Diseases of Iron Metabolism

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Normal Iron Metabolism

A well-balanced diet contains sufficient iron to meet body requirements. About 10% of the normal 10 to 20 mg of dietary iron is absorbed each day, and this is sufficient to balance the 1 to 2 mg daily losses from desquamation of epithelia. Greater iron utilization via growth in childhood, greater iron loss with minor hemorrhages, menstruation in women, and greater need for iron in pregnancy will increase the efficiency of dietary iron absorbtion to 20%.

Iron is mainly absorbed in the duodenum and upper jejunum. A transporter protein called divalent metal transporter 1 (DMT1) facilitates transfer of iron across the intestinal epithelial cells. DMT1 also facilitates uptake of other trace metals, both good (manganese, copper, cobalt, zinc) and bad (cadmium, lead). Iron within the enterocyte is released via ferroportin into the bloodstream. Iron is then bound in the bloodstream by the transport glycoprotein named transferrin. Both DMT-1 and ferroportin are found in a wide variety of cells involved in iron transport, such as macrophages. (Fuqua et al, 2012)

Normally, about 20 to 45% of transferrin binding sites are filled (the percent saturation). About 0.1% of total body iron is circulating in bound form to transferrin. Most absorbed iron is utilized in bone marrow for erythropoiesis. Membrane receptors on erythroid precursors in the bone marrow avidly bind transferrin. About 10 to 20% of absorbed iron goes into a storage pool in cells of the mononuclear phagocyte system, particularly fixed macrophages, which is also being recycled into erythropoiesis, so there is a balance of storage and use. The trace elements cobalt and manganese are also absorbed and transported via the same mechanisms as iron. (Nemeth, 2008)

Iron absorbtion is regulated by:

  • Dietary regulator: a short-term increase in dietary iron is not avidly absorbed, as the mucosal cells have accumulated iron and "block" additional uptake.

  • Stores regulator: as iron stores increase in the liver, the hepatic peptide hepcidin is released that diminishes intestinal mucosal iron ferroportin release and the enterocytes retain any absorbed iron and are sloughed off in a few days; as body iron stores fall, hepcidin diminishes and the intestinal mucosa is signaled to release their absorbed iron into circulation.

The composition of the diet may also influence iron absorbtion. Citrate and ascorbate (in citrus fruits, for example) can form complexes with iron that increase absorbtion, while tannates in tea can decrease absorbtion. The iron in heme found in meat is more readily absorbed than inorganic iron by an unknown mechanism. Non-heme dietary iron can be found in two forms: most is in the ferric form (Fe+++) that must be reduced to the ferrous form (Fe++) before it is absorbed. Duodenal microvilli contain ferric reductase to promote absorbtion of ferrous iron.

Only a small fraction of the body's iron is gained or lost each day. Most of the iron in the body is recycled when old red blood cells are taken out of circulation and destroyed, with their iron scavenged by macrophages in the mononuclear phagocyte system, mainly spleen, and returned to the storage pool for re-use. Iron homeostasis is closely regulated via intestinal absorption. Increased absorption is signaled via decreased hepcidin by decreasing iron stores, hypoxia, inflammation, and erythropoietic activity. The 'set point' for hepcidin synthesis may also be infuenced by the bone morphogenetic protein (BMP) pathway.

Storage iron occurs in two forms:

  • Ferritin
  • Hemosiderin

Iron is initially stored as a protein-iron complex ferritin, but ferritin can be incorporated by phagolysosomes to form hemosiderin granules. There are about 2 gm of iron in the adult female, and up to 6 gm iron in the adult male. About 1.5 to 2 gm of this total is found in red blood cells as heme in hemoglobin, and 0.5 to 1 gm occur as storage iron, mainly in bone marrow, spleen, and liver, with the remainder in myoglobin and in enzymes that require iron.

