Anemia – AAFP 2013


  • A decrease in RBC mass that can be detected by [Hb], hematocrit, and RBC count
  • Adult males: Hb <130g/L or Hct <0.41
  • Adult female: Hb
  • Anemia symptoms – fatigue, malaise, weakness, dyspnea, decreased exercise tolerance, palpitations, h/a, dizziness, tinnitus, syncope
  • Acute / chronic, bleeding, systemic illness
  • diet, alcohol, family hx
  • Menstural hx: menorrhagia, menometrorrhagia, dysfunctional uterine bleeding
  • r/o pancytopenia – recurrent infection, mucosal bleeding / easy bruising
  • HEENT: pallor in mucous membranes and conjunctiva at Hb <90
  • Ocular bruits at Hb <55, angular chelosis, jaundice
  • Cardiac: tachycardia, orthostatic HoTN, systolic flow murmur, wide pulse pressure, CHF
  • Dermatologic: pallor in palmar skin crease Hb<75, jaundice (hemolysis), nail changes, glossitis
  • CBC, reticulocyte count, blood film

1  Assess the risk of decompensation of anemic patients (e.g., volume status, the presence of congestive heart failure [CHF], angina, or other disease states) to decide if prompt transfusion or volume replacement is necessary.

  • If the patient’s clinical status is compromised by moderate to severe anemia, consider admission to an acute care facility and blood transfusion. Once the patient is stable, iron replacement can be commenced.
  • Oral iron replacement is preferred to intravenous (IV) therapy.
    • It is safer, more cost-effective, and convenient when compared to IV therapy.
    • However, intravenous therapy may be substituted when there is:
      • inadequate iron absorption, continued blood loss, noncompliance or intolerance to oral iron therapy.
    •  Internal medicine/hematologist consultation is recommended.
  • Intramuscular (IM) iron therapy is not recommended except in institutions with facility for treating anaphylactic reactions.
    • Additional risks of IM iron therapy include unpredictable absorption and local complications (e.g. pain, staining of the skin, sarcoma formation).

2  In a patient with anemia, classify the anemia as microcytic, normocytic, or macrocytic by using the MCV (mean corpuscular value) or smear test result, to direct further assessment and treatment.

Microcytic – MCV

  • Thalassemia
  • Anemia of chronic dz
  • Iron deficiency
    • angular cheilitis, Pica, atrophic glossitis, koilonychia (opposite of clubbing), Plummer-Vinson syndrome – esophageal web, atrophic glossitis, dysphagia
  • Lead Poisoning
  • Sideroblastic anemia – defects in heme biosynthesis

Normocytic – MCV 80-100: ABCD

  • Acute blood loss
  • Bone Marrow Failure
  • Chronic dz
  • Destruction (Hemolysis)

1) High reticulocyte Count – increased Destruction (retics >2-3%)

  1. Hemolysis
    • Inherited:
      • hemoglobinopathy: sickle cell, thalassemia, unstable Hb
      • Membrane: spherocytic
      • Metabolic: HMP shunt, glycolytic pathway
    • Acquired:
      • Immune – Coombs positive, drug-related, cold agglutinin
      • Infection – malaria
      • Microangiopathic hemolytic anemia – DIC, TTP, HUS, HELLP
      • Oxidative / drug-related
  2. Bleeding: GI, GU, other
    • With blood loss, reticulocytes should increase 2-3x initially and then 5-7x over the next week

2) Low reticulocyte count – decreased production (Retics <2%) – a normal reticulocytes in anemia is interpreted as a sing of ↓ reticulocytes production

  1. Pancytopenia
    • Aplastic anemia, MDS, myelofibrosis, Leukemia
    • TB
    • Amyloidosis, sarcoidosis
    • Drugs – chemotherapy
  2. Non-pancytopenia
    • Anemia of chronic dz
    • Renal / liver dz

Macrocytic – MCV >100: ABCDEF

  • Alcoholism (liver dz)
  • B12 deficiency
    • Symmetric peripheral neuropathy, paresthesias, ataxia, glossitis, Memory loss, personality changes, dementia
    • Late: severe weakness, spasticity, clonus
    • causes: metformin, PPi, H2 blocker, bacteria overgrowth at terminal ileum, pernicious anemia
  • Compensatory reticulocytosis
  • Drugs (cytotoxic, AZT) / Dysplasia
  • Endocrine (hypothyroidism)
  • Folate Deficiency / Fetus (pregnancy)
  1. Megaloblastic (usually has pancytopenia, hypersegmented neutrophils, megaloblastic bone marrow)
    • B12 and/or folate deficiency
    • Drugs that impair DNA synthesis (methotrexate, sulfa, chemotherapy)
  2. Non-megaloblastic
    • Liver dz, hypothyroidism
    • Alcoholism
    • Myelodysplasia, Reticulocytosis

