HEREDITARY HEMOCHROMATOSIS
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1 CLINICAL GUIDELINES For use with the UnitedHealthcare Laboratory Benefit Management Program, administered by BeaconLBS HEREDITARY HEMOCHROMATOSIS Policy Number: PDS Effective Date: January 1, 2015 Table of Contents Page GUIDELINES 1 BACKGROUND 2 CLINICAL EVIDENCE 3 Guidelines and Recommendations 4 US FOOD AND DRUG ADMINISTRATION (US FDA) 6 CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) 6 APPLICABLE CODING 6 REFERENCES 7 POLICY HISTORY/REVISION HISTORY 8 INSTRUCTIONS FOR USE Physician Decision Support (PDS) is a lab ordering tool operated by BeaconLBS. This Clinical Guideline supports the Questions and Answers that appear in PDS for tests referenced in this document. UnitedHealthcare reserves the right, in its sole discretion, to modify its Clinical Guidelines as necessary. This Clinical Guideline is provided for informational purposes. It does not constitute a Medical Policy or medical advice. GUIDELINES DNA testing for hereditary hemochromatosis (HH) is recommended in individuals with any of the following characteristics: Elevated fasting serum transferrin saturation (>45%) Elevated serum ferritin level (greater than upper limit of normal) First-degree relative with HH These recommendations are consistent with current evidence-based guidelines from the American Association for the Study of Liver Diseases (AASLD), Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities of the Centers for Disease Control and Prevention (CDC), European Association for the Study of the Liver (EASL), Health Technology Assessment Programme of the National Institute of Health Research in the UK (HTA-NIHR), US Preventive Services Task Force and American Association of Family Physicians (USPSTF & AAFP), and American College of Physicians (ACP). Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 1
2 BACKGROUND Hereditary hemochromatosis (HH) is a genetic disorder characterized by excessive absorption of iron from the digestive tract that results in iron overload in multiple tissues. The iron overload is progressive and injures organs, such as the liver, joints, skin, and heart, resulting in clinical consequences such as cirrhosis, arthropathy, diabetes mellitus, cardiomyopathy, and increased skin pigmentation. 1 Patients with HH are 200 times more likely to develop liver cancer than the general population; liver cancer in patients with HH is usually related to liver cirrhosis. 2 HH usually manifests in men in their 40s and women after menopause, but can be symptomatic at younger ages. 1, 3 It is the most common of the characterized genetic disorders in Caucasian individuals with Northern European ancestry. 4 The predisposition toward HH is almost always inherited in an autosomal recessive manner, but mutations causing HH exhibit incomplete penetrance. Therefore, it is important to interpret results of mutation testing for HH in the context of clinical signs and symptoms associated with this disorder. 4, 5 Mutations in several genes involved in iron metabolism are associated with HH, but the most common mutations are in the HFE gene on chromosome 6. 2 HFE encodes HLA-H, a human leukocyte antigen-like (HLA- like) protein that plays a role in the transport of iron. 2 Together, the p.cys282tyr (A at rs ), p.his63asp (G at rs ), and p.ser65cys (T at i ) mutations in the HFE gene (Table 1) comprise the vast majority of the mutations associated with HH. 2 The remainder of this clinical policy focuses on HFE-associated HH. 2, 5-8 Table 1. Mutations in HFE-associated HH Mutation in HFE protein a Allelic Frequency in Percentage of Patients Mutation in HFE gene General Population (%) with Symptomatic HH p.cys282tyr G-to-A at nt p.his63asp C-to-G at nt b p.ser65cys A-to-T at nt b a Indicates location of mutation and resulting amino acid change, e.g., p.cys282tyr indicates C is substituted for Y at amino acid position 282 in HLA-H, the protein encoded by the HFE gene. b As compound heterozygote with p.cys282tyr. Abbreviations: A, alanine; C, cysteine; D, aspartic acid; H, histidine; nt, nucleotide; S, serine; Y, tyrosine. p.cys282tyr is the most common HFE mutation in patients with HFE- and non-hfe-associated HH. 4-6 Among individuals with Northern European ancestry, about 1 in 10 are heterozygous for p.cys282tyr, and about 1 in 200 are homozygous for this mutation. 1 p.cys282tyr exhibits incomplete penetrance in patients who are homozygous and does not cause symptoms in those who are carriers of an HFE mutation (e.g., heterozygous, meaning one p.cys282tyr and one normal allele). Among p.cys282tyr homozygotes, 38% to 50% develop iron overload, 10% to 33% develop symptoms of HH, 5% of men and 0.5% of women develop liver cirrhosis. 5 Like p.cys282tyr homozygosity, compound heterozygosity for p.cys282tyr and p.his63asp can be associated with symptoms of HH, but with even lower penetrance; only about 1% of individuals with p.cys282tyr / p.his63asp compound heterozygosity develop iron overload. 1 In addition, symptoms of HH are less severe in patients with p.cys282tyr / p.his63asp compound heterozygosity than in those homozygous for pcys282tyr. Patients with compound heterozygosity for p.cys282tyr and p.ser65cys may develop HH with milder symptoms than those with p.cys282tyr homozygosity. 7, 8 Patients who are homozygous for p.his63asp or p.ser65cys do not develop 1, 4, 5 symptomatic HH. Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 2
