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.
• In December 2016, 147,128 liver transplants were performed in the US as compared to 7217 in 1998 based on data from the United Organ Sharing (UNOS) network.

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

Absolute contraindications:

• Metastasis outside the liver, past the curative stage
• Hepatocellular carcinoma with metastasis (Stage 1V)
• Acute Liver Failure with persistently elevated intracranial pressure ICP >50mmHg( due to hepatic encephalopathy)
• Hemangiosarcoma
• Hilar cholangiocarcinoma with liver involvement
• Sepsis
• Active alcohol or drug abuse
• Anatomic anomalies that may be a deterrent to transplantation
• Poor adherence to medical treatment
• Absence of social support

Relative contraindications:

• Infection with HIV (AIDS)
• Age >65 years
• Any serious pathologies of the lung or heart that cannot be corrected
• BMI ≥40
• Alcoholic liver disease:Only performed if abstinent for ≥ 6 months
• Presence of social support
• Participation in an alcohol abstinence and rehabilitation program

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 pediatric 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).

Orthotopic Liver Transplantation

• Donor selection based on biomarkers and risk indices is a crucial aspect of orthotopic liver transplantation and involves:
  • Preference of younger to older donors
  • Appropriate selection of recipients
  • Age based matching of donors and recipients
• Surgery involves the following steps:
  • Excision of the liver of the recipient
  • Separation of:
    • Common bile duct
    • Superior vena cava
    • Inferior vena cava
    • Hepatic artery
    • Portal vein
  • During surgery, venovenous bypass helps in diversion of flow from disrupted Inferior Vena Cava (IVC) and portal vein to Superior Vena Cava (SVC).
  • In order to maintain blood flow of the hepatic artery, anastomosis of donor liver at vascular sites is done.
  • Anastomosis of the bile ducts of the graft and recipient is performed.
  • In addition, choledochojejunostomy may also be performed.
  • Postoperatively, stenting of the bile duct using a T-tube may help monitor:
    • Production of bile
    • Postoperative function of the hepatic graft

Immunosuppressive management

• Postimplant immunosuppression ensures survival of the patient and allograft.
• Immunosuppressive agents used in patients receiving a liver transplant include the following:
  • Cyclosporine
  • Everolimus
  • Mycophenolate
  • Corticosteroids
  • Azathioprine
  • Tacrolimus
  • Sirolimus
• Agents used for induction therapy include:
  • High-dose corticosteroids
  • Antithymocyte globulin
  • Monoclonal antibody
  • Azathioprine
  • Cyclosporine/Tacrolimus (calcineurin inhibitors)
  • Antiproliferative agents
• Agents for long-term immunosuppression:
  • Cyclosporine or Mycophenolate Mofetil
  • Tacrolimus
  • Azathioprine
  • Prednisone
• The risk of chronic rejection in patients with liver transplantation decreases with time,although recipients may need to take immunosuppresive therapy for the rest of their lives.

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.

Complications of Liver Transplantation

• Complications that may develop in transplant recipients include the following:
  • Acute rejection of the graft
  • Adverse effects of immunosuppressive therapy
  • Biliary stricture
  • Biliary leak
  • Vascular thrombosis
  • Sepsis
  • Malignancy

• Immediate postoperative complications of liver transplantation include:
  • Acute rejection
  • Early graft failure
  • Biliary complications
  • Vascular complications
• The most common causes of death in liver transplant patients are as follows:
  • Infection
  • Malignancy
  • Rejection
• To monitor the patient for complications, the following investigations are used:

Laboratory investigations

• The following laboratory investigations help in providing evidence of rejection, and also help in the assessment of drugs( Azathioprine, Cyclosporine and Tacrolimus) along with their effect on bone marrow and renal function:
  • CBC
  • Electrolyte panel
  • Liver function tests
  • Kidney function tests (KFTs)
    • Blood urea nitrogen (BUN)
    • Creatinine levels
  • Drug levels in case of altered Kidney Function Tests, or suspected rejection:
    • Cyclosporine levels
    • Tacrolimus levels
  • In case of suspected infection:
    • Blood culture
    • Urine culture
    • Pharyngeal culture
    • Sputum culture

