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IRON DEFICIENCY ANEMIA: WHAT THE

DIETITIAN NEEDS TO KNOW

Sandra I. Austhof, MS, RD, LD, CNSC

2015 Dietitians in Nutrition Support Symposium

Baltimore, MD

June 12, 2015

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OBJECTIVES

Discuss iron metabolism and the etiology of iron deficiency anemia.

Be able to interpret the Complete Blood Count (CBC) and iron laboratory tests to determine iron deficiency anemia verses anemia from inflammation.

Identify the correct iron treatment for oral and intravenous therapy.

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IRON METABOLISM Found in every living cell

60% in the form of hemoglobin in circulating erythrocytes 20% stored as ferritin, primarily in the liver 15% myoglobin ~5% enzymes and other proteins

Transports oxygen, DNA synthesis, electron transport, cell proliferation

Major iron supply for hemoglobin synthesis: Diet Recycling from old erythrocytes by macrophages

Tightly regulated to prevent iron toxicity > tissue damage

1-2 mg lost and absorbed daily to maintain normal homeostasis No excretory pathway for iron except blood loss & basal losses

(sloughing of skin cells & mucosal surfaces, sweat, urine, stool)

Chan LN, et al. JPEN 2014;38:656-672. Abbaspour N, et al. J Res Med Sci 2014; 19(2):164-174.deBack DZ, et al. Front Physiol 2014;5:1-11.

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IRON ABSORPTION Duodenum and proximal jejunum (~1-2 mg iron daily) Colon - only one tenth of duodenal iron absorbed in colon.

Heme: animal sources (15-35% absorbed) Non-Heme: plant sources (2-20% absorbed)

Enhances absorption: Hinders absorption:Ascorbic acid and meat, Milk and dairy products,poultry, fish. calcium, eggs, tea, coffee,

spinach, legumes, and fiber.

Antacids, H2 antagonists, proton pump inhibitors.

Concurrent intake of zinc or manganese supplement.  Chan LN, et al. JPEN 2014;38:656-672.

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ABSORPTION

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ERYTHROPOIESIS Erythropoietin triggers stimulation of red blood cell production

stimulating heme and globin synthesis.

Hemoglobin synthesis not only requires adequate supply of iron, but also, Copper, Vitamin B12, Folate, Biotin, Vitamin B6, Zinc, and Vitamin A, and normal production of protoporphyrin and globin.

Rate of hemoglobin synthesis is determined by the availability of transferrin iron and levels of intracellular heme.

Heme synthesis begins in mitochondria by a series of biochemical reactions

Fe++ combines with protoporphyrin to form Heme Excess porphyrin binds to zinc (zinc protoporphytin)

Globin synthesized in cytosol combines with Heme once it exits the mitochondria.

Khan AA, et al. Biochim Biophys Acta. 2011; 1813(5): 668–682DeLoughery TG. NEJM 2014;371:1324-1331.Chan LN, et al. JPEN 2014;38:656-672.Abbaspour N, et al. J Res Med Sci 2014;19(2):164-174

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IRON DEFICIENCY ANEMIA

Most common form of anemia

A condition where there is a lack of iron delivery to the heme group of hemoglobin, the protein that transports oxygen in blood

Blood cells are abnormally small (microcytic) and pale (hypochromic)

DeLoughery TG. NEJM 2014;371:1324-1331.

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ANEMIA FROM INFLAMMATION

The restriction of iron delivery to the heme group Renal production of Erythropoietin suppressed Hepcidin production blocks release of iron from enterocytes & other

cells

Obesity – emerging as risk factor for Fe def anemia1 Inflammatory state – increased Hepcidin Impaired duodenal absorption

1Aigner E, et al. Nutrients 2014;6:3587-3600.

