It is a constituent of all body cells being present in the sulfur-containing amino acids of proteins. Small amounts of inorganic sulfur are also present in tissues. Sulfur is found in certain carbohydrates, e.g., chondroitin sulfuric acid in cartilage, tendons and bone matrix. It is a constituent of the sulfatides, glutathione, insulin, biotin and thiamine. Little is known about the human requirement of sulfur but it is presumably closely related to the need of sulfur-containing amino acids. These are discussed in connection with protein metabolism.
Iron deficiency may be nutritional in origin or result from loss of blood, particularly from chronic hemorrhage. Dietary deficiency of iron may be observed during the growth period, especially in infancy and adolescence, and during the reproductive life of the female. The newborn infant has a certain amount of stored iron the quantity being related to maternal supply during pregnancy.
Iron has a number of important functions in the body. It is an essential component of the hemin chromoproteins, hemoglobin, myoglobin, the cytochromes, peroxidase and catalase. All of these play vital roles in the transport and utilization of oxygen for energy requirements.
Knowledge of certain features of iron metabolism is necessary for estimation of the adequacy of dietary intake and for diagnosis of potential iron deficiency before overt anemia occurs. Many factors influence iron absorption and once iron is absorbed, only small quantities are lost from the body. Studies with radioactive iron indicate that absorption of iron salts is dependent on bodily need; normal adults absorb only small amounts whereas persons with iron deficiency anemia absorb much larger quantities. Moore and Dubach (73) have shown that normal subjects absorb about 10 per cent of iron from foodstuffs. During the growth period, absorption appears to be related to requirement and ranges from 8 to 28 per cent. An increase in absorption occurs in the latter months of pregnancy, presumably due to fetal need.
It has been postulated that absorption is regulated by an iron containing protein, ferritin, in the intestinal mu-coma. According to this theory, iron becomes attached to the iron free form of this protein, apoferretin, in the mucosal cell to produce ferretin and is subsequently released from ferretin at the blood stream end of the cell. Apoferretin is presumably formed in the mucosal cell in response to a decrease in the iron stores of the body.
Factors other than bodily need which may influence absorption of dietary iron include: (1) The chemical nature of the iron in the food, i.e., compounds which can be readily converted into ionized form are more available, as is ferrous as compared to ferric iron, (2) the acidity of the gastric juice (of relatively minor importance) and (3) the quantity of phosphates and phytates in the diet which can combine with iron to form insoluble salts. Ascorbic acid enhances iron absorption, while administration of hydrochloric acid and antacids are without significant effect. These factors must be considered in evaluating the physiologically available iron of the diet.
Iron is transported in the serum in ferric form attached to a specific beta-l-globulin, siderophilin, – also called transferrin: The normal level of serum iron ranges from about 80 to 180 ug/100 ml. while the maximum iron-binding capacity of serum varies from 300 to 360 4ug/100 ml. Thus the beta-l-globulin is normally about 33 per cent saturated with iron. Measurement of these levels are important in the diagnosis of iron deficiency as will be discussed subsequently.
The total amount of iron in the body is about 4 to 5 gm. of which approximately 72 per cent is found in hemoglobin, slightly over 3 per cent in myoglobin, 0.2 per cent in parenchymal iron including that present in cytochromes, catalase and peroxidase, and the remaining 23 per cent or more as storage iron. Iron is stored in two forms, ferritin and hemosiderin in the liver, spleen and bone marrow. The extent of the iron stores of the body may be measured by estimating the amount of hemosiderin in bone marrow.
Iron excretion is extremely small, only about 0.5 to 1.5 mg. daily by all routes including urine, bile, sweat, intestines, loss of hair and desquamation of body cells. In view of the conservation of iron by the body and its continuous reutilization, the dietary requirement is much less than the amount of iron needed daily in the formation of hemoglobin (26-27 mg.). In ,the normal adult, requirement represents only replacement of the iron lost through excretion. Moore and Dubach (73) have suggested that the adult male must assimilate 0.5 to 1 mg. of iron daily to maintain balance, the adult female 1 to 2 mg. daily. Normal women lose an average of 1 mg. per day in the menses which accounts for the higher requirement. During pregnancy, an average of 2.7 mg. of iron per day is supplied to the fetus, thus increasing maternal need by this amount. During growth, there is an additional requirement for the building of new tissues and expansion of blood volume. The increment for growth amounts to 0.3 to 0.6 mg. daily in the first 20 years of life. Since only about 10 per cent of food iron is absorbed, the daily dietary requirement for iron is determined by multiplying physiologic need by a factor of 10. Recommended dietary allowances are of this order . In pathologic conditions which are associated with blood loss, requirement is greatly increased. Gastrointestinal disturbances such as diarrhea, achlorhydria or intestinal disease may interfere with absorption and enhance dietary need. Considerable iron may be lost by regular blood donors.
