7  Acquired Underproduction Anemias

Key Points
  • Underproduction anemia: ↓ Hb w/ low reticulocyte count
    • Bone marrow fails to replace senescent RBCs adequately
    • Classify by MCV after confirming underproduction
  • Iron deficiency anemia: most common cause worldwide
    • Microcytic, hypochromic, ferritin <15 μg/L
    • Causes: blood loss (GI, menses), malabsorption, dietary
    • Oral Fe first-line; IV Fe for refractory/intolerant
  • Megaloblastic anemias: B₁₂/folate deficiency → impaired DNA synthesis
    • B₁₂ deficiency: absorption impairment (autoimmune gastritis) > dietary
      • ↑ MMA, ↑ HCy = sensitive markers; neuropsych symptoms reversible early
      • Rule out before folate monotherapy (masks neuro disease)
    • Folate deficiency: ↓ dietary intake (rare) > absorption/↑ requirements
      • ↓ serum/RBC folate; NO neurologic symptoms (contrast B₁₂)
  • Drug-induced megaloblastic anemias: 5-FU, methotrexate, antiretrovirals

7.1 Introduction

  • Underproduction anemia: ↓ Hb w/ ↓ absolute reticulocyte count
    • Body makes ~200B RBCs/day (iron, EPO, vitamins, marrow microenvironment)
    • Deficiency of any component → inadequate RBC production
    • Classify by MCV after confirming underproduction

7.2 Iron Deficiency Anemia

7.2.1 Background & Epidemiology

  • Most common anemia globally, affecting >1B people
    • Predominantly: menstruating women (ages 12-55), children
    • ~7% adolescent girls; ~16% nonpregnant adult women
    • Higher risk: pregnancy, vegans, elderly w/ GI bleeding
  • Iron stores: normal 20-300 μg/L (♀) / 50-300 μg/L (♂)
    • Depletion: <15 μg/L
    • Daily RBC recycling provides ~25 mg/day iron

7.2.2 Iron Metabolism

  • Iron absorption: duodenum & proximal jejunum (tightly regulated)
    • Hepcidin = master regulator
      • ↑ w/ iron overload & infection
      • ↓ w/ iron deficiency, anemia, hypoxia, inflammation
    • Heme iron (animal): ~30% absorbed; nonheme (plant): ~10%
      • ↑ by vitamin C; ↓ by tannins, phytates, polyphenols
  • Transport: Fe → transferrin → erythropoiesis, myoglobin, other proteins

7.2.3 Etiologies

Causes of Iron Deficiency
Mechanism Causes
Insufficient intake Exclusive breastfeeding w/o supplementation; Excess cow milk; Vegan/vegetarian diet
Impaired absorption Celiac, gastric bypass, IBD, autoimmune gastritis, H. pylori
↑ Requirements Rapid growth, ESAs, pregnancy, lactation
Congenital IRIDA (TMPRSS6 mutation), hemochromatosis, DMT1 deficiency
↑ Losses Abnormal uterine bleeding, GI bleeding/malignancy, parasites

7.2.4 Stages & Clinical Features

  • Stage 1 (iron depletion): ↓ ferritin; normal CBC/iron labs
  • Stage 2 (early IDA): ↓ iron, ↑ TIBC, ↑ sTfR; normal CBC
  • Stage 3 (IDA): ↓ Hb, hypochromia, microcytosis
  • Clinical features (mild-severe): fatigue, dyspnea, tachycardia, restless legs, pica, glossitis, angular cheilitis

7.2.5 Diagnosis

Laboratory

  • CBC: microcytic (MCV <80 fL), hypochromic (MCH <27 pg, MCHC <32)
    • ↓ RBC count, ↑ RDW
    • ↓ Ret-He (earliest marker of Fe deficiency)
  • Ferritin: <15 μg/L = iron deficiency
    • <20 μg/L (♀) / <30 μg/L (♂) consistent w/ deficiency

    • 200 μg/L excludes IDA (unless severe inflammation)

    • Caveat: ↑ w/ liver disease, inflammation, malignancy
  • Serum iron & TIBC: ↓ iron, TIBC variable
    • TSAT = serum Fe ÷ TIBC × 100%; <16% suggests deficiency
  • sTfR (soluble transferrin receptor): ↑ = iron deficiency
    • Unaffected by inflammation (vs. ferritin)
    • Helpful in hemolysis + Fe deficiency
    • sTfR:ferritin ratio >1 = likely Fe deficiency

