Coverage Policy Manual
Policy #: 1998104
Category: Surgery
Initiated: February 1998
Last Review: August 2018
  Transplant, Liver

Description:
Liver transplantation (either from cadaver liver or living donor) has become the treatment of last resort for selected patients whose chronic or acute liver disease is progressive, life threatening, and unresponsive to medical therapy.  Patients are prioritized for transplant by mortality risk and severity of illness criteria developed by the Organ Procurement and Transplantation Network (OPTN) and the United Network of Organ Sharing (UNOS). The severity of illness is determined by the model for end-stage liver disease (MELD) and pediatric end-stage liver disease (PELD) scores.
 
As with most other solid organ transplants, donor liver availability is less than the number of patients on the nationwide liver transplant lists.  General consensus amongst liver transplant centers has identified appropriate candidates for transplant.  Arkansas BCBS coverage guidelines follows the national consensus recommendations.
 
The original liver allocation system was based on assignment to status 1, 2A, 2B, or 3. Status 2A, 2B, and 3 were based on the Child-Turcotte-Pugh score, which included a subjective assessment of symptoms as part of the scoring system. In February 2002, Status 2A, 2B, and 3 were replaced with 2 disease severity scales: the model for end-stage liver disease (MELD) and pediatric end-stage liver disease (PELD) for patients younger than age 12 years scoring systems. In June 2013, OPTN/UNOS published its most recent allocation system, which previously expanded Status1 to Status 1A and 1B in September 2012.(1) Status 1A patients have acute liver failure with a life expectancy of less than 7 days without a liver transplant. Status 1A patients also include primary graft nonfunction, hepatic artery thrombosis and acute Wilson’s disease. Status 1A patients must be recertified as Status 1A every 7 days. Status 1B patients are pediatric patients (age range, 0-17 years) with chronic liver disease listed as: fulminant liver failure, primary nonfunction, hepatic artery thrombosis, acute decompensated Wilson’s disease, chronic liver disease; and nonmetastatic hepatoblastoma. Pediatric patients move to Status 1A upon age18 but still qualify for pediatric indications.
 
Following Status 1, donor livers will be prioritized to those with the highest scores on MELD or PELD. With this allocation system, the highest priority for liver transplantation is given to patients receiving the highest number of points. The scoring system for MELD and PELD is a continuous disease severity scale based entirely on objective laboratory values. These scales have been found to be highly predictive of the risk of dying from liver disease for patients waiting on the transplant list. The MELD score incorporates bilirubin, prothrombin time (ie, international normalized ratio [INR]), and creatinine into an equation, producing a number that ranges from 6 to 40. The PELD score incorporates albumin, bilirubin, INR growth failure, and age at listing. Waiting time will only be used to break ties among patients with the same MELD or PELD score and blood type compatibility. The MELD and PELD scores range from 6 (less ill) to 40 (gravely ill). The MELD and PELD scores will change during the course of a patient's tenure on the waiting list.
 
In the previous system, waiting time was often a key determinant of liver allocation, and yet, waiting time was found to be a poor predictor of the urgency of liver transplant because some patients were listed early in the course of their disease, while others were listed only when they became sicker. In the revised allocation systems, patients with a higher mortality risk and higher MELD/PELD scores will always be considered before those with lower scores, even if some patients with lower scores have waited longer. Status 7 describes patients who are temporarily inactive on the transplant waiting list due to being temporarily unsuitable for transplantation. Pediatric patients who turn 18 are Status 1A upon age18 but still qualify for pediatric indications.
 
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Effective August 2017
Cadaver liver transplant meets primary coverage criteria for effectiveness and is covered for adults whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
  • Autoimmune Hepatitis  (Effective August 2017)
  • Primary biliary cirrhosis;
  • Secondary biliary cirrhosis;
  • Primary sclerosing cholangitis;
  • Multiple cystic dilatations of the intrahepatic biliary tree (Caroli’s disease);
  • Cryptogenic cirrhosis;
  • Chronic hepatitis and cirrhosis;
  • Fulminant hepatitis;
  • Alcoholic cirrhosis (see exclusions);
  • Chronic viral hepatitis;
  • Hepatic metastasis of neuroendocrine tumor (carcinoid) with progressive disease despite drug therapy and ablation when there is no evidence of extrahepatic metastases;
  • Hemochromatosis (Effective August 2017)
  • Primary hepatocellular malignancies with no evidence of extrahepatic disease (see exclusions);
  • Trauma and toxic reactions in the liver;
  • Polycystic disease of the liver with one or more of the following: (Effective June 2014)
  • Enlargement of liver impinging on respiratory function
  • Extremely painful enlargement of liver
  • Enlargement of liver significantly compressing and interfering with function of other abdominal organs
  • NASH (non-alcoholic steatohepatitis) that has progressed to the stage of fibrosis; and Cholangiocarcinoma
  • Alpha 1 anti-trypsin deficiency;
  • Unresectable hilar cholangiocarcinoma (Effective June, 2014)
  • Vascular Disease (Budd-Chiari Syndrome) (Effective August 2017)
 
 
Effective 12/12/2006 a liver transplant for one of the above indications may meet primary coverage criteria for effectiveness and be covered for a HIV-positive member when all of the following are met:
  • There is no antiretroviral drug intolerance; AND
  • The CD4 count is > 100 cells/μL; AND
  • The HIV viral load is < 400 copies/mL.
 
Cadaver and living donor liver transplant meets primary coverage criteria for effectiveness and is covered for children whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
  • Autoimmune Hepatitis (Effective August 2017)
  • Biliary atresia;
  • Neonatal hepatitis;
  • Congenital hepatic fibrosis;
  • Alagille’s disease;
  • Byler’s disease;
  • Alpha 1 anti-trypsin deficiency;
  • Wilson’s Disease;
  • Tyrosinemia;
  • Glycogen storage diseases;  
  • Lysosomal storage diseases;
  • Protoporphyria;
  • Crigler-Najjar disease type I;
  • Familial amyloid polyneuropathy  (Effective August 2017)
  • Hemochromatosis (Effective August 2017)
  • Familial hypercholesterolemia; and
  • Hereditary oxalosis; and
  • Unresectable hepatoblastoma (Effective June 2013).
  • Pediatric non-metastatic hepatoblastoma (Effective June 2014)
  • Unresectable hilar cholangiocarcinoma (Effective June 2014)
  • Vascular Disease (Budd-Chiari Syndrome) (Effective August 2017)
 
Adult living donor transplantation is covered for the same conditions that cadaveric transplant is covered, but the donor and the recipient must be aware of the risk to the donor. According to some information in the medical literature:
  • There is a lack of agreement on the technique that is most effective and that provides the greatest safety for donor and recipient;
  • Indications for the surgery have not been clearly defined or standardized; and
  • The procedure has been developed with variable standards for approval by institutional review boards.
 
