78 year old Alcoholic With Anaemia


An 78 year old man presented with fatigue and breathlessness. Examination showed pallor. There was no icretus, clubbing, lymphadenopathy or hepatomegaly. There was mild splenomegaly. There was no history of haemoptysis, malena or haematochesia.

An haemogram was performed that showed a haemoglobin was 8g/dL with an MCV of 101fl. The leucocyte count was 4.5 x 109/L and the platelet count was 265 x 109/L. The differential leucocyte count was neutrophils 58% lymphocytes 32%, monocytes 6% and eosinophils 4%. The Reticulocyte count was normal. 


Anaemia in alcoholics is multifactorial. The causes of Anaemia include

  1. Direct toxic effect of alcohol: Most alcoholics have macrocytosis in the range of 100-110fl. Macrocytosis is seen before anaemia develops. Anaemia reverses after a few months of abstaining from alcohol.
  2. Iron deficiency from gastrointestinal blood loss from varices and alcoholic gastritis may presents with hypochromic microcytic anaemeia. The transferrin saturation and serum ferritin are low. Alcohol and alcohol associated disease affect MCV, transferrin saturation and serum ferritin making interpretation of test difficult.
    • Microcytosis may not be seen in alcoholics with iron deficiency. A study showed 48% of the patients with chronic liver disease and iron deficiency diagnosed by absence of bone marrow iron had an MCV more than 100fl (J Intern Med. 1998 Mar;243(3):233-41).
    • Alcohol effects transferrin saturation. Transferrin levels may be decrease because of infection or inflammation. In a study of transferrin saturation in cirrhotics a transferrin saturation of <12% was of value in diagnosing iron deficiency. But transferrin saturation did not add to the value of ferritin in diagnosis.
    • Ferritin is an acute phase reactant and can be increase in chronic liver disease. A study has suggested different cutoffs be used in patients with chronic liver disease. Iron deficiency should be diagnosed with a ferritin ≤50 μg/L. Values >400 μg/L were associated with a low probability of iron deficiency (Annals of Gastroenterology (2017) 30, 1-9).
    • sTrasnferrin receptors levels is a iron deficiency (sensitivity 91.6%, specificity 84.6%) in patients with chronic liver disease provided that hemolysis and recent blood loss have been excluded (Clin Lab Haematol. 1999 Apr;21(2):93-7)
  3. Folate and Cobalamine deficiency: Folate and cobalamin deficiency causes macrocytosis and should be suspected in patients with MCV greater than 110fl, those with decreased platelet and/or leucocyte counts and when peripheral smear shows hypersegmantation of neutrophils.
  4. Hypersplenism: Hypersplenism causes anaemia and pancytopenia. The spleen is enlarged but there is no correlation between the degree of anaemia and size of the spleen. Unlike patients with folate or cobalamin deficiency the MCV patient with hypersplenism do not have an markedly (>110fl) increased MCV.
  5. Anaemia of chronic disease: Anaemia of chronic disease may be seen in alcoholics because concurrent infection or inflammation.
  6. Haemolytic anaemia with spur cells: Patients with severe hepatocellular disease develop spur cells that result in haemolytic anaemia. This may be associated with increased jaundice and/or deteriorating liver function. Appearance of spur cells may be related to continued alcohol abuse in the presence of severe chronic liver disease. Transfused blood cells also become acanthocytic and are haemolysed. Abstinence from alcohol can eliminate/reduce spur cells. Spur cell anaemia has been cured by liver transplant.

 

The patient has a serum iron of 24 µg/dL the total iron binding capacity of 202µg/dL and a  transferrin saturation of 11.9%. The serum ferritin was 30 µg/L. The B 12 and folic acid levels were normal. The serum albumin was 3.2g/dL. The AST, ALT, prothrombin time and bilirubin were normal.