Peripheral Blood film

  • Hypochromic microcytosis: RBCs has low Hb levels due to lack of iron
  • Pencil forms, anisocytosis
  • Target cells (thin)

3  In all patients with anemia, determine the iron status before initiating treatment.

Iron Indices
  • Ferritin ≤ 30 ug/ml – dx of iron deficiency (<18ug/ml – very likely)
  • Ferritin 31-99 ug/ml – Assess other iron indices
    • ↑TIBC, ↓ serum Fe, ↓ transferrin saturation – dx of iron deficiency
    • ↓TIBC, ↑ serum Fe, ↑ saturation – No Iron deficiency
    • Any other combination of TIBC/FE/Saturation – order sTfR (useful in dx iron deficiency in chronic inflammatory disorders)
      • ↑ sTfR (soluble transferrin receptor) – dx of iron deficiency
      • Normal sTfR
        • Erythrocyte protoporphyrin level increased – Iron deficiency
        • No increased erythrocyte protoporphyrin level:
          • Consider bone marrow biopsy – gold standard but rarely done (for bone marrow iron level)
      • ↓ sTfR – No iron deficiency
  • Ferritin ≥ 100 – No iron deficiency anemia

4  In a patient with iron deficiency, investigate further to find the cause.

  1. inadequate iron intake
    • Low socioeconomic status, lack of balanced diet or poor intake
    • Alcoholism, elderly, high risk ethnic groups: 1st nations, indo-canadians
    • Vegetarian diet
  2. decreased iron absorption:
    • Upper GI pathology: chronic gastritis, gastric lymphoma
      • celiac dz, chron’s dz
    • Dietary factors: calcium in milk, tea, coffee, carbonated drinks, phytates in fibre
    • Medications – decrease gastric acidity or bind iron
    • gastrectomy, Intestinal resection, bacterial overgrowth
    • Chronic renal failure pt
  3. increased iron demand
    • Pregnancy, lactation, multiparity, Growing infants & children
    • Menstruating women, parturition
  4. increased iron loss:
    • Abnormal uterine bleeding/menorrhagia > epistaxis, hematuria
    • GI bleed: ASA/NSAID use > colonic carcinoma >angiodysplasia
    • PUD, H Pylori infection, esophagitis, intestinal parasites, Gastric antral vascular ectasia
    • Esophageal carcinoma, Gastric carcinoma, small bowel tumor
    • Intravascular hemolysis: hemoglobinuria, pathological – hemolytic anemia
    • Extreme physical exercise (endurance athletes)
    • Regular blood donation, post-op pt with sig blood loss


1) Premenopausal women
  1. With abnormal uterine bleeding
    • Initiate workup for bleeding and observe
  2. Without abnormal uterine bleeding
    • Tx with Iron and if no response, initial evaluation for occult GI blood loss
2) Men & postmenopausal women

→ Upper endoscopy & colonoscopy – consider celiac serology

  1. GI source – Tx underlying cause
  2. No evidence of GI source – Tx with Iron and observe if + response
    • If no response – repeat upper endoscopy & colonoscopy
      • Evidence of GI source – Tx underlying cause
      • No evidence of GI source – Capsule endoscopy
        • If abnormal – Tx underlying cause; push enteroscopy
        • If normal – ? repeat capsule endoscopy

5  Consider and look for anemia in appropriate patients (e.g., those at risk for blood loss [those receiving anticoagulation, elderly patients taking a NSAIDs]) or in patients with hemolysis (mechanical valves), whether they are symptomatic or not, and in those with new or worsening symptoms of angina or CHF.

Asymptomatic men and postmenopausal women should not be screened for iron deficiency anemia


  1. Early stage iron deficiency can exist without overt anemia, but with other non-hematological symptoms.
  2. Symptoms of anemia: Fatigue, malaise, weakness, dyspnea, decreased exercise tolerance, palpitations, h/a, dizziness, tinnitus, syncope
  3. Investigate based on clinical suspicion, not only on presence of anemia. Other symptoms include:
    1. Adults: hair loss, fatigue, cold intolerance, restless leg syndrome, irritability.
    2. Children: tiredness, restlessness, attention-deficit/hyperactivity disorder (ADHD), irritability, growth retardation, cognitive and intellectual impairment.

