|MP 2.04.80||Genetic Testing for Hereditary Hemochromatosis|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/4:2014
|Return to Medical Policy Index|
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Hereditary hemochromatosis (HH), a common genetic disorder of iron metabolism, can lead to inappropriate iron absorption, toxic accumulation of iron, and organ damage. Genetic testing is available to assess mutations in the HFE gene, which are responsible for most clinically significant cases of hereditary hemochromatosis.
Iron overload syndromes may be hereditary, secondary to some other disease (eg iron-loading anemias, parenteral iron overload, chronic liver disease, or dysmetabolic iron overload syndrome), or due to other miscellaneous conditions (eg, neonatal iron overload, aceruloplasminemia, congenital atransferrinemia).
Iron overload, if left untreated, can lead to secondary tissue damage in a wide range of organs resulting in chronic liver disease (hepatic fibrosis, cirrhosis, hepatocellular carcinoma), endocrine dysfunction (diabetes, hypogonadism), arthralgia or arthritis (typically involving the second and third metacarpophalangeal joints), and cardiomyopathy (with either symptomatic cardiac failure or arrhythmias).
HH, an autosomal recessive disorder, is the most common identified, genetic disorder in Caucasians, with an estimated prevalence of 1 in 250 Caucasians. However, fully expressed disease with end-organ manifestations is seen in less than 10% of affected individuals. Factors that influence phenotypic expression of HFE (high iron-related HH (ie, the clinical appearance of iron overload) are not clearly defined. Low clinical penetrance may be due to a complex interplay of genetic status and other factors such as age, sex, environmental influences, and comorbid diseases.
HH leads to inappropriate iron absorption from the intestine and progressive increase in intracellular iron concentrations. Untreated HH leads to premature death, usually by liver complications. Treatment by removing excess iron with serial phlebotomy is simple and effective, and if started before irreversible end-organ damage, restores normal life expectancy.
Diagnosis of Hemochromatosis
Patients with hemochromatosis may present with nonspecific systemic symptoms or specific organ-related symptoms, or they may be asymptomatic. Clinical diagnosis of hemochromatosis is based on documentation of increased iron stores as demonstrated by abnormal serum iron indices, specifically elevated transferrin saturation and elevated serum ferritin concentration. Liver biopsy has been used to confirm diagnosis but is now generally limited to determining the degree of hepatic fibrosis and cirrhosis during disease management.
Genetic testing can confirm a hereditary nature of iron overload.
Genetics of Hereditary Hemochromatosis
Most patients with HH have mutations in the HFE gene, located on the short arm of chromosome 6. The HFE gene was identified and cloned in 1996. The most common mutation in the HFE gene is C282Y, a missense mutation that changes cysteine at position 282 in the HFE protein to tyrosine. Homozygosity for the C282Y mutation is associated with 60% to 90% of all cases of HH. Additionally, 3% to 8% of affected individuals are heterozygous for this mutation. Penetrance for elevated serum iron indices among C282Y homozygotes is relatively high, but not 100%. However, penetrance for characteristic clinical end points (ie, end-organ damage) is quite low. There is no test that can predict whether a C282Y homozygote will develop clinical symptoms.
Another significant mutation is referred to as H63D, which changes histidine at position 63 to aspartic acid. Homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of modifying factors. However, compound heterozygosity for C282Y/H63D has been associated with increased hepatic iron concentrations; approximately 1% to 2% of patients with this genotype will develop clinical evidence of iron overload, usually in the presence of another liver disease.(1)
The clinical significance of a third HFE mutation, S65C (serine at position 65 changed to cysteine), appears to be minimal. This rare variant displays very low penetrance. Compound heterozygosity for C282Y/S65C may confer a low risk for mild HH. Individuals who are heterozygous for S65C and either the wild-type (normal) or H63D alleles do not seem to be at an increased risk for HH. Other mutations in HFE and in non-HFE genes (eg, transferrin receptor 2, TFR2) resulting in iron overload syndromes are rare.(2-4)
With the advent of genetic testing in the late 1990s, HFE-related HH is now frequently identified in asymptomatic probands and in presymptomatic relatives of patients who are known to have the disease. (5) Therefore, a genetic diagnosis can be made in subjects who have not yet developed phenotypic expression; these subjects have a genetic susceptibility to developing iron overload but may never do so. A 2000 consensus conference of the European Association for the Study of Liver Diseases led to a recognition of different stages and progression of hemochromatosis. These stages were defined as:
- Stage 1: Patients with “genetic susceptibility” who have the genetic disorder but no increase in iron stores.