The patients was diagnosed to have iron deficiency. An upper gastrointestinal endoscopy showed gastro-oesophageal varices. Colonoscopy did nor show any cause of bleeding. A diagnosis of iron deficiency anaemia was made, iron supplementation given and varices banded.

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Anaemia with Thrombocytosis


A 49 year old woman presented with weakness and fatigability. On examination, other than pallor of the skin and mucosa there was no other finding.  A haemogram was done that showed a haemoglobin: 6.7g/dL, leucocyte count: 9.1 X 109/L and a platelet: 664 X 109/L.

Anaemia and thrombocytopenia is a feature of

  1. Myeloproloferative neoplasm
  2. Chronic inflammation
  3. Underlying malignancy (Paraneoplastic)
  4. Iron deficiency

A haemogram from a automated haematological counter hides a lot of information. Before more investigations are done it is important to assimilate all the information in the haemogram. The haemogram in the above listed conditions shows:

  1. Myeloproliferative Neoplasm: The myeloproliferative neoplasm are diseases characterised by proliferation of bone marrow. They are distinct from acute leukaemia. According to the 2016 WHO classification myeloproliferative neoplasm include chronic myeloid leukaemia (CML), chronic neutrophilic leukaemia (CNL), polycythaemia vera (PV), progressive myelofibrosis (PMF), essential thrombocytosis (ET), chronic myeloproliferative neoplasm unclassified (CMPN-U) and chronic eosinophilic leukaemia (CEL).  Myeloproliferative diseases associated with anaemia and thrombocytosis are CML, prefibrotic phase of PMF and CMPN-U. Haemogram of patients with myeloproliferative diseases shows leucocytosis with presence of immature leucocyte forms. This is most pronounced in patients with CML. In fact leucocytosis with the presence of immature leucocyte forms is the dominant feature of the haemogram of patients with CML. Anaemia of myloproliferative is normocytic and normochromic.
  2. Chronic Inflammation and Paraneoplastic Diseases: Anaemia and thrombocytosis can also be seen in patients with chronic inflammation and as a paraneoplastic finding. An occasional immature leucocyte form may also be seen in these conditions. This picture may be indistinguishable from that myeloproliferative diseases other than CML. The anaemia is normocytic and normochromic. When the chronic disease or neoplasm is associated with blood loss as may be the case in cancers of the gastrointestinal tract or inflammatory bowel disease, microcytosis due to a coexisting iron deficiency may be seen.
  3. Iron Deficiency: Iron deficiency is associated with microcytic hypochromic anaemia. The degree of microcytosis co-relates with the degree of iron deficiency. The leucocyte counts depends on the cause of iron deficiency. Commonly the leucocyte is normal or slightly decreased. Patients who have iron deficiency because of blood loss due to an inflammatory condition may have leucocytosis. Iron deficiency from blood loss due to helmethiasis may cause eosinophilia.

The differential leucocyte count showed 67% polymorphs, 27% lymphocytes, 2% monocytes and 4% basophils. The erythrocyte indices were MCV 61fl, MCH 15.3pg and MCHC 24.9g/dL. The red cell distribution width was 28.5%. The peripheral smear showed hypochromia, microcytosis, anisocytosis and poikilocytosis.

Of the causes of anaemia and thrombocytosis listed above only iron deficiency is characterised by hypochromic microcytic anaemia. Iron deficiency is also characterised by anisocytosis and poikilocytosis. This manifests as increased red cell distribution on the haemogram.

The serum iron was 27.9 µg/dl, the total iron binding capacity 488 µg/dl with a transferrin saturation 5.7%. The serum ferritin was 8.53 ng/ml. The haemoglobin electrophoresis showed a haemoglobin A2 of 2.8%, the HbA 96% and haemoglobin F 1.2%.

