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Aetna Aetna
Clinical Policy Bulletin:
Liver Transplantation
Number: 0596


Policy

Aetna considers liver transplantation medically necessary for the indications listed below for adolescents and adults with either (i) a Model of End-stage Liver Disease (MELD) score (see Appendix) greater than 10; or (ii) who are approved for transplant by the United Network for Organ Sharing (UNOS) Regional Review Board, and for children less than 12 years of age who meet the transplanting institution's selection criteria.  Requests for liver transplantation for adolescents and adults with a MELD score of 10 or less who have not been approved by the UNOS Regional Review Board are subject to medical necessity review.  In the absence of an institution's selection criteria, Aetna considers liver transplantation medically necessary for adolescents and adults with a MELD score greater than 10 or who are approved by the UNOS Regional Review Board and for children who meet the medical necessity criteria specified below.

  1. Medically Necessary Indications (not an all inclusive list)

    Aetna considers orthotopic (normal anatomical position) liver transplantation (with cadaveric organ, reduced-size organ, living related organ, and split liver) medically necessary for members with end-stage liver disease (ESLD) due to any of the following conditions.

    1. Cholestatic diseases:

      1. Biliary atresia
      2. Familial cholestatic syndromes
      3. Primary biliary cirrhosis
      4. Primary sclerosing cholangitis with development of secondary biliary cirrhosis  
         
    2. Hepatocellular diseases:

      1. Alcoholic cirrhosis
      2. Chronic active hepatitis with cirrhosis (hepatitis B or C)
      3. Cryptogenic cirrhosis
      4. Idiopathic autoimmune hepatitis
      5. Post-necrotic cirrhosis due to hepatitis B surface antigen negative state  
         
    3. Malignancies:

      1. Primary hepatocellular carcinoma confined to the liver when all of the following criteria are met:

        1. Any lung metastases that have been shown to be responsive to chemotherapy; and
        2. Member is not a candidate for subtotal liver resection; and
        3. Member meets UNOS criteria for tumor size and number; and
        4. There is no identifiable extra-hepatic spread of tumor to surrounding lymph nodes, abdominal organs, bone or other sites; and
        5. There is no macrovascular involvement.

        Note: These criteria are intended to be consistent with UNOS guidelines for selection of liver transplant candidates for hepato-cellular carcinoma (HCC).

      2. Hepatoblastomas in children when all of the following criteria are met:

        1. Member is not a candidate for subtotal liver resection; and
        2. Member meets UNOS criteria for tumor size and number; and
        3. There is no identifiable extra-hepatic spread of tumor to surrounding lungs, abdominal organs, bone or other sites.  (Note: spread of hepatoblastoma to veins and lymph nodes does not disqualify a member for coverage of a liver  transplant.)  
           
      3. Epithelioid hemangioendotheliomas;
      4. Intra-hepatic cholangiocarcinomas (i.e., cholangiocarcinomas confined to the liver);
      5. Large, unresectable fibrolamellar HCCs;
      6. Metastatic neuroendocrine tumors (carcinoid tumors, apudomas, gastrinomas, glucagonomas) in persons with severe symptoms and with metastases restricted to the liver, who are unresponsive to adjuvant therapy after aggressive surgical resection including excision of the primary lesion and reduction of hepatic metastases.
         
    4. Vascular diseases:

      1. Budd-Chiari syndrome
      2. Veno-occlusive disease.
         
    5. Metabolic disorders and metabolic liver diseases with cirrhosis (not an all-inclusive list):

      1. Alpha 1-antitrypsin deficiency
      2. Hemochromatosis
      3. Inborn errors of metabolism
      4. Protoporphyria
      5. Wilson's disease.
         
