Hemochromatosis & Iron Overload
(Hepatology 2001;33:1321-28)
DEFINITIONS:
Hereditary Hemochromatosis (HH): Autosomal recessive inherited disorder of iron overload
Increased iron absorption from the gut, with preferential deposition of iron in liver parenchyma, heart, pancreas, and other endocrine glands (Wilson’s disease is decreased copper secretion, not an increased absorptive process like HH)
Secondary iron overload: some other stimulus causes the GI tract to absorb increased amounts of iron; There is an underlying disorder:
I.e. anemias due to ineffective erythropoiesis, chronic liver disease, and rarely, excessive intake of medical iron
Parenteral iron overload: received excessive iron either as RBC transfusions or iron-dextran parenterally (always iatrogenic)
In patients requiring routine transfusions, a chelation program with deferoxamine should be initiated to prevent toxic iron overload
Neonatal iron overload: Rare; Most likely related to intrauterine viral infection; Infants do very poorly and generally die without transplant
African iron overload (Bantu hemosiderosis): previously thought to be related to excessive iron in ETOH due to brewing in iron drums
Recent studies suggest there may be a genetic component distinct from HH (i.e. not the HFE gene).
Other inheritable forms of liver disease: α1-AT, Wilson’s
EPIDEMIOLOGY:
1 in 300 is homozygous for the hemochromatosis mutation and 1 in 10 is a heterozygous carrier; Usually manifests in middle-age ♂
HH is most common identified single-gene disorder in Caucasians
ETIOLOGIES:
Gene responsible is HFE, which codes for MHC type-1 like protein; The mutation replaces a cysteine with a tyrosine at position 282 (C282Y)
The result is a problem with transferring receptor-mediated iron uptake into cells, leading to increased iron absorption = HH
A second mutation, where histidine is replaced by aspartate at position 63 (H63D) is common but less important in cellular iron metabolism
Hepcidin: a small polypeptide produced in the liver inhibits iron absorption in small intestines and prevents iron release from macrophages
May function as a iron regulator; increased in infectious/inflammatory diseases (may be responsible for anemia of chronic disease)
PATHOPHYSIOLOGY:
Western diet consumes 10-20 mg iron/day; Absorption 1-2 mg/day, representing about 10% efficiency in absorption
Patients with iron deficiency, HH, or ineffective erythropoiesis absorb increased amounts of iron (up to 3-6 mg/day)
Iron storage (normal 4 gm of total body iron): 2.5 gm hemoglobin, 1 gm reticuloendothelial (spleen, bone marrow, liver), 400 mg myoglobin
All cells contain some iron due to mitochondrial usage; Clinical manifestations occur when body iron levels reach 15-40 grams
Iron is bound to transferrin in both the intra- and extravascular compartments
Iron is stored as ferritin in cells, and as this amount increases it is found in hemosiderin
Serum ferritin equals total body iron stores in patients with iron deficiency and HH and is biochemically different from tissue ferritin
Chronic iron overload = oxidant stress = lipid peroxidation of cells (such as the membranes) = organelle damage
Phagocytosis by Kupffer cells; These iron overloaded Kupffer cells become activated resulting in activated hepatic stellate cells:
Leads to increased collagen synthesis and fibrosis (hepatocellular injury)
The DDX of increased hepatic iron is long, the pattern of iron distribution may help. See also Liver-Histopathology of Liver (Chapter 4.19)Related posts:
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