3 HH diagnosis is based on clinical findings, serum transferrin-iron saturation and serum ferritin levels to establish iron status, and DNA testing, and may also include histological studies of affected tissues. In the early stages, patients who develop symptomatic HH may exhibit elevated serum transferrin saturation (>45%) and serum ferritin levels above the upper limit of normal; other signs and symptoms develop later, when iron deposition reaches a critical level. 1, 2, 4 In patients who are acutely ill, serum transferrin saturation and serum ferritin level may not be accurate indicators of HH because they are a positive and negative acute phase reactant, respectively. Therefore, clinical assessment, DNA testing, sequential measurements of these parameters, other testing, or a combination 1, 2, 4 may be required to confirm diagnosis of HH in these patients. The standard treatment for symptomatic HH is phlebotomy (venesection) at least once weekly to reduce iron load and thereby reduce the rates of HH-associated morbidity and death. 1, 2, 4 The number of phlebotomies required depends on the degree of iron overload and the patient s response to treatment, but the duration of initial treatment can be 2 to 3 years. The patient may need ongoing, periodic phlebotomies to maintain a normal iron load. 1 Symptomatic HH typically occurs more often and in a more severe form in men than in women. 1, 4, 5 Other factors associated with increased severity of HH symptoms include excess alcohol intake, diabetes, tobacco smoking, increased age, and concurrent liver disease. 1, 4 Liver cancer occurs more often in patients with HH who have cirrhosis than in those who do not. 1, 4 CLINICAL EVIDENCE DNA testing is important to confirm the diagnosis of symptomatic HH. In almost all cases, DNA testing specific for p.cys282tyr, p.his63asp, and p.ser65cys is adequate to identify the mutation involved. 5 However, the implications of DNA testing and expected outcomes should be discussed with the patient prior to testing. In particular, it is important that the patient understands that DNA testing does not identify all mutations that cause HH, negative results may be inconclusive. In addition, DNA testing indicates risk for but not the presence of iron overload, and 1, 2, 9 patients may not understand that the results do not change the patient s treatment options. The advantages of DNA testing include 1, 2, 9 : Cost-effective confirmation of diagnosis with HH Identification of asymptomatic carriers of HFE mutation(s) Cost-effective method for HH screening of children of patients with HH Early diagnosis and treatment may lead to reduced occurrence or sequelae of iron overload Information to guide personal decisions regarding insurance, employment, and family planning Diagnosis with HH or HFE mutation has the potential to affect personal, family, financial, health, and insurancerelated decisions or relationships. 9 DNA testing for HH was associated with lower anxiety levels and improved quality of life in studies of the psychosocial impact of this test. 2 The DNA testing methods available include polymerase chain reaction (PCR)-based, restriction enzyme-based, and DNA denaturation-based approaches, DNA sequencing, or a combination. 2, 5 The clinical specificity of these tests is >99%. 2 DNA sequencing is necessary to identify rare or novel mutations in the HFE gene, and other studies are Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 3
4 required to identify non-hfe-associated mutations. 2, 5 High-quality comparative studies of the various methods available for DNA testing for HH have not been reported. 2 Recently, multiple systematic reviews were performed to determine whether or not available evidence supported routine screening for HH with serum or DNA testing in the general population. 