Liver Transplants 

Updated: Dec 15, 2016
  • Author: Lemi Luu, MD, RDMS, FACEP, FAAEM; Chief Editor: Barry E Brenner, MD, PhD, FACEP  more...
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Practice Essentials

Liver transplantation has become accepted therapy for several causes of irreversible liver disease.

Indications

The most common indications for liver transplantation in the United States are hepatitis C virus (30%) and alcoholic liver disease (18%). Other indications include the following:

  • Idiopathic/autoimmune liver disease (12%)
  • Primary biliary cirrhosis (10%)
  • Primary sclerosing cholangitis (8%)
  • Acute liver failure (7%)
  • Hepatitis B virus (6%)
  • Metabolic liver disease (eg, inborn errors of metabolism) (3%)
  • Cancer (3%)
  • Other (3%)

Biliary atresia is a common indication for liver transplantation in pediatric patients.

Postimplant immunosuppression

Immunosuppressant agents used in patients receiving a liver transplant include the following:

  • Cyclosporine
  • Tacrolimus
  • Sirolimus
  • Azathioprine
  • Everolimus
  • Mycophenolate
  • Corticosteroids

At the time of transplant, induction is achieved with high-dose corticosteroids and antithymocyte globulin or monoclonal antibody, followed by the addition of azathioprine and cyclosporine. [1] Survival of the allograft and the patient is made possible by immunosuppression following transplantation.

Standard therapy to control graft rejection generally involves a combination of corticosteroids, a calcineurin inhibitor (cyclosporine or tacrolimus), and an antiproliferative agent. However, standard regimens often change during the course of a liver transplant recipient's life.

Long-term immunosuppression is usually maintained with cyclosporine, azathioprine, and prednisone. Tacrolimus appears to be superior to cyclosporine in liver transplantation and is used in many centers.

Complications following transplantation

The most common problems in the liver transplant recipient are the following:

  • Acute graft rejection
  • Vascular thrombosis
  • Biliary leak or stricture
  • Infection [2]
  • Malignancy
  • Adverse effects of immunosuppressant drugs [3]

Laboratory studies

In all but minor complaints, the following laboratory tests are indicated to assess for evidence of rejection, effects of azathioprine on bone marrow function, and effects of cyclosporine or tacrolimus on renal function:

  • Complete blood count
  • Electrolyte panel
  • Blood urea nitrogen and creatinine levels
  • Liver function panel
  • Cyclosporine or tacrolimus level: Obtain in the presence of renal dysfunction or if rejection is suspected
  • Cultures of blood, urine, pharynx, and/or sputum: Obtain if infection is suspected

Imaging studies

  • Chest radiography: Obtain in the presence of fever, cough, dyspnea, or abnormalities on chest examination
  • Abdominal ultrasonography, computed tomography scan, or endoscopic retrograde cholangiopancreatography, as indicated

Management of rejection or infection

Every clinical complaint by the transplant patient should be taken seriously, and the transplant team should at least know of every emergency department visit made by the transplant patient. Contact a transplant gastroenterologist or the liver transplant service for admission or prior to discharge.

Evaluate for evidence of infection or rejection in patients who present with compatible symptoms. Other considerations include the following:

  • Admission for fever of unknown origin or suspicion of rejection
  • Obtaining cultures and administering antibiotics if bacterial infection is suspected, based on likely bacterial pathogens
  • Administration of early stress-dose steroid administration and intravenous antibiotics in consultation with the transplant medicine service for stress of infection or other intercurrent illness
  • Review for drug interactions between commonly prescribed drugs and immunosuppressants before prescribing such medications
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Orthotopic Liver Transplantation

Application and success of orthotopic liver transplantation (OLT) has continued to grow, and liver transplantation has become accepted therapy for several causes of irreversible liver disease. As of December 2016, 147,128 liver transplants had been reported to the United Organ Sharing (UNOS) network since it created a national database in 1988; in 2015, 7127 liver transplants were performed. [4] As of mid-December 2016, 14,538 patients remained on the waiting list for liver transplantation. [5]

