Corporate Medical Policy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: hereditary_hemochromatosis 01/01/2019 N/A 01/01/2020 01/01/2019 Description of Procedure or Service Policy Effective April 1, 2019 Definitions Hereditary hemochromatosis is a genetic disease which causes excessive absorption of dietary iron and storage particularly in the skin, heart, liver, pancreas, and joints due to hepcidin insufficiency (Zoller, 2016). ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for hereditary hemochromatosis when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. When Hereditary Hemochromatosis is covered 1. Serum ferritin testing and determination of serum transferrin saturation (using serum iron and serum iron binding capacity measurements) is considered medically necessary for the evaluation of iron overload in: A. Symptomatic individuals (See policy guidelines below) B. Individuals with first degree relatives with confirmed HH (Refer to the Ferritin AHS G2011 policy for additional information on ferritin testing). 2. HFE genotyping I(to confirm the presence of mutation in C282Y, H63D, or S65 ) is considered medically necessary for: A. Individuals with serum transferrin saturation >45% B. Individuals with a first degree relative with confirmed HH Page 1 of 6
When Hereditary Hemochromatosis is not covered General population screening for HH via genetic testing is considered investigational. Policy Guidelines Policy Guidelines Symptoms and signs of iron overload include the following: chronic fatigue, joint pain, abdominal pain, liver disease (cirrhosis, liver cancer), diabetes mellitus, skin color changes (bronze, ashen-gray green), decreased libido, osteoarthritis, osteoporosis, hair loss, heart failure, cardiac arrhythmias, enlarged liver or spleen, impotence, infertility, hypogonadism, hypothyroidism, hypopituitarism, depression, adrenal function problems, early onset neurodegenerative disease, elevated blood sugar, elevated liver enzymes, elevated iron (serum iron, serum ferritin). Background Hereditary hemochromatosis (HH) is an iron-storage disease caused by genetic mutations, most often in the HFE gene, resulting in inappropriately low production of the hormone hepcidin (Powell, 2016). This leads to chronic hyperabsorption of dietary iron and iron accumulation in parenchymal organs, primarily the liver, which can potentially result in impaired organ structure and function. This can ultimately result in liver cirrhosis, liver cancer, diabetes, congestive heart failure and osteoarthritis, as well as other serious conditions. Left untreated, iron overload can result in death (Fleming, 2012). HH can result from any mutation that affects any of the proteins that help hepcidin to monitor serum iron, most commonly HFE and in rarer instances, transferrin-receptor 2 and hemojuvelin (Pietrangelo, 2015). C282Y HFE mutations are relatively common, especially in Caucasians of northern European origin, particularly Nordic or Celtic ancestry, in which it occurs with a prevalence of approximately 1 per 220-250 individuals. However, complete organ disease develops only in a minority of these, due to alcohol abuse or concurrent genetic modifiers that are now being identified (Evangelista, 2016). Rare variants (TFR2-, HJV- or HAMP-related) are associated with more profound iron overload and hepcidin inactivation. Disruption of either HJV or HAMP genes leads to early onset juvenile HH, the most severe form of the disease (Pietrangelo, 2015). Clinically, increased transferrin saturation is the principal biochemical finding of all forms of HH, and is the preferred screening tool with HFE genetic screening recommended for patients with a serum ferritin above 45% in the general population (Bacon, 2013; Evangelista, 2015; Porto, 2016). HFE gene testing can be used to diagnose hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-hfe forms of the disease. Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis (Pietrangelo, 2015). Symptomatic HH is more common in men than in women, and symptoms usually do not appear until after age 40 in men and after age 50 (or after menopause) in women. Initial symptoms are usually non-specific, including fatigue, joint pain and diabetes. People with HH can also have a bronze pigmentation of their skin, as a result of iron stores in skin cells. Alcoholism can exacerbate the condition, with symptoms appearing earlier and with more severity. Page 2 of 6
The standard of care for all forms of HH is reduction of iron via therapeutic phlebotomy (Powell, 2016). Iron chelation and modifications to diet such as avoidance of iron, discontinuance of iron-containing supplements and avoidance of alcohol can also be recommended. Applicable Federal Regulations Recently, Food and Drug Administration has authorized direct-to-consumer Genetic Health Risk Hereditary Hemochromatosis test developed by 23andMe. This test provides information on an individual s genetic predisposition from European descent for Hereditary Hemochromatosis by testing 2 variants (C282Y; H63D) in the HFE gene in genomic DNA obtained from a human saliva. However, this test cannot determine an individual s overall risk of developing a disease (CLN, 2017; FDA, (CLN, 2017; FDA 2017). Guidelines and Recommendations United States Preventive Services Task Force (USPSTF) The United States Preventive Services Task Force (USPSTF) recommends against genetic screening for HH in the general, asymptomatic population, due to the low penetrance of the disease among those with causative mutations (USPSTF, 2007) (USPSTF, 2014) Centers for Disease Control and Prevention The Centers for Disease Control and Prevention also do not recommend screening for HFE mutations in the general population. American Association for the Study of Liver Diseases (AASLD) American Association for the Study of Liver Diseases (AASLD) Recommendations (Bacon, 2013): 1. We recommend that patients with abnormal iron studies should be evaluated as patients with hemochromatosis, even in the absence of symptoms. (A) 2. All patients with evidence of liver disease should be evaluated for hemochromatosis. (1B) 3. In a patient with suggestive symptoms, physical findings, or family history, a combination of TS and ferritin should be obtained rather than relying on a single test. (1B) If either is abnormal (TS 45% or ferritin above the upper limit of normal), then HFE mutation analysis should be performed. (1B) 4. Diagnostic strategies using serum iron markers should target high-risk groups such as those with a family history of HH or those with suspected organ involvement. (1B) 5. We recommend screening (iron studies and HFE mutation analysis) of first-degree relatives of patients with HFE-related HH to detect early disease and prevent complications. (1A) European Molecular Quality Network Recommendations for diagnostic and predictive testing (Porto, 2016): 1. Population screening for the p.c282y variant is not currently recommended (1B). 2. It is considered to be good practice to confirm elevated TS before HFE genetic diagnosis testing (1B). Page 3 of 6
