Iron

Published on 01/03/2015 by admin

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57

Iron

Iron is an essential element in humans, being the central ion in haem, the non-protein component of haemoglobin, myoglobin and the cytochromes (Fig 57.1). Iron deficiency causes a failure in haem synthesis and since haemoglobin is required for delivery of oxygen to the tissues, this leads to anaemia and tissue hypoxia. However, free iron is highly toxic to cells and must be bound to protein at all times.

Iron physiology

Iron levels are controlled by regulating iron uptake, since there is no mechanism for controlling its excretion. Dietary intake of iron is about 0.35 mmol (20 mg) per day and there are 50–70 mmol (3–4 g) of iron in the body, distributed as shown in Figure 57.2. Iron in the tissue stores is bound to the iron storage proteins ferritin (soluble) and haemosiderin (insoluble). The 1% of body iron in the plasma is associated with the iron binding glycoprotein, transferrin, each molecule of which binds two Fe2+ ions.

Serum iron concentrations differ with age and sex. Normal adult concentrations are 10–40 µmol/L. There is a marked circadian rhythm in serum iron concentrations, which can vary by 50% over 24 hours. Although it is usually accepted that iron concentration peaks in the morning and is lowest in the evening, the predictability of this variation is debatable.

Laboratory investigation of iron disorders

image Serum iron determinations are of limited routine value, being of most assistance in the diagnosis of iron overload and acute iron poisoning.

image Transferrin can be measured directly or indirectly as the total iron binding capacity (TIBC). Normally transferrin is about 30% saturated with iron. When saturation falls to 15%, iron deficiency is likely and some degree of clinical effect can be expected. A higher percentage saturation indicates iron overload. Transferrin and, therefore, also total serum iron, is decreased as part of the acute phase response. Protein energy malnutrition decreases transferrin synthesis and hence its serum concentration.

image Serum ferritin is the best indicator of body iron stores. The concentration is normally greater than 12 µg/L. The acute phase response can result in increases in serum ferritin, making the diagnosis of marginal iron deficiency difficult or impossible in these circumstances.

image Zinc protoporphyrin (ZPP) is markedly increased in iron deficiency and sometimes used as a screening test in children; it is expressed as µmol ZPP/mole haem and is usually <60. Concentrations are also increased following chronic exposure to lead, though in children ZPP rise is a late phenomenon so less reliable than measurement of lead levels. For a full investigation of iron status, the haemoglobin concentration, the appearance of the erythrocytes (deficiency), and liver biopsy (excess) may be required.

Iron deficiency

Iron deficiency anaemia is the commonest of all single-nutrient deficiencies, causing seriously impaired quality of life. The principal causes are chronic blood loss and poor dietary intake of bio-available iron. Uptake of iron can be decreased by a number of dietary constituents, such as phytic acid, and can also occur in malabsorptive conditions, such as coeliac disease. In iron deficiency anaemia it is important to diagnose the underlying condition, especially malignant disease, the presence of intestinal parasites or any other intestinal pathology that may cause chronic blood loss. In women, even when well-nourished, iron deficiency may develop during pregnancy due to the increased iron requirements of the developing fetus.

Iron deficiency anaemia develops in three stages:

Iron overload

Iron overload may be caused by chronic blood transfusions, inappropriate total parenteral nutrition and where there is ineffective haematopoiesis, as in renal failure. Other important causes of iron overload are haemochromatosis and iron poisoning. Since there is no major mechanism for excretion of iron except by cell desquamation and occult blood loss, iron overload is also a possibility when iron therapy is prescribed. In iron overload the serum ferritin concentrations may rise to 500–5000 µg/L.

Haemochromatosis

This is a relatively common inherited disease characterized by increased iron absorption (2–3 × normal) that leads to iron deposition in various organs. Whole body iron content may be increased tenfold. The excess iron leads to free radical generation, fibrosis and organ failure. The commonest mutation (C282Y) in the HFE gene results in decreased production of a small peptide, hepcidin, which is the main regulator of iron absorption and distribution. Hepcidin targets ferroportin, a transmembrane protein. The latter is present in intestinal cells and binds to the absorbed iron. Hepcidin binds to ferroportin and induces its internalization and degradation, thereby retaining the iron within the cells; this iron is then lost with cellular desquamation. Low hepcidin production leads to dysregulated and excessive iron absorption. African iron overload is related to a similar but separate mutation. The clinical presentation varies widely depending upon dietary iron uptake, alcohol abuse or the presence of hepatotoxins. Women are less severely affected than men, being protected by physiological iron loss during menstruation and in pregnancy.

image Clinical note

A microcytic hypochromic anaemia, and the absence of stainable iron in a bone marrow biopsy, are the best diagnostic indices of established iron deficiency.

Clinical features include chronic fatigue and, in extreme cases, skin pigmentation, diabetes mellitus, cardiomyopathy, hepatic cirrhosis and hepatoma. Serum iron is increased, with almost complete saturation of transferrin. Transferrin saturation is the test with the greatest sensitivity and specificity for haemochromatosis, but serum ferritin is also increased to greater than 500 µg/L. The best way to confirm hereditary haemochromatosis is genotyping, which is 99% sensitive. Liver biopsy is also used to confirm iron overload. Chronic iron overload is usually treated by venesection, the removal of 500 mL blood accounting for approximately 250 mg iron. In chronic treatment, ferritin levels should be maintained below 100 µg/L.

Case history 46

A 42-year-old woman presented with a history of increasing lethargy, dizziness and breathlessness. She had brittle hair and nails. She complained of heart palpitation on exercise and reported particularly heavy periods. Biochemical investigation revealed the following results:

Serum iron 4 µmol/L
Transferrin saturation 10%
Ferritin <5 µg/L

Comment on page 169.

Iron poisoning

Iron poisoning in children is common and may be life-threatening. Symptoms include nausea and vomiting, abdominal pain and haematemesis. In severe cases, hypotension and coma can result. Serum iron is increased and transferrin is >70% saturated. Treatment is by chelation of the iron in the stomach and the plasma with desferrioxamine. Chelated iron is excreted in the urine as a deep orange coloured complex (Fig 57.4).

Iron

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