Describe Pathophysiology of Iron absorption and elimination Define Iron Deficiency Anemia Describe Causes, Laboratory and Diagnoses of Iron Deficiency Anemia in Adults Discuss Non-Pharmacological Treatment Discuss Pharmacological Treatment and Management of Iron Deficiency

1. Treatment of
Iron Deficiency Anemia
in Adults
Dieu LinhThiVo. CaliforniaTouro University. COP2019
Kaiser San Jose. Fall 2017 - Community Practice Rotation

2. Iron DeficiencyTrending
• Dosing may be appropriate with EVERY OTHER DAY rather than DOSING
DAILY
IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin”. J. Clin. Invest. 113:1271–1276 (2004). doi:10.1172/JCI200420945.
Moretti et. Al. “Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women.” 22 OCTOBER 2015 x VOLUME 126, NUMBER 17. © 2015 by The American Society of Hematology
Possible rationals
• Dosing Daily orTwice daily increase serum Hepcidin
level
• Hepcidin is a protein that negatively regulate intestinal
iron absorption and iron recycling by macrophages
à↓Iron absorption
• RCTs shown no significant different in correcting
anemia with dosing 15mg, 50mg vs 150mg, but there is
a significant increase in AEs of abdominal pain, nausea,
vomiting, constipation and black stools with higher
dosing.
• Un-absorbed iron may alter the intestine microbiota
which increase concentration of pathogens and
associate with infections

3. November 2017. Practice Changing Updates
Consideration
Oral iron supplements increase HEPCIDIN and decrease iron absorption from daily or twice-daily
doses in iron-depleted young women.
Intervention • 54 nonanemic young women with plasma ferritin ≤20 µg/L
• (1) a dose-finding investigation with 40-, 60-, 80-, 160-, and 240-mg daily
• (2) a three 60-mg Fe doses , twice-daily dosing (2 doses in the morning and 1 dose
in the afternoon) vs once daily dosing (three 60-mg Fe once daily)
Outcomes • Doses ≥60 mg, resulted in ↑ serum HEPCIDIN (P<.01) and fractional iron
absorption was ↓ by 35% to 45% (P<.01)
• A sixfold increase in iron dose (40-240 mg) only resulted in a threefold increase in
iron absorbed (6.7-18.1 mg)
• Absorption from dosing twice daily was not significantly greater than from once
daily
Conclusion • Lower dosage decrease side effects and maximize fractional iron absorption
Moretti et. Al. “Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women.” 22 OCTOBER 2015 xVOLUME 126,
NUMBER 17. © 2015 byThe American Society of Hematology

4. November 2017. Practice Changing Updates
Consideration
Iron absorption from oral iron supplements given on CONSECUTIVE versus ALTERNATE days and as SINGLE
morning doses versusTWICE-DAILY split dosing in iron-depleted women: two open-label, randomised controlled
trials.
Intervention • Two prospective, open-label, RCT in women aged 18-40 years with serum ferritin ≤25μg/L
(Zurich, Switzerland)
• (1) 60mg QAM x14d vs 60mg QoD x28d
• (2) 120mg q8amx14d vs 60mg BID x14d
Outcomes • Cumulative fractional iron absorptions of 16.3% in consecutive-day vs 21.8% in the
alternate-day (p=0.0013), and cumulative total iron absorption of 131.0 mg vs 175.3 mg
(p=0.0010) respectively
• No significant differences were seen in absorption with dosing once vs twice daily.
• Twice-daily divided doses resulted in a higher serum hepcidin than once-daily dosing
(p=0.013)
Conclusion • Dosing twice daily increase serum hepcidin concentration and decrease iron absorption
Stoffel Et. Al. “Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two
open-label, randomised controlled trials.” © 2017 byThe Lancet Haematology

5. Learning Objectives
• Describe Pathophysiology of Iron absorption and elimination
• Define Iron Deficiency Anemia
• Describe Causes, Laboratory and Diagnoses of Iron Deficiency Anemia in
Adults
• Discuss Non-Pharmacological Treatment
• Discuss PharmacologicalTreatment and Management of Iron Deficiency