3. Testing adult siblings (brothers and sisters) of p.c282y homozygotes is recommended owing to the increased risk of p.c282y homozygosity and related increased morbidity (1B). 4. Testing adult offspring of p.c282y homozygotes is recommended owing to increased risk of p.c282y homozygosity and related increased morbidity (1C). 5. Testing asymptomatic parents of p.c282y homozygotes is not recommended systematically but rather as a clinical decision depending on their age, sex and ferritin, all three influencing the probability to develop severe iron overload (1C). 6. Systematic testing of adult first-degree relatives of p.c282y heterozygotes is not currently recommended, in the absence of evidence of benefit (2C). 7. HFE testing of minors is not recommended (1B). 8. Prenatal diagnosis is not appropriate in HFE-related HH because it is a treatable, adult onset condition (1C). American College of Gastroenterology (ACG) Clinical Guideline: Evaluation of Abnormal Liver Chemistries Hereditary hemochromatosis is one of the most common causes of inherited liver disorders which causes abnormal liver chemistries. In the cases where patients have abnormal liver chemistries without acute hepatitis, ACG recommends that those patients should undergo testing for hereditary hemochromatosis with an iron level, transferrin saturation, and serum ferritin. HFE gene mutation analysis should be performed in patients with transferrin saturation >45% and/or elevated serum ferritin (Kwo et al, 2017). American College of Medical Genetics and Genomics (ACMG) ACMG has listed HFE genetic testing on its Choosing Wisely list. They recommend against ordering HFE genetic test for a patient without iron overload or a family history of HFEassociated HH (ACMG, 2016) Billing/Coding/Physician Documentation Information This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page. Applicable service codes: 81256, 82728, 83540, 83550 Code Number PA Required PA Not Required Not Covered 81256 X 82728 X 83540 X 83550 X BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. Scientific Background and Reference Sources Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358:221. Page 4 of 6
American College of Medical Genetics and Genomics. Choosing Wisely list of Recommendations Released July 10, 2015; sources updated September 15, 2016. http://www.choosingwisely.org/clinician-lists/american-college-medical-genetics-genomics-hfegenetic-testing/ Clinical Laboratory News Jun.1.2017. 23andMe Continues Rebound With FDA OK for First DTC Genetic Risk Tests.Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS: Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54: 328 343 Evangelista, A. S., Nakhle, M. C., de Araújo, T. F., Abrantes-Lemos, C. P., Deguti, M. M., Carrilho, F. J., & Cançado, E. L. R. (2015). HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases. BioMed Research International, 2015, 164671. http://doi.org/10.1155/2015/164671 Fleming RE, Ponka P: Iron overload in human disease. N Engl J Med 2012; 366: 348 359. Food and Drug Administration (FDA), 2017. EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR The 23andMe Personal Genome Service (PGS) Genetic Health Risk Test for Hereditary Thrombophilia, Alpha-1 Antitrypsin Deficiency, Alzheimer s Disease, Parkinson s Disease, Gaucher Disease Type 1, Factor XI Deficiency, Celiac Disease, G6PD Deficiency, Hereditary Hemochromatosis and Early-Onset Primary Dystonia DECISION SUMMARY Correction Date: May 2, 2017 This Decision Summary contains corrections to the April 6, 2017 Decision Summary Kwo, P.Y., Cohen, S.M., Lim, J.K. (2017). ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol; 112:18-35; doi:10.1038/ajg.2016.517. National Institute of Health (NIH). 2016. Hereditary hemochromatosis. https://ghr.nlm.nih.gov/condition/hereditary-hemochromatosis Pietrangelo A. (2015). Genetics, genetic testing, and management of hemochromatosis: 15 years since hepcidin. Gastroenterology 149, 1240 1251. 10.1053/j.gastro.2015.06.045 Porto, G, et al. (2016). EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH). European Journal of Human Genetics (2016) 24, 479 495 Powell L. W., Seckington R. C., Deugnier Y. (2016). Haemochromatosis. Lancet.. [Epub ahead of print].10.1016/s0140-6736(15)01315-x U.S. Preventative Services Task Force. Screening for Hemochromatosis: Recommendation Statement. Am Fam Physician. 2007 Jun 1;75(11):1696-1698. U.S. Preventative Services Task Force. (2014). The Guide to Clinical Preventative Services 2014: Hemochromatosis. AHRQ Pub. No. 14-05158 May 2014. van Bokhoven MA, van Deursen CT, Swinkels DW: Diagnosis and management of hereditary haemochromatosis. BMJ 2011; 342: c7251. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR: Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006; 145: 209 223 Page 5 of 6
Zoller H, Henninger B, Pathogenesis, Diagnosis and Treatment of Hemochromatosis. Dig Dis 2016;34:364-373 Policy Implementation/Update Information 1/1/2019 BCBSNC will provide coverage for hereditary hemochromatosis is when it is determined to be medically necessary because criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd) Medical policy is not an authorization, certification, explanation of benefits or a contract. Benefits and eligibility are determined before medical guidelines and payment guidelines are applied. Benefits are determined by the group contract and subscriber certificate that is in effect at the time services are rendered. This document is solely provided for informational purposes only and is based on research of current medical literature and review of common medical practices in the treatment and diagnosis of disease. Medical practices and knowledge are constantly changing and BCBSNC reserves the right to review and revise its medical policies periodically. Page 6 of 6