Clinical Features of Megaloblastic Anaemia


Megaloblastic anaemia is a macrocytic anaemia resulting from the deficiency of vitamin B12 or folic acid characterised by the presence of megaloblasts in the bone marrow. It has haematological and neurological manifestations. The haematological manifestations are seen with folate as well as vitamin B12 deficiency. Folate deficiency in adults does not affect the nervous system.

Cobalamin deficiency is slow and “pure”. Folate deficiency is rapid and “impure”. Deficiecy of vitamin B12 occurs because of loss of intrinsic factor resulting in an isolated defect of B12 absorption. No other nutrients are affected. The body stores of B12 can last months. This results in B12 deficiency being a slow and “pure” deficiency. Symptoms come on slowly, over months. Folate deficiency evolves relatively quickly and is most commonly because of alcoholism or malabsorption. It is associated with other deficiencies and is rapid and “not pure”.

 

Manifestationf o megaloblastic anaemia

Figure 1. Clinical Manifestations of Megaloblastic Anaemia

Haematological Manifestations

Haematological changes resulting from vitamin B12 deficiency and folate deficiency are indistinguishable. Megaloblastic anaemias are macrocytic anaemia but macrocytosis is not specific to megaloblastic anaemia. It is however exceptional for other diseases characterised by macrocytosis to have an mean capsular volume (MCV) > 110fl.  This value can considered the threshold above which an anaemia is unlikely to be anything other than megaloblastic anaemia.

The earliest change in a megaloblastic anaemia is macrocytosis. This precedes changes in erythrocyte indices. Changes in mean capsular haemoglobin (MCH) follow and then the MCV rises. Haemoglobin usually falls after the MCV increases to >97 fl. As the severity of anaemia increases the peripheral smear shows aniscytosis and poikilocytosis, nucleated cells, Howell-Jolly bodies and Cabot’s ring. Microcytes and erythrocyte fragments that represent dyserythropoiesis may be seen. Polychromasia is absent and this distinguishes megaloblastic anaemia from haemolytic anaemia.

The term megaloblatic anaemia is a misnomer. The disease is actually a panmyelosis.  Erythroid, myeloid and megakaryocytic series are affected. Thrombocytopenia and leucopenia (neutropenia and to a lesser extent lymphopenia) usually occur late in the course. It is uncommon for patients with mild anaemia to have platelets and neutrophils but occasionally changes in leucocytes and/or platelets may dominate.

Iron deficiency or β-thalassaemia trait result in microcytosis and hypochromia and may incidentally co-exist with megaloblastic anaemia. Co-existence of either of these diseases with megaloblastic anaemia may mask macrocytosis of megaloblastic anaemia. Presence of hypersegmented neutrophils in a patients with normocytic normochromic anaemia should raise the suspicion of a megaloblastic anaemia co-existing with Iron deficiency or β-thalassaemia trait.

Neurological Manifestations

Cobalamine deficiceny causes neurological dysfunction. Folate deficiency causes symptoms only in children. Children with inborn errors of folate metabolism may have myelopathy, brain dysfunction and seizures.

The neurological manifestations of B12 deficiency are a result of a combination of upper motor neuron manifestations from subacute combined degeneration of the spinal cord, sensory and lower motor neuron manifestations from peripheral neuropathy and neurophychiatratic manifestations. Subacute combined degeneration of the spinal cord (SACD) is a degerative disease of the spinal cord involving the posterior and lateral column (corticospinal and spinoceribellar tracts) that starts in the cervical and the thoracic region.

The earliest neurological manifestations are impaired sense of vibration and position and symmetric dysesthasia that involve the lower limb. This is frequently associated with sensory ataxia. With progression spastic paraparesis develops. The patients have brisk knee reflexes, reflecting an upper motor neuron involvement and depressed ankle reflex, reflecting a peripheral neuropathy. Bladder involvement is unusual. Some patients may have optic atrophy.

Neuropsychiatric manifestation include memory loss, depression, hypomania, paranoid psychosis with auditory and visual hallucinations.

Other manifestations

Skin and nails can show pigmentations. Mucosa of the villi undergoes megalobkastic change resulting in temporary malabsorption.

Response to therapy

Haematological Recovery

  • Day 1: Feeling better
  • Day2-3: Reticulocytosis appears
  • Day 7-10: Peak retuculocytosis
  • Day 15 onwards: Neutrophilic hypersegmentation disappears
  • Day 56 (8 weeks): Blood counts become fully .normal

Neurological Recovery

Neurologic improvement begins within the first week also and is typically complete in 6 weeks to 3 months. Its course is not as predictable as hematologic response and may not be complete.