Iron deficiency is diagnosed by documenting low body iron stores and/or impaired iron delivery of iron to the erythroid precursors. The gold standard for depletion of iron stores is absence of stainable iron in the bone marrow. Serum ferritin accurately reflects body iron stores. It has become the preferred method to demonstrate depletion of body iron stores because of the invasive nature of bone marrow aspiration. Levels less than 15ng/ml strongly suggest iron deficiency. Serum ferritin is specific but not sensitive for iron deficiency. Its has a sensitivity of 59% if the cutoff is 15ng/mL and 75% if the cutoff is less than 16ng/ml. The low sensitivity makes the test of limited value to exclude iron deficiency. Ferritin in an acute phase reactant. It has a limited value in the presence of inflammation.

Unlike low serum ferritin, low serum iron is of limited value in diagnosis of iron deficiency. Iron delivery to the haemoglobinizing erythroid precursors is a function of transferrin saturation rather than the serum iron levels. One can have a low serum iron and a low total iron binding capacity as may be seen in anaemia of chronic disease and yet have a normal transferrin saturation. Such patients do not benefit from iron supplementation. Patients with iron deficiency have a low transferrin saturation indicated impaired iron delivery to the developing erythroid cells. Lower the iron saturation higher the probability of iron deficiency being present. Patients are considered to be iron deficient if the transferrin saturation is less than 16%. This patient had a transferrin saturation of 5.7% and a serum ferritin of 8.63ng/ml along with microcytic hypochromic anaemia. A diagnosis of iron deficiency anaemia was made.

The diagnosis of iron deficiency is incomplete without diagnosing the cause of anaemia. Iron deficiency in a 49 year old woman frequently is a result of blood loss that is often menstrual.  This woman had attained menopause and is being evaluated for a gastrointestinal blood loss.

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.

Why Blood Loss From Sites other than Gastrointestinal Tract Rarely Causes Iron Deficiency?


A 55 year old man presented with breathlessness on climbing stairs. He saw his family physician who found the patient to be pale. The patient was advised a complete haemogram. He was found to be anaemic and was asked to see a haematologist.

The haemogram showed an haemoglobin of 3.1 g/dL with an MCV of 63fl. The WBC count was 5600 with 65% neutrophils, 30% lymphocyte, 3% monocytes and 2% eosinophils. The platelet count was 475 X 1009/L. The reticulocyte count was 1%.

The serum iron was 15μg/dL and the total iron binding capacity 450μg/dL and a transferrin saturation of 3.3%. The serum ferritin was 8ng/ml. A diagnosis of iron deficiency anaemia was made he was initiated on oral iron which he responded to. 

Iron deficiency is common in 

  1. Growing children because of dietary deficiency
  2. Women in the reproductive age group because of menstrual blood losses and iron depletion because of foetal transfer of iron during pregnancy.

When iron deficiency occurs in a well nourished man or a well nourished post-menopausal women it is invariably due to a gstrointestinal blood loss. Why is gastrointestinal blood loss different from other forms of blood loss?

Bleeding is an alarming symptom. It is rare for a person to ignore bleeding. Bleeding from the respiratory system, urinary system and skin is apparent and alarming. Such bleeding prompts the patient to promptly seek medical attention. Gastrointestinal bleeding may be of three types. The patient may pass fresh blood, the patient may have malaena or the patient may have occult bleeding. Passage of fresh blood with stools is a symptom of a lower gastrointestinal pathology. Such patients seek attention early and usually do not become anaemia. Haemorrhoids is an exception not because the patient does not realise that there is bleeding but because the patient may ignore the bleeding because he/she attributed it to a known cause. Some patients may not realise the significance of malaena and may present only when anaemic. A patient may loose upto  30ml of blood without a change in the consistency or colour of stools. Such patients present with iron deficiency anaemia. As the anaemia has a gradual onset the it may become severe and yet not cause symptoms. 