2, 4, 5, 10, 11 In every case, the investigators concluded that routine screening for HH was not appropriate in the general population, but recommended diagnostic use of biochemical or DNA testing in certain subpopulations (see next section). The next section reviews the recommendations for DNA testing. GUIDELINES AND RECOMMENDATIONS This section summarizes recent, evidence-based guidelines that make recommendations for clinical use of DNA testing for HH. In general, the authors reported performing systematic reviews of the literature, meta-analyses, or both, and use of a formal framework to evaluate the quality of the evidence available. All of the guidelines recommended using DNA testing for HH as a diagnostic test, not as a screening test. None of the guidelines recommended any particular type of DNA testing over any other type. American Association for the Study of Liver Diseases (AASLD) 4 In 2011, the AASLD issued recommendations for diagnosis and management of HH based on an evaluative review of recently published, relevant literature worldwide, policies on development of practice guidelines, and expert opinion. Citing moderate to high level evidence according to the GRADE system, 12 AASLD strongly recommended that individuals with any of the following characteristics undergo DNA testing for HFE-associated HH: Transferrin saturation >45% Serum ferritin level above the upper limit of normal First-degree relative with HH AASLD recommended that DNA testing of the children of an individual with HFE-associated HH be delayed until results of DNA testing of the other parent are available. If the other parent is normal, the children are by definition heterozygotes, are not at risk of symptoms of HH, and do not require further testing. AASLD recommended evaluation of serum iron status rather than DNA testing for HH as a first step in evaluation of patients considered at high risk of HH, such as those with a non-first-degree relative with HH or with suspected organ damage related to iron overload. As in other patients, AASLD recommended that these patients undergo DNA testing for HH only if serum transferrin saturation or serum ferritin levels were abnormally high. AASLD did not recommend routine genetic screening for HH in the general population. Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC) 13 In its online training on HH for healthcare professionals, the CDC recommended DNA testing for HH in individuals with symptoms of HH and in family members of patients with HH. CDC explicitly did not recommend routine screening for HH in the general population. Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 4
5 European Association for the Study of the Liver (EASL) 5 EASL developed a clinical practice guideline for management of HFE-associated HH based on a systematic review of the relevant literature from 1966 to EASL used the GRADE system 12 to evaluate the strength of the evidence, and rated the level of evidence supporting its recommendations for use of genetic testing for HH as low or moderate. Accordingly, EASL made weak or strong recommendations, respectively. EASL strongly recommended DNA testing for HFE-associated HH in patients with both elevated serum transferrin saturation and unexplained chronic liver disease. EASL recommended that clinicians also consider genetic testing for HFE-associated HH in certain patients with porphyria cutanea tarda, well-defined calcium deposits in joints, liver cancer, and type 1 diabetes. However, EASL did not recommend genetic testing for HFE-associated HH in the general population because only a small fraction of patients with p.cys282tyr homozygosity progress to iron overload. In addition, this group explicitly did not recommend genetic testing for HH in patients with type 2 diabetes, or with unexplained arthritis or arthalgia. Health Technology Assessment Programme of the National Institute of Health Research in the UK (HTA-NIHR) 2 HTA-NIHR conducted a systematic review of the literature on HH that was published from 1966 to April 2007, in order to evaluate the clinical validity and utility of DNA testing for HH in 2 groups: patients suspected of having this disorder and family members of patients with HH. HTA-NIHR used the ACCE process to evaluate the clinical validity, clinical utility, psychosocial effects, and economic cost of DNA testing for the p.cys282tyr mutation. ACCE stands for Analytical validity, Clinical validity, Clinical utility, and Ethics; the ACCE process is a way to evaluate data on genetic tests. HTA-NIHR also systematically evaluated the quality of the evidence available with a modification of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. 