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Iron Deficiency Anemia in Adults

Recommendations Editor Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS
Deputy Editor William Aird, MD
ACP Reviewer Gabriel Marcelo Aisenberg, MD, FACP

Overview and Recommendations

Background

 Iron deficiency anemia, which occurs when iron deficiency has progressed to iron-deficient

erythropoiesis, is the most common cause of anemia worldwide, accounting for about 50% of cases.

 Anemia is defined by hemoglobin (Hb) levels according to the Centers for Disease Control

and Prevention and World Health Organization.

o For menstruating women, Hb < 12 g/dL (120 g/L)

o For pregnant women, Hb < 11 g/dL (110 g/L)
o For men Hb, < 13 g/dL (130 g/L)

 Causes of iron deficiency anemia:

o Iron deficiency and iron deficiency anemia may occur due to increased need for iron
(for example, during pregnancy), decreased iron intake (for example, lack of iron sources in the diet), d
example, Celiac disease) or loss of iron (for example, bleeding).
o Menstrual blood loss is the most common cause of iron deficiency anemia in
premenopausal women, while blood loss from the gastrointestinal tract is most common cause
in adult men and postmenopausal women
o Iron deficiency anemia may be a predictor of asymptomatic colonic and gastric carcinoma,
especially in adult men and postmenopausal women
o In some patients, iron deficiency anemia may be multifactorial, or may coexist with other
o causes of anemia, especially anemia of inflammation
 Patients may be asymptomatic or present with signs and symptoms of:
o iron deficiency, including pica, restless legs, atrophic gastritis, and angular cheilosis
o anemia, including fatigue, shortness of breath, alopecia, and headache
o underlying condition causing the anemia
 Food-based approaches or routine iron supplementation may be used in specific populations
 such as, pregnant women, menstrurating girls and women, vegetarians and vegans, to prevent iron defic

Evaluation

 Iron deficiency anemia is diagnosed when iron deficiency is accompanied by anemia

 (low Hb level).
 Suspect iron deficiency anemia in patients with:
o signs and symptoms of iron deficiency, but iron deficiency may be asymptomatic and
o physical exam findingsare not sensitive for anemia
o microcytic and hypochromic anemia
 If iron deficiency anemia suspected, consider performing tests to assess iron status including:
o serum ferritin
o serum iron
o total iron binding capacity (TIBC)
o Diagnosis of iron deficiency is generally made based on serum ferritin levels below 15 mcg/L
o in the absence of inflammation) or below 100 mcg/L in the presence of inflammation
o (since ferritin is an acute phase reactant) and transferrin saturation (TSAT) below 16%-20%.
o Recommended serum ferritin cutoffs and TSAT cutoffs to determine iron deficiency
o according to various organizations:
 Diagnosis of iron deficiency may be supported by:
o

Decrease in mean corpuscular volume (< 80 fL)

Increase in total iron-binding capacity (> 68 mmol/L)

Increase in percentage of hypochromic red blood cells (HRC) (> 6%)

Decrease in reticulocyte Hb content (CHr) or Ret-Hb (< 29 pg)
 For patients with unexplained iron deficiency or iron deficiency anemia, consider
tests to determine source of iron deficiency.
o In all men and postmenopausal women with iron deficiency anemia:
 perform upper and lower gastrointestinal investigations (unless history of
significant overt non gastrointestinal blood loss is present) (Strong
recommendation)
 consider testing for Helicobacter pylori infection in patients with recurrent
iron deficiency anemia and normal esophagogastroduodenoscopy (OGD)
and colonoscopy findings (Weak recommendation)
 consider screening for celiac disease in all patients with iron deficiency
anemia (Weak recommendation).
o In premenopausal women, consider:
 gynecologic workup for excessive or irregular menstrual bleeding
 pregnancy and thyroid-stimulating hormone (TSH) tests

Screening:

o Consider screening nonpregnant women of childbearing age for anemia


annually for women at high risk for iron deficiency including those with
extensive menstrual or other blood loss, low iron intake, or previous diagnosis
of iron deficiency anemia
 every 5-10 years in all others
o Screen all pregnant women for anemia using blood count at booking and at 28
weeks (Strong recommendation).