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STAGES OF IRON DEFICIENCY ANEMIA

Stage 1 – Negative iron balance (iron intake does not meet daily need; normocytic, normochromic)

Stage 2 - Iron Depletion (iron stores exhausted; Hgb still normal)

Stage 3 – Iron-deficient erythropoiesis (erythrocytes deficient in iron; hypochromic)

Stage 4 – Iron deficiency anemia (severe iron depletion blood levels cannot meet daily needs; Hgb depleted)

Clark S. Nutr Clin Prac.2008;23:128-141

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ETIOLOGY OF IRON DEFICIENCY Increased loss

Acute or chronic bleeding Multiple surgeries

Increased demand Rapid periods of growth – pregnancy, newborns, infants, young

children, adolescents, menstruating women.

Decreased intake or absorption Lack of dietary iron or consuming foods that inhibit absorption Reduction of gastric acid (due to proton-pump inhibitors, H2

blockers) Damage to intestinal lining of duodenum/prox jejunum (e.g., Crohn’s,

Celiac disease) Long-term parenteral nutrition therapy without iron therapy

  Decreased production of red cells

Erythropoietin deficiency (ESRD) – due to lack of erythropoietin production by kidneys to promote formation of RBC in bone marrow

It’s important to know the cause of anemia before treating.

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CLINICAL MANIFESTATIONS Feeling weak or tired more often

than usual.

Headaches / Problems concentrating.

Brittle or spoon-shaped nails (koilonykia).

Desire to eat ice or other non-food things (pica).

Pale skin, gums, and nail beds.

Shortness of breath.

Rapid or irregular heartbeats.

Glossitis - Smooth, shiny, reddened tongue.

Clark S. Nutr Clin Prac. 2008;23:128-141.

12WHO; http://www.who.int/vmnis/indicators/hemoglobin.pdf

Lab Test Normal values Comments

Hemoglobin • Women ≥12.0 g/dL

• Pregnant women ≥11.0 g/dL

• Men ≥13.0 g/dL

• Iron-containing protein in RBC that carries oxygen.

• Most commonly used.• Inexpensive.• Easy to perform.

Hematocrit • Women >36 % • Pregnant women >33 % • Men >39 %

• Percentage of blood volume that is made up of red blood cells.

Mean Corpuscular Volume • 80-100 fL • Average volume of red cells.• Low in iron deficiency

anemia indicating small RBCs.

Red Cell Distribution Width • 11.5-15 % • Represents the heterogeneity of

red blood cell volume width. • Helps determine cause of

anemia.• Elevated in Fe Def Anemia

(anisocytosis-red blood cells of unequal sizes).

LABORATORY DATA COMPLETE BLOOD COUNT (CBC)

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EXAMPLES OF COMPLETE BLOOD COUNT

Component Latest Ref RngWBC 3.70 - 11.00 k/uL 4.87RBC 3.90 - 5.20 m/uL 4.91Hemoglobin 11.5 - 15.5 g/dL 13.3Hematocrit 36.0 - 46.0 % 39.7MCV 80.0 - 100.0 fL 80.9MCH 26.0 - 34.0 pG 27.1MCHC 30.5 - 36.0 g/dL 33.5RDW-CV 11.5 - 15.0 % 13.5

Component Latest Ref Rng  

WBC 3.70 - 11.00 k/uL 5.27RBC 4.20 - 6.00 m/uL 3.95 (L)Hemoglobin 13.0 - 17.0 g/dL 9.4 (L)Hematocrit 39.0 - 51.0 % 30.3 (L)MCV 80.0 - 100.0 fL 76.7 (L)MCH 26.0 - 34.0 pG 23.8 (L)MCHC 30.5 - 36.0 g/dL 31.0RDW-CV 11.5 - 15.0 % 15.9 (H)

Component Latest Ref Rng  

WBC 3.70 - 11.00 k/uL 8.77RBC 3.90 - 5.20 m/uL 3.83 (L)Hemoglobin 11.5 - 15.5 g/dL 11.1 (L)Hematocrit 36.0 - 46.0 % 34.6 (L)MCV 80.0 - 100.0 fL 90.3MCH 26.0 - 34.0 pG 29.0MCHC 30.5 - 36.0 g/dL 32.1RDW-CV 11.5 - 15.0 % 13.5