Cadaver and living donor liver retransplantation meets primary coverage criteria for effectiveness and may be considered medically necessary in patients with:
  • Primary graft nonfunction
  • Hepatic artery thrombosis
  • Hepatic vein thrombosis
  • Chronic rejection
  • Ischemic type biliary lesions after donation after cardiac death
  • Recurrent nonneoplastic disease causing late graft failure
 
 
The member certificate of coverage limits the restrictions that may be placed on medical services.
Members should be aware of the lack of data on the safety and effectiveness of adult living donor liver transplantation.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Liver transplantation does not meet Primary Coverage Criteria, based on lack of scientific evidence of effectiveness, when used to treat the following indications:
  • Extrahepatic malignancy, active or within the preceding 2 years;
  •  Active alcohol or drug abuse;
  •  Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the
  • liver;
  •  Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
 
For contracts without primary coverage criteria, liver transplantation for members with liver disease is considered investigational for:
  • Extrahepatic malignancy, active or within the preceding 2 years;
  • Active alcohol or drug abuse;
  • Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the liver;
  • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
 
Investigational services are exclusions in the member benefit certificate of coverage.
 
Effective Prior to August 2017
   
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Cadaver liver transplant meets primary coverage criteria for effectiveness and is covered for adults whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
  • Primary biliary cirrhosis;
  • Secondary biliary cirrhosis;
  • Primary sclerosing cholangitis;
  • Multiple cystic dilatations of the intrahepatic biliary tree (Caroli’s disease);
  • Cryptogenic cirrhosis;
  • Chronic hepatitis and cirrhosis;
  • Hepatic vein thrombosis;
  • Fulminant hepatitis;
  • Alcoholic cirrhosis (see exclusions);
  • Chronic viral hepatitis;
  • Viral hepatitis (either A, B, C, or non-A, non-B)
  • Autoimmune Hepatitis
  • Hemochromatosis
  • Protoporphyria
  • Wilson Disease
  • Budd-Chiari Syndrome
  • Familial amyloid polyneuropathy
  • Hepatic metastasis of neuroendocrine tumor (carcinoid) with progressive disease despite drug therapy and ablation when there is no evidence of extrahepatic metastases;
  • Primary hepatocellular malignancies with no evidence of extrahepatic disease (see exclusions);
  • Trauma and toxic reactions in the liver;
  • Polycystic disease of the liver with one or more of the following:
      • Enlargement of liver impinging on respiratory function
      • Extremely painful enlargement of liver
      • Enlargement of liver significantly compressing and interfering with function of other abdominal organs
  • NASH (non-alcoholic steatohepatitis) that has progressed to the stage of fibrosis; and
  • Cholangiocarcinoma
  • Alpha 1 anti-trypsin deficiency;
  • Unresectable hilar cholangiocarcinoma  
 
Effective 12/12/2006 a liver transplant for one of the above indications may meet primary coverage criteria for effectiveness and be covered for a HIV-positive member when all of the following are met:
  • There is no antiretroviral drug intolerance; AND
  • The CD4 count is > 100 cells/μL; AND
  • The HIV viral load is < 400 copies/mL.
 
Cadaver and living donor liver transplant meets primary coverage criteria for effectiveness and is covered for children whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
  • Biliary atresia;
  • Neonatal hepatitis;
  • Congenital hepatic fibrosis;
  • Alagille’s disease;
  • Byler’s disease;
  • Alpha 1 anti-trypsin deficiency;
  • Wilson’s Disease;
  • Tyrosinemia;
  • Glycogen storage diseases;
  • Lysosomal storage diseases;
  • Protoporphyria;
  • Crigler-Najjar disease type I;
  • Familial hypercholesterolemia;
  • Hereditary oxalosis; and
  • Unresectable hepatoblastoma
  • Pediatric non-metastatic hepatoblastoma  
  • Unresectable hilar cholangiocarcinoma  
  • Viral hepatitis (either A, B, C, or non-A, non-B)
  • Autoimmune Hepatitis
  • Hemochromatosis
  • Budd-Chiari Syndrome
  • Familial amyloid polyneuropathy
 
Adult living donor transplantation is covered for the same conditions that cadaveric transplant is covered, but the donor and the recipient must be aware of the risk to the donor. According to some information in the medical literature:
  • There is a lack of agreement on the technique that is most effective and that provides the greatest safety for donor and recipient;
  • Indications for the surgery have not been clearly defined or standardized; and
  • The procedure has been developed with variable standards for approval by institutional review boards.
 
The member certificate of coverage limits the restrictions that may be placed on medical services.
Members should be aware of the lack of data on the safety and effectiveness of adult living donor liver transplantation.
 
Liver retransplantation meets primary coverage criteria for effectiveness and is covered for members whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
  • primary graft nonfunction
  • hepatic artery thrombosis
  • chronic rejection
  • ischemic type biliary lesions after donation after cardiac death
  • recurrent nonneoplastic disease causing late graft failure
 
Liver transplantation does not meet Primary Coverage Criteria, based on lack of scientific evidence of effectiveness, when used to treat the following indications:
  • Extrahepatic malignancy, active or within the preceding 2 years;
  • Active alcohol or drug abuse;
  • Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the liver;
  • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
 
For contracts without primary coverage criteria, liver transplantation for members with liver disease is considered investigational for:
  • Extrahepatic malignancy, active or within the preceding 2 years;
  • Active alcohol or drug abuse;
  • Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the liver;
  • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;  
 
Investigational services are exclusions in the member benefit certificate of coverage.
 
Effective Prior to March 2017
 
 
Effective May 2011
Cadaver liver transplant meets primary coverage criteria for effectiveness and is covered for adults whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Primary biliary cirrhosis;
    • Secondary biliary cirrhosis;
    • Primary sclerosing cholangitis;
    • Multiple cystic dilatations of the intrahepatic biliary tree (Caroli’s disease);
    • Cryptogenic cirrhosis;
    • Chronic hepatitis and cirrhosis;
    • Hepatic vein thrombosis;
    • Fulminant hepatitis;
    • Alcoholic cirrhosis (see exclusions);
    • Chronic viral hepatitis;
    • Hepatic metastasis of neuroendocrine tumor (carcinoid) with progressive disease despite drug therapy and ablation when there is no evidence of extrahepatic metastases;
    • Primary hepatocellular malignancies with no evidence of extrahepatic disease (see exclusions);
    • Trauma and toxic reactions in the liver;
    • Polycystic disease of the liver with one or more of the following: (Effective June 2014)
      • Enlargement of liver impinging on respiratory function
      • Extremely painful enlargement of liver
      • Enlargement of liver significantly compressing and interfering with function of other abdominal organs  
    • NASH (non-alcoholic steatohepatitis) that has progressed to the stage of fibrosis; and
    • Cholangiocarcinoma
    • Alpha 1 anti-trypsin deficiency;
    • Unresectable hilar cholangiocarcinoma (Effective June, 2014)
 
Effective 12/12/2006 a liver transplant for one of the above indications may meet primary coverage criteria for effectiveness and be covered for a HIV-positive member when all of the following are met:
    • There is no antiretroviral drug intolerance; AND
    • The CD4 count is > 100 cells/µL; AND
    • The HIV viral load is < 400 copies/mL.
 