- Stage 2: Patients who have the genetic disorder and phenotypic evidence of iron overload but no tissue or end-organ damage.
- Stage 3: Patients who have the genetic disorder with iron overload and iron deposition to the degree that tissue and end-organ damage occurs.
No U.S. Food and Drug Administration (FDA)‒cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
Genetic testing for HFE gene mutations may be considered medically necessary in a patient with abnormal serum iron indices indicating iron overload. (See Policy Guidelines)
Genetic testing for HFE gene mutations may be considered medically necessary in individuals with a family history of hemochromatosis in a first-degree relative. (See Policy Guidelines)
Genetic testing for hereditary hemochromatosis in screening of the general population is considered investigational.
Serum Iron Indices in the Diagnosis of HH(6)
- Elevated fasting transferrin saturation (the ratio of serum iron to total iron-binding capacity) is the most sensitive initial phenotypic screening test. A minimum cut-off value of 45% will detect almost all affected C282Y homozygotes.
- Serum ferritin reflects body iron stores and generally rises later in the progression of iron overload. In the absence of other causes of hyperferritinemia (alcohol abuse, metabolic syndrome, inflammatory states [eg, infection, cancer, active rheumatoid arthritis], acute and chronic hepatitis), serum ferritin is a good marker of the degree of iron overload.
The negative predictive value of a normal transferrin saturation and serum ferritin is 97%. In this situation, no further testing is recommended.(6)
2011 Practice Guidelines by the American Association for the Study of Liver Diseases recommend HFE gene mutation testing in patients with abnormal serum iron indices (ie, serum ferritin and transferrin saturation), even in the absence of symptoms (eg, abnormal serum iron indices on routine screening chemistry panel).
Genetic Testing in an Individual With a Family History of HH
2011 Practice Guidelines by the American Association for the Study of Liver Diseases recommend screening (iron studies [serum ferritin and transferrin saturation] and HFE mutation analysis) of first-degree relatives of patients with HFE-related HH to detect early disease and prevent complications.(5) For children of an identified proband, HFE testing of the other parent is generally recommended because, if results are normal, the child is an obligate heterozygote and need not undergo further testing because there is no increased risk of iron loading.
If C282Y homozygosity or compound heterozygosity is found in adult relatives of a proband, and if serum ferritin levels are increased, then therapeutic phlebotomy can be initiated. If ferritin level is normal in these patients, then yearly follow-up with iron studies is indicated. When identified, C282Y heterozygotes and H63D heterozygotes can be reassured that they are not at risk for developing progressive or symptomatic iron overload. Occasional H63D homozygotes can develop mild iron overload.
Beginning in 2012, there is specific CPT coding for genetic testing for HFE common variants:
81256: HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)
BlueCard/National Account Issues
No applicable information
This policy was created in 2012 and is based on a search of the MEDLINE database through March 23, 2014.
Recent reviews highlight the pathogenesis, diagnosis and management of hereditary hemochromatosis (HH).(6-9)
A 2001 TEC Assessment on genetic testing for HFE gene mutations related to HH concluded the following:
- Genetic testing and counseling for HFE mutations in the management of patients with symptoms of iron overload consistent with hereditary hemochromatosis, in the setting of 2 consecutive transferrin saturation values of 45% or more and a serum ferritin value of less than 200–300 mcg/L, met the TEC criteria.
- Genetic testing and counseling for HFE mutations in asymptomatic relatives of subjects with hereditary hemochromatosis also met the TEC criteria.
The Assessment did not address the use of genetic testing for HFE gene mutations in screening of the general population.(10)
Validation of the Clinical Use of a Genetic Test
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; (2) clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease; and (3) clinical utility (ie, how results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes).