Special patient populations

 pregnancy
o reported prevalence of anemia during pregnancy from all causes 5.4% in the United
States to > 80% in developing countries
o estimated prevalence of iron deficiency anemia in pregnant women 10 to 20%
o References -
 Obstet Gynecol Surv 2017 Dec;72(12):730
 Nutrients 2017 Dec 6;9(12): full-text
o in cohort of 1,283 pregnant adolescent girls and women (aged 12-49 years) from
National Health and Nutrition Examination Survey (NHANES) 1999-2010
 estimated prevalence of iron deficiency anemia 2.6%
 higher prevalence of iron deficiency anemia in multiparous women compared to
primiparous women (but not nulliparous women)
 Reference - Am J Clin Nutr 2017 Dec;106(Suppl 6):1640S

 elderly
in cohort of 4,199 adults ≥ 65 years old from National Health and Nutrition
o
Examination Survey (NHANES) 1988-1994, estimated prevalence of iron deficiency
anemia 10.6%; prevalence 11% in men and 10.2% in women ( Blood 2004 Oct
15;104(8):2263 full-text)
 chronic kidney disease (CKD)
o in cohort of 410 adults (aged > 18 years) with CKD from NHANES survey (2007-2008
and 2009-2010), prevalence of anemia (from any cause) 15.4%
 prevalence of anemia according to CKD stage

 heart failure
o anemia from all causes
 reported in about one-third of patients with heart failure ( Nat Rev Cardiol
2015 Nov;12(11):659)
 in cohort of 4,456 patients (median age 73 years) with heart failure in Britain,
anemia in 27.8%; among patients with anemia, iron deficiency in 43.2%-68%
depending on the definition of iron deficiency used for analysis ( JAMA
Cardiol 2016 Aug 1;1(5):539 full-text)
o iron deficiency anemia
 reported in 17% of patients with heart failure (NIH Fact Sheet 2018 Mar 2)
 in cohort of 37 patients (mean age 57.9 years) in Greece with
decompensated advanced congestive heart failure and anemia, iron
deficiency anemia confirmed by bone marrow aspiration in 73% ( J Am Coll
Cardiol 2006 Dec 19;48(12):2485 full-text), editorial can be found in J Am
Coll Cardiol 2006 Dec 19;48(12):2490, commentary can be found in J Am
Coll Cardiol 2007 Jun 12;49(23):2301
 gastrointestinal (GI) disease
o inflammatory bowel disease (IBD)
 12%-24% reported prevalence of anemia from all causes in patients with
inflammatory bowel disease (Ann Gastroenterol 2017;30(1):15, full-text, J
Allergy Clin Immunol 2015 May;135(5):1099)
 in cohort of 5,104 patients with Crohn disease and 6,249 patients with
ulcerative colitis followed for median 2 years
 o prevalence of anemia 32.4% among patients with Crohn disease and
27.6% among patients with ulcerative colitis
o in cohort of 669 patients with sufficient information to determine cause of
anemia, iron deficiency anemia in
 79.2% of 361 patients with Crohn disease
 85.1% of 308 patients with ulcerative colitis
o Reference - BMJ Open Gastroenterol 2017;4(1):e000155 full-text
o hiatal hernia - reported prevalence of iron deficiency anemia 8%-42% (mean
20%)
o celiac disease
 about 80% of anemic patients with celiac disease reported to have iron
deficiency
 iron deficiency reported to be sole detectable abnormality in about 50% of
anemic patients with celiac disease
 prevalence of biopsy-confirmed celiac disease 3.2% among patients with
iron deficiency anemia
o based on systematic review of observational studies
o systematic review of 18 observational studies evaluating prevalence of
biopsy-confirmed celiac disease in 2,998 patients with iron-deficiency
anemia
o anemia definitions differed across studies, but most studies defined
anemia as hemoglobin < 13.5 g/dL (135 g/L) in males and < 12 g/dL (120
g/L) in females
o pooled prevalence of biopsy-confirmed celiac disease 3.2% in analysis of
18 studies, results limited by significant heterogeneity
o Reference - Gastroenterology 2018 Aug;155(2):374
o colorectal cancer
 reported prevalence of anemia and iron deficiency anemia 50%-60%
 reported to be cause of lower gastrointestinal bleeding in 11%-14% of cases
 malignant polyps associated with greater blood loss and more frequent
occurrence of iron deficiency anemia compared to benign polyps
 Reference - World J Gastroenterol 2016 Sep 21;22(35):7908 full-text
 chronic liver disease - in cohort of 72 patients (median age 49 years) with liver
cirrhosis and anemia, no stainable iron in bone marrow demonstrated in 40.3%
( J Intern Med 1998 Mar;243(3):233)
 bariatric surgery
o reported prevalence of anemia from all causes
 33%-49% in patients with bariatric procedures (within 2 years after surgery)
 17% in patients with laparoscopic sleeve gastrectomy
 45%-50% in patients with Roux-en-Y gastric bypass (RYGB) or
biliopancreatic diversion
o iron deficiency most common cause of post-bariatric anemia
 reported prevalence of iron deficiency anemia
o 6.6%-22.7% in patients after RYGB
o 3.6%-52.7% in patients after laparoscopic sleeve gastrectomy
o References -
 World J Diabetes 2017 Nov 15;8(11):464 full-text
 