With the increased number of transplants, chances are greater that a transplant patient will present with posttransplant problems. Basic knowledge of medical care involved in treatment of the transplant patient will assist in evaluation. [6, 7, 8]

The most common indications for liver transplantation in the United States are as follows:

  • Hepatitis C virus (30%)
  • Alcoholic liver disease (18%)

Less common indications include the following:

  • Idiopathic/autoimmune liver disease (12%)
  • Primary biliary cirrhosis (10%)
  • Primary sclerosing cholangitis (8%)
  • Acute liver failure (7%)
  • Hepatitis B virus (6%)
  • Metabolic liver disease (eg, inborn errors of metabolism) (3%)
  • Cancer (3%)
  • Others (3%)

Biliary atresia is a common indication in pediatric patients.

Chances of survival following OLT are good, with a 5-year survival rate of 72%. The most common causes of death in liver transplant patients (beyond the early in-hospital transplant period) are infection, rejection, and malignancy.

For patient education information, see the Digestive Disorders Center and Infections Center, as well as Cirrhosis.

Transplantation considerations

OLT involves excision of the recipient's liver and division of the inferior vena cava, superior vena cava, portal vein, hepatic artery, and common bile duct. Because of the disruption of portal and inferior vena caval blood flow, venovenous bypass is necessary to divert blood from these vessels to the superior vena cava during the anhepatic phase of the procedure.

The donor liver is anastomosed at the vascular sites, with care taken to preserve hepatic arterial blood flow. The bile duct is usually anastomosed to the recipient's, but choledochojejunostomy may be performed. A T-tube is used to stent the biliary duct postoperatively for several weeks, allowing monitoring of bile production as one marker of postoperative hepatic graft function.

A number of complications are possible in the immediate postoperative period, [9] including acute rejection and early graft failure, as well as vascular and biliary complications. However, these early complications usually are identified during the posttransplant hospital stay.

Donor selection is important. In a literature review, Sutherland found that overall outcomes of liver transplantation from older deceased donors were good but not as good as those of transplantation from younger donors. [10] This review provided evidence that careful donor selection based on risk indices (and potentially biomarkers), special schemes to match elderly donors with elderly recipients, and robust recipient selection enable good outcomes as the age of donors and recipients increases.

For additional information on liver transplantation, see Acute Liver Failure.

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Immunosuppressive Agents

Survival of both allograft and patient is made possible through immunosuppression following transplantation. Graft rejection is controlled through an immunosuppressant regimen. Standard therapy generally involves a combination of corticosteroids, a calcineurin inhibitor (cyclosporine or tacrolimus), and an antiproliferative agent. At the time of transplant, induction is achieved with high-dose corticosteroids and antithymocyte globulin or monoclonal antibody, followed by the addition of azathioprine and cyclosporine. Newer agents sometimes used in induction include tacrolimus (which, like cyclosporine, inhibits T-cell proliferation) and mycophenolate (a less selective inhibitor similar to azathioprine). [11]

Long-term immunosuppression usually is maintained with cyclosporine, azathioprine, and prednisone. Tacrolimus appears to be superior to cyclosporine in liver transplantation and is being used in many centers. Standard regimens often change during the course of a liver transplant recipient's life.

Studies have shown that dual therapy with steroids and a calcineurin inhibitor are just as efficacious as triple therapy while decreasing serious side effects such as bone marrow suppression. In addition, steroid withdrawal has been shown to be relatively safe in liver transplant recipients, and this has been done in some centers. If steroids are successfully tapered within the first few months of the transplant, there will likely be only minimal increased episodes of acute rejection without any increase in graft loss. Consequently, patients may be weaned down to monotherapy with a calcineurin inhibitor from a previous triple-therapy regimen.

Cyclosporine

Cyclosporine (cyclosporine A) is a cyclic polypeptide immunosuppressant derived from the fungus Beauvaria nivea. Cyclosporine achieves its effects through reversible inhibition of immunocompetent lymphocytes in the G0 and G1 phases of cell division. T-helper cells are the primary targets of the drug, although T-suppressor cells may be affected. Cyclosporine also works by inhibiting calcineurin and thereby impairing interleukin 2 (IL-2) transduction. Since IL-2 is crucial to the recruitment and activation of T-helper cells and is one of the major determinants of the magnitude of the immune response to a donor allograft, blocking its production profoundly influences the rejection process.

