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The most common form of iron overload in the United States is a genetically determined disorder, the homozygous state for hereditary hemochromatosis, occurring in about 0.26% of the total population, or approximately 1 in 385 persons.  Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by inappropriate dietary absorption of iron and abnormal iron cycling causing progressive accumulation of iron in tissues, particularly the liver, pancreas, heart, endocrine organs, and skin which may lead to end-stage organ damage during or after middle age.  HH is one of the most common inherited disorders in people of northern European descent with an incidence of 1:200 and carrier rate of 1:10 persons.  Although the homozygous hemochromatosis genotype is relatively common, the clinical penetrance of the disorder is highly variable, and only a minority of affected persons develop severe or life-threatening organ dysfunction.  The considerable variability in clinical penetrance of C282Y homozygosity, both in rate of accumulation or iron stores and appearance or organ dysfunction, may be the result of environmental, lifestyle, and genetic factors.

Hereditary HFE-associated hemochromatosis with the great majority of affected persons being homozygous for the mutation designated C282Y (i.e., C282Y/C282Y) or are compound heterozygotes for the C282Y mutation and either the mutation identified as H63D (C282Y/H63D) or, in a smaller proportion or cases, that termed S65C (C282Y/S65C).   This is located on chromosome 6, and one mutation leads to the substitution of the 282nd amino acid. Cysteine becomes tyrosine, therefore the mutation is called C282Y. The switch of amino acids is thought to affect how the HFE protein interacts with the transferrin receptor (TFR1), which plays an important role in iron homeostasis. A less common mutation, H63D, has also been identified in the HFE gene.

Hereditary non-HFE-associated hemochromatosis is due to mutations in the gene for transferrin receptor 2 that is clinically indistinguishable from those with the FHE-associated form.

Juvenile hemochromatosis has the same pattern of tissue iron deposition found in hereditary HFE-associated hemochromatosis but develop severe iron overload much earlier, with hypogonadism and cardiac disese manifesting in the second decade of life.  The rate of iron accumulation increases substantially and has been estimated to be 3-4 times greater that that of HFE-associated disease.  The gene responsible has recently been identified as HJV with the protein product hemojuvelin.

Autosomal dominant hemochromatosis results from mutations in the ferroportin gene and share the same characteristics of reticuloendothelial iron overload rather than the relative sparing of reticuloendothial macrophages in patients with hereditary HFE-associated hemochromatosis.

Congenital atransferrinemia (hypotransferrinemia) is an autosomal recessive inheritance in which plasma transferring is nearly absent and extremely rare with only 9 cases having been reported.  The iron circulates as non—transferrin-bound plasma iron which can not be transported into erythroid percursors but is progressively deposited in the liver, pancreas, heart and other parenchymal tissues. Given that the entry into precursors is not available, eythropoiesis is not effective and the presentation is hypochromic, microcytic anemia. The patient will die without transferring infusion or blood transfusions.

Hereditary aceruloplasminemia (hypoceruloplasminemia) is an autosomal recessive trait in the ceruloplasmin gene causing a disorder or iron metabolism characterized by absence or severe deficiency of ceruloplasmin.  The ceruloplasmin seems to have an essential role in iron metabolism oxidizing ferrous to ferric iron.  The ceruloplasmin is synthesized in the Central Nervous System by the choroids plexus epithelial cells and astrocytes and a glycosylphosphatidylinositol-anchored form seems to have a protective effect from iron-mediated oxidant damage.  The presentation is typically in the fourth or fifth decade of life with a triad of diabetes mellitus, progressive neurologic disease (dementia, dysarthria, and dystonia), and retinal degeneration.  Marked iron accumulation is seen in brain, pancreas, and liver with smaller amounts of excess iron in the spleen, heart, kidney, thyroid, and retina.  Liver injury or fibrosis is not seen.  The serum iron is low, total iron binding capacity is normal, serum ferritin is moderately elevated with a mild normchrhomic, normocytic anemia usually present.  Phlebotomy does not mobilize hepatic iron but chelation with deferoxamine is effective and also ameliorates neurologic symptoms.

Iron Metabolism
Iron is an essential metal for all mammalian cells, serving as a mediator of enzymatic electron exchange and a carrier of oxygen.  Iron homeostasis is meticulously regulated to avoid deleterious extremes of iron deficiency and iron overload.

Iron absorption: enters through dietary absorption at a rate that balances small losses due to bleeding and exfoliation of skin and mucosal cells.

Iron excretion in the gut is fixed at 1 mg per day, therefore normal iron balance must be maintained by meticulous control of iron absorption in the intestine (mainly in the duodenum) and iron release from macrophages.  This is modulated in response to body iron stores and the erythropoietic demand for iron.

Iron cannot freely diffuse across cellular membranes; therefore, transmembrane transfer requires specialzed transport mechanisms.  Some cells, including intestinal epithelial cells, hepatocytes, and macrophages, are equipped to take in (import) iron and to release (export) iron and play roles in the acquisition, storage, and mobilization or iron.  Other cells, namely erythroid precursors, use most or all of the iron they import and do not export it.

Each day, normal adults need 25mg iron to support hemoglobin production in maturing erythrocytes.

