HEMOCHROMATOSIS
Disease characterized by the excessive accumulation of body iron, most of which is deposited in
parenchymal organs such as the liver and pancreas. Also can accumulate in the heart, joints, or endocrine
organs. It is a homozygous-recessive inherited disorder. Its acquired formed, either by blood transfusion or
parenteral administration is termed hemosiderosis
IRON METABOLISM
Free iron is highly toxic (accepts a free electron and catalyzes free radical formation) and it is therefore
important that storage iron be sequestered. Excessive iron is directly to toxic to tissue (lipid peroxidation
via iron free radical reactions, stimulation of collagen formation, interaction of reactive oxygen species and
interaction iron itself with DNA) leading to lethal injury or predisposition to hepatocellular carcinoma.
Hepcidin is a small circulating peptide that is synthesized and released from the liver in response to
increases in intrahepatic iron levels. Hepcidin acts to inhibit iron transfer from the enterocyte to plasma by
binding to ferriportin. Thus, iron absorption is regulated in away by when the body is replete with iron,
high hepcidin levels inhibit its absorption into the blood. Conversely, with low body stores or iron, hepcidin
synthesis falls and this facilitates iron absorption. Hepcidin also suppresses iron release form macrophages.
Thus, hepcidin lowers plasma iron levels, and a deficiency causes iron overload.
PATHOGENESIS
HJV, TfR2 and HFE are other proteins involved in iron metabolism that regulate hepcidin in which their
action is through hepcidin that regulates intestinal absorption of dietary iron. Lack of hepcidin expression
caused by mutations in hepcidin, HJV, TfR2 and HFE causes iron overload (Hemochromatosis). The most
common mutation seen in adult is in HFE. Thus the pathophysiology is increased unregulated iron
absorption by enterocytes in the duodenum
MORPHOLOGY
Deposition of hemosiderin in the following organs (in decreasing order of severity). Liver, pancreas,
myocardium, pituitary gland, adrenal gland, thyroid and parathyroid glands, joints and skin. Deposition is
detected by Prussian blue histologic reaction.
Liver: Iron is a direct hepatotoxin. Inflammation is absent. Fibrous septa develop slowly, leading ultimately
to a micronodular pattern of cirrhosis in a intensely pigmented liver and hepatomegaly. There is a 20 to
200-fold increased risk for development of Hepatocellular Carcinoma
Pancreas: becomes intensely pigmented, has diffuse interstitial fibrosis, and may exhibit some parenchymal
atrophy. Hemosiderin is found in acinar cells, islet cells (selective for β-cells) and interstitium
Skin: Although skin pigmentation is partially attributable to hemosiderin deposition in dermal macrophages
and fibroblasts, most of the pigmentation results from increased epidermal melanin production.
“bronze diabetes”:
Myocradium: Iron deposition in myocytes, Fibrosis, Cardiomegaly
Testicles: Testicular atrophy, Interstitial fibrosis, thickened basement membrane, absent spermatogenesis
Not significantly pigmented.
CLINICAL FEATURES
More often disease of males, and rarely becomes evident before age 40. Principle manifestations include
hepatomegaly, abdominal pain, skin pigmentation. Deranged glucose hemeostasis, or frank diabetes
mellitus due to destruction of pancreatic islets (Early-Insulin resistance:β-cell dysfunction, Late-insulin
deficiency), cardiac dysfunction (arrhythmia, cardiomypathy, and atypical arthritis. In some patients the
presenting complaint is hypogonadism (amenorrhea in female, impotence and loss of libido in males).
Hypogonadism due to excess iron deposition in pituitary, selectively in gonadotropic cells leading of
decreased LH, FSH.
Screening involves demonstration of very high levels of serum iron and ferretin.
EPIDEMIOLOGY
Northern European: celtic,
Autossomal Recessive: 1 of every 220 persons, 11& heterozygous
Very low Penetrance in homozygous :
Most cases homozygous for mutation in the HFE gene
Screening with serum transferrin - iron saturation
Most common cause of primary iron overload