Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) represents one of several primary iron overload disorders, such as aceruloplasminemia, ahypotransferrinemia, H-ferritin–associated iron overload, and African iron overload syndrome, and should be distinguished from secondary iron overload disorders such as dietary or parenteral iron overload, chronic liver disease, and iron-loading anemias (e.g., thalassemia minor, aplastic anemia), as well as other conditions such as ineffective erythropoiesis and porphyria cutanea tarda.

HH represents a spectrum of inherited disorders associated with parenchymal iron deposition in multiple organ systems caused by the excessive absorption of iron from a normal diet ( Fig. 172.1 ). Iron deposition occurs in multiple organs, including the liver, heart, pancreas, skin, joints, and anterior pituitary gland. The long-term consequences include cirrhosis and hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, “bronze diabetes” with hyperpigmentation of the skin and impaired glucose tolerance, arthropathy involving the metacarpophalangeal (MCP) joints, and hypogonadotropic hypogonadism.

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Secondary Iron Overload and Hereditary Hemochromatosis.

The term “hereditary hemochromatosis” is typically used to indicate human factors engineering (HFE)-associated hereditary hemochromatosis, a disorder found predominantly in white populations. Initially described by Trousseau in 1865, and linked to the human leukocyte antigen (HLA)-A haplotype by Simon in the mid-1970s, the HFE hemochromatosis gene was discovered in 1996. Two common mutations were initially described, the C282Y mutation, indicating a cysteine-to-tyrosine substitution at amino acid 282, and the H63D mutation, a histidine-to-aspartate substitution at amino acid 63. Type 1 HFE-associated HH is classified as type 1a (C282T homozygosity), type 1b (compound C282T/H63D heterozygosity), or type 1c (other HFE genotypes such as S65C). Other forms of HH are less common and include type 2 HH (juvenile HH involving either hemojuvelin or hepcidin mutations), type 3 HH (TfR2 mutation-associated HH), and type 4 HH (ferroportin-associated HH). Table 172.1 lists common mutations in the HFE gene with their clinical interpretations.

HH is the most common genetic liver disease among persons of northern European descent, with an estimated prevalence of 1 : 200 to 1 : 500. The highest allelic frequency for the C282Y mutation is observed in northern Europe (6.4%–9.5%). An estimated 10% of the general U.S. population carries a single HFE mutation, whereas 0.5% are estimated to have a homozygous HFE mutation (1 in 200). However, the penetrance is low, with only 1% of C282Y homozygotes developing end-organ damage. Importantly, the development of clinically relevant iron overload is influenced by genetic and environmental factors such as alcohol, diabetes, exogenous iron intake, blood loss, celiac disease, and vitamin C intake.

The body iron stores in the human are regulated through gastrointestinal (GI) absorption. This is accomplished by variable expression of different iron transporters in response to physiologic signals in small intestinal crypt cells. In iron deficiency, iron absorption in the proximal small intestine is upregulated, characterized by increased expression or activity of DMT1 (mucosal iron transporter), ferroportin (FPN1), basolateral iron transporter, and transferrin receptor, and by decreased mucosal ferritin content. A similar pattern was found in some patients with HH, suggesting that the crypt cell senses a state of iron deficiency. Recent studies have revealed that a novel antimicrobial peptide produced in the liver called hepcidin appears to have an inhibitory effect on iron absorption. Patients with HFE -associated HH have inappropriately low hepcidin levels compared with healthy subjects, suggesting that the HFE mutation may lead to decreased efficiency in signaling hepatic iron content to crypt or intestinal absorptive cells, resulting in greater iron absorption.