iron-deficiency anemia

Introduction

Microcytic hypochromic anemia.

Etiology

• blood losses from:
  • gastrointestinal losses
    • gastritis & peptic ulcer disease
    • GI malignancy
    • varices
    • angiodysplasia
    • inflammatory bowel disease
  • genitourinary losses
    • menstrual bleeding
    • iron loss with each menstrual period is about 20 g
  • blood donation
    • each unit of blood contains 250 mg of iron
  • phlebotomy
  • chronic hemoptysis
  • hemodialysis
• malabsorption
  • achlorhydria
    • atrophic gastritis
    • proton pump inhibitors (RR=2.5)
    • H2-receptor antagonists (RR=1.6)
  • surgery
    • gastric
    • small bowel
  • high intestinal transit time
  • celiac disease
  • parasitic infection by hookworms
  • Helicobacter infection
• nutritional deficiency
  • infants with unsupplemented milk
  • vegan or vegetarian diet
• pregnancy: iron loss is 500-1000 mg in pregnancy
• lactation
• idiopathic pulmonary hemosiderosis

Pathology

• depletion of iron stores
• compromised iron delivery to sites of utilization
• iron-deficient erythropoiesis

Clinical manifestations

• most patients asymptomatic
• symptoms are those common to all forms of anemia
  • fatigue
  • exercise intolerance
  • headache
  • dizziness
  • faintness
  • exertional dyspnea
  • angina pectoris
  • palpitation
  • claudication
  • tachycardia
  • cold intolerance
• symptoms develop only when Hgb < 7 g/dL if anemia is chronic unless coexistent pulmonary or cardiovascular disease
• pica, pagophagia
• skin & conjunctival pallor
• cheilosis, cheilitis, stomatitis, glossitis
• hair loss
• brittle or "spoon nails" (koilonychia)
• restless legs syndrome
• iron-deficiency may cause cognitive impairment/poor performance on standardized tests in children & adolescents even in the absence of anemia

Laboratory

• complete blood count (CBC)
  • red blood cell (RBC) count
    • < 5 X10E12/L in iron deficiency;
    • > 5 X10E12/L in thalassemia
    • anemia precedes hypochromia & microcytosis
  • red cell distribution width (RDW)
    • > 16 in iron deficiency
    • < 16 in thalassemia
  • mean corpuscular volume (MCV)
    • decreased in iron-deficiency anemia (< 80 fL)
    • may be normal (33% of patients)
      • when iron stores are adequate
      • mild iron deficiency anemia
      • patients with liver disease
      • in association with inflammation
      • combined iron & B12 or folate deficiency
  • mean corpuscular hemoglobin is decreased (MCHC < 32 g/dL)
  • platelet count is often elevated (may exceed 1,000,000/uL early in disease)
• reticulocyte count: inappropriately low for degree of anemia
• peripheral smear: anemia which precedes morphological changes
  • microcytosis
  • poikilocytosis
  • anisocytosis
  • hypochromia
• iron studies: abnormalities precede anemia
  • microcytic anemia in menstruating women precludes need to prove iron deficiency provided prior normal blood hemoglobin (MKSAP19)
  • serum iron
    • decreased in iron-deficiency anemia (< 60 ug/dL)
    • decreased with compromised delivery of iron to sites of utilization (see pathology)
    • low serum iron also occurs in:
      • acute inflammation
      • chronic inflammation
      • malignancy
      • infection
  • total-iron binding capacity (TIBC)
    • usually increased (> 400 ug/dL) in iron-deficiency anemia
    • largely reflects transferrin concentration
    • increased with compromised delivery of iron to sites of utilization (see pathology)
    • may be normal or low in:
      • inflammation
      • infection
      • malignancy
  • serum ferritin
    • earliest marker of iron deficiency
    • low serum ferritin (<12-15 ng/mL) indicates iron-deficiency
    • ferritin is an acute-phase reaction, thus high or normal levels may mask iron-deficiency; ferritin is elevated in:
      • infection
      • inflammatory conditions
      • hepatic disorders
      • malignancy
      • chronic renal failure
    • serum ferritin > 100 ng/mL rules out iron deficiency even with inflammation
    • low serum ferritin in the absence of anemia
      • may be associated with fatigue in menstruating women
      • symptoms may respond to iron supplementation
  • transferrin saturation
    • measured by serum iron/total-iron binding capacity (TIBC)
    • <9% is consistent with iron deficiency
    • <15% is consistent with iron deficiency
    • >15% is consistent with anemia of chronic disease
    • 9-15% requires a bone marrow biopsy to distinguish iron deficiency from anemia of chronic disease
    • decreased with compromised delivery of iron to sites of utilization (see pathology)
  • serum hepcidin levels are low
  • serum transferrin receptor is increased (not routine)
• fecal occult blood
• urinalysis:
  • examine for hematuria, hemoglobinuria, hemosiderinuria
• serum free erythrocyte protoporphyrin (FEP) not routine
  • increased in:
    • iron deficiency
    • anemia of chronic disease
    • heavy metal exposure
  • normal in:
    • thalassemia
    • sideroblastic anemia
• resistance to oral iron
  • H pylori antigen in stool (prior to trial of different form of oral iron) cites
  • H pylori serology (not mentioned in)
  • testing for celiac disease if white
    • tissue transglutaminase IgA in serum
    • gliadin antibody in serum
• bone marrow biopsy (not routine)
  • gold standard for diagnosis of iron deficiency
  • decreased absent stainable iron indicates iron deficiency
  • adequate iron stores in the bone marrow rule out iron deficiency unless the patient has recently received iron through supplementation or transfusion
• osmotic fragility
• lead in blood

