Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

Condition: Hemochromatosis, Type 1
Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Hereditary hemochromatosis (HHC) is a common genetic disorder that can lead to iron overload. Estimates of prevalence in the general population vary due to a long pre-clinical period and lack of consistent definitions of "case." The prevalence of hemochromatosis cases defined biochemically (elevated serum iron) will be higher than prevalence of cases based on documented iron overload, with or without clinical signs and symptoms. The prevalence will be lower for cases based on diagnosed disease (cirrhosis, diabetes).
In North America, an estimated 80% of clinically recognized cases are due to homozygosity of the HFE C282Y polymorphism, and an additional 4% are due to compound heterozygosity of the C282Y and H63D polymorphisms. In Caucasians, the prevalence of HFE-associated HHC (HFE-HHC) has been estimated as 1/220-1/250. However, the prevalence of HFE-HHC with clinical manifestations is much lower, estimated as 1/2500.
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Clinical Features
(Signs / symptoms)
HHC is a disorder of iron metabolism characterized by an abnormally high absorption of dietary iron by the gastrointestinal mucosa. Iron overload may be detected biochemically as increased transferrin-iron saturation and increased serum ferritin concentrations. Clinical manifestations are due to excess iron which can be deposited in the liver, pancreas, heart joints, pituitary gland, skin, and testes. The rate of iron accumulation and the frequency and severity of clinical symptoms can vary markedly. Early symptoms include fatigue, weakness, joint pain, palpitations, abdominal pain, and weight loss. If left untreated, disease progression can lead to hyperpigmentation of the skin, arthritis, cirrhosis, diabetes mellitus, chronic abdominal pain, severe fatigue, hypopituitarism, hypogonadism, cardiomyopathy, primary liver cancer, or an increased risk of certain bacterial infections.
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Natural History
(Important subgroups & survival / recovery)
Symptoms of HHC typically appear between ages 40 and 60 in males and after menopause in females. The prevalence of both iron overload and clinical disease is generally higher in males than females. Presenting signs and symptoms of HHC also vary by sex, with women more likely to present with fatigue, arthralgia, and pigmentation changes and men presenting more often with symptoms of liver disease. Symptoms and disease complications increase with age. With disease progression, liver cirrhosis may develop and may be complicated by portal hypertension, hepatocellular carcinoma, and end-stage liver disease. By the time cirrhosis is recognized, approximately 50% have diabetes mellitus and 15% have congestive heart failure or arrhythmias. Patients diagnosed and treated prior to the development of cirrhosis have a normal life expectancy. Death most often occurs due to cirrhosis, primary liver cancer, diabetes, and cardiomyopathy. On the basis of clinically diagnosed or compatible disease age-adjusted mortality rates for hemochromatosis deaths in the US was 1.8 per million in 1992. These rates were about twice as high in males as in females, and in white persons as in nonwhite persons.
Not all cases of C282Y homozygotes or have iron overload and not all cases that have iron overload have iron deposits in tissues or organs to the degree that damage occurs. Additionally, no test can predict whether a C282Y homozygote will develop clinical disease manifestations. For cases of C282Y/H63D compound heterozygosity, few develop clinical manifestations, but among those who do, many have a complicating factor (e.g., fatty liver, viral hepatitis) that leads to iron overload.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease, the following evaluations are recommended at the initial diagnosis of an individual determined to be a C282Y homozygote:
• Serum ferritin concentrations should be measured to establish disease status and prognosis.
• MRI to estimate parenchymal iron content, including the liver and possibly the heart
• When serum ferritin and liver enzyme levels are abnormal, liver biopsy can establish or exclude cirrhosis.
• Consultation with a medical geneticist and/or genetic counselor. (Tier 3)
C282Y homozygotes without evidence for iron overload could be monitored annually and treatment instituted when the ferritin rises above normal. Phlebotomy is the mainstay of treatment once iron overload is present. There is little evidence to guide when to initiate phlebotomy, though the threshold is typically any ferritin level above the normal range. Though there is no survival data specific to homozygous C282Y, phlebotomy has been shown to be effective in clinically diagnosed hemochromatosis: 5-year survival of 93% for adequately phlebotomized patients compared to 48% for inadequately phlebotomized patients (10-year survival of 78% and 32%, respectively). Survival of treated patients without cirrhosis and diabetes has been found to be equivalent to that of the normal population, whereas those with these complications have a significantly reduced survival, indicating the benefits of the early initiation of iron removal. (Tier 2)
Family Management
Given the autosomal recessive transmission of HFE-HHC, genetic testing of siblings should be carried out. Siblings should be screened for serum ferritin and transferrin saturation. Genetic testing of other first degree relatives should also be considered. (Tier 1)
For children of an affected proband, HFE testing of the other parent is generally recommended to determine whether the child is an obligate heterozygote. Testing children in affected families is generally not recommended until age 18 years unless symptomatic. (Tier 2)
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Circumstances to Avoid
Medicinal iron, mineral supplements, excess vitamin C, uncooked seafood, and alcohol consumption in those with hepatic involvement. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Mutations
The allelic frequency of the C282Y variant in the general population (worldwide) has been estimated as 6.2%. Based on Hardy-Weinberg, the frequency of C282Y homozygotes is estimated as 0.38%. However, reported frequencies (worldwide) of homozygotes are higher at 0.41%. The US has an estimated prevalence of 0.44%. US prevalence estimates are lower among Hispanic persons (0.027%), Asian Americans (<0.001%), Pacific Islanders (0.012%), and black persons (0.014%).
