Liver transplantation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and the donor organ is placed in the same anatomic location as the original liver. Liver transplantation nowadays is a well accepted treatment option for end-stage liver disease and acute liver failure.

Liver Transplantation

History

• In the 1960s, Thomas Starzl used dogs as the first animals for research on liver transplantation in Boston and Chicago.
• In 1963, the first liver transplant in humans was attempted by a surgical team led by Dr. Thomas Starzl of Denver, Colorado, United States.
• Dr. Starzl performed several additional transplants over the next few years before the first short-term success was achieved in 1967 with the first one-year survival post-transplantation.
• In 1970, the regimen for immunosuppressive therapy following transplant was introduced, but azathioprine and steroids did not improve survival rates of patients.
• In the 1980s, with the introduction of cyclosporine by Sir Roy Calne, there was an improvement in rejection rates.
• In 1983, liver transplantation was no longer an experimental modality, but a clinically acceptable form of therapy for both adult and pediatric patients with appropriate indications.
• In 1986, the introduction of monoclonal antibodies such as muromonab-CD3 [OKT3] further contributed to improvement of quality of immunosuppressive therapy used in patients, with significant decline in rejection rates.
• In 1988, University of Wisconsin (UW) solution was developed, which ensured a smooth surgery and longer preservation period.
• In 1992, the concept of xenotransplantation and cloning techniques were introduced by Starzl.
• In 1999, approximately 5000 procedures were carried out, in contrast to 100 which had been performed a decade earlier.
• Recently, the introduction of newer immunosuppressive agents such as IL-2 receptor blockers and tacrolimus, have drastically increased patient survival rates to 1 and 5-year rates of approximately 85 and 70 percent respectively.
• Liver transplantation is now performed at over one hundred centers in the USA, as well as numerous centers in Europe and elsewhere. One year patient survival is 85-90%, and outcomes continue to improve, although liver transplantation remains a formidable procedure with frequent complications.
• Unfortunately, the supply of liver allografts from non-living donors is far short of the number of potential recipients, a reality that has spurred the development of living donor liver transplantation.

Indications

• Liver transplantation is applicable to any acute or chronic condition resulting in irreversible liver dysfunction, provided that the recipient does not have other conditions that will preclude a successful transplant.
• Most liver transplants are performed for chronic liver diseases that lead to irreversible scarring of the liver, or cirrhosis.
• The most common indications for liver transplantation in the United States are:
  • Hepatitis C virus
  • Alcoholic liver disease
  • Idiopathic/autoimmune liver disease
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Hepatitis B virus
  • Metabolic liver disease (eg, inborn errors of metabolism)
  • Cancer
  • Biliary atresia
  • Acute liver failure :
    • Severe acute liver injury with impaired synthetic function of the liver(INR ≥1.5) and encephalopathy in the absence of pre existing liver disease or cirrhosis.
    • Common causes:
      • Viral
      • Drug-induced
    • Acute liver failure has the highest priority for liver transplantation, and warrants immediate referral to transplantation centre
    • In the absence of transplantation, patients may recover or die
  • Cirrhosis:
    • Only in cases of complications such as portal hypertension, or compromised hepatic function (marker for impaired survival)
    • Signs of decompensated cirrhosis include:
      • Ascites
      • Encephalopathy
      • Variceal hemorrhage
      • Hepatorenal syndrome
    • Transplantation evaluation is commenced in patients with MELD score >10:
    • This gives the patient time for pretransplantation evaluation
    • Patient has ample time for education, before the development of symptoms of hepatic encephalopathy that may impair cognition
    • Patients with cirrhosis are candidates for liver transplantation in the following scenarios:
      • Biologic Model for End-stage Liver Disease (MELD) score is ≥15
      • Cases of Child B cirrhosis with portal hypertension but a low MELD score
      • MELD exception points are given to patients with pathologies that may impair survival without impacting the MELD score such as:
        • Cancer: HCC, Hilar cholangiocarcinoma
        • Complications of cirrhosis:
          • Hepatopulmonary syndrome
          • Portopulmonary hypertension
        • Vascular pathologies:
          • Hepatic artery thrombosis
        • Cystic fibrosis:
          • Primary hyperoxaluria
          • Familial amyloid polyneuropathy
        • Other conditions that may also be indications for transplantation that do not qualify for MELD or MELD exception points include:
          • Intractable pruritus in case of primary biliary cirrhosis
          • Refractory variceal hemorrhage
          • Refractory ascites
          • Refractory hepatic encephalopathy
          • Portal hypertensive gastropathy leading to chronic blood loss
          • Recurrent cholangitis in patients with PSC
          • HCC: a single lesion ≤5 cm or up to three separate lesions all <3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastasis.
          • Neuroendocrine tumors that have metastasized to the liver
          • HCC (including fibrolamellar HCC)
          • Large hepatic adenomas
          • Epithelioid hemangioendothelioma
          • Metabolic disorders:
            • Alpha-1 antitrypsin deficiency
            • Wilson disease
            • Acute intermittent porphyria
            • Glycogen storage disease (type I and type IV)
            • Tyrosinemia
            • Hemochromatosis
• CONTRAINDICATIONS
• Metastatic cancer outside liver, active drug or alcohol abuse and active septic infections are absolute contraindications.
• While infection with HIV was once considered an absolute contraindication, this has been changing recently.
• Advanced age and serious heart, pulmonary or other disease may also prevent transplantation (relative contraindications).

