Nutritional anemia

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Nutritional Anemia

Nutritional anemia refers to anemia caused by inadequate intake or absorption of one or more essential nutrients required for red blood cell (RBC) formation. The three main culprits are iron, folate (folic acid), and vitamin B12 (cobalamin). These anemias are classified by RBC size (mean corpuscular volume, MCV).

Classification by RBC Size

Type	MCV	Cause
Microcytic hypochromic	Below normal (<80 fL)	Iron deficiency
Macrocytic (megaloblastic)	Above normal (>100 fL)	Folate or Vitamin B12 deficiency

"Nutritional anemias can be classified according to the size of the red blood cells (RBCs), or mean corpuscular volume (MCV). Microcytic anemia, caused by lack of iron, is the most common form of nutritional anemia." - Lippincott Illustrated Reviews: Biochemistry, 8th ed.

1. Iron Deficiency Anemia (IDA)

Epidemiology

IDA affects approximately 1.2 billion individuals worldwide - roughly half of all anemic persons. Prevalence is highest in:

Preschool children (~25%)
Young women (37-40%)
Pregnant women (>40% with severe forms in low-income countries)

- Harrison's Principles of Internal Medicine, 22nd ed.

Causes

Chronic blood loss (most important in high-income countries): GI sources (peptic ulcer, colon cancer, hemorrhoids), gynecologic (menorrhagia, endometrial cancer)
Low dietary intake / poor bioavailability: Common in low-income countries; predominantly vegetarian diets; exclusively milk-fed infants; food insecurity
Increased demand: Pregnancy, infancy, rapid growth
Malabsorption: Celiac disease, various gastritides, post-gastrectomy

Pathophysiology (Sequence of Events)

Iron depletion develops in stages:

Iron stores depleted first - serum ferritin falls, bone marrow macrophages lose stainable iron
Serum iron falls, transferrin rises (TIBC increases)
Transferrin saturation <15-20% - iron supply to erythropoiesis becomes insufficient
Microcytic, hypochromic anemia develops

Maturing RBCs continue to divide past their normal stopping point due to insufficient hemoglobin, resulting in small, pale cells. The molecular explanation involves hepcidin - in iron deficiency, hepcidin levels are low, which normally would upregulate ferroportin to release iron from stores; mutations in TMPRSS6 (negative regulator of hepcidin) cause hereditary iron-refractory IDA (IRIDA).

Clinical Features

Mild/asymptomatic in most cases
Weakness, listlessness, pallor in severe cases
Koilonychia (spooning of nails), thinning and flattening of nails in long-standing cases
Pica - compulsion to eat non-food substances (dirt, clay, ice [pagophagia])
Impaired cognitive performance, reduced immunocompetence
In chronic heart failure: iron deficiency causes symptoms even independent of anemia

Laboratory Findings

Test	IDA Finding
MCV	Low (microcytic)
MCHC	Low (hypochromic)
Serum ferritin	Low (falls first)
Serum iron	Low
TIBC	High
Transferrin saturation	Low (<15%)
Platelet count	Often elevated
Reticulocyte count	Low/normal

- Robbins & Kumar Basic Pathology; Harrison's 22nd ed.

"Persons often die with iron deficiency anemia but virtually never of it. Microcytic hypochromic anemia is not a disease but rather a symptom of another underlying disorder." - Robbins & Kumar Basic Pathology

Treatment

Oral iron (ferrous sulfate/gluconate/fumarate) is first-line
IV iron preparations for malabsorption, intolerance, or non-response
Treat the underlying cause (e.g., stop GI bleeding)
Dietary advice: increase heme-iron foods; vitamin C enhances absorption; avoid tea/calcium with iron supplements

2. Megaloblastic Anemias (Folate and Vitamin B12 Deficiency)

Both folate and B12 are required for DNA synthesis. Deficiency causes accumulation of large, immature RBC precursors (megaloblasts) in the bone marrow and hypersegmented neutrophils in peripheral blood.

Bone marrow histology comparing normal (A) vs megaloblastic/folate-deficient (B) marrow. In B, markedly enlarged erythroid precursors with open chromatin are visible.

Bone marrow histology: Normal (A) vs. Megaloblastic (B) - Lippincott Illustrated Reviews: Biochemistry, 8th ed.

Mechanism

Folate (as tetrahydrofolate, THF) transfers one-carbon units for synthesis of purine nucleotides and thymidine monophosphate (TMP) for DNA
B12 is required to recycle THF - B12 deficiency "traps" folate as 5-methylTHF (the "methyl-folate trap"), making it metabolically unavailable for DNA synthesis
Without DNA synthesis, nuclear division lags behind cytoplasmic maturation - cells become large and immature

A. Folate Deficiency

Causes:

Increased demand: pregnancy and lactation (2nd most common nutritional anemia in pregnancy)
Poor dietary intake (folate is found in leafy vegetables; cooking destroys it)
Malabsorption: small intestine pathology
Alcoholism (impairs absorption and increases demand)
Drug-induced: methotrexate (dihydrofolate reductase inhibitor), trimethoprim, phenytoin
Body stores are limited - a folate-free diet can cause deficiency within a few weeks

Key distinction from B12: Folate deficiency causes ONLY hematologic abnormalities, NOT neurologic damage.

