Coverage Policy Manual
Policy #: 2004039
Category: Laboratory
Initiated: July 2004
Last Review: July 2023
  Genetic Test: HFE Hemochromatosis

Description:
Hereditary hemochromatosis, 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.
 
Background
 
Iron overload
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 with increased hepatic iron concentrations; approximately 1-2% of patients with this genotype will develop clinical evidence of iron overload.
 
The 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 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 (Bacon, 2011). 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:
 
  1. Stage 1: those patients with the genetic disorder with no increase in iron stores who have “genetic susceptibility”.
  2. Stage 2: those patients with the genetic disorder who have phenotypic evidence of iron overload but who are without tissue or end organ damage.
  3. 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.
 
Regulatory Status
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 (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) 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/
Coverage:
Effective December 2018
 
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for HFE hemochromatosis meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with laboratory tests indicating iron overload (e.g., transferrin saturation greater than 45%).  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for HFE hemochromatosis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes if above listed criteria is not met. For members with contracts without primary coverage criteria, genetic testing for HFE hemochromatosis not meeting above listed criteria is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for non-HFE hemochromatosis for any indication, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, genetic testing for non-HFE hemochromatosis for any indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The member benefit certificate of coverage excludes genetic testing to determine the likelihood of a disease or the presence of a disease in a relative. Therefore, genetic testing for HFE hemochromatosis for screening of the general population or for screening of individuals with a family history of HFE hemochromatosis is a specific contract exclusion and is not covered.
 
Effective Prior to December 2018
 
Genetic testing for hemochromatosis meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with laboratory tests  indicating iron overload (e.g., transferrin saturation greater than 45%).  
 
The member benefit certificate of coverage excludes genetic testing to determine a likelihood of a disease or the presence of a disease in a relative. Therefore, genetic testing for hemochromatosis for screening of the general population or for screening of individuals with a family history of hemochromatosis is a specific contract exclusion and is not covered.
 
Effective prior to October 2012
Genetic testing for hemochromatosis meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for patients with laboratory tests (e.g., iron binding capacity – transferrin saturation) greater than 45%.  
 
Genetic testing for hemochromatosis does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes as a screening test for any purpose.
 
For contracts without primary coverage criteria, genetic testing for hemochromatosis as a screening test for any purpose is considered investigational.  Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures). The U.S. Preventive Services Task Force recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population.
 

Rationale:
Routine genetic screening for hemochromatosis is not recommended by most authorities.  The American Academy of Pediatrics (Pediatrics, 2001; 107:1451-1455) recommends against routine screening of infants and children.  The Agency for Health Research and Quality recommends against routine screening (http://archive.ahrq.gov/research/feb01/201RA4).  
 
Conn’s Current Therapy, 2004 provides an algorithm regarding testing for hemochromatosis:
 
    • Transferrin saturation <45%- HHC Excluded
    • Transferrin saturation >45%- Further Workup
      • Not C282Y homozygous or C282Y/H63D compound heterozygous- Liver Biopsy
      • C282Y homozygous or C282Y/H63D compound heterozygous
        • Ferritin Normal- Follow yearly Ferritin
        • Ferritin elevated
          • Ferritin <1000 ng/ml- Begin phlebotomy
          • Ferritin >1000 ng/ml- Liver Biopsy
 
It has been proposed that all infants be tested for defects in the HFE gene.  No state mandate has been proposed in Arkansas, yet.  Knowing that one has both genes could allow for the affected individual to have their iron, TIBC, and ferritin monitored to prevent disease before it occurs (by having periodic phlebotomies).
 
2011 Update
A review of the literature has been conducted through December 2010.  There was no new literature identified that would prompt a change in the coverage statement. The U.S. Preventive Services Task Force (USPSTF), in a recommendation statement published in 2006 in the Annals of Internal Medicine, recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population.
 
Clinical Utility:
The clinical utility of a direct diagnostic genetic test for the detection of the presence of  a gene mutation in the HFE gene resulting in Hemochromatosis has been found to have little, if any, risks associated with it, and the benefits of this test can be invaluable in this selected population of patients.
 
New York State Validation Program:
Currently there is no evidence that Laboratories performing genetic testing for HFE gene mutation resulting in Hemochromatosis have been validated by the New York State Validation program.
 
Clinical Appropriateness:
Genetic testing for HFE gene mutations in applicable patients is deemed appropriate at this juncture.
 
EGAPP:
Genetic testing for mutations in the HFE gene (Hemochromatosis) has not been evaluated by EGAPP. It has been identified as a topic of interest, and it is currently on the list of tests to be evaluated in the future.
 
