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Understanding Iron Metabolism.

Biochemistry

Iron is one of the most abundant earth elements, yet only trace amounts are essential for living cells of plants and animals. In humans, most of the iron is contained within the porphyrin ring of heme in proteins such as hemoglobin, myoglobin, catalase, peroxidases, and cytochromes, [3] as well as iron-sulfur proteins, such as NADH dehydrogenase and succinate dehydrogenase, in which iron is present in clusters with inorganic sulfur. In all these systems, iron has the ability to interact reversibly with oxygen and to function in electron transfer reactions that makes it biologically indispensable.

The average adult male contains approximately four grams of body iron. About 65-70% is found in hemoglobin, 4% in myoglobin, and less than 1% in other iron-containing enzymes and proteins. The remaining 25-30% represent the storage pool of iron. By comparison, women have a much smaller iron reserves with the adult female body containing about three grams of iron. Women also have a slightly lower hemoglobin concentration in blood than males.

Metabolism and Requirements

Daily requirements for iron vary depending on sex, age, and physiological status. Although iron is not excreted in the conventional sense, there is a daily loss of about one milligram due to the normal shedding of intestinal mucosal cells and skin epithelial cells and the loss of small numbers of erythrocytes in urine and feces. Pregnancy, breast feeding and blood loss increase the iron requirement.

Absorption

The average North American diet supplies 10-20 mg of iron per day. Only 5-10% of this amount is absorbed, mainly in the duodenum and upper small intestine. Most dietary iron is in the ferric ([Fe.sup.3+]) state, which is poorly absorbed. Gastric secretion and hydrochloric acid reduce ferric iron to the absorbable ferrous ([Fe.sup.2+]) form. Vitamin C, amino acids, especially cysteine, cystine, and methionine and other compounds that form soluble iron chelates enhance the iron absorption, but substances, such as phosphates (found in eggs, milk and cheese), oxalates (found in spinach and rhubarb), phytates (found in vegetables and grains), and tannates (found in tea), reduce iron absorption.

A Finnish study demonstrated that breast-fed babies had a far superior dietary iron intake than bottle-fed infants. While the small intestines of babies are quite capable of utilizing up to 50% of the iron found in breast milk, the iron absorption rate in cow's milk is only 20%.

Many factors inhibit iron absorption:

* Antacids

* Excessive intake of thiamin (vitamin B1)

* Lack of pyridoxine (vitamin B6)

* Digestive problems

* High calcium/iron ratio

* Elevated phosphorus levels

* Excessive intake of phytates (whole grains)

* Excessive zinc, copper, and manganese intake

Transport mechanism

Transferrin, a single-chain polypeptide, is the transport protein for iron in blood. Each transferrin molecule has two binding sites for ferric iron, and these sites are normally 20-50% saturated. The need for a specific carrier protein derives from the toxicity and relative insolubility of free iron. Virtually all of the plasma iron is protein-bound and at any given moment, plasma transferrin carries about 3-4 mg of iron.

Storage

About one-third of body iron is stored in the liver, one-third in the bone marrow, and the remainder in the spleen and other tissues. Iron is bound in tissues in two forms: ferritin and hemosiderin.

Deficiency

Iron is necessary for cell function and oxygen utilization. Deficiency is relatively common and blood loss is the most common cause. The high prevalence of iron deficiency among women is due to menstrual blood loss. Causes of iron deficiency especially in men are bleeding from the intestinal tract (i.e., peptic ulcer, diverticulosis) or malignancy. Inadequate nutritional intake as seen among people who eat junk food, or place a heavy emphasis on milk and cereals, frequently causes iron deficiency among pregnant women, adolescents and young children. Frequent diarrhea or partial or total gastroectomy can cause malabsorption problems, leading to iron deficiency symptoms, such as iron deficiency anemia indicated by pallor and extreme fatigue, shortness of breath, and poor appetite.

Numerous symptoms are associated with iron deficiency:

* Anorexia

* Growth problems

* Sore tongue

* Lethargy

* Dysphagia

* Irritability

* Poor concentration

* Hypochromic anemia

* Impaired protein metabolism

* Geophagia

* Hyperplastic bone marrow

* Low DNA and RNA levels in the bone marrow

* Degenerative changes of the gastric mucosa

Factors influencing iron-deficiency anemia

Pyridoxine (B6) deficiency can mimic iron deficiency anemia. In the case of B6 deficiency, serum iron levels and bone marrow hemosiderin are often elevated.