Component Latest Ref Rng 5/7/2014

WBC 3.70 - 11.00 k/uL 5.98RBC 3.90 - 5.20 m/uL 3.56 (L)Hemoglobin 11.5 - 15.5 g/dL 11.0 (L)Hematocrit 36.0 - 46.0 % 35.8 (L)MCV 80.0 - 100.0 fL 100.6 (H)MCH 26.0 - 34.0 pG 30.9MCHC 30.5 - 36.0 g/dL 30.7RDW-CV 11.5 - 15.0 % 17.4 (H)

BA

C D

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IRON STUDIES Lab Test Normal values Comments

Iron • Male: 60-170 mcg/dL • Female: 50-170 mcg/dL

• Measure of all iron in the body bound mostly to transferrin 

• Low in iron deficiency anemia

Ferritin • Male: 12-300 ng/mL • Female: 12-150 ng/mL

• Stored iron • Low in iron deficiency anemia • Most sensitive and cost-

effective indicator of iron deficiency anemia  

• May be elevated during infection even if iron stores are low • High levels may suggest

anemia of chronic disease since normal or elevated levels can occur during inflammation, malignancy

or conditions causing organ or tissue damage (e.g., arthritis, hepatitis)

TIBC • 240-450 mcg/dL • Measures amount of circulating transferrin that is available to bind iron

 • Elevated in iron deficiency

anemia

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IRON STUDIES (CON’T)

Lab Test Normal values Comments

Transferrin saturation • 20-50% • The percentage of how much iron is actually bound to available transferrin

 • Serum iron ÷ TIBC x 100 = % Sat Example: 50 ÷ 475 x 100 = 10.5% • Low in iron deficiency anemia

Reticulocyte count • 0.5-1.5% • Measures circulating immature RBC

• Low in Fe def anemia.

Zinc (Erythrocyte) Protoporphytin (ZPP)

• ≤40 µmol/mol heme

• Elevated in Fe Def Anemia (>70 mmol/mol heme)

• If iron levels low, zinc binds with protoporphyrin IX to produce ZPP instead of heme

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IRON STUDIES (CON’T)

Lab Test Normal Values CommentsSerum Transferrin Receptors (TfR)

• Male: 2.2-5 mg/L

• Female: 1.9-4.4 mg/L

• Levels not established for pregnant women, children.

• A glycoprotein that transfers circulating iron into RBCs

• Elevated in Fe Def Anemia due to increase in transferrin receptors on RBCs to maximize Fe uptake

• Sensitive and not affected by inflammation

• Not widely available

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EXAMPLES OF IRON STUDIES

Component Latest Ref Rng  Iron 30 - 140 ug/dL 89TIBC 210 - 415 ug/dL 348Transferrin Saturation 11 - 46 % 26Ferritin 9.0 - 150.0 ng/mL 90.9

A

Component Latest Ref Rng 11/25/2008Iron 30 - 140 ug/dL 19 (L)TIBC 210 - 415 ug/dL 221Transferrin Saturation 11 - 46 % 9 (L)Ferritin 18.0 - 300.0 ng/mL 419.8 (H)

Component Latest Ref Rng 11/21/2013

Iron 30 - 140 ug/dL 18 (L) TIBC 210 - 415 ug/dL 406Transferrin Saturation 11 - 46 % 10 (L)Ferritin 18.0 - 300.0 ng/mL 17.0 (L)

B

C

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LAB NORMAL LEVELS

FE DEFICIENCY without ANEMIA

FE DEFICIENCY with ANEMIA

ANEMIA of CHRONIC DISEASE

Hemoglobin (g/dL) Men Women

 >13>12

 >13>12

 <13<12

 <13<12 

MCV (fL) 80-100 80-100(normal)

<80(low)

<80 (low to low normal)

Ferritin (ng/mL)  

100 ± 60 

10 – 20(low) 

<10 (low)

>100(high)

Iron (µg/dL) 115 ± 50 <60 – 115(low)

<40(low)

Low 

TIBC (µg/dL) 330 ± 30 360(high)

410(high)

Low 

Transferrin Sat (%) 35 ± 15 <15 – 30(low)

<15(low)

Low-normal 

Camaschella C. NEJM. 2015;372:1832-1843.Clark S. Nutr Clin Prac. 2008;23:128-141.

