Laboratory Evaluation of Hereditary Hemochromatosis

Excerpt

Hemochromatosis, a syndrome caused by excessive iron absorption, was first described in the mid-1800s as a syndrome of "bronze diabetes and pigmentary cirrhosis." It is believed that the term hemochromatosis was coined by von Recklinghausen in 1889. A genetic origin of this metabolic problem was first suggested in the 1930s. In 1977, Simon et al reported the association between an HLA class I-like molecule and the presumed hemochromatosis gene on chromosome 6p, establishing the genetic basis of what is now referred to as hereditary hemochromatosis (HH).

Although one of the most common genetic disorders in the United States, affecting over 1 million people, hereditary hemochromatosis (HH) is frequently an incidental discovery during routine laboratory iron measurements or the diagnostic workup of other conditions. However, increasing awareness of HH has also contributed to early detection. Early diagnosis allows for intervention before tissue damage occurs due to excessive iron deposition. Iron can deposit in the liver, pancreas, heart, joints, and other endocrine organs if left untreated.

Current classifications for HH identify 4 classes or types, with 5individual molecular subtypes, based on the age of onset, underlying genetic mutation, and mode of inheritance.

Type I HH is considered the classic form of the disorder, and the onset of symptoms begins in adulthood. Loss-of-function mutations in the HFE (Hereditary Fe [iron]) gene are present in approximately 70% of patients diagnosed with HH. This form of HH disproportionately affects males, although females can also be affected.

Type 2 HH is frequently called "juvenile" hemochromatosis, as symptoms begin in childhood, and the disease is typically more clinically severe. Unlike Type I HH, there is no preference for a particular sex. Type 2 HH has 2 subtypes, 2a and 2b. Type 2a HH is caused by mutations in the gene initially known as hemojuvelin (HJV) and is now referred to as HFE2. Type 2b HH is due to hepcidin antimicrobial peptide (HAMP) gene mutations.

Type 3 HH has a typical onset at approximately 30 years of age and is caused by mutations in the transferring-receptor 2 (TFR2) gene.

Type 4 HH, also known as ferroportin disease, is caused by mutations in the SLC4OA1 gene. Ferroportin is an iron transmembrane transport protein, and Type 4 HH is the only known form of hemochromatosis that can be inherited in an autosomal dominant fashion. The onset of type 4 HH typically occurs in mid-adulthood.