6. Pathophysiology and Distribution of Iron in the Body
• Why do we need iron?
• Iron is an important element in helping
production of hemoglobin in RBC and
protein myoglobin for muscle cells. Iron
is also a crucial element for many proteins
and enzymes that are important for energy
metabolism and immunity.
• The body is containing approximately
45mg/Kg of elemental iron; of which,
(shown in table)
• 2/3 is in the hemoglobin form
• 15-20% in storage form
• 10% as myoglobin
• 5% as other iron containing enzymes
• Iron is tightly regulated and circulating in
a closed form, thus losses and gain is
almost equal.
Schrier et. Al., “Causes and diagnosis of iron deficiency and iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
Schrier et. Al., “Treatment of iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
Normal Distribution of Iron
Content in the Body
70 Kg Men 60 Kg Women
Iron Stores –Transferrin, Ferritin,
Hemosiderin
0.7g 0.3g*
(*about 20% of
menstruating women
have no iron stores)
Hemoglobin (RBC) 2.5g 1.9g
Myoglobin (Muscles) 0.14g 0.13g
Heme Enzymes 0.01g 0.01g
TOTAL 3.35g 2.34g

7. What’s Iron Deficiency?
• Is defined as A REDUCTION IN SERUM HEMOGLOBIN due to the DEFICIENCY OF
IRON STORES in the body

8. Risk Factors of Iron Deficiency
Schrier et. Al., “Causes and diagnosis of iron deficiency and iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
Schrier et. Al., “Treatment of iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
• ↑ demands (infancy, adolescence, menstrual blood loss, pregnancy, blood donation)
• ↓ intake (resulting from poverty, vegetarian, etc.)
• ↓ absorption (Gi ulcer, IBS, H. Pylori infxn)
• Drugs induced iron-deficiency: (not limited to..)
• Antibiotics
• NSAIDs
• Salicylates
• Glucocorticoids
• PPI
• Anticancer drugs
• Others; Insulin, Ranitidine, MTX,Triamterene

9. Clinical Signs and Symptoms of
Iron Deficiency
• Typical Symptoms:
• Fatigue, weakness, headache, irritability, exercise intolerance, exertional dyspnea,
vertigo, angina pectoris (rare)
• Atypical Symptoms:
• Pagophagia (pica for ice or craving for ice)
• Beeturia (red in urine after eating beets)
• Complications
• Pallor (pale)
• Dry or rough skin
• Blue sclerae
• Atrophic glossitis with LOSS OFTONGUE PAPILLAE
• KOILONYCHIA (spoon nails)
• RBC Morphology:
• MICROCYTIC, HYPOCHROMIC, irregular size and shape
Atrophic glossitis
Koilonychia (spoon nail)
Schrier et. Al., “Causes and diagnosis of iron deficiency and iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
Schrier et. Al., “Treatment of iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017

10. Staging of Iron Deficiency
NORMAL IRON DEFICIENCY WITHOUT ANEMIA IRON DEFICIENCY WITH MILD
ANEMIA
SEVERE IRON DEFICIENCY WITH
SEVERE ANEMIA
Marrow reticuloendothelial iron 2+ to 3+ None None None
Serum iron (Fe), mcg/dL 60 to 150 60 to 150 <60 <40
Plasma or serum FERRITIN, ng/mL
or microg/L (iron storage)
40 to 200 <40 <20 <10
Total iron-binding capacity
(TRANSFERRIN,TIBC), mcg/dL
(iron utilization)
300 to 360 300 to 390 350 to 400 >410
Transferrin saturation (Fe/TIBC), % 20 to 50 30 <15 <10
Hemoglobin, g/dL
Normal
Men: 15.7 (14.0 to 17.5)
Women: 13.8 (12.3 to 15.3)
Normal 9 to 12 6 to 7
Red cell morphology Normal Normal Normal or slight hypochromic HYPOCHROMIC AND
MICROCYTOSIS
Erythrocyte protoporphyrin,
ng/mL RBC
30 to 70 30 to 70 >100 100 to 200
Other tissue changes None None None Nail and Epithelial changes
©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
• Development of IRON DEFICIENCY over several Stages
• First iron stores depletion, then iron availablility for hemoglobin synthesis
• Depends on individual baseline iron storage

