Disease Characterized by the Excessive Accumulation of Body Iron, Most of Which Is Deposited

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 inintrahepatic iron levels. Hepcidin acts to inhibit iron transfer from the enterocyte to plasma by binding toferriportin. 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, hepcidinsynthesis falls and this facilitates iron absorption. Hepcidin also suppresses iron release form macrophages. Thus,hepcidinlowers 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 riskfor 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