IDA

Fig 8. Suggest an overview of Iron metabolism and its principal regulator.

So how does one make a realistic diagnosis of iron restricted erythropoiesis and what parameters are of value in making this diagnosis are shown in table 2.Some of these tests are available like sTfR but not routinely. As hematologist community in India become more and more aware about the challenges of its commonest problem IDA these tests would become available and they are required in specialized complex situations to recognize presence of treatable iron restricted erythropoiesis. What would be the impact of serum Hepcidin levels on diagnosis and management of iron-restricted erythropoiesis will depend on its availability and interpretability of Iron restricted erythropoiesis. Newer parameters can judge very early presence of Iron-restricted erythropoiesis, flow cytometry based determination of retic count can help determine (CHr) Reticulocyte Hb Content and this is a real time parameter (48hrs), while % hypochromic cells is regarded as a time averaged marker (20-120 days) of Iron restricted erythropoiesis.

What does various Fe parameters suggest?

Serum iron & TIBC & TSAT (Transferrin SATuration) suggest availability of Iron to erythron. Hemoglobinization stops once TSAT falls below 16%. Serum Ferritin represents Iron Stores. CHr real time measure of Hb changes normal range 36 pg; < 29 suggest iron restricted erythropoiesis.; % hypochromic cells > 5% suggest iron restricted erythropoiesis. The sensitivity and specificity of all tests in detection of IDA and Iron restricted erythropoiesis is variable and in a complex situation the surest test for the presence of Iron restricted erythropoiesis is a THERAPEUTIC RESPONSE TO Iron therapy. A rise in Hb of > 1.0 gm./dl over a mth is considered a positive response.

What issues exist in treatment of iron deficiency & Iron restricted erythropoiesis?

1. Oral Iron vs. parenteral Iron

2. Which oral Iron preparation is the best? Ferrous vs. Ferric vs. Carbonyl Iron vs. colloid Iron vs. iron polymaltose

3. Ferrous Sulphate, Fumarate, Ascorbate, Gluconate, Succinate, Citrate

4. Role of Vitamin C.

5. Role of combinations; e.g. B12, Folic acid, Cu++, Zinc, Sorbitol

6. Enteric coated vs. plain

7. Best time to take Iron 1 hr before food, with food, with juice

8. Frequency; 1 tab thrice a day, twice a day or once a day at night time

9. How long? 6 or 3 mths after normal Hb achieved

10. What is normal Hb?

11. How do we monitor patients, how frequently and why

12. What adverse reactions occur to oral Fe therapy and how do we handle them.

13. Over all response to oral Fe therapy.

14. IM vs. IV

15. IM Iron: is there any role for IM Iron? should we give it up?

16. IV Iron. HMW ID vs. LMW ID

17. Ferric Gluconate (FG)

18. Iron Sucrose (IS)

19. Newer Iron preparations; Ferumoxytol, Iron carboxymaltose, Iron isomaltoside.

20. Frequency of administration, can total dose be given? What are the IV Iron infusion protocols?

21. Cost of treatment.

22. Side effects

The best oral iron treatment is the simplest Ferrous Sulphate; there is not much to choose among various salts of Iron. Knowing the elemental Iron content is very important so as to ensure adequate intake of elemental Iron of approximately 200 mg per day. Ferrous iron is preferred over Ferric form. Ferric iron needs to be converted to ferrous form before it can be absorbed. Gastric acidity is important to form ferrous iron and majority of Iron is absorbed in the 1^st 100 cm of duodenum & Jejunum. In normal, iron replete individuals, 5 to 15% of dietary iron is absorbed while in Iron deficient individuals 20 to 30% of oral Iron is absorbed. Among the ferrous salts there is no significant difference in absorption among various forms of Ferrous salts like ferrous Sulphate, gluconate, fumarate, succinate. The absorption is poor if the iron is in form of carbonate, Citrate or pyrophosphate. Ferric forms of Iron are available as Iron polymaltose complex or colloidal iron. Iron Polymaltose Complex is a novel polysaccharide-iron complex, contains non-ionic ferric iron and polymaltose in a stable complex. This facilitates a controlled absorption of the ferric iron when it comes in contact with the mucosal cell surface. Being non-ionic, it does not release any free radicals and thus takes care of all the toxic effects found due to the release of free radicals by the traditional ionized iron salt preparations. It does not interact with the food components and other medications and so, unlike ferrous salts, there is no decrease in bioavailability of Iron Polymaltose Complex. Carbonyl Iron has to first be solubilized by gastric acidity to ferrous form and then absorbed; a very small proportion of carbonyl Iron is actually available for absorption. Colloidal Iron is ferric Hydroxide salt in colloidal form and has the highest Iron content 52.26%. Vitamin C can improve absorption by 30% approximately 200 mg of Vitamin C is required for 30 mg of elemental Iron.

