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A. Introductionnavigator

  1. About 5300 liver transplants carried out in 2002
  2. About 15,000 patients on transplant waiting list
  3. Average waiting time on transplant list is ~795 days
  4. Types of Liver Transplant
    1. Cadavaric Donor - 90% of transplants
    2. Living Donor (right hepatic lobe) - both pediatric and adult cases [2,3]
    3. Xenotransplantation being investigated
  5. Small liver cancer found during transplant evaluation does not rule out transplant [4]
  6. For organ donation sites, see reference [5]; organ procurement [6]
  7. Recipients who are >60, had alcoholic liver disease, or very sick had poorer outcomes and much higher costs associated with transplantation [7]

B. Indications navigator

  1. Hyperbilirubinemia
  2. Intractable Ascites [8]
  3. Spontaneous Bacterial Peritonitis (SBP)
  4. Synthetic Dysfunction
    1. Coagulopathy
    2. Hypoalbuminemia
  5. Hepatorenal Syndrome [8]
  6. Bleeding esophageal or gastric varices
  7. Encephalopathy
    1. Stage I: Confused
    2. Stage II: Arouse to verbal
    3. Stage III: Arouse to pain
    4. Stage IV: Not arousable
  8. Severe malnutrition
  9. Hepatopulmonary Syndrome
  10. Recurrent cholangitis in patients with primary sclerosing cholangitis
  11. Unacceptable quality of life (malaise, weakness, cholestasis)

C. Liver Diseases Leading to Transplantationnavigator

  1. Cirrhosis (70%)
    1. Divided into non-cholestatic (60%) and cholestatic (10%) causes of cirrhosis
    2. Hepatitis C Virus (HCV) infection leading to cirrhosis is the most common single indication for transplantation (40% overall)
    3. Alcoholic liver disease
  2. Acute Hepatitic (fulminant) Necrosis (~8%)
    1. Toxin induced - especially acetaminophen ± alcohol
    2. Mushroom poisoning
  3. Biliary Atresia (neonatal): ~3%
  4. Inflammatory Disease
    1. Primary Biliary Cirrhosis
    2. Sclerosing Cholangitis
  5. Liver neoplasm with confined primary tumor (~7%)
  6. Inborn Errors of Metabolism (~3%)
    1. Wilson's Disease
    2. Glycogen Storage Diseases
  7. Budd-Chiari Syndrome (Coagulopathy)

D. Contraindications [1]navigator

  1. In Acute Fulminant Hepatitic Failure:
    1. Sustained increased intracranial pressure (>40mmHg)
    2. Very low perfusionn pressure (<60mm Hg)
  2. Severe pulmonary artery hypertension (>60mm Hg)
  3. Stage III or IV hepatocellular carcinoma
  4. Extrahepatitic malignancy (except non-melanoma skin cancers, some neuroendocrine tumors)
  5. Uncontrolled sepsis
  6. Active substance abuse
  7. Noncompliance with medical care
  8. HIV infection - relative contraindication

E. Preoperative Treatment navigator

  1. National Computerized Waiting List
    1. Patients who meet criteria for transplant are placed on waiting list
    2. Urgency is determined using the MELD score
    3. MELD score estimates mortality risk
    4. MELD incorporates serum bilirubin, creatinine, international normalization ratio (INR)
    5. Thus, combines liver metabolic function, renal dysfunction, coagulopathy
  2. Immunizations are updated
    1. Hepatitis A and B Virus
    2. Influenza
    3. Pneumococcus
  3. Compatibility
    1. Blood Group compatibility required
    2. HLA compatibility not required
  4. Hepatitis Virus B (HBV) Titers [10]
    1. Hepatitis B virus sAg+ is a relative contraindication
    2. Long term administration of anti-HBV Ig may reduce recurrence of infection [11]
    3. Anti-HBV Ig may also have anti-HCV Abs present (prior to 1990) [11]
    4. Lamivudine may be useful post-transplant to prevent recurrence [12]
    5. Combination therapy with anti-HBV Ig and lamivudine may be used
    6. Persons positive for HBV DNA in blood, or HBV e antigen, do even more poorly
    7. Famciclovir is also being investigated for prophylaxis
  5. Immunosuppression
    1. Pulse methylprednisolone (Solumedrol®)
    2. Cyclosporine A (Neoral®) OR Tacrolimus (FK506; Prograf®) [13]
    3. Mycophenolate mofetil (Celcept®)
    4. Adding anti-IL2 receptor monoclonal antibody (basiliximab or daclizumab) to standard regimen reduces acute rejection rate from 43% to 35% [1]
    5. Following induction with antithymocyte globulin, tacrolimus alone has been used as maintenance monotherapy and tapered to alternating day or 1-2 doses per week [14]
    6. Possible that this antithymocyte globulin + tacrolimus induces tolerance to graft
    7. If glucocorticoid resistance occurs, antithymocyte globulin or anti-T cell monoclonal (anti-CD3) antibody can be used
  6. Efficacy of CsA versus Tacrolimus [15]
    1. Tacrolimus showed better overall control of acute resistant rejection episodes
    2. Nephro- and neurotoxicity were major problems with both agents
    3. Tacrolimus more diabetogenic than CsA
    4. Overall 1 year 88% patient survival with ~80% graft survival equal for both drugs
    5. At 1 year, tacrolimus had reduced retransplantation or treatment failure
    6. Sepsis and multiorgan failure are main causes of death in transplanted patients
    7. Main cause or retransplantation is hepatic artery thrombosis
  7. Perioperative aproprotin clearly reduces blood loss and transfusion requirements [16]
  8. Oxygenation [17]
    1. May be particularly problematic in patients with hepatopulmonary syndrome
    2. Methylene blue, a guanylate cyclase (nitric oxide) inhibitor, may be effective
  9. Living Donor [2,3]
    1. Over 500 living donor transplants per year
    2. For eligible patients, reduced time on waiting lists
    3. Allows scheduled (versus urgent with cadavaric) surgery
    4. Reduced cold ischemia time (usually <1 hour) versus 8-12 hour average for cadavaric
    5. Short term outcome similar for living donor and cadavaric
    6. Donor problems are minimal: 5% bile leaks, ~15% with mild abdominal problems
    7. 96% of donors return to employment within 10 weeks of surgery