Techniques

• Before transplantation liver support therapy might be indicated (bridging-to-transplantation).
• Artificial liver support like liver dialysis or bioartificial liver support concepts are currently under preclinical and clinical evaluation.
• Virtually all liver transplants are done in an orthotopic fashion, that is the native liver is removed and the new liver is placed in the same anatomic location.
• The transplant operation can be conceptualized as consisting of the hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the postimplantation phase.
• The operation is done through a large incision in the upper abdomen.
• The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, and portal vein.
• Usually, the retrohepatic portion of the inferior vena cava is removed along with the liver, although an alternative technique preserves the recipient's vena cava ("piggyback" technique).
• The donor's blood in the liver will be replaced by an ice-cold organ storage solution, such as UW (Viaspan) or HTK until the allograft liver is implanted.
• Implantation involves anastomoses (connections) of the inferior vena cava, portal vein, and hepatic artery.
• After blood flow is restored to the new liver, the biliary (bile duct) anastomosis is constructed, either to the recipient's own bile duct or to the small intestine.
• The surgery usually takes between five and six hours, but may be longer or shorter due to the difficulty of the operation and the experience of the surgeon.
• The large majority of liver transplants use the entire liver from a non-living donor for the transplant, particularly for adult recipients.
• A major advance in paediatric liver transplantation was the development of reduced size liver transplantation, in which a portion of an adult liver is used for an infant or small child.
• Further developments in this area included split liver transplantation, in which one liver is used for transplants for two recipients, and living donor liver transplantation, in which a portion of healthy person's liver is removed and used as the allograft.
• Living donor liver transplantation for pediatric recipients involves removal of approximately 20% of the liver (Couinaud segments 2 and 3).

Immunosuppressive management

• Like all other allografts, a liver transplant will be rejected by the recipient unless immunosuppressive drugs are used.
• The immunosuppressive regimens for all solid organ transplants are fairly similar, and a variety of agents are now available.
• Most liver transplant recipients receive corticosteroids plus either tacrolimus or Cyclosporin or Mycophenolate Mofetil.
• Liver transplantation is unique in that the risk of chronic rejection also decreases over time,although recipients need to take immunosuppresive medication for the rest of their lives.
• It is theorized that the liver may play a yet-unknown role in the maturation of certain cells pertaining to the immune system.
• There is at least one study by Dr. Starzl's team at the University of Pittsburgh which consisted of bone marrow biopsies taken from such patients which demonstrate genotypic chimerism in the bone marrow of liver transplant recipients.

