Diseases of Iron Metabolism

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). Absorbed iron is bound in the bloodstream by the glycoprotein named transferrin. 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, 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.

Iron absorbtion is regulated by three mechanisms:

Dietary regulator: a short-term increase in dietary iron is not absorbed as the mucosal cells have accumulated iron and "block" additional uptake.
Stores regulator: as body iron stores fall, the mucosa is signalled to moderately increase absorbtion.
Erythropoietic regulator: in response to anemia the erythroid cells will signal the mucosa to increase iron absorbtion more significantly.

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. The ferrous form of iron is more readily absorbed than ferric iron. 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, and returned to the storage pool for re-use. Iron homeostasis is closely regulated via intestinal absorption. Increased absorption is signalled by decreasing iron stores, hypoxia, and erythropoietic activity.

Storage iron occurs in two forms:

Ferritin
Hemosiderin

Iron is initially stored as ferritin, but ferritin can be incorporated by phagolysosomes to hemosiderin. 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, 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 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.

Hereditary Hemochromatosis

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism. The incidence for 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.

Most cases 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.

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. Chronic alcoholics 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 testing for the mutant gene with a blood specimen. HHC can be suggested by measuring serum iron and iron binding capacity with calculation of % saturation. The iron and the % saturation should be high. Serum ferritin is also a good indicator of the amount of storage iron in the body. The diagnosis of the severity of disease is made by liver biopsy with quantitation of the amount of iron.

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.

The following images illustrate findings with hereditary hemochromatosis:

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 sprue (celiac disease).

The end result of decreased dietary iron, decreased iron absorbtion, or blood loss is iron deficiency anemia. This anemia is characterized by a decreased size of red blood cells, so that the mean corpuscular volume (MCV) is lower. 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%.

The following images illustrate findings with iron deficiency:

Anemia of Chronic Disease

This is a condition in which there is impaired utilization of iron, without either a 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. 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 normal to decreased saturation. This condition is treated by treating the underlying condition.

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 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. This free iron can damage blood vessels and produce vasodilation with increased vascular permeability, leading to hypotension and metabolic acidosis. In addition, excessive iron damages mitochondria and causes lipid peroxidation, manifest mainly as renal and hepatic damage.

Early signs of iron poisoning 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.

References

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

Bothwell TH. Overview and mechanisms of iron regulation. Nutr Rev. 1995;53:237-45.

El-Serag HB, Inadomi JM, Kowdley KV. Screening for hereditary hemochromatosis in siblings and children of affected patients. A cost-effective analysis. Ann Intern Med. 2000;132:261-269.

Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34:275-278.

Provan D. Mechanisms and management of iron deficiency anaemia. Br J Haematol. 1999;105 Suppl 1:19-26.

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.

Uchida T. Overview of iron metabolism. Int J Hematol. 1995;62:193-202.

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