Background

Iron Overload Syndromes

Iron overload syndromes may be hereditary, secondary to another disease (e.g, iron-loading anemias, parenteral iron overload, chronic liver disease, dysmetabolic iron overload syndrome), or due to other miscellaneous conditions (e.g, neonatal iron overload, aceruloplasminemia, congenital atransferrinemia).

Iron overload, if 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).

Hereditary Hemochromatosis

HH, an autosomal recessive disorder, is the most commonly identified genetic disorder in white people, with an estimated prevalence of 1 in 250. However, fully expressed disease with end-organ manifestations is seen in less than 10% of affected individuals. Factors that influence phenotypic expression of human hemochromatosis(HFE; high iron-related HH [ie, the clinical appearance of iron overload]) are not defined. Low clinical penetrance may be due to the 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.

Diagnosis

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 the diagnosis but is now generally limited to determining the degree of hepatic fibrosis and cirrhosis during disease management. Most patients diagnosed with hemochromatosis will exhibit a familial pattern. However, the familial pattern may not be obvious due to the large percentage of undiagnosed patients in some families, and further evaluation of family members may be required to establish whether a familial pattern is present.

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 the high cost and low success rate of late diagnosis and treatment. However, because penetrance is low, and the natural history of asymptomatic individuals is unpredictable, support for population-based screening is lacking. A U.S. Preventive Services Task Force (2006) review of the literature suggested that 38% to 50% of individuals with C282Y homozygotes may develop iron overload, with 10% to 33% eventually developing hemochromatosis-associated morbidity.^1, The American Academy of Family Physicians, Centers for Disease Control and Prevention, and U.S. Preventive Services Task Force have recommended against population-based general screening.^1,

Treatment

Treatment to remove excess iron with serial phlebotomy is simple and effective, and if started before irreversible end-organ damage, restores normal life expectancy. While there has never been a randomized controlled trial comparing phlebotomy with no phlebotomy in the treatment of HH, there is evidence from nonrandomized studies that initiation of phlebotomy before the development of cirrhosis and/or diabetes will significantly reduce HH-associated morbidity and mortality.^2,3,4,

Genetics

Most patients with HH have variants in the HFE gene, located on the short arm of chromosome 6. The HFE gene was identified and cloned in 1996. The most common variant in the HFE gene is C282Y, a missense variant that changes cysteine at position 282 in the HFE protein to tyrosine. Homozygosity for the C282Y variant is associated with 60% to 90% of all cases of HH. Additionally, 3% to 8% of affected individuals are heterozygous for this variant. Penetrance for elevated serum iron indices among C282Y homozygotes is variable. However, penetrance for characteristic clinical endpoints (ie, end-organ damage) is quite low. There is no test that can predict whether an individual with a C282Y homozygote will develop clinical symptoms. A specific variant in PCSK7, which is associated with iron metabolism, has been investigated as a possible predictor of cirrhosis risk in HH patients homozygous for the HFE C282Y variant.^5,

Another significant HFE variant is 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.^6,

The clinical significance of a third HFE variant, 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 variants in HFE and non-HFE genes (e.g, transferrin receptor 2 [TFR2] gene) resulting in iron overload syndromes are rare.^7,8,9,10,

HFE-related HH is now frequently identified by genetic testing in asymptomatic probands and in asymptomatic relatives of patients who are known to have the disease.^2, 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 the recognition of different stages and progression of hemochromatosis.^11, These stages were defined as:

1. Stage 1: Patients with "genetic susceptibility" who have the genetic disorder but no increase in iron stores.
2. Stage 2: Patients who have the genetic disorder and phenotypic evidence of iron overload but no tissue or organ damage.
3. Stage 3: Patients who have the genetic disorder with iron overload and iron deposition to the degree that tissue and organ damage occurs.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• None

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)


1. Genetic testing for human hemochromatosis (HFE) gene variants is considered medically necessary in a member with abnormal serum iron indices indicating iron overload (see Policy Guidelines section).

2. Genetic testing for HFE gene variants is considered medically necessary in individuals with a family history of hemochromatosis in a first-degree relative (see Policy Guidelines section).