Am J Hematol 2008 May;83(5):403

Proc Nutr Soc 2018 Apr 5:1
 hospitalized patients
o in cohort of 771 patients (mean age 75.5 years) hospitalized in internal
medicine ward in Portugal
 519 patients (67%) had anemia
 316 patients (41%) had iron deficiency anemia
 Reference - Eur J Haematol 2017 Dec;99(6):505
o in cohort of 107 patients (median age 63 years, 77% men) with anemia at
discharge from intensive care unit (ICU) (≥ 5 days stay) in France, iron
deficiency in 8.4%
 at 28 days after discharge, anemia in 80% and iron deficiency in 25%
 at 6 months after discharge, anemia in 25% and iron deficiency in 35%
 Reference - Crit Care 2014 Sep 30;18(5):542 full-text

Risk factors

 populations at increased risk for iron deficiency anemia include (1, 2, 3, 4)

o
females, especially
 menstruating girls and women
 pregnant women; especially those with
o iron-poor diet (for example, vegetarian diet with inadequate sources of iron)
o gastrointestinal disease and/or taking medications that can decrease iron
absorption (for example, antacids)
o short interval between pregnancies
o non-Hispanic black and Mexican American women compared white women and
women with parity of ≥ 2
o lower educational level and family income (less consistent evidence)
o Reference - Ann Intern Med 2015 Oct 6;163(7):529, commentary can be found
in Ann Intern Med 2015 Oct 6;163(7)
o infants and young children
o adolescents
o elderly persons
o persons living in developing countries
o obese persons
o vegetarians and vegans
o frequent blood donors
o endurance athletes
o people with cancer (NIH Fact Sheet March 2018)
o people who have gastrointestinal disorders or have had gastrointestinal surgery(NIH
Fact Sheet March 2018)
o people with heart failure (NIH Fact Sheet March 2018)
 see Causes section for additional information on individual conditions associated with
increased risk of iron deficiency
 vegetarian diet associated with lower serum ferritin levels in adult men and
women
o based on systematic review of mostly observational studies
 o systematic review of 30 studies (24 cross-sectional studies, 4 interventional studies, 2
randomized trials) evaluating association between consumption of vegetarian diet and
iron deficiency in adults
o compared to nonvegetarian diet, vegetarian diet associated with lower serum ferritin
levels
 in all adults (pooled mean difference -29.71 mcg/L, 95% CI -39.69 to -19.73) in
analysis of 23 cross-sectional studies with 1,085 adults, results limited by
heterogeneity
 in men (pooled mean difference -61.88 mcg/L, 95% CI -85.59 to -38.17) in analysis
of 10 cross-sectional studies with 394 men, results limited by heterogeneity
 in all women (pooled mean difference -13.5 mcg/L, 95% CI -22.9 to -4.04) in
analysis of 23 cross-sectional studies
 in premenopausal women (pooled mean difference -17.7 mcg/L, 95% CI -29.8 to -
5.6) in analysis of 6 cross-sectional studies with 286 women, results limited by
heterogeneity
o Reference - Crit Rev Food Sci Nutr 2018 May 24;58(8):1359
 frequent blood donation associated with increased risk for iron deficiency and
anemia compared to less frequent blood donation
o based on nonclinical outcomes from randomized trial
o 45,263 blood donors were randomized to 3 different blood donation intervals