The diagnosis of anaemia is complete only if the type of anaemia and the cause of anaemia are determined. A rule of thumb is that unexplained iron deficiency anaemia in a man or a postmenopausal woman should be considered to be due to a occult gastrointestinal blood loss unless proven otherwise. The importance of this practice can not be overemphasised. A colon cancer develops in an adenoma. Completing the evaluation of an iron deficency anaemia provides an opportunity to diagnose a colorectal cancer either in the premalignment stage or when the disease has a limited extent. Not perusing the diagnostic evaluation of an iron deficiency anaemia to completion may close the window of early diagnosis of gastrointestinal cancer.

Intravenous Iron


Iron deficiency, the commonest cause of anaemia, is treated by iron supplementation. Oral iron, introduced by the French physician Pierre Blaud in the 19th century is the mainstay of therapy of iron deficiency. Oral iron is inexpensive and safe but is poorly absorbed and causes abdominal adverse effects in 35-59% of the patients. Injectable iron preparations were initially developed for the treatment of iron deficiency in patients intolerant to iron. Their use became more prevalent when it became clear that iron deficiency was a common cause of failure of erythropoiesis stimulating agent therapy and that oral iron was insufficient for this indication. The acceptance of intravenous iron was accelerate by the improved safety profile of the recently introduced parental iron preparation. The threshold for opting for intravenous iron is much lower than it was about two decades ago.

Is it possible to inject an iron salt, say ferric chloride, for iron deficiency, like it is to inject calcium chloride for hypocalcaemia? Iron, unlike calcium or potassium,  produces free radicals (oxyradicals) that can damage macromolecules and result in cellular injury. Ferric hydroxide,  the first injectable iron preparation used, caused an immediate release of iron in circulation resulting in severe reactions.  When an iron oxide, hydroxide or an iron salt is used, only a small dose can be safely administered. One estimate calculated the maximum iron permissible as 8mg/day (this is equivalent of the unbound iron binding capacity of transferrin). It would take about 6 months to bring up haemoglobin at this dose.

About  25mg of iron is delivered each day to the erythroid precursors for haemoglobin synthesis. Iron is a poorly absorbed micronutrient and stores are needed to  provide for sudden increase in demand as may be seen in patients with acute blood loss. Given the propensity of iron to cause free radical induced cellular injury, transport and storage systems capable of protecting the body from iron have evolved. Iron is transported bound to transferrin and stored as ferritin and haemosidin. In both the situations iron is bound to apoproteins (apotrasferrin and apoferritin) and this binding does not allow free radical generation.

Erythrocyte destruction takes place in the macrophages and macrophages have systems for the handling, storage and recycling of iron. Injectable iron preparations have a carbohydrate shell that prevents exposure of the plasma to free iron.  Injectable iron preparations are taken up by macrophages of the reticuloendothelial system by endocytosis. The iron is released and enters the macrophages iron pool. This iron has a fate similar to iron reaching the macrophage from other sources viz. intestinal absorption and erythrocyte destruction. Binding iron to carbohydrate shell has made it possible to administer as high as dose as 1000mg over as short a time as 15 minutes. This is a 125 fold increase over the amount of iron that can be administered without the carbohydrate shell.

Injectable iron preparations share a common structure. They have a core of iron oxide/hydroxide that is associated with a carbohydrate shell. The carbohydrate shell  keeps free iron from entering the plasma and in a way performs the same function as transferrin. The antigenicity of the shell and the strength of binding between the iron core and the carbohydrate shell determines the side effects and the maximum dose per injection.