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TREATMENT > GOAL TO RESTORE HEMOGLOBIN AND IRON STORES

Blood transfusion indicated if Hbg <7.0 g/dL with SOB, extreme fatigue.

Oral therapy• Preferred line of treatment• Safer, cost-effective• GI-related side effects

common• Elemental iron/d dose 100-

200 mg• Ferrous salts best absorbed• Take with ascorbic acid 250

mg (or ½ cup OJ)

IV therapy• Provides faster response rate• Hgb <10 g/dL• Lack of response to oral iron• Malabsorption states (e.g.,

IBD, Celiac disease, SBS)• Iron loss too great (ongoing

bleeding)• Given as intermittent IV or

injection

Chan LN, et al. JPEN 2014;38:656-672.Bayraktar UD et al. World J Gastroenterol 2010;16:2720-2725.

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ORAL TREATMENTOral Iron Treatment

Brand Name Tablet dose Elemental Iron

Ferrous sulfate Feosol

Feosol elixir

325 mg

5 mL

65 mg

44 mg

Ferrous gluconate

Fergon

Fergon elixir

325 mg

5 mL

36 mg

34 mg

Ferrous fumarate

Feostat

oral suspension

325 mg

5 mL

106 mg

100 mg

Iron polysaccharide(better tolerated)

Niferex

Niferex Elixir

150 mg

5 mL

100 mg

100 mg

Goal: 100 – 200 mg Elemental Iron per day Enteric-coated iron tabs better tolerated but less effective (may not release in

duodenum)

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IV TREATMENT IV Iron Treatment

Brand Name Single Dose Comments

Iron Dextran –high molecular weight

DexFerrum No longer recommended.

(Black Box Warning)

>Compatible with 2 in1 PN>Can be given in 1 high dose>Highest reaction rate>Test dose required

Iron Dextran –low molecular weight

INFeD(50 mg/mL elemental Fe)

500-1000 mg over 1 hr

>Compatible with 2 in1 PN>Can be given in 1 high dose>Test dose required

Ferric Gluconate FerrlecitNulecit(12.5 mg/mL elemental Fe)

Max 125 mgover 20-30 mins

>No test dose required>Can cause hypotension>Administration requires several clinic visits to provide 1000 mg

Iron Sucrose Venofer(20 mg/mL elemental Fe)

200 mg over 60 mins

>No test dose required>Best tolerated>Can cause hypotension>Expensive >Administration requires several clinic visits to provide 1000 mg

Ferumoxytol Feraheme(30 mg/mL elemental Fe)

510 mg over15 mins

>Can cause severe hypotension>Administration: 2 doses 3-8 days apart

Ferric carboxymaltose

Injectafer(50 mg/mL elemental Fe)

Up to 750 mgover 15 mins

(<50 kg give 15 mg/kg on 1st day)

>Approved by FDA July 2013>Can cause hypophosphatemia and HTN

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CALCULATING IV IRON REPLETION DOSE

Iron (mg) = 0.3 x Body weight (lbs) x (100 – [actual Hgb (g/dl) x 100/desired Hgb]

Example: (Weight-154 lbs; Hgb–10.3g/dL; Target Hemoglobin: Men 13.5

Women 12.5

Iron (mg) = 0.3 x 154 lbs x (100 – [10.3 g/dL x 100/12.5]

Iron (mg) = 46.2 x (100 – [82.4])

Iron (mg) = 813 mg

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IV IRON TREATMENT

Two examples of how to give 813 mg IV iron…

1.) IV Iron Sucrose: 200 mg per dose per week given over 60 mins for a total of 4 doses

2.) IV Iron Dextran (LMW):

a.) Test dose required (25 mg by slow IV push)

b.) 1000 mg per dose given over 1 hour.

i.) extra mg iron given can go to stores

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MONITORING• Pica or restless leg syndrome should disappear once therapy begun.