 men randomized to blood donation frequency of 8 weeks vs. 10 weeks vs. 12
weeks
 women randomized to blood donation frequency of 12 weeks vs. 14 weeks vs. 16
weeks
o 99.5% were included in analysis
o in men, comparing 8-week vs. 10-week vs. 12-week blood donation interval at 2 years
 serum ferritin levels < 15 mcg/L in 23.78% vs. 17.61% vs. 12.12% (p < 0.0001,
pairwise comparisons not reported)
 hemoglobin concentration < 13.5 g/dL (135 g/L) in 18.02% vs. 14.03% vs. 10.25%
(p < 0.0001, pairwise comparisons not reported)
 deferral for low hemoglobin in 5.72% vs. 3.74% vs. 2.56% (p < 0.0001, pairwise
comparisons not reported)
o in women, comparing 12 weeks vs. 14 weeks vs. 16 weeks blood donation interval at
2 years
 serum ferritin levels < 15 mcg/L in 26.64% vs. 26.43% vs. 21.77% (p < 0.0001,
pairwise comparisons not reported)
 hemoglobin concentration < 12.5 g/dL (125 g/L) in 19.39% vs. 18.5% vs. 15.65% (p
< 0.0001, pairwise comparisons not reported)
 deferral for low hemoglobin in 7.92% vs. 6.63% vs. 5.07% (p < 0.0001, pairwise
comparisons not reported)
o Reference - INTERVAL trial ( Lancet 2017 Nov 25;390(10110):2360 full-text)
 black women and increased years of menstruating each associated with
increased risk for iron deficiency anemia in women aged 22-49 years
o based on retrospective cohort study
o 6,602 adolescent girls and women from National Health and Nutrition Examination
Survey (NHANES) 2003-2010 were assessed
o iron deficiency anemia in
 5.5% of 3,617 women aged 22-49 years
 2.4% of 2,985 adolescent girls and women aged 12-21 years
o factors associated with increased risk for iron deficiency anemia in women aged 22-
49 years (2,707 women included in multivariable analysis)
 
black women compared to white women (risk ratio 2.31, 95% CI 1.33-4.02)
increased years (≥ 25 years compared to < 25 years) of menstruating (risk ratio

1.93, 95% CI 0.99-3.76)
o among adolescent girls and women aged 12-21 years (2,174 adolescent girls and
women included in multivariable analysis), use of contraceptives associated with
decreased risk for iron deficiency anemia (risk ratio 0.5, 95% CI 0.25-1)
o Reference - J Womens Health (Larchmt) 2016 May;25(5):505 full-text
 obesity or being overweight associated with decreased iron absorption in women
aged 18-45 years
o based on cohort analysis of nonclinical outcome from randomized trial
o 62 healthy women (aged 18-45 years) without anemia receiving stable isotope labeled
wheat based test meal with or without ascorbic acid were assessed
 19 women were obese (BMI 30-39 kg/m2)
 19 women were overweight (BMI 25-29.9 kg/m2)
 24 women were of normal weight (body mass index [BMI] 18.5-24.9 kg/m2)
o comparing obesity or being overweight vs. normal weight
 mean iron absorption from meals without ascorbic acid 12.9% vs. 19% (p = 0.049)
 mean iron absorption from meals with ascorbic acid 16.6% vs. 29.5% (p = 0.004)
o Reference - Am J Clin Nutr 2015 Dec;102(6):1389 full-text
 absolute iron deficiency anemia reported in athletes
o based on cross-sectional analysis of cohort study
o 30 elite row athletes or professional soccer players were assessed
o absolute iron deficiency (serum ferritin < 30 mcg/L) at end of season in 27%
o mild anemia in 10%
o Reference - Int J Cardiol 2012 Apr 19;156(2):186