11. Clinical Laboratory Findings in
Iron Deficiency
Laboratory Definition Serum Level (↑/↓)
Mean corpuscular volume (MCV) Average Volume of RBC ↓
Mean corpuscular hemoglobin
concentration (MCHC)
Average Concentration of
hemoglobin in your RBC
↓
Iron Serum iron ↓
Ferritin Iron storage ↓
Transferrin Iron utilization ↑
Total iron binding capacity (TIBC) To raise iron absorption ↑
Transferrin saturation (iron/TIBC) iron available for
erythropoiesis
↓
RBC smear RBC morphology MICROCYTIC,
HYPOCHROMIC
Hepcidin Level Hepcidin is a protein that’s
negative regulate serum
iron
No reliable test for
hepcidin levels is
available
Schrier et. Al., “Causes and diagnosis of iron deficiency and iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
Schrier et. Al., “Treatment of iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017

12. Goals ofTreatment
• Restore RBC Hgb concentration
• Reestablish RBC indices (MCV, MCH, MCHC)
• Replenish iron stores
• Treat Underlying causes
MATTHEWW. SHORT, “Iron Deficiency Anemia: Evaluation and Management”. 2013 American Academy of Family Physicians.

13. Non-Pharmacologic
Treatment Recommended Dietary Allowances (RDAs) for Iron
Age Male Female Pregnancy Lactation
Birth to 6
months
0.27mg 0.27mg
7–12 months 11 mg 11 mg
1–3 years 7 mg 7 mg
4–8 years 10 mg 10 mg
9–13 years 8 mg 8 mg
14–18 years 11 mg 15 mg 27 mg 10 mg
19–50 years 8 mg 18 mg 27 mg 9 mg
51+ years 8 mg 8 mg
Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes forVitamin A,Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon,
Vanadium, and Zinc : a Report of the Panel on Micronutrients.Washington, DC: National Academy Press; 2001.
Consider foods with iron-rich
sources:
• E.g. Breakfast cereals, oysters, white
beans, chocolate, beef liver, lentils,
spinach, tofu, kidney beans, sardines,
chickpeas, tomatoes, beef, potatoes,
cashew nuts
Avoid Foods impaired absorptions of
Iron:
• E.g. tannates, phosphates, phytates
(usually founds in grains, and seeds) or
food high in calcium
• Medications impaired absorption of Iron:
Acid reducers (e.g. PPI, H2RA, antacids)

14. Source of Iron-Rich Food
Food
Milligrams
per serving Percent DV*
Breakfast cereals, fortified with 100% of the DV for iron, 1 serving 18 100
Oysters, eastern, cooked with moist heat, 3 ounces 8 44
White beans, canned, 1 cup 8 44
Chocolate, dark, 45%–69% cacao solids, 3 ounces 7 39
Beef liver, pan fried, 3 ounces 5 28
Lentils, boiled and drained, ½ cup 3 17
Spinach, boiled and drained, ½ cup 3 17
Tofu, firm, ½ cup 3 17
Kidney beans, canned, ½ cup 2 11
Sardines, Atlantic, canned in oil, drained solids with bone, 3 ounces 2 11
Chickpeas, boiled and drained, ½ cup 2 11
Tomatoes, canned, stewed, ½ cup 2 11
Beef, braised bottom round, trimmed to 1/8” fat, 3 ounces 2 11
Potato, baked, flesh and skin, 1 medium potato 2 11
Cashew nuts, oil roasted, 1 ounce (18 nuts) 2 11
Non-PharmacologicTreatment (Cont.)
U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 26. Nutrient Data Laboratory Home Page, 2013.

