Oral Iron Therapy


Iron deficiency anaemia is treated by iron supplementation that may be administered orally or parenterally.  Oral iron absorption is inefficient, is interfered by food and is associated with high incidence of gastrointestinal adverse effects. About 17% of the world population is estimated to be suffering from iron deficiency. Iron deficiency is more common the poorer regions of the world. These regions have limited resources allocated for healthcare. Oral iron is inexpensive and convenient to administer making it the modality of choice for initiation of treatment of iron deficiency. The availability of safer parenteral iron preparations that can replete the iron deficit in one dose has reduced the threshold of switching a person intolerant to iron to parenteral iron.

Oral Iron Absorption

Dietary iron may be heme iron or non-heme iron. Heme iron is absorbed after oxidation to hematin. The absorption of heme iron is more efficient. Dietary non-heme iron is present in the ferric state. Ferric iron is insoluble and needs to be reduced to ferrous iron. Gastric acidity aids this conversion. Medicinal iron is most often administered in the ferrous state. Ferrous iron tends to oxidize to ferric iron at physiological pH. Gastric acid lowers the pH and retards oxidation. The absorption of non-heme iron is aided by ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates and retarded by phytates present in grains and vegetables, dietary fibre, polyphemols present in tea, coffee and wine, phosphates and phosphoproteins present in egg yolk, bovine milk, calcium and zinc. For a detailed discussion on iron absorption see intestinal iron absorption. Preparations containing iron in the ferric state have a 3-4 fold lower bioavailability than ferrous iron preparations. Ferric iron is insoluble in the alkaline medium of the duodenum and needs to be converted to ferrous iron (ScientificWorldJournal. 2012; 2012: 846824).

Oral Iron Preperations

Oral iron preparations may be heme or non-heme. Heme iron is available as heme iron polymer. Non-heme iron may be in the ferrous or ferric form. Carbonyl is pure iron prepared from the decomposition of iron pentacarbonyl. The preparations are listed in the table below.

 

Preparations Iron Content
Ferrous Sulfate, anhydrous 30%
Ferrous Fumarate 33%
Ferrous Sulfate 20%
Ferrous carbonate, anhydrous 48%
Ferrous Gluconate 12%
Ferric Ammonium Citrate 18%
Ferric bisglycinate 20%
Ferric pyrophosphate 12%
Carbonyl iron ~100%
Heme-iron peptide 100%
Polysaccharide iron complex 100%

Indications of Oral Iron Therapy

Oral iron is indicated for prevention and treatment of iron deficiency anaemia. The rate of iron delivery is insufficient to provide iron when erythropoiesis is stimulated by erythrocyte stimulating agents like erythropoietin and darbepoetin. Oral iron should not be used for such patients.

Trial of Oral Iron Therapy

Serum ferritin is an indicator of total body iron. It is also an acute phase reactant. Low ferritin indicates iron deficiency. The traditional cutoff is 12ng/mL. At this cutoff the sensitivity of ferritin for the diagnosis of iron deficiency anaemia is only 25%. The sensitivity can be increased to 92% with a positive predictive value of 83% if a cutoff of 30ng/mL is used. A trial of oral iron may be given if other causes of anaemia are excluded.

Contraindications to Oral Iron Therapy

  1. Primary hemachromatosis: Primary hemochromatosis is a is absolute contraindication
  2. Peptic ulcer, regional enteritis, or ulcerative colitis can be exacerbated by oral iron.
  3. β-Thalassaemia trait is a relative contraindication. Some patients may develop iron overload. Patients should be given iron only if iron deficiency is established by laboratory investigation.

