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Hereditary Haemochromatosis

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Dr Marita Dednam - MBChB (UP) Mmed (Chem Path) (UP)

PATHCHAT NO 20: HEREDITARY HAEMOCHROMATOSIS

Introduction

The haemochromatosis protein (HFE) is, amongst others, a body iron sensing protein. It plays a part in regulating the synthesis in hepatocytes of the central iron regulating protein hepcidin. Hepcidin regulates the function of ferroportin, a protein in the basolateral membranes of duodenal enterocytes, macrophages and hepatocytes. Ferroportin transports intracellular iron to the circulation. Hepcidin binds to ferroportin and causes its internalization and degradation within the cell. High hepcidin levels will cause a decrease in iron absorption (Figure1). Low hepcidin levels, e.g. with mutations in the HFE gene, will cause an increase iron absorption.

Genetics and pathophysiology

Inheritance of HH is autosomal recessive. The C282Y mutation in the HFE gene was discovered in 1996. In patients of Northern European descent with HH, >90% will be homozygous for C282Y. In a population of Northern European descent 1:200 will be homozygous and 1:8 will be heterozygous for the C282Y mutation. Note: other mutations are present in the HFE gene e.g. H63D and S56C but they are usually not associated with iron overload. In patients with clinical HH, <3-5% will be C282Y/H63D compound heterozygotes.

On ly 30 -50% of homozygotes will deve lop haemochromatosis due to the incomplete penetrance of the C282Y variant. Most C282Y homozygotes will, however, develop abnormal iron indexes in their lifetime. Factors that may influence the penetrance of the disease include the genetic variant, liver diseases, alcoholism, dietary iron, obesity, menstruation and pregnancy.

The excess iron that is absorbed in HH is deposited in the liver, pancreas, heart, endocrine organs, skin and brain.

 

 

 

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