Preparations of Injectable Iron

The preperations of injectable iron include

  1. Preparations with a strong association between iron core and the carbohydrate shell
    1. High-Molecular weight iron dextran
    2. Low -molecular weight iron dextran
    3. Ferric carboxymaltose
    4. Ferumoxytol
  2. Perperations with a weak association between iron core and carbohydrate shell
    1. Iron Sucrose
  3. Preperations that have a labile low molecular weight components
    1. Ferric Gluconate
    2. Iron-Sorbitol-Citric Acid Complex, Dextrin-Stabilized
Table 1 – parentral iron preparations
Drug Shell MW T1/2 Labile
Iron
Maximum
Dose and administration
HMW ID High moleculer weight dextran 265 60 1-2% Should be administered 1 hr after an intravenous test dose (0.5ml over at least 5 minutes) Maximum dose 20mg/kg. Administered as intravenous bolus 100mg/day slowly. A total dose infusion may be given over a prolonged period.
LMW ID  Low molecular weight dextan  165  20  1-2% Should be administered 1 hr after an intravenous test dose (0.5ml over at least 30 seconds). It may be administered as daily iv bolus of 100mg over 2 mins or a a total dose infusion over 3-4 hours may be administered 20mg/kg
Iron Sucrose  Sucrose 30-60  6  4-5% up to 300mg in a single dose, higher doses have been administered over as a prolonged infusion. May be administered undiluted as an iv bolus 200mg over at least 10 mins or as an infusion in 0.9% saline over 15-60 minutes
Ferric Gluconate  Gluconate  289-440  1  5-6% 125mg, iv bolus at 12.5mg/min or as a 1 hr infusion in 0.9% saline
Ferric Carboxy-maltose Carboxy-maltose  150  16  1-2% The maximum dose is 20mg/kg (max 1000mg). Doses of 200-500mg should be administered at 100mg/min, doses between 500mg and 1000mg should be administered over 15 minutes. It may be administered as an iv infusion diluted in 0.9% saline
Ferric Isomaltoside Isomaltoside 150  20  <1% May be administered as an intravenous bolus dose of 500mg un to three times a week at the rate of 50mg/min or 20mg/kg (maximum 1000mg) in 0.9% saline over 1 hour
Ferumoxytol Carboxy-methyl Dextran 750 15 <1% 510mg as a iv bolus at the rate of 30mg/sec. A second dose may be administered after 3-8 days

The parental iron preparations differ in the carbohydrate that surrounds the iron core. The therapeutic implications of these differences are:

  1. Antigenicity: Dextran is antigenic. Patinets may have performed antibodies to dextran or may develop antibodies during therapy. All iron preparations  containing dextran can give rise to anaphylaxis. The risk is greatest with high molecular weight iron dextran. Anaphylaxis may also be seen with low molecular weight iron dextran though the risk is lower and has also been reported with ferumoxytol that contains carboxymethyl dextran.
  2. Maximum dose per injection: All intravenous iron preparations tend to release labile iron. There is an inverse relationship between the amount of labile iron released and the strength of association between the iron core and carbohydrate shell. Higher the molecular weight of the iron preparation, stronger is the association. Labile iron is taken up by transferrin. Non-transferrin bound iron (NTBI) appears when the binding capacity of transferrin is overwhelmed. NTBI is responsible for tissue damage and restricts the dose of a injectable preparation that can be given in a single infusion. Iron preparations may be classified on the basis of strength of the associations between iron core and the carbohydrate shell. Iron dextran, ferric carboxymaltose and ferumoxytol, that have a high molecular weights have a tight binding between iron core and the carbohydrate shell, release up to 2% labile iron. These can be given in a large single dose and are suitable for total dose infusion. Iron sucrose has a weaker association between iron core and carbohydrate shell and has 4-5% labile iron. This limits the amount of drug that can be administered at one time to 300mg. Ferric gluconate is a large molecule but has two types of polymers. Lower weight polymers (about 18,000) have a weaker association between iron and carbohydrate limiting the dose to 125mg per dose.

Dose and Administration

The total dose of parenteral iron is calculated as follows

Total iron dose (mg) = weight (kg) X Hemoglobin deficit  X 0.24 + 500

Haemoglobin deficit (g/L) = Target Haemoglobin (g/L) – Actual Haemoglobin (g/L)

Adverse Effects

  1. Infusion Related Events: the risk of infusion related events (per million) is 0.6 for iron sucrose, 0.9 for ferric gluconate, 3.3 for low molecular weight dextran iron and 11.3 for high molecular weight iron dextran.  Iron sucrose has been safely administered to patients who having sensitivity to iron dextran.  Despite the fact that some studies suggest that low molecular weight iron dextran in as safe as iron sucrose, a test dose must be administered before any iron dextran preparation.
  2. Delayed Reactions to Intravenous Iron: A syndrome charecterized by fever, arthralgia and lymphadenopathy may be seen as a delayed consequence of intravenous iron therapy. Premedication with steroids may reduce the risk of this manifestation.