Failure of Oral Iron Therapy

  1. Failure to take prescribed medication: Oral iron therapy causes gastrointestinal adverse effects in a large proportion patients that are severe enough in some to discontinue therapy. A detailed history must be taken to ascertain that the patient has taken the prescribed dose.
  2. Incorrect or incomplete diagnosis: Iron deficiency anaemia is hypochromic microcytic (see Evaluating Anaemia). Other diseases that result in hypochromic microcytic anaemia are thalassaemia and anaemia of chronic disease. Both are common and can both be confused with iron deficiency as well as co-exist with iron deficiency. Thalassemia trait affects about 1.5% of the world population. About 1.4% of the population is estimated to have anaemia due to infection, inflammation or chronic renal disease (https://dx.doi.org/10.1016%2FS0140-6736(15)60692-4). Incidental occurrence of iron deficiency with thalassaemia trait or anaemia of chronic disease will result in an incomplete response to iron supplementation. Some inflammatory conditions e.g. ulcerative colitis cause blood loss. Blood loss may be seen due to use of non-steroidal inflammatory agents in patients with autoimmune arthritis. Anaemia in these patients shows an incomplete response to iron supplementation because part of the anaemia results from chronic inflammation.
  3. Insufficient amount or inappropriately taken oral iron: The ideal dose is 200mg of elemental iron taken 2 hours before or 1 hour after food. Food interferes with iron absorption but also relieves gastrointestinal adverse effects. Gastrointestinal adverse effects are related to dose. Prescriptions of oral iron may have an insufficient dose or may be administered after food to reduce gastrointestinal adverse effects. This results in an inappropriate haemoglobin response.
  4. Iron demand exceeding intake: Iron demand may exceed supply if there is continued blood loss or in patients where erythropoiesis is stimulated with an erythropoiesis stimulating agent like erythropoietin or darbepoietin. In both these situations the rate of oral iron absorption limits iron availability. These patients need intravenous iron.
  5. Malabsorption of iron: Food interferes with oral iron absorption. Ferrous iron is rapidly oxidised to ferric iron at physiological pH. Gastric acid reduces ferric iron to ferrous iron. Proton pump inhibitors, H2 antagonists, antacids and gastrectomy reduce acidity and can interfere with iron absorption. Iron malabsorption may be seen as part of a malabsorption syndrome. Iron deficiency refractory to iron is rare. Iron refractory iron deficiency anaemia is a disorder resulting from mutations in the TMPRSS6. This mutations results in increase hepcidin production which is sensed by the body as an iron repeated state. Iron is not absorbed despite iron deficiency. The patients do not respond to oral iron and shows a partial response to parenteral iron.

 Interactions

  1. Interaction of iron with food: The absorption of non-heme iron is affected by food (See Intestinal Iron Absorption).
    1. Foods enhancing iron absorption: Ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates with iron enhance absorption of non-heme iron.
    2. Inhibiting iron absorption: `Inhibitors of absorption of non-heme iron include
      1. Phytates present in grains and vegetables
      2. Dietary fibre
      3. Polypohenols present in tea, coffee and wine,
      4. Phosphates and phosphoproteins present in egg yolk, bovine milk
      5. Calcium and zinc.
  2. Drug-Iron interactions
    1. Iron decreases the absorption of ACE inhibitors, bisphosphonates, levodopa, levothyroxine, penicillamine, quinolone and tetracyclines
    2. The absorption of iron is decreased by drugs that reduce gastric pH. These include H2 antagonists(Cimetidine, ranitidine, famotidine), proton pump inhibitors (omeprazole, pantoprqzole, esomeprazole, lansoprazole, rabeprazole, etc), antacids and cholesterol lowering agents (Cholestyramine and Colestipol).

Dose

  1. Children: 3–6 mg/kg daily in 3 divided doses.
  2. Adult: Usual therapeutic dosage: 50–100 mg 3 times daily but a dose of 200mg produces the maximal results. A smaller dosages (e.g. 60–120 mg daily) may be given if patients are intolerant of oral iron, but response in such patients takes a longer time.

Side Effects Of Oral Iron

  1. Gastrointestinal: The commonest adverse effects of iron are gastrointestinal symptoms, including heartburn, nausea, abdominal cramps, diarrhoea or constipation. These may be seen in up to a fifth of the patients. They can be reduced by decreasing the dose or taking iron after food. Taking iron with food can reduce the absorption by about 50%. Enteric coated preparation decrease the side effects by delaying the release of iron. Delaying release may bypass the duodenum that is the site of absorption of iron. The decrease in absorption is particularly marked in patients with aclorhydria as they can not dissolve the enteric coating. The stool of patients taking iron supplements may be discoloured black or green.
  2. Discolouration of teeth: Iron syrups may cause staining to teeth.
  3. Iron overload: Iron overload from oral iron therapy is rare. It has been described in patients with hemachromatosis and chronic haemolytic anaemias.
  4. Iron Poisoning: Iron poisoning usually occurs in children, particularly those younger than 5 years of age, because of accidental ingestion of medicinal iron. Children are likely to ingest these believing them to be candies.
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Intestinal Iron Absorption