Gene Reviews:
Gene testing for a mutation in the HFE gene for the detection of Hemochromatosis has been evaluated by Gene Reviews, and a full explanation of this genetically acquired disease is present on this web site. The efficacy of genetic testing for the diagnosis of this disease is substantiated on the Gene Reviews web site.
 
American College of Medical Genetics:
Gene testing for the detection of a mutation in the HFE gene for the diagnosis of Hemochromatosis is not currently listed on the website of the American College of Medical Genetics.
 
Hayes Inc Assessment:
Hayes Inc. Assessment states that gene testing for a mutation in the HFE gene to substantiate a diagnosis of Hemochromatosis in an applicable patient has been evaluated and assessed, and Hayes gives a B rating (Some proven benefit) to this genetic testing modality.  
 
2012 Update
A search of the MEDLINE database was conducted through September 2012.  The following is a summary of the key identified literature.
 
Clinical Validity
Bryant and colleagues 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 (Bryant, 2008). 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.
 
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 (Bacon, 2011; Adams, 1991; Niederau, 1996).
 
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 (Picot, 2009). 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.
 
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 (McLaren, 2009). 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.
 
Practice Guidelines and Position Statements
The American Association for the Study of Liver Diseases (AASLD) recommends (Bacon, 2011):
  • 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)
 
2013 Update
A search of the MEDLINE database through September 2013 did not reveal any new information that would prompt a change in the coverage statement.
 
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 (AAFP, 2006; CDC, 2013; USPSTF, 2006).
 
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 (McLaren, 2009). 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.
    
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A significant mutation  referred to as H63D, 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 (Kanwar, 2014).
 
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 (Sood, 2013; Vujic, 2014; Radio, 2014).
 
In a substudy of Caucasian participants in the HEIRS study, Adams et al (2013) assessed the prevalence of HFE mutations in patients who had elevated serum ferritin levels less than 1000 mcg/L (300-1000 mcg/L for men, 200-1000 mcg/L for women) (Adams, 2013). Among 3359 men and 2416 women, prevalence of potential iron-loading HFE genotypes (defined as C282Y homozygote, C282Y/H63D compound heterozygote, or H63D homozygote) was 10% and 12% in men and women, respectively. Prevalence of C282Y homozygosity was 2% and 4% among men and women, respectively. Likelihood of C282Y homozygosity increased with increasing serum ferritin levels, from 0.3% to 16% in men, and from 0.3% to 30% in women. Post-test likelihood ratios (likelihood of C282Y homozygosity given a positive test result) exceeded 1 at serum ferritin levels of 500 mcg/L or more for men and at levels greater than 300 mcg/L forwomen. In Caucasian subjects with mild hyperferritinemia, causes of elevated serum ferritin level other than C282Y or H63D HFE mutations (eg, liver disease, diabetes) were more likely.
 
In summary hereditary hemochromatosis is a common genetic disorder in the Caucasian population. Abnormal serum iron indices, clinical symptoms of iron overload or a family history of hereditary hemochromatosis may provoke testing for diagnosis. Testing for mutations in the HFE gene, which contributes to most cases of hereditary hemochromatosis, can confirm a genetic etiology; if clinically indicated, serial phlebotomy may be initiated, which can lead to a restored normal life expectancy. Therefore, genetic testing for HFE gene mutations may be considered medically necessary for patients with a clinical suspicion of hemochromatosis (signs and symptoms of iron overload) or in patients with fasting serum iron indices that are suggestive of iron overload, as well as in individuals with a family history of hemochromatosis.
 
General population screening has been proposed because of the high prevalence of disease, absence of or nonspecific early clinical findings, simplicity and effectiveness of treatment, and low success rate of late diagnosis and treatment. However, because genotype penetrance is low, and the natural history of untreated individuals is unpredictable, support for population-based screening is lacking. Therefore, genetic testing for hereditary hemochromatosis screening in the general population is considered investigational.
 
U.S. Preventive Services Task Force
 
USPSTF recommends against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population. (Grade D recommendation: at least fair evidence that [the service] is ineffective or that harms outweigh benefits) (USPSRF, 2006).
 
