as (HCV)-related cirrhosis, usually over iron depletion treatment (venesection) is polycystic liver disease. longer than 20 years. Several risk factors are associated with more rapid progres- Acute liver failure sion of disease: Table 2. Metabolic indications for liver • male sex transplantation. Aetiology is the most important variable excess alcohol intake predicting survival in acute liver failure. • •Wilson’s disease The commonest cause of acute liver HBV co-infection, and • •genetic haemachromatosis failure in the UK is toxicity • route of transmission (blood •alpha-1-antitrypsin followed by seronegati ve hepatitis, products providing the highest risk). • oxalosis hepatitis B, drug reactions and Patients with Childs C disease should •Crigler-Najjar syndrome hepatitisA. Seronegati ve hepatitis be considered for transplantation. •familial amyloidosis (non-A to non-E hepatitis) confers the Timing of transplantation is important •hereditary tyrosinaemia least favourable outcome, drug-induced because graft reinfection with HCV is •urea cycle defects liver failure has an intermediate prog- universal and graft cirrhosis is reported •galactosaemia. nosis and paracetamol-induced failure in up to 20% of patients at fiveyears 8 the best9. Age is another predictor, with (although five-year survival is about 70%). Transplantation should be delayed until there is objective evidence of liver Table 3. King’s College Hospital criteria for transplantation in acute liver failure. failure because accelerated cirrhosis may develop after transplantation. Paracetamol related •pH <7.30 despite adequate fluid resuscitation (regardless of grade of encephalopathy) or Carcinoma •Prothrombin time >100sec and >300µ mol/l and grade III or IV It was hoped that hepatic transplantation might cure many malignant . Non-paracetamol related •Prothrombin time >100sec (regardless of grade of encephalopathy) Unfortunately, results have been disap- or pointing and transplantation in malig- •Any three of the following (regardless of grade of nancy is now restricted to HCC, some encephalopathy) neuroendocrine tumours and a few other (a)aetiology: non-A non-B hepatitis, idiosyncratic rarities. drug reactions HCC has a poor outcome. Median sur- (b)age <10 or >40years vival without treatment is around (c)jaundice to encephalopathy of >7days (d)prothrombin time of >50 sec sixmonths. Improvement in survival (e)serum bilirubin >300µ mol/l post-transplant for patients with HCC

Clinical Medicine Vol 2No 4 July/August 2002 315 CME Liver disease extremes of age being associated with the can be employed in patients with acute worst outcomes. and chronic liver disease. Optimal timing The selection of patients for transplan- is extremely important. Objective mea- tation in acute liver failure is directed sures of liver failure should be assessed, by the use of predictive models. The one of the most important of which is King’s College criteria (T able3), serum albumin especially in the formulated following retrospect ive non-jaundiced patient. A serum albumin analysis of 588 patients with acute liver of less than 25 g/l suggests a poor out- failure, are adhered to by transplant look. Serum albumin should not be over- units in the UK. Several studies have looked since this is often the most subtle validated these criteria. They have a high sign of liver failure. Subjective aspects specificity and positive predictive value, should also be considered: quality of life but a low negative predictive value for a and the ability to work and participate in poor outcome. Fulfilling the criteria con- society. fers less than 10% chance of survival 10. Careful consideration of these factors In acute liver failure it is vital that should be given to optimise the use of a patients are referred for consideration scarce resource, whilst ensuring that for transplantation at an appropriate patients with liver failure are not denied time – before their disease fulfills the the opportunity of assessment for liver King’s College criteria. It is advisable that transplantation. the management of any patient who has acute liver failure and is becoming encephalopathic, developing renal References failure or has a rising internati onal 1European Liver Transplant Registry website: normalised ratio should be discussed www.eltr.org with a transplant centre. Sometimes a 2Pugh RN, Murray-Lyon IM, Dawson JL, matter of hours can mean the difference Pietroni MC, Williams R. Transection of the between life and death. oesophagus for oesophageal varices. Br J Surg 1973;60:646–9. 3Yacavone RF, Locke GR 3rd, Provenzale DT, Eisen GM. Quality of life measurement in Contraindications : what is available? Review. There are no absolute contraindications Am J Gastroenterol 2001;96:285–97. 4Mayo Clinic model: www.mayo.edu/ to liver transplantation. Many patients int-med/gi/model/mayomodl.htm who previously would not have been 5Farges O, Malassagne B, Sebagh M, Bismuth transplanted can now be assessed and H. Primary sclerosing cholangitis: liver transplanted safely. However, some transplantation or biliary . Surgery patients have conditions which confer 1995;117:146–55. 6Sanchez-Urdazpal L, Czaja AJ, van Hoek B, high risks, including: Krom RA, Wiesner RH. Prognostic features extrahepatic organ failure and role of liver transplantation in severe • corticosteroid-treated autoimmune chronic extrahepatic malignancy • active hepatitis. Hepatology 1992;15: • severe extrahepatic infection 215–21. AIDS and HIV positivity 7De Jongh FE, Janssen HL, De Man RA, Hop • WC, et al. Survival and prognostic indica- • portal venous system thrombosis tors in hepatitis B surface antigen-positive on-going substance misuse cirrhosis of the liver. Gastroenterology 1992; • 103 comorbidity (egdiabetes mellitus). :1630–5. • 8Prieto M, Berenguer M, Rimola A, Loinaz Chronological age is not a contra- C, et al. Liver transplantation in hepatitis C. indication to transplantation, although A Spanish multicentre experience. Eur J Gastroenterol Hepatol 1998;10:771–6. transplantation in patients over the age 9Trey C. The hepatic failure sur- of 65 requires careful consideration. veillance study. Brief review of the effects of presumed etiology and age of survival. Can Med Assoc J 1972;106:525–7. Conclusion 10 O’Grady JG, Alexander GJ, Hayllar K, Williams R. Early indicators of prognosis in Liver transplantation is a relatively safe fulminant hepatic failure. Gastroenterology and successful treatment modality that 1989;97:439–45.

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