Laboratory testing for iron may include tests for:

  • Serum iron
  • Serum iron binding capacity
  • Serum ferritin
  • Complete blood count (CBC)
  • Bone marrow biopsy
  • Liver biopsy

The simplest tests that indirectly give an indication of iron stores are the serum iron and total iron binding capacity, with calculation of the percent transferrin saturation. The serum ferritin correlates well with iron stores, but it can also be elevated with liver disease, inflammatory conditions, and malignant neoplasms. The CBC will also give an indirect measure of iron stores, because the mean corpuscular volume (MCV) can be decreased with iron deficiency. The amount of storage iron for erythropoiesis can be quantified by performing an iron stain on a bone marrow biopsy. Excessive iron stores can be determined by bone marrow and by liver biopsies. (Fleming and Bacon, 2005; Franchini and Veneri, 2005)

Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC) due to mutations in the HFE gene is an autosomal recessive disorder of iron metabolism. The incidence for this form of HHC is between 1:200 and 1:500 for populations of Northern European, Caucasian descent. The genetic defect likely arose in a Celtic population in the early Middle Ages and may have provided a selective advantage to persons living under conditions in which iron deficiency was common and for whom the life expectancy was in the 40's. The gene frequency is as high as 1:9, or 11% of persons with this ancestry. However, cases of HHC can be found in other racial groups, and there is considerable variability in expression of the disease.

Most cases of adult HHC are the result of a single faulty gene on chromosome 6 that codes for a protein called HFE. The HFE protein binds to the transferrin receptor and reduces its affinity for iron-bound transferrin. The two most common mutations are missense mutations, designated C282Y and H63D. The C282Y mutation, a single point mutation with substitution of tyrosine for cysteine at position 282, accounts for most cases of HHC. The exact mechanism for development of HHC is not known, but there appears to be interaction of HFE with transferrin and movement of iron across epithelial surfaces. The mutant HFE does not bind properly to transferrin receptor.

Additional genetic mutations affecting iron absorption include transferrin receptor 2 (TFR2) and hemojuvelin (HJV). Persons with a juvenile form of hemochromatosis often have HJV mutations. The three genes - HFE, TFR2, and HJV - all encode for proteins that affect hepcidin.

The normal total body iron stores may range from 2 to 6 gm, but persons with HHC have much greater stores because they absorb dietary iron at 2 to 3 times the normal rate. Persons with HHC accumulate iron at a rate of 0.5 to 1.0 gm per year. Eventually, their total iron stores may exceed 50 gm. Persons heterozygous for the C282Y mutation have increased levels of transferrin saturation, but rarely have organ damage. Persons homozygous for C282Y are at high risk for HHC. Compound heterozygotes for C282Y/H63D have a milder form of HHC than homozygotes for C282Y. Persons homozygous for H63D are unlikely to develop HHC.

Symptoms of HHC usually develop after 20 gm of iron has accumulated in the body. Thus, men tend to become symptomatic in middle age (40's) and women (because of increased iron loss from menstruation in reproductive years) after menopause (60's). Alcohol consumption can accelerate the effects of iron overload. Persons who abuse alcohol can exhibit hepatic fibrosis or cirrhosis almost twice as frequently as non-alcoholic men. It is interesting to note that about 10% of alcoholics with cirrhosis have extensive iron deposition, and this is roughly the frequency of heterozygosity for HHC. The iron deposition associated with chronic alcoholism, however, is typically limited to the liver and not seen extensively in other organs.

Iron deposition in many organs occurs. The excess iron affects organ function, presumably by direct toxic effect. Excessive iron stores exceed the body's capacity to chelate iron, and free iron accumulates. This unbound iron promotes free radical formation in cells, resulting in membrane lipid peroxidation and cellular injury. The major affected organ with complications of HHC are:

  • Liver, with cirrhosis
  • Heart, with cardiomyopathy
  • Pancreas, with diabetes mellitus
  • Skin, with pigmentation
  • Joints, with polyarthropathy
  • Gonads, with hypogonadotrophic hypogonadism

All of these complications are much more commonly seen because of other diseases in the population, so without a family history or genetic testing, HHC will not be suspected. It should be noted that, throughout most of human history, the average lifespan was not great enough to allow manifestation of HHC, so the appearance of persons with complications of HHC is a relatively modern phenomenon.

The diagnosis of HHC can be made by screening for transferrin saturation, the most sensitive laboratory test for evaluation of body iron stores, using a cutoff of 45%. Serum ferritin is a good indicator of the amount of storage iron in the body, and gives an indication of liver damage, but lacks specificity because many inflammatory conditions increase ferritin as an acute phase protein. Confirmation of HHC is made by testing for the mutant gene with a blood specimen.