Elimination is primarily biliary, with some excretion into the urine. Cyclosporine is dosed according to blood levels and renal function. The dose is highly individualized because of variable absorption, elimination, and effect on renal function. The drug is initiated at 1-2 mg/kg/day in two divided doses and advanced as tolerated, but the maintenance dosage ranges widely, from 1-10 mg/kg/day.

Such target dosing levels are developed by various centers primarily on the basis of experience, given that no clear correlation has been seen between level and immunosuppressive activity. Generally, the 2-hour postdose level is measured and is believed to reflect immunosuppression  better than the trough level does.

Cyclosporine toxicity

The principal toxic effect of cyclosporine is nephrotoxicity due to intrarenal vasoconstriction. Nephrotoxicity from cyclosporine occurs in 40-70% of patients and is manifested acutely by elevations in blood urea nitrogen (BUN) and creatinine levels. Whereas acute nephrotoxicity is usually reversible with reductions in dosage, chronic nephrotoxicity is not. This irreversible form is associated with histologic changes in the kidney that may ultimately necessitate renal support through dialysis or retransplantation. Other toxic effects include hyperkalemia, hypertension, venous thrombosis, tremor, headache, paresthesia, gout, gingival hyperplasia, and hepatotoxicity.

Tacrolimus

Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis. It has immunosuppressant activity similar to that of cyclosporine. Tacrolimus also inhibits calcineurin, which, in turn, results in decreased IL-2 production. Once again, T-cell recruitment and activation is dampened. The drug may produce this effect by binding to intracellular FK 506 proteins and is as much as 100 times more potent than cyclosporine in inhibiting IL-2 synthesis.

Tacrolimus, like cyclosporine, also suppresses humoral immunity through inhibition of B-cell activation by blocking IL-2 production. It is metabolized in the liver via the cytochrome P-450 system. Tacrolimus is approved for use in liver, renal, heart, bone marrow, and other transplantations, and the usual oral dosage in liver transplant recipients is 0.1-0.15 mg/kg/day. Dosing is also based on measuring blood levels, and target levels vary among institutions.

Tacrolimus toxicity

Toxicity is slightly different from that of cyclosporine. Although it has the same degree of nephrotoxicity as cyclosporine, studies have shown a lower incidence of hypertension and hyperlipidemia. However, a higher rate of diabetes and neurotoxicity has been seen.

In general, tacrolimus and cyclosporine are fairly similar in terms of graft and patient survival. However, rates of graft rejection are lower and the need for steroids is less when tacrolimus is used.

When used as part of telaprevir-based triple-drug therapy for posttransplantation HCV recurrence, daily low-dose tacrolimus appears to be a safe and effective immunosuppressive regimen. [12]

Sirolimus

Sirolimus is structurally related to tacrolimus, forming a complex with FK506 binding protein. However, it does not inhibit calcineurin as cyclosporine and tacrolimus do. The mechanism is not clear, but it appears to work by inhibiting IL-2 transduction and inducing the cell to arrest at the G1 to S phase of the cell cycle. Interestingly, sirolimus appears to have antitumorigenic effects through inhibition of angiogenesis. Studies are currently under way investigating this property.

It generally takes 3-5 days for serum levels of sirolimus to equilibrate, and often the sample must be sent out to specialized laboratories that are equipped to perform such studies.

Sirolimus toxicity

The main adverse effects include bone marrow suppression (thrombocytopenia, anemia, leukopenia), hyperlipidemia, peripheral edema, and poor wound healing. Sirolimus alone does not appear to cause significant nephrotoxicity.

Azathioprine

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. The drug inhibits nucleic acid synthesis, suppressing cell-mediated hypersensitivity and altering antibody production. This results in inhibition of T-cell activation, reduction of antibody production, and a decrease in the number of circulating monocytes and granulocytes. It is effective in preventing rejection but does not have a large effect on an immune response already activated.

