Hemochromatosis Guidelines

Updated: Jun 08, 2023
  • Author: Andrea Duchini, MD; Chief Editor: Praveen K Roy, MD, MSc  more...
  • Print

Guidelines Summary

CDC-suggested screening guidelines

The Centers for Disease Control and Prevention (CDC) does not recommend universal screening for hemochromatosis but rather suggests evaluating iron overload in individuals with a family history and in individuals who are symptomatic. [103]

Overall, the clinical expressivity of C282Y homozygosity appears to be much lower than previously thought, and the cost effectiveness of screening has been challenged, because many people must be screened in order to prevent severe disease in only a few. During a screening program conducted in a health appraisal clinic, classic multiorgan disease was detected in only 1 of 152 homozygotes. [104, 105, 106]

Screening for hemochromatosis should be considered in the following individuals [107] :

  • All first-degree relatives of subjects known to have hemochromatosis: Human leukocyte antigen (HLA) typing is no longer necessary; family members identified as having C282Y homozygosity should be tested for transferrin saturation, serum ferritin, and liver enzymes; screening of young children of patients with hemochromatosis does not need to be performed if the spouse is tested and does not have the C282Y mutation

  • Individuals presenting for a standard medical check: Transferrin saturation should be measured; if levels are higher than 45%, the estimation should be repeated after fasting—if the fasting level still is higher than 45%, further investigation is warranted. [108]  An initial fasting sample will obviate the necessity for repeating the test.

  • The general population: This group possibly should be screened, although screening is more difficult and debatable in these individuals, [109] and cost is a major consideration; a consensus stated that population screening is best performed by phenotype (using iron-binding capacity), but using genotype screening (using C282Y mutation) is considered premature until all unanswered questions are clarified

  • If a proband is negative for C282Y mutation, family members must be screened by other means, such as serum iron studies or HLA typing; HLA typing or tissue typing has been used to detect homozygous hemochromatosis in a sibling of a proband who has hemochromatosis by other means, such as liver biopsy or quantitative phlebotomy—in this setting, a sibling who is HLA-A identical and HLA-B identical to the proband is considered homozygous; if only 1 haplotype is shared with the proband, the sibling is considered heterozygous

AMA-suggested screening guidelines

As a result of the high frequency of hereditary hemochromatosis–associated mutations, the American Medical Association recommended the establishment of guidelines for population screening, as follows:

  • Screening tests for the general population comprise measurement of serum transferrin saturation or serum iron concentration; when transferrin saturation is greater than 60% or greater than 50% in women who are premenopausal, or when serum iron concentration is greater than 150 mcg/dL, other measurements are recommended

  • Screening and diagnosis cannot be based on single-measurement transferrin saturation or serum iron concentrations, because they can be falsely increased as the result of diet, alcohol consumption, or other liver diseases

  • Adams and coworkers suggested the introduction of the unbound iron-binding capacity measurement to preselect patients for genotyping [110]

  • Detection of homozygosity for the C282Y mutation or compound heterozygosity for the C282Y/H63D mutations is believed to be diagnostic; however, negative results on DNA tests do not exclude hereditary hemochromatosis, which can also be the result of other mutations [111]

  • Liver biopsy is not required for the diagnosis of hereditary hemochromatosis; however, liver biopsy may be useful in C282Y homozygotes with suspected liver disease, in C282Y homozygotes or heterozygotes with serum ferritin levels greater than 1000 mcg/L, in patients without C282Y mutations with unexplained iron overload, and in patients with additional risk factors for liver disease [112]

  • Relatives of patients with hereditary hemochromatosis should undergo DNA testing to detect subclinical cases of hereditary hemochromatosis so that early treatment for the disease can be begun [46]

AASLD-suggested screening guidelines

Measurement of transferrin saturation after an overnight fast should be considered the initial screening of individuals with suspected iron overload and first-degree relatives of patients with hereditary hemochromatosis older than 20 years. Measurement of serum ferritin at the same time increases the predictive accuracy for diagnosis of iron overload. [8]

HFE gene mutation analysis should be performed for all individuals with abnormal iron study results and on those who are first-degree relatives of identified homozygotes. Patients younger than 40 years may be treated by therapeutic phlebotomy without the need for liver biopsy.


Hemochromatosis Clinical Practice Guidelines (EASL, 2022)

Clinical practice guidelines on hemochromatosis were published August 1, 2022 by the European Association for the Study of the Liver (EASL) in the Journal of Hepatology. [113]

Patients who should receive genetic testing for hemochromatosis include individuals with elevated serum ferritin and transferrin saturation, clinical and biochemical symptoms of hemochromatosis, or idiopathic persistently elevated transferrin saturation.

Patients who have increased hepatic iron on MRI or biopsy should receive biochemical testing and clinical assessment for hemochromatosis.

Adults with first-degree relatives diagnosed with hemochromatosis should receive genetic testing.

Evaluation of serum iron results should be the primary assessment for hemochromatosis. These results should include transferrin saturation and serum ferritin levels, although measuring hepcidin is not recommended.

Patients of European descent who exhibit evidence of iron overload (transferrin saturation >45% and serum ferritin >200 μg/L in females and transferrin saturation >50% and ferritin >300 μg/L in males, or transferrin saturation that is persistently elevated) should be genotyped for the p.C282Y variant in HFE, even if clinical signs of hemochromatosis are absent. Additionally, any adult first-degree relatives of individuals with evidence of p.C282Y homozygous hemochromatosis should receive testing for p.C282Y.

Genotype should not be the sole guiding factor in the management of patients with p.C282Y/p.H63D compound heterozygosity or p.H63D homozygosity. Rather, management should depend on phenotypic presentation and any additional risk factors. Additionally, individuals with confirmed iron overload who are compound heterozygous for p.C282Y/p.H63D or homozygous for p.H63D should be worked up for alternative causes of iron overload.

Assessment for liver fibrosis should be non-invasively performed at the time of diagnosis for all patients with hemochromatosis.

Iron deficiency should be avoided in all patients with hemochromatosis who are planning to become pregnant.

Phlebotomy management for hemochromatosis consists of an induction and maintenance phase. During the induction phase, phlebotomy should be undertaken weekly or every 2 weeks until depletion of iron stores. A serum ferritin of 50 μg/L is the target goal but no lower to avoid iron deficiency.

Dietary modifications and control should not take the place of iron removal therapy. Foods fortified with iron or high in iron should be avoided when possible, and iron supplementation should not be undertaken.