The treatment of HHC is simple: therapeutic phlebotomy to remove excess iron. The most common causes of death in individuals with HHC are hepatocellular carcinoma associated with cirrhosis, hepatic failure, and cardiac failure. There appears to be a subgroup of young patients who present with severe cardiac involvement and in whom outcome is poor as a result of congestive heart failure if they remain untreated. In one series of patients who presented with cardiomyopathy associated with hemochromatosis, therapeutic phlebotomy improved the prognosis in 70%; untreated patients had a worsening of their condition and mean survival of only one year.

The gene associated with HHC is located on chromosome 6. This locus is associated with the HLA A-3 antigen. Seventy percent of HHC individuals have the HLA A-3 genotype, whereas it is present in only 25% of normal individuals. HFE gene testing for the C282Y mutation is a cost-effective method of screening relatives of patients with herediatary hemochromatosis. Measurement of transferrin saturation and ferritin are less specific methods of screening. Early diagnosis and institution of therapeutic phlebotomy can prevent the above manifestations and normalize life expectancy, but once organ damage is established, many of the manifestations are irreversible. (Steinberg et al, 2001; Franchini and Veneri, 2005; Kanwar and Kowdley, 2014)

The following images illustrate findings with hereditary hemochromatosis:

  1. Hereditary hemochromatosis, liver, pancreas, lymph nodes, gross.
  2. Normal liver, microscopic.
  3. Liver with hemochromatosis and cirrhosis, low power microscopic.
  4. Liver with hemochromatosis, iron stain, low power microscopic.
  5. Pancreas with hemochromatosis, medium power microscopic.
  6. Pancreas with hemochromatosis, medium power microscopic.
  7. Heart with hemochromatosis, medium power microscopic.
  8. Heart with hemochromatosis, high power microscopic.
  9. Heart with hemochromatosis, iron stain, high power microscopic.

Iron Deficiency Anemia

The most common dietary deficiency worldwide is iron, affecting half a billion persons. However, this problem affects women and children more. A growing child is increasing the red blood cell mass, and needs additional iron. Women of reproductive age who are menstruating require double the amount of iron that men do, but normally the efficiency of iron absorbtion from the gastrointestinal tract can increase to meet this demand. Also, a developing fetus draws iron from the mother, totaling 200 to 300 mg at term, so extra iron is needed in pregnancy. An infant requires formula with 4 - 12 mg/L of iron. Iron in breast milk is more readily absorbed.

Of course, hemorrhage will increase the iron need to replace lost RBC's. Aside from trauma, the most common form of pathologic blood loss is via the gastrointestinal tract. Gastrointestinal lesions that can bleed include: ulcers, carcinomas, hemorrhoids, and inflammatory disorders. Also, ingestion of aspirin will increase occult blood loss in the GI tract. A disease that could impair iron absorbtion would be celiac disease (sprue). Hence, in adults with iron deficiency, endoscopic procedures may be indicated to find the gastrointestinal source of bleeding.

The end result of decreased dietary iron, decreased iron absorbtion, or blood loss is iron deficiency anemia. This anemia is characterized by a decreased amount of hemoglobin per RBC, so the mean corpuscular hemoglobin (MCH). There is reduced size of red blood cells, so that the mean corpuscular volume (MCV) is lower. Hence, this is a hypochromic microcytic anemia . Also, the serum iron will be decreased, while the serum iron binding capacity is somewhat increased, so that the percent transferrin saturation is much lower than normal--perhaps only 5 to 10%. Serum soluble transferrin receptors will increase (though persons living at the altitude of Denver, Colorado [the 'mile high' city] or above and persons of African ancestry have slightly higher values, too). (Andrews, 1999; Clark, 2009)

The following images illustrate findings with iron deficiency:

  1. Normal bone marrow, microscopic.
  2. Normal peripheral blood smear.
  3. Normal CBC, diagram.
  4. Iron deficiency anemia, peripheral blood smear.
  5. Iron deficiency anemia, peripheral blood smear.
  6. Iron deficiency anemia, CBC, diagram.