Azathioprine is metabolized in the liver and erythrocytes. Renal function has minor effects on levels. The drug causes a dose-dependent decrease in leukocyte and platelet counts via bone marrow suppression. It is typically dosed according to white blood cell (WBC) and platelet counts, with an initial dosage of 3-5 mg/kg/day. The maintenance dosage usually is lower, at 1-3 mg/kg/day.

Azathioprine toxicity

Development of severe renal dysfunction warrants closer monitoring with possible reduction in dosage. However, monitoring of blood levels is generally not required. The major toxic effects are neutropenia and thrombocytopenia. Less common adverse effects include nausea, vomiting, pancreatitis, hepatotoxicity, and development of cancer.

Everolimus

Everolimus is an mTOR kinase inhibitor that inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. It is indicated for prophylaxis of allograft rejection in adult liver transplant recipients in combination with reduced doses of tacrolimus and with corticosteroids. The use of mTOR inhibitors provides a calcineurin inhibitor-sparing regimen to avoid impaired renal function associated with tacrolimus or cyclosporine.

Everolimus toxicity

Use of everolimus for liver transplant rejection is not initiated until at least 30 days post liver transplant. Hepatic artery thrombosis has been reported with mTOR inhibitors when they are used within the first 30 days post transplantation.

Mycophenolate

Mycophenolate or mycophenolate with its morpholino ester (MMF) is an antibiotic isolated from Penicillium species that has immunosuppressant properties. Its mechanism of action is similar to that of azathioprine, but it does not cause as much bone marrow suppression. It works by selectively inhibiting purine synthesis, and thus, it is a potent inhibitor of B-cell and T-cell proliferation.

At present, mycophenolate's major role is in treating acute rejection; however, the drug is finding an increasing role in maintenance immunosuppression. It is currently approved in renal transplantation but is increasingly being used in liver and heart transplantation. Mycophenolate is metabolized in the liver to its active form (ie, mycophenolic acid), is subsequently gluconurated in the liver to an inactive form, and is then excreted renally. The oral dosage is 2-4 g/day, with reductions in the face of renal failure. Monitoring of blood levels is generally not required.

Mycophenolate toxicity

The major toxic effect is neutropenia, but this appears to be less pronounced than with azathioprine. Other less common adverse effects include gastrointestinal symptoms.

Corticosteroids

Nearly all patients receive corticosteroids following transplantation. Corticosteroids are nonspecific anti-inflammatory agents working primarily to inhibit cytokine gene transcription. By doing so, steroids prevent the recruitment and activation of T cells. Typically initiated as methylprednisolone, the drug is switched to oral prednisone (~1 mg/kg) once oral intake is adequate and then is tapered. Acute rejection episodes are treated with higher doses followed by retapering.

Corticosteroids adverse effects

The use of steroids is associated with many adverse effects, including hypertension, cushingoid appearance, personality changes, weight gain, dyslipidemia, osteoporosis, hyperglycemia, diabetes, cataracts, and increased risk of infection.

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Posttransplant Problems

The most common problems in the liver transplant recipient are the following:

  • Acute graft rejection
  • Vascular thrombosis
  • Biliary leak or stricture
  • Infection

These patients are also at increased risk for developing malignancy, which must be considered in the evaluation process. Adverse effects of immunosuppressive drugs also may complicate the patient's presentation. [3]

Acute and chronic graft rejection

Acute rejection occurs in 20-70% of cases, most often at 7-14 days post transplant, and results in graft dysfunction. Acute rejection is represented clinically as jaundice with laboratory evidence of abnormal liver function tests. Bilirubin and alkaline phosphatase levels rise initially, followed by elevations in the hepatocellular enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Other symptoms may include fever, liver tenderness, and eosinophilia.

