Chapter 16 Hemochromatosis
1 Hereditary hemochromatosis (HH) is an inherited disorder characterized by iron-mediated tissue injury secondary to impaired regulation of intestinal iron absorption.
2 HH is associated with mutations in genes encoding proteins, with the common feature of iron overload resulting from unregulated intestinal iron absorption.
3 Type 1 HH, or HFE-associated HH, is the most common form of HH and is inherited as an autosomal recessive trait.
4 Although the HFE gene mutation is highly prevalent in the white population, its penetrance is quite low; therefore, relatively few patients homozygous for the C282Y mutation in the HFE gene manifest the complete phenotype.
5 The features of iron overload are often unrecognized and diagnosed only in the setting of advanced disease, including diabetes mellitus, cirrhosis, and cardiomyopathy.
6 Patients in whom hemochromatosis is detected early and who are treated with iron depletion therapy (phlebotomy) have a normal life expectancy.
7 Suspected cases of HH should be evaluated with the following: biochemical markers of iron overload (serum transferrin iron saturation, and ferritin); HFE gene mutation analysis; and, in selected cases, liver biopsy (for staging or for diagnosis).
Epidemiology
1. In the white population, the C282Y mutation of the HFE gene, the genetic defect underlying the most common form of hereditary hemochromatosis (HH), is present in 1 in 200 to 1 in 250 in the homozygous form and in 1 in 8 to 1 in 12 in the heterozygous form.
TABLE 16.1 Penetrance of the C282Y mutation
| Penetrance | Definition | Frequency among C282Y homozygotes identified by population screening |
|---|---|---|
| Biochemical | Elevated serum transferrin-saturation and ferritin | |
| Clinical | Hepatocellular carcinoma, hepatic fibrosis or cirrhosis, metacarpophalangeal arthritis, or elevated aminotransferase levels |
TABLE 16.2 Mutations associated with hereditary hemochromatosis
| Type of Hemochromatosis | Common name | Associated gene and gene product |
|---|---|---|
| Type 1 | Classic hemochromatosis | HFE (HFE) |
| Type 2A | Juvenile hemochromatosis | HFE2 (haemojuvelin) |
| Type 2B | Juvenile hemochromatosis | HAMP (hepcidin) |
| Type 3 | Tfr2-related hemochromatosis | Tfr2 (transferrin receptor-2) |
| Type 4 | Ferroportin-related iron overload | SLC40A1 (ferroportin) |
Genetics
HH is associated with mutations in different genes involved in iron homeostasis (see Table 16.2).
Classification
HFE hemochromatosis (type 1)
1. The HFE gene is a major histocompatibility complex (MHC) class I–like gene and is located on the short arm of chromosome 6 telomeric to the A3 MHC class 1 histocompatibility locus.
2. HFE is primarily expressed in the crypt cells of the upper intestinal mucosa, where it interacts with the transferrin receptor and beta-2 microglobulin.
5. Factors known to influence iron absorption and accumulation may in part explain the clinical variability in phenotype:
Non-HFE hemochromatosis
2. Unlike the case of HFE HH, numerous different mutations are associated with each type of non-HFE HH.
3. Type 2 HH is associated with more severe iron overload and resultant tissue damage that develop earlier in life than in patients with HFE HH.
Pathophysiology
Iron absorption
1. Only approximately 10% of dietary iron is absorbed in physiologically normal persons, and this absorption is regulated in accordance with body iron stores.
2. Iron absorption is downregulated when serum transferrin saturation is high and following high dietary iron intake.
3. In HH, iron absorption is increased and is not downregulated as in normal individuals, and the result is in a positive iron balance.
4. Small bowel mucosal ferritin and ferritin mRNA levels are inappropriately decreased in HH; this pattern is normally associated with iron deficiency and is corrected by iron repletion.
5. Iron absorption involves uptake of iron from the intestinal lumen to the enterocytes, and then transfer from enterocytes to plasma, and both processes are increased in HH. In vivo kinetic studies indicated that increased transport of iron from the serosal side of the intestine into plasma drives the increased iron absorption.
Parenchymal iron deposition in types 1 to 3
1. Iron is deposited in multiple organs including liver, heart, pancreas, joints, skin, gonads, and other endocrine organs.
2. The major site of iron deposition in HH is the liver, consistent with its role as the major storage organ for iron.
3. Iron is deposited primarily in hepatocytes as ferritin and subsequently also as hemosiderin, with a decreasing gradient of iron absorption from periportal (zone 1) to pericentral (zone 3) hepatocytes.
5. Saturation of serum transferrin precedes hepatic iron accumulation and is responsible initially for increased iron delivery to the tissues.
Effect of alcohol intake
1. Heavy alcohol intake is associated with higher serum iron markers, increased severity of clinical disease, and increased risk of cirrhosis and hepatocellular carcinoma (HCC) in C282Y homozygotes.