Treatment: Oral folic acid (nontoxic, excreted in urine). Give before conception and during the first trimester to significantly reduce neural tube defects (spina bifida, anencephaly). The CDC recommends 400 mcg/day for reproductive-age women.

B. Vitamin B12 (Cobalamin) Deficiency

Absorption pathway (unlike folate, very complex):

Schematic of vitamin B12 absorption through the GI tract, showing the key roles of haptocorrin, intrinsic factor, pancreatic proteases, and the cubilin receptor on ileal cells.

Vitamin B12 absorption - Robbins & Kumar Basic Pathology

B12 freed from food by pepsin in stomach
Binds haptocorrin (salivary protein)
In duodenum, pancreatic proteases release B12 from haptocorrin
B12 binds intrinsic factor (IF) - secreted by gastric parietal cells
IF-B12 complex absorbed in terminal ileum via cubilin receptor
Within ileal cells, B12 binds transcobalamin II for transport to liver and bone marrow
Stored in liver - reserves last 5-20 years

Causes (almost always malabsorption, not dietary):

Pernicious anemia (most frequent cause): autoimmune atrophic gastritis destroying parietal cells; autoantibodies block IF or IF-B12 binding to cubilin
Gastrectomy (loss of IF-producing cells)
Ileal resection or disease (Crohn disease, Whipple disease)
Gastric atrophy/achlorhydria (elderly)
Strict veganism (no animal products including milk/eggs) - the rare dietary cause

Clinical Features - unique to B12 deficiency:

All the hematologic features of megaloblastic anemia PLUS
Subacute combined degeneration of the spinal cord: demyelination of dorsal columns and lateral corticospinal tracts
Tingling/paresthesias in hands and feet
Difficulty walking, gait ataxia
Dementia, cognitive impairment
In extreme cases: hallucinations, paranoia, schizophrenic presentation
Neurologic damage is IRREVERSIBLE if untreated

Treatment:

Intramuscular hydroxocobalamin (preferred - rapid response, highly protein-bound, longer plasma levels)
Oral/sublingual cyanocobalamin for dietary deficiency
In pernicious anemia: therapy must be continued for life
In bariatric surgery patients: daily sublingual or monthly parenteral B12

Critical Clinical Warning: Folate vs. B12

"If folate is given alone, it may reverse the hematologic abnormalities; however, the subsequent vitamin B12 deficiency could go on to cause neurologic complications." - Lippincott Illustrated Reviews: Pharmacology, 16th ed.

Rule: When megaloblastic anemia is suspected, empirical treatment should use both folate AND B12 until a full workup is complete.

Distinguishing B12 from Folate Deficiency

Test	B12 Deficiency	Folate Deficiency
Serum B12	Low	Normal
Serum folate	Normal	Low
Methylmalonic acid (MMA)	High	Normal
Homocysteine	High	High
Neurologic signs	Present	Absent

MMA elevated + Homocysteine elevated = B12 deficiency
MMA normal + Homocysteine elevated = Folate deficiency only
Methylmalonic acid is the most sensitive and specific marker of B12 deficiency

- Goldman-Cecil Medicine; Lippincott Illustrated Reviews: Pharmacology

Summary Comparison Table

Feature	Iron Deficiency	Folate Deficiency	Vitamin B12 Deficiency
MCV	Low (microcytic)	High (macrocytic)	High (macrocytic)
Peripheral smear	Hypochromic, microcytic	Megaloblasts, hyperseg. neutrophils	Megaloblasts, hyperseg. neutrophils
Neurologic signs	No	No	Yes
Ferritin	Low	Normal	Normal
MMA	Normal	Normal	Elevated
Homocysteine	Normal	Elevated	Elevated
Body stores	Months	Weeks	5-20 years
Common in	Women of reproductive age, infants	Pregnancy, alcoholics	Elderly, strict vegans, pernicious anemia
Treatment	Oral/IV iron	Oral folic acid	IM hydroxocobalamin

Sources: Lippincott Illustrated Reviews: Biochemistry 8th ed. | Basic Medical Biochemistry 6th ed. | Robbins & Kumar Basic Pathology | Harrison's Principles of Internal Medicine 22nd ed. | Lippincott Illustrated Reviews: Pharmacology 16th ed. | Goldman-Cecil Medicine

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