Stuhrmann et al (2005) initiated a pilot study on DNA-based screening of hereditary hemochromatosis in Germany.(11) A focus of the study was the analytic validity of different test methods. A total of 3961 subjects provided blood samples for testing of the C282Y HFE mutation; of these, 3930 samples were successfully tested by 2 independent test methods (either polymerase chain reaction and restriction digest, reverse allele-specific oligonucleotide hybridization, solid-phase oligonucleotide ligation assay, or microarray [DNA-chip]). In all, 67 of the tested subjects were homozygous for C282Y; 42.6% of the homozygotes already knew their clinical diagnosis of HH before sending the blood sample. Iron accumulation with further signs or symptoms of HH was present in 8 (24%) of 34 newly diagnosed C282Y homozygous subjects. Of 7860 tests performed, 7841 (99.6%) gave correct results. The overall error rate was 0.24% (95% confidence interval [CI], 0.15 to 0.38). Analytic specificity of the test methods for detecting homozygosity for C282Y was 100% (7726/7726 nonhomozygous test challenges; 95% CI, 99.95 to 100), and analytic sensitivity was 97% (130/134 homozygous test challenges; 95% CI, 92.5 to 99.2). This evidence indicates that test methods for C282Y are robust and highly sensitive and specific.
Bryant et al (2008) evaluated the clinical validity and clinical utility of DNA testing in people suspected of having hereditary hemochromatosis and in family members of those diagnosed with the disorder by conducting a systematic review of 15 electronic databases (including MEDLINE and the Cochrane library) up to April 2007.(12) Clinical validity, defined as the ability of the test to detect or predict the phenotype (disorder) of interest, involved establishing the probability that the test would be positive in people with clinical HH (sensitivity) and the probability that the test would be negative in people without the disease (specificity). Studies were included if they reported the use of DNA tests in Caucasians of northern European origin with iron overload suggestive of HH compared with a control population, and reported or allowed the calculation of sensitivity and specificity. Clinical utility studies were included if they reported the use of DNA tests in Caucasians with iron overload suggestive of HH (or relatives of suspected cases) compared with any case-identification strategy not involving DNA, and reported patient-based outcomes (such as morbidity or mortality).
Eleven observational studies that evaluated the clinical validity of genotyping for the C282Y mutation in the diagnostic workup for HH were identified. Criteria used to define hemochromatosis varied among studies. Clinical sensitivity of C282Y homozygosity ranged from 28.4% to 100%; when considering studies that used strict criteria to classify HH, clinical sensitivity ranged from 91.3% to 92.4%. No clinical utility studies were found. The authors concluded that DNA testing for HH in at-risk populations has clinical validity and may have clinical utility.
The clinical utility of genetic testing for HH depends on how results can be used to improve patient management. Although there has never been a randomized controlled trial of phlebotomy versus no phlebotomy in the treatment of HH, there is evidence that initiation of phlebotomy before the development of cirrhosis and/or diabetes will significantly reduce HH-associated morbidity and mortality.(5,13,14)
Data exists on the psychosocial aspect of genetic testing for HH. Picot et al (2009) conducted a systematic review of the psychosocial aspects of DNA testing for HH in at-risk subjects.(15) Databases were searched through 2007 for any quantitative or qualitative primary research that considered DNA testing of subjects considered at-risk for HH and that reported psychosocial outcomes. Three observational studies were included; each had methodologic limitations. After receiving test results, patient anxiety levels fell or were unchanged, and general health-related quality-of-life outcomes improved in some aspects from pretest assessments, or were unchanged. Outcomes were not reported separately for those referred for diagnosis and those with a family history of HH. The authors concluded that, although evidence is limited, results suggested that genetic testing for HH in at-risk subjects is accompanied by few negative psychosocial outcomes.
Population Screening for HH
General population screening for HH has been proposed because of the high prevalence of disease, absence of or nonspecific early clinical findings, specificity of findings once they appear, low cost of diagnosis and treatment, and high cost and low success rate of late diagnosis and treatment. However, because genotype penetrance is low, and the natural history of untreated individuals is unpredictable, support for population-based screening is lacking. The American Academy of Family Physicians, Centers for Disease Control and Prevention, and U.S. Preventive Services Task Force recommend against population-based general screening.(16-18)
McLaren and Gordeuk conducted the Hemochromatosis and Iron Overload Screening (HEIRS) study to evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal impact of hemochromatosis and iron overload in a multiethnic, primary care-based sample of 101,168 adults enrolled over a 2-year period at 4 centers in the U.S. and 1 in Canada.(19) Initial screening included genotyping for the HFE C282Y and H63D alleles, measurement of serum ferritin, and calculation of transferrin saturation. The yield of HFE genotyping for identifying persons with C282Y homozygosity was low in racial/ethnic groups other than non-Hispanic Caucasians. Overall frequency of homozygosity for the C282Y mutation in non-Hispanic Caucasians was 4.4 per 1000. There was marked heterogeneity of disease expression in C282Y homozygotes. The authors concluded that (1) future studies to discover modifier genes that affect phenotypic expression in C282Y hemochromatosis should help identify patients who are at greatest risk of developing iron overload who may benefit from continued monitoring of iron status, and (2) although genetic testing is well-accepted and associated with minimal risk of discrimination, generalized population screening in a primary care population as performed in the HEIRS study is not recommended.
