# Presentation: 151691

## Iron Deficiency Anemia

Reema Batra, MD
George Washington University

- Reema Batra, MD
- George Washington University

## Essential Nutrients for Erythropoiesis

- Folic Acid
- Cobalamin
- Iron

## Essential Nutrients for Erythropoiesis

- Folic Acid	      Cobalamin       Iron

**Enzyme**

**Function**

**Source**

**Absorp.**

**Storage**

**Thymidylate **
**synthetase**

**Methionine **
**synthetase**

**Ferro-chelatase**

**DNA synth.**

**DNA synth.**

**Hb synth.**

**Vegetables, **
**fruit, liver**

**Meats, milk,**
**eggs**

**Meats, **
**fortification**

**Prox. Intest.**

**Prox. Intest.**

**Term. Ileum**

**Liver**

**Liver, kidney**

**Macrophages**

## Essential Nutrients, cont’d

- Folic Acid	   Cobalamin       Iron

**Dietary**
**content**

**Daily **
**absorption**

**20 mg**

**0.2 mg**

**0.002 mg**

**1.0-1.5 mg**

**Stores**

**5-10 mg**

**1-10 mg**

**500-1000 mg**

**1.0 mg**

**0.01 mg**

## Iron- essential nutrient

_**Reversible binding O**__**2**__**:**_** **
**	****	****	****	****hemoglobin**
**	****	****	****	****myoglobin**
_**Enzymes:**_**	****heme (cytochromes)**
**	****	****	****	****iron sulfur cluster (aconitase)**
**	****	****	****	****other (ribonucleotide reductase)**
_**Immunity:**_** ****	****free radicals  to destroy microbes**

## Iron- potentially toxic

**Highly reactive with O****2****; can cause fatal toxicity.**
**Cardiomyopathy**
**Liver cirrhosis**
**Endocrine abnormalities**

## Iron Metabolism: Broad Themes

** ****Absorption of iron is highly regulated to prevent excess iron from being absorbed.**
** ****No physiologic pathway for excreting excess iron exists.**

## Body Iron Compartments

|  | 60 kg F | 70 kg M |
| --- | --- | --- |
| Functional compounds |  |  |
| Hemoglobin | 1750 mg | 2300 mg |
| Myoglobin | 290 mg | 320 mg |
| Enzymes | 160 mg | 180 mg |
| Transferrin | 2.5 mg | 3 mg |
| Storage compounds |  |  |
| Ferritin & hemosiderin | 300 mg | 1000 mg |
| Total | 2500 mg | 3800 mg |

## Iron Requirements

**	****	****	****	****	*****Men*****           *****Women***
**Obligatory losses  ****	****	****1.0 mg/d    1.0 mg/d**
**Menstruation****	****  ****	****	****   0 mg/d    0.5 mg/d**
**Total losses****	****	****   ****	****1.0 mg/d    1.5 mg/d**
**Iron absorbed****	****    ****	****	****1.0 mg/d    1.5 mg/d**

## Iron Absorption

- 1.  Heme iron (meats) absorbed better than non-heme    iron (grains).
- 2.  Gastric acid keeps Fe reduced to Fe++ form that is absorbed.
- 3.  Occurs in proximal small bowel
- 4.  Increases with:  - high erythropoiesis
-                            - low iron stores
- 5.  Inhibited by inflammation, tea

## (18 mg Fe/day)

** ****intestine**
**(1 mg/day)**

**Erythroid precursors **
**in bone marrow **
**produce hemoglobin **
**(18 mg Fe/day****)**

**Macrophages in spleen**
** ****remove and break down **
**senescent RBCs**
**(18 mg Fe/day)**

**Transferrin in plasma carries Fe back to bone marrow **
**(17 mg/day)**

## Iron Metabolism

- Fe circulates in plasma bound to _transferrin_ (approx 0.1% of body Fe)
- Fe stored intracellularly as _ferritin_.
- 3.  Serum Fe concentration and transferrin saturation reflect Fe delivery to erythroid precursors.
- 4.  Serum ferritin concentration reflects stores in macrophages.