3. Genetic testing for hereditary hemochromatosis in screening of the general population is considered investigational.


Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Serum Iron Indices for Diagnosing Hereditary Hemochromatosis

Elevated fasting transferrin saturation (the ratio of serum iron to total iron-binding capacity) is the most sensitive initial phenotypic screening test. A minimum cutoff 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.

The 2011 practice guidelines from the American Association for the Study of Liver Diseases (AASLD) recommended human hemochromatosis(HFE) gene variant testing in patients with abnormal serum iron indices (ie, serum ferritin and transferrin saturation), even in the absence of symptoms.

Genetic Testing of an Individual With a Family History of Hereditary Hemochromatosis

The 2011 practice guidelines from AASLD recommended screening (iron studies [serum ferritin and transferrin saturation] and HFE variant analysis) of first-degree relatives of patients with HFE-related hereditary hemochromatosis to detect early disease and prevent complications. 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 overload.

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, individuals with C282Y heterozygotes and H63D heterozygotes can be reassured that they are not at risk for developing progressive or symptomatic iron overload. Some individuals with H63D homozygotes can develop mild iron overload.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society's nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology-"pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"-to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medicare 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. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that Genetic testing for HFE gene mutations is covered. Please refer to Novitas Solutions Inc, LCD Biomarkers Overview (L35062) for eligibility and coverage. Available at: https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35062&ver=58&Date=&PolicyType=Both&ArticleType=SAD%7cEd&Cntrctr=323*1&SearchType=Advanced&CoverageSelection=Both&CptHcpcsCode=81240&kq=true&bc=IAAAACAAAAAAAA%3d%3d&.



[RATIONALE: This policy was created in 2012 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 20, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

The policy was informed by a TEC Assessment (2001) on genetic testing for human hemochromatosis (HFE) gene variants related to hereditary hemochromatosis (HH).^12, The Assessment 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, meets the TEC criteria.

Genetic testing and counseling for HFE mutations in asymptomatic relatives of subjects with hereditary hemochromatosis also meets the TEC criteria."

Testing Individuals With Abnormal Iron Indices or Signs of Iron Overload
Clinical Context and Test Purpose

The purpose of genetic testing of individuals with abnormal iron indices or clinical signs of iron overload is to determine the underlying cause of iron overload, detect disease at an earlier stage, and direct treatment to prevent irreversible organ damage.

The relevant question addressed in this policy is: Does genetic testing for HFE lead to improved health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with abnormal iron indices or clinical signs of iron overload.

Interventions

The test being considered is genetic testing for HFE.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The potential beneficial outcome of primary interest is early detection of disease to prevent disease complications of iron overload. The time frame for outcome measures varies from the short-term development of clinical signs of iron overload to long-term complications such as liver failure and cirrhosis.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary treatments (eg, phlebotomy) that may not be efficacious. False-negative test results can lead to lack of appropriate treatments to prevent complications from iron overload.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Bryant et al (2008) conducted a systematic review of 15 electronic databases to April 2007 to evaluate the clinical validity and utility of DNA testing in people suspected of having HH and in family members of those diagnosed with the disorder.^13, 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 whites of northern European origin with iron overload suggestive of HH, compared with a control population and reported or allowed for the calculation of sensitivity and specificity.

Eleven observational studies were identified that evaluated the clinical validity of genotyping for the C282Y variant in the diagnostic workup for HH. Criteria used to define hemochromatosis varied among studies. The clinical sensitivity of C282Y homozygosity ranged from 28.4% to 100%; when considering studies that used strict criteria to classify HH, the clinical sensitivity ranged from 91.3% to 92.4%.

Section Summary: Clinically Valid

Observational studies have demonstrated that pathogenic variants in the HFE gene are responsible for most clinically significant cases of HH. Studies that used strict criteria to classify HH revealed that the clinical sensitivity of genetic testing for HFE common variants is high.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No studies reporting direct evidence of the clinical utility of genetic testing were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The clinical utility of genetic testing for HH relies on whether a strong chain of evidence exists.

