Iron

IRON

Iron has for long been considered important for the body. Lauha bhasma (calcined iron) has been used in ancient Indian medicine. According to Greek thought Mars is the God of strength and iron is dedicated to Mars: thus, iron was used for weakness, which is common in anaemia. In 1713 iron was shown to be present in blood. In the early 19th century Blaud developed his famous ‘Blaud’s pill’ consisting of ferrous sulfate and potassium carbonate for anaemia. All important aspects of iron metabolism have been learned in the past 60 years.

Distribution Of Iron In Body

Iron is an essential body constituent. Total body iron in an adult is 2.5–5 g (average 3.5 g). It is more in men (50 mg/ kg) than in women (38 mg/kg). It is distributed into:

Haemoglobin (Hb) : 66%

Iron stores as ferritin and haemosiderin : 25%

Myoglobin (in muscles) : 3%

Parenchymal iron (in enzymes, etc.) : 6%

Haemoglobin is a protoporphyrin; each molecule having 4 iron containing haeme residues. It has 0.33% iron; thus loss of 100 ml of blood (containing 15 g Hb) means loss of 50 mg elemental iron. To raise the Hb level of blood by 1 g/dl— about 200 mg of iron is needed. Iron is stored only in ferric form, in combination with a large protein apoferritin.

Ferritin can get saturated to different extents; at full saturation it can hold 30% iron by weight. The most important storage sites are reticuloendothelial (RE) cells. Parenchymal iron occurs as prosthetic group in many cellular enzymes— cytochromes, peroxidases, catalases, xanthine oxidase and some mitochondrial enzymes. Though, the primary reflection of iron deficiency occurs in blood, severe deficiency affects practically every cell.

Daily Requirement

To make good average daily loss, iron requirements are:

Adult male : 0.5–1 mg (13 μg/kg)

Adult female : 1–2 mg (21 μg/kg)

(menstruating)

Infants : 60 μg/kg

Children : 25 μg/kg

Pregnancy : 3–5 mg (80 μg/kg)

(last 2 trimesters)

Dietary Sources Of Iron

Rich : Liver, egg yolk, oyster, dry beans, dry

Fruits, wheat germ, yeast.

Medium : Meat, chicken, fish, spinach, banana, apple.

Poor : Milk and its products, root vegetables.

Iron Absorption

The average daily diet contains 10–20 mg of iron. Its absorption occurs all over the intestine, but majority in the upper part. Dietary iron is present either as haeme or as inorganic iron. Absorption of haeme iron is better (upto 35% compared to inorganic iron which averages 5%) and occurs directly without the aid of a carrier (Fig. 43.1).

However, it is a smaller fraction of dietary iron. The major part of dietary iron is inorganic and in the ferric form. It needs to be reduced to the ferrous form before absorption. Two separate iron transporters in the intestinal mucosal cells function to effect iron absorption. At the luminal membrane the divalent metal transporter 1 (DMT1) carrys ferrous iron into the mucosal cell. This along with the iron released from haeme is transported across the basolateral membrane by another iron transporter ferroportin (FP). These iron transporters are regulated according to the body needs. Absorption of haeme iron is largely independent of other foods simultaneously ingested, but that of inorganic iron is affected by several factors.

Factors Facilitating Iron Absorption

1.    Acid: by favouring dissolution and reduction of ferric iron.

2.    Reducing substances: ascorbic acid, amino acids containing SH radical. These agents reduce ferric iron and form absorbable complexes.

3.    Meat: by increasing HCl secretion and providing haeme iron.

Factors Impeding Iron Absorption

1.   Alkalies (antacids) render iron insoluble, oppose its reduction.

2.   Phosphates (rich in egg yolk)

3.   Phytates (in maize, wheat)

4.   Tetracyclines

5.   Presence of other foods in the stomach.

In general, bioavailability of iron from cereal based diets is low.

Mucosal Block

The gut has a mechanism to prevent entry of excess iron in the body. Iron reaching inside mucosal cell is either transported to plasma or oxidised to ferric form and complexed with apoferritin to form ferritin (Fig. 43.1). This ferritin generally remains stored in the mucosal cells and is lost when they are shed (lifespan 2–4 days). This is called the ‘Ferritin curtain’.