F. Rejection Post-Operativelynavigator

  1. High dose methylprednisolone (Solumedrol®, 0.5-1gm per day)
  2. Anti-CD3 (OKT3 McAb) - usually 3-7 day course of therapy
  3. Tacrolimus - save about 70% of grafts undergoing post-operative rejection (even on CsA)
  4. Tacrolimus associated with less acute rejection than CsA
  5. Tacrolimus/glucocorticoids versus Ciclosporin micoemulsion/glucocorticoids/azathioprine [25]
    1. Studied in 185 children undergoing liver transplant
    2. Tacrolimus regimen clearly superior with reduced acute rejections (45% versus 60%)
    3. Patients free from glucocorticoid resistant acute rejection 95% for tacrolimus versus 70%
    4. Similar adverse events

G. Infection navigator

  1. About 70% of patients will have at least 1 infection after transplant
  2. Types of Infections
    1. Bacterial 70%
    2. Viral 20%
    3. Fungal 10%
  3. In first month, most infections are bacterial or fungal
    1. Wound infection
    2. Intrabdominal infection
    3. Cholangitis
    4. Urinary tract infection
    5. Central venous catheter infection
    6. Pneumonia
  4. Infections from 1 to 6 Months
    1. Cytomegalovirus
    2. Herpes simplex virus
    3. Epstein-Barr virus
    4. Fungi: Aspirgillus fumigatus [], cryptococcus
  5. Risk of infection is low after 6 months
  6. Cytomegalovirus (CMV)
    1. CMV is major problem; serologic evidence of CMV predicts poor outcome [18]
    2. High dose acyclovir (800mg po qid) probably not effective to prevent disease
    3. Surveillance cultures should be done
    4. Ganciclovir (5mg/kg IV bid, usually 7 days) if positive cultures
    5. Oral valganciclovir may be acceptable in mild CMV infection
    6. Bacterial / fungal superinfections common
  7. Fungal Infections [19]
    1. Liver transplant patients have highest risk of fungal infections of all solid organ recipients
    2. Fungal infections, both superficial and invasive occur in 10-30% within 6-12 months
    3. Cryptococcus may contribute to mental status changes, meningitis, fungemia [9]
    4. Invasive aspirgilosis can occur and may be fatal []
    5. Prophylactic fluconazole 400mg po qd reduced risk of fungal infection ~75%
    6. Fluconazole also reduced risk of death from fungal infections, but not overall deaths
  8. Perioperative Infection Prophylaxis for 3 Months
    1. Ampicillin-sulbactam (Unasyn®)
    2. Valganciclovir
    3. Fluconazole
  9. Trimethoprim/Sulfamethoxazole (Bactrim®) for life to prevent Pneumocystis carinii

