AUTHOR AND EDITOR INFORMATION

Section 1 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

INTRODUCTION

Section 2 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

Background

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 2005, 76,575 liver transplants had been reported to the United Organ Sharing network since it created a national database in 1988. In 2005, 6,444 liver transplants were performed and 17,645 patients were on the waiting list for transplantation. With the increased number of transplants, chances are greater that a transplant patient will present to the ED. Basic knowledge of medical care involved in treatment of the transplant patient will assist ED physicians in evaluation.

The most common indications for liver transplantation in the United States are hepatitis C virus (30%) and alcoholic liver disease (18%). Others include 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%), and others (3%). Biliary atresia is a common indication in pediatric patients. Chances of survival following orthotopic liver transplantation 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 excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article, Cirrhosis.

Transplantation considerations

Orthotopic liver transplantation 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, 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 and are not observed by the emergency physician. Complications likely to be observed in the ED are discussed later in this article.

IMMUNOSUPPRESSION

Section 3 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

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).

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. Current 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 off 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. As such, patients may be weaned down to monotherapy with a calcineurin inhibitor from a previous triple therapy regimen.

The ED physician who may encounter transplant patients should be familiar with these agents. An overview of the common immunosuppressant drugs follows.

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/d in 2 divided doses and advanced as tolerated, but maintenance dose ranges widely from 1-10 mg/kg/d. Such target dose levels are developed by various centers primarily based on experience since no clear correlation has been seen between level and immunosuppressive activity. Generally, the 2-hour postdose level is measured and believed to better reflect immunosuppression than the trough level.

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

Tacrolimus

Known during development as FK 506, 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-lymphocyte 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 dose in liver transplant recipients is 0.1-0.15 mg/kg/d. Dosing is also based on measuring blood levels, and target levels vary between institutions. Toxicity is slightly different from that of cyclosporine. Although it has the same degree of nephrotoxicity, 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.

Sirolimus

Sirolimus is structurally related to tacrolimus, forming a complex with FK506 binding protein. However, it does not inhibit calcineurin as cyclosporin 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 underway investigating this property.

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

The main side 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. Typically dosed according to WBC and platelet counts, the initial dose is 3-5 mg/kg/d. The maintenance dose usually is lower, at 1-3 mg/kg/d. 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 effects include nausea, vomiting, pancreatitis, hepatotoxicity, and development of cancer.

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 is a potent inhibitor of B-cell and T-cell proliferation.

Mycophenolate's major role at present is in treating acute rejection; however, the drug is finding an increasing role in maintenance immunosuppression. While currently approved in renal transplantation, mycophenolate is being used in liver and heart transplantation with increasing frequency. 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 dose is 2-4 g/d, with reductions in the face of renal failure. Monitoring of blood levels is generally not required.

The major toxic effect is neutropenia, but this appears to be less pronounced than with azathioprine. Other less common 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 (about 1 mg/kg) once oral intake is adequate and then is tapered. Acute rejection episodes are treated with higher doses followed by retapering.

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

POSTTRANSPLANT PROBLEMS

Section 4 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

The most common problems in the liver transplant recipient, which may be observed in the ED, are acute graft rejection, vascular thrombosis, biliary leak or stricture, and infection. These patients are also at increased risk of developing malignancy, which needs to be considered in the evaluation process. Adverse effects of immunosuppressant drugs also may complicate the patient's presentation.

Acute and chronic graft rejection

Acute rejection occurs in 20-70% of cases, most often at 7-14 days posttransplant, 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 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 d) or 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 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 mo) is most commonly bacterial, although the risk of fungal infection is high. This is the period when patients are most immunosuppressed. Infections are primarily nosocomial and are those seen in other surgical patients such as enterococci, staphylococcus, 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 transplanted patients may present with fever, abdominal pain, jaundice, or possibly asymptomatic due to immunosuppression. A complete fever/septic workup that includes a CBC, chemistries, liver function tests, coagulation panel, urinalysis, urine culture, blood culture, and abdominal and chest radiographs should be obtained. Further studies may include CT scan, abdominal ultrasonography, T-tube cholangiogram, ERCP, and liver biopsy.

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

The most common causes of infection in the outpatient setting are the typical community-acquired pathogens, which are treated with 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 the first and third posttransplant months. 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 often present with fevers, malaise, arthralgias, atypical lymphocytes, thrombocytopenia, and mildly elevated transaminases 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.

Presenting symptoms

Liver transplant recipients may present to the ED 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 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 low-grade fever, fatigue, malaise, generalized weakness, and/or 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.

Fever is most commonly caused by infection but also may be due to rejection or drugs. 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.

Physical findings

Acute rejection is most commonly detected clinically by the presence of jaundice. Right upper quadrant tenderness or generalized abdominal tenderness may be present. Signs of infection are related to the type and location of infection. 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.

EMERGENCY DEPARTMENT EVALUATION

Section 5 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

Laboratory studies

Laboratory studies are indicated on the basis of the presenting complaint. In all but minor complaints, CBC, electrolyte panel, BUN, 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 ERCP may need to be performed, and consultation with a transplant surgeon or gastroenterologist is recommended.

TREATMENT

Section 6 of 7  

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

Emergency department care

The ED 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 ED visit made by the transplant patient and should see most of them. Patients who may be infected require admission because they will need a decrease in their immunosuppressants and are at risk for rejection.

A major goal of ED 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.

Since 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 requires admission, as does a febrile illness without an obvious source. Inability to take immunosuppressants orally due to GI disturbances requires admission for intravenous drug administration.

Further inpatient care

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.

REFERENCES

Section 7 of 7

• Authors and Editors
• Introduction
• Immunosuppression
• Posttransplant Problems
• Emergency Department Evaluation
• Treatment
• References

• Friend PJ. Liver transplantation. Transplant Proc. Sep 1997;29(6):2716-8. [Medline].
• Levitsky J, Cohen SM. The liver transplant recipient: what you need to know for long-term care. J Fam Pract. Feb 2006;55(2):136-44. [Medline].
• McCaughan GW, Koorey DJ. Liver transplantation. Aust N Z J Med. Aug 1997;27(4):371-8. [Medline].
• Middleton PF, Duffield M, Lynch SV. Living donor liver transplantation--adult donor outcomes: a systematic review. Liver Transpl. Jan 2006;12(1):24-30. [Medline].
• Munoz SJ. Long-term management of the liver transplant recipient. Med Clin North Am. Sep 1996;80(5):1103-20. [Medline].
• Organ Procurement and Transplantation Network. Waiting list candidates: Liver. Transplants: Liver. Organ Procurement and Transplantation Network [Web site]. Accessed June 14, 2006. [Full Text].
• Perry I, Neuberger J. Immunosuppression: towards a logical approach in liver transplantation. Clin Exp Immunol. Jan 2005;139(1):2-10. [Medline].
• Savitsky EA, Uner AB, Votey SR. Evaluation of orthotopic liver transplant recipients presenting to the emergency department. Ann Emerg Med. Apr 1998;31(4):507-17. [Medline].
• Tintinalli, JE. Liver transplantation. In: Emergency Medicine: A Comprehensive Study Guide. 5th ed. 2004:587-588.

Article Last Updated: Jun 30, 2006