4. Macrocytic anemia

Question 1

Definition of macrocytic anemia

Answer 1

Anemia with MCV > 100 fL

Question 2

Mechanism of macrocytic anemia

Answer 2

1. Insufficient nucleus maturation relative to cytoplasm expansion due to:
   a. Defective DNA synthesis
   b. Defective DNA repair

Question 3

Diseases that can result in macrocytic anemia

Answer 3

1. Megaloblastic anemia: impaired DNA synthesis and/or repair with hypersegmented neutrophils
   a. Vitamin B12 deficiency
   b. Folate deficiency
   c. Medications (e.g. Phenytoin, Sulfa drugs, Trimethoprim, Hydroxyurea, MTX, 6- mercaptopurine)
   d. Fanconi anemia
   e. Orotic aciduria
2. Nonmegaloblastic anemia: normal DNA synthesis without hypersegmented neutrophils
   a. Liver disease
   b. Alcohol use
   c. Diamond-Blackfan anemia
   d. Myelodysplastic syndrome
   e. Multiple myeloma
   f. Hypothyroidism

Question 4

Etiology of Vitamin B12 deficiency

Answer 4

1. Malabsorption
   a. ↓ Intrinsic factor (IF)
   i. Atrophic gastritis due to
   - Autoimmune atrophic gastritis: most common cause of vitamin B12 deficiency
   - H. pylori infection
   ii. Gastrectomy
   b. Reduced uptake of IF-vitamin B12 complex in terminal ileum due to:
   i. Alcohol use disorder
   ii. Crohn disease, celiac disease
   iii. Pancreatic insufficiency
   iv. Surgical resection of the ileum
2. Malnutrition
   a. Anorexia nervosa
   b. Strict vegan diets: occurs only after years of a strict diet that excludes all animal products (unlike folate deficiency, which occurs within a few months of insufficient intake)
3. Increased demand: e.g., during pregnancy, breastfeeding, fish tapeworm (Diphyllobothrium latum) infection, and leukemia

Question 5

Pathophysiology of Vitamin B12 deficiency

Answer 5

1. Physiological function: Vitamin B12 is a water-soluble cofactor for enzymatic reactions of DNA synthesis (via methionine synthase) and odd-chain fatty acid metabolism (via methylmalonyl CoA mutase). A deficiency of vitamin B12 leads to enzyme dysfunction.
2. Dysfunctional methionine synthase (normally converts homocysteine to methionine, thereby demethylating N5-methyl-THF to THF)
   a. ↓ Tetrahydrofolate (THF; cofactor in purine synthesis) → ↓ DNA synthesis → large, nucleated hematopoietic cells, including megaloblasts → megaloblastic precursors undergo apoptosis or are phagocytosed by macrophages → pancytopenia (including megaloblastic anemia)
   b. ↓ Methionine → neuropathy
   c. ↑ Homocysteine → endothelial damage → predisposes to cardiovascular disease
3. Dysfunctional methylmalonyl CoA mutase
   a. Methylmalonyl CoA cannot be converted to succinyl CoA → accumulation of methylmalonyl CoA and its precursor propionyl CoA, as well as their associated odd-chain fatty acids, which cannot be completely metabolized
   b. Propionyl CoA replaces acetyl CoA in neuronal membranes → demyelination → neurological manifestations

Question 6

Definition of pernicious anemia

Answer 6

A type of vitamin B12 deficiency caused by autoantibodies against intrinsic factor and/or gastric parietal cells (type II hypersensitivity reaction)

Question 7

Pathophysiology of pernicious anemia

Answer 7

1. Antiparietal cell antibodies: target gastric parietal cells
   a. Causes ↓ acid production and atrophic gastritis
   b. ↓ Intrinsic factor production → ↓ vitamin B12 absorption in terminal ileum
2. Anti-IF antibodies: bind intrinsic factor and block the vitamin B12 binding site

Question 8

What is pernicious anemia associated with?

Answer 8

Other autoimmune diseases (e.g., hypothyroidism, vitiligo)

Question 9

Pernicious anemia results in an increase risk for which disease?

Answer 9

Gastric cancer

Question 10

Clinical presentations in Vitamin B12 deficiency

Answer 10

1. Signs of anemia (e.g., fatigue, pallor)
2. Mild scleral icterus and/or jaundice
3. Neurological disturbances are generally symmetrical
   a. Peripheral neuropathy
   b. Subacute combined degeneration of spinal cord
   i. Paresthesia, impaired proprioception, loss of vibratory sensation, tactile sensation, and position discrimination due to demyelination of the dorsal columns
   ii. Spastic paresis due to demyelination of the lateral corticospinal tracts (axons of upper motor neurons)
   iii. Gait abnormalities (spinal ataxia) resulting from the damage of spinocerebellar tracts and dorsal columns
   c. Neuropsychiatric disease (e.g., reversible dementia, depression, paranoia)
   d. Worsening vision
   e. Autonomic dysfunction: impotence and incontinence
4. Glossitis

Question 11

Lab studies of Vitamin B12 deficiency

Answer 11

1. Signs of megaloblastic anemia
   a. ↓ Hb
   b. ↑ MCV (macrocytic), ↑ MCH (hyperchromic)
   c. Hypersegmented neutrophils
   d. ↓ Reticulocytes
2. Frequently thrombocytopenia and leukopenia (possibly pancytopenia)

Question 12

Etiology of folate deficiency

Answer 12

1. Malnutrition:
   a. Insufficient intake, malnutrition
   b. Chronic alcohol use
2. Malabsorption:
   a. Small bowel disease (e.g., tropical sprue, celiac disease, inflammatory bowel disease)
   b. Surgical resection of the small intestine
3. Increased requirement:
   a. Pregnancy/lactation
   b. Severe hemolytic anemia
4. Drug-related:
   a. Methotrexate
   b. Antiepileptic drugs (e.g., phenytoin)
   c. Sulfonamides
   d. Trimethoprim

Question 13

Pathophysiology of folate deficiency

Answer 13

Decreased folate levels leads to decreased levels of tetrahydrofolate. This, in term, leads to the following effects:

1. ↓ DNA synthesis → megaloblastic erythropoiesis → megaloblastic anemia (and ↓ in other cell lines)
2. ↓ Methionine and ↑ homocysteine → endothelial damage → ↑ risk of cardiovascular disease and thromboembolic events
3. During fetal development: nucleotide synthesis impairment → neural tube defects
4. Aberrant DNA methylation → ↑ risk of cancer

Question 14

Clinical presentations in folate deficiency

Answer 14

1. Signs of anemia (e.g., fatigue, pallor)
2. Glossitis
3. Maternal deficiency: fetal spina bifida/anencephaly

Question 15

Lab studies for folate deficiency

Answer 15

1. Macrocytic, megaloblastic anemia: ↑ MCV (> 100 μm3)
2. ↑ Homocysteine
3. Methylmalonic acid (MMA) is normal (unlike in vitamin B12 deficiency, where MMA is ↑)
4. Hypersegmented polymorphonuclear cells (PMNs)