Anemia of Chronic Disease

This is the most common anemia in hospitalized persons. It is a condition in which there is impaired utilization of iron, without either an absolute deficiency or an excess of iron. The probable defect is a cytokine-mediated blockage in transfer of iron from the storage pool to the erythroid precursors in the bone marrow. The defect is either inability to free the iron from macrophages or to load it onto transferrin. Inflammatory cytokines also depress erythropoiesis, either from action on erythroid precursors or from erythropoietin levels proportionately too low for the degree of anemia.

Inflammatory conditions release cytokines such as interleukin-6 (IL-6) that stimulate hepatic production of hepcidin. Iron absorption is reduced when hepcidin levels increase. Hepcidin also decreases release of iron from stores in macrophages.

The result is a normochromic, normocytic anemia in which total serum iron is decreased, but iron binding capacity is reduced as well, resulting in a somewhat decreased saturation, but increased ferritin. Serum soluble transferrin receptors will be unaffected by chronic disease states. Anemia of chronic disease is addressed by treating the underlying condition. (Cullis, 2011)

Disease processes that may lead to anemia of chronic disease can include:

  • Chronic infections
  • Ongoing inflammatory conditions (e.g., inflammatory bowel diseases, vasculitides)
  • Autoimmune diseases
  • Neoplasia

Iron Overload

Excessive iron can accumulate acutely or chronically.

Iron Poisoning: Acute iron poisoning is mainly seen in children. A single 300 mg tablet (or 11 of the more commonly sold 27 mg tablets) of ferrous sulfate will contain 60 mg of elemental iron. Toxicity producing gastrointestinal symptoms, including vomiting and diarrhea, occurs with ingestion of 20 mg of elemental iron per kg of body weight. If enough iron is ingested and absorbed, about 60 mg per kg body weight, systemic toxicity occurs. Toxicity results when free iron not bound to transferrin appears in the blood and leads to formation of free radicals that poison cellular mitochondria and uncouple oxidative phosphorylation. This free iron can damage blood vessels and produce vasodilation with increased vascular permeability, leading to hypotension and metabolic acidosis. In addition, excessive iron damage to mitochondria causes lipid peroxidation, manifested mainly as renal and hepatic damage.

Early signs of iron poisoning within 6 hours include vomiting and diarrhea, fever, hyperglycemia, and leukocytosis. Later signs include hypotension, metabolic acidosis, lethargy, seizures, and coma. Hyperbilirubinemia and elevated liver enzymes suggest liver injury, while proteinuria and appearance of tubular cells in urine suggest renal injury.

Chronic Iron Overload: This can occur in patients who receive multiple transfusions for anemias caused by anything other than blood loss. Patients with congenital anemias may require numerous transfusions for many years. Each unit of blood has 250 mg of iron.

Ineffective Erythropoiesis: Increased iron absorbtion can occur in certain types of anemia in which there is destruction of erythroid cells within the marrow, not peripheral destruction. This phenomenon signals the erythroid regulator to continually call for more iron absorbtion. These conditions include: thalassemias, congenital dyserythropoietic anemias, and sideroblastic anemias. (Madiwale and Liebelt, 2006)


Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:1986-1995.

Clark SF. Iron deficiency anemia: diagnosis and management. Curr Opin Gastroenterol. 2009;25:122-128.

Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol. 2011;154(3):289-300.

Fleming RE, Bacon BR. Orchestration of iron hemostasis. N Engl J Med. 2005;352:1741-1744.

Franchini M, Veneri D. Recent advances in hereditary hemochromatosis. Ann Hematol. 2005 Jun;84(6):347-152..

Fuqua BK, Vulpe CD, Anderson GJ. Intestinal iron absorption. J Trace Elem Med Biol. 2012;26(2-3):115-119.

Kanwar P, Kowdley KV. Metal storage disorders: Wilson disease and hemochromatosis. Med Clin North Am. 2014;98(1):87-102.

Madiwale T, Liebelt E. Iron: not a benign therapeutic drug. Curr Opin Pediatr. 2006;18:174-179.

Nemeth E. Iron regulation and erythropoiesis. Curr Opin Hematol. 2008;15:169-175.

Steinberg KK, Cogswell ME, Chang JC, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001;285:2216-2222.

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