|MP 2.04.80||Genetic Testing for Hereditary Hemochromatosis|
|Original Policy Date
|Last Review Status/Date
Created with literature search/4:2013
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Hereditary hemochromatosis (HH), a common genetic disorder of iron metabolism, can lead to inappropriate iron absorption, toxic accumulation and organ damage. Genetic testing is available to assess mutations in the HFE gene, which are responsible for the majority of clinically significant cases of hereditary hemochromatosis.
Iron overload syndromes may be hereditary, secondary to some other disease (e.g. iron-loading anemias, parenteral iron overload, chronic liver disease or dysmetabolic iron overload syndrome), or due to other miscellaneous conditions (e.g., 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 metacarpo-phalangeal joints), and cardiomyopathy (either with symptomatic cardiac failure or arrhythmias).
Hereditary hemochromatosis (HH), an autosomal recessive disorder, is the most common, identified, genetic disorder in Caucasians and may be seen in approximately 1 in 250 Caucasians. However, fully expressed disease with end-organ manifestations is seen in <10% of those individuals. The factors that influence phenotypic expression of HFE-related HH (that is the clinical appearance of iron overload) are not clearly defined. The low clinical penetrance appears to be due to a complex interplay of genetic status and other factors such as age, sex, environmental influences and the presence of other 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, specific organ-related symptoms, or they may be asymptomatic. The 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 in the past to confirm diagnosis but is now generally limited to determining the degree of hepatic fibrosis and cirrhosis during management of the disease.
Genetic testing can confirm a hereditary nature of the iron overload.
Genetics of hereditary hemochromatosis
The majority of patients with HH have mutations in the HFE gene, which is 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 substitutes a cysteine residue for tyrosine at amino acid position 282 on the HFE protein. Homozygosity for the C282Y mutation is associated with 60-90% of all cases of HH. Additionally, 3-8% of individuals affected with HH are heterozygous for this mutation. Penetrance for elevated serum iron indices among C282Y homozygotes is relatively high, but not 100%. However, the penetrance for the characteristic clinical endpoints (end organ damage) is quite low. There is no test that can predict whether a C282Y homozygote will develop clinical symptoms.
The other significant mutation is referred to as H63D, which results in the substitution of aspartic acid for histidine at position 63. Homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of modifying factors. However, heterozygosity for C282Y/H63D has been associated with increased hepatic iron concentrations; approximately 1-2% of patients with this genotype will develop clinical evidence of iron overload.
The clinical significance of a third HFE mutation, S65C, appears to be minimal. This rare variant displays very low penetrance. Compound heterozygosity for C282Y and 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.
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. (1) Therefore, a genetic diagnosis can be applied to individuals who have not yet developed phenotypic expression. These individuals have a genetic susceptibility to developing iron overload but may never do so. A consensus conference of the European Association for the Study of Liver Diseases in 2000 led to a recognition of the different stages and progression of hemochromatosis. These stages were defined as:
- Stage 1: those patients with the genetic disorder with no increase in iron stores who have “genetic susceptibility”.
- Stage 2: those patients with the genetic disorder who have phenotypic evidence of iron overload but who are without tissue or end organ damage.
- Stage 3: those individuals who have the genetic disorder with iron overload and have 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
Elevated fasting transferrin saturation (the ratio of serum iron to total iron-binding capacity) is the most sensitive initial phenotypic screening test. A 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 confounding causes of hyperferritinemia (alcohol abuse, the metabolic syndrome, inflammatory states and acute and chronic hepatitis), serum ferritin is a good marker of the degree of iron overload. (2)
The negative predictive value of a normal transferrin saturation and serum ferritin is 97%. In this situation, no further testing is recommended. (2)
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, even in the absence of symptoms (e.g., abnormal serum iron indices on routine screening chemistry panel).
Genetic testing in an individual with a family history
The 2011 Practice Guidelines by the American Association for the Study of Liver Diseases 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. (1) 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) (e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., 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 February 2013.