Iron should be given in 3 divided doses preferably 1 hr before meal if there is intolerance it can be given along with food. But food contains phytates and substances that can decrease iron absorption.. Concomitant use of Antacids, Calcium Supplements, Coffee, eggs, food or medications containing bicarbonates, carbonates, oxalates, phosphates; milk or milk products, tea containing tannic acid, whole grain bread and cereals will decrease absorption of oral iron & thus should not be administered with in 1 hr before or 2 hrs. after ingestion of these substances. Gastric acidity is necessary hence atrophic gastritis or Proton pump inhibitors or Helicobacter Pylori infection can affect iron absorption. Certain drugs may interfere with absorption of Iron and should not be given concomitantly like cimetidine, Desferal, Dimercapol, Etidronate, Fluoroquinolones, pancreatin, penicillamine, tetracycline and Zinc supplements; there should be a gap of at least 2 hrs. after administration of iron.

Since only 25 to 30% of oral iron is absorbed and absorption decreases with correction of IDA do not decrease dose of iron as pt’s Hb improves. Patients with gluten-induced enteropathy may not absorb Fe very well. Also patients with associated AOI (Anemia of Inflammation) due to high serum Hepcidin levels have low absorption of iron due to down regulation of DMT1. There may be a case of giving oral Fe at nighttime as decreased motility may allow for more absorption and mild gastric & GI discomfort may be slept over. Oral iron administered twice a week works but is not widely used.

Response is judged by rise I Hb by at least 1 gm. over 1 mth. Retic responses is seen on day 3, peaks by day 5 and subside by day 10. The commonest side effects to oral Fe is GI toxicity that can be divided in to upper GI or Lower GI toxicity. Lower GI toxicity is either constipation or diarrhea. Though seen in almost 10 to 15% of patients it can be overcome by changing the brand and is possibly not related to Fe therapy. It does not warrant discontinuing oral Fe therapy. Upper GI toxicity is related to gastric discomfort. There is feeling of bloating, discomfort and severe gastritis. Severe upper GI toxicity is an indication to offer parenteral iron therapy. Upper GI toxicity may be related to free iron radicle generation with Fe. Duration of treatment is at least 3 to 6 mths after maximum Hb is attained to build up reserves of iron.

Certain diagnostic tests may be affected by Iron administration (Oral or IV)

1. Stool Occult Blood would be falsely positive

2. Serum Iron estimation with in 4 hrs. of oral Iron is erroneous. Or 1 to 2 weeks after iron dextran injection

3. Tc99m labeled phosphates & phosphonates decreased uptake

4. Ga67 Gallium Citrate

5. MRI Scan cannot be done up to 2 to 3 mths after Ferumoxytol injection.

Compliance is a major problem in treatment of Iron deficiency by oral Fe therapy. Certain situations oral Fe may be difficult like patients with IBD, pregnancy, Fe restricted erythropoiesis like AOI, on going blood loss. In these situations and need for prolonged treatment make oral iron therapy a less than ideal treatment for iron deficiency and iron restricted erythropoiesis.

Certain diseases are exacerbated by oral Iron and it may be contraindicated in rheumatoid Arthritis, inflammatory bowel disease, diverticulosis, peptic ulcer, asthma & hepatitis.

Oral iron should not be given along with parental Iron therapy. It should be started after a week after stopping IV Iron.

Parental Iron Therapy:

IM & IV both preparations are available. There is a dramatic increase in use of IV Iron with better understanding of Iron metabolism and understanding of Iron restricted erythropoiesis. Introduction of ESA’s (Erythropoietin Stimulating Agents) increased the use of IV Iron exponentially. So today we see more of nephrologists using IV iron therapy in CKD & patients on Hemodialysis.