Pernicious anemia is a B 12 deficiency, caused by the lack of intrinsic factor. Due to the lack of intrinsic factor, B12 is not sufficiently absorbed and B12 injections become necessary. In addition, improved dietary intake of folic acid and enzyme supplementation (with hydrochloric acid and pepsin) are recommended. The typical pernicious anemia patient is in most cases, well fed, 40 years of age or older, Northern European, with blue eyes and prematurely graying hair. There appears to be a genetic involvement.

Folic acid deficiency anemia is mostly found in alcoholics, but can also be the result of faulty diet or malabsorption problems (disease of the intestine), or cirrhosis of the liver. Anticonvulsant drugs can cause folate deficiency. Low serum folate levels confirm folic acid deficiency anemia.

Therapeutic considerations

In the case of acute deficiency, the absorption rate or iron is slightly higher than normal. The average diet provides 5-7 mg of iron per 1,000 calories, and anemia is often the result of insufficient dietary supply, especially in children, juveniles, and adults who consume a low-calorie diet over a long period of time. Before iron supplementation is implemented, the individual iron requirements must be based on laboratory tests to distinguish iron deficiency from other causes, and attention must be paid to the following factors: age and sex, blood loss (menstruation, hemorrhage), and pregnancy. Also, several metals should be checked. High tissue levels of copper and manganese (hair mineral analysis) can block iron absorption, and chronic lead overexposure can cause iron-deficiency anemia.

Iron Overload or Hemochromatosis

This hereditary disease is characterized by a progressive increase in body iron stores leading to organ impairment and damage. Inheritance is autosomal recessive. Among populations of Northern European descent, 10% carry the gene and the age of onset is usually 40 years and older. Men are affected five to ten times more frequently than women, because females are more protected due to the menstrual blood loss and pregnancy.

Hemochromatosis patients absorb about four mg of iron per day, even on a normal diet, and the mechanism for this enhanced iron absorption is largely unknown. Under normal conditions, excess iron is processed by cells of the reticuloendothelial system, whereas in hemochromatosis, iron is deposited directly into parenchymal cells of the liver, pancreas, heart, and other organs. Long-term accumulation leads to tissue injury and, ultimately, organ failure. Storage iron may exceed 20 g at this stage.

Iron overload or acquired hemochromatosis may be a complication of chronic anemia such as thalassemia and sideroblastic anemia. In the initial stage of iron overload, referred to as hemosiderosis, tissues remain anatomically and functionally normal. As the iron load increases, the clinical pattern resembles that of hemochromatosis. Acquired hemochromatosis can result from frequent blood transfusions or excess iron ingestion. The Banto of South Africa, who drink home-brewed alcoholic beverages with a very high iron content, have a high incidence of the disease. Alcoholics with chronic liver disease, such as cirrhosis, are also susceptible to develop an increase in iron storage; however, a genetic predisposition may be present.

Symptoms of hemochromatosis

Signs and symptoms are related to the organs involved:

* Liver enlargement and cirrhosis

* Hepatocellular carcinoma

* Diabetes mellitus (in about two thirds of the patients)

* Increase in skin pigmentation, caused by increased melanin production, is found in 90% of patients.

* Cardiac involvement may lead to congestive heart failure or arrhythmia.

* Testicular atrophy

* Loss of libido, caused by drop in production of gonadotropins by the impaired hypothalamuspituitary axis

Sources of Excess Iron

Excess iron can come from several sources, including iron-rich drinking water, cooking acidic food in iron cookware, excessive iron supplementation or prolonged iron therapy, repeated blood transfusions, and protein malnutrition.

Treatment

Therapeutic considerations consist of phlebotomy therapy (treatment of choice), iron-chelation with deferoxamine, a vegetarian diet, and normalizing the often low levels of manganese, copper, and zinc.

Laboratory Diagnosis

There are three iron compartments, accounting for more than 90% of the total body iron: hemoglobin, serum ferritin, and circulating iron.

In defined iron-deficiency anemia, cell size (MCV) and hemoglobin content (MCH) are reduced and the concentration of hemoglobin per cell (MCHC) is also down. At an early stage of iron depletion, both hemoglobin concentration and red cell indices are normal, but tissue mineral analysis may indicates a low iron status. Red blood cell parameters define the presence of absence of anemia and its morphological character, but other tests are required to identify the cause and type of anemia. Anemic patients who don't respond to iron therapy may show high hair iron levels, indicating a need for nutrients that support an increased need for iron mobilization (i.e., vitamin C, B-vitamins, amino acids) from the liver and other tissues rather than iron therapy.