 

 

Evolution and Spread of HbS


The gene for β globin (OMIM  is present on chromosome 11 (11p15.4) along with other globin genes (ε, γ, γ and δ). This is known as the β-globin cluster . Individuals carrying identical genes on the β-globin gene cluster may not have identical DNA sequences in non-codeing regions of the DNA of the cluster. The non-coding regions include segments of DNA between genes and introns within genes. . Differences in DNA exist between individuals every 1000-2000 bases in the form of single nucleotide polymorphisms (SNPs). Single nucleotide polymorphisms are variations in a single nucleotide that occurs at a specific position in the genome. Many of these differences have no consequences on gene expression because either they do not result in change in amino acid sequence or they occur in regions of DNA that neither code for the gene nor regulate the gene. SNPs evolve by spontaneous mutations over time. The lesser the number of such differences between two individuals closer the individuals are the each other genetically (and in terms of evolution). Fewer differences in SNPs between individuals mean a more recent common ancestor.

One of the meanings of the word haplotype is a pattern of SNPs. A haplotype may be considered as a DNA “environment” in which the gene(s) occurs. This “environment” is created by the sequence of single nucleotide polymorphisms in which the gene(s) exists. As mentioned above differences in SNPs (and hence the “environment” the gene(s) exist in) evolve by spontaneous mutations over period of time. Fewer the differences between the “environments” the genes occurs in the more the likelihood that they come from related individuals.

HbS results from a single base substitution in the codon 6 of the β-globin gene. GAG becomes GTA resulting in substitution of valine for glutamate. This change results in a haemoglobin that crystallizes in hypoxic conditions resulting in a haemolytic anaemia. HbS occurs in diverse population groups including African, Mediterranean, Middle-Eastern and Indian. Is the haplotype of the HbS gene in these regions similar?

The HbS mutation occurs on five different haplotypes four African and one Arab-Indian. The mutation is the same (GAG to GTA on codon 6) but the SNPs are different. The haplotypes are

  1. Senegal: The Senegal HbS haplotype is found in Atlantic West Africa and Portugal
  2. Benin: The Benin HbS haplotype is found Central West Africa, Northern Africa and Mediterranean Europe (Greece, Sicily)
  3. Central African Republic or Bantu: The Central African Republic or Bantu is found in South Central and Eastern Africa
  4. Cameroon: The Cameroon haplotype is found in the Eton ethnic group of eastern Cameroon
  5. Arab-Indian: The Arab-Indian haplotype is the only non-African phenotype of HbS found in the eastern oasis of Saudi Arabia and India.

Origin of Haplotypes

There are two theories about the origin of haplotypes. The first, and the more accepted one, states that the five haplotypes arose from five independent mutations. An alternative hypothesis states that HbS mutation occurred only once and spread to other haplotypes by gene conversion.

 

Haplotypes and Severity of Symptoms

Symptoms of sickle cell anaemia are a consequence of crystallisation of haemoglobin under hypoxic conditions. HbF inhibits sickling. Patients with high HbF have fewer symptoms. The Arab-Indian and the Senegal haplotype are associated with higher HbF levels (17% and 12.4% respectively). In general patients carrying these haplotypes have milder symptoms than the Bantu or Benin haplotypes (Blood 2014; 123: 481)

 

Haplotypes and Human Migrations

Trade, conquests and human migrations (voluntary and slave trade) have disseminated the African haplotypes beyond Africa.

  1. The Mediterranean: Most of the Mediterranean (Greece and Scilly) has the Benin haplotype. This reflects pre-historic migrations from Central West Africa along the then fertile Sahara to North Africa. From here it spread to the Mediterranean via the interactions (Trade and wars) between the two regions. The only exception is Portugal. Portugal has the Senegal haplotype which reflects the trading contacts between Portugal and Atlantic West Africa (Angola and Mozambique).
  2. Americas: Neither the native americans nor the original European settlers to the Americas carried the HbS gene. HbS was imported to the Americas with the slaves from Africa. Jamaica was an important slave import hub and records for where tthe slaves arrived from are available. Jamaica has 73% Benin haplotype, 17% Bantu and 10% Senegal haplotypes. These numbers are close to the actual number of slaves who arrived in Jamaica from regions of Africa where these haplotypes are prevalent. Similarly the distribution of haplotype correspond to the origins of slaves in Baltimore and South Carolina (Mariam Bloom. Understanding Sickle Cell Disease, Page 34).
  3. Arab or Indian: It is not clear if the Arab-Indian haplotype originated in India or Saudi Arabia. But considering that all of tribal India has only one haplotype but the East and West Arabian Peninsula have different haplotypes it is possible that the haplotype originated in India.
  4. Spread to Other Parts: As opposed to the era of slave trade modern migration of people in the recent past have been voluntary. These populations have spread across the world as have those form mediterranean but to a lesser extent. These migrations have introduced the HbS gene in areas where it was not indigenous.