Indications for parental Iron therapy:

1. Upper GI Intolerance to Oral Iron therapy.

2. Concomitant blood loss in IDA (Telangiectasia’s, Bleeding piles, Menorrhagia)

3. Poor Compliance & Logistical considerations.

4. AOI (Anemia of Inflammation)

5. Anemia of CKD

6. Anemia associated with IBD

7. Anemia with RA

8. Pregnancy

9. Gluten Induced Enteropathy.

10. CIA (Cancer Induced Anemia)

11. CCF & others.

IM Iron use:

IM Injection needs to be given by Z technique; 2 preparations were very popularly used; Iron Dextran (Imferon) & Iron Sorbitol citric acid complex Dextrin stabilized (Jectofer). Inj. Iron Sorbitol has a low mol. Wt. It is rapidly absorbed from the injection site and is stable in tissue fluids. Two-thirds of the injected dose is absorbed from an i.m. site, within 3 hours, most of it directly into the blood circulation and, to a lesser extent, via lymphatics. Within approximately 10 days, little or no residue of iron remains at the injection site. Clearance from circulation is rapid and a proportion of iron is available for transfer to transferrin & thus to the erythron. Absorption is followed by a rapid increase in serum iron concentration. Maximum plasma levels are attained in about 2 hours and return to normal values within 24 hours. This pattern of absorption is repeated in day-by-day injections and appears to be constant from patient to patient. A proportion of absorbed Iron is rapidly bound to transferrin while RES takes up majority & a small proportion is filtered by glomeruli and taken up by proximal convoluted tubule. Iron sorbitol, a low molecular weight complex, contains 6% dialyzable iron. If given i.v. this fraction will rapidly saturate the transferrin and the excess can cause a toxic reaction, i.e., hypotension, flushing, dizziness and vomiting. When iron sorbitol is given i.m. the iron release proceeds at a controlled rate, greatly reducing the potential for a toxic reaction. Dose of Iron sorbitol should not exceed 1.5 mg/kg/day as excess dose can result in toxicity. 30% of Iron sorbitol is excreted through kidneys. Since there are a few reports of abortion after iron sorbitol its use is not recommended in the 1^st 3 to 4 mths of pregnancy. (Available in India as Inj Jectofer but now Inj Jectofer content has been changed to Iron Sucrose & Iron Sorbitol is available as Inj Jectocos 1.5 ml, 50 mg/ml costing Rs 25/-)

Imferon iron dextran for IM use has very little renal excretion and can also cause allergic anaphylactic reactions like Iron sorbitol. Iron dextran is absorbed from the injection site in to capillaries and lymphatic system. The majority of IM injection is absorbed with in 72 hrs. The remaining iron will be absorbed in 3 to 4 weeks. IM injections are painful and can form hematomas, local discoloration, abscess formation and there is a risk of tumor formation. IM injections also can result in anaphylactic reactions. Commonest side effects besides local pain are jt pain, arthralgia, and arthritis in a proportion of patients.

In view of newer safer IV Iron being available is it necessary to continue with IM preparations of Iron is a question which medical fraternity will have to address soon.

No parental iron should be co administered with oral iron as it increase toxicity of iron.

IV Iron preparations:

IV iron has been 1^st introduced in 1932 as fe(OH)3, High Mol. Wt. Iron Dextran (HMW ID) was introduced in 1954 followed by Low Mol. Wt. Iron Dextran (LMW ID) in 1991. IV Ferric Gluconate was introduced in 1999 followed by Iron Sucrose in 2000. Ferumoxytol was introduced in 2009 while Iron Carboxyl Maltose and Iron isomaltoside are in development.