15. PharmacologyTreatment
MATTHEWW. SHORT, “Iron Deficiency Anemia: Evaluation and Management”. 2013 American Academy of Family Physicians.
Guideline: Daily iron supplementation in adult women and adolescent girls. Geneva:World Health Organization; 2016.
2016 World Health Organization Guidelines for Daily Iron Supplementation in
Menstruating AdultWomen “non-pregnant females in a reproductive age” and
Adolescent girls
• 30 to 60mg of elemental iron per day for 3 months
• An ↑ hemoglobin of 1g/dL after 1 month of treatment show an adequate response and
confirms the diagnoses
• Continue treatment for 3 months after anemia is corrected for adequate replenish of
iron stores
2013 American Academy of Family Physicians (AAFP) guidelines for Adults
• 120 mg of elemental iron per day for 3 months
• An ↑ hemoglobin of 1g/dL after 1 month of treatment show an adequate response and confirms the
diagnoses
• Continue treatment for 3 months after anemia is corrected for adequate replenish of iron stores

16. Oral Iron Supplements
FERROUS GLUCONATE FERROUS SULFATE FERROUS FUMARATE
Strength 300mg 325mg 324mg
% element iron ~11% ~20% ~33%
Elemental iron/tablet ~38mg ~65mg ~106mg
Dosing 1 to 3 tab BID orTID 1 tabTID 1 tab BID
ADME Onset: hematologic response: ~3-10days
Time to Peak:
↑RBC ~ 5-10days
↑hemoglobin within 2-4wks
Absorption: occurs at upper intestine
(duodenum, and upper jejunum)
In person with normal serum iron stores:
~10%
In person with deficit serum iron stores:
~20 to 30%
Common SEs Nausea, epigastric pain, dark stools, constipation, teeth staining (liquid preparation)
Common DDIs • PPIs or other factors decrease gastric secretion (e.g. Antacids, H2RA), cholestyramine ↓absorption of iron
• ↓Absorption of Fluoroquinolones, Tetracycline, Levothyroxine, Mycofenolate mofetil and Penicillamine,
Levodopa and Methyldopa
• Chloramphenicol, Vitamin E may ↓ hematological response
Counseling Points • Take on Empty Stomach (w/ Food may ↓ absorption by 40%)
• Vitamin C ↑ absorption up to 30% (Take w/ orange juice or ascorbic acid 250-500mg BID w/ iron)
• Avoid Antacids, Coffee, Tea, Dairy products, Eggs, or whole-grain cereals or breads 1 hour before or 2 hour
after
MATTHEW W. SHORT, “Iron Deficiency Anemia: Evaluation and Management”. 2013 American Academy of Family Physicians.