 

Anaemia with Hyperbilirubinaemia


A 49-year-old female presented with dyspnoea on exertion of 1 month duration. Examination reviled pallor and icterus. There was no lymphadenopathy, clubbing, koilonychia, platonychia, petechiae or purpura. There was no oedema of feet. The pulse was 90/min and the blood pressure 130/70 mm of Hg. Examination of the respiratory, cardiac and nervous systems did not show any abnormality. There was no organomegaly.

The haemoglobin was 4.9 g/dL with an erythrocyte count 1.37 x 1012/L, haematocrit of 16%, MCV of 116.78 fL, MCH of 35.77 pg and MCHC 30.63 of g/L.  The leucocytes count was 2800 with 35% neutrophils and 65% lymphocytes. The platelet count was 90 x 109/L. The peripheral smear showed macrocytosis and anisocytosis. Hypersegmented neutrophils were seen. The reticulocyte count was 3%.

The bilirubin was 2.1 mg/dL with a direct bilirubin of 1.8mg/dL and an indirect bilirubin of 0.3mg/dL. The Lactate dehydrogenase was 1417IU (normal 105 – 333 IU/L).

Anaemia and unconjugated hyperbilirubinaemia are characteristic of haemolysis. Does this patient have haemolytic anaemia?

Haemolysis shortens erythrocyte lifespan and results in increases haemoglobin breakdown. Haemoglobin is made of heme and globin. Heme consists of porphyrin ring at the centre of which is iron in the ferrous state. Iron released from catabolism of heme is reused. The porphyrin ring is catabolised to bilirubin. The bilirubin is transported to the liver for conjugation and excretion (see haemoglobin catabolism). Patients of haemolytic anaemia have unconjugated hyperbilirubinaemia because the increased bilirubin production overwhelms the hepatic bilirubin conjugation capacity.

One of the characteristics of megaloblastic anaemia is ineffective erythropoiesis. Ineffective erythropoiesis is defined as a sub-optimal (fewer) production of mature erythrocytes from a proliferating pool of immature erythroblasts. Each immature erythroblast produces less than the optimal number of erythrocytes because of premature death of erythroid precursors including haemoglobinized precursors. The haemoglobin released from haemoglobinized erythroid precursors is catabolised in the same manner as haemoglobin released from lysed erythrocytes (see haemoglobin catabolism). Megaloblastic anaemias are associated with unconjugated hyperbilirubinaemia because of death of haemoglobinized erythroid precursors.

The treatment of haemolytic anaemia and megaloblastic anaemia are different? How does one differentiate megaloblastic anaemia from that because of haemolytic anaemia? Does this patients have a haemolytic anaemia or megaloblastic anaemia?

Haemolytic anaemia is characterised by shortened erythrocyte survival. Erythrocytes survival is estimated by the use of radionucleotides something that is not possible at most centres. In clinical practice, a shortened erythrocyte survival is inferred from a high reticulocyte count. Reticulocytes are erythrocytes that have been produced in the preceding 24 hours. The erythrocytes survival is about 120 days and about 1% of erythrocytes are produced every day. Consistent with this the normal reticulocyte count is 0.5-1.5%.In patients of haemolytic anaemia, ddestruction of erythrocytes is matched by an increased production by the bone marrow. This manifests as reticulocytosis (see reticulocyte count). Megaloblastic anaemia occurs because of decreased production of erythrocytes and this manifests as reticulocytopenia. The difference between haemolytic anaemia and megaloblastic anaemia is the reticulocytosis in the former reticulocytopenia in the latter. This patient had a high reticulcoyte count but after correction both the reticulocyte production index [0.43] and corrected reticulocyte count [1.07%] were low excluding haemolysis. This patient was evaluated for megaloblastic anaemia.

The haemogram has clues to differentiate between haemolytic anaemia and megaloblastic anaemia. These include

  1. A very high MCV: The MCV is very high. Patients with haemolytic anaemia have a mild elevation in MCV. An MCV value >110fL is almost exclusively found in megaloblastic anaemias because of folate and/or B12 deficiency.
  2. Pancytopenia: B12 and folate deficiency impair DNA synthesis impairing erythrpoieis, myelopoiesis and megakaryopoiesis. Nutritional megaloblastic anaemias because of vitamin B12 and/or folate deficiency may show pancytopenia.
  3. Hypersegmented neutrophils (>5% neutrophils with >5lobes) is a feature of megaloblastic anaemia

Other features of megaloblastic anaemia include rise serum transferrin receptor, increased serum iron, serum ferritin and methemalbumin levels. Like haemolytic anaemia the serum haptoglobin is low and the LDH high. LDH levels in megaloblastic anaemia can ve very high.