In a substudy of Caucasian participants in the HEIRS study, Adams et al (2013) assessed the prevalence of HFE mutations in patients who had elevated serum ferritin levels less than 1000 µg/L (300-1000 µg/L for men, 200-1000 µg/L for women).(20) Among 3359 men and 2416 women, prevalence of potential iron-loading HFE genotypes (defined as C282Y homozygote, C282Y/H63D compound heterozygote, or H63D homozygote) was 10% and 12% in men and women, respectively. Prevalence of C282Y homozygosity was 2% and 4% among men and women, respectively. Likelihood of C282Y homozygosity increased with increasing serum ferritin levels, from 0.3% to 16% in men, and from 0.3% to 30% in women. Posttest likelihood ratios (likelihood of C282Y homozygosity given a positive test result) exceeded 1 at serum ferritin levels of 500 µg/L or more for men and at levels greater than 300 µg/L for women. In Caucasian subjects with mild hyperferritinemia, causes of elevated serum ferritin level other than C282Y or H63D HFE mutations (eg, liver disease, diabetes) were more likely.
Hereditary hemochromatosis is a common genetic disorder in the Caucasian population. Abnormal serum iron indices, clinical symptoms of iron overload or a family history of hereditary hemochromatosis may provoke testing for diagnosis. Testing for mutations in the HFE gene, which contributes to most cases of hereditary hemochromatosis, can confirm a genetic etiology; if clinically indicated, serial phlebotomy may be initiated, which can lead to a restored normal life expectancy. Therefore, genetic testing for HFE gene mutations may be considered medically necessary for patients with a clinical suspicion of hemochromatosis (signs and symptoms of iron overload) or in patients with fasting serum iron indices that are suggestive of iron overload, as well as in individuals with a family history of hemochromatosis.
General population screening has been proposed because of the high prevalence of disease, absence of or nonspecific early clinical findings, simplicity and effectiveness of treatment, and low success rate of late diagnosis and treatment. However, because genotype penetrance is low, and the natural history of untreated individuals is unpredictable, support for population-based screening is lacking. Therefore, genetic testing for hereditary hemochromatosis screening in the general population is considered investigational.
Practice Guidelines and Position Statements
American Academy of Family Physicians
AAFP recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population. (Grade D recommendation: at least fair evidence that [the service] is ineffective or that harms outweigh benefits).(16)
American Association for the Study of Liver Diseases
A 2011 practice guideline from AASLD recommends(5):
- Patients with abnormal iron studies should be evaluated as patients with hemochromatosis, even in the absence of symptoms (based on high quality evidence [A]).
- In a patient with suggestive symptoms, physical findings, or family history of HH, a combination of transferrin saturation and ferritin should be obtained rather than relying on a single test, and if either is abnormal (transferrin saturation ≥45% or ferritin above the upper limit of normal), then HFE mutation analysis should be performed (strength of recommendation 1 [strong] by the classification of the Grading of Recommendation Assessment, Development, and Evaluation [GRADE] workgroup; based on moderate quality evidence [B]).
- Screening (iron studies and HFE mutation analysis) of first-degree relatives of patients with HFE-related HH is recommended to detect early disease and prevent complications. (1A)
- Screening for non-HFE-related HH is not recommended. Average risk population screening for HH is not recommended. (1B)
Centers for Disease Control and Prevention
CDC does not currently recommend population screening for HFE mutations.(17)
U.S. Preventive Services Task Force
USPSTF recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population. (Grade D recommendation: at least fair evidence that [the service] is ineffective or that harms outweigh benefits).(21)
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Kanwar P, Kowdley KV. Metal storage disorders: Wilson disease and hemochromatosis. Med Clin North Am 2014; 98(1):87-102.