* also see ARUP consult

Diagnostic procedures

• upper GI endoscopy*
  • upper GI bleed
  • suspected celiac disease (obtain duodenal biopsies)
  • telangiectasias (hereditary hemorrhagic telangiectasias)
  • prior to colonoscopy if the source of bleeding is unknown
• colonoscopy*
  • if upper GI endoscopy is negative
  • prior to upper GI endoscopy if lower GI bleeding is anticipated
    • radiation proctitis
• also see upper gastrointestinal hemorrhage*

* in men & non-menstruating women, GI bleed is the presumed cause of iron deficiency until proven otherwise; upper GI endoscopy & lower GI endoscopy (bidirectional endoscopy) indicated

* repeat upper GI endoscopy & lower GI endoscopy if source of iron loss (bleeding) not found & initial studies of low quality

* ref suggests colonoscopy prior to upper GI endoscopy

Radiology

• see upper gastrointestinal hemorrhage

Complications

• complications of hypoxemia
  • myocardial ischemia
• preoperative anemia associated with increased perioperative mortality & perioperative morbidity due to increased risk for need of blood transfusion
• dysphagia with solid food due to esophageal webs
• atrophic gastritis
• pseudotumor cerebri, papilledema, ncreased intracranial pressure
  • corrected with iron therapy
• impaired immune function
• hypothyroidism

• disease interaction(s) of vitamin B12 deficiency with iron deficiency anemia

Differential diagnosis

• iron deficiency accounts for the majority of all hypochromic microcytic anemias
• thalassemia
• hemoglobinopathy
• anemia of chronic disease
• sideroblastic anemia
  • lead
  • isoniazid
  • pyrazinamide
• Plummer-Vinson syndrome

Management

• treat underlying cause of iron deficiency
  • ensure dietary iron
  • uncomplicated asymptomatic patients with negative upper GI endoscopy & negative colonoscopy can be treated empirically with iron supplementation rather than video capsule endoscopy
• transfusion if indicated
  • symptomatic
  • risk of damage to vital organ
• iron supplementation (see iron replacement therapy)
  • FeSO4 325 mg (65 mg of elemental iron)
    • QD or QOD dosing on an empty stomach for 6 months
    • side effects in 25%
    • least expensive
    • QOD dosing (60 mg iron) associated with better absorption than QD, BID or TID dosing in iron-deficient women
  • QD or QOD dosing in elderly
    • GRS11 favors QOD dosing
    • ferrous gluconate 300 mg (36 mg of elemental iron) QD in elderly
    • 15 mg elemental iron PO QD in the elderly
    • ferrous gluconate not any better tolerated than FeSO4 (this claim not consistent with other literature)
  • children: 3 mg/kg of elemental iron QD as ferrous sulfate drops
  • iron uptake may be saturable
    • 15-20 mg/day of elemental iron can be as effective as higher doses
  • do not use ascorbate to facilitate absorption of iron
    • ascorbate increases iron absorption
    • 500-unit vitamin C supplements along with their iron once daily
      • this claim is not consistent with other literature
    • ascorbate may result in GI bleed via Fenton reaction
  • adding vitamin C to iron does not improve blood hemoglobin
  • lack of response to iron supplementation suggests malabsorption
    • celiac disease or other cause, see etiology
  • avoid tea & coffee (of questionable benefit)
• parenteral iron (iron sucrose)
  • reserved for patients not candidates for oral therapy
    • hemodialysis
  • patients with comorbid anemia of chronic renal failure
  • reduces need for transfusion relative to oral iron
  • iron dextran (imferon), iron sucrose
  • ferric gluconate for dialysis patients
  • four 200-mg infusions of iron sucrose over 2-weeks may reduce fatigue in women with low serum ferritin (< 15 ng/mL) but without anemia
  • rarely anaphylaxis will occur with parenteral iron
• maximal reticulocyte response occurs in 7-10 days of initiation of iron supplementation
• hemoglobin should normalize within 2 months
• continue iron for 3-4 months after normalization of hemoglobin to replenish iron stores

Follow-up: 6-8 weeks to assess response to therapy.

Screening not recommended

• evidence insufficient to recommend for or against screening of asymptomatic infants age 6-24 months or asymptomatic pregnant women

More general terms

• hypochromic anemia
• hypoplastic anemia
• microcytic anemia
• iron-deficiency

Additional terms

• iron replacement therapy

Patient information

iron-deficiency anemia patient information