Recent reviews highlight the pathogenesis, diagnosis and management of HH. (2-5)
A 2001 TEC Assessment on the 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 individuals 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. (6)
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, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; 2) clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and 3) clinical utility, i.e., how the 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 and colleagues (7) initiated a pilot study on DNA-based screening of hereditary hemochromatosis in Germany. One of the major aspects of the study was the analytic validity of different test methods. A total of 3,961 individuals provided blood samples for testing of the HFE mutation C282Y; of these, 3,930 samples were successfully tested with two independent test methods (either polymerase chain reaction [PCR] and restriction digest, reverse allele-specific oligonucleotide hybridization, solid-phase oligonucleotide ligation assay [SPOLA], or microarray [DNA-chip]). In all, 67 of the tested individuals 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 of 34 newly diagnosed C282Y homozygous individuals. Of 7,860 tests performed, 7,841 (99.6%) gave correct results. The overall error rate was 0.24% (95% confidence interval [CI]: 0.15–0.38%). The analytic specificity of the tests methods with respect to the detection of homozygosity for C282Y was 100% (7,726 of 7,726 non-homozygous test challenges, 95% CI: 99.95–100%), while the analytic sensitivity was 97% (130 of 134 homozygous test challenges, 95% CI: 92.5–99.2%). The authors concluded that the test methods for C282Y are robust, highly sensitive and specific.
Bryant and colleagues (8) 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. 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 had to report patient-based outcomes (such as morbidity or mortality).
Eleven observational studies that could be used to evaluate clinical validity of genotyping for the C282Y mutation in the diagnosis of HH were identified. Criteria used to define hemochromatosis varied between studies. Clinical sensitivity of C282Y homozygosity for HH 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 the results can be used to improve patient management. Although there has never been a randomized controlled trial of phlebotomy versus no phlebotomy in treatment of HH, there is evidence that initiation of phlebotomy before the development of cirrhosis and/or diabetes will significantly reduce the morbidity and mortality of HH. (1, 9, 10)
Data exists on the psychosocial aspect of genetic testing for HH. Picot and colleagues conducted a systematic review of the psychosocial aspects of DNA testing for HH in at-risk individuals. (11) Databases were searched through 2007 for any quantitative or qualitative primary research that considered DNA testing of individuals considered at-risk of HH and reported psychosocial outcomes. Three observational studies met their inclusion criteria; each had methodologic limitations. After receiving test results, patient anxiety levels fell or were unchanged, general health-related quality-of-life outcomes improved in some aspects, or were unchanged with respect to pretest results. Outcomes were not reported separately for those referred for diagnosis and those with family history of HH. The authors concluded that, while evidence is limited, the results suggest that genetic testing for HH in at-risk individuals 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 the disease, the lack of early clinical findings/nonspecific early clinical findings, the specificity of the findings once they appear, the low cost of diagnosis and treatment, and the high cost and low success rate of late diagnosis and treatment. However, because the penetrance of the genotype is low, and the natural history of untreated individuals cannot be predicted, there is a lack of support for population-based screening. 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. (12-14)
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 multi-ethnic, primary care-based sample of 101,168 adults enrolled over a 2-year period at 4 centers in the U.S. and one in Canada.(15) Initial screening of the participants included genotyping for the HFE C282Y and H63D alleles, serum ferritin, and a calculated transferrin saturation. The yield of HFE genotyping in identifying persons with C282Y homozygosity was low in racial/ethnic groups other than non-Hispanic Caucasians. The overall frequency homozygosity for the C282Y mutation in non-Hispanic Caucasians was 4.4 per 1,000. There was marked heterogeneity of disease expression in C282Y homozygotes. The authors concluded that 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 and who may benefit from continued monitoring of iron status, and that, 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.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
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 the majority of 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.
As hereditary hemochromatosis is common, general population screening has been proposed because of the high prevalence of the disease, the lack of early clinical or nonspecific early clinical findings, the simplicity and effectiveness of treatment, and the low success rate of late diagnosis and treatment. However, because the penetrance of the genotype is low, and the natural history of untreated individuals cannot be predicted, there is a lack of support for population-based screening. Therefore, genetic testing for hereditary hemochromatosis in screening of the general population is considered investigational.
Practice Guidelines and Position Statements
The American Association for the Study of Liver Diseases (AASLD) recommends (1):
- that patients with abnormal iron studies should be evaluated as patients with hemochromatosis, even in the absence of symptoms (strength of recommendation A by the classification used by the Grading of Recommendation Assessment, Development, and Evaluation [GRADE] workgroup).
- 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 (1B).
- 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)
- screening for non-HFE-related HH is not recommended. Average risk population screening for HH is not recommended. (1B)
Medicare National Coverage
No national coverage determination.
- 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/online/en/home/clinical/exam/hemochromatosis.html. Last accessed February 2013.
- Centers for Disease Control and Prevention. Hemochromatosis (iron storage disease). Training-Epi Prevalence. 2013. Available online at: http://www.cdc.gov/ncbddd/hemochromatosis/training/epidemiology/prevalence.html. Last accessed February 2013.
- 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.
|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 10/1/14)||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 10/1/14)||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|