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LIVER TRANSPLANTATION Dr Sudeep R Shah MS DNB FRCS (Edin) Consultant GI & Hepatobiliary Pancreatic Surgeon Email: HYPERLINK "mailto:[email protected]" [email protected] Liver transplantation is, today, the only curative option for end-stage liver disease. Dr Thomas Starzl in the USA and Sir Roy Calne in the UK who pioneered these surgeries in the 1960s initially had success rates of 30%. However, paralleling advances in immunosuppression, anesthesia, intensive care and refining of surgical techniques, survival of >80% have been achieved. INDICATIONS These are summarized in Table 1. For end- stage liver disease, the timing is crucial and transplantation should be offered when the patient is sick enough to need a transplant but well enough to withstand this complex operation with good chance of success. This assessment is best carried out by a team of transplant hepatologists, surgeons and anesthetists. Hepatitis C induced cirrhosis is rapidly becoming the commonest indication worldwide. The MELD (Model for end stage liver disease) score based on bilirubin, INR and serum creatinine is a useful prognostic score and is used by the organ sharing networks in the USA. For patients with fulminant liver failure fulfilling the Kings College criteria, with intact neurological function, timely transplantation is lifesaving CONTRAINDICATIONS Systemic illnesses precluding anesthesia, untreated sepsis, AIDS and extrahepatic malignancy, non neuroendocrine liver metastases, liver angiosarcoma and cholangiocarcinoma are considered absolute contraindications. Patients with HCC beyond the Milan criteria (> 5 cm tumour, >3 tumours each < 3cm) have post transplant survival reduced by tumour recurrence. HCC with tumour thrombus in the portal vein inevitably recurs. HBV DNA positive patients have high graft loss. Porto-pulmonary hypertension, if severe, is a contraindication. Noncompliers with treatment and active substance abusers are usually not considered. DONOR SELECTION AND PROCEDURE The donor may be a brain-stem dead cadaver from whom the whole liver may be retrieved, or a relative who is fit, free of liver pathology and willing to donate part of the liver. An anatomical lobe or sector may be removed amounting to 0.8 to 1% of recipient body weight. Living donor risk to life is estimated at <0.5% , with a 10% risk of major morbidity. The donor liver regenerates to near normal volume. Brain stem dead cadavers may not provide a good quality liver if they have poor hemodynamic stability, are on high pressor doses, have fatty change, long ICU stay or prolonged starvation. Potential brain dead organ donors require careful maintainance in ICU. Cadaver livers may be divided along anatomical planes to reduce size for children or alternately split to provide two grafts- a smaller left lobe for children and right lobe for small adults, either in situ or on the bench after retrieval. The liver is perfused with University of Wisconsin (UW) solution or Histidine-tryptophanketoglutarate (HTK) solution. The liver may preserve for upto 24 hours in UW and 15 hours in HTK solution. THE RECIPIENT PROCEDURE The native liver is removed, a step that is difficult because of portal hypertension collaterals and coagulopathy, and replaced by the donor liver, joining the vena cava, portal vein, hepatic artery and bile duct. T-tubes or stents are occasionally employed across the biliary anastomosis. In case of bile duct disease such as biliary atresia, a Roux loop of jejunum is used. Veno-venous bypass is no longer considered essential. The native vena cava is left in place in all living related transplants and also in select cadaveric transplants. IMMUNOSUPPRESSION AND REJECTION Only blood group matching is required for liver transplantation. Though acute rejection may occur in up to 50% of cases, chronic rejection leading to graft loss takes place in < 5% of transplants. Diagnosis is suspected on altered LFT and established by biopsy. Lifelong immunosuppression is required. Modern immunosuppression centers on the use of calcineurin inhibitors- Tacrolimus (FK 506) or microemulsified Cyclosporine A levels are closely monitored to limit toxicity. Steroids are started in high doses and rapidly tapered. In the majority of cases these can be stopped by 3 months post operatively. Episodes of acute rejection are treated by pulsed steroids for 3 days. In rare cases, severe rejection requires treatment with antilymphocytic globulin or OKT3. Mycophenolate moefetil is used as an adjunct, especially to reduce calcineurin inhibitor dose in case of renal