The iron status of the body and erythropoietic activity govern the balance between these two processes, probably through a ‘haematopoietic transcription factor’, and thus the amount of iron that will enter the body. A larger percentage is absorbed during iron deficiency. When body iron is low or erythropoiesis is occurring briskly, ferritin is either not formed or dissociates soon— the released iron is transported to the blood.

Mucosal block however, can be overwhelmed by gross excess of iron.

Transport, Utilization, Storage And Excretion

Free iron is highly toxic. As such, on entering plasma it is immediately converted to the ferric form and complexed with a glycoprotein transferrin (Tf). Iron circulates in plasma bound to Tf (two Fe³⁺ residues per molecule). The total plasma iron content (~3 mg) is recycled 10 times everyday (turnover of iron is 30 mg/day).

Iron is transported into erythropoietic and other cells through attachment of transferrin to specific membrane bound transferrin receptors (TfRs). The complex is engulfed by receptor mediated endocytosis. Iron dissociates from the complex at the acidic pH of the intracellular vesicles; the released iron is utilized for haemoglobin synthesis or other purposes, while Tf and TfR are returned to the cell surface to carry fresh loads. In iron deficiency and haemolytic states when brisk erythropoiesis is occurring, TfRs in erythropoietic cells increase in number. This does not occur in other cells. Thus, the erythron becomes selectively more efficient in trapping iron.

Iron is stored in RE cells in liver, spleen, bone marrow, also in hepatocytes and myocytes as ferritin and haemosiderin after entering these cells through TfRs. Apoferritin synthesis is regulated by iron status of the body. When it is low—the ‘iron regulating element’ (IRE) on mRNA is blocked—transcription of apoferritin does not occur, while more Tf is produced. On the other hand, more apoferritin is synthesized to trap iron when iron stores are rich. Plasma iron derived from destruction of old RBCs (lifespan ~120 days), from stores and from intestinal absorption forms a common pool that is available for erythropoiesis, to all other cells and for restorage.

Iron is tenaciously conserved by the body; daily excretion in adult male is 0.5–1 mg, mainly as exfoliated g.i. mucosal cells, some RBCs and in bile (all lost in faeces). Other routes are desquamated skin, very little in urine and sweat. In menstruating women, monthly menstrual loss may be averaged to 0.5–1 mg/day. Excess iron is required during pregnancy for expansion of RBC mass, transfer to foetus and loss during delivery; totalling to about 700 mg. This is to be met in the later 2 trimesters.

Preparations And Dose

Oral Iron

The preferred route of iron administration is oral. Dissociable ferrous salts are inexpensive, have high iron content and are better absorbed than ferric salts, especially at higher doses. Gastric irritation and constipation (the most important side effects of oral iron) are related to the total quantity of elemental iron administered. If viewed in terms of iron content, nearly all preparations have the same degree of gastric tolerance, the limits of which are fairly well defined in individual patients. Some simple oral preparations are:

1)  Ferrous sulfate: (hydrated salt 20% iron, dried salt 32% iron) is the cheapest; may be preferred on this account. It often leaves a metallic taste in mouth; FERSOLATE 200 mg tab.

2)  Ferrous gluconate (12% iron): FERRONICUM 300 mg tab, 400 mg/15 ml elixer.

3)  Ferrous fumarate (33% iron): is less water soluble than ferrous sulfate and tasteless; NORIA 200 mg tab.

4)  Colloidal ferric hydroxide (50% iron): NEOFERUM 200 mg tab, 400 mg/5 ml liquid, 100 mg/ml drops.

Other forms of iron present in oral formulations are:

Ferrous succinate (35% iron)

Iron choline citrate

Iron calcium complex (5% iron)

Ferric ammonium citrate (scale iron)

Ferrous aminoate (10% iron)

Ferric glycerophosphate

Iron hydroxy polymaltose

These are claimed to be better absorbed and/or produce less bowel upset, but this is primarily due to lower iron content. They are generally more expensive.