• Hemoglobin should begin to improve by 1-2 g/dL the first 2 weeks then

0.7 -1 g/dL per week.

• Ferritin may take up to 32 weeks to improve.

• If Reticulocyte count increases within 4 weeks, treatment is probably effective.

• Inadequate response may be related to continued blood loss (e.g., heavy menses or analgesic use), inflammation, ineffective absorption, or poor compliance.

• Once hemoglobin normal, monitor CBC and iron studies every 3-4 months up to a year.

• Continue therapy until iron stores replete.

Clark SF. Nutr Clin Prac. 2008;23:128-141.

Chan LN, et al. JPEN 2014;38:656-672.

DeLoughery TG. NEJM 2014;371:1324-1331.

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CASE STUDY A 42 year old female with a history of ulcerative colitis and

heavy menstrual losses was admitted to the hospital for fatigue and weakness. Her surgical history showed that she had total abdominal colectomy one year ago.

A diet history is obtained which shows that she consumes hot cereal with a banana and hot tea for breakfast; pasta and canned fruit for lunch; and chicken or fish, potatoes or rice with a cooked vegetable for dinner. She avoids red meat and craves ice chips.

Her CBC reveals: Hemaglobin-10.3, Hematocrit-25.0, Mean Cell Volume-77, Red Cell Distribution Width-17%, C-reactive protein: 1.0.

Weight: 60 kg (132 lbs); Heart rate: 105; Respiratory rate: 19; Blood pressure: 125/85.

You suspect iron deficiency anemia. You examine the patient using the Nutrition-focused physical assessment.

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QUESTION 1

What physical characteristics are you looking for to confirm a diagnosis of iron deficiency anemia?

A.) Pallor, easy pluckable hair, koilonychia

B.) Pallor, koilonychia, glossitis

C.) Koilonychia, angular stomatitis, dry skin

D.) Koilonychia, bleeding gums, glossitis

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QUESTION 2

What laboratory data would be best to order next to confirm iron deficiency anemia?

A.) Ferritin, red blood cell count, serum iron, transferrin saturation percent 

B.) Ferritin, serum iron, red cell distribution width, total iron binding capacity 

 C.) Ferritin, total iron binding capacity, serum iron, transferrin saturation percent 

D.) Ferritin, transferrin saturation percent, total iron binding capacity, mean cell volume

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QUESTION 3

What is the most effective iron treatment for this patient?

A.) Oral ferrous sulfate one 325 mg tab three times per day

B.) Intravenous iron sucrose 200 mg/dose each week for 5 doses over 5 weeks.

C.) Oral ferrous gluconate one 125 mg tab per day

D.) Intravenous infusion of low molecular weight iron dextran 1000 mg over 3 hours

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QUESTION 4

The patient received 325 mg ferrous sulfate TID, however, developed nausea and constipation 3 weeks into the therapy and had to stop. What would be the next best iron therapy? 

A.) Intravenous iron sucrose 200 mg/dose each week for 5 doses over 5 weeks.  

B.) Oral ferrous gluconate one 150 mg tab twice per day  

C.) Oral iron polysaccharide two 150 mg tabs per day 

D.) Oral ferrous fumarate one 325 mg tabs four times per day 

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QUESTION 5

The patient tolerated her new iron treatment and has been taking it for 2 months. Which of the labs listed below would you expect to be in normal range at this point?

A.) Ferritin and hemoglobin 

B.) Reticulocyte count, ferritin

C.) Hemoglobin, reticulocyte count  

D.) Hemoglobin, serum iron

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SUMMARY Fe Deficiency Anemia most common form of anemia

Diagnosis is confirmed with Hemoglobin and Ferritin levels due to highest accuracy in identification

Dietitian completes Nutrition Focused Physical Exam to confirm clinical diagnosis

Oral iron attempted first

IV iron used if oral iron not tolerated, malabsorptive state, severe case of iron deficiency anemia

Close monitoring required to restore Hemoglobin and iron stores

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QUESTIONS