Penetrance

Environmental factors. Some environmental factors modify penetrance of laboratory phenotypes of persons with HFE HC. Increased dietary consumption of heme iron was associated with higher serum ferritin levels in postmenopausal females . Nonalcoholic fatty liver in referred adults with HFE HC with iron overload was associated with significantly higher median serum ferritin and greater prevalence of diabetes mellitus type 2, after adjustment for other factors, although nonalcoholic fatty liver did not significantly influence the quantity of iron removed by phlebotomy to achieve iron depletion . Gastric acid suppression reduces phlebotomy requirements . Nonetheless, effects of these factors on penetrance of HFE HC is probably small.

Source: GeneReviews — "HFE-Related Hemochromatosis"

Diagnostic Criteria

In 2022, a new classification of hemochromatosis based on genetic and clinical manifestations was proposed by an expert group, although this classification excludes persons who have loss-of-function SLC40A1 alleles ("ferroportin disease"). This classification also suggests clinical management when molecular genetic characterization of hemochromatosis is not available . In 2022, the European Association for the Study of the Liver updated guidelines for diagnosis of hemochromatosis . For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care .

Suggestive Findings

HFE-related hemochromatosis (HFE HC) should be suspected in an individual with laboratory features of hemochromatosis, clinical ma...

Source: GeneReviews — "HFE-Related Hemochromatosis"

Differential Diagnosis

HFE-related hemochromatosis (HFE HC) differs from rarer primary iron overload disorders and secondary iron overload disorders. Primary Iron Overload Disorders Primary iron overload disorders (summarized in ) are characterized by increased absorption of iron from a normal diet in subjects without severe anemia. Juvenile hemochromatosis and TFR2-related hemochromatosis result from hepcidin deficiency and thus the clinical manifestations of these disorders are similar to, but typically more severe than, those of HFE HC. Table 2. Primary Iron Overload Disorders in the Differential Diagnosis of HFE-Related Hemochromatosis

Management Guidelines

In 2022, the European Association for the Study of the Liver updated guidelines for management of hemochromatosis, including the use of hepatic elastography, erythrocytapheresis, dietary recommendations, and management of persons with HFE p.Cys282Tyr/His63Asp compound heterozygosity . Experts at the 2017 Hemochromatosis International meeting published an objective and practical set of recommendations on treatment of persons with HFE-related hemochromatosis (HFE HC) based on scientific studies and guidelines .

Evaluations Following Initial Diagnosis

To establish the extent of iron overload and optimal management of persons diagnosed with HFE HC, the evaluations summarized in are recommended if not performed as part of the evaluation that led to the diagnosis .

Table 3.

HFE-Related Hemochromatosis: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Biochemical iron parameters

| Serum iron, transferrin saturation, serum ferritin |

Joints

| Radiographs of affected joint(s) | In those w/arthralgias or joint deformity, esp hands, hips, knees

Diabetes

| Fasting serum glucose Hb A1c level | At diagnosis of iron overload to assess for diabetes mellitus

Liver

| Serum AST, ALT, ALP, bilirubin, albumin |

Liver biopsy for eval of abnormal liver tests establishing prognosis | In those w/clinical evidence of cirrhosis those w/serum ferritin 1,000 g/L, esp those w/non-HC liver disease (e.g., excessive alcohol consumption, viral hepatitis) (See .)

Source: GeneReviews — "HFE-Related Hemochromatosis"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for individuals with HFE HC due to p.Cys282Tyr homozygosity in Europe and North America . Table 5. HFE-Related Hemochromatosis: Recommended Surveillance

Source: GeneReviews — "HFE-Related Hemochromatosis"