    6. Miscellaneous:

      1. Familial amyloid polyneuropathy
      2. Polycystic disease of the liver
      3. Porto-pulmonary hypertension (pulmonary hypertension associated with liver disease or portal hypertension) in persons with a mean pulmonary artery pressure by catheterization of less than 35 mm Hg
      4. Toxic reactions (fulminant hepatic failure due to mushroom poisoning, acetaminophen (Tylenol) overdose, etc.)
      5. Trauma
      6. Hepato-pulmonary syndrome when the following selection criteria are met:
         
      • Arterial hypoxemia (PaO2 less than 60 mm Hg or AaO2 gradient greater than 20 mm Hg in supine or standing position); and
      • Chronic liver disease with non-cirrhotic portal hypertension; and
      • Intrapulmonary vascular dilatation (as indicated by contrast-enhanced echocardiography, technetium-99 macroaggregated albumin perfusion scan, or pulmonary angiography).
         
  2. Retransplantation

    Aetna considers retransplantation following a failed liver transplant medically necessary if the initial transplant was performed for a covered indication.

  3. Contraindications

    Aetna considers liver transplantation not medically necessary for members with any of the following absolute contraindications to liver transplantation:

    1. Active alcoholism or active substance abuse
    2. Active sepsis outside the biliary tract
    3. Other effective medical treatments or surgical options are available
    4. Presence of significant organ system failure other than kidney, liver or small bowel.
       
  4. Experimental and Investigational Procedures

    Aetna considers the following indications/procedures regarding liver transplantation experimental and investigational because their safety and effectiveness has not been established:

    1. Bioartificial liver transplantation 
    2. Ectopic or auxiliary liver transplantation
    3. Hepatocellular (hepatocyte) transplantation
    4. Malignancies other than those listed as covered above
    5. Xenotransplantation.

Note: For policy on hepatitis B immune globulin for prophylaxis of recurrent hepatitis B infection in HbsAg positive liver transplant recipients, see CPB 0544 - Immune Globulins for Post-exposure Prophylaxis.



Background

Progressive liver diseases that result in death either in short-term or long-term is known as end-stage liver disease (ESLD), which is evidenced by irreversible, progressive liver dysfunction, variceal bleeding, encephalopathy, synthetic dysfunction, poor growth, or poor nutritional status.  The most common causes of ESLD include infection (e.g., acute or chronic hepatitis), toxic effects (e.g., alcohol, medications), disorders of metabolism (e.g., hemochromatosis, Wilson's disease), tumors (primary or metastatic), and malformations (e.g., primary biliary atresia).  Liver transplantation is an effective treatment for fulminant (acute) hepatic failure and for many chronic liver diseases.

A liver transplant is usually positioned in the normal anatomical position (orthotopic) following a total hepatectomy of the recipient.  In auxiliary liver transplantation, a second liver is implanted ectopically and the recipient's own liver remains in-situ.  A major concern of ectopic transplantation is the recipient's diseased liver may harbor bacterial, fungal or viral infection or cancer.  Advances in surgical techniques and immunosuppressive drugs have resulted in increased survival rates (with 1-year survival rates in the 85 to 90 % range, and 5-year survival rates exceeding 70 %).  Currently, 10 to 20 % of liver transplanted patients are retransplanted with a success rate of greater than 50 %.

Hepatitis C cirrhosis is the most common indication for liver transplantation.  Alcoholic liver disease remains a controversial indication for liver transplantation but carefully selected patients do well.  Some of the common indications for liver transplantation are as follows:

  1. Alcoholic liver disease (after a period of abstinence)
  2. Chronic active hepatitis (usually secondary to hepatitis B and C)
  3. Cryptogenic cirrhosis
  4. Primary biliary cirrhosis
  5. Primary sclerosing cholangitis

Hepato-cellular carcinoma (HCC) complicates many chronic liver diseases.  However, a small tumor is not a contraindication to transplantation since tumor rarely recurs in these patients.  In contrast, most patients with large (greater than 5 cm in diameter) or multiple hepatomas or most other types of cancer are not considered for transplantation since tumors recur rapidly.  At present, there is insufficient evidence that liver transplantation is an effective treatment for other malignancies that affect the liver such as metastatic disease, bile duct carcinoma, and epitheloid hemangioendothelioma, among others.  An assessment by the Agency for Healthcare Research and Quality (Beavers et al, 2001) on liver transplantation for malignancies other than HCC concluded that “[t]he available evidence does not provide a clear profile of patients who might be optimal candidates for such therapy.”  Contraindications to liver transplantation include extra-hepatic malignancy, severe cardiopulmonary disease, systemic sepsis, and an inability to comply with regular pharmacotherapy.