The initial hitch with HMW ID was development of allergic anaphylactic reactions due to formation of Abs or preformed Antibodies, which could be fatal. Introduction of LMW ID decreased the risk of anaphylaxis substantially. Current newer IV Iron preparations like Iron Sucrose, Ferric Gluconate are much safer and they do not need any test dose prior to their administration. But their biggest limitations are that they need to be given every day and the dose should not exceed 125 mg / day, as higher doses result in vasoactive reactions with drop in BP, acute edema of extremities and acute onset of diarrhoea. Due to this they need to be administered frequently requiring frequent patient visit. LMW ID has the advantage that it can be used to give total dose Iron and one can administer > 1000 mg in a single infusion. Ferumoxytol the newest kid on the block can administer 510 mg of elemental iron over 1 to 3 minutes without the need for test dose prior to administration.

IV iron preparations and their properties are listed in Table 2. Adapted from Hematology 2010 page 338.

The Indications for IV Iron therapy are already listed but it’s use increased tremendously with the introduction of ESA’s Erythropoiesis Stimulating Agents. The understanding of pathophysiology of Anemia Of Inflammation (AOI) (see fig 9), and the concept of Iron restricted erythropoiesis led to an upsurge in use of IV Iron. At about the same time, introduction of IV Sucrose and approval of Ferric gluconate in USA, which was already widely used in Europe; marked the availability of a safe IV Iron in which the BLACK BOX WARNING in the package insert was not there and there was also no need to do test dose.

All IV Iron has a core iron oxyhydroxyl gel stabilized by outer shell of carbohydrate that maintain fe in a colloid form and ensure a slow release of Iron. The currently approved IV iron differs in the core size and the identity and density of outer carbohydrate shell. Pharmacokinetics differs depending on the strength of the complex. Stronger the complex slower the release of Iron, lesser the possibility of saturating transferrin and thus no excess free iron to cause any toxicity. IV Iron when administered mixes with plasma and is phagocytosed by the RES. Outer carbohydrate shell is degraded and the iron is stored as ferritin and then released in by exporting it out in to the circulation via ferroportin iron exporter. (See fig 1 & 5). Once in circulation it binds transferrin and transported to erythroblast where it enters transferrin cycle and is utilized in formation of Hemoglobin (See fig 5).

HMW ID is not available and the only available Iron Dextran is LMW ID. So this should help remove confusion, which lots of physicians have about various iron dextran molecules available. During infusion there are certain symptoms, which may seem to suggest anaphylactic reactions. Patients complain of acute chest and back tightness; but if there is no accompanying hypotension, wheezing, stridor or periorbital edema than one can safely continue IV Iron without any reaction. Pre medication with anti histaminic paradoxically increase chances of reaction. Those likely to have reactions may benefit by premedication with Steroids.

One of the advantage of IV LMW ID is that it can be given as IV daily boluses as well as for TDI (Total Dose Iron) of 1000 mg over 1 to 4 hrs. This allows one to correct anemia with lesser no of injections especially allowing TDI to home care dialysis patients.

Ferric Gluconate (FG) millions of doses used with good safety. It is given as IV bolus with doses of 125 mg IV Short infusion. Max dose of 200 mg may be given over 1 hr. higher doses result I vasoactive reactions as mentioned before. 80% of drug iron is released to transferrin as a mononuclear ionic iron with in 24 hrs. of administration. FG cannot be used unlike LMW ID for TDI therapy.

Iron Sucrose (IS) is a very safe IV iron preparation that needs to be given as IV bolus over 2 minutes. Ideal bolus dose of IS is 200 mg but doses up to 300 mg can be given safely. Do not exceed a max dose of 300 mg. at higher doses adverse events like hypotension, nausea and low backache may be seen. Like FG millions of doses of IS have been used and is approved for Anemia of CKD (Chronic Kidney Disease); AOI (Anemia of Inflammation), IDA and pregnancy, anemia post operative setting. IS can help reduce the dose of ESA’s and save cost in CKD patients. IV IS can not be used like FG for TDI therapy.

So though we now have safer IV Iron preparations, which do not require test dose prior to administration still we need to give them in small boluses and that necessitates frequent administration and inconvenience of frequent visits to hospital. Also it becomes much more expensive. The generic drug cost approximately Rs 300/-, while Original drug may cost double; add to this the cost of administration of equivalent amount and say if 10 doses per patient are required, it amounts to a total cost of approximately Rs. 6000 to 10,000/- per patient, for correction of IDA. Considering even 0.1% of India’s population requiring therapy with IV Iron it can send an economist in to Tizzy and budgets & GDP’s haywire. So the search for a preparation which is equally safe and can allow us to give large amount of Iron safely continues.