Intestinal Iron Absorption-900pxIntestinal absorption of iron (figure 1)

Iron absorption occurs in two steps

  1. Absorption of iron into the enterocyte at the luminal surface of the enterocytes
  2. Transport of iron to the lamina propria at the basilateral surface of the enterocyte

click here for fig 1

Absorption of iron into the enterocyte

Dietary iron is in two forms, heme and non-heme. Animal foods have 40% iron as heme iron and 60% as non-heme iron. Plant foods contain only non-heme iron. Most of the iron available for absorption comes from non-meat sources even in meat eaters. The widely held perception that vegetarian diets contain less iron than meat eaters is not true. Vegetarian diets contain as much or more iron than meat diets (MJA Open 2012; 1 Suppl 2: 11-16). Vegetarian foods have less heme iron. Different pathways absorb heme and non-heme iron.

Absorption of heme iron

Digestion of proteins releases heme which is oxidized to haemin and absorbed by the enterocytes. A receptor for the absorption of heme has been postulated but not identified. Once within the cell the haemin is acted upon by heme oxygenase 1 to release the iron. The heme iron is added to the enterocyte iron pool and follows the same path out of the cell as non-heme iron. Food does not affect the absorption of heme iron. Some heme may be absorbed directly and is bound to hemoprixin.

Non-Heme Iron

Dietary non-Heme iron is present in the ferric state. Ferric iron is insoluble and needs to be converted to the more soluble ferrous state for absorption. The reduction of ferric iron is aided by the acidic environment of the stomach, dietary components like ascorbic acid and duodenal cytochrome b (Dcytb). Dcytb does not appear to be essential for iron absorption. Ferrous iron is absorbed by the divalent metal ion transporter (DMT1). In addition to  Fe2+,DMT 1 also transports Mn2+, Co2+, Ca2+, Zn2+, Cd2+ and Pb2+. DMT1 is expressed at the brush-border of the enterocyte near the tips of small intestinal villi. DMT1 needs protons to co-transport with iron. Protons come from the gastric juice and are most abundant in the duodenum. Most of the iron is absorbed in the duodenum. Antacid, H2 antagonists and proton pump inhibitors hamper iron absorption by reducing hydrogen ion availability. All these drugs have been shown to impair the efficacy of medicinal iron.

The absorption of non-heme iron, unlike heme iron, is affected by food.

  1. Foods enhancing iron absorption: Ascorbate, animal proteins, human milk, keto sugars, organics, amino acids that form soluble chelates with iron enhance absorption of non-heme iron.
  2. Inhibiting iron absorption: `Inhibitors of absorption of non-heme iron include
    1. Phytates present in grains and vegetables
    2. Dietary fibre
    3. Polypohenols present in tea, coffee and wine,
    4. Phosphates and phosphoproteins present in egg yolk, bovine milk
    5. Calcium and zinc.

Transport of iron to the lamina propria

Iron is transported to the lamina propria by an iron transporter ferroportin. Ferroportin transports iron in the ferrous form. This needs to be oxidized to the ferric form for binding to transferrin. Hephaestin oxidizes ferrous iron to ferric iron.

Ferroportin is the key to controlling body iron. In iron deficient state ferroportin expression at the basolateral surface of the enterocyte is increased and more iron is transferred to the blood. When the body is iron repleted ferroportin expression is low and the iron remains in the enterocyte as ferritin.  Iron stored as ferritin is lost with the enterocytes when it is shed at the end of it’s lifespan of 5-6days.

Ferroportin levels are controlled by enhancing it’s degradation when iron stores are adequate. The liver, on sensing adequate iron stores, secretes a peptide hepcidin that binds to ferroportin. Binding of ferroportin to hepcidin causes internalisation and degradation of ferroportin preventing iron transport. Mutations ferroportin, hepcidin and molecules that promote the secretion of hepcidin  (haemachromatosis protein (HFE),  haemojuvelin (HJV), transferrin receptor 2 (TFR2)) result in increased iron absorption and haemachromatosis.  Mutations in TMPRSS6 a negative regulator of hepcidin results in iron refractory iron deficiency anaemia.