Liver transplantation is an effective treatment for a variety of acute and chronic diseases of the liver in the pediatric (less than 18 years of age) population.  Approximately 15 % of the liver transplantations performed yearly in the United States are in pediatric patients.  Most children who need liver transplantation are young (age less than 3 years) and small (body weight less than 45 pounds).  Size-matched organs are given preference in organ allocation.  However, because of the severe scarcity of pediatric donor livers, techniques such as reduced size (“cut down”) and split (a liver is split between 2 recipients) liver transplantations are used to reduce the size of adult donor livers to fit pediatric recipients.  Donation of the left lobe of the liver by a living adult relative (“living related donor”) is also an option.  Liver transplantation in children is indicated for ESLD from any etiology in the absence of contraindications.  The most common indication for pediatric liver transplantation is biliary atresia, often after failure to respond to a porto-enterostomy.  In addition, unresectable tumors and liver-based metabolic deficiencies may be indications for liver transplantation.

The Model for End-Stage Liver Disease (MELD) is a numerical scale, ranging from 6 (less ill) to 40 (gravely ill), that is used for adult liver transplant candidates.  It gives each individual a 'score' (number) based on how urgently he or she needs a liver transplant within the next 3 months.  The number is calculated by a formula using bilirubin, prothrombin time, and creatinine.  Candidates under the age of 12 are placed in categories according to the Pediatric End-stage Liver Disease (PELD) scoring system.  PELD is similar to MELD but uses some different criteria to recognize the specific growth and development needs of children.  PELD scores may also range higher or lower than the range of MELD scores.  The PELD scoring system takes into account the patient's bilirubin, prothrombin time, albumin, growth failure, and whether the child is less than 1 year old.  A liver transplantion is rarely necessary for persons with a MELD score of less than 10.  According to data from the United Network for Organ Sharing (UNOS), of almost 5,000 liver transplants that were performed in 2002, only 181 transplants were performed on patients with a MELD score of less than 10. 

The MELD/PELD score is a well-validated measure of short-term mortality from liver disease; however, referring physicians who believe a patient faces a greater mortality risk than predicted by the MELD/PELD score can request accelerated listing.  UNOS Regional Review Boards can approve or deny these requests, and a study by Voight et al (2004) concluded that these boards fairly and accurately distinguish between high- and low-risk patients.  The study found that the denials of physicians' requests for accelerated listings did not increase mortality for those patients.  To determine the effect of UNOS Regional Review Board decisions on the mortality of physician-referred patients, investigators analyzed 1,965 nationwide referrals to UNOS Regional Review Boards.  They noted which cases were approved and which were denied, and gathered information about patient deaths while awaiting transplantation.  The investigators found that there was no significant difference in survival to transplantation whether accelerated listing was approved or denied for adult or pediatric cases.  In addition, the researchers examined whether or not referring physicians predicted death better than the MELD/PELD score.  The investigators found that the physicians had poor predictive capacity and added no additional information to to the risk assessment by the MELD/PELD score.  The investigators concluded that  the MELD-PELD score is a better predictor of mortality than the judgement of the referring physician, but the UNOS Regional Review Board process adds additional information (e.g., Voight et al, 2004).

The success of transplantation has led to a marked increase in the number of candidates to over 16,000 places on the national waiting list.  However, there has been little growth in the supply of available cadaveric organs, resulting in an organ shortage crisis.  With waiting times often exceeding 1 to 2 years, the waiting list death rate now exceeds 10 % in most regions.  Researchers have investigated novel approaches such as xenotransplantation, hepato-cellular transplantation and bioartificial liver to address the growing disparity between the limited supply and excessive demand for suitable organs.  However, all these approaches are considered investigational in nature at this juncture.