Cadaver and living donor liver transplant meets primary coverage criteria for effectiveness and is covered for children whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Biliary atresia;
    • Neonatal hepatitis;
    • Congenital hepatic fibrosis;
    • Alagille’s disease;
    • Byler’s disease;
    • Alpha 1 anti-trypsin deficiency;
    • Wilson’s Disease;
    • Tyrosinemia;
    • Glycogen storage diseases;
    • Lysosomal storage diseases;
    • Protoporphyria;
    • Crigler-Najjar disease type I;
    • Familial hypercholesterolemia; and
    • Hereditary oxalosis; and
    • Unresectable hepatoblastoma (Effective June 2013).
    • Pediatric non-metastatic hepatoblastoma  (Effective June 2014)
    • Unresectable hilar cholangiocarcinoma (Effective June 2014)  
 
Adult living donor transplantation is covered for the same conditions that cadaveric transplant is covered, but the donor and the recipient must be aware of the risk to the donor.  According to some information in the medical literature:
    • There is a lack of agreement on the technique that is most effective and that provides the greatest safety for donor and recipient;
    • Indications for the surgery have not been clearly defined or standardized; and
    • The procedure has been developed with variable standards for approval by institutional review boards.
 
The member certificate of coverage limits the restrictions that may be placed on medical services.  Members should be aware of the lack of data on the safety and effectiveness of adult living donor liver transplantation.
 
Liver transplantation does not meet Primary Coverage Criteria, based on lack of scientific evidence of effectiveness, when used to treat the following indications:
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the liver;
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
 
For contracts without primary coverage criteria, liver transplantation for members with liver disease is considered investigational for:
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy (e.g. unresectable hepatoblastoma) that extends outside the liver;
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
 
Investigational services are exclusions in the member benefit certificate of coverage.
  
Effective September 29, 2009 to April 2011
Cadaver liver transplant meets primary coverage criteria for effectiveness and is covered for adults whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Primary biliary cirrhosis;
    • Secondary biliary cirrhosis;
    • Primary sclerosing cholangitis;
    • Multiple cystic dilatations of the intrahepatic biliary tree (Caroli’s disease);
    • Cryptogenic cirrhosis;
    • Chronic hepatitis and cirrhosis;
    • Hepatic vein thrombosis;
    • Fulminant hepatitis;
    • Alcoholic cirrhosis (see exclusions);
    • Chronic viral hepatitis;
    • Hepatic metastasis of neuroendocrine tumor (carcinoid) with progressive disease despite drug therapy and ablation when there is no evidence of extrahepatic metastases;
    • Primary hepatocellular malignancies with no evidence of extrahepatic disease (see exclusions);
    • Trauma and toxic reactions in the liver;
    • Polycystic disease of the liver;
    • NASH (non-alcoholic steatohepatitis) that has progressed to the stage of fibrosis; and
    • Cholangiocarcinoma
 
Effective 12/12/2006 a liver transplant for one of the above indications may meet primary coverage criteria for effectiveness and be covered for a HIV-positive member when all of the following are met:
    • There is no antiretroviral drug intolerance; AND
    • The CD4 count is > 100 cells/µL; AND
    • The HIV viral load is < 400 copies/mL.
 
Cadaver and living donor liver transplant meets primary coverage criteria for effectiveness and is covered for children whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Biliary atresia;
    • Neonatal hepatitis;
    • Congenital hepatic fibrosis;
    • Alagille’s disease;
    • Byler’s disease;
    • Alpha 1 anti-trypsin deficiency;
    • Wilson’s Disease;
    • Tyrosinemia;
    • Glycogen storage diseases;
    • Lysosomal storage diseases;
    • Protoporphyria;
    • Crigler-Najjar disease type I;
    • Familial hypercholesterolemia; and
    • Hereditary oxalosis.
 
Adult living donor transplantation is covered for the same conditions that cadaveric transplant is covered, but the donor and the recipient must be aware of the risk to the donor.  According to some information in the medical literature:
    • There is a lack of agreement on the technique that is most effective and that provides the greatest safety for donor and recipient;
    • Indications for the surgery have not been clearly defined or standardized; and
    • The procedure has been developed with variable standards for approval by institutional review boards.
 
The member certificate of coverage limits the restrictions that may be placed on medical services.  Members should be aware of the lack of data on the safety and effectiveness of adult living donor liver transplantation.
 
Liver transplantation does not meet Primary Coverage Criteria, based on lack of scientific evidence of effectiveness, when used to treat the following indications.
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy that extends outside the liver;
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
    • Hepatic failure secondary to alpha 1 anti-trypsin deficiency in patients who do not have severe lung disease
 
For contracts without primary coverage criteria, liver transplantation for members with liver disease  is considered investigational for:
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy that extends outside the liver;
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
    • Hepatic failure secondary to alpha 1 anti-trypsin deficiency in patients who do not have severe lung disease
Investigational services are an exclusion in the member benefit contract.
 
 
Coverage statement effective prior to 9/29/09:
Cadaver liver transplant meets primary coverage criteria for effectiveness and is covered for adults whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Primary biliary cirrhosis;
    • Secondary biliary cirrhosis;
    • Primary sclerosing cholangitis;
    • Multiple cystic dilatations of the intrahepatic biliary tree (Caroli’s disease);
    • Cryptogenic cirrhosis;
    • Chronic hepatitis and cirrhosis;
    • Hepatic vein thrombosis;
    • Fulminant hepatitis;
    • Alcoholic cirrhosis (see exclusions);
    • Chronic viral hepatitis;
    • Hepatic metastasis of neuroendocrine tumor (carcinoid) with progressive disease despite drug therapy and ablation when there is no evidence of extrahepatic metastases;
    • Primary hepatocellular malignancies with no evidence of extrahepatic disease (see exclusions);
    • Trauma and toxic reactions in the liver;
    • NASH (non-alcoholic steatohepatitis) that has progressed to the stage of fibrosis.
 
Effective 12/12/2006 a liver transplant for one of the above indications may meet primary coverage criteria for effectiveness and be covered for a HIV-positive member when all of the following are met:
    • There is no antiretroviral drug intolerance; AND
    • The CD4 count is > 100 cells/µL; AND
    • The HIV viral load is < 400 copies/mL.
 
Cadaver and living donor liver transplant meets primary coverage criteria for effectiveness and is covered for children whose chronic or acute liver disease is progressive, life-threatening, unresponsive to medical therapy, and due to one of the following diagnoses:
    • Biliary atresia;
    • Neonatal hepatitis;
    • Congenital hepatic fibrosis;
    • Alagille’s disease;
    • Byler’s disease;
    • Alpha 1 anti-trypsin deficiency;
    • Wilson’s Disease;
    • Tyrosinemia;
    • Glycogen storage diseases;
    • Lysosomal storage diseases;
    • Protoporphyria;
    • Crigler-Najjar disease type I;
    • Familial hypercholesterolemia; and
    • Hereditary oxalosis.
 
Adult living donor transplantation is covered for the same conditions that cadaveric transplant is covered, but the donor and the recipient must be aware of the risk to the donor.  According to some information in the medical literature:
    • There is a lack of agreement on the technique that is most effective and that provides the greatest safety for donor and recipient;
    • Indications for the surgery have not been clearly defined or standardized; and
    • The procedure has been developed with variable standards for approval by institutional review boards.
 
The member certificate of coverage limits the restrictions that may be placed on medical services.  Members should be aware of the lack of data on the safety and effectiveness of adult living donor liver transplantation.
 
Liver transplantation for members with liver disease that have:
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy that extends outside the liver;
    • Cholangiocarcinoma
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
    • Hepatic failure secondary to alpha 1 anti-trypsin deficiency in patients who do not have severe lung disease
is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, liver transplantation for members with liver disease that have:
    • Extrahepatic malignancy, active or within the preceding 2 years;
    • Active alcohol or drug abuse;
    • Primary hepatocellular malignancy that extends outside the liver;
    • Cholangiocarcinoma
    • Uncontrolled, extrahepatic bacterial, mycobacterial or fungal infections;
    • Hepatic failure secondary to alpha 1 anti-trypsin deficiency in patients who do not have severe lung disease
is considered investigational.  Investigational services are an exclusion in the member benefit contract.

