Liver Transplantation

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. Liver transplantation is used to treat persons at high risk of dying from liver diseases, most of whom have cirrhosis of the liver. Such patients undergo a pre-transplant evaluation, then are considered for being placed on a "wait-list" for transplantation. As of early 2005, 17,000 patients in the U.S. have undergone an evaluation, were found to be suitable candidates, and are currently awaiting liver transplants on a United Network for Organ Sharing (UNOS) waitlist. Approximately 5,000 liver transplants are performed in the U.S. per year. Cirrhosis due to hepatitis C (HCV) is the leading indication for liver transplantation in the U.S., accounting for at least 40% of transplants.(1)

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 is long, 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 serious medical conditions. Even if they go through the evaluation process, they should understand that placement on a 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 hepatitis C-related cirrhosis have a past history of substance 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 and marijuana) before being able to be listed for transplant.
	Social support: Cirrhosis is an illness characterized by poor memory, fatigue, and alterations in levels of consciousness. As such, patients cannot go through an evaluation, a transplant, and a post-transplant course 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 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 if the patient is to survive a peri-transplant period. Coronary artery disease, cardiac function, pulmonary function, renal function, and other major medical problems need to be non-life-threatening in their own right and controlled before listing for transplant can be carried out.
	Severity of liver dysfunction: The MELD score [0.957 x loge(creatinine, mg/dl)+0.378 x loge(bilirubin, mg/dl) + 1.12 x loge(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 have a Child-Turcotte-Pugh (CTP) score of 7 or greater, and/or a MELD score of 12 or greater. The UNOS Web site provides a Meld calculator.
	Hepatocellular carcinoma (HCC): This is a common complication of HCV cirrhosis, occurring at a rate of 1-3% per year (2). Limited HCC--defined as 1 cancer <5 cm in diameter or ≤3 cancers, each <3 cm in diameter, with no vascular nor extrahepatic cancer (3)--is still considered to be an indication for liver transplantation. HCC outside of these criteria should be treated in a multidisciplinary fashion.

Contraindications to liver transplant:

	non-HCC cancer (other than simple skin cancer) treated in the last 3-5 years
	advanced HIV disease
	severe behavioral disease or social condition that would prevent following medical instructions

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 HCV. This generally includes 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 will reveal evidence of cirrhosis, when it is present.

The VA Hepatitis C Resource Center Program has created a set of recommendations for clinicians: Treatment of Patients with Cirrhosis and Portal Hypertension, which 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. These actions may delay or prevent the need for liver transplantation, improve the chance of survival until a liver becomes available, and enhance the chances of many years of healthy life after transplantation.

Other recommendations:

	Abstinence from all illegal drugs including marijuana. Prescription drugs with abuse potential, like opiates or benzodiazepines, should also be limited in patients being considered for transplant.
	Treatment of any substance abuse or behavioral condition
	Treatment of liver disease (for example, antiviral therapy for hepatitis B or C)
	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 ultrasound or CT scan, in conjunction with serum alphafetoprotein, every 6 months

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

Over 300 liver transplants have been performed within VA in the past 5 years, with survival that meets or exceeds UNOS averages. 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:

	Portland, OR
	Nashville, TN
	Pittsburgh, PA
	Richmond, VA

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 and its web site.

Hepatitis C disease with or without alcohol abuse is the leading indication for liver transplantation in VA transplant centers, accounting for over 50% of transplants.(4)

Many patients with HCV cirrhosis are "too sick" to tolerate interferon-based therapy while they are being referred for transplant. Recent consensus recommendations, however, encourage practitioners to consider therapy in patients with compensated cirrhosis.(1) Some points about the use of interferon and ribavirin in this setting:

	Strongly consider for CTP <7, MELD <18; consider for CTP <11, MELD <25
	Adverse events (including severe AE) likely greater than in non-cirrhotics
	Viral clearance at transplantation is achievable

Transplanted patients with HCV nearly always have the virus infect their new liver, and progression of liver disease can be faster than pre-transplant, with 15-30% developing cirrhosis within 5 years of transplant.(5) Patients with HCV now have been shown to have decreased survival compared to patients transplanted for other reasons(6). Recurrent HCV, at times, can be treated with interferon and ribavirin,(7) but this should be done in consultation with the transplant center.

Survival and quality of life for most liver transplant patients are quite good. One-year survival rates are above 80%(4), and most patients are able to return to active lives within months of liver transplantation. Most patients live for many years after transplantation.

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

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

1. 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.

2. 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.

3. 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.

4. Austin GL, Sasaki AW, Zaman A, et al. Comparative analysis of outcome following liver transplantation in US veterans. Am J Transplant 2004 May;4(5):788-95.

5. Feray C, Caccamo L, Alexander GJ, et al. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group. Gastroenterology 1999 Sep;117(3):619-25.

6. Berenguer M, Prieto M, San Juan F, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002 Jul;36(1):202-10.

7. Samuel D, Bizollon T, Feray C, et al. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Gastroenterology 2003 Mar;124(3):642-50.