Most individuals with HH can be diagnosed without genetic testing, based on a clinical diagnosis of hemochromatosis that occurs in a familial pattern. Individuals with an established diagnosis of HH will not directly benefit from genetic testing if irreversible organ damage has already occurred. However, some patients with signs and/or symptoms of HH may not have a definitive diagnosis after standard clinical workup. In these cases, genetic testing can confirm the diagnosis of HH when a pathogenic variant is identified. Following confirmation of diagnosis, management changes (ie, treatment with phlebotomy) are likely to occur. Furthermore, early treatment of HH may prevent irreversible organ damage due to iron overload. As a result, genetic testing to confirm the diagnosis of HH has clinical utility in individuals with signs and symptoms of HH but in whom a definitive diagnosis cannot be made without genetic testing.

Section Summary: Clinically Useful

For individuals who have abnormal iron indices or clinical signs of iron overload studies have demonstrated that current genetic testing detects the large majority of HH disease, but that, among those with positive tests (HH homozygotes), penetrance for the clinical disease is low. While there is no direct evidence of the clinical utility of genetic testing, a strong chain of evidence can be constructed that supports the definitive genetic diagnosis of persons with early signs of HH.

Testing Asymptomatic First-Degree Relatives With Hereditary Hemochromatosis
Clinical Context and Test Purpose

The purpose of genetic testing of first-degree relatives of individuals with HH is to determine the need surveillance for iron overload, detect disease at an early stage, and initiate early treatment before irreversible organ occurs.

The relevant question addressed in this policy is: Does genetic testing for HFE in asymptomatic first-degree relatives lead to improved health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is first-degree relatives of individuals with HH.

Interventions

The test being considered is genetic testing for HFE.

Comparators

The following practice is currently being used: standard clinical management without genetic testing.

Outcomes

The potential beneficial outcomes of primary interest are to determine the need for surveillance of iron overload, to detect disease at an earlier stage, and to prevent irreversible organ damage. The time frame for outcome measures varies from the short-term development of clinical signs of iron overload to long-term complications such as liver failure and cirrhosis.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary surveillance for iron overload and treatments (eg, phlebotomy) that may not be efficacious. False-negative test results can lead to lack of surveillance for iron overload and treatments to prevent disease progression and irreversible organ damage.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Bulaj et al (2000) studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis.^14, The results showed that if the proband had a hemochromatosis-related condition, male relatives were more likely to have morbidity than if the proband had no hemochromatosis-related condition. Homozygous relatives were found to have hemochromatosis-related conditions that had yet to be detected clinically. The summary of results is shown in Table 1.

Table 1. Prevalence of Hemochromatosis-Related Conditions Among Relatives of Probands

Condition	Men (n=113)	Women (n=101)
Iron overload, n (%)	96 (85)	69 (68)
≥1 hemochromatosis-related conditiona	43 (38)	10 (10)
	Men >40 Years Old (n=52)	Women >50 Years Old (n=43)
≥1 hemochromatosis-related conditiona	27 (52)	7 (16)

^a Cirrhosis, hepatic fibrosis, elevated aminotransferase values, or hemochromatotic arthropathy.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

No studies that report direct evidence on the clinical utility of genetic testing were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

The clinical utility of genetic testing for HH relies on whether a strong chain of evidence exists.

Individuals with a first-degree relative with HH are at risk for developing the disease themselves. When there is a known pathogenic variant in the family, genetic testing of family members can confirm the presence or absence of the variant with a high degree of certainty. Homozygous relatives of patients with hemochromatosis have conditions related to hemochromatosis that were not previously detected clinically. For asymptomatic patients who test negative, surveillance for iron overload is not indicated. For asymptomatic patients who test positive, surveillance is indicated, and early initiation of treatment may potentially prevent organ damage due to iron accumulation.

Section Summary: Clinically Useful

For individuals who are asymptomatic with a first-degree relative with HH, studies have demonstrated that current genetic testing detects the large majority of HH disease, but that, among those with positive tests (HH homozygotes), penetrance for clinical disease is low. While there is no direct evidence of the clinical utility of genetic testing, a strong chain of evidence can be constructed that supports the definitive genetic diagnosis of persons who are first-degree relatives of persons with HH.

Testing Asymptomatic Individuals (Population Screening)
Clinical Context and Test Purpose

The purpose of genetic testing of individuals in the general population is to screen individuals with no markers for increased risk for iron overload for HFE genetic variants that might lead to abnormal iron indices and/or signs and symptoms of iron overload.

