Liver transplantation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

When a healthy liver allograft is used in place of damaged liver tissue, it is termed as liver transplantation. Thomas Starzl used dogs as the first animals for research on liver transplantation in the 1960s. In 1963, the first liver transplant in humans was attempted by Dr. Thomas Starzl of Colorado, United States. The most common indications for liver transplantation in the United States are hepatitis C virus, alcoholic liver disease, autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, hepatitis B virus, liver disease due to inborn errors of metabolism, cancer, biliary atresia and acute liver failure. On the other hand, absolute contraindications to liver transplantation include hepatocellular carcinoma with metastasis, acute liver failure with persistently elevated intracranial pressure ICP >50mmHg, hemangiosarcoma, hilar cholangiocarcinoma, sepsis, and active alcohol or drug abuse. Pretransplant measures such as cardiopulmonary evaluation, screening for occult cancer, infection, and psychosocial evaluation must be performed prior to surgery. The most commonly used technique employed in patients is orthotopic transplantation. This involves removal of the native liver and placement of the donor organ in the same anatomic location as the original liver. Immunosuppressive agents used after transplantation include cyclosporine, everolimus, mycophenolate, corticosteroids, azathioprine, and tacrolimus in different combinations. The most common causes of death in liver transplant patients are infection, malignancy, and rejection. It is necessary to monitor patients for signs of complications and treat them effectively.

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 many additional transplants until he was successful 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.
• 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
  • Alcoholic liver disease
  • Idiopathic or autoimmune liver disease
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Hepatitis B
  • Metabolic liver disease (e.g. inborn errors of metabolism)
  • Carcinoma
  • 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:
    • Cirrhosis is an indication only in the presence 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 pre transplantation evaluation (as a MELD score ≥15 is an indication for transplantation)
    • 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 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 for liver transplantation include:

• Metastasis outside the liver, past the curative stage
• Hepatocellular carcinoma with metastasis (Stage 1V)
• Acute Liver Failure with persistently elevated intracranial pressure ICP > 50 mmHg (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 for liver transplantation include:

• Infection with HIV (AIDS)
• Age > 65 years
• 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

Patient evaluation prior to transplantation

Pre-transplant patient evaluation has the following objectives:

• Assesment of ability of the patient to withstand surgery
• Assesment of ability of the patient to withstand immunosuppression
• Assessment of patients demands of post-transplantation care

Pre-transplant evaluation is particularly aggressive in patients prior to transplantation to minimize post operative morbidity and mortality due to effects of surgery and immunosuppressive therapy.The following evaluations are required:

• Cardiopulmonary
• Screening for occult cancer
• Screening for occult infection
• Psychosocial evaluation

Laboratory investigations

Laboratory investigations essential for patient evaluation prior to liver transplantation are as follows:

General investigations

• Liver function tests:
  • Bilirubin levels
  • ALT levels
  • AST levels
  • ALP levels
  • International normalized ratio [INR]
• ABO-Rh blood typing
• Calcium levels
• Vitamin D levels
• Complete blood count
• Creatinine clearance

Cause specific investigations

• Serum Na levels
• Serum alpha-fetoprotein
• Serology:
  • Hepatitis A, B and C
  • Human immunodeficiency virus
  • Cytomegalovirus
  • Epstein-Barr virus
  • Varicella
• Urinalysis
• Urine drug screen

Cardiopulmonary evaluation

Cardiopulmonary evaluation helps in the evaluation of the patient for pathologies that need to be ruled out prior to transplantation:

• Cardiac pathologies:
  • Coronary artery disease
  • Valvular heart disease
  • Cardiomyopathy
• Pulmonary pathologies:
  • Pulmonary hypertension
  • Hepatopulmonary syndrome
  • Restrictive lung disease
  • Obstructive lung disease

• The following tests are done for the cardiopulmonary evaluation of a patient:
  • Pulse oximetry
  • Screening for hepatopulmonary syndrome:
    • Indicates worse prognosis in cirrhotic patients and qualifies patients for standard Model for End-stage Liver Disease (MELD) exception points
      • Hepatopulmonary syndrome is characterized by the following:
        • Liver disease
        • Intrapulmonary vascular dilatations
        • Impaired oxygenation
  • Arterial blood gas (ABGs):
    • ABGs are performed in patients with normal pulse oximetry in order to calculate age-adjusted alveolar-arterial gradient
  • Chest imaging
  • Pulmonary function testing
  • Electrocardiogram:
    • Electrocardiogram helps detect the presence of the following conditions:
      • Cardiac arrhythmias
      • Conduction defects
  • Signs of the following:
    • Hypertrophy of the cardiac chamber
    • Prior cardiac ischemia
  • Cardiac stress testing:
    • Noninvasive cardiac testing is performed in the following cases:
      • Patients older than 40 years of age
      • Patients younger than forty years of age, with multiple risk factors for coronary artery disease
  • If abnormalities are noticed on cardiac stress testing, the patient undergoes cardiac catheterization
  • In case of presence of clinically significant coronary artery stenosis, revascularization before transplantation is considered
  • Echocardiography:
    • Transthoracic contrast-enhanced echocardiography:
      • Valvular heart disease
      • Suspected cases of hepatopulmonary syndrome:
        • If the oxygen saturation on pulse oximetry is low (<96 percent)
      • Portopulmonary hypertension:
        • Pulmonary arterial hypertension (PAH) associated with portal hypertension