## Iron Transport 

**into Plasma**

## Receptor-Mediated Endocytosis

**Andrews N, NEJM 1999;341:1986**

**Receptor-Mediated Endocytosis**

## Normal Peripheral Smear

**Normal Peripheral Smear**

## Iron Deficiency Anemia

**H=hypochromic RBC; p=pencil RBC; T=target RBC; M=microcytic RBC**** **
**The Lancet 2000;355:1260**

**Iron Deficiency Anemia**

## Iron Deficiency Anemia

**Iron Deficiency Anemia**

## Iron Deficiency Anemia

**Iron Deficiency Anemia**

## Causes of Iron Deficiency

- 1.  _Chronic blood loss_
-  gastrointestinal (carcinoma, ulcers, diverticuli, a-v malformations, hookworm)
-  genitourinary (menorrhagia, bladder ca)
-  pulmonary (hemoptysis, pulmonary hemosiderosis)
-  frequent blood donors (220 mg Fe lost with each blood donation

## Causes of Iron Deficiency

- 2.  _Dietary insufficiency_
- rapidly growing children
- women of child-bearing age.
- _Malabsorption_
- s/p gastrectomy
- s/p resection proximal small bowel
- Crohns disease
- Celiac disease

## Causes of Iron Deficiency

- 4.  _Pregnancy and lactation_
- _Hemoglobinuria_
- secondary to intravascular hemolysis:
- paroxysmal nocturnal hemoglobinuria
- runner’s anemia

## Fe Deficiency:  Clinical Manifestations

- Impaired growth, psychomotor development
- Fatigue, irritable,  work productivity
- Pica
- Dysphagia, esophageal web (Plummer-Vinson or Patterson-Kelly Sx)
- Koilonychiae, glossitis, angular stomatitis

## Fe Deficiency: Lab Findings  

- CBC
-  RDW, platelets
-  MCV, MCH, MCHC, RBC, Hb, Hct
- Retic count not 
- Serum tests
-  Fe , Tf Sat, Ferritin (< 12 g/L)
- TIBC, transferrin, transferrin receptor

## Fe Deficiency: Lab Findings-II  

- Bone marrow aspirate
- - Absent macrophage Fe
- -  sideroblasts
- - Erythroid hyperplasia

## BM aspirate: iron stain, increased macrophage iron

**BM aspirate: iron stain, increased macrophage iron**

## BM aspirate: iron stain, absent macrophage iron

**BM aspirate: iron stain, absent macrophage iron**

## Fe Deficiency: Management

- First, look for source of blood loss. Rule out malignancy. *Test stools for occult blood.*
- 	*Gastrointestinal*		*Genitourinary*
- Colorectal			- Endometrial
- Gastric			- Cervical
- Esophageal			- Bladder
- Hepatoma
- Second, correct cause of blood loss.

## Treatment

- General principles
- Iron absorption occurs at the duodenum and proximal jejunum
- Extended release capsules or enteric coated capsules get absorbed lower parts of the GI tract and are not very effective
- Iron salts should not be given with food because the salts bind the iron and impair absorption

## Treatment

- Iron should be given two hours before or four hours after the ingestion of antacids
- Iron is best absorbed as the ferrous salt in a mildly acidic medium
- Can give with tablet of Vitamin C
- Iron preparation used should be based upon cost and effectiveness with minimal side effects
- Cheapest is iron sulfate (65 mg of elemental iron)

## Treatment

- GI tract symptoms is directly related to the amount of elemental iron ingested
- These symptoms may be less in the iron elixir preparation.

