Hereditary haemochromatosis

Hereditary haemochromatosis is a systemic iron-overload disorder affecting the liver, joints, pancreas, heart, and skin. Clinical manifestations of iron overload usually appear between 40 and 60 years of age in men and after menopause in women. Early features often include arthropathy of the metacarpophalangeal joints, diabetes mellitus, raised serum hepatic transaminases, and progressive skin pigmentation. Cardiac involvement and hypogonadism may also occur. Presentation before 40 years of age is uncommon, and hepatic fibrosis or cirrhosis is rare before this age. With progressive iron accumulation, cirrhosis can develop and be complicated by portal hypertension, primary liver cancer (hepatocellular carcinoma or cholangiocarcinoma), and end-stage liver disease. In addition to HFE-related hereditary haemochromatosis, rarer inherited iron disorders include juvenile haemochromatosis caused by pathogenic variants in HJV or HAMP, which presents with severe early-onset iron overload, and TFR2-related haemochromatosis, which often has an earlier onset than classic HFE disease. Pathogenic variants in BMP6 can also cause a haemochromatosis-like phenotype. In contrast, aceruloplasminemia (CP) is characteried by systemic and brain iron accumulation, while FTL-related hyperferritinaemia is typically associated with elevated serum ferritin without true iron overload.

The prevalence of HFE p.Cys282Tyr homozygosity, the genotype underlying most hereditary haemochromatosis in people of European ancestry, is 1/200 to 1/400. This is the frequency of the at-risk genotype, not of clinical iron-overload disease, and non-HFE forms are considerably rarer.

This panel analyses eight genes governing systemic iron homeostasis: HFE, HJV, HAMP, TFR2, SLC40A1, BMP6, CP, and FTL. HFE is the most common cause in European-ancestry populations, acting predominantly through germline p.Cys282Tyr homozygosity. Loss of HFE function reduces hepcidin, the master regulator of iron metabolism; when hepcidin is low, activity of the iron exporter ferroportin rises, increasing intestinal iron absorption and reticuloendothelial iron recycling and producing parenchymal iron overload. The remaining genes underlie rarer, clinically distinct iron-overload disorders.

Inheritance varies across the panel. HFE, HJV, HAMP, TFR2, and CP related disorders are autosomal recessive; SLC40A1-related iron overload and BMP6-related iron overload are autosomal dominant. FTL-related phenotypes (neuroferritinopathy and ) are also autosomal dominant, but these are not classic iron-overload disorders. Where a familial pathogenic variant is known, predictive testing of at-risk adult relatives is possible. Clinical penetrance of HFE p.Cys282Tyr homozygosity is incomplete and typically lower in women than in men, so a positive genotype result should not, on its own, be interpreted as predicting clinical iron overload.

Diagnosis relies on biochemical iron studies. A raised fasting transferrin saturation (≥60% in males, ≥50% in females) with an elevated serum ferritin concentration prompts further evaluation. Molecular confirmation rests on identifying HFE p.Cys282Tyr homozygosity. In case of iron overload in the absence of HFE p.Cys282Tyr homozygosity, a non-HFE form may underlie the presentation.

Main differential diagnoses include:

• Secondary iron overload from ineffective erythropoiesis, transfusion, or chronic liver disease

• Molecular genetic testing establishes the diagnosis at the molecular level and can confirm a clinically suspected condition.
• Identification of the germline pathogenic variant supports condition-specific monitoring and management decisions, including surveillance for iron-overload complications, made by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, testing of at-risk relatives can identify those who would benefit from early monitoring and iron-status assessment.

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