Results

• Prognosis is quite good. 1-year survival (in Finland) is 83%, 5-year survival is 76% and 10-year survival is 66%. Majority of deaths happen during the first three months after transplantation.

Living donor transplantation

• Living donor liver transplantation (LDLT) has emerged in recent decades as a critical surgical option for patients with end stage liver disease, such as cirrhosis and/or hepatocellular carcinoma often attributable to one or more of the following: long-term alcohol abuse, long-term untreated Hepatitis C infection, long-term untreated Hepatitis B infection.
• The concept of LDLT is based on (1) the remarkable regenerative capacities of the human liver and (2) the widespread shortage of cadaveric livers for patients awaiting transplant. In LDLT, a piece of healthy liver is surgically removed from a living person and transplanted into a recipient, immediately after the recipient’s diseased liver has been entirely removed.
• Historically, LDLT began as a means for parents of children with severe liver disease to donate a portion of their healthy liver to replace their child's entire damaged liver.
• The first report of successful LDLT was by Dr. Silvano Raia at the Universidade de São Paulo (USP) Medical School in 1986.
• Surgeons eventually realized that adult-to-adult LDLT was also possible, and now the practice is common in a few reputable medical institutes.
• It is considered more technically demanding than even standard, cadaveric donor liver transplantation, and also poses the ethical problems underlying the indication of a major surgical operation (hepatectomy) on a healthy human being.

External Links

• American Liver Foundation: Comprehensive information about Hepatitis C, Liver Transplant and other liver diseases, including links to chapters for finding local resources
• Management of HBV Infection in Liver Transplantation Patients
• Management of HCV Infection and Liver Transplantation
• Antiviral therapy of HCV in the cirrhotic and transplant candidate
• Living Donors Online
• Liver Donor
• History of pediatric liver transplantation
• ABC Salutaris: Living Donor Liver Transplant
• Organ Donation Awareness and former potential donor blog
• All You Need to Know about Adult Living Donor Liver Transplantation

References

• Eghtesad B, Kadry Z, Fung J (2005). "Technical considerations in liver transplantation: what a hepatologist needs to know (and every surgeon should practice)". Liver Transpl. 11 (8): 861–71. PMID 16035067.CS1 maint: Multiple names: authors list (link)
• Adam R, McMaster P, O'Grady JG, Castaing D, Klempnauer JL, Jamieson N, Neuhaus P, Lerut J, Salizzoni M, Pollard S, Muhlbacher F, Rogiers X, Garcia Valdecasas JC, Berenguer J, Jaeck D, Moreno Gonzalez E (2003). "Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry". Liver Transpl. 9 (12): 1231–43. PMID 14625822.CS1 maint: Multiple names: authors list (link)
• Reddy S, Zilvetti M, Brockmann J, McLaren A, Friend P (2004). "Liver transplantation from non-heart-beating donors: current status and future prospects". Liver Transpl. 10 (10): 1223–32. PMID 15376341.CS1 maint: Multiple names: authors list (link)
• Tuttle-Newhall JE, Collins BH, Desai DM, Kuo PC, Heneghan MA (2005). "The current status of living donor liver transplantation". Curr Probl Surg. 42 (3): 144–83. PMID 15859440.CS1 maint: Multiple names: authors list (link)
• Martinez OM, Rosen HR (2005). "Basic concepts in transplant immunology". Liver Transpl. 11 (4): 370–81. PMID 15776458.
• Krahn LE, DiMartini A (2005). "Psychiatric and psychosocial aspects of liver transplantation". Liver Transpl. 11 (10): 1157–68. PMID 16184540.
• Nadalin S, Malagò M, et al. Current trends in live liver donation. Transpl. Int. 2007;20:312-30.
• Vohra V. Liver transplantation in India. Int Anesthesiol Clin. 2006;44:137-49.
• Strong RW. Living-donor liver transplantation: an overview. J Hepatobiliary Pancreat Surg. 2006;13:370-7.
• Fan ST. Live donor liver transplantation in adults. Transplantation. 2006;82:723-32.

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