Acute rejection is most commonly treated with high-dose steroids (prednisolone 200 mg or methylprednisolone 1 g for 3 days) or a high-dose steroid bolus followed by a rapid taper over 5-7 days. These treatment regimens are effective in 65-80% of transplant recipients. Alternative therapies include antibody treatments such as monoclonal therapy with OKT3 or rabbit antithymocyte globulin.

Chronic graft rejection, manifested by gradual obliteration of small bile ducts and microvascular changes, occurs in about 5% of patients. Diagnosis is made by means of liver biopsy. Chronic graft rejection is the major cause of late graft failure. The primary finding is persistently elevated serum alkaline phosphatase and bilirubin levels, suggesting a cholestatic liver injury pattern. This may manifest as jaundice and/or pruritus. Loss of liver synthetic function may not be evident until very late in the course.

Infection

Infection in the early posttransplant period (<1 month) is most commonly bacterial, though the risk of fungal infection is high. This is the period when patients are most immunosuppressed. Infections are primarily nosocomial and are caused by the same organism seen in other surgical patients, such as enterococci, staphylococci, gram-negative aerobes, anaerobes, or candidal species (75% of fungal infections). They are frequently intra-abdominal (cholangitis, liver, and other abdominal abscesses) and are typically observed during the posttransplant hospitalization.

Infected transplant patients may present with fever, abdominal pain, or jaundice, or they may possibly be asymptomatic because of immunosuppression. A complete fever/sepsis workup that includes a complete blood count (CBC), chemistries, liver function tests, coagulation panel, urinalysis, urine culture, blood culture, and abdominal and chest radiographs should be obtained. Further studies may include computed tomography (CT), abdominal ultrasonography, T-tube cholangiography, endoscopic retrogrande cholangiopancreatography (ERCP), and liver biopsy.

During months 1-6, the most common infections are due to viruses or opportunistic organisms. After the first 6 months, risk of infection is similar to that of the general population. However, a high index of suspicion should always be maintained in transplant recipients.

The most common causes of infection in the outpatient setting are the typical community-acquired pathogens, which are treated with the antimicrobials typically prescribed for nonimmunosuppressed patients (with caution regarding drug interactions). Incidence declines after 6-12 months if the recipient is on a stable immunosuppressant regimen.

Cytomegalovirus (CMV) is the most common viral infection, occurring most commonly between posttransplant months 1 and 3. CMV is a herpes virus and infects between 25 and 85% of all liver transplant patients. CMV infection is rarely fatal unless disseminated and has little effect on the graft itself. The viral infection may be primary or reactivated.

Patients with CMV infection often present with fevers, malaise, arthralgias, atypical lymphocytes, thrombocytopenia, and mildly elevated transaminase levels. CMV pneumonitis often results in radiographic findings of bilateral infiltrates. Diagnosis is made serologically using an indirect immunofluorescence testing method. Treatment is effective when a diagnosis is made early, and ganciclovir is administered intravenously for 2-4 weeks.

Pneumocystis carinii pneumonia (PCP) may present with CMV infection or alone. Diagnosis sometimes requires a bronchoalveolar biopsy. Transplant recipients may be placed on long-term pneumocystic suppression therapy with trimethoprim-sulfamethoxazole. However, this infection is typically a problem when immunosuppression is more severe, such as during treatment of rejection.

When recipients are on increased immunosuppression therapy for additional induction or combating rejection, other less-common opportunistic pathogens may be involved. These include fungi (especially Candida species), herpes simplex, herpes zoster, P carinii, and Toxoplasma. Graft reinfection with hepatitis C virus (HCV) is very common, occurring in 50-80% of patients. Many of these patients will require treatment for HCV to avoid progression to cirrhosis. However, recurrent hepatitis B infection is less common (occurring in only 10% of patients) due to the prophylactic hepatitis B immunoglobulin and antiviral medications.

Malignancy

One of the adverse effects of immunosuppressants is the increased risk of malignancy, which is the second leading cause of late death in liver transplant recipients. Patients are at increased risk of developing lymphomas, squamous cell carcinoma, and posttransplant lymphoproliferative disorder. Squamous cell carcinoma of the skin is the more common posttransplant malignancy. However, no increased risk exists of developing colon, prostate, breast, or lung cancer.