Associated conditions

 iron deficiency anemia associated with of squamous cell carcinoma of the pharynx and
the oesophagus (1)

History and Physical

Clinical Presentation

 patients with iron deficiency or iron deficiency anemia may be asymptomatic(2)

 iron deficiency may contribute to symptoms even in the absence of anemia(1, 2, 4)
o symptoms depend on the rapidity with which the condition develops
o findings associated with all anemias
 frequent
o pallor of the skin, conjunctivae, and nail beds (reported in 45%-50%)
o fatigue (reported in 44%)
o dyspnea on exertion
o headache (reported in 63%)
o weakness
o poor work productivity
 less common
o vertigo
o syncope
o angina pectoris
o findings more specific to iron deficiency anemia
 frequent
o alopecia (reported in 30%) - evidence for association with iron deficiency is
inconsistent (J Am Acad Dermatol 2006 May;54(5):903), editorial can be found
in J Am Acad Dermatol 2006 May;54(5):824, commentary can be found in J Am
Acad Dermatol 2007 Mar;56(3):518
o dry and damaged hair
o atrophic glossitis (reported in 27%)
 in early disease, tongue papillae initially redden and may enlarge
 in late disease, tongue may appear atrophic and smooth, with beefy red
appearance
 not specific for iron deficiency (occurs in other nutritional deficiencies)
 Reference - Clin Dermatol 2016 Jul-Aug;34(4):458
o angular cheilosis (also called angular cheilitis, angular stomatitis)
 in early stages, grayish white thickening with adjacent erythema may present
at corners of mouth
 in later stages, granulation tissue forms and adjacent skin often develops scaly
dermatitis
 symptoms include soreness, pain, burning, or pruritus
 Reference - Cutis 2011 Jun;87(6):289
o restless legs syndrome (RLS) (reported in 24%)
 patients often have difficulty describing their symptoms
 patient may use wide range of descriptive terms to describe their leg
paresthesia, which include crawling, tingling, restless, cramping, creeping,
pulling, painful, electric, tension, itching, burning, and prickly
 Reference - Pract Neurol 2017 Dec;17(6):444 full-text
o dry and rough skin
o brittle nails
o pica
 ingestion of non-nutritive materials (Am J Hematol 2016 Jan;91(1):31)
 specifically ask about pica as patients are often reluctant to mention pica
symptoms (J Med Case Rep 2010 Mar 12;4:86 full-text)
o cold intolerance
o irritability
 less common
o koilonychia (nail deformity, spoon-shaped finger nails)
 longitudinal and/or transverse concave nail dystrophy where the nail plate is
depressed centrally and everted laterally (nail flattened in the middle with
everted lateral edges)
 primarily affects fingernails of first 3 digits
 finding is more clearly observed when the nail is viewed laterally
 often associated with nail thinning and brittleness
 development of koilonychia may not correlate with severity of iron deficiency
 reported in
o 5.4% of patients with iron deficiency
o 37%-50% of patients with Plummer-Vinson syndrome
 Reference - J Eur Acad Dermatol Venereol 2016 Nov;30(11):1985
o Plummer-Vinson syndrome (reported in < 0.1%)
 in addition to common symptoms of anemia such as weakness, fatigue and
tachycardia, may present with additional signs and symptoms including
o dysphagia
 o angular cheilitis
o pigmentation of oral mucosa
o severe pallor
o koilonychia
o enlargement of spleen and thyroid
 Reference -
o BMJ Case Rep 2012 Jul 25;2012: full-text
o Orphanet J Rare Dis 2006 Sep 15;1:36 full-text
 reported in pregnant women
o irritability
o cold intolerance
o Reference - Br J Haematol 2012 Mar;156(5):588
o References -
 Am J Hematol 2017 Oct;92(10):1068 full-text
 Best Pract Res Clin Obstet Gynaecol 2017 Apr;40:55