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Hemochromatosis is an iron overload disorder caused by 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 male adults 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 symptom onset, whereas 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 C282Y, H63D, and S65C variants in 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 in 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-associated HH (HFE HH) is indicated if biochemical or clinical findings are suggestive of the disorder 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 hemochromatosis, diabetes, cirrhosis, and bronze skin pigmentation may be observed, and symptoms of heart disease may be present.
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, which are associated with type 2A HH, 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 male adults of northern European descent, with symptoms of iron overload such as unexplained weakness, fatigue, abnormal liver enzyme tests, impotence, cirrhosis, and bronze coloration of the skin, should be tested. , , Additionally, family members (i.e., parents, adult siblings, and adult children) of individuals with a homozygous HFE C282Y 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.
Laboratory Testing
Initial Evaluation
Serum Ferritin
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 individuals with increased serum ferritin in the absence of elevated serum transferrin saturation and an alternative cause of hyperferritinemia, consider aceruloplasminemia, non-HFE HH (i.e., 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. If an initial test reveals an elevated serum transferrin saturation, 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.
Diagnosis
Genetic Testing for Hereditary Hemochromatosis
HH may result from pathogenic variants in several genes related to iron storage.
Adult Patients
Most adult cases of HH are linked to variants in the HFE gene. 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 who don't have iron overload or 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.
Pediatric Patients
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 an elevated serum transferrin saturation, elevated serum ferritin, and without any secondary iron overload, consider HFE2 gene testing. A positive finding confirms a diagnosis of hemochromatosis. If HFE2 testing is negative, consider genetic testing for HAMP 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 for patients with confirmed HH with elevated serum ferritin and/or elevated liver enzymes. Quantitative magnetic resonance imaging (MRI) may be used as an alternative to liver biopsy. ,
Monitoring
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, until serum ferritin reaches target levels. Refer to the guidelines from the American Association for the Study of Liver Diseases (AASLD) and the British Society for Haematology for more information.
Asymptomatic patients who are homozygous for C282Y should be monitored annually and treated if serum ferritin becomes elevated.
ARUP Laboratory Tests
Quantitative Spectrophotometry
Quantitative Chemiluminescent Immunoassay
Polymerase Chain Reaction (PCR) / Fluorescence Monitoring
Quantitative Enzymatic Assay
Quantitative Enzymatic Assay
Quantitative Enzymatic Assay
References
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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.
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