Studies on xenotransplantation are performed using primates (e.g., baboons, and smaller monkeys).  Transmission of diseases, which can be transmitted from animals to humans under natural conditions (zoonoses) as well as hyper-acute rejection remains major concerns in xenotransplantation.  Hepatocellular transplantation is used either to temporarily or permanently replace the diseased liver.  Hepatocytes are seeded onto biodegradable polymer that serves as a temporary extra-cellular matrix and to induce vascular in-growth.  The seeded polymer is then implanted into a vascular rich area, such as the mesentery of the small intestine.  Other techniques including direct injection into the spleen or liver.  A bioartificial liver is designed to treat liver disease in the manner similar to a dialysis machine treats renal disease.  Investigators use porcine hepatocytes or a transformed line of hepatocytes housed in a bioreactor allowing plasma from patients with liver failure to perfuse through it.  It can be used either as a bridge to liver transplantation or to allow recovery of the native liver.

Artificial and bioartificial livers have been developed for use as a bridge to transplant in patients with liver failure or to allow recovery in persons with acute liver failure.  Liu et al (2004) reported on the results of a meta-analysis of 12 trials of artificial or bioartificial support systems versus standard medical therapy, involving 483 patients, and 2 trials comparing different artificial support systems, involving 105 patients.  Most trials had unclear methodological quality.  Compared to standard medical therapy, support systems had no significant effect on mortality (relative risk [RR] 0.86; 95 % confidence interval [CI]: 0.65 to 1.12) or bridging to liver transplantation (RR 0.87; 95 % CI: 0.73 to 1.05), but a significant beneficial effect on hepatic encephalopathy (RR 0.67; 95 % CI: 0.52 to 0.86).  Subgroup analysis indicated that artificial and bioartificial livers may reduce mortality by 1/3 in acute-on-chronic liver failure (RR 0.67; 95 % CI: 0.51 to 0.90), but not in acute liver failure (RR 0.95; 95 % CI: 0.71 to 1.29).  The authors noted that the incidence of adverse events was inconsistently reported.  They concluded that, although artificial support systems may reduce mortality in acute-on-chronic liver failure, “considering the strength of the evidence additional randomised clinical trials are needed before any support system can be recommended for routine use.”

More recently, Demetriou et al (2004) reported on the first prospective, randomized controlled trial of bioartificial liver, the HepatAssist Liver Support System in 171 patients with severe acute liver failure, including both fulminant/subfulminant hepatic failure and primary non-function following liver transplantation.  For the entire patient population, survival at 30 days was 71 % for patients assigned to the bioartificial liver versus 62 % for patients in the control group (p = 0.26).  After exclusion of primary non-function patients, survival was 73 % for persons assigned to the bioartificial liver versus 59 % for persons in the control group (p = 0.12).  When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; p = 0.13).  However, differences in survival between bioartificial liver and control patients with fulminant/subfulminant hepatic failure reached marginal statistical significance (risk ratio = 0.56; p = 0.048).  The authors concluded that this study demonstrated improved survival in patients with fulminant/subfulminant hepatic failure.  These results would need to be confirmed in additional prospective randomized studies before conclusions can be drawn about the effectiveness of the bioartificial liver.

Dimmock et al (2008) noted that deoxyguanosine kinase (DGUOK) deficiency is the commonest type of mitochondrial DNA depletion associated with a hepato-cerebral phenotype.  These researchers assessed predictors of survival and therapeutic options in patients with DGUOK deficiency.  A systematic search of MEDLINE, LILAC, and SCIELO was performed to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other studies with clinical pertinence.  Deoxyguanosine kinase deficiency was searched with the terms dGK, DGUOK, mitochondrial DNA depletion, mtDNA, and hepatocerebral.  Bibliographies of identified articles were reviewed for additional references.  A total of 13 identified studies met the inclusion criteria and were used in this study.  The analysis revealed that DGUOK deficiency is associated with a variable clinical phenotype.  Long-term survival is best predicted by the absence of profound hypotonia, significant psychomotor retardation, or nystagmus.  In the presence of these features, there is increased mortality, and liver transplantation does not confer increased survival.  The authors concluded that liver transplantation appears to be futile in the presence of specific neurological signs or symptoms in patients affected with DGUOK deficiency.  Conversely, in the absence of these neurological features, liver transplantation may be considered a potential treatment.

