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  • Hemochromatosis is caused by excessive deposition of iron diffusely throughout the body due to progressive iron accumulation from a pathological imbalance between iron intake and loss. The reader should refer to iron homeostasis for a discussion of how iron levels are normally regulated.
  • Overview
    • It is important to note that hemochromatosis can be caused by a variety of etiologies which may be hereditary or environmental in origin. Non-hereditary etiologies are sometimes referred to as "Secondary Iron Overload" because they are not caused by direct genetic lesions of iron-regulatory proteins. Whatever the etiology, all of these processes ultimately lead to similar clinical and pathological consequences as discussed in later sections of this page.
  • Hereditary Hemochromatosis
    • Recall from iron homeostasis that the HFE gene is critical for proper regulation of GI iron absorption. Hereditary hemochromatosis can be caused by several mutations which inactivate HFE and thus result in excessive alimentary iron absorption. These disorders are inherited in an autosomal recessive pattern.
  • Excessive Blood Transfusions
    • Direct parenteral intake of iron through transfussions bypasses normal iron homeostatic mechanisms. Because iron cannot be actively secreted, this naturally leads to a buildup of iron over time.
  • Anemias due to Ineffective Erythropoesis
    • Certain anemias associated with ineffective erythropoesis, primarily beta-thalassemia and sideroblastic anemia, also result in iron overload. Repeated blood transfusions may contribute to the iron overload observed in these diseases but excess GI iron absorption may also be to blame.
  • Overview
    • Whatever the etiology, the common denominator of hemochromatosis is an imbalance in iron intake compared to iron loss. Over time, total body iron stores increase from their normal 3-4g to more than 20g. Iron deposits widely in a variety of tissues and can generate a number of biochemical injuries.
  • Cellular Injury by Iron
    • Local cells take up deposited iron particles within their lysosomes. The presence of the iron particles appears to physically damage lysosomes which release their luminal proteases within the cell, causing cellular injury. Additionally, iron appears to stimulate collagen synthesis by Ito Cells of the liver.
Morphology and Clinical Consequences
  • Overview
    • Iron deposits widely throughout the body but demonstrates some geographic preferences. Because the liver is a primary location for physiological iron storage, hepatic deposition is observed first. Deposited iron primarily manifests as granules of yellow-brown hemosiderin. Clinical consequences are a direct result of iron deposition which results in cellular damage and ultimately dysfunction of the organ.
  • Liver
    • Hemosiderin granules are first observed in hepatocytes near portal tracts but with increasing overload are observed diffusely throughout the organ. Over time the entire liver darkens and enlarges, resulting in hepatomegaly. Because iron activates Ito Cells, significant hepatic fibrosis ensues, which can progress to frank cirrhosis and eventually hepatic failure. Generation of free radicals by iron particles may damage hepatocyte DNA, increasing risk of hepatocellular carcinoma.
  • Pancreas
    • Hemosiderin deposits in both the exocrine pancreas and the Islets of Langerhans of the endocrine pancreas. Over time the entire organ becomes pigmented and fibrosis becomes apparent. Deposition in the Islets disrupts their function over time, causing a secondary Type II Diabetes Mellitus.
  • Heart
    • Hemosiderin deposits within the myocardium and over time darkens the entire heart. Eventually cardiac dysfunction may manifest as heart failure or arrhythmias
  • Skin
    • Hemosiderin deposits within dermal macrophages, giving the skin a characteristic grey hue.
  • Joints
    • Hemosiderin may deposit in synovial cells in some cases causing synovitis. This may manifest as a polyarthritis and can result in sudden gout-like attacks, termed "Pseudo-gout".
  • Hypothalamus and Pituitary Gland
    • Hemosiderin deposits in both of these endocrine organs and disrupts their function. This can manifest as hypogonadism in either gender.
    • Men: Impotence, loss of libido, gynecomastia, testicular atrophy.
    • Women: Amenorrhea and loss of libido.
  • Hereditary Hemochromatosis is one of the most common genetic diseases. However, clinical manifestation is highly variable and may not be severe in many patients. Regardless, accumulation of toxic levels of iron takes years to occur and so patients generally present far into adulthood, usually in their fourth through sixth decade. Because Women lose iron through menstruation, clinical disease is much more common in men.