Adult Liver Transplantation Michael J. Moritz, M.D. Drexel University College of Medicine

Case Presentation: 16yo HF transferred to HUH History 2 wks of lethargy, anorexia, nausea ? days of dark urine, light stools 2 days of jaundice

ER Encephalopathy Dense icterus, mild ascites, splenomegaly, edema Elevated LFT’s, total bilirubin 30mg/dL Anemia, thrombocytopenia, coagulopathy Oliguria and elevated creatinine

Diagnostic Testing 1) Ultrasound 2) Blood tests 3) Specialty exam Cirrhosis, patent portal vein with hepatopetal flow, edematous gall bladder 2) Blood tests Ceruloplasmin, serum copper 3) Specialty exam Slit lamp with Kayser-Fleischer rings 4) Bx Copper content per gram of liver tissue 5) Specific confirmatory testing Urinary copper excretion, gene analysis

Wilson’s Disease Copper overload Defective ATP7B copper transmembrane transporter in the Golgi apparatus Copper not appropriately transferred out of hepatocytes to ceruloplasmin and bile Accumulates in liver, CNS, red cells, bone Fulminant (hepatic) vs. chronic (neuropsychiatric) presentation Gene frequency 1:90 Homozygosity 1:30,000

Wilson’s Disease Medical Treatment Copper chelation: trientene, D-penicillamine, tetrathiomolybdate Zinc supplementation Low copper diet (avoid organ meats, shellfish, dried beans, peas, whole wheat, chocolate,…)

Wilson’s Disease Transplantation Corrects the genetically defective liver Life long immunosuppression Indications: FHF or Chronic Liver Dz

Explant—FHF Wilson’s Disease

Liver Transplantation Liver transplantation is the OPTIMAL treatment for end stage liver disease (ESLD) ESLD has 2 forms: Acute and Chronic Acute=Fulminant Hepatic Failure Chronic=Cirrhosis

Common Diagnoses in Liver Tplt. Pts. Last 118 Pts. 1°Dx 2°Dx Hepatitis C 50% Alcoholism 13% 12% Cryptogenic 9% FHF, Autoimmune 7% PBC 4% Hepatitis B 3% 4% PSC 3% HCC 7%

Less Common Diagnoses in Adults for Liver Transplantation Wilson’s Dz—acute and chronic Hemachromatosis Budd-Chiari Syndrome Congenital Hepatic Fibrosis Polycystic Disease Inborn errors of metabolism Familial Amyloidotic Polyneuropathy

Fulminant Hepatic Failure (FHF) Synonymous with Acute Liver Failure Definition: Development of encephalopathy within ~8 weeks of the onset of symptoms or within ~2 weeks of the onset of jaundice Pathology: Panlobular or Submassive necrosis

Causes of FHF Idiopathic Acetaminophen toxicity Hepatitis B, A, E, other viruses Drug reactions (INH, halothane, others) Wilson’s Disease Mushroom poisoning

FHF-Clinical Manifestations Encephalopathy Coagulopathy Hypoglycemia Cerebral edema Sepsis—Multiorgan Failure

FHF-Prognosis A race between progressive liver failure and its complications vs. liver regeneration Age Etiology Rapidity of onset

FHF-Treatment Supportive ICU care Support of renal fxn, plasmaphoresis ICP monitoring Transplantation

Chronic Liver Disease—Indications for Transplantation Ultimately, the decision to transplant is based upon the patient’s likelihood of survival Survival with transplantation: One-year ~85-90% Two-year ~80-88% Five-year ~65-75%

Patient Survival After Primary Liver Transplantation

Chronic Liver Disease—Indications for Transplantation Ascites Encephalopathy Portal Hypertensive Bleeding Hepatocellular Carcinoma in the setting of Cirrhosis

Chronic Liver Disease—Indications for Transplantation Ascites Ascites has a two-year mortality of 50% SBP has a two-year mortality of 80% Usual treatment-diuretics; when severe-Large Volume Paracentesis with Albumin Replacement At its end stage, ascites and resultant ARF is called HepatoRenal Syndrome