14 HTA-NIHR recommended DNA testing for HH in the following groups: Patients at risk for HH on the basis of serum transferrin saturation and serum ferritin level Patients at risk for HH on the basis of family history HTA-NIHR indicated that DNA testing for HH should be performed in conjunction with assessment of serum iron status. US Preventive Services Task Force and American Association of Family Physicians (USPSTF & AAFP) 15 In 2006, USPSTF& AAFP supported a systematic review of the literature on HH published from 1966 to The goal of the review was to assess the likely clinical utility of routine screening for HH, including routine genetic screening, in the general population. USPSTF & AAFP concluded that such screening was not warranted, because people who are homozygous for p.cys282tyr often do not progress to symptomatic HH. The USPSTF & AAFP did not try to determine when DNA testing for HH was appropriate, but did note that DNA testing for p.cys282tyr is an accurate way to diagnose HH in individuals with symptoms of HH and in those with relatives with HH. American College of Physicians (ACP) 3 In a clinical practice guideline based on a 2005 systematic review of literature regarding screening of primary care patients for HH from 1966 to 2004, 10 ACP did not recommend screening for HH with either DNA testing or Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 5
6 measurement of serum iron status in the general population. The group did recommend that clinicians discuss DNA testing for HH with patients who have a family history of HH; elevated serum ferritin level, elevated serum transferrin saturation; or a combination. ACP stated that identification of HFE mutations was controversial because such mutations may not progress to symptomatic HH. However, the evidence base for these guidelines predated much of the currently available published information about DNA testing for HH. US FOOD AND DRUG ADMINISTRATION (US FDA) The performance characteristics of these tests have generally been determined by the performing institution in a manner consistent with CLIA requirements. The DNA-based tests have not been cleared or approved by the U.S. Food and Drug Administration (FDA). CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) For Medicare populations, CMS does not pay for screening procedures (tests) performed in the absence of signs or symptoms. (Section 1862(a)(7) of the Social Security Act) There are several CMS policies that apply to genetic testing. Genetic testing for certain conditions may be medically appropriate if after history, physical examination, pedigree analysis, genetic counseling, and completion of conventional diagnostic studies, a definitive diagnosis remains uncertain. Physicians should consult their state s regulations. APPLICABLE CODING CPT Code Description HFE (hemochromatosis)(e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D) Additional CPT code modifiers may be required for procedures performed to test for oncologic or inherited disorders. Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 6
7 REFERENCES 1. Alexander J and Kowdley KV, HFE-associated hereditary hemochromatosis. Genetics in medicine (5): p Bryant J, Cooper K, et al., Diagnostic strategies using DNA testing for hereditary haemochromatosis in atrisk populations: a systematic review and economic evaluation. Health technology assessment (Winchester, England), (23): p. iii, ix-xi, Qaseem A, Aronson M, et al., Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Annals of internal medicine, (7): p Bacon BR, Adams PC, et al., Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.), (1): p EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol., : p Adams PC, Reboussin DM, et al., Hemochromatosis and iron-overload screening in a racially diverse population. The New England journal of medicine, (17): p Asberg A, Thorstensen K, et al., Hereditary hemochromatosis: the clinical significance of the S65C mutation. Genetic testing, (1): p Mura C, Raguenes O, and Férec C, HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood, (8): p Cepmed. Personalized Medicine Portal: Hemochromatosis. San Francisco, CA: DNA Direct, Inc; 2013.Available at (Accessed December 20, 2013). 10. Schmitt B, Golub RM, and Green R, Screening primary care patients for hereditary hemochromatosis with transferrin saturation and serum ferritin level: systematic review for the American College of Physicians. Annals of internal medicine, (7): p Whitlock EP, Garlitz BA, et al., Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Annals of internal medicine, (3): p Hsu J, Brozek JL, and Terracciano L, Application of GRADE: Making evidence-based recommendations about diagnostic tests in clinical practice guidelines. Implement Sci (1 ): p Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Diagnostic testing. Hemochromatosis for Health Care Professionals Online training course. Available at: (Accessed October 21, 2011). 14. Whiting P, Rutjes AWS, et al., The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC medical research methodology, : p USPSTF. Screening for hemochromatosis: recommendation statement. Ann Intern Med, (3 ): p Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 7
8 POLICY HISTORY/REVISION HISTORY Date Action/Description 11/05/2015 Annual Policy Review Completed no changes. Proprietary Information of UnitedHealthcare. Copyright 2015 United HealthCare Services, Inc. Page 8
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