Further Reading

  1. Rodolfo Delfini Cançado, Manuel Muñoz. Intarvenous iron therapy: How far have we come? Rev Bras Hematol Hemoter. 2011; 33(6): 461–469.
  2. Hayat A. Safety Issues With Intravenous Iron Products in the Management of Anemia in Chronic Kidney Disease. Clin Med Res. Dec 2008; 6(3-4): 93–102.
  3. Peter Geisser and Susanna Burckhardt The Pharmacokinetics and Pharmacodynamics of Iron Preparations. Pharmaceutics. Mar 2011; 3(1): 12–33.

 

Clinical Manifestation of Iron Deficiency


The manifestations of Iron deficiency evolve insidiously and are multi-systemic. They include

Anaemia

Iron deficiency causes hypochromic microcytic anaemia. The anaemia has an insidious onset and the patient may become severely anaemic before symptoms of anaemia become evident.

Non-Specific Symptoms

Iron deficiency can cause fatigue, irritability, dizziness, breathlessness, and headache. One may attribute these symptoms to anaemia but  these symptoms are seen in patients with iron deficiency even in the absence of anaemia. Iron therapy has been shown to correct many of these manifestations.

Skin and Hair

Iron deficiency results in brittle nails that have longitudinal ridges. The nails become thin, brittle and become flat (platonychia) or concave (koilonychia). Hair may become thin and brittle.

Gastrointestinal System

Next to blood the effects of iron deficiency are most pronounced on the gastrointestinal system

  1. Tongue: Iron deficiency causes atrophy of the papillae of the tongue. The filiform papillae of the anterior part of the tongue are the first to be affected. The fungiform papillae of the posterior tongue atrophy later resulting in a smooth red tongue.  Papillary atrophy results in soreness of the tongue. The changes reverse after about 1-2 weeks of iron therapy.
  2. Mouth: Iron deficiency results in angular stomatitis. This anomalies is not specific to iron deficiency may be seen in pyridoxine and riboflavin deficiency.
  3. Dysphagia: Iron deficiency results in the formation of webs at the junction of hypopharynx and oesophagus. These manifest as dysphagia that has an insidious onset. The patients complains of discomfort on swallowing, initially for solids, at the level of the cricoid cartilage. Mild dysphagia may be corrected by iron replenishment but dysphagia persists in most patients despite iron replenishment and dilatation may be needed. Oesophageal webs predispose to carcinoma. (See Plummer-Vinson Syndrome/Peterson-Kelly Syndrome)
  4. Pica: Pica is craving for non-nutritive substances like chalk, paint and ice. Pagophagia, the craving for ice is a common form of pica.

Neuromuscular Symptoms

Iron deficiency impairs performance of muscles. Children with iron deficiency show irritability, are disruptive, have impaired attention span and may show scholastic impairment. Iron deficiency has also been shown to be associated with developmental delay, ischaemic stroke and raised intracranial pressure.

Effect on Immunity and Infections

Iron deficiency decreases the number of T lymphocytes and impairs phagocytosis. This however does not appear to result in an increased risk of infections.

Menstrual Anomalies

While menstrual anomalies can be a cause of iron deficiency, they can often be a consequence of iron deficiency. Only response to treatment can tell which of the two is the case in a given patient.

Skeletal Expansion

Young patients who have prolonged iron deficiency may develop bone changes line haemolytic anaemia or thalassaemia because of bone marrow expansion.

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.