Requirements for Transplantation End stage liver disease Physiologic ability to tolerate surgery Cardiac, pulmonary, renal, cerebral function Portal inflow Social support No extrahepatic infection or malignancy Alcohol abstinence for 6 months

Contraindications Age>70? Cardiac-pulmonary-renal-cerebral function Inability to safely be immunosuppressed Substance problems EtOH, tobacco, opiate analgesics, illicit drugs Social problems

Hepatitis C-Natural History Approx. 3 million infected in the US Only 25% of infected individuals develop cirrhosis Median--innoculation to cirrhosis=20years Median—innoculation to HCC=30 years, prevalence of HCC unknown

Hepatitis C and Liver Transplantation Near universal recurrence of viremia at high levels, 40% with hepatitis at one-year (bx) 40% with or mild hepatitis-negligible risk 40% with moderate hepatitis-not in <5years 20% with severe hepatitis and cirrhosis within 5 years of transplantation

Hepatitis C and Liver Transplantation-New News The newest interferons (Pegylated interferon and consensus interferon) plus ribavirin have a 15-20% Sustained Viral Response in post-transplant patients!

Alcoholic Cirrhosis Alcoholics have a post-tplt prognosis no different from patients with other diagnoses Risk of Recidivist Drinking 10% pathologic drinking within one year Predictors of Increased Risk Recidivism Abstinence<6 months Psychiatric dx, character disorder Polysubstance abuse

Liver Transplant--Numbers UNOS Waiting List 17,231 (2/8/05) 5,657 Cadaver donor liver transplants in from 6,549 cadaver donors (2004) 298 Living donor liver transplants (2004) Waiting list mortality~15% Cirrhotic complications Progression HCC Substance and social issues

Donor Liver

Donor Liver

Diagram of Piggyback Orthotopic Liver Transplant

Schematic of Venovenous Bypass

Liver Transplantation: Outcomes Patient Survival at 1, 3, and 5 years 86% 78% 72% Graft Survival 81% 71% 64% Immunosuppression/Tolerance Recurrent Dz Immunosuppressive risks

Review—Liver Transplantation Diagnoses—acute, chronic Indications and contraindications Hepatitis C, Alcohol Insufficient numbers of cadaver donors to meet demand

Conclusions With appropriately selected patients, Liver Transplantation offers an excellent chance for long-term, good quality of life survival for patients facing death from ESLD Post-transplant Recurrent Hepatitis C is the largest clinical problem at present Donors are in short supply

Organ Allocation for Adults Status 1 FHF, Acute Wilson’s Disease Early Post-transplant Complications: PNF, HAT <7 Days Allocated by Waiting Time, Blood Group Status 2 All Others Allocated by MELD Score Waiting Time at that score as tie breaker

MELD Score R=9.57ln(creat)+3.78ln(bili)+11.2ln(INR) +6.43 Scale from 6-40 Validation, c=0.82 for 90-day mortality for cirrhotics, almost the same as Child-Turcotte-Pugh score (c=0.84)

MELD Special Cases Hepatocellular Carcinoma Hepatopulmonary Syndrome Familial Amyloidosis OTC Deficiency, Crigler-Najjar Syn., etc. Currently Special Cases constitute: 0 of 19 Status 1 0% 52 of 138 with MELD >30 38% 214 of 807 with MELD 20-29 26% 7 OF 6844 with MELD 10-19 0.1% 0 of 6228 with MELD <10 0%

MELD UNOS: Transplanted 3/02-7/02 1786+570 HCC 428 Hepatopulmonary Syndrome 24 Portopulmonary Hypertension 2 Familial Amyloidotic Polyneuropathy 2 Oxalosis 3 Hepatoblastoma 1 Other Special Cases 105 Total 570

MELD & HCC Evaluation of # and size of tumors (US, CT or MR of abdomen and chest, bone scan) and Enhancing tumor >1cm, or AFP >200, or + arteriogram, or + biopsy, or Have had treatment with PEI, RITA, cryo, or TACE, and Not be a candidate for resection

Conclusions Liver transplantation is the optimal treatment for many end stage liver diseases Allocation of deceased donor organs is driven by acuity (MELD) and exceptions Survival outcomes are steadily improving, hampered by Donor limitations Recurrent disease