Chronic iron overload and toxicity: Clinical chemistry perspective

Clinical Laboratory Science, Summer 2001 by Kang, Jae O

FOCUS: IRON OVERLOAD

The content of body iron is regulated primarily by absorption since humans have no physiological mechanism by which excess iron is excreted. This regulation, however, is not absolute. Many factors such as the content of diets, iron doses, life styles, etc. influence iron absorption. In the past, nutrition programs for iron fortification and the ingestion of iron preparations have been widely practiced because of the seriousness of worldwide iron deficiency. Also, we now know that a significant number of asymptomatic people carry the hemochromatosis gene, HFE, indicating that these people have the potential to accumulate excess body iron in their lifetime. Excess body iron can be highly toxic. This toxicity involves many organs leading to a variety of serious diseases such as liver disease, heart disease, diabetes mellitus, hormonal abnormalities, dysfunctional immune system, etc. The tissue damage associated with iron overload is believed to result primarily from free radical reactions mediated by iron. Iron is an effective catalyst in free radical reactions. The diseases associated with iron overload can be managed effectively or prevented. Therefore, early diagnosis of iron overload and appropriate therapy are critical. By providing the necessary laboratory data, clinical chemistry laboratories can play the pivotal role in the management of these health problems.

INDEX TERMS: clinical chemistry laboratories; diagnosis; free radical reactions; hemochromatosis; iron overload; iron toxicity.

Clin Lab Sci 2001; 14(3):209

LEARNING OBJECTIVES

1 . Describe the regulation of iron absorption.

2. List the three primary causes of iron overload.

3. Describe various chronic diseases associated with secondary iron overload and the mechanisms involved.

4. Contrast the absorption process for heme iron with that for non-heme iron.

5. List compounds in the diet that inhibit iron absorption and those that enhance iron absorption.

6. List the organs most frequently damaged by hemachromatosis.

7. Identify the clinical chemistry laboratory procedures that would detect damage to each of the organs most frequently damaged by hemachromatosis.

8. Discuss the biochemical theories most often proposed to explain the mechanisms that cause tissue damage due to excess iron.

Iron is an essential element in the body. It is required for growth, maintenance, and cell division. A normal 70 kg male adult contains about 4 g of iron. Of this amount, about 70% is present in hemoglobin; about 25% in ferritin and hemosiderin as iron stores; 5% in muscle myoglobin; and some in tissue enzymes and plasma transferrin.1,2 The average American daily diet contains 15 to 40 mg of iron. Less than 10% of this dietary iron is absorbed to balance the daily loss of approximately 1 mg. This loss is mainly via exfoliating dead cells from the skin, the intestine, and the urinary tract. Healthy females of reproductive age lose about 1.5 mg/day because of the additional loss of iron from menstruation and childbirth. Humans have no obvious physiological mechanism for iron excretion. Therefore, the homeostasis of body iron is dependent mainly on its absorption that appears to be regulated in the mucosa of the small intestine. Thus, more iron is absorbed in the face of iron deficiency and increased needs of erythropoiesis while the amount absorbed is reduced in the presence of iron overload.1,3 This regulation, however, is not absolute.

Various causes of chronic iron overload have been identified (Table 1).4 Iron overload is now being recognized as a health problem particularly in industrialized countries where red meat consumption is high and where cultural practices encourage iron intake, e.g., iron fortification of food and iron preparations.4,5 In the advanced state of iron overload, the iron content of the body can reach iron stores 20 to 30 times greater than the normal values. The iron store for normal men is about 1 g and for menstruating women about 0.3 g.6 Excessive amounts of iron in the body may cause a variety of serious medical problems. This review will focus on the primary causes of chronic iron overload, the pathophysiology associated with iron overload, the chemistry of iron toxicity, and the role of clinical laboratories in diagnosing and managing iron overload.

CAUSES OF CHRONIC IRON OVERLOAD

Chronic accumulation of excess body iron occurs for various reasons (Table I).4 In this review, the three primary ones will be discussed. First, individuals with hereditary hemochromatosis absorb more iron than the amount necessary to compensate for iron loss. This condition is associated with an autosomal recessive HLAlinked trait. The second situation is observed in patients with a number of pathological conditions that are linked to the elevation of body iron. In the third situation, iron overload results from the acquisition of excess iron from diets.

Hereditary hemochromatosis

A significant portion of the general populations of Western countries is now known to have the potential to accumulate excess iron during their lifetime because of the inheritance of the mutant gene for hemochromatosis. Hereditary hemochromatosis is characterized by excess absorption of iron from the gastrointestinal tract and its progressive accumulation in the body. Edwards discovered that approximately 10% of the population carry the hemochromatic gene rather than the previous estimate of 0.01% to 0.2%.7 These authors, who made this observation from a large-scale screening of healthy blood donors in the United States, also found that as many as 0.8% of men and 0.3% of women are homozygous. Numerous subsequent studies have established that hereditary hemochromatosis is a common genetic disorder among the populations of northern European origin; it is very rare among other populations.