The relevant question addressed in this policy is: Does genetic testing for HFE in asymptomatic patients in the general population lead to improved health outcomes?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals without markers for increased risk for iron overload.

Interventions

The test being considered is genetic testing for HFE.

Comparators

The following practice is currently being used: routine clinical management without genetic screening.

Outcomes

The potential beneficial outcome of primary interest is early detection of the disease to prevent disease complications of iron overload. The time frame for outcome measures varies from the short-term development of clinical signs of iron overload to long-term complications such as liver failure and cirrhosis.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary surveillance for iron overload and treatments (eg, phlebotomy) that may not be efficacious. False-negative test results can lead to lack of surveillance for iron overload and treatments to prevent disease progression and irreversible organ damage.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

See the clinical validity discussion in the Testing Individuals With Abnormal Iron Indices or Signs or Symptoms of Iron Overload section.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

McLaren and Gordeuk (2009) 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 101168 adults enrolled over a 2-year period at 4 centers in the U. S. and 1 in Canada.^15, Initial screening included genotyping for the HFE C282Y and H63D alleles, measurement of serum ferritin, and calculation of transferrin saturation. The HFE genotyping yield for identifying persons with C282Y homozygosity was low in racial/ethnic groups other than non-Hispanic whites. The overall frequency of homozygosity for the C282Y variant in non-Hispanic whites 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 and 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 was not recommended. This study was not designed to evaluate the efficacy of general population genetic screening but the results are consistent with minimal clinical utility of such screening.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Individuals who are not at increased risk for developing HH will not likely benefit from genetic testing for HFE. Direct evidence of the clinical utility of genetic testing in the general population is lacking. In contrast to first-degree relatives of individuals with hemochromatosis, where a homozygous genotype is relatively strongly associated with clinically undetected iron overload or disease-related conditions, a chain of evidence cannot be constructed to show potential clinical utility or improvements in health outcomes from screening individuals not at increased risk for HH. The HEIRS study revealed that the prevalence of C282Y homozygotes in non-Hispanic whites was 4.4 per 1000 or 0.44% in an unselected population. Given low homozygous frequency in the population and the variable penetrance of disease, long-term follow-up (eg, 5-10 years) is required to determine the true clinical sensitivity (expected to be <0.44% due to variable penetrance). Additionally, in the absence of long-term prospective studies and observational treatment data, the chain of evidence does not show that identification of HFE common variants in an unselected, normal-risk population leads to improved outcomes.

Section Summary: Clinically Useful

For individuals who are asymptomatic with no family history of HH, studies have established population prevalence of genetic HH, and serve as partial evidence to estimate penetrance of disease. The low prevalence of HH homozygosity in the general population and incomplete penetrance of clinical disease does not support the clinical utility of genetic testing in an unselected population.

Summary of Evidence

For individuals who have abnormal iron indices or clinical signs of iron overload who receive genetic testing for HFE, the evidence includes retrospective and prospective observational studies. Relevant outcomes are test accuracy, test validity, and change in disease status. Studies have demonstrated that current genetic testing detects the large majority of HH disease, but that, among those with positive tests (HH homozygotes), penetrance for clinical disease is low. There is no direct evidence of the clinical utility of genetic testing, but, along with prior knowledge of the effectiveness of treatment for clinical iron overload, there is a strong chain of evidence that supports the definitive genetic diagnosis of persons with early signs of HH. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic with a first-degree relative with HH who receive genetic testing for HFE, the evidence includes retrospective and prospective observational studies. Relevant outcomes are test accuracy, test validity, and change in disease status. Studies have demonstrated that current genetic testing detects the large majority of HH disease, but that, among those with positive tests (HH homozygotes), penetrance for clinical disease is low. There is no direct evidence of the clinical utility of genetic testing, but, along with prior knowledge of the effectiveness of treatment for clinical iron overload, there is a strong chain of evidence that supports the definitive genetic diagnosis of persons who are first-degree relatives of persons with HH. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are asymptomatic with no family history of HH who receive genetic testing for HFE, the evidence includes observational studies of screening in population samples. Relevant outcomes are test accuracy, test validity, and change in disease status. These studies have established population prevalence of genetic HH and serve as partial evidence to estimate penetrance of disease. The low prevalence of HH homozygosity in the general population and incomplete penetrance of clinical disease does not support the clinical utility of genetic testing in an unselected population. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
American Association for the Study of Liver Diseases

