06: Megaloblastic Anemia

Question 1

Anemia

Answer 1

• Decreased hemoglobin/hematocrit
• Caused by:
  
  • Blood loss
  • Decreased production of RBCs
  • Increased destruction of RBCs
• Distinguished by reticulocyte count (measures bone marrow function)

Question 2

Marrow failure

Answer 2

• Metabolically highly active, 2/2 rapid cell turnover
  
  • Nl WBC lifespan 12-24 hrs
  • Nl platelet lifespan 7 days
  • Nl RBC lifespan 120 days
• Any slowing of DNA production –> marrow failure

Question 3

Megaloblastic anemia

Answer 3

• Hemoglobin production normal
• Defect in nuclear replication & division
• Affects all marrow elements
• Signs:
  
  • Trademark cell: oval macrocyte (MCV >100fl)
  • Hypersegmented neutrophils- 98%
  • Pancytopenia (reduction in all hema cells), especially if severe anemia
  • Reticulocytopenia
  • LDH elevated (90%)
  • Serum Fe normal or elevated
  • Serum B₁₂ or folate low
  • Marrow –> classic megaloblastic changes

Question 4

Folic acid

Answer 4

• One carbon fragment forms important for:
  
  • Thymidylate biosynthesis (making DNA)
  • Purine biosynthesis
  • Transport
• Dietary folates absorbed as methyl THF, converted to **THF **by B12 and methionine homocysteine

Question 5

Causes of folate deficiency