Rationale:
As experience with liver transplant has matured, patient selection criteria have broadened to include a wide variety of etiologies. The most controversial etiologies include viral hepatitis and primary hepatocellular cancer. In particular, the presence of hepatitis B virus (HBV) has been a controversial indication for liver transplantation because of the high potential for recurrence of the virus and subsequent recurrence of liver disease. However, registry data indicate a long-term survival rate (7 years) of 47% in HBV+ transplant recipients, which is lower than that seen in other primary liver diseases such as primary biliary cirrhosis (71%) or alcoholic liver disease (57%). Although these statistics raise questions about the most appropriate use of a scarce resource (donor livers), the long-term survival rate of 45% is significant in a group of patients who have no other treatment options. Similarly, the long-term outcome in patients with primary hepatocellular malignancies (19%) is poor compared to the overall survival of liver transplant recipients. Nevertheless, transplant represents the only curative approach for many of these patients who present with unresectable organ-confined disease. However, liver transplant cannot be considered curative in patients with locally extensive or metastatic liver cancer, or in patients with isolated liver metastases with extrahepatic primaries or in cholangiocarcinoma.
 
Due to the scarcity of donor organs and the success of living donation between parent and child, adult-to-adult living liver transplantation has been investigated and is now performed at several transplant centers. Specifically, the living donor undergoes hepatectomy of the right lobe, which is then transplanted into the recipient. Since right hepatectomy involves the resection of 60%– 70% of the total volume of the donor liver, the safety of the donor has been the major concern.
 
For example, the surgical literature suggests that right hepatectomy of diseased or injured livers is associated with mortality rates of about 5%. However, initial reports suggest that right hepatectomy in healthy donors has a lower morbidity and mortality. The Medical College of Virginia appears to have the most extensive experience and has reported the results of their first 40 adult-to-adult living donor liver transplantations, performed between June 1998 and October 1999.  There were an equal number of related and unrelated donors. Minor complications occurred in 7 donors. The outcomes among recipients were similar to those associated with cadaveric donor livers performed during the same period of time. However, in the initial series of 20 patients, 4 of the 5 deaths occurred in recipients who were classified as 2A. In the subsequent 20 patients, recipients classified as 2A were not considered candidates for living donor transplant. Other case series have reported similar success rates.  Reports of several donor deaths re-emphasizes the importance of careful patient selection based in part on a comprehensive consent process and an experienced surgical team.  In December 2000, the National Institutes of Health convened a workshop focusing on living donor liver transplantation. A summary of this workshop was published in 2002.  According to this document, the risk of mortality to the donor undergoing right hepatectomy was estimated to be approximately 0.2%-0.5%. Based on survey results, the workshop reported that donor morbidity was common; 7% required re-exploration, 10% had to be re-hospitalized, and biliary tract complications occurred in 7%. The median complication rate reported by responding transplant centers was 21%.
 
Due to the potential morbidity and mortality experienced by the donor, the workshop also noted that donor consent for hepatectomy must be voluntary and free of coercion, therefore it was preferable that the donor have a significant long-term and established relationship with the recipient. According to the workshop summary, “At the present time, nearly all centers strive to identify donors who are entirely healthy and at minimal risk during right hepatectomy. As a result, only approximately one third of persons originally interested in becoming a living liver donor complete the evaluation process and are accepted as candidates for this procedure.”
 
Criteria for a recipient of a living-related liver are also controversial, with some groups advocating that living-related donor livers be only used in those most critically ill, while others state that the risk to the donor is unacceptable in critically ill recipients due to the increased risk of postoperative mortality of the recipient. According to this line of thought, living-related livers are best used in stable recipients who have a higher likelihood of achieving long-term survival.
 
In 2000 the American Society of Transplant Surgeons issued the following statement:
“Living donor transplantation in children has proven to be safe and effective for both donors and recipients and has helped to make death on the waiting list a less common event. Since its introduction in 1990, many of the technical and ethical issues have been addressed and the procedure is generally applied.
 
The development of left or right hepatectomy for adult-to-adult living donor liver transplantation has been slower. Because of the ongoing shortage of cadaver livers suitable for transplantation, adult-to-adult living donor liver transplantation has been undertaken at a number of centers. While early results appear encouraging, sufficient data are not available to ascertain donor morbidity and mortality rates. There is general consensus that the health and safety of the donor is and must remain central to living organ donation.”
 
As discussed in the Description section, in 2002, the United Network for Organ Sharing adopted a new method of allocation. The use of MELD and PELD scores is designed to allocate livers to those most seriously ill, as opposed to favoring those with the longest time on the waiting list.
 
Medical literature, searched in Dec 2006,  reveals support for renal and liver transplants in HIV-positive indiviuals who have very low levels of viral load (may be higher for liver transplant candidates who are unable to take antiretroviral drugs due to their liver dysfunction) and who do not have extremely low CD4 levels.
 
2009 Update
Becker (2008) reported results of 280 patients with cholangiocarcinoma treated with OLT from 1987 to 2005 identified in The United Network for Organ Sharing database. Patient and allograft survivals were calculated and the potential prognostic value of multiple clinicopathologic variables was assessed. At a median follow-up interval of 452 days (range: 0-6,166 days), 1- and 5-year patient survivals were 74 and 38%, respectively, with 49 actual 5-year survivors and 21 actual 10-year survivors. Posttransplant 1- and 5-year allograft survivals were 69 and 36%, respectively. Study variables associated with improved survivals included diagnosis of cholangiocarcinoma pre-OLT [5-year overall survival (OS): 68 vs. 20% for patients with incidental diagnoses at the time of OLT, p<0.001] and OLT after 1993 (5-year OS: 45 vs. 30% pre-1994, p<0.01). In contrast, the diagnosis of concomitant primary sclerosing cholangitis did not impact survivals (5-year OS: 41 vs. 50% without primary sclerosing cholangitis, p=0.402). Selected cholangiocarcinoma patients treated with OLT experience a survival benefit. Diagnosis of cancer prior to OLT allows for better staging and pre-OLT therapy that may translate into improved outcomes.
 
2013 Update
This policy has been reviewed and is updated with a search of the MEDLINE database through May 2013. The update addresses only liver transplant for children with hepatoblastoma, which includes a change to the coverage statement. No information was identified for other indications that would prompt a change in the coverage statement.
 
Surgical resection is essential to long-term survival and cure in children with hepatoblastoma (Otte, 2004;  Meyers, 2012; Trobaugh, 2012). Studies have shown 80-90% long-term survival in children with unresectable hepatoblastoma who undergo primary transplantation (Brown, 2008; Otte, 2005; Faraj, 2008; Tiao, 2005).
 
In 2004, Otte and colleagues analyzed results from the International Society of Pediatric Oncology Study SIOPEL-1 and reviewed world experience of liver transplant for hepatoblastoma (Otte, 2004). Overall survival at 10 years post liver transplant was 85% for seven children who received a primary transplant and 40% for those children who received a rescue transplant. The authors report that liver transplant “should be considered for every child presenting with unresectable disease due to involvement of all four sectors of the liver or involvement of three sectors when a complete tumor excision is unlikely” (Otte, 2004).
 
