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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 mutations in the HFE gene, which are responsible for the majority of clinically significant cases of hereditary hemochromatosis.
Iron Overload Syndromes
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, 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 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 Hereditary 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 to confirm diagnosis but is now generally limited to determining the degree of hepatic fibrosis and cirrhosis during management. Most patients with a diagnosis of hemochromatosis will exhibit a familial pattern, thereby confirming the diagnosis of HH. 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 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 (USPSTF) review of the literature suggested that up to 38% to 50% of C282Y homozygotes may develop iron overload, with up to 10% to 33% eventually developing hemochromatosis-associated morbidity. The American Academy of Family Physicians, Centers for Disease Control and Prevention, and USPSTF recommend against population-based general screening.
Treatment of Hereditary Hemochromatosis
The main treatment modality for patients with HH is periodic phlebotomy. While there has never been a randomized controlled trial of phlebotomy versus 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 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 60-90% of all cases of HH. Additionally, 3-8% of affected individuals are heterozygous for this mutation. 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 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 mutation.
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, 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, usually in the presence of another liver disease.
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.
With the advent of genetic testing in the late 1990s, HFE-related HH is now frequently identified 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 recognition of different stages and progression of hemochromatosis. These stages were defined as:
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 Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosed not to require any regulatory review of this test.
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.
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 in the Diagnosis of HH
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 recommend HFE gene mutation testing in patients with abnormal serum iron indices (ie, serum ferritin and transferrin saturation), even in the absence of symptoms.
Genetic Testing in an Individual with a Family History of HH
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. Some H63D homozygotes can develop mild iron overload.
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 Nervous/Mental Conditions, 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 Medically Necessary, “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 HISTORY07/19/2012: 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.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.80
CODE REFERENCEThis 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.
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