H. Prognosisnavigator

  1. Acute rejection episodes predict poor long term outcome
  2. Overal Survival for Deceased Donor Tranpslants
    1. One Year: 86%
    2. Three Year: 78%
    3. Five year: 72%
    4. The 3 and 5 year surivival rates are reduced ~10% in HCV infected patients
  3. Drug Induced Renal Dysfunction
    1. Common post-transplant problem that may dictate reduction in CsA or FK506
    2. Mycophenolate can replace calcineurin inhibitors in renal dysfunction [20]
    3. Rejection rate with mycophenolate is higher than calcineurin inhibitors
    4. However, renal dysfunction can resolve when mycophenolate is used
    5. Mycophenolate can be used (with increased rejection risk) as single agent post-transplant [21]
  4. HCV Associated Renal Dysfunction
    1. Glomerulonephritis (GN, immune complex) may occur after transplant in HCV patients [27]
    2. HCV associated renal dysfunction includes membranoproliferative GN, IgA nephropathy, or mesangial GN, and may progress to renal failure [27]
    3. Monitoring renal function in HCV+ patients after liver transplant is important
  5. CMV status of donor and recipient predict one year mortality [18]
    1. Seronegative donor and recipient had 1 year mortality of 11%
    2. Seronegative donor and seropositive recipient - 1 year mortality 22%
    3. Seropositive donor and recipient - 1 year mortality 30%
    4. Seropositive donor and seronegative recipient - 1 year mortality 44%
  6. Increased number of transfusions required - poor prognosis
  7. Invasive fungal infection or bacteremia was poor prognosis
  8. Hepatitis Virus [10]
    1. Positive HBV is a risk factor for poor outcome, particularly if HBeAg positive
    2. HCV infection appears not to alter long term outcome but may cause renal dysfunction due to glomerulonephritis (see above) [27]
    3. Anti-HBV immunoglobulin prior to 1990 may have anti-HCV activity [11]
  9. Osteoporosis is a problem in organ transplant patients [23]
    1. Calcium and vitamin D may be helpful
    2. Bisphosphonate therapy is generally recommended
    3. Zoledronic acid prevents bone loss after liver transplant, though effects wain after 12 months [26]
    4. Fracture rates are fairly low in renal transplant recipients, higher in liver transplants
  10. African Americans and Asians have poorer outcomes than white Americans or Hispanics [24]
  11. Liver donor increasingly used but complications relatively common, mortality low [3]

Resources navigator

calcMELD Score

References navigator

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  2. Trotter JF, Wachs M, Everson GT, Kam I. 2002. NEJM. 346(14):1074 abstract
  3. Brown RS Jr, Russo MW, Lai M, et al. 2003. NEJM. 348(9):818 abstract
  4. Mor E, Kaspa RT, Sheiner P, Schwartz M. 1998. Ann Intern Med. 129(8):643 abstract
  5. Organ Donation. 1995. Med Let. 37(952):60 abstract
  6. Hauptman PJ and O'Connor KJ. 1997. NEJM. 336(6):4210
  7. Showstack J, Katz PP, Lake JR, et al. 1999. JAMA. 281(15):1381 abstract
  8. Gines P, Cardenas A, Arroyo V, Rodes J. 2004. NEJM. 350(16):1646 abstract
  9. Fishman JA, Gonzalez RG, Branda JA. 2008. NEJM. 358(15):1604 (Case Record) abstract
  10. Poterucha JJ and Wiesner RH. 1997. Ann Intern Med. 126(8):805
  11. Feray C, Gigou M, Samuel D, et al. 1998. Ann Intern Med. 128(10):810 abstract
  12. Lamivudine. 1997. Med Let. 39(1003):57
  13. Tacrolimus. 1994. Med Let. 36(931):81
  14. Starzl TE, Murase N, Abu-Elmagd K, et al. 2003. Lancet. 361(9368):1502 abstract
  15. O'Grady JG, Burroughs A, Hardy P, et al. 2002. Lancet. 360(9340):1119 abstract
  16. Porte RJ, Molenaar IQ, Begliomini B, et al. 2000. Lancet. 355(9212):1303 abstract
  17. Schenk P, Madl C, Rezaie-Majd S, et al. 2000. Ann Intern Med. 133(9):701 abstract
  18. Falagas ME, Snydman DR, Griffith J, et al. 1997. Ann Intern Med. 126(4):275 abstract
  19. Winston DJ, Pakrasi A, Busuttil RW. 1999. Ann Intern Med. 131(10):729 abstract
  20. Schlitt HJ, Barkmann A, Boker KHW, et al. 2001. Lancet. 357(9256):587 abstract
  21. Stewart SF, Hudson M, Talbot D, et al. 2001. Lancet. 357(9256):609 abstract
  22. Rodino MA and Shane E. 1998. Am J Med. 104(5):459 abstract
  23. Nair S, Eustace J, Thuluvath PJ. 2002. Lancet. 359(9303):287 abstract
  24. Kelly D, Jara P, Rodeck B, et al. 2004. Lancet. 364(4439):1054
  25. Crawford BA, Kam C, Pavlovic J, et al. 2006. Ann Intern Med. 144(4):239 abstract
  26. McGuire BM, Julian BA, Bynon JS Jr, et al. 2006. Ann Intern Med. 144(10):735 abstract
  27. Seton M, Pless M, Fishman JA, et al. 2008. NEJM. 358(24):2619 (Case Record) abstract