The carrier frequency of the H63D mutations is estimated as 22% in Europe and 23% in North America. C282Y/H63D compound heterozygosity of has a frequency of 2% in the European general population and in 2% in the for North America. (Tier 1)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
Penetrance is incomplete and is generally higher in males than females. Differences in inclusion criteria and the definition of biochemical and disease penetrance have produced a range of estimates for the penetrance of C282Y homozygosity. A summary of penetrance estimates from two meta-analysis are presented:
Elevated transferrin saturation: Males = 75-94%, Females = 40-94%
Increased serum ferritin: Males = 32-76%, Females = 26-58%
Excess liver iron: Males = 42%, Females = 19%, All = 24%
Diabetes: All = 0-5.6%
Liver fibrosis: Males = 18%, Females = 5%, All = 6%
Cirrhosis: Males = 6%, Females = 2%, All = 1.4% (Tier 1)
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A recent study has published penetrance estimates from the eMERGE Network:
C282Y homozygotes:
Elevated transferrin saturation: Males = 100%, Females = 50%
Increased serum ferritin: Males = 78%, Females = 31%
Diabetes: Males = 45%, Females = 12%
Cirrhosis: Males = 5%, Females = 3%
C282Y/H63D compound heterozygotes:
Elevated transferrin saturation: Males = 38%, Females = 38%
Increased serum ferritin: Males = 33%, Females = 30%
Diabetes: Males = 28%, Females = 20%
Cirrhosis: Males = 5%, Females = 5% (Tier 5)
Information on the prevalence of mutations was not available.
A meta-analysis of 202 case-control studies indicated an increased risk for several outcomes among clinically ascertained (i.e. cases defined by disease status related to an organ):
C282Y homozygotes compared to controls:
• Liver disease: OR=3.9 (99% CI: 1.9-8.1)
• Hepatocellular carcinoma: OR=11 (99% CI: 3.7-34)
• Hepatitis C: OR=4.1 (99% CI: 1.2-14)
• Nonalcoholic steahohepatitis: OR=10 (99% CI: 2.1-53)
• Porphyria cutanea tarda: OR=48 (99% CI: 24-95).
• Diabetes mellitus: OR=3.4 (99% CI: 1.1-11; among North Europeans only).
C282Y/H63D compound heterozygotes compared to controls:
• Porphyria cutanea tarda: OR=8.1 (99% CI: 3.9-17). (Tier 1)
The phenotypic expression of HFE-HHC is highly variable, including the rate of iron accumulation and the frequency and severity of clinical outcomes. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Surveillance to monitor serum iron levels is noninvasive and likely well tolerated in patients. Following initial diagnosis and/or presentation of symptoms, weekly or biweekly phlebotomy may be needed to reduce serum ferritin concentration to below 50ng/mL. However, maintenance therapy to keep serum ferritin concentrations below 50ng/mL typically occurs every 3 to 4 months for men and once or twice a year for women.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Given that the early symptoms of HFE-HHC (fatigue, joint pain, etc.) are nonspecific, HFE-HHC is often not diagnosed at the early stages. Even advanced complications (cardiomyopathy, liver cancer, etc.) are also common primary disorders, and thus iron overload can be missed unless it is screened for specifically.

Final Consensus Scores
Outcome / Intervention Pair
Nature of the
Clinically apparent disease / Monitoring of ferritin levels
Clinically apparent disease / Phlebotomy
To see the scoring key, please go to:
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. . easl clinical practice guidelines for hfe hemochromatosis. J Hepatol. (2010) 53(1):3-22.
2. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS. Diagnosis and management of hemochromatosis: 2011 practice guideline by the american association for the study of liver diseases. Hepatology. (2011) 54(1):328-43.
3. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive services task force. Ann Intern Med. (2006) 145(3):209-23.
4. Hanson EH, Imperatore G, Burke W. HFE gene and hereditary hemochromatosis: a HuGE review. Human genome epidemiology. Am J Epidemiol. (2001) 154(3):193-206.
5. R Seckington, L Powell. Hfe-associated hereditary hemochromatosis. 2000 Apr 03 [Updated 2015 Sep 17]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from:
6. Genetic counselling and testing. guidelines for preventive activities in general practice. (2012) Website:
7. Gallego CJ, Burt A, Sundaresan AS, Ye Z, Shaw C, Crosslin DR, Crane PK, Fullerton SM, Hansen K, Carrell D, Kuivaniemi H, Derr K, de Andrade M, McCarty CA, Kitchner TE, Ragon BK, Stallings SC, Papa G, Bochenek J, Smith ME, Aufox SA, Pacheco JA, Patel V, Friesema EM, Erwin AL, Gottesman O, Gerhard GS, Ritchie M, Motulsky AG, Kullo IJ, Larson EB, Tromp G, Brilliant MH, Bottinger E, Denny JC, Roden DM, Williams MS, Jarvik GP. Penetrance of hemochromatosis in hfe genotypes resulting in p.cys282tyr and p.[cys282tyr];[his63asp] in the emerge network. Am J Hum Genet. (2015) 97(4):512-20.
8. Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology. (2007) 46(4):1071-80.
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