Underlying etiology

  • Young children: dietary history, Fe intake
  • Menstruating ♀: menstrual bleeding assessment; rule out GI source
  • Adult ♂ & postmenopausal ♀: upper/lower GI endoscopy for occult bleeding
  • Unexplained Fe deficiency: assess malabsorption (celiac, bypass, IBD); H. pylori testing

7.2.6 Treatment

Dietary goals

  • ~10-20 mg Fe/day: heme (red meat, poultry, fish) + nonheme (cereals, legumes)
    • Heme absorption ~30% vs. nonheme ~10%
    • Enhance nonheme w/ vitamin C; avoid tannins, phytates

Oral iron (first-line)

  • Agents: ferrous sulfate (65 mg elem), ferrous fumarate, bisglycinate
  • Dosing: 65-130 mg elem Fe daily or QOD
    • QOD > QD (↑ absorption, ↓ GI AE)
    • ↓ dose (65-100 mg) may ↑ tolerance
  • Side effects (dose-dependent): nausea, dyspepsia, constipation, diarrhea
    • Darkens stools (counsel patient)
    • Take w/ vitamin C (enhances absorption)
    • Avoid w/ calcium, dairy, phytates (↓ absorption)
  • Response: reticulocytosis (3-7 days), Hb ↑ (2 weeks)
    • Continue 3 months after Hb normalizes (replete stores)
    • Failure → assess adherence, absorption, ongoing loss, undiagnosed pathology

IV iron (refractory/intolerant)

  • Indications: refractory IDA, oral intolerance, excessive GI losses, severe anemia
    • Also endorsed by AHA for heart failure + Fe deficiency
  • Dosing: Total deficit [mg] = target Hb [g/dL] × weight [kg] × 2.4 + stores (500-1000 mg)
  • Formulations (6 available):
    • Lower cost: iron sucrose, ferric gluconate, LMWD
      • Safe & effective; 200-300 mg/infusion limit
    • 3rd generation: ferumoxytol, ferric carboxymaltose, iron isomaltoside
      • Allow larger doses, shorter infusion time
    • LMWD allows total-dose infusion (up to 1000 mg)
  • Side effects: hypersensitivity (>200-400 mg)
    • Iron dextran & ferumoxytol: black box warning
    • Arthralgias, myalgias, flushing
    • Rare: permanent skin staining
Clinical Pearl: Iron Deficiency Management

Failure to respond to oral iron → reassess regimen (dosing, adherence, absorption) & evaluate for ongoing/occult blood loss, occult malignancy, celiac disease, bleeding disorder. Consider IV iron for refractory disease, severe anemia, intolerance, or hemoglobinopathy.

7.3 Megaloblastic Anemias

7.3.1 Overview

  • Megaloblastic anemia: impaired DNA synthesis (hematopoietic cells)
    • Macrocytosis w/ abnormal nuclear-cytoplasmic asynchrony
    • Macroblasts, hyperlobulated myeloid precursors, giant promyelocytes
    • Marrow erythroid predominance (reversed myeloid:erythroid ratio)
  • Pathophysiology: ↓ purine/pyrimidine synthesis
    • B₁₂: cofactor for methionine synthase, methylmalonyl-CoA mutase
    • Folate: 1-carbon metabolism → purine/pyrimidine synthesis
    • Either deficiency → impaired DNA synthesis

7.3.2 Vitamin B₁₂ Deficiency

Absorption pathway

  • Stomach: dietary B₁₂ bound to haptocorrin
  • Duodenum: pancreatic enzymes degrade haptocorrin → cobalamin binds intrinsic factor (IF)
  • Terminal ileum: IF-cobalamin endocytosed, IF degraded → cobalamin binds transcobalamin II (TCII)
  • Plasma: TCII transports cobalamin to tissues

Etiologies

Etiologies of B₁₂ Deficiency
Category Causes
Absorption impairment Pernicious anemia (PA; IF Abs), H. pylori, gastric bypass, ileal resection, antacids, tapeworm (D. latum)
Dietary insufficiency Strict vegans, breastfed infants of B₁₂-deficient mothers
Congenital CUBAM defects, transcobalamin deficiency, Imerslund-Gräsbeck, IF deficiency

