Hemochromatosis is an iron overload disorder caused by the excess storage of iron in the body, which may lead to organ damage. Hereditary hemochromatosis (HH) is one of the most common genetic disorders, and is most prevalent in adult males of northern European descent. HH has been linked to a number of variants in several genes related to iron regulation. The severity of the causative variant correlates with the time course of iron overload and organ damage; more severe variants lead to pediatric onset of symptoms, while less severe variants may lead to adult symptom onset, or may never result in symptoms. The most common form of adult HH has been linked to variants (C282Y, H63D, and S65C) of the HFE gene, which codes for a protein responsible for iron regulation. Pediatric HH is rare. The majority of pediatric cases are linked to variants of the HFE2 gene, which codes for hepcidin. Initial testing for hemochromatosis involves assessment of iron overload via serum transferrin saturation, which is calculated from serum iron and iron binding capacity, and serum ferritin testing. Genetic testing for HFE HH is indicated if biochemical or clinical findings are suggestive, and is recommended for adult family members of individuals with a homozygous C282Y genotype and for reproductive partners of individuals diagnosed with HFE HH. Once HFE HH is diagnosed, ongoing monitoring of iron status is required, particularly if venesection or blood donation is used to control iron overload.
Quick Answers for Clinicians
Early symptoms of hemochromatosis are nonspecific and include fatigue, lethargy, loss of libido, arthralgia, impotence, and abdominal pain. Liver enzyme abnormalities are often observed. In fully established disease, diabetes, cirrhosis, and bronze skin pigmentation may be observed, and symptoms of heart disease may be present.
Although the iron that accumulates in hemochromatosis is dietary iron, no link has been established between a low-iron diet and decreased iron stores in patients with hemochromatosis. Patients with hereditary hemochromatosis (HH) should not be advised to avoid red meat and other iron-rich foods, but should be encouraged to eat a healthy diet. Iron supplements and iron-fortified foods should be avoided. Vitamin C supplements may adversely affect patients with iron overload, and should be avoided as well.
Type 1 hereditary hemochromatosis (HFE HH) is the most common form of HH and generally exhibits adult onset. Adults with biochemical findings of iron overload should first be tested for HFE variants. All forms of pediatric-onset HH are rare, although variants in HFE2 (type 2A) are most common. If variants in HFE/HFE2 are not present, consider testing for variants in HAMP, TFR2, or SLC401A genes, which are associated with less common HH types 2A (in pediatric patients), 3,and 4, respectively.
Indications for Testing
Individuals, particularly males of northern European descent, with symptoms of iron overload (such as unexplained weakness, fatigue, abnormal liver enzyme tests, impotence, cirrhosis, and bronze coloration of skin) should be tested. Additionally, family members (parents, adult siblings, and adult children) of individuals with a homozygous C282Y HFE genotype should be tested for HH, as should reproductive partners of individuals diagnosed with HFE HH. Testing should be considered in patients with unexplained chronic liver disease and increased serum transferrin saturation, porphyria cutanea tarda, well-defined chondrocalcinosis, hepatocellular carcinoma, arthralgia, cardiomyopathy, and type 1 diabetes. General population screening is not recommended.
Serum ferritin is increased in individuals with untreated HFE HH. Increased serum ferritin levels may also be caused by inflammation. However, hyperferritinemia should raise suspicion for HH in cases with no identified alternative cause of elevated serum ferritin. In patients with increased serum ferritin in the absence of elevated serum transferrin saturation and an alternative cause of hyperferritinemia, consider aceruloplasminemia, non-HFE HH (ie, HH related to transferrin receptor 2 or ferroportin), or hyperferritinemia with cataracts.
Serum Transferrin Saturation
Serum transferrin saturation is calculated from serum iron and iron binding capacity. A saturation cutoff of 45% is sufficiently sensitive to detect mild hemochromatosis, but also identifies patients with HH who are heterozygous and not at risk for developing clinically concerning findings. If an an initial test reveals serum transferrin saturation of ≥45%, a repeat fasting test is recommended. Patients with elevated serum transferrin saturation and serum ferritin should first be evaluated for secondary iron overload; genetic testing should be performed in those without secondary iron overload to confirm a diagnosis of HH.