- Sood R, Bakashi R, Hegade VS et al. Diagnosis and management of hereditary haemochromatosis. British Journal of General Practice 2013; 63(611):331-32.
- Vujic M. Molecular basis of HFE-hemochromatosis. Front Pharmacol 2014; 5:42.
- Radio FC, Majore S, Binni F et al. TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. Blood Cells Mol Dis 2014; 52(2-3):83-7.
- Bacon BR, Adams PC, Kowdley KV et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54(1):328-43.
- Clark P, Britton LJ, Powell LW. The diagnosis and management of hereditary haemochromatosis. Clin Biochem Rev 2010; 31(1):3-8.
- Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med 2009; 11(5):307-13.
- Gan EK, Powell LW, Olynyk JK. Natural history and management of HFE-hemochromatosis. Semin Liver Dis 2011; 31(3):293-301.
- Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician 2013; 87(3):183-90.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic Testing for HFE Gene Mutations Related to Hereditary Hemochromatosis. TEC Assessments 2001; Volume 16, Tab 22.
- Stuhrmann M, Strassburg C, Schmidtke J. Genotype-based screening for hereditary haemochromatosis. I: Technical performance, costs and clinical relevance of a German pilot study. Eur J Hum Genet 2005; 13(1):69-78.
- Bryant J, Cooper K, Picot J et al. A systematic review of the clinical validity and clinical utility of DNA testing for hereditary haemochromatosis type 1 in at-risk populations. J Med Genet 2008; 45(8):513-8.
- Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 1991; 101(2):368-72.
- Niederau C, Fischer R, Purschel A et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110(4):1107-19.
- Picot J, Bryant J, Cooper K et al. Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review. Genet Test Mol Biomarkers 2009; 13(1):7-14.
- American Academy of Family Physicians. Hemochromatosis, 2006. Available online at: http://www.aafp.org/patient-care/clinical-recommendations/all/hemochromatosis.html. Last accessed March 2014.
- Centers for Disease Control and Prevention. Hemochromatosis (iron storage disease). Training & education - epidemiology prevalence. Available online at: http://www.cdc.gov/ncbddd/hemochromatosis/training/epidemiology/prevalence.html. Last accessed March 2014.
- Whitlock EP, Garlitz BA, Harris EL et al. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006; 145(3):209-23.
- McLaren GD, Gordeuk VR. Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology Am Soc Hematol Educ Program 2009:195-206.
- Adams PC, McLaren CE, Speechley M et al. HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 microg/L. Can J Gastroenterol 2013; 27(7):390-2.
- U.S. Preventive Services Task Force (USPSTF). Screening for hemochromatosis, August 2006. Available online at: http://www.uspreventiveservicestaskforce.org/uspstf/uspshemoch.htm. Last accessed March 2014.
|CPT||81256||HFE (hemochromatosis)(e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D)|
|ICD-9-CM Diagnosis||275.01-275.09||Disorders of iron metabolism code range|
|V18.19||Family history of other endocrine and metabolic diseases|
|ICD-10-CM (effective 10/1/15)||E83.10||Disorder of iron metabolism, unspecified|
|E83.110-E83.119||Hemochromatosis code range|
|Z83.49||Family history of other endocrine, nutritional and metabolic diseases|
|ICD-10-PCS (effectve 10/1/15)||Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.|
Genetic testing, hereditary hemochromatosis
Hemochromatosis, genetic testing
|4/12/12||New Policy add to Medicine – Pathology/ Laboratory section||Genetic testing for HFE gene mutations may be considered medically necessary in patients with abnormal serum iron indices indicating iron overload and in individuals with a family history of hemochromatosis in a first degree relative. Investigational in screening of the general population.|
|04/11/13||Replace Policy||Policy updated with literature search through February 2013. Reference 5 and 12-14 added. No change in policy statements.|
|05/09/13||Replace policy - correction only||Reference 15 added|
|4/10/14||Replace policy||Policy updated with literature review through March 23, 2014; references 1-4 and 20-21 added; references 16-17 updated. No change in policy statements.|