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

Patient evaluation prior to transplantation

Pretransplant patient evaluation has the following objectives: Assesment of ability of the patient to withstand surgery Assesment of ability of the patient to withstand immunosuppression Assesment of demands of post-transplantation care The following evaluations are required: Cardiopulmonary Screening for occult infection Screening for occult cancer Psychosocial evaluation

Laboratory testing — Laboratory essential for patient evaluation prior to liver transplantation are as follows: ●ABO-Rh blood typing ●Liver function tests: alanine aminotransferase aspartate aminotransferase alkaline phosphatase bilirubin international normalized ratio [INR]). ●Complete blood count with differential. ●Creatinine clearance. ●Serum sodium. ●Serum alpha-fetoprotein. ●Calcium and vitamin D levels. ●Serologies for: cytomegalovirus, Epstein-Barr virus, varicella, human immunodeficiency virus, hepatitis A, hepatitis B, hepatitis C, rapid plasma reagin. ●Urinalysis. ●Urine drug screen. Cardiopulmonary evaluation — The cardiopulmonary evaluation is designed to evaluate for: significant coronary artery disease, valvular heart disease, cardiomyopathy obstructive or restrictive lung disease hepatopulmonary syndrome, and pulmonary hypertension noninvasive cardiac testing for all patients over 40 years of age and for those younger than forty if there are multiple risk factors for coronary artery disease. pulse oximetry arterial blood gas pulmonary function testing chest imaging Electrocardiogram — We obtain an electrocardiogram to look for signs of cardiac arrhythmias, conduction defects, signs of prior cardiac ischemia, or chamber enlargement/hypertrophy. Cardiac stress testing — To screen for coronary artery disease, we obtain noninvasive cardiac testing for all patients over 40 years of age and for those younger than 40 years if there are multiple risk factors for coronary artery disease. However, the ideal evaluation of coronary artery disease prior to liver transplantation is unclear: submaximal cardiopulmonary exercise testing. If initial noninvasive testing is abnormal, cardiac catheterization is indicated. If clinically significant coronary artery stenoses are present, patients should be evaluated for revascularization prior to transplantation Echocardiography — We obtain transthoracic contrast-enhanced echocardiography to look for evidence of valvular heart disease or portopulmonary hypertension. Contrast-enhanced echocardiography is also part of the evaluation of patients with suspected hepatopulmonary syndrome. Portopulmonary hypertension refers to pulmonary arterial hypertension that is associated with portal hypertension. Symptoms and signs of pulmonary hypertension (PH) may be difficult to recognize because they are nonspecific. Initially, patients present with fatigue, exertional dyspnea and a loud pulmonic component of the second heart sound. If the echocardiography suggests PH, additional testing is required to confirm the diagnosis and to rule out other causes of PH. Pulse oximetry — Patients should undergo pulse oximetry to screen for hepatopulmonary syndrome. Hepatopulmonary syndrome is considered present when the following triad exists: ●Liver disease ●Impaired oxygenation ●Intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations The presence of hepatopulmonary syndrome worsens the prognosis of patients with cirrhosis. As a result, patients with hepatopulmonary syndrome receive standard Model for End-stage Liver Disease (MELD) exception points. If the oxygen saturation on pulse oximetry is low (<96 percent [38]), patients should have a blood gas obtained while breathing room air and undergo transthoracic contrast-enhanced echocardiography. Testing should also be obtained to rule out alternative causes for a low oxygen saturation. Testing to rule out other causes includes a chest radiograph, pulmonary function tests, and chest computed tomography (CT). We also perform an arterial blood gas in patients with normal pulse oximetry to calculate their age-adjusted alveolar-arterial gradient. Additional testing for pulmonary disease — We obtain pulmonary function testing with diffusing capacity of the lungs for carbon monoxide to look for evidence of restrictive or obstructive lung disease in patients who are able to undergo testing. We also obtain a chest radiograph and chest CT scan to look for signs of pulmonary disease. Cancer screening — Cancer screening should include abdominal CT scanning or magnetic resonance imaging (MRI) to look for hepatocellular carcinoma (HCC) and a skin examination to look for evidence of skin cancer. Patients over the age of 50 years (younger if there is a history of colon cancer in a first-degree relative) or who have primary sclerosing cholangitis should undergo colonoscopy. Screening for cervical cancer, breast cancer, and prostate cancer should be obtained when indicated based on the patient's sex and age. Infectious disease evaluation and vaccinations — In addition to obtaining serologies for several viral infections, the infectious disease evaluation should include skin testing or interferon-gamma release assay for tuberculosis. If positive, treatment may be initiated prior to transplantation or deferred until after transplantation, depending on the clinical assessment of the patient (eg, treatment should be initiated prior to transplantation if the patient has any signs or symptoms of tuberculosis). Similarly, any required dental extractions should be carried out prior to transplantation. Patients from endemic areas should be screened for coccidiomycosis or strongyloides Several vaccinations are recommended prior to liver transplantation including hepatitis A, hepatitis B, pneumococcus, influenza, diphtheria, pertussis, and tetanus. Immunizations in solid organ transplantation candidates are discussed in detail elsewhere. Hepatic imaging and HCC staging — Hepatic imaging should be obtained to assess the vasculature (to ensure there are no anatomic barriers to transplantation) and, in the case of HCC, for tumor staging. This is typically done with multiphase contrast-enhanced CT scanning or contrast-enhanced MRI. If cross-sectional imaging cannot be obtained, the hepatic vasculature can be assessed with transabdominal ultrasonography with Doppler imaging or contrast-enhanced ultrasonography (where available).

Upper endoscopy — Upper endoscopy should be performed in patients with cirrhosis or portal hypertension to evaluate for varices

Bone density testing — Patients should be screened for osteoporosis with bone density testing. If osteoporosis is present, treatment should be initiated prior to transplantation. Oral bisphosphonates should be used with caution in patients with esophageal varices, and patients should be aware of the importance of taking the drugs as instructed (eg, sitting upright for at least 30 minutes after taking the drug). Patients who are osteopenic should receive calcium and vitamin D supplementation.

Psychosocial evaluation and education — In addition to a standard medical evaluation, initial assessment should include an educational session discussing the risks and benefits of transplantation, including the potential for poor outcomes. A psychological evaluation and assessment of the patient's social supports is another key part of the evaluation. The purpose of this assessment is to identify issues that may impair a successful outcome after transplantation. These potential problems include a lack of insight into the nature of the transplantation procedure, post-transplantation care, and substance use disorders. The assessment includes education of the family and/or the patient's support network. The ability to comply with complex medical and behavioral regimens is crucial after any organ transplantation procedure. Recipients must be able to incorporate complicated medication regimens, follow-up appointments, and frequent laboratory visits into their lives. Making spouses, friends, and family aware of these requirements encourages patient compliance and may improve long-term success In patients with a history of a substance use disorder (drugs or alcohol), treatment should be provided prior to transplantation in an effort to increase the likelihood of success after transplantation. The treatment requirements vary among different transplantation centers but often include participation in a structured rehabilitation and abstinence program, adequate social support to help maintain sobriety, and a minimum period of sobriety prior to listing for transplantation (eg, six months).

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 operation is done through a large incision in the upper abdomen.
• The hepatectomy involves 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 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 is 83%
  • 5-year survival is 76%
  • 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:
  • 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 recipient’s diseased liver 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
  • 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:

• 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

• <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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