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
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)” (ACG, 2019).  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Eckerström et al performed a cohort study of blood donors in Sweden with signs of iron overload to investigate the feasibility and utility of an iron overload screening program to identify persons with HFE C282Y mutations (Eckerstrom, 2020)). Among 50,493 blood donors newly registered between 1998 and 2015, 2,864 were recommended for HFE genotyping based on transferrin saturation >50% or elevated serum ferritin (>130 mcg/L for men or >100 mcg/L for women). HFE typing was performed for 840 donors, and identified a prevalence of C282Y homozygosity of 0.23%. The sensitivity and specificity for identification of C282Y homozygotes varied across men and women based on cutoff values for transferrin saturation and s-ferritin.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Hasan et al retrospectively studied the penetrance of the C282Y/H63D compound heterozygote genotype in developing clinically significant iron overload using electronic health records of patients in Canada (Hasan, 2022). Data were collected for up to 10 years following the initial genotyping. Between 1996 and 2009, 247 individuals tested positive for C282Y/H63D compound heterozygosity. At the time of genotyping, 4% of all patients had features of iron overload-related disease on the background of documented iron overload. Over the 10 years of follow-up, the proportion of patients with iron overload-related disease on the background of documented iron overload increased from 4% to 5.3%. The total number of patients with documented iron overload increased from 8.1% to 10.1%, the proportion of patients with provisional iron overload increased from 16.2% to 23.1%, and the number of patients with no evidence of iron overload decreased from 75.7% to 66.8%.

CPT/HCPCS:
81256HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)

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

American Academy of Family Physicians.(2006) Hemochromatosis, 2006. Available online at: http://www.aafp.org/patient-care/clinical-recommendations/all/hemochromatosis.html. Last accessed March 2014.

American Academy of Family Physicians.(2006) Hemochromatosis. Available online at: http://www.aafp.org/online/en/home/clinical/exam/hemochromatosis.html. Last accessed February 2013.

American Academy of Pediatrics. Committee on Bioethics.(2001) Ethical Issues With Genetic Testing in Pediatrics. Pediatrics 2001; 107 (6):1451-1452.

Bryant J, Cooper K, Picot J et al.(2008) 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.

Centers for Disease Control and Prevention. Hemochromatosis (iron storage disease). Training-Epi Prevalence. Available online at: http://www.cdc.gov/ncbddd/hemochromatosis/training/epidemiology/prevalence.html. Last accessed February 2013.

Centers for Disease Control and Prevention.(2014) Hemochromatosis (iron storage disease). Training & education - epidemiology prevalence. Available online at: http://www.cdc.gov/ncbddd/hemochromatosis/training/epidemiology/prevalence.html. Last accessed March 2014.

Crownover BK, Covey CJ.(2013) Hereditary hemochromatosis. Am Fam Physician 2013; 87(3):183-90.

Eckerstrom C, Frandberg S, Lyxe L, et al.(2020) Evaluation of a screening program for iron overload and HFE mutations in 50,493 blood donors. Ann Hematol. Oct 2020; 99(10): 2295-2301. PMID 32844323

Hasan SMM, Farrell J, Borgaonkar M.(2022) C282Y/H63D Compound Heterozygosity Is a Low Penetrance Genotype for Iron Overload-related Disease. J Can Assoc Gastroenterol. Oct 2022; 5(5): 240-247. PMID 36196271

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

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

Many questions remain regarding the optimal screening strategy for hereditary hemochromatosis. http://archive.ahrq.gov/research/feb01/201RA4.htm. Last accessed May 2011.

McLaren GD, Gordeuk VR.(2009) Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology Am Soc Hematol Educ Program 2009:195-206.

McLaren GD, Gordeuk VR.(2009) Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology Am Soc Hematol Educ Program 2009:195-206.

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

Picot J, Bryant J, Cooper K et al.(2009) Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: a systematic review. Genet Test Mol Biomarkers 2009; 13(1):7-14.

Radio FC, Majore S, Binni F et al.(2014) TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. Blood Cells Mol Dis 2014; 52(2-3):83-7.

Sood R, Bakashi R, Hegade VS et al.(2013) Diagnosis and management of hereditary haemochromatosis. British Journal of General Practice 2013; 63(611):331-32.

U. S. Preventive Services Task Force.(2006) Screening for Hemochromatosis: Recommendation Statement. Ann Intern Med. 2006;145:204-208.

U.S. Preventive Services Task Force (USPSTF).(2006) Screening for hemochromatosis, August 2006. Available online at: http://www.uspreventiveservicestaskforce.org/uspstf/uspshemoch.htm. Last accessed March 2014.

Vujic M.(2014) Molecular basis of HFE-hemochromatosis. Front Pharmacol 2014; 5:42.

Whitlock EP, Garlitz BA, Harris EL et al.(2006) Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006; 145(3):209-23.


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