## Oral Iron Therapy

- Most appropriate oral iron therapy is use of a tablet containing ferrous salts
- Ferrous fumarate, 106 mg elemental iron/tab
- Ferrous sulfate, 65 mg elemental iron/tab
- Ferrous gluconate, 28-36 mg iron/tab
- Recommended daily dose= 150-200 mg/day of elemental iron
- No evidence that one preparation is better than another

## Side effects

- 10-20% patients nausea, constipation, epigastric distress and/or vomiting
- Treatment
- Smaller dose of elemental iron, or switch to elixir form
- Slow increase in dose from 1 tablet to 3 tablets per day
- Take tablet with meals (may decrease absorption)

## Duration of Treatment

- Depends on physician
- May discontinue when hgb level is normal
- Some continue for six months after the hgb is normal

## Treatment Failures

- Incorrect diagnosis
- Pressure of coexisting disease (ACD)
- Noncompliance
- Difficulty with absorption (antacids, enteric-coated tablets)
- Iron loss > amount ingested
- Iron malabsorption (Celiac disease, H. Pylori)

## Parenteral Iron Therapy

- Indications
- Rarely given when patients cannot tolerate oral form
- If iron loss exceeds oral iron replacement
- Inflammatory bowel disease
- Dialysis patients
- Anemic cancer patients

## Available Preparations

- Iron dextran (INFeD, Dexferrum)
- 50 mg elemental iron/mL, given either IM or IV
- INFeD is low molecular weight, Dexferrum is high molecular weight
- Side effects: Usually in ~ 5% patients
- Local rxns: Pain, muscle necrosis, phlebitis
- Systemic: Anaphylaxis seen in 1%, fever, urticaria, arthritic flares
- Side effects seen more with high molecular weight preparations.

## Available Preparations

- Ferric Gluconate (Ferrlecit, 12.5 mg iron/mL)
- Iron sucrose (Venofer, 20 mg iron/mL)
- Both can only be used in IV formulation
- Ferric gluconate has less allergic reactions as compared to Iron dextran (3.3 vs. 8.7 allergic events per 1 million doses per year)
- Iron sucrose also has less side effects, even if there is a prior history of rxn to Iron dextran

- Faich, G. Am J  Kidney Dis 1999; 33:464

## IM Iron

- Usually slow iron mobilization and occasionally incomplete
- Therefore usually not used, even though available in the Iron dextran form

## IV Iron

- Most commonly used in dialysis setting
- If Ferric gluconate used, test dose not recommended anymore
- 2 mL of ferrlecit, diluted in 50 mL of NS and infused over 60 min.
- If no reaction seen, up to 10 mL is given in any setting, diluted in 100 mL of NS and given over 60 minutes

## Calculation of IV Iron Dose

- Calculate iron defecit
- 1 gram of hemoglobin = 3.3 mg of elemental iron
- 60 kg woman with hgb of 8 g/dL needs IV iron in the form of iron sucrose (20 mg/mL)
- Normal blood vol 65 mL/kg, thus her blood volume is 3900 mL
- Normal hgb is 14 g/dL, therefore hgb deficit is 6 g dL, with a total of 234 grams (6 x 39 dL)

## Calculation of IV iron Dose

- Each gram of hemoglobin = 3.3 mg of iron
- Total RBC iron deficit is 772 mg (234 g x 3.3)
- Iron sucrose has 20 mg/mL, therefore, this would require a total of 38.6 mL

## Oral Iron Therapy

- Dose
- 100-200 mg elemental Fe/d (adults)
- 5.0 mg elemental Fe/kg per day (children)
- administer on empty stomach if tolerated
- Duration
- 1-2 months to correct anemia
- 2-4 additional months to replenish stores
- Side effects- diarrhea, constipation, cramps

## Oral Iron Therapy

- 4.  Preparations
- FeSO4 (325 mg FeSO4 = 65 mg Fe)
- one tab tid
- GI side effects
- risk of poisoning in small children
- Carbonyl iron
- elemental Fe powder- 150 mg/d
- Similar side effects; safer

## Parenteral Iron Therapy

- Indications (rare)
- Unable to absorb oral iron
- Intractable non-compliance to oral iron
- Preparations
- Fe dextran (risk of anaphylaxis)
- 50 mg/ml, 100 mg/d im/iv
- Sodium ferric gluconate complex
- Given with EPO in hemodialysis pts.