17. IV Iron Supplements
FERRIC GLUCONATE
(FERRLECIT)
FERROUS SUCROSE
(VENOFER)
FERUMOXYTOL
(FERAHEME)
FERRIC CARBOXYMALTOSE
(INJECTAFER)
IRON DEXTRAN
(INFED OR DEXFERRUM)
Element iron 12.5mg/mL 20mg/mL 30mg/mL 50mg/mL 50mg/mL
Administration
Route
IV IV IV IV IM or IV
Test Dose Not required, but
recommended if hx of
drug allergies
Not required, but
recommended if hx of
drug allergies
Not required Not required 0.5mL (0.25mg) IV over 30 seconds,
observed x1hr
Dosing 125mg/10-60min
Max: 250mg/60min
100-400mg/2-90min
Max: 300mg/2hr
510mg/5min
Max: 510-1020/15-60min
750-1000mg/15-30min
Max:
750-1500mg/15-30min
Multiple doses of 100 mg, or
Single dose of 1000 mg diluted in
250 mL normal saline) given
over one hour
Total Iron Deficit in
mg
Dosing needed = weight (Kg) x 2.3 x hemoglobin deficiency + 500 to 1000mg iron
Hemoglobin deficiency =Target hemoglobin level – patient hemoglobin level
BBW None None None None Anaphylaxis
Common SEs Headache, nausea, diarrhea, hypoTN or hyperTN, injection site rxn, rash
Myalgia, arthralgia, back and chest pain is usually resolved in 48 hours
Hypersensitivity, severe or life threatening are RARE. Usually occurs due to rapid infusion
Clinical Pearls • Benefits for anemia patients with CKD requiring ESA (since iron supplement helps delay ESA administration)
• IV Iron is preferred when high level of HEPCIDIN that may create a refractory to oral iron supplement
• IV iron should be avoided in 1st
trimester pregnancy because lack of safety data
• IV iron significantly improve physical performance and QoL in patients with CHF (1 yr treatment reduce in hospitalization)
• Premedication with antihistamine is no longer advises because it may cause hypotension and tachycardia
• Larger RCTs are required to determined risk of iron related infections inT2DM or metabolic syndrome
MATTHEW W. SHORT, “Iron Deficiency Anemia: Evaluation and Management”. 2013 American Academy of Family Physicians.
Dan L. Longo, “Iron-Deficiency Anemia”. May 7, 2015DOI: 10.1056/NEJMra1401038

18. Take Home Points
• Iron is an important element in helping Production of Hemoglobin In RBC
• Risk Factors include: ↑ demands, ↓ intake, ↓ absorption, and Drugs induced iron-deficiency
• Early Sign and Symptoms: Fatigue, weakness, headache, irritability, exercise intolerance,
exertional dyspnea, vertigo, angina pectoris (rare)
• Complications: pallor, dry or rough skin, blue sclerae, Loss ofTounge Papillae, Spoon Nails, and
possible precipitating infections, induce heart failure, and restlessness leg syndrome
• Laboratory Diagnoses: First lab decreases will be serum Ferritin then serum iron once iron
stores deficit
• Treatment Goals: Restore RBC hemoglobin concentration, replenish iron stores and prevent
complications
• Dosing strategy recommendation is EVERY OTHER DAY
• Pick the oral formulation that’s best fit for the patients, less AEs and increase adherence

19. REFERENCES
• Moretti et. Al. “Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young
women.” 22 OCTOBER 2015 xVOLUME 126, NUMBER 17. © 2015 byThe American Society of Hematology
• Stoffel Et. Al. “Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-
daily split dosing in iron-depleted women: two open-label, randomised controlled trials.” © 2017 byThe Lancet Haematology
• MATTHEW W. SHORT, “Iron Deficiency Anemia: Evaluation and Management”. 2013 American Academy of Family Physicians.
• ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
• ©2017 UpToDate. “Acute iron intoxication: Rapid overview”
• IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin”. J. Clin. Invest. 113:1271–1276
(2004). doi:10.1172/JCI200420945.
• Schrier et. Al., “Causes and diagnosis of iron deficiency and iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
• Schrier et. Al., “Treatment of iron deficiency anemia in adults”. ©2017 UpToDate accessed on December 5th, 2017
• Liebelt et. Al., “Acute iron poisoning”. ©2017 UpToDate accessed on December 5th, 2017
• Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes forVitamin A,Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine,
Iron, Manganese, Molybdenum, Nickel, Silicon,Vanadium, and Zinc : a Report of the Panel on Micronutrients.Washington, DC: National Academy
Press; 2001.
• U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 26. Nutrient
Data Laboratory Home Page, 2013.
• Dan L. Longo, “Iron-Deficiency Anemia”. May 7, 2015DOI: 10.1056/NEJMra1401038

20. Iron DeficiencyTrending
• Un-absorbed iron might alter the intestine microbiota which may increase
concentration of pathogens.
• Dosing may be appropriate with EVERY OTHER DAY RATHERTHAN EVERY DAY.
IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin”. J. Clin. Invest. 113:1271–1276 (2004). doi:10.1172/JCI200420945.
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