6  In patients with macrocytic anemia:
a)  Consider the possibility of vitamin B12 deficiency.

b)  Look for other manifestations of the deficiency (e.g., neurologic symptoms) in order to make the diagnosis of pernicious anemia when it is present.

  • B12 (cobalamin) binds to intrinsic factor secreted by gastric parietal cells, absorbed in terminal ileum.
  • Total body stores sufficient for 3-4 yr
Etiology of B12 deficiency
  • Diet: Strict vegan & vegetarian in pregnancy
  • Gastric:
    • Mucosal atrophy: gastritis, autoimmune
    • Pernicious anemia – auto-ab against gastric parietal cells → achlohydria + lack of intrinsic factor secretion (↓ ileal absorption)
      • Associated with autoimmune disorders: polyglandular endocrine insufficiency
      • Female>male, often >60yo
    • Post-gastrectomy
  • Intestinal Absorption
    • Malabsorption: Crohn’s, Celiac sprue, pancreatic insufficiency
    • Stagnant bowel: blind loop, stricture
    • Fish tapeworm
    • Resection of ileum
    • Drugs: Neomycin, biguanides, PPI, N2O
  • Genetic: Transcobalamin II deficiency
Clinical Feature: Neurological
  • Cerebral (common, reversible with B12): confusion, delirium, dementia
  • Cranial nerves (rare): optic atrophy
  • Cord (irreversible damage): subacute combined degeneration
    • Posterior columns: ↓ vibration sense, proprioception & 2point discrimination
    • Pyramidal tracts: spastic weakness, hyperactive reflexes
  • Peripheral neuropathy (variable reversibility)
    • symmetrical, affecting lower limbs > upper limbs
  • CBC, reticulocyte count: severe anemia ± neutropenia / throbocytopenia & MCV >110 & low reticulocyte count <2%
  • Serum B12 & RBC folate: low B12 leads to low RBC folate (failure of folate polyglutamate synthesis in the absence of B12)
    • Alt: measure urine metabolites (methylmalonate, homocysteine)
  • Blood film: oval macrocytes, hypersegmented neutrophils
  • Bone marrow: hypercellularity, nulcear-cytoplasmic asynchrony in RBC precursors
  • Bilirubin & LDH: ↑ due to breakdown of cells in BM
  • Schilling test to distinguish pernicious anemia from other causes
    • Part 1: radiolabeled B12 po then unlabeled B12 IM 1hr to saturate tissue binders to allow radioactive B12 to be excreted in urine
      • 24h urine radiolabeled B12 measure: normal >5% (due to dietary deficiency)
    • Part 2: radiolabeled B12 po with intrinsic factor po, then unlabeled B12 IM (same as part 1)
      • only if abnormal part 1
      • >5% excretion = pernicious anemia
      • <5% excretion = intestinal malabsorption
  • Vit B12 1000ug IM monthly for life or 1000-1200 ug po daily if intestinal absorption intact
  • Watch for hypokalemia & rebound thrombocytosis when treating severe megaloblastic anemia

7  As part of well-baby care, consider anemia in high-risk populations (e.g., those living in poverty) or in high-risk patients (e.g., those who are pale or have a low-iron diet or poor weight gain).

Universal hemoglobin screening and evaluation of risk factors for iron deficiency anemia in all children at one year of age.

Risk factors include
  • low birth weight, history of prematurity (screen before 6mo of age if not given iron-fortified formula)
  • exposure to lead,
  • exclusive breastfeeding beyond four months of life, and weaning to whole milk and complementary foods without iron-fortified foods

Iron Deficiency in Pediatric Populations

  1. IDA in children is associated with motor and cognitive deficits which may be irreversible.
    1. Consider the introduction of iron rich foods/formula or routine iron supplementation for asymptomatic children aged 6-12 months who are at increased risk for IDA.
    2. Recommended dose is 1 to 2 mg/kg/day of elemental iron (max 15 mg of elemental iron/day).
  2. Recommend infants and toddlers with suspected IDA begin treatment with oral ferrous sulphate.
    1. Recommended treatment dose for infants and children is 3 to 6 mg of elemental iron/kg/day in divided doses
  3. Advise patients that iron can be toxic to children and should always be safely stored.