Clinical manifestations

  • Hematologic: anemia (insidious, may be asymptomatic)
  • Neurologic (demyelination central/peripheral nervous system; often irreversible)
    • Paresthesias, ataxia, posterior lateral column degeneration
    • Loss vibratory sense & proprioception
    • Central cord syndrome
  • Psychiatric: mania, paranoia, psychosis, delirium, dementia, personality changes
  • GI: glossitis, anorexia, diarrhea
  • Key point: early recognition critical—neurologic damage irreversible if delayed

Diagnosis

  • Initial screen: serum B₁₂, folate, methylmalonic acid (MMA), homocysteine (HCy) simultaneously
    • B₁₂ assay lacks sensitivity/specificity
    • Low B₁₂ (<200 pg/mL) + ↑ MMA & ↑ HCy = confirmed deficiency
    • MMA & HCy ↑ before B₁₂ falls below normal (early marker)
    • Caution: B₁₂ >200 pg/mL does NOT exclude deficiency if MMA/HCy ↑
  • Subclinical B₁₂ deficiency: ↓ B₁₂ alone (normal MMA/HCy)
    • No treatment indication clear; unclear if progressive

Treatment

  • Parenteral replacement (preferred): IM B₁₂ injections
    • Marrow response: ↓ megaloblasts (1 week)
    • CBC improvement (2-3 weeks)
    • Neutrophil hypersegmentation may persist (up to 2 weeks)
  • Oral replacement: selected patients (good absorption, dietary deficiency)
    • High-dose oral B₁₂ (bypasses IF-dependent absorption)
  • Response: erythropoiesis ↑, ↑ reticulocyte count early
    • Monitor: iron stores may deplete w/ ↑ marrow activity (may need concurrent Fe)
Clinical Pearl: B₁₂ & Neurologic Symptoms

Early recognition critical—B₁₂ deficiency neurologic changes irreversible. Folate monotherapy masks progressive demyelination. Always confirm B₁₂ before folate initiation.

7.3.3 Folate Deficiency

Background

  • Rare (less common than B₁₂ deficiency)
  • Body stores: adequate (develop deficiency within months if ↓ intake)
  • Causes: ↓ dietary (primary), malabsorption (sprrue, Crohn, celiac), ↑ requirements
  • No neuropsychiatric manifestations (contrast B₁₂)

Etiologies

Etiologies of Folate Deficiency
Category Causes
↓ Dietary intake Alcoholism; ↓ fruits, vegetables; prolonged cooking
Impaired absorption Celiac, Crohn disease, intestinal dysfunction
↑ Requirements Cellular proliferation, pregnancy, hemolytic anemia, hemodialysis, medications (methotrexate, phenytoin, carbamazepine)

Diagnosis

  • Hematologic: indistinguishable from B₁₂ deficiency
    • Macrocytic anemia w/ megaloblasts
  • Lab differentiation: folate ↓; MMA & HCy normal
    • Serum folate <2 ng/mL = deficiency (reflects short-term status)
    • RBC folate (reflects long-term stores) also ↓
  • Key: Folate deficiency does NOT cause neurologic disease

7.4 Medication-Induced Megaloblastic Anemia

  • Common agents:
    • 5-Fluorouracil (pyrimidine analog, antimetabolite)
    • Methotrexate (folic acid antagonist)
    • Antiretrovirals (esp. zidovudine at high doses)
    • Mycophenolate, hydroxyurea, azathioprine
  • Mechanism: ↓ purine/pyrimidine synthesis
  • Management: discontinue offending agent; replete B₁₂/folate as needed

7.5 Copper Deficiency (Rare)

  • Causes: malabsorption, GI surgery w/o Cu supplementation, ↑ Zn intake
    • Congenital (Menkes disease, enteropathy-related)
  • Presentation: anemia (microcytic, normocytic, or macrocytic), neutropenia, pancytopenia
    • Marrow: ringed sideroblasts, dysplasia
    • Neurologic symptoms possible
  • Mechanism: Cu cofactor for hephaestin, ceruloplasmin (ferric Fe transport)
    • Also cytochrome c oxidase cofactor
    • ↓ activity → ringed sideroblasts
Clinical Pearl: Diagnostic Testing in Megaloblastic Anemia

Obtain B₁₂, folate, MMA, HCy simultaneously. B₁₂ & folate assays lack sensitivity. MMA & HCy more sensitive; may ↑ before B₁₂ falls. Consider elevated markers even w/ normal B₁₂.