Introduction

Liver transplantation is the surgical replacement of a diseased liver by all or part of a donated liver. Generally, the donated liver comes from a person who has suffered brain death or severe brain injury, but healthy people can also sometimes donate a part of their livers for transplantation. Liver transplantation is used to treat persons at high risk of dying from liver diseases, most of whom have cirrhosis or cancer of the liver. Such patients undergo a pre-transplant evaluation to decide whether they should be placed on a "wait-list" for transplantation. Approximately 7,000 liver transplants are performed in the U.S. per year. Cirrhosis due to hepatitis C (HCV) has been a leading indication for liver transplant in recent years, however patients with clinical profiles for NASH are increasing.

Transplant Candidacy

Any patient at high risk of dying from liver disease can be considered for referral for liver transplant evaluation. The process of evaluation and listing for liver transplantation involves many tests and consultations, and patients need to be committed to undergoing intensive medical and psychiatric evaluation.

Many patients with complications of cirrhosis are not candidates for transplantation due to ongoing substance use problems, inadequate social support, or other serious medical conditions. Even if they go through the evaluation process, patients should understand that placement on a United Network for Organ Sharing (UNOS) transplant waiting list is a decision that is made by each transplant center. Many patients who complete an evaluation ultimately are not placed on a waiting list. On the other hand, for patients who are good candidates, liver transplantation is an important, life-saving procedure. The following are some important factors to consider prior to referral:

• Substance use: Many patients with cirrhosis have a past history of substance use or abuse. All patients need to have achieved durable sobriety (generally for at least 6 months) from all substances they have used or abused (including alcohol) before being able to be listed for transplant. Patients will need to undergo an evaluation by someone with expertise in substance use to talk about the plan for maintaining sobriety before and after transplantation. Patients may be asked to undergo further substance use treatment prior to determining eligibility for transplantation.
• Social support: Cirrhosis is an illness characterized by poor memory, fatigue, and alterations in levels of consciousness. As such, patients cannot go through transplant evaluation, surgery, and the post-transplant period alone. They require an attentive person, or preferably more than one, who can learn how to take care of them and, if necessary, do what is needed to get them help. A primary social support person (not the living donor) needs to be identified and available throughout the transplant referral process.
• Medical problems: A liver transplant is a long, complicated surgery, and a patient's other organs need to be healthy for the patient to survive this procedure. Coronary artery disease, cardiac function, pulmonary function, renal function, and other major medical problems need to be non-life-threatening and controlled before a patient can be listed for transplantation.
• Severity of liver dysfunction: The MELD score [0.957 x log_e(creatinine, mg/dl)+0.378 x log_e(bilirubin, mg/dl) + 1.12 x log_e(INR) + 0.643, rounded, multiplied by 10] is now used to determine priority for transplantation. MELD scores vary from 6 (less ill) to 40 (gravely ill). Before they are listed for liver transplantation, patients generally should be symptomatic of cirrhosis and have a MELD score of 14 or greater.
• Hepatocellular carcinoma (HCC)

Contraindications to liver transplant:

• non-HCC cancer (other than simple skin cancer) treated in the last 3-5 years
• severe behavioral disease or social condition that would prevent following medical instructions
• any non-liver-related uncontrolled/severe medical illness

Clinical Management of Cirrhosis

Early detection of cirrhosis and recognition of advancing liver disease by clinicians are very important so that the widest range of treatment options can be offered to patients. Staging of liver disease should be performed in any patient with chronic liver disease. This generally includes non-invasive fibrosis staging or a liver biopsy, which can show mild, moderate, or severe liver scarring, with severe scarring being cirrhosis. Physical examination or abdominal imaging with ultrasound, CT scan, or MRI generally also may reveal evidence of cirrhosis, when it is present.

The American Association for the Study of Liver Diseases recommendations on management and treatment of patients with cirrhosis and portal hypertension should be consulted for more detail. Patients with cirrhosis should not drink any alcohol and should be encouraged to remain active, eat a healthy diet, and not smoke cigarettes.