dysfunction.. Recently induction agents such as anti IL2 receptor antibodies- basiliximab and daclizumab and new drugs rapamycin and sirolimus are also being used. POST OPERATIVE COMPLICATIONS Primary failure of graft function is most feared- occurring in 5% of cases. The causes include poor donor liver quality- especially steatohepatitis., preservation injury and hepatic artery thrombosis (HAT), which almost invariably requires retransplantation. HAT occurs in 5% of adult and 15% of pediatric transplants. Portal vein thrombosis is rarer, occurring in 2%. Biliary complications have been called the Achilles’ heel of liver transplantation and occur in 1230% of cases. HAT may be associated with this as the artery is the main supply to the bile duct. Corrective surgery is often required. Liver dysfunction due to a small graft is a particular problem of living related transplant in case of small donor graft. Failure to establish adequate venous outflow especially from middle hepatic vein branches of a right lobe graft may lead to graft congestion . Infections owing to immunosuppression are the common cause of morbidity and mortality. Besides nosocomial organisms, opportunistic infections of note are cytomegalovirus (CMV) which occurs as fever, leucopenia and colitis, hepatitis, pneumonia or meningitis after the third week. Prophylaxis is instituted especially if the donor has previous exposure and recipient does not. Viral and fungal infections too are common. Live vaccines should be avoided post transplant. Drug toxicity is a major morbidity. Calcineurin inhibitors cause hypertension, hyperlipidemia and diabetes. High levels are nephrotoxic and may lead to tremors, neuropsychiatric changes and rarely, convusions. Cyclosporin leads to hirsuitism and gingival hypertrophy. Mycophenolate causes leucopenia and diarrhoea. Rapamycin leads to retarded wound healing. Drug interactions are common and complex, requiring physicians to be careful while adding new drugs. Post transplant lymphoproliferative disorders and skin cancers occur in up to 7% of immunosuppressed patients. Disease recurrence is a major issue, especially in Hepatitis C, where accelerated cirrhosis may occur in up to 25% cases. Autoimmune hepatitis, primary sclerosing cholangiitis and tumours may recur. Recidivism causes graft loss in alcoholics. PROGNOSIS Modern transplant techniques offer a one year survival of 80-90% and 5 year survival of 70-80% for appropriately selected patients with chronic liver disease undergoing timely transplants. The survival for fulminant liver failure is marginally lesser. Living related and cadaver transplant have similar survival rates. Table: Indications for liver transplantation Hepatitis C cirrhosis Hepatitis B cirrhosis Alcoholic liver disease Cholestatic liver disease Primary sclerosing cholangiitis Biliary cirrhosis- primary and secondary Autoimmune liver disease Budd-Chiari syndrome Metabolic disorders: Wilsons disease Haemochromatosis Oxalosis Alpha 1 antitrypsin deficiency Erythropoetic porphyria Hypercholesterolemia Familial amyloid polyneuropathy Liver space occupying lesions: Polycystic disease Multiple adenomatosis Caroli’s disease Fulminant liver failure Viral hepatitits (B, A, E) Drug toxicity Paracetamol overdose Halothane Wilson’s disease In children: Biliary atresia Progressive familial intrahepatic cholestasis Metabolic disorders incl Criggler Najjar syndrome, Urea cycle disorders Unresectable hepatoblastoma RECOMMENDED READING Humar A. Manual of liver transplant medical care. Minneapolis: Fairview Press 2002. 72 page monograph on post operative management Busuttil RW, Klintmalm GB (eds). Transplantation of the Liver. 2nd ed.: WB Saunders 2005. Comprehensive book on all aspects of the subject. HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlu s&list_uids=15062657&query_hl=13&itool=pubmed_docsum" Tanaka K, Kiuchi T, Kaihara S. Living related liver donor transplantation: techniques and caution. Surg Clin North Am. 2004;84:481-93. A summary of the technique and pitfalls of living donor transplant by one of the pioneers. Rela M, Dhawan A. Liver transplantation in children. Indian J Pediatr 2002;69:175-83. Review of indications, techniques and prognosis in children. Sutcliffe R, Maguire D, Portmann B, Rela M, Heaton N. Selection of patients with hepatocellular carcinoma for liver transplantation. Br J Surg 2006;93:11-8. Detailed review of transplantation for hepatocellular cancer HYPERLINK "http://www.eltr.org" www.eltr.org Website of the European liver transplant registry giving data on indications, survival and evolution of transplantation