Professional Statements and Societal Positions Guidelines
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
2012 Input
In response to requests, input was received from three (3) physician specialty societies and five (5) academic medical centers while this policy was under review in 2012. There was a consensus among reviewers that liver transplantation may be medically necessary for end-stage liver failure due to irreversibly damaged livers from various disease states such as those considered during the report update. There was also a consensus among reviewers that liver retransplantation is appropriate in individuals with acute or chronic liver failure such as primary graft nonfunction, ischemic-type biliary injury after donation after cardiac death, hepatic artery thrombosis, chronic rejection or recurrent diseases such as primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis C resulting in end-stage liver failure. There was general support for the use of liver transplantation as a treatment for cholangiocarcinoma in individuals who meet strict eligibility criteria. In general, there was no support for the use of liver transplantation for a neuroendocrine tumor metastatic to the liver.
Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
International Consensus Conference
In 2010, an International Consensus Conference, including representation from the United States, convened with the goal of reviewing current practice regarding liver transplantation in individuals with hepatocellular carcinoma (HCC). The Conference ultimately came up with recommendations beginning from the assessment of candidates with HCC for liver transplantation and managing individuals on waitlists, to the role of liver transplantation and post-transplant management. Some notable recommendations are described.
The Milan criteria were recommended for use as the benchmark for individual selection, although it was suggested that the Milan criteria might be modestly expanded based on data from expansion studies that demonstrated outcomes are comparable with outcomes from studies using the Milan criteria. Candidates for liver transplantation should also have a predicted survival of five (5) years or more. The consensus criteria indicate alpha-fetoprotein concentrations may be used with imaging to assist in determining individual prognosis.
Regarding liver retransplantation, the consensus criteria issued a weak recommendation for retransplantation after graft failure of a living donor transplant for HCC in individuals meeting regional criteria for a deceased donor liver transplant. A strong recommendation was issued against liver retransplantation with a deceased donor for graft failure for individuals exceeding regional criteria. Also, the consensus criteria issued a strong recommendation that liver retransplantation for recurrent HCC would not be appropriate. However, a de novo case of HCC may be treated as a new tumor, and retransplantation may be considered even though data to support this is limited.
American Association for the Study of Liver Diseases and American Society of Transplantation
In 2013, the American Association for the Study of Liver Diseases (AASLD) and the American Society of Transplantation (AST) issued joint guidelines on evaluating individuals for a liver transplant. These guidelines indicated liver transplantation for severe acute or advanced chronic liver disease after all effective medical treatments have been attempted. The formal evaluation should confirm the irreversible nature of the liver disease and lack of effective alternative medical therapy.
The guidelines also stated that liver transplant is indicated for the following conditions:
- Acute liver failure from complications of cirrhosis
- Liver-based metabolic condition with systemic manifestations
- 1
-Antitrypsin deficiency
- Familial amyloidosis
- Glycogen storage disease
- Hemochromatosis
- Primary oxaluria
- Wilson disease
- Systemic complications of chronic liver disease.
The guidelines also included 1-A recommendations (strong recommendation with high-quality evidence) for a liver transplant that:
- 'Tobacco consumption should be prohibited in LT [liver transplant] candidates.'
- 'Individuals with HIV [Human Immunodeficiency Virus] infection are candidates for LT if immune function is adequate and the virus is expected to be undetectable by the time of LT.'
- 'LT candidates with HCV [hepatitis C virus] have the same indications for LT as for other etiologies of cirrhosis.'
Contraindications to liver transplant included:
- 'MELD [Model for End-stage Liver Disease] score less than (<)15
- Severe cardiac or pulmonary disease
- AIDS [acquired immunodeficiency syndrome]
- Ongoing alcohol or illicit substance abuse
- Hepatocellular carcinoma with metastatic spread
- Uncontrolled sepsis
- Anatomic abnormality that precludes liver transplantation
- Intrahepatic cholangiocarcinoma
- Extrahepatic malignancy
- Fulminant hepatic failure
- Hemangiosarcoma
- Persistent noncompliance
- Lack of adequate social support system.'