Cancer screening

Prior to transplantation, screening for the following carcinomas is recommended:

• Hepatocellular carcinoma (HCC):
  • Investigations for the staging of HCC include:
    • Abdominal CT scan
    • MRI

• • Investigations for the assessment of invasion of vasculature:
    • Multiphase contrast-enhanced CT scanning
    • Contrast-enhanced MRI
    • Transabdominal ultrasonography with Doppler imaging
    • Contrast-enhanced ultrasonography

• Skin cancer:
  • Skin examination
  • Biopsy incase of suspected lesions
• Colon cancer:
  • Colonoscopy for screening of colon cancer is done in case of:
    • Age of 50 years
    • History of colon cancer in a first-degree relative
    • Patients with primary sclerosing cholangitis

• Screening is also done for the following:
  • Cervical cancer
  • Breast cancer
  • Prostate cancer

Upper GI endoscopy

• To detect varices

Bone densitometry

• Screening for osteoporosis
• Osteoporotic patients are treated with bisphosphonates before transplanatation

Vaccinations and evaluation for infection

• Viral serologies

• Workup for tuberculosis:
  • Skin testing
  • Interferon-gamma release assay

• Screening in endemic areas for:
  • Strongyloides
  • Coccidiomycosis

• Vaccinations recommended before liver transplantation include:
  • Pneumococcus
  • Tetanus
  • Pertussis
  • Diphtheria
  • Hepatitis A, B

Psychosocial evaluation and education

• Discussion of risks and benefits of transplantation
• Ensuring social support
• Substance use disorders eg alcohol must be treated prior to transplantation:
  • Rehabilitation
  • Abstinence program
• Education of the family
• Patient compliance with elaborate behavioral and medical regimens

Techniques

• Before transplantation, liver support therapy might be indicated ( called 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 may be conceptualized as consisting of:
  • Hepatectomy (liver removal) phase
  • Anhepatic (no liver) phase
  • Postimplantation phase
• The surgery is done through a large incision in the upper abdomen.
• The hepatectomy involves the division of:
  • All ligamentous attachments to the liver
  • Common bile duct
  • Hepatic artery
  • 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 is 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 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 the liver of a healthy person 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).

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Orthotopic Liver Transplantation

• Donor selection based on biomarkers and risk indices is a crucial aspect of orthotopic liver transplantation and involves:
  • Preference of younger over older donors
  • Appropriate selection of recipients
  • Age based matching of donors and recipients
• Surgery for liver transplantation 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 performed
  • Then, anastomosis of the bile ducts of the graft and recipient is performed
  • In addition, choledochojejunostomy may also be performed incase of bile duct pathology
  • 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 lifelong immunosuppresive therapy

Results

• The prognosis of liver transplantation is good:
  • 1-year survival is 83%
  • 5-year survival is 76%
  • 10-year survival is 66%
• Majority of deaths occur 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:
  • Remarkable regenerative capacities of the human liver
  • 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 diseased liver of the recipient has been entirely removed
• Historically, LDLT was used as a means for parents of children with severe liver disease to donate a portion of their healthy liver to replace the damaged liver of their children
• In 1986, the first successful LDLT was performed at the Universidade de São Paulo (USP) Medical School, by Dr. Silvano Raia.
• More technically demanding than standard, cadaveric donor liver transplantation
• Has faced several ethical problems

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
  • Transplant 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
      • Renal function tests (RFTs)
        • Blood urea nitrogen (BUN)
        • Creatinine levels
      • Drug levels in case of altered renal 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:

• Vigilance is required for detection of rejection due to subtle presentations
• Occurrence: roughly 20-70 percent patients
• Timing: 1-2 weeks post- transplantation, within first three months of transplantation
• Outcome: Graft dysfunction
• Clinical presentation:
  • Jaundice
  • Fever
  • Right-upper-quadrant tenderness
  • Generalized abdominal tenderness
  • Eosinophilia
• In case of mild rejection, symptoms may be nonspecific and include:
  • Low-grade fever
  • Fatigue
  • Malaise
  • Generalized weakness
• 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
  • Pruritus
• Laboratory investigations:
  • Elevated serum alkaline phosphatase
  • Elevated bilirubin levels
• Gold standard diagnostic modality: Liver biopsy

Infection

Infections may be classified based on the duration post transplantation.

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

• 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: May be non-specific
    • Fever (absent or low grade)
    • Abdominal pain
    • Jaundice
    • Masking of symptoms may occur due to immunosuppression
    • Minimal pain at infection site

• 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 non-immunosuppressed 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:
  • Fever
  • 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 in 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

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