Hereditary haemochromatosis – targeted analysis

Haemochromatosis is a multisystem iron-overload disorder affecting the liver, joints, endocrine organs, heart, and skin. Clinical disease usually emerges between 40 and 60 years in males and after menopause in females; hepatic fibrosis or cirrhosis is rare before 40 years. Early features commonly include arthropathy of the metacarpophalangeal joints, diabetes mellitus, raised hepatic transaminases, and progressive skin pigmentation; weakness, chronic fatigue, abdominal pain, and weight loss are common but nonspecific. Progressive iron deposition can lead to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hypogonadotropic hypogonadism may produce erectile dysfunction in males and amenorrhoea or infertility in females. Cardiac involvement is uncommon overall; about 15% of individuals with cirrhosis or liver failure also have congestive heart failure or arrhythmias. Expressivity is highly variable, with clinical features differing substantially in age of onset and severity between affected males and females.

The estimated prevalence of HFE p.Cys282Tyr homozygosity is 1:200 to 1:500 in populations of European ancestry; clinically apparent disease is markedly less frequent, because most homozygotes do not develop overt iron overload.

HFE-related HH is caused by biallelic germline pathogenic variants in HFE. Among individuals of European ancestry with HH type 1, approximately 60-90% are p.Cys282Tyr homozygotes. Compound heterozygosity of p.Cys282Tyr and p.His63Asp is associated with elevated serum iron parameters. However, this genotype is not considered sufficient to cause clinical iron overload in the absence of additional risk factors and is therefore not classified as haemochromatosis. HFE encodes a hepatocyte cell-surface protein interacting with beta-2 microglobulin, transferrin receptor proteins, the bone morphogenic protein receptor, and hemojuvelin. Loss-of-function variants disrupt this complex, so hepatocytes can no longer upregulate hepcidin, the master regulator of iron metabolism; the resulting low hepcidin raises ferroportin activity and drives excessive intestinal iron absorption.

HFE-related HH is inherited in an autosomal recessive manner. Both parents of an affected individual are typically heterozygous carriers; with each pregnancy, the recurrence risk for full siblings is 25% affected, 50% heterozygous carriers, and 25% unaffected non-carriers. Once the familial pathogenic variants have been identified, predictive testing of asymptomatic at-risk relatives is technically possible.

Diagnosis relies on biochemical iron studies followed by HFE molecular genetic testing. Clinical suspicion is raised by elevated serum transferrin saturation together with raised serum ferritin concentration. The diagnosis is established by identification of HFE p.Cys282Tyr homozygosity or, less commonly, of other biallelic HFE pathogenic genotypes.

Main differential diagnoses include:

• SLC40A1-related haemochromatosis (gain-of-function alleles): adult-onset iron overload phenotype resembling HFE-related HH, but inheritance is autosomal dominant; SLC40A1
• Juvenile haemochromatosis: parenchymal iron accumulation with earlier onset and more severe manifestations than HFE-related HH in young adults; HAMP, HJV
• TFR2-related haemochromatosis: parenchymal iron accumulation with earlier onset, clinically resembling juvenile haemochromatosis; TFR2

• Establishing the molecular diagnosis, which confirms the clinical suspicion and provides a definitive aetiological classification.
• Enabling specific and individualised surveillance for hepatic, articular, endocrine, and cardiac complications as a prerequisite for targeted medical care; surveillance decisions are made by the treating physicians in consultation with the affected individual.
• Identifying at-risk family members through cascade testing for HFE p.Cys282Tyr, enabling early biochemical and clinical monitoring in covert homozygotes in the family.

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