In 2013, Kim and colleagues published results of seven patients who underwent liver transplant for hepatoblastoma at a single center.  The median age at surgery was 47 months (range, 11 months to 10.3 years). Liver transplant was performed for PRETEXT stage III with a central location (n=2) and for PRETEXT stage IV cases (n=5). Postoperative serum AFP level remained below 20 ng/mL during follow-up period in six patients who were free of recurrences or metastases. Postoperative serum AFP levels in one patient with pulmonary metastasis were never below 20 ng/mL and increased gradually thereafter. A Pulmonary metastasis was discovered in the 2nd month post-operative. The other 6 patients are free of tumor recurrences with 29.9 month median follow-up. The authors conclude, “liver transplant for unresectable HB confined to the liver following chemotherapy seemed to show good clinical results” (Kim, 2013).
 
In 2013, an observational study was reported evaluating data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry, the United Network for Organ Sharing (UNOS) and the Children’s Hospital of Pittsburg database (Cruz, 2013). The authors report a 4-fold increase in hepatoblastoma cases and a 20-fold increase in liver transplant for hepatoblastoma during the last 20 years. Five year patient survival exceeded 75%. At CHP, 4 children died from recurrences and one from sepsis. The authors conclude, “Outcomes after liver transplant for hepatoblastoma may benefit from improved detection and treatment of pretransplantation metastases, adequate tumor lysis after chemotherapy, and perioperative antithrombotic agents but are unaffected by undifferentiated tumor histology”(Cruz, 2013).
 
2014 Update
A literature search conducted through May 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Patient selection criteria for liver transplantation for HCC have focused mainly on the number and size of tumors. In 1996 Mazzafaro et al identified patient criteria associated with improved outcomes after liver transplantation for HCC with cirrhosis (Mazzaferro, 1996). This patient selection criteria became known as the Milan criteria and specifies patients may have either a solitary tumor with a maximum tumor diameter of 5 cm or less, or up to 3 tumors 3 cm or less.
 
Liver transplantation is the criterion standard treatment for HCC meeting Milan criteria in decompensated livers such as Child-Pugh class B or C (moderate to severe cirrhosis). Liver resection is generally used for early HCC in livers classified as Child-Pugh class A (NCCN, 2013). Additionally, current UNOS criteria indicate a liver transplant candidate must not be eligible for resection.(1) However, the best treatment approach for early HCC in well-compensated livers is controversial. In 2013, Zheng et al reported on a meta-analysis of 62 cohort studies (n=10,170 total patients) comparing liver transplantation to liver resection for HCC.(34) Overall 1-year survival was similar between procedures (OR=1.08; 95% CI, 0.81 to 1.43; p=0.61). However, overall 3- and 5-year survival significantly favored liver transplantation over resection (OR=1.47; 95% CI, 1.18 to 1.84; p<0.001; OR=1.77; 95% CI, 1.45 to 2.16; p<0.001, respectively). Disease-free survival in liver transplant patients was 13%, 29%, and 39% higher than in liver resection patients at 1, 3, and 5 years, all respectively (p<0.001). Recurrence rates were also 30% lower in liver transplantation than resection (OR=0.20; 95% CI, 0.15 to 0.28; p<0.001).
 
In patients who have a recurrence of HCC after primary liver resection, salvage liver transplantation has been considered a treatment alternative to repeat hepatic resection, chemotherapy, or other local therapies such as radiofrequency ablation, transarterial chemoembolization, percutaneous ethanol ablation, or cryoablation.
 
Several systematic reviews have evaluated the evidence on outcomes of salvage transplant compared with primary transplant. In a 2013 meta-analysis of 14 nonrandomized comparative studies by Zhu et al, (n=1272 for primary transplant and n=236 for salvage),(Zhu. 2013) overall survival at 1, 3, and 5 years and disease-free survival at 1 and 3 years was not significantly different between groups. Disease-free survival, however, was significantly lower at 5 years in salvage liver transplantation compared with primary transplantation (OR=0.62; 95% CI, 0.42 to 0.92; p=0.02). There was insufficient data to evaluate outcomes in patients exceeding Milan criteria, but in patients meeting Milan criteria, survival outcomes were not significantly different suggesting salvage liver transplantation may be a viable option in these patients.
 
 Living Donor versus Deceased Donor Liver Transplant Recipient Outcomes
In 2013, Grant et al reported on a systematic review and meta-analysis of 16 studies to compare recipient outcomes between living donor liver transplants and deceased donor liver transplants for HCC (Grant, 2013). For disease-free survival after living donor liver transplantation, the combined hazard ratio (HR) was 1.59 (95% confidence interval [CI], 1.02 to 2.49) compared with deceased donor liver transplantation. For overall survival, the combined HR was 0.97 (95% CI, 0.73 to 1.27). The studies included in the review were mostly retrospective and considered to be of low quality. Further study is needed to determine any differences between living and deceased liver transplantation outcomes.
 
In 2013, Chan et al systematically reviewed 16 nonrandomized studies (n=319) on salvage liver transplantation after primary hepatic resection for HCC (Chad, 2014). The authors found that overall and disease-free survival outcomes with salvage liver transplantation were similar to reported primary liver transplantation outcomes. The median overall survival for salvage liver transplantation patients was 89%, 80% and 62% at 1, 3, and 5 years, respectively. Disease-free survival was 86%, 68% and 67% at 1, 3, and 5 years, respectively. Salvage liver transplantation studies had median overall survival rates of 62% (range, 41%-89%) compared with a range of 61% to 80% in the literature for primary liver transplantation. Median disease-free survival rates for salvage liver transplantation were 67% (range, 29%-100%) compared with a range of 58% to 89% for primary liver transplantation. Given a limited donor pool and increased surgical difficulty with salvage liver transplantation, further studies are needed. UNOS criteria indicate liver transplant candidates with HCC who subsequently undergo tumor resection must be prospectively reviewed by a regional review board for the extension application.
 
Nonalcoholic Steatohepatitis
Liver transplantation is a treatment option for patients with nonalcoholic steatohepatitis (NASH) who progress to liver cirrhosis and failure. In a 2013 systematic review and meta-analysis, Wang et al evaluated 9 studies comparing liver transplantation outcomes in patients with and without NASH (Wang, 2013). Patients with NASH had similar 1-, 3-, and 5-year survival outcomes after liver transplantation as patients without NASH. Patients with NASH also had lower graft failure risk than those without NASH (OR=0.21; 95% CI, 0.05 to 0.89; p=0.03). However, NASH liver transplant patients had a greater risk of death related to cardiovascular disease (OR=1.65; 95% CI, 1.01 to 2.70; p=0.05) and sepsis (OR=1.71; 95% CI, 1.17 to 2.50; p=0.006) than non-NASH liver transplant patients.
 
