Genetic Testing for Hereditary Hemochromatosis

POLICY NUMBER

L.2.04.460

DESCRIPTION

Hereditary hemochromatosis, 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 variants in the human hemochromatosis (HFE) gene, which is responsible for most clinically significant cases of hereditary hemochromatosis.

Iron Overload Syndromes

Iron overload syndromes may be hereditary, secondary to another 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 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

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.

Hereditary hemochromatosis 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 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. 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.

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.

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 end points (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.

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.

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 (eg, transferrin receptor 2, [TFR2]) resulting in iron overload syndromes are rare.

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. Therefore, a genetic diagnosis can be made in individuals who have not yet developed phenotypic expression. These individuals 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. 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 disorderand phenotypic evidence of iron overload but no tissue or organ damage.

3. Stage 3: Patients who have the genetic disorder with iron overload and have 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 (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

In November 2017, the 23andMe® Personal Genome Service (PGS) Genetic Health Risk was granted a de novo classification by the FDA (class II with general and special controls, FDA product code: PTA). This is a direct-to-consumer test that has been evaluated by the FDA for accuracy, reliability, and consumer comprehension. This test reports whether an individual has variants associated with HH and a higher risk of developing iron overload. This report is based on a qualitative genetic test for the C282Y (rs1800562) and H63D (rs1799945) variants in the HFE gene.

POLICY

Genetic testing for human hemochromatosis (HFE) gene variants may be considered medically necessary in an individual with abnormal serum iron indices indicating iron overload. (See Policy Guidelines)

Genetic testing for HFE gene variants 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 for screening of the general population is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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 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.

The 2011 Practice Guidelines by 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 HemochromatosisThe 2011 practice guidelines from the American Association for the Study of Liver Diseases 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 evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization (HUGO), 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 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/19/2012: Approved by Medical Policy Advisory Committee.

08/07/2013: Policy reviewed; no changes.

06/13/2014: Policy reviewed; description updated regarding genetics of hereditary hemochromatosis. Policy statement unchanged. Added examples of inflammatory states to the policy guidelines section.

08/28/2015: Medical policy revised to add ICD-10 codes. Code Reference section updated to correct the following ICD-9 diagnosis code range: 275.0 - 275.9 was changed to 275.01 - 275.09. Code description updated for ICD-9 diagnosis code V26.31.

09/14/2015: Policy description updated regarding genetics of hereditary hemochromatosis. Policy statement unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

03/30/2016: Policy description updated regarding diagnosis and treatment of hereditary hemochromatosis. Policy statements unchanged. Policy guidelines updated to add genetic counseling information.

06/06/2016: Policy number A.2.04.80 added.

06/12/2017: Policy description and statement updated to change "mutation" to "variant." Policy Guidelines updated with standard terminology for variant classification.

06/12/2018: Policy description updated. Policy statements unchanged. Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

06/05/2019: Policy description updated. Policy statements unchanged.

06/16/2020: Policy reviewed; no changes.

08/02/2021: Policy description updated regarding tests. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

06/17/2022: Policy reviewed. Policy statement updated to change "patient" to "individual." Policy Guidelines updated regarding genetic counseling.

07/12/2023: Policy reviewed; no changes.

06/17/2024: Policy reviewed; no changes.

08/27/2024: Policy updated to change the medical policy number from “A.2.04.80” to “L.2.04.460.”

08/12/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.80

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

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