In 2011, the practice guidelines from the American Association for the Study of Liver Diseases made the following statements on genetic testing for hereditary hemochromatosis (see Table 2).^2,

Table 2. Guidelines on Genetic Testing for Hereditary Hemochromatosis

Recommendation	Grade
"We recommend that family members, particularly first-degree relatives, of patients diagnosed with HH should be screened for HH."	A
"In a patient with suggestive symptoms, physical findings, or family history [of HH], 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
"[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
"Average risk population screening for HH is not recommended."	1B

HH: hereditary hemochromatosis; TS: transferrin saturation.
American College of Gastroenterology

In 2019, practice guidelines from the American College of Gastroenterology made the following statement on genetic testing for hereditary hemochromatosis: "We recommend that family members, particularly first-degree relatives, of patients diagnosed with HH should be screened for HH (strong recommendation, moderate quality of evidence)".^16,

U.S. Preventive Services Task Force Recommendations

A literature review by the U.S. Preventive Services Task Force (2006) concluded that evidence was not sufficient to support population screening for hemochromatosis.^1,The Task Force "decided not to review the evidence again or update its recommendations" for hemochromatosis screening.^17,

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in March 2020 did not identify any ongoing or unpublished trials that would likely influence this policy]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for Hereditary Hemochromatosis
Hereditary Hemochromatosis, Genetic Testing for
Hemochromatosis, Hereditary, Genetic Testing for

References:
1. 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. Aug 01 2006; 145(3): 209-23. PMID 16880463

2. 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. Jul 2011; 54(1): 328-43. PMID 21452290

3. Adams PC, Speechley M, Kertesz AE. Long-term survival analysis in hereditary hemochromatosis. Gastroenterology. Aug 1991; 101(2): 368-72. PMID 2065912

4. Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology. Apr 1996; 110(4): 1107-19. PMID 8613000

5. Stickel F, Buch S, Zoller H, et al. Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis. Hum Mol Genet. Jul 15 2014; 23(14): 3883-90. PMID 24556216

6. Kanwar P, Kowdley KV. Metal storage disorders: Wilson disease and hemochromatosis. Med Clin North Am. Jan 2014; 98(1): 87-102. PMID 24266916

7. Sood R, Bakashi R, Hegade VS, et al. Diagnosis and management of hereditary haemochromatosis. Br J Gen Pract. Jun 2013; 63(611): 331-2. PMID 23735405

8. Vujic M. Molecular basis of HFE-hemochromatosis. Front Pharmacol. 2014; 5: 42. PMID 24653703

9. 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. Feb-Mar 2014; 52(2-3): 83-7. PMID 24055163

10. Ekanayake D, Roddick C, Powell LW. Recent advances in hemochromatosis: a 2015 update : a summary of proceedings of the 2014 conference held under the auspices of Hemochromatosis Australia. Hepatol Int. Apr 2015; 9(2): 174-82. PMID 25788196

11. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol. Sep 2000; 33(3): 485-504. PMID 11020008

12. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic testing for HFE gene mutations related to hereditary hemochromatosis. TEC Assessments. Dec 6 2001;Volume 16:Tab 22. PMID

13. 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. Aug 2008; 45(8): 513-8. PMID 18310265

14. Bulaj ZJ, Ajioka RS, Phillips JD, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med. Nov 23 2000; 343(21): 1529-35. PMID 11087882

15. 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. PMID 20008199

16. Kowdley KV, Brown KE, Ahn J, et al. ACG Clinical Guideline: Hereditary Hemochromatosis. Am J Gastroenterol. Aug 2019; 114(8): 1202-1218. PMID 31335359

17. U.S. Preventive Services Task Force (USPSTF). Hemochromatosis: Screening (inactive). 2006; https://www.uspreventiveservicestaskforce.org/BrowseRec/InactiveTopic/219. Accessed March 23, 2020.

81256