3 new IV Iron preparations, Ferric Carboxymaltose (FC), Iron Isomaltoside (II) and Ferumoxytol are now available, since 2009 and they may fulfill these needs. Ferumoxytol is approved for use in USA but not in Europe; while Ferric Carboxymaltose (FC) & Iron Isomaltoside (II) is approved for use in Europe awaiting approval in USA.

Ferric Carboxymaltose (FC) was the 1^st agent approved and doses of 500-1500 mg can be given safely over 15 min. current recommendation is to give FG 1000 mg over 15 min. NO test dose is required. Approved for use in Europe, Asia and Australia. Trials in patients with Congestive Cardiac Failure, AOI, anemia with inflammatory bowel disease and IDA have established its efficacy. However US FDA failed to approve it because of higher incidence of cardiac death in the treatment arm and unexplained incidence of Hypophosphatemia. Approval is pending results of larger studies which are adequately powered.

Ferumoxytol has received US FDA approval for use in correction of anemia of CKD and AOI. The dose is 510 mg as a bolus over 1 to 3 minutes. NO TEST dose is required. TDI in a patient can be administered by 2 to 3 very short boluses. Published safety profile is consistent with FG, IS and LMW ID. Not yet approved in Europe. More safety data awaited and post marketing surveillance data is observed. Its use in other indications is being studied and may revolutionize the way we give IV. Iron. One caution which a clinician need to be aware of is that since ion remains in circulation for a long time MRI cannot be done for 3 mths after administration of Ferumoxytol.

Iron Isomaltoside (II) was approved for use in Europe in Nov 2009. It is given in a dose of 20 mg/kg more rapidly than Iron Dextran and no test dose is required. II bind iron strongly and thus iron release is slow with controlled release of bioavailable to iron proteins and minimal free iron release resulting in expected minimal toxicity. II is not approved for use in USA and is being tried in all iron restricted erythropoiesis setting. TDI is feasible to give with II.

Summary:

We as hematologist have large no of issues, which we need to sort out so as to, allow us to treat the commonest problem in hematology iron deficiency anemia in a judicious cost effective manner. We need to ask questions as to is oral iron ideal way of treatment and how do we overcome the pharmaceutical gimmick of promoting one preparation over the other. Oral iron treatment is cumbersome we need to find a better approach. I.M. Parental Iron therapy does it have any role in todays setting when safer IV Iron preparations are available? In India pregnant lady still receive IM Iron sorbitol. & IM Iron Dextran. Is it time to discard I.M> Iron therapy all together? IV Iron indications have expanded and we are finding its effectiveness in anemia of CKD, AOI, anemia with IBD, anemia with RA, anemia with CCF and CIA (Cancer Induced Anemia). Anemia of pregnancy is increasingly being treated with IV Iron adding to the cost and frequency of visits to obstetrician. A lot of over dosage of IV Iron especially iron sucrose, ferric gluconate with infusional hypotension and vasoactive reactions are seen in India due to lack of awareness about dosage and administration of newer IV Iron preparations. Education is the key and our obligation to society demands that we rationalize through this maze of choices and spread the knowledge. I fore see a phase of tremendous increase in use of IV Iron followed by rationalization of its use.

AVAILABLE IV IRON PREPARATIONS & THEIR COST IN INDIA>

Table 2:

Blood 2010;116(23); 4754-4761

Fig 9: pathophysiology of AOI is described in this cartoon; various factors & cytokines play role in ACD; Three factors play an important role; A) High Hepcidin levels resulting in sequestration of Iron in to tissues with very little iron in circulation; this is an innate response to prevent access of iron to the invading organism. B) Suppression of Epo production & Hypo responsiveness to endogenous erythropoietin. C) Shortened red cell survival. A low TSAT , 20% with elevated serum Ferritin > 100 ug/L, low serum Iron suggest AOI.

Fig 10: Intra Cellular Regulation of Iron

Fig 11 : Proteins with IRE and being regulated by Intracellular Iron

Fig 11: Factors regulating Hepcidin Expression:

Fig 12 : Genetic HEmachromatosis.