Diagnostic Definition
With molecular testing and the variability in clinical penetrance of the homozygous genotype, the diagnosis of hemochromatosis is now established by the detection of two mutated HFR alleles.  This definition does not require active symptoms or signs of illness or the presence of iron overload.  4 stages are recognized below:

  • Genetic predisposition with no other abnormalities (age 0-20, 0-5g of tissue iron storage).
  • Iron overload without symptoms (age >20, >5g of iron storage).
  • Iron overload with early symptoms (age >30, >8g of iron storage).
  • Iron overload with organ damage (age >40, 10-20 grams of iron storage).

Common Clinical Presentation
Persons with hereditary hemochromatosis absorb only a few milligrams or iron each day in excess of need; therefore, clinical manifestations often occur only after 40 years of age when body iron stores have reached 15 to 40 grams (normal is 4grams of iron).  Most commonly present with nonspecific symptoms such as unexplained chronic fatigue, weakness, impotence, arthralgia or arthritis, sexual dysfunction, hepatomegaly, or elevated liver function studies.  Skin changes to grayish or gray-brown, bronzing is rare, hypothyroidism.

Screening for iron overload is indicated for patients with any of the symptoms and signs associated as listed above.

Factors Influencing Clinical Penetrance


  • Alcohol use
  • Oral iron supplement
  • Dietary habits (meat-rich diets)
  • Exogenous estrogen, vitamin C
  • Genetic/Acquired Disorders
  • Hepatitis B or C infection
  • Nonalcoholic steatohepatitis
  • Porphyria cutanea tarda
  • Alph-1 anti-trypsin deficiency
  • Mutations in hepcidin, ferroportin, transferring receptor, other genes

Factors that lessen iron overload

  • Blood donation
  • Multiparity/menorrhagia
  • Dietary habits (vegetarian diet, tea, high calcium)

Laboratory Testing
CBC, Serum iron, plasma ferritin, and transferrin saturation, HFE mutation analysis, plasma ceruloplasmin level, testing for diabetes, cardiax examination, liver functions and if cirrhosis present evaluation for hepatoma.

Diagnostic Testing
Liver biopsy can establish a definitive diagnosis of hereditary and juvenile hemochromatosis regardless of genotype and can demonstrate the reticuloendothelial pattern of iron loading found with ferroportin mutations and the characteristic histologic appearance of insulin resistance-associated hepatic iron overload.  It is also a prognostic indicator to detect cirrhosis if the serum ferritin is >1000mcg/L.  The hepatic iron index (the hepatic iron concentration [expressed as micromoles Fe/g of liver, dry weight] divided by the age of the patient [in years]) can help differentiate homozygotes for hereditary hemochromatosis from heterozytes or from patients with increased body iron associated with chronic liver disease.  If other causes of iron overload can be excluded, a value greater than 1.9 for the hepatic iron index suggests the diagnosis of homoyzygous hereditary hemochromatosis.

Bone marrow examination is of limited usefulness in the evaluation of patient for hereditary or juvenile hemochromatosis because no information about the extent of parenchymal iron deposition is provided.  In the detection and diagnosis of iron-loading anemias, measurement of the plasma transferrin receptor and examination of the bone marrow may demonstrate the ineffective erythropoiesis in combination with the eyrthroid hyperplasia.

The goal of therapy for iron overload is the reduction and maintenance of the body iron at normal or near-normal amounts.  Phlebotomy is the treatment of choice for hereditary hemochromatosis, and should begin promptly because any delay extends the exposure to potentially toxic iron accumulations.  Phlebotomy should remove 500mL of blood conatine 200-250mg iron, once weekly until storage iron is depleted.  Maintenance phlebotomy should preserve a plasma ferritin <50mcg/L.

In aceruloplasminemia, phlebotomy cannot remove the excess iron, but iron chelation therapy with deferoxamine can provide effective treatment.

Patients with hereditary hemochromatosis should refrain from using iron supplements, including multivitamins that contain iron.  A ‘low-iron diet’ is not necessary, but meat should be consumed in moderation.  Patients with the disorder should avoid consuming or even handling raw seafood because of the associated increased risk of Vibrio vulnificus infection.  Also the use of alcohol should be avoided or minimized because iron and alcohol are synergistic hepatotoxins.

Whatever the penetrance, among affected persons the hepatic iron concentration is a major determinant of the risk of cirrhosis of the liver and, in turn, of hepatocellular carcinoma, now the two major causes of death in hereditary hemochromatosis.  The development of cirrhosis increases the risk of hepatocellular carcinoma more than 200-fold.  If the disease is diagnosed before tissue injury has occurred, phlebotomy therapy to remove the excess iron can prevent all of the complications of hemochromatosis, including cirrhosis, and return the patients life expectancy to normal.  If organ damage is present progression is prevented by phlebotomy along with amelioration of symptoms.


  • Handbook of Clinical Hematology, Rodgers, Griffin and Young, Neal; 2005.
  • Hematology Basic Principles and Practice, Hoffman, Ronald M.D., Benz, Edward, M.D…et al…; Fourth Edition, 2005
  • Hereditary Hemochromatosis,
  • Recognition and Management of Hereditary Hemochromatosis, American Family Physician,, March 1, 2002
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