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.
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 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.
Diagnosis
Genetic Testing for Hereditary Hemochromatosis
HH may result from pathologic variants in several genes related to iron storage:
Types of HH and Genes Involved
Type |
Gene |
Inheritance |
Protein |
Onset |
Phenotype |
---|
1 |
HFE |
AR |
HFE |
40-50 yrs of age in males
After menopause in females
|
Moderate |
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
Sources: EMQN, 2016 ; Bardou-Jacquet, 2014 ; Zarrilli, 2013
|
Adult Patients
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.
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 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
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. In patients with mildly elevated iron indices, regular blood donation may be appropriate. Blood donated by patients with HH has been approved for transfusion by the U.S. Food and Drug Administration and UK Transfusion Services. Asymptomatic patients who are homozygous for C282Y should be monitored annually and treated if serum ferritin becomes elevated.
Recommended Monitoring Strategy for Patients with HFE HH
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%)
|
CBC |
Weekly |
Serum ferritin |
Monthlyb |
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 ferritin |
Annually |
Serum transferrin saturation |
Annually |
Patients with HFE HH C282Y homozygous genotype and normal iron indices (not undergoing treatment)
|
Serum ferritin |
Annually |
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.
Source: BSH, 2018
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