Other recommendations:

• Abstinence from all illegal drugs. Prescription drugs with abuse potential, like opioid medications or benzodiazepines, should also be limited in patients being considered for transplant.
• Treatment of any substance use or mental health symptoms
• Treatment of liver disease (for example, antiviral therapy for hepatitis B; hepatitis C treatment should be determined by the transplant center)
• Vaccination against hepatitis A or B
• Weight loss for obese persons
• Optimal treatment of other health conditions (such as diabetes, hypertension, high cholesterol)
• Consultation with the hepatologist before using any medication (prescribed or over-the-counter), nutritional supplement, or herbal preparation
• Screening of cirrhotic patients for HCC, with abdominal imaging (ultrasound or contrasted MRI or CT scan) every 6 months

Timing of Referral for Consideration of Liver Transplantation

Patients with cirrhosis can have certain forms of decompensation, which should alert the clinician that their liver disease is progressing:

• Elevated bilirubin
• Ascites
• Falling albumin (<3.5), loss of lean body mass
• PT or INR prolongation
• Variceal hemorrhage
• Hepatic encephalopathy
• HCC

VA Transplant Referral

Veterans listed at VA transplant centers are listed with and are allocated organs by standardized criteria on equal footing with non-Veteran patients. Veterans being served by VA facilities may be referred for consideration of liver transplantation either through their VA health benefits or through other forms of health insurance.

If Veterans wish to use their VA health benefits, a "transplantation packet" is completed by providers at their local VAMC and forwarded to VA Central Office in Washington, D.C. The packet is reviewed by members of the VA Liver Transplant Board, and if approved as an appropriate referral, is forwarded to one of four national VA liver transplant centers:

• Houston, Texas
• Madison, Wisconsin
• Nashville, Tennessee
• Pittsburgh, Pennsylvania
• Portland, Oregon
• Richmond, Virginia

The Veteran and their support person are then asked to present for an in-person evaluation at the transplant center, which generally takes 3-5 days. After this evaluation, the Veteran is discussed at the transplant center's "selection conference," and either accepted, and placed on a waiting list for a future transplant; deferred, pending further evaluation; or declined as a candidate.

The specifics of this process, expenses covered by Central Office versus referring centers, and all necessary forms and contact information are available through the National VA Transplant Office.

Clinical Management Post-Transplant

Survival and quality of life for most liver transplant patients are quite good. More than 90% of transplant recipients are alive 1 year after the procedure, and most patients are able to return to active lives within months of liver transplantation. Most patients live for many years after transplantation. However, transplant care does not stop at the time of surgery.

Patients are required to take medications daily to prevent rejection of the new liver and must follow up frequently with their health care providers. Provision of medications within the VA system is the responsibility of the referring VA facility. No substitution of formulation should be undertaken without consulting with the transplant center. Drug interactions are very common and new drugs (especially lipid-lowering drugs, antibiotics, antifungal agents, ACE inhibitors, some calcium channel blockers, and St. John's Wort) should not be started without notifying the transplant center. A variety of immunosuppressive protocols are used by VA transplant centers, which include:

• cyclosporine (Neoral, Gengraf, Sandimmune)
• tacrolimus (Prograf)
• mycophenolate mofetil (Cellcept)
• sirolimus (Rapamune)
• prednisone

Patients must be capable of maintaining a good collaborative relationship with the medical team to assure the health of the new liver and to deal with medical conditions that commonly affect liver transplant recipients. These conditions may include:

• liver allograft rejection
• diabetes
• hypertension
• high cholesterol
• mild renal insufficiency
• occasional infections
• increased risk for a number of different cancers (for example, skin cancer)

Treatment of the disease that caused liver failure must be continued after transplant, whether the condition is hepatitis B, hepatitis C, or substance abuse.

Additional Resources

VA Transplant Program

References

Wiesner RH, Sorrell M, Villamil F, et al. Report of the First International Liver Transplantation Society Expert Panel Consensus Conference on Liver Transplantation and Hepatitis C. Liver Transpl 2003 Nov;9(11):S1-9.

Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors.. Gastroenterology 2004 Nov;127(5 Suppl 1):S35-50.

Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.. N Engl J Med 1996 Mar 14;334(11):693-9.

United Network for Organ Sharing (UNOS) Transplant Trends