Iron Deficiency in Pregnancy

  1. There is an increase in iron requirement during pregnancy, parturition and lactation. Total iron loss associated with pregnancy and lactation is about 1000 mg.
    1. An increase in iron consumption by about 15-30 mg of elemental iron/day is recommended for non-anemic women, an amount readily met by most prenatal vitamin formulations
    2. Women with iron deficiency anemia should receive an additional iron supplement as per treatment guidelines above.
  2. Iron is mandatory for normal fetal development. It is important to prevent iron deficiency in the fetus by preventing iron deficiency in pregnant women.
  3. Iron deficiency anemia is the most frequent form of anemia in pregnant women. Anemia in pregnancy is defined as:
    • 1st trimester – hemoglobin of less than 110 g/L
    • 2nd trimester – hemoglobin of less than 104 g/L
    • 3rd trimester – hemoglobin of less than 110 g/L
  4. If necessary intravenous iron is considered to be safe for the second and third trimester

Iron Deficiency in the Elderly

  1. Anemia in the elderly is a common clinical finding, often multifactorial, and has significant impact on quality of life, functional decline, and mortality. Treatment of iron deficiency and its underlying cause(s) may improve outcomes.
    1. Investigation of anemia in the elderly is recommended if the life expectancy is more than a year.25
    2. Replacement options are similar to younger patients. Low dose iron therapy (15 mg elemental iron per day) is an effective treatment in octogenarians if standard dosing is not tolerated, with significantly reduced adverse effects. Iron stores take longer to replete with lower iron doses.

8  When a patient is discovered to have a slightly low hemoglobin level, look carefully for a cause (e.g., hemoglobinopathies, menorrhagia, occult bleeding, previously undiagnosed chronic disease), as one cannot assume that this is normal for them.

9  In anemic patients with menorrhagia, determine the need to look for other causes of the anemia.

Tx of Iron Deficient Anemis

1) Lifestyle Management –  dietary advice

  1. Commonly used oral iron preparations include: ferrous gluconate, ferrous fumarate, and ferrous sulfate.
    • One preparation is not preferred over another; patient tolerance should be the guide.
  2. The usual adult dose is 180 mg of elemental iron/day in divided doses. 
    • Therapeutic doses can range from 100 to 200 mg of elemental iron/day, depending on severity of symptoms, ferritin levels, age of the patient, and gastrointestinal side effects.
  3. Iron intolerance is very common;
    • Oral iron preparations may cause nausea, vomiting, dyspepsia, constipation, diarrhea or dark stools.
    • Strategies to minimize these effects include: start at a lower dose and increase gradually over 4 to 5 days; giving divided doses or the lowest effective dose, or taking supplements with meals (note: iron absorption is enhanced if supplements are taken on an empty stomach; however, it may not be tolerated).
    • Although sustained release iron preparations tend towards less gastrointestinal side effects, they may not be as effective as standard film coated products due to reduced/poor iron absorption.
  4. Iron absorption can be decreased by various medications and supplements; space administration apart by at least 2 hours.
  5. Iron absorption from pharmaceutical preparations can be enhanced by taking them on an empty stomach (at least 1.5 to 2 hours after a meal), with acidic juices or vitamin C, and not with other multivitamin, calcium, or antacid tablets.
  6. Iron replacement therapy may begin as soon as iron deficiency is detected; however, it is essential to determine and correct the underlying causes of iron deficiency
    • Oral iron therapy in iron deficient anemia will increase hemoglobin by 10-20 g/L in 2 to 4 weeks. Order a Hematology Profile initially at 2 to 4 weeks to monitor response to replacement regime.
    • Anemia will correct within 2 to 4 months if appropriate iron dosages are administered and underlying cause of iron deficiency is corrected.
    • Continue iron therapy an additional 4 to 6 months (adults) after the hemoglobin normalizes to replenish the iron stores. The frequency of subsequent monitoring depends upon the severity of the anemia, the underlying cause of the iron deficiency, and the clinical impact upon the patient.
  7. Complete or partial failure of monitored iron therapy trial (in compliant patients) may be due to insufficient absorption or ongoing loss (e.g. hemorrhage) or both. It should be investigated appropriately. Intravenous iron preparations may be considered in these patients.

Ongoing Care

Iron Supplementation

  • Once anemia has corrected and iron stores have normalized; a low maintenance dose may be prescribed if an ongoing need for additional iron (e.g. menorrhagia, growth spurt). Dietary modification may also be considered. Consider similar supplementation for iron depleted but not anaemic patients.

Note: Exercise caution in supplementation in patients at risk for iron overload.


Posted in 4 Anemia, 99 Priority Topics, FM 99 priority topics, Hem
2 comments on “Anemia – AAFP 2013
  1. […] myelodysplasia, antiretroviral drugs, liver disease, myxedema), Normocytic (many causes, with MCV 80-100: ABCD acute blood loss, bone marrow failure, chronic disease, destruction […]


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