A number of oral formulations containing one of the iron compounds along with one to many vitamins, yeast, amino acids and other minerals are widely marketed and promoted. Some of these are listed in Table 43.1, but should be considered irrational.

A technical Advisory Board (India) has recommended that B complex vitamins and zinc should not be included in iron and folic acid containing haematinic preparations.

Iron hydroxy polymaltose has been marketed by many pharmaceuticals and vigorously promoted for its high iron content, no metallic taste, good g.i. tolerability and direct absorption from the intestines. Because the complex releases little free iron in the gut lumen—g.i. irritation is minimal. However, the high bioavailability observed in rats has not been found in humans and reports of its poor efficacy in treating iron deficiency anaemia have appeared. Preparations of iron hydroxy polymaltose are 4–5 times costlier than other iron salts and its therapeutic efficacy is questionable.

The elemental iron content and not the quantity of iron compound per dose unit should be taken into consideration. Sustained release preparations are more expensive and not rational because most of the iron is absorbed in the upper intestine, while these preparations release part of their iron content lower down. Liquid formulations may stain teeth: should be put on the back of tongue and swallowed. In general they are less satisfactory.

A total of 200 mg elemental iron (infants and children 3–5 mg/kg) given daily in 3 divided doses produces the maximal haemopoietic response. Prophylactic dose is 30 mg iron daily. Absorption is much better when iron preparations are taken in empty stomach. However, side effects are also more; some prefer giving larger amounts after meals, while others like to give smaller doses in between meals.

Adverse Effects Of Oral Iron

These are common at therapeutic doses and are related to elemental iron content. Individuals differ in susceptibility. Epigastric pain, heartburn, nausea, vomiting, staining of teeth, metallic taste, bloting, colic.

Constipation is more common (believed to be due to astringent action of iron) than diarrhoea (thought to reflect irritant action). However, these may be caused by alteration of intestinal flora as well.

Parenteral Iron

Iron therapy by injection is indicated only when:

1.   Oral iron is not tolerated: bowel upset is too much.

2. Failure to absorb oral iron: malabsorption; inflammatory bowel disease. Chronic inflammation (rheumatoid arthritis) decreases iron absorption, also the rate at which iron can be utilized is decreased.

3.   Noncompliance to oral iron.

4.   In presence of severe deficiency with chronic bleeding.

5.   Along with erythropoietin: oral ion may not be absorbed at sufficient rate to meet the demands of induced rapid erythropoiesis. Parenteral iron therapy needs calculation of the total iron requirement of the patient.

Iron Requirement (mg) = 4.4 × Body Weight (Kg) × Hb Deficit (g/dl)

This formula includes iron needed for replenishment of stores. The rate of response with parenteral iron is not faster than with optimal doses given orally. However, stores can be replenished in a shorter time by parenteral therapy.

The ionized salts of iron used orally, cannot be injected because of their strong protein precipitating action. Two organically complexed preparations for parenteral use are:

·    Irondextran: as a colloidal solution containing 50 mg elemental iron/ml is the preparation of choice; IMFERON 2 ml ampoule.

·            Iron-sorbitol-citric acid complex: 50 mg iron/ml; JECTOFER 1.5 ml ampoule.

The i.m. dose of both irondextran and ironsorbitol is 30% higher than the calculated requirement of a patient. A test dose of the preparation (few drops) must be injected first to screen sensitive patients.

Intramuscular: Injection is given deeply in the gluteal region using Z track technique (to avoid staining of the skin). Iron dextran can be injected 2 ml daily, or on alternate days, or 5 ml each side on the same day (local pain lasting weeks may occur with the higher dose). More than 1.5–2 ml of ironsorbitol should not be injected at one time.

Intravenous: After a test dose of 0.5 ml irondextran injected i.v. over 5–10 min, 2 ml can be injected per day taking 10 min for the injection. Alternatively the total calculated dose is diluted in 500 ml of glucose/saline solution and infused i.v. over 6–8 hours under constant observation. Injection should be terminated if the patient complains of giddiness, paresthesias or constriction in chest. Intravenous iron injection is more risky than i.m. injection. Iron sorbitol is not suitable for i.v. use or for total dose infusion because it would rapidly saturate transferrin and very high levels of free iron in blood will be attained.