Pediatric Hepatoblastoma
Hepatoblastoma is a rare malignant primary solid tumor of the liver that occurs in children. Treatment consists of chemotherapy and resection; however, often tumors are not discovered until they are unresectable. In cases of unresectable tumors, liver transplantation with pre- and/or postchemotherapy is a treatment option with reports of good outcomes and high rates of survival (Czauderna, 2005). UNOS guidelines list nonmetastatic hepatoblastoma as a condition eligible for pediatric liver transplantation. In 2011, Barrena et al reported on 15 children with hepatoblastoma requiring liver transplantation (Barrena, 2011). Overall survival after liver transplant was 93.3% (6.4%) at 1, 5, and 10 years. In 2010, Malek et al reported on liver transplantation results for 27 patients with primary liver tumor identified from a retrospective review of patients treated between 1990 and 2007 (Malek, 2010). Tumor recurrence occurred in 1 patient after liver transplantation, and overall survival was 93%. In 2008 Browne et al reported on 14 hepatoblastoma patients treated with liver transplantation. Mean follow-up was 46 months, with overall survival in 10 of 14 patients (71%). Tumor recurrence caused all 4 deaths. In the 10 patients receiving primary liver transplantation, 9 survived while only 1 of 4 patients transplanted after primary resection survived (90% vs 25%, p=0.02) (Browne, 2008). While studies on liver transplantation for pediatric hepatoblastoma are limited, case series have demonstrated good outcomes and high rates of long-term survival. Additionally, nonmetastatic pediatric hepatoblastoma is included in UNOS criteria for patients eligible for liver transplantation. Therefore, liver transplantation for nonmetastatic pediatric hepatoblastoma may be considered medically necessary.
 
2015 Update
A literature search conducted through December 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Metastatic Neuroendocrine Tumors
In 2014, Fan et al reported on a systematic review of 46 studies on liver transplantation for NET liver metastases of any origin (Fan. 2015). A total of 706 patients were included in the studies reviewed. Reported overall 5-year survival rates ranged from 0 to 100%, while 5-year disease-free survival rates ranged from 0 to 80%. In studies with more than 100 patients, the 5-year overall survival rate and disease-free survival rate averaged about 50% and 30%, respectively. Frequent and early NET recurrences after liver transplantation were reported in most studies.
 
The NCCN guidelines on neuroendocrine tumors V1.2015 indicate liver transplantation for neuroendocrine tumor liver metastases is considered investigational (NCCH 2015).
AASLD and the American Society of Transplantation issued a 2013 guideline for the long-term medical management of the pediatric patient after liver transplant (AASLD, 2013). The guideline makes the following statement regarding liver transplant in children:
 
Pediatric liver transplant has dramatically changed the prognosis for many infants and children with liver failure and metabolic disease. As survival increases, long-term maintenance resources exceed perioperative care requirements. The most common indication for liver transplant in children is biliary atresia which accounts for 50% of all children requiring transplant in the U.S. and 74% in Europe.
 
Update 2017
A literature search conducted through February 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
HCC Selection Criteria
Patient selection criteria for liver transplantation for HCC have focused mainly on the number and size of tumors. In 1996 Mazzafaro and colleagues identified patient criteria associated with improved outcomes after liver transplantation for HCC with cirrhosis (Mazzafaro, 1996). Patient selection criteria became known as the Milan criteria and specifies patients may have either a solitary tumor with a maximum tumor diameter of 5 cm or less, or up to 3 tumors 3 cm or less. An editorial by Llovet noted that the Milan criteria is considered the criterion standard for selecting transplant candidates (Llovet, 2005). Patients with extrahepatic spread or macrovascular invasion have a poor prognosis. UNOS adopted the Milan criteria, combined with 1 additional criteria (no evidence of extrahepatic spread or macrovascular invasion), as its liver transplantation criteria. Interest in expanding liver transplant selection criteria for HCC and other indications is ongoing. A 2001 paper from the University of California, San Francisco (UCSF) (Yao, 2001), proposed expanded criteria to include patients with a single tumor 6.5 cm or less in diameter, 3 or fewer tumors 4.5 cm or less, and a total tumor size of 8 cm or less. It should be noted that either set of criteria can be applied preoperatively (with imaging) or with pathology of the explanted liver at the time of intended transplant. Preoperative staging often underestimates what is seen on surgical pathology. To apply pathologic criteria, a backup candidate must be available in case preoperative staging is inaccurate. Given donor organ scarcity, any expansion of liver transplant selection criteria has the potential to prolong waiting times for all candidates. Important outcomes in assessing expanded criteria include waiting time duration, death, or deselection due to disease progression while waiting (dropout), survival time, and time to recurrence (or related outcomes such as disease-free survival). Survival time can be estimated beginning when the patient is placed on the waiting list, using the intention-to-treat principal, or at the time of transplantation. Llovet stated that 1- year dropout rates for patients meeting Milan criteria are 15% to 30%, and 5-year survival rates not reported by intention-to-treat should be adjusted down by 10% to 15%.
 
Relevant outcomes for studies on liver transplantation include waiting time duration, dropout rates, survival time, and recurrence. As experience with liver transplant has matured, patient selection criteria have broadened to include a wide variety of etiologies. The most controversial etiologies include viral hepatitis and primary hepatocellular cancer (HCC). In particular, the presence of hepatitis B virus (HBV) and hepatitis C virus (HCV) have been controversial indications for liver transplantation because of the high potential for recurrence of the virus and subsequent recurrence of liver disease. However, registry data indicate a long-term survival rate (7 years) of 47% in HBV-positive transplant recipients, which is lower than that seen in other primary liver diseases such as primary biliary cirrhosis (71%) or alcoholic liver disease (57%) (Belle, 1995). Recurrence of HCV infection in transplant recipients has been nearly universal, and 10% to 20% of patients will develop cirrhosis within 5 years (Sheiner, 2012).  Although these statistics raise questions about the most appropriate use of a scarce resource (donor livers), the long-term survival rates are significant in a group of patients who have no other treatment options. Similarly, the long-term outcome in patients with primary hepatocellular malignancies was poor (19%) in the past compared with the overall survival of liver transplant recipients. However, recent use of standardized patient selection criteria, such as the Milan criteria (a solitary tumor with a maximum tumor diameter of £5 cm, or up to 3 tumors £3 cm and without extrahepatic spread or macrovascular invasion), has dramatically improved overall survival rates. In a systematic review of liver transplant for HCC in 2012, Maggs and colleagues found 5-year overall survival rates ranged from 65% to 94.7% in reported studies (Maggs, 2012). Nevertheless, transplant represents the only curative approach for many of these patients who present with unresectable organ-confined disease, and expansion of patient selection criteria, bridging to transplant or downstaging of disease to qualify for liver transplantation is frequently studied. Liver transplant cannot be considered curative in patients with locally extensive or metastatic liver cancer or in patients with isolated liver metastases with extrahepatic primaries or in cholangiocarcinoma (Belle, 1995).
 