 

Appendix

A tool to calculate MELD score is available at the following website: http://optn.transplant.hrsa.gov/resources/professionalResources.asp?index=8.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
47133
47135
47140
47141
47142
47143
47144
47145
47146
47147
CPT codes not covered for indications listed in the CPB:
47136
Other CPT codes related to the CPB:
47120 - 47130
ICD-9 codes covered if selection criteria are met:
070.20 - 070.23 Viral hepatitis B with hepatic coma
070.30 - 070.33 Viral hepatitis B without mention of hepatic coma
070.41 Acute hepatitis C with hepatic coma
070.44 Chronic hepatitis C with hepatic coma
070.51 Acute hepatitis C without mention of hepatic coma
070.54 Chronic hepatitis C without mention of hepatic coma
070.70 - 070.71 Unspecified viral hepatitis C
155.0 Malignant neoplasm of liver, primary
155.1 Malignant neoplasm of intrahepatic bile ducts
235.3 Neoplasm of uncertain behavior of liver and biliary passages [Epithelioid hemangioendotheliomas]
270.0 - 270.9 Disorders of amino-acid transport and metabolism
273.4 Alpha-1-antitrypsin deficiency
275.01 - 275.03 Hemochromatoses
275.09 Other disorders of iron metabolism
275.1 Disorders of copper metabolism
277.1 Disorders of porphyrin metabolism
277.30 - 277.39 Amyloidosis [Familial amyloid polyneuropathy]
453.0 Budd-Chiari syndrome
571.2 Alcoholic cirrhosis of liver
571.42 Autoimmune hepatitis
571.49 Chronic active hepatitis
571.5 Cirrhosis of liver without mention of alcohol
571.6 Biliary cirrhosis
573.5 Hepatopulmonary syndrome
576.1 Cholangitis
576.2 Obstruction of bile duct
751.61 Biliary atresia
751.62 Congenital cystic disease of liver
996.82 Complications of transplanted organ, liver
ICD-9 codes not covered for indications listed in the CPB:
303.00, 303.01, 303.02, 303.90, 303.91, 303.92, 304.00, 304.01, 304.02, 304.10, 340.11, 304.12, 304.20, 304.21, 304.22, 304.30, 304.31, 304.32, 304.40, 304.41, 304.42, 304.50, 340.51, 304.52, 304.60, 304.61, 304.62, 304.70, 304.71, 304.72, 304.80, 304.81, 304.82, 304.90, 304.91, 304.92, 305.00, 305.01, 305.02, 305.20, 305.21, 305.22, 305.30, 305.31, 305.32, 305.40, 305.41, 305.42, 305.60, 305.61, 305.62, 305.70, 305.71, 305.72, 305.80, 305.81, 305.82, 305.90, 305.91, 305.92 Alcohol dependence syndrome, drug dependence, and nondependent abuse of drugs, unspecified, continuous, or episodic
995.91 Sepsis
Other ICD-9 codes related to the CPB:
038.0 - 038.9 Septicemia
140.0 - 208.91 Malignant neoplasms
196.2 Secondary malignant neoplasm of intra-abdominal lymph nodes
197.0 Secondary malignant neoplasm of lung
198.5 Secondary malignant neoplasm of bone and bone marrow
303.03, 303.93, 304.03, 304.13, 304.23, 304.33, 340.43, 304.53, 304.63, 304.73, 304.83, 304.93, 305.03, 305.23, 305.33, 305.43, 305.53, 305.63, 305.73, 305.83, 305.93 Alcohol dependence syndrome, drug dependence, and nondependent abuse of drugs
415.0 Acute cor pulmonale
416.0 Primary pulmonary hypertension
416.8 Other chronic pulmonary heart disease
428.0 - 428.9 Heart failure
518.81 Acute respiratory failure
518.83 Chronic respiratory failure
518.84 Acute and chronic respiratory failure
572.3 Portal hypertension
572.8 Other sequelae of chronic liver disease
V42.7 Organ or tissue replaced by transplant, liver


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