Serum iron concentration is decreased in iron-deficiency anemia, in chronic anemias, in malignancies, in inflammation and infections, myocardial infarction and after surgery. Conversely, it is increased in red cell disorders such as megaloblastic anemias, thalassemia, and sideroblastic anemia, bone marrow hypoplasia, viral hepatitis, acute iron poisoning, and hemochromatosis. Serum iron values should always be interpreted with total iron-binding capacity (TIBC) and transferrin saturation

TIBC and transferrin saturation

TIBC measures the maximum amount of iron that serum protein can bind and is an indirect way of assessing transferrin levels.

Transferrin Levels = Serum Iron Concentration/TIBC

TIBC is increased in iron deficiency, hepatitis, pregnancy, and women taking oral contraceptives. It is decreased in malignancies, nephrosis, inflammation, chronic disease, starvation, megaloblastic and hemolytic anemias, and hemochromatosis.

Transferrin saturation is decreased in the presence of low serum iron and high TIBC, pregnancy, and chronic disease. It is increased in iron overload, hemochromatosis, thalassemia, sideroblastic anemia, and acute iron poisoning.

Serum Ferritin

This is an especially useful indicator of total body stores and are an important measure of a patient's overall health. Levels are decreased in acute iron deficiency. Ferritin levels drop early in the development of iron deficiency, before serum iron and transferrin saturation levels fall. Levels are increased in iron overload, the early stages of hemochromatosis (before symptoms develop), hepatitis, acute inflammatory conditions, and a variety of tumors.

Free erythrocyte protoporphyrin (FEP)

A decrease in available iron increases the formation of zinc protoporphyrin and FEP, and this test is most commonly used as a screening test for iron deficiency and lead poisoning. Levels are increased in iron deficiency, chronic disease, and lead poisoning.

Significance of HMA Iron levels

Iron levels in hair represent the iron status of tissues and have been reported to reflect cytochrome changes. HMA, in conjunction with blood analysis, can be an early indication of an inadequate iron intake or of a disturbed iron metabolism.

Low Hair Iron Levels

When the HMA shows low Fe levels, low tissue storage and anemic tendency must be suspected. An inadequate iron intake or absorption problems may be present. Before iron therapy is implemented, other laboratory analytes should be evaluated.

Significance of Elevated HMA Iron Levels

High iron levels reflect the inability of the system to mobilize or excrete excess iron. Elevated liver storage may be present, indicating a need for liver support and therapeutic measures that improve the mobilization of iron from the tissue. High HMA levels can be present in conjunction with low serum iron levels and symptoms of anemia.

Symptoms associated with elevated hair iron levels include ascorbic acid depletion, lipid oxidation, increased bacterial proliferation, and disturbed phosphorus metabolism.

Chandra and other researchers demonstrated that iron deficiency results in poor immunity and reduces the bactericidal capacity of neutrophils and lymphocyte response. In fact, immunosuppression can already occur at a 10% reduction of iron intake, but while the iron metabolism is important for immune functions, nutrients that support the iron metabolism may be more needed than iron itself.

About the Author

Eleonore Blaurock-Busch, PhD, is a laboratory director for Trace Minerals International, Boulder, Colorado, and president of Micro Trace Minerals, Hersbruck, Germany. She has written hundreds of articles on orthomolecular therapy, and her work has been published in several languages around the world She has lectured to professional and lay audiences since the early 1970s. She co-chairs The First Congress on Trace Elements and Cancer in Beijing, China and has also written several books.

SELECTED READINGS

(1.) Beisel WR. "Single nutrients and immunity." Am J Clin Nutr, 1982; 35:417-68.

(2.) Blaurock-Busch E. Mineral and Trace Element Analysis, Laboratory and Clinical Application. TMI/MTM, Boulder, Co 1996.

(3.) Kaplan LA. Clinical Chemistry, CV Mosby Co, 1989:496-511.

(4.) Chandra RK. "Trace element regulation of immunity and infection." J Am Coll Nutr, 1985; 4:5-16.

(5.) Levy JA. "Nutrition and the immune system." in: Basic and Clinical Immunology. 4th Edition. Lange Med Pub: Los Altos, CA, 1982:297-305.

(6.) Walter T, et al. "Effect of iron therapy on phagocytosis and bactericidal activity in neutrophils of iron-deficient infants." Am J Clin Nutr, 1986; 44:877-882.
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Author:Blaurock-Busch, E.
Publication:Original Internist
Geographic Code:1USA
Date:Jun 1, 2001
Words:2188
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