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Evaluation for Rejection and Infection

Symptoms and signs

Rejection

Liver transplant recipients may present for any complaint observed in the general population. Vigilance must be maintained to detect rejection and infection, because these conditions may have subtle presentations. Acute rejection is most commonly detected clinically by the presence of jaundice. Right-upper-quadrant tenderness or generalized abdominal tenderness may be present. [3]

Acute cell-mediated rejection is not uncommon in the first 3 months following transplant and decreases in frequency with time. Symptoms of mild rejection are nonspecific and may include the following:

  • Low-grade fever
  • Fatigue
  • Malaise
  • Generalized weakness
  • Jaundice

Right-upper-quadrant pain also may be present. The rejection process may be subclinical, with laboratory abnormalities as the only sign of its presence.

Infection

Fever is most commonly caused by infection but also may be due to rejection or drugs. Signs of infection are related to the type and location of infection.

Because of immunosuppression, liver transplant recipients do not often show classic signs and symptoms of infection. They have a wider variety of common and opportunistic infections, many of which are typically more challenging to diagnose and treat. [13] Symptoms associated with infection may be masked because of the immunosuppressant regimen; therefore, a high index of suspicion is required during evaluation of the patient.

Fever may be low-grade or absent, and leukocytosis may not be present. Pain at sites of infection may be minimal because of the patient's decreased ability to mount an inflammatory response. Infection may progress more rapidly than in the nonimmunocompromised patient and may be more difficult to eradicate. [14] Adrenal insufficiency must also be considered in these patients due to their chronic steroid use, and stress-dose steroids such as hydrocortisone may be needed. [3]

Workup

Laboratory studies

Laboratory studies are indicated on the basis of the presenting complaint. In all but minor complaints, complete blood count, electrolyte panel, blood urea nitrogen, creatinine, and liver function panel are ordered to assess for evidence of rejection, effects of azathioprine on bone marrow function, and effects of cyclosporine or tacrolimus on renal function. Obtain a cyclosporine or tacrolimus level if renal dysfunction is identified or if rejection is suspected. If infection is suspected, obtain cultures of blood, urine, pharynx, and/or sputum.

Imaging studies

Radiographs are obtained for routine indications. Fever, cough, dyspnea, or abnormalities on chest examination should prompt a chest radiograph since pneumonia can present with only mild symptoms. Other studies such as abdominal ultrasonography, CT scan, or endoscopic retrograde cholangiopancreatography may need to be performed, and consultation with a transplant surgeon or gastroenterologist is recommended.

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Treatment of Rejection or Infection

The clinician must remember that most liver transplant patients are very immunosuppressed and typically come to medical attention as a last resort. Every complaint should be taken seriously, and the transplant team should at least know of every emergency department (ED) visit made by the transplant patient. Patients who may be infected require admission because they will need a decrease in their immunosuppressants and are at risk for rejection. [15, 16]

A major goal of care is to evaluate for evidence of infection or rejection in patients who present with compatible symptoms. Fever of unknown origin or suspicion of rejection should lead to consideration for admission for further evaluation. If bacterial infection is suspected, obtain cultures and initiate antibiotics based on likely bacterial pathogens, as in the nonimmunocompromised patient. Broad-spectrum antibiotics are used if the source is unknown.

Because these patients are on long-term corticosteroids, stress of infection or other intercurrent illness should lead to consideration of early stress-dose steroid administration and intravenous antibiotics in consultation with the transplant medicine service. Be aware that a large number of commonly prescribed drugs can affect the blood levels of immunosuppressants and should be prescribed only after reviewing prescribing information for drug interactions.

Consultations

Contact a transplant gastroenterologist or the liver transplant service for admission or prior to discharge. Graft failure mandates admission, as does a febrile illness without an obvious source. Inability to take immunosuppressants orally due to gastrointestinal disturbances necessitates admission for intravenous drug administration.

Arrange for early admission for any infection other than minor infections. If rejection is suspected, the transplant physician needs to be involved early in the course for evaluation and management.

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