In 2014, the AASLD, AST, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition issued joint guidelines on the evaluation of the pediatric individuals for liver transplant. The guidelines stated that 'disease categories suitable for referral to a pediatric LT program are similar to adults: acute liver failure, autoimmune, cholestasis, metabolic or genetic, oncologic, vascular, and infectious. However, specific etiologies and outcomes differ widely from adult individuals, justifying independent pediatric guidelines.' The indications listed for liver transplantation included biliary atresia, Alagille syndrome, pediatric acute liver failure, hepatic tumors, HCC, hemangioendothelioma, cystic fibrosis-associated liver disease, urea cycle disorders, immune-mediated liver disease, along with other metabolic or genetic disorders.
In 2019, the AASLD guideline on alcohol-associated liver disease provided recommendations on the timing of referral and selection of candidates for liver transplant. The guidance notes that the individual's history of addiction to alcohol is a primary driver in selecting appropriate candidates for liver transplantation. Clinical characteristics that should trigger an evaluation and consideration for liver transplant include decompensated alcohol-associated cirrhosis, Child-Pugh-Turcotte class C cirrhosis, or a MELD-Na score 21. Additionally, the guideline notes that candidate selection 'should not be based solely on a fixed interval of abstinence' and instead a formal psychological evaluation can help stratify individuals into higher- or lesser-risk strata for relapse.
In 2023, the AASLD released a practice guideline on the management of hepatocellular carcinoma. Evidence recommendations by the expert panel are rated based on the Oxford Center for Evidence-Based Medicine and the strength of recommendations are categorized based on the level of evidence, risk-benefit ratio, and individual preferences. Recommendations regarding liver transplantation are listed below.
- 'Liver transplantation should be the treatment of choice for transplant-eligible individuals with early-stage HCC occurring in the setting of clinically significant portal hypertension and/or decompensated cirrhosis (Level 2, Strong Recommendation)
- AASLD advises the use of pre-transplant locoregional bridging therapy for individuals being evaluated or listed for liver transplantation, if they have adequate hepatic reserve, to reduce the risk of waitlist dropout in the context of anticipated prolonged wait times for transplant (Level 3, Strong Recommendation)
- AASLD advises individuals with decompensated cirrhosis who develop T1 HCC and are eligible for LT be monitored with cross-sectional imaging at least every three (3) months until criteria are met for MELD exception before pursuing LRT [locoregional therapy] (Level 3, Weak Recommendation)
- Individuals who are otherwise transplant-eligible except with initial tumor burden exceeding the Milan criteria, especially those meeting United Network of Organ Sharing (UNOS) downstaging criteria, should be considered for LT following successful downstaging to within Milan criteria after a three (3) to six (6)-month period of observation (Level 2, Strong Recommendation)
- AASLD advises surveillance for detection of post-transplant HCC recurrence using multiphasic contrast-enhanced abdominal CT [computed tomography] or MRI [magnetic resonance imaging] and chest CT scan (Level 2, Strong Recommendation)'
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines on hepatocellular carcinoma (v 1.2023) recommend referral to a liver transplant center or bridge therapy for individuals with HCC meeting UNOS criteria of a single tumor measuring two (2) to five (5) cm, or two (2) to three (3) tumors three (3) cm or less with no macrovascular involvement or extrahepatic disease. In individuals who are ineligible for transplant and in select individuals with Child-Pugh class A or B liver function with tumors that are resectable and who fit UNOS criteria/extended criteria, the NCCN indicates that these individuals could be considered for resection or transplant. Individuals with unresectable HCC should be evaluated for liver transplantation; if the Individual is a transplant candidate, then referral to a transplant center should be given or bridge therapy should be considered. The NCCN guidelines also indicate that individuals with unresectable disease who are not a transplant candidate should receive locoregional therapy with ablation, arterially directed therapies, or external beam radiation therapy or may receive systemic therapy, best supportive care, or be enrolled in a clinical trial. These are level 2A recommendations based on lower-level evidence and uniform consensus.
The NCCN guidelines on neuroendocrine tumors (v.2.2022) indicate that liver transplantation for neuroendocrine liver metastases is considered investigational despite 'encouraging' five (5)-year survival rates.