This patients had a low serum B12 and was treated with parental B12 (1mg alternate day for 5 doses) and was evaluated for cause of vitamin B12 deficiency. As Schilling’s test was not available a diagnosis of pernicious anaemia was made by documenting gastric atrophy and anti-parietal cell antibodies.

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.

Classification of β-Thalassaemia


β-Thalassaemia is a term applied to describe heterozygous group of diseases that are characterised by a decrease in the production of β globin  chain. Over 200 mutations in the β-globin gene and promoter regions that cause β-thalassaemia have been recognised. Thalassaemic alleles that produce no β-chain are designated β0 and those producing some β chain are designated as β+.  Before the genetic basis of thalassaemia was understood the disease was classified according to the clinical presentation and natural history of the disease. The genetic defects need to be determined for prenatal diagnosis but the clinical patterns remains relevant for clinical management of β-thalassaemia.

Based of the severity of disease three patterns of disease have been identified, thalassaemia major, thalassaemia minor and thalassaemias intermedia

  1. Thalassaemia Major: Thalasaemia major is a transfusion dependent anaemia that usually appears early in life, often in the first year. Anaemia is associated with splenomegaly, skeletal deformities and growth retardation. Iron overload develops by the end of second decade unless chelation is used. Unless treated with blood transfusion and chelation or allogeneic stem cell transplant, it is a fatal illness. There is a severe impairment of β-chain synthesis. Genetically these patients may be β0β0, β0β+ or β+β+.
  2. Thalassaemia Minor: patients with thalassaemia minor are asymptomatic. They are diagnosed when a complete haemogram is performed as a part of antenatal care or as a pert of investigations of another illness. Genetically they me be β0β or β+β.
  3. Thalassaemia Intermedia: Thalassaemia intermedia has a clinical presentation between that of thalassaemia major and thalassaemia minor. It is a very heterogeneous condition. The patient is not transfusion dependent but anaemic with a low and stable haemoglobin. Transfusion may be needed during periods of stress like infection and pregnancy. Advancing age is also associated with transfusion requirement. This may in part be due to hyperplenism associated with splenomegaly. The genetics of thalassaemia intermedia are complex. It may result from a mild β chain defect or because of interaction of β chain defects with other defects of haemoglobin synthesis

Transferrin and Transferrin Receptors


Free iron is toxic by its ability to generate oxygen free radicals and cause damage to macromolecules. Iron in transported in the plasma bound to transferrin. Uptake of transferrin by the cell is mediated by transferrin receptors of which there are two types transferrin receptor 1 (TfR1) and transferrin receptor 2 (TfR2).

Transferrin

Transferrin (Tf) is an iron transport protein synthesised by the liver responsible for iron transport of iron. It is coded by the gene TF on 3q22.1 (OMIM 190000) There are 30 variants of Tf . Tf C is found in majority of individuals. Tf is synthesised in the liver as a single chain 80kDa in size. Each transferrin can bind two ferric atoms in a pH dependent manner. Alkaline pH promotes binding and acidic pH promotes release. Tf may exist as api-Tf, monoferric Tf and diferric Tf. Normally Monoferric Tf dominates. Diferric Tf dominates in iron overload.

Atrasnferrinaemia is characterised by hypochromic microcytic  anaemia with iron overload.

Transferrin Receptor

Two transferrin receptors have been identified TfR1 and TfR2. TfR1 is found in all cells  while TfR2 is found mainly in hepatocytes

Transferrin Receptor (TfR1) encoded by the TFRC gene on 3q29 (OMIM: 190010). It consists of two similar 760 amino acid peptide chains held together by a disulfide bone.  It binds transferrin in a pH dependent manner binding at physiological pH and releasing at acidic pH. On binding transferrin the the receptor is endocytosed. A V -type proton ATPase acidifies the endocytosed vesicles. Acidification weakens the binding of iron with transferrin releasing the iron in the vesicle.  The released ferric iron needs to be reduced to ferrous iron by  STEAP3. STEAP3 is an endosomal ferrireductase. Reduces iron is transported to the cytosol by DMT1.  TfR1 is recycled back to the surface where it is free to bind another transferrin.

Transferrin Receptor (TfR2) shares about 45% homology with TfR1. It had a lower affinity for transferrin and it’s role in transferrin uptake is not clear. It is involved in regulating hepcidin. Mutations of TfR2 are associated with haematochromatosis

 

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.