Cartwright and associates have pointed out that iron deficiency may occur in two forms, latent and manifest. The clinician commonly thinks of microcytic hypochromic anemia as the outstanding feature of iron deficiency but before anemia occurs, deficiency is relatively far advanced. Diagnosis of latent iron deficiency is de-pendent upon laboratory procedures which demonstrate a depletion of bodily iron stores, a reduced level of plasma iron, or an increased total iron binding capacity of the plasma. Presumably the first change in deficiency is diminution of available iron stores which may be estimated by the simple method of Rath and Finch . The amount of hemosiderin in unstained bone marrow smears is graded 0 to 6 plus; in iron deficiency no hemosiderin or only a trace will be noted.
The plasma iron level is decreased in all patients with manifest iron deficiency and in most patients with depleted tissue stores. In iron-deficiency anemia, a concentration of less than 50 g. per 100 ml. is usually observed. Unfortunately, hypoferremia is not specific for iron deficiency and is encountered in association with infections, even with such mild ones as the common cold. Nevertheless, estimation of plasma iron is of value in assessing the adequacy of nutrition for if normal levels are obtained, manifest deficiency is ruled out and iron stores have not been exhausted.
Determination of the iron-binding capacity of plasma will differentiate between hypoferremia due to iron deficiency and that associated with infection. In the former, total iron binding capacity is increased to over 400 ug/100 ml, in the latter it is decreased. In iron deficiency anemia, in view of the hypoferremia and increased iron binding capacity, the saturation of the protein which carries iron is reduced from about 33 to less than 10 per cent.
The anemia of manifest iron deficiency is characterized by small cells which are poorly filled with hemoglobin. The severity of the anemia is usually proportionate to the extent of iron deficiency. Deficiency can be suspected by examination of a properly prepared and stained blood smear. The presence of microcytes with pronounced central pallor are almost specific; only Thalassemia, a rare condition, need be ruled out. This can be done readily by looking for target cells, stippling and nucleated red cells, as well as by physical findings, normal plasma iron, reduced iron binding capacity and in-creased hemosiderin in the bone marrow.
The anemia of iron deficiency can be characterized more adequately by estimation of mean corpuscular volume ( M.C.V.) and mean corpuscular hemoglobin concentration (M.C.H.C.) both of which are reduced below the normal values of 82-92 cubic microns and 32-34 per cent respectively. In order to obtain reliable figures for M.C.V. and M.C.H.C., the volume of packed red cells, hemoglobin concentration, and erythrocyte counts must be determined with great accuracy. With proper techniques, accuracy of the determination of volume of packed red cells may be about ±1 per cent, that of hemoglobin concentration about ±2 per cent and of erythrocyte counts ±11 per cent. In nutrition surveys, determination of hemoglobin in conjunction with stained blood smears can suffice as indicators of iron deficiency anemia, although estimation of the volume of packed erythrocytes gives additional useful information.
In iron-deficiency anemia, the clinical findings are those common to all anemias of comparable severity. Pallor of the skin and mucous membranes, fatigability, weakness, giddiness and syncopal attacks are observed frequently. Heart failure of the high output type may develop. In children, there is retardation of growth. In some subjects, glossitis, characterized by papillary atrophy, angular stomatitis and dysphagia may be noted. In anemia of considerable chronicity, the finger nails become flattened and concave giving them a spoon shape to which the term koilonychia has been applied.
Iron in excessive amounts may be toxic. Large amounts of iron are stored after frequent transfusions or intravenous injections of iron. In hemochromatosis, which probably represents an inborn metabolic abnormality, iron is absorbed in excessive amounts and massive deposits accumulate in the tissues especially in the liver, pancreas, adrenals and other endocrine glands. In this disease, cirrhosis of the liver, pancreatic fibrosis and adrenal insufficiency are observed. Acute toxicity may result from accidental ingestion of medicinal iron and fatalities have been reported. Characteristic symptoms are severe vomiting, often of blood, watery stools which later become tarry, and profound shock. The pulse is rapid, weak or imperceptible and the blood pressure is low. Hypotonia, hyporeflexia, dilated pupils, and a semicomatose or comatose state complete the clinical picture. Death has occurred in from 4 to 40 hours.