Adverse Effects Of Parenteral Iron

Local Pain at site of i.m. injection, pigmentation of skin, sterile abscess—especially in old and debilitated patient.

Systemic Fever, headache, joint pains, flushing, palpitation, chest pain, dyspnoea, lymph node enlargement. A metallic taste in mouth lasting few hours occurs with iron-sorbitol injection.

An anaphylactoid reaction resulting in vascular collapse and death occurs rarely. Iron sorbitol causes more immediate reactions than iron-dextran.

Iron-sorbitol should be avoided in patients with kidney disease.

Use

1. Iron Deficiency Anaemia

It is the most important indication for medicinal iron. Iron deficiency is the commonest cause of anaemia, especially in developing countries where a sizable percentage of population is anaemic. The RBC are microcytic and hypochromic due to deficient Hb synthesis. Other metabolic manifestations are seen when iron deficiency is severe. Apart from nutritional deficiency, chronic bleeding from g.i. tract (ulcers, hookworm infestation) is a common cause. Iron deficiency also accompanies repeated attacks of malaria and chronic inflammatory diseases. The cause of iron deficiency should be identified and treated. Iron should be normally administered orally; parenteral therapy is to be reserved for special circumstances. A rise in Hb level by 0.5– 1 g/dl per week is an optimum response to iron therapy. It is faster in the beginning and when anaemia is severe. Later, the rate of increase in Hb% declines. However, therapy should be continued till normal Hb level is attained (generally takes 1–3 months depending on the severity) and 2–3 months thereafter to replenish the stores, because after correction of anaemia, iron absorption is slow.

Prophylaxis: The amount of iron available from average diet and the absorptive processes in the intestine place a ceiling on iron absorption of ~3 mg/day. Thus, iron balance is precarious in most menstruating women. Later half of pregnancy and infancy are periods when iron deficiency will develop unless medicinal iron is supplemented.

In these situations as well as others (chronic illness, menorrhagia, after acute blood loss, etc.) prophylactic use of iron is indicated.

2. Megaloblastic Anaemia

When brisk haemopoiesis is induced by vit B12 or folate therapy, iron deficiency may be unmasked. The iron status of these patients should be evaluated and iron given accordingly.

3. As An Astringent

Ferric chloride is used in throat paint.

ACUTE IRON POISONING

It occurs mostly in infants and children: 10–20 iron tablets or equivalent of the liquid preparation (> 60 mg/kg iron) may cause serious toxicity in them. It is very rare in adults.

Manifestations are vomiting, abdominal pain, haematemesis, diarrhoea, lethargy, cyanosis, dehydration, acidosis, convulsions; finally shock, cardiovascular collapse and death. In few cases death occurs early (within 6 hours), but is typically delayed to 12– 36 hours, with apparent improvement in the intervening period. The pathological lesion is haemorrhage and inflammation in the gut, hepatic necrosis and brain damage.

Treatment

It should be prompt.

To Prevent Further Absorption Of Iron From Gut

·      Induce vomiting or perform gastric lavage with sodium bicarbonate solution—to render iron insoluble.

·      Give egg yolk and milk orally: to complex iron. Activated charcoal does not adsorb iron.

To Bind And Remove Iron Already Absorbed

Desferrioxamine (an iron chelating agent—see Ch. No. 66) is the drug of choice. It should be injected i.m. (preferably) 0.5–1 g (50 mg/kg) repeated 4–12 hourly as required, or i.v. (if shock is present) 10–15 mg/kg/hour; max 75 mg/kg in a day till serum iron falls below 300 μg/dl. Early therapy with desferrioxamine has drastically reduced mortality of iron poisoning.

Alternatively DTPA or calcium edetate (see Ch. No. 66) may be used if desferrioxamine is not available. BAL is contraindicated because its iron chelate is also toxic.

Supportive Measures

Fluid and electrolyte balance should be maintained and acidosis corrected by appropriate i.v. infusion. Respiration and BP may need support. Diazepam i.v. should be cautiously used to control convulsions, if they occur.