Imaging studies

• Chest radiography:
  • May be done if the patient has any of the following cardinal signs of respiratory disease such as:
    • Fever
    • Cough
    • Dyspnea
    • Abnormal findings on chest examination
• Abdominal ultrasonography
• Computed tomography scan
• Endoscopic retrograde cholangiopancreatography (ERCP)

Acute and chronic graft rejection

Acute graft rejection:

• Occurrence: roughly 20-70 percent patients
• Timing: 1-2 weeks post- transplantation
• Outcome: Graft dysfunction
• Clinical presentation:
  • Jaundice
  • Fever
  • Liver tenderness
  • Eosinophilia
• Laboratory evidence:
  • Abnormal liver function tests
  • Elevated Bilirubin
  • Elevated alkaline phosphatase levels
  • Elevation of hepatocellular enzymes:
    • Alanine aminotransferase (ALT)
    • Aspartate aminotransferase (AST)
• Treatment of acute rejection:
  • High-dose steroids:
    • Prednisolone 200 mg
    • Methylprednisolone 1 g for 3 days)
    • High-dose steroid bolus followed by a rapid taper over 1 week

• Alternative therapies include:
  • Antibody treatments:
    • Monoclonal therapy (OKT3 )
    • Antithymocyte globulin

Chronic graft rejection:

• Occurence: 5% of patients
• Main cause of late stage graft failure
• Features of chronic graft rejection include:
  • Gradual obliteration of small bile ducts
  • Microvascular changes
• Symptoms:
  • Jaundice
  • Pruritu
• Laboratory investigations:
  • Elevated serum alkaline phosphatase
  • Elevated bilirubin levels
• Gold standard diagnostic modality: Liver biopsy

Infection

• <1 month : Common conditions developing in patients in the early posttransplant period include intra-abdominal infections such as:
  • Cholangitis
  • Liver abcess
  • Abdominal abcess

• 1-6 months: Infections commonly occur due to:
  • Viruses
  • Opportunistic organisms

• After the first 6 months, risk of infection in transplant patients is equal to that of the population.

• Infection is primarily nosocomial. Common organisms responsible for causing infection post-transplant are as follows:
  • Bacterial (most common):
    • Enterococci
    • Staphylococci
    • Gram-negative aerobes
    • Anaerobes
  • Fungal: Candida (75% of fungal infections)
  • Presenting symptoms:
    • Fever
    • Abdominal pain
    • Jaundice

• Laboratory investigations:
  • Complete blood count (CBC)
  • Serum chemistries
  • Liver function tests
  • Coagulation panel
  • Urinalysis
  • Urine culture
  • Blood culture
• Imaging:
  • Abdominal radiographs
  • Chest radiographs
  • Computed tomography (CT)
  • Abdominal ultrasonography
  • T-tube cholangiography
  • Endoscopic retrogrande cholangiopancreatography (ERCP) Liver biopsy

• Treatment of infection:
  • Antimicrobials prescribed for nonimmunosuppressed patients

Cytomegalovirus (CMV)

• Most common viral infection (affects 25-85% patients)
• Occurrence: Between posttransplant months 1 and 3
• Infection may be:
  • Primary
  • Reactivated

• Clinical presentation:
  • Fevers
  • Malaise
  • Arthralgias

• Laboratory investigations:
  • Atypical lymphocytes
  • Thrombocytopenia
  • Mildly elevated transaminase levels

• Imaging findings:
  • CXR: CMV pneumonitis patients may have bilateral infiltrates on CXR
• Serology:Indirect immunofluorescence testing method
• Treatment: Ganciclovir intravenously for 2-4 weeks

Pneumocystis carinii pneumonia (PCP)

• May occur along with CMV infection or alone
• Diagnosis:Bronchoalveolar biopsy
• Treatment: Trimethoprim-sulfamethoxazole

Other less common organisms causing infection include:

• Fungi (especially Candida species)
• Herpes simplex
• Herpes zoster
• Toxoplasma
• Hepatitis C virus (HCV)
• Hepatitis B infection
• Malignancy:
  • In transplant patients, malignancy is the second leading cause of late mortality.
  • Common malignancies occuring patients after transplantation include:
    • Lymphomas
    • Squamous cell carcinoma : SCC of skin is the most common malignancy that occurs pos-tranplantation
    • Posttransplant lymphoproliferative disorder

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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