Genetic Testing for Hereditary Hemochromatosis
HH may result from pathologic variants in several genes related to iron storage:
|1||HFE||AR||HFE||40-50 yrs of age in males
After menopause in females
|2A||HFE2 (HJV)||AR||Hemojuvelin||~15 yrs of age||Severe|
|2B||HAMP||AR||Hepcidin||~15 yrs of age||Severe|
|3||TFR2||AR||Transferrin receptor||~30 yrs of age||Moderate|
|4A||SLC40A1 (loss of function)||AD||Ferroportin||Adulthood||Moderate|
|4B||SLC40A1 (gain of function)||AD||Ferroportin||At any point||Moderate|
AD, autosomal dominant; AR, autosomal recessive
Approximately 85-90% of adult HH cases are linked to variants in the HFE gene. More information about common HFE HH variants is available in the Hemochromatosis (HFE) 3 Variants Additional Technical Information document.
HFE testing can be used to confirm a clinical diagnosis of HFE HH in an individual with biochemical findings of iron overload. Genetic testing is also recommended for adult first-degree relatives of individuals diagnosed with HFE HH with a homozygous C282Y genotype, and for reproductive partners of individuals diagnosed with HFE HH. Genetic testing is not recommended for patients with neither iron overload nor a family history of HFE HH. Genetic tests should not be repeated unless there is doubt regarding results or a new testing methodology is developed.
Hereditary pediatric iron overload is most often linked to variants in HFE2 (also referred to as HJV), and less frequently, pathogenic variants in the HAMP gene. In pediatric patients with a serum transferrin saturation ≥45%, elevated serum ferritin, and without any secondary iron overload, consider performing HFE2 gene testing. A positive finding confirms a diagnosis of hemochromatosis. If HFE2 testing is negative, consider performing genetic testing for HAMP disease variants.
Other Methods for Diagnosis of Hereditary Hemochromatosis
Although no longer recommended for diagnosis of HH, liver biopsy may be used to confirm diagnosis of HH in individuals with hemochromatosis without a diagnostic genotype, or in patients with hyperferritinemia with confounding cofactors. Liver biopsy for disease staging is recommended in patients with confirmed HH with a serum ferritin of >1,000 µg/L and/or elevated liver enzymes. Quantitative magnetic resonance imaging (MRI) may be used as an alternative to liver biopsy.
Monitoring of iron status in patients with HH depends on treatment. Regular venesection or blood donation may be recommended for patients with HFE HH, depending on the severity of iron overload. Weekly venesection is recommended in fit patients with HFE HH whose iron indices are markedly elevated until serum ferritin reaches target levels, defined as 20-30 µg/L by the British Society for Haematology (BSH) and 50-100 µg/L by the American Assocation for the Study of Liver Diseases (AASLD). Thereafter, phlebotomy or blood donation is recommended as needed to maintain concentrations of <50 µg/L. Asymptomatic patients who are homozygous for C282Y should be monitored annually and treated if serum ferritin becomes elevated.
|Patient Population||Recommended Tests||Recommended Frequency|
|Patients with HFE HH and confirmed cirrhosis||α-fetoprotein||Every 6 mos|
|Hepatic ultrasound||Every 6 mos|
|Patients with HFE HH and elevated iron indices in the depletion phase (undergoing weekly venesection until serum ferritin reaches approximately 20-30 µg/La and transferrin saturation reaches <50%)
|Serum transferrin saturation||Every 1-3 mos|
|Patients with HFE HH elevated iron indices in the maintenance phase (undergoing phlebotomy as required to maintain serum ferritin <50 µg/La)
|Serum ferritin||Every 3-6 mos|
|Patients with HFE HH C282Y heterozygous genotype and mildly elevated iron indices (undergoing periodic blood donation)
|Serum transferrin saturation||Annually|
|Patients with HFE HH C282Y homozygous genotype and normal iron indices (not undergoing treatment)
|Serum transferrin saturation||Annually|
aAASLD 2011 recommends a target serum ferritin of 50-100 µg/L.
bAASLD 2011 recommends testing after every 10-12 phlebotomies (approximately every 3 months); test more frequently as serum ferritin approaches the target range.
ARUP Laboratory Tests
Porto G, Brissot P, Swinkels DW, et al. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH). Eur J Hum Genet. 2016;24(4):479-495.
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. 2011;54(1):328-343.
Fitzsimons EJ, Cullis JO, Thomas DW, et al. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br J Haematol. 2018;181(3):293-303.
European Association for the Study of the Liver (EASL). EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3-22.
Bardou-Jacquet E, Brissot P. Diagnostic evaluation of hereditary hemochromatosis (HFE and non-HFE). Hematol Oncol Clin North Am. 2014;28(4):625-635,v.
Zarrilli F, Elce A, Scorza M, et al. An update on laboratory diagnosis of liver inherited diseases. Biomed Res Int. 2013;2013:697940.