In their 2008 review, Schwartz and colleagues argue that selection based exclusively on the Milan criteria risks prognostic inaccuracy due to the diagnostic limitations of imaging procedures and the surrogate nature of size and number of tumors (Schwartz, 2008). They predict that evolution of allocation policy will involve the following: (1) the development of a reliable prognostic staging system to help with allocation of therapeutic alternatives; (2) new molecular markers that might improve prognostic accuracy; (3) aggressive multimodality neoadjuvant therapy to downstage and limit tumor progression before transplant and possibly provide information about tumor biology based on response to therapy; and (4) prioritization for transplantation should consider response to neoadjuvant therapy, time on waiting list, suitability of alternative donor sources. Two papers describe work on identifying predictors of survival and recurrence of disease. Loannou and colleagues analyzed UNOS data pre- and postadoption of the Model for End-stage Liver Disease (MELD) allocation system finding a 6-fold increase in recipients with HCC and that survival in the MELD era was similar to survival in patients without HCC (Loannou, 2008). The subgroup of patients with larger (3-5 cm) tumors, serum alpha-fetoprotein level 455 mg/mL or greater, or a MELD score 20 or greater, however, had poor transplantation survival. A predicting cancer recurrence scoring system was developed by Chan and colleagues based on a retrospective review and analysis of liver transplants at 2 centers to determine factors associated with recurrence of HCC (Chan, 2008). Of 116 patients with findings of HCC in their explanted livers, 12 developed recurrent HCC. Four independent significant explant factors were identified by stepwise logistic regression: size of 1 tumor greater than 4.5 cm, macroinvasion, and bilobar tumor were positive predictors of recurrence, and the presence of only well-differentiated HCC was a negative predictor. Points were assigned to each factor in relation to its odds ratio (OR). The accuracy of the method was confirmed in 2 validation cohorts.
 
In 2010, Guiteau and colleagues reported on 445 patients transplanted for HCC in a multicenter, prospective study in UNOS Region 4 (Guiteau, 2010). On preoperative imaging, 363 patients met Milan criteria, and 82 patients were under expanded Milan criteria consisting of 1 lesion less than 6 cm, 3 or less lesions, none greater than 5 cm and total diameter less than 9 cm. Patient allograft and recurrence-free survival at 3 years did not differ significantly between patients meeting Milan criteria versus patients under the expanded criteria (72.9% and 77.1%, 71% and 70.2% and 90.5% and 86.9%, all respectively). While preliminary results showed similar outcomes when using expanded Milan criteria, the authors noted their results were influenced by waiting times in Region 4 and that similar outcomes may be different in other regions with different waiting times. Additionally, the authors noted that a report from a 2010 national HCC consensus conference on liver allocation in HCC patients does not recommend expanding Milan criteria nationally and encourages regional agreement (Pomfret, 2010). The report addressed the need to better characterize the longterm outcomes of liver transplantation for patients with HCC and to assess whether it is justified to continue the policy of assigning increased priority for candidates with early-stage HCC on the transplant waiting list in the United States. Overall, the evidence base is insufficient to permit conclusions about health outcomes after liver transplantation among patients exceeding Milan criteria and meeting expanded UCSF or other criteria.
 
Liver Transplantation versus Liver Resection for HCC
In a 2012 meta-analysis, Li and colleagues compared primary liver transplantation to salvage liver transplantation (liver transplantation after liver resection) for HCC (Li, 2012). Included in the meta-analysis were 11 case-controlled or cohort studies totaling 872 primary liver transplants and 141 salvage liver transplants.
 
Overall survival and disease-free survival rates between primary liver transplantation and salvage liver transplantation were not statistically significant at 1, 3, and 5 years (p>0.05). Survival rates of patients who exceeded the Milan criteria at 1, 3, and 5 years were also not significantly different between the 2 groups (1-year OR=0.26; 95% CI, 0.01 to 4.94; p=0.37; 3-year OR=0.41; 95% CI, 0.01 to 24.54; p=0.67; 5-year OR=0.55; 95% CI, 0.07 to 4.48; p=0.57).
 
HIV-Positive Patients
In 2011, Cooper and colleagues conducted a systematic review to evaluate liver transplantation in patients coinfected with HIV and hepatitis (Cooper, 2011). The review included 15 cohort studies and 49 case series with individual patient data. The survival rate of patients was 84.4% (95% CI, 81.1% to 87.8%) at 12 months. Patients were 2.89 (95% CI, 1.41 to 5.91) times more likely to survive when HIV viral load at the time of transplantation was undetectable compared with those with detectable HIV viremia.
 
Cholangiocarcinoma
Reports on outcomes after liver transplantation for cholangiocarcinoma, or bile duct carcinoma generally distinguish between intrahepatic and extrahepatic tumors, the latter including hilar or perihilar tumors. Recent efforts have focused on pretransplant downstaging of disease with neoadjuvant radiochemotherapy.
 
Gu and colleagues reported on a systematic review and meta-analysis of 14 clinical trials on liver transplantation for cholangiocarcinoma (Gu, 2012). Overall 1-, 3-, and 5-year pooled survival rates from 605 study patients were 0.73 (95% CI, 0.65 to 0.80), 0.42 (95% CI, 0.33 to 0.51), and 0.39 (95% CI, 0.28 to 0.51), respectively. When patients received adjuvant therapies preoperatively, 1-, 3-, and 5-year pooled survival rates improved and were 0.83 (95% CI, 0.57 to 0.98), 0.57 (95% CI, 0.18 to 0.92), and 0.65 (95% CI, 0.40 to 0.87), respectively.
 
Darwish Murad and colleagues reported on 287 patients from 12 transplant centers treated with neoadjuvant therapy for perihilar cholangiocarcinoma followed by liver transplantation (Darwish, 2012). Intention-to-treat survival (after a loss of 71 patients before liver transplantation) was 68% at 2 years and 53% at 5 years, and recurrence-free survival rates posttransplant were 78% at 2 years and 65% at 5 years. Survival time was significantly shorter for patients who had a previous malignancy or did not meet UNOS criteria by having a tumor size greater than 3 cm, metastatic disease, or transperitoneal tumor biopsy (p<0.001).
 
The European Liver Transplant Registry was cited by a review article (Pascher, 2003).  Among 186 patients with intrahepatic cholangiocarcinoma, 1-year survival was 58%, and 5-year survival was 29%. In 169 patients with extrahepatic cholangiocarcinoma, the probabilities were 63% and 29%, respectively. The Cincinnati Transplant Registry (Meyer, 2000) reported on 207 patients with either intrahepatic or extrahepatic cholangiocarcinoma, finding a 1-year survival of 72% and a 5-year rate of 23%. The multicenter Spanish report (Robles, 2004) included 36 patients with hilar tumors and 23 with peripheral intrahepatic disease. One-year survival was 82% and 77%, while 5-year survival was 30% and 23% in the 2 groups, respectively.
 
Of all the values discussed in this paragraph, among the individual centers, the Mayo Clinic in Minnesota has the most experience and most favorable results ((Heimbach, 2006; Rea, 2005). Between 1993 and 2006, 65 patients underwent liver transplantation for unresectable perihilar cholangiocarcinoma or had perihilar tumor due to primary sclerosing cholangitis. Unresectable patients underwent neoadjuvant radiochemotherapy. One-year survival was 91% and 5-year survival was 76%. The University of California, Los Angeles/Cedars-Sinai (Shimoda, 2001) reported on 25 cases of both intrahepatic and extrahepatic cholangiocarcinoma. One-year survival was 71% and 3-year survival was 35%. The University of Pittsburgh found 1-year survival of 70% and 5-year survival of 18% among 20 patients with intrahepatic cholangiocarcinoma (Casavilla, 1997).  A German study of 24 patients reported the poorest results (Weimann. 2000). In 2011, Friman and colleagues reported on 53 patients who received liver transplants for cholangiocarcinoma during the period of 1984-2005, in Norway, Sweden, and Finland (Friman, 2011). The 5-year survival rate was 25% overall, 36% in patients with TNM stage 2 or less, and 10% in patients with TNM greater than 2. On further analysis using only data from those patients transplanted after 1995, the 5-year survival rate increased to 38% versus 0% for those transplanted before 1995. Additionally, the 5-year survival rate increased to 58% in those patients transplanted after 1995 with TNM stage 2 or less and a CA 19-9 100 or less.
 
Some articles have reported recurrence data using survival analysis techniques. In a series of 38 patients from the Mayo Clinic, cumulative recurrence was 0% at 1 year, 5% at 3 years, and 13% at 5 years (Rea, 2005). The series of 20 patients from the University of Pittsburgh experienced 67% 1-year tumor-free survival and a 31% 5-year rate (Shimoda, 2001). The multicenter Spanish series reported crude recurrence rates of 53% and 36% for extrahepatic and intrahepatic cholangiocarcinoma, respectively (Robles, 2004). The German center at Hannover found a crude recurrence rate of 63% (Weimann, 2000).
 
Mayo Clinic has reported promising results after liver transplantation for cholangiocarcinoma. Five-year patient survival among 65 patients who received neoadjuvant radiochemotherapy was 76%. No other center or group of centers reported 5-year survival above 30%. The Mayo Clinic found a 5-year cumulative recurrence rate of 13% among 38 patients and additional recurrence data are quite limited.
While a single center’s results are encouraging, it is important to see if other centers can produce similar findings before forming conclusions about outcomes after liver transplantation for cholangiocarcinoma.
 
Wu and colleagues describe an extensive surgical procedure combined with radiotherapy (Wu, 2008). They retrospectively review their experience with surveillance and early detection of cholangiocarcinoma and en bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) in a small series of patients with early-stage cholangiocarcinoma complicating primary sclerosing cholangitis. Surveillance involved endoscopic ultrasound and endoscopic retrograde cholangiopancreatography and cytological evaluation. Patients diagnosed with cholangiocarcinoma were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple. Cholangiocarcinoma was detected in 8 of the 42 patients followed up according to the surveillance protocol between 1988 and 2001, and 6 patients underwent OLT-Whipple. One died at 55 months after transplant of an unrelated cause without tumor recurrence, and 5 are without recurrence at 5.7 to 10.1 years.
 
Hepatitis C
Mukherjee and Sorrell, reviewing controversies in liver transplantation for hepatitis C, indicate that the greatest opportunity for HCV eradication is pretransplant before hepatic decompensation (Mukherjee, Sorrell, 2008). Challenges of treatment posttransplantation include immunosuppressive drugs and abnormal hematologic, infectious, and liver function parameters. The authors list the following factors associated with poor outcomes in liver transplantation for recurrent HCV: high HCV-RNA level pretransplant, non-Caucasian ethnicity, advanced donor age, T cell-depleting therapies, inappropriate treatment of Banff A1 acute cellular rejection (ACR) with steroid boluses, cytomegalovirus disease, and year of transplantation (worse with recent transplants). They cite the International Liver Transplantation Society Consensus on Retransplantation, which states that the following are associated with worse outcomes of retransplantation: total bilirubin level greater than 10mg/dL, creatinine level greater than 2 mg/dL, age greater than 55 years, development of cirrhosis in the first posttransplant year, and donor age greater than 40 years.
 
Metastatic Neuroendocrine Tumors
Mathe and colleagues conducted a systematic review of the literature to evaluate patient survival after liver transplant for pancreatic NETs (Mathe, 2011). Data from 89 transplanted patients from 20 clinical studies were included in the review. Sixty-nine patients had primary endocrine pancreatic tumors, 9 patients were carcinoids, and 11 patients were not further classified. Survival rates at 1, 3, and 5 years were 71%, 55%, and 44%, respectively. The mean calculated survival rate was 54.45 (6.31) months, and the median calculated survival rate was 41 months (95% CI, 22 to 76 months). While there may be centers that perform liver transplantation on select patients with NETs, further studies are needed to determine appropriate selection criteria. The quality of available studies is currently limited by their retrospective nature and heterogeneous populations.
 
Pediatric Hepatoblastoma
Barrena and colleagues reported on 15 children with hepatoblastoma requiring liver transplantation (Barrena, 2011).  Overall survival after liver transplant was 93.3% (6.4%) at 1, 5, and 10 years. In 2010, Malek and colleagues reported on liver transplantation results for 27 patients with primary liver tumor identified from a retrospective review of patients treated between 1990 and 2007 (Malek, 2010). Tumor recurrence occurred in 1 patient after liver transplantation, and overall survival was 93%. In 2008 Browne et al reported on 14 hepatoblastoma patients treated with liver transplantation. Mean follow-up was 46 months, with overall survival in 10 of 14 patients (71%). Tumor recurrence caused all 4 deaths. In the 10 patients receiving primary liver transplantation, 9 survived while only 1 of 4 patients transplanted after primary resection survived (90% vs 25%, p=0.02) (Browne, 2008). While studies on liver transplantation for pediatric hepatoblastoma are limited, case series have demonstrated good outcomes and high rates of long-term survival. Additionally, nonmetastatic pediatric hepatoblastoma is included in UNOS criteria for patients eligible for liver transplantation. Therefore, liver transplantation for nonmetastatic pediatric hepatoblastoma may be considered medically necessary.
 
Retransplantation
Bellido and colleagues reported on a retrospective cohort study of 68 consecutive adult liver retransplantations using registry data (Bellido, 2012). Survival probability using Kaplan-Meier curves with log-rank tests to compare 21 urgent versus 47 elective retransplantations were calculated. Overall survival rates were significantly better in patients undergoing urgent procedures (87%), which were mostly due to vascular complications than elective procedures (76.5%), which were mostly related to chronic rejection.
 
Remiszewski  and colleagues examined factors influencing survival outcomes in 43 liver retransplantation patients (Remiszewski, 2011). When compared with primary liver transplantation patients, retransplantation patients had significantly lower 6-year survival rates (80% vs 58%, respectively; p<0.001). The authors also reported low negative correlations between survival time and time from original transplantation until retransplantation and between survival time and patient age. Survival time and cold ischemia time showed a low positive correlation.
 
Hongan colleagues reported on a prospective study of 466 adults to identify risk factors for survival after liver retransplantation (Hong, 2011). Eight risk factors were identified as predictive of graft failure, including age of recipient, MELD score greater than 27, more than 1 prior liver transplant, need for mechanical ventilation, serum albumin of less than 2.5 g/dL, donor age older than 45 years, need for more than 30 units of packed red blood cells transfused intraoperatively, and time between prior transplantation and retransplantation between 15 and 180 days. The authors propose this risk-stratification model can be highly predictive of long-term outcomes after adult liver retransplantation and can be useful in patient selection.
 
2018 Update
A literature search was conducted through July 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American Association for the Study of Liver Diseases et al
The American Association for the Study of Liver Diseases, the American Society of Transplantation, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition provided joint guidelines on the evaluation of the pediatric patients for liver transplant in 2014 (AASLD, 2014; AST, 2014; NASPGHN, 2014). 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 patients, justifying independent pediatric guidelines.” The indications listed for liver transplantation included biliary atresia, Alagille syndrome, pediatric acute liver failure, hepatic tumors, hepatocellular carcinoma, hemangioendothelioma, cystic fibrosis-associated liver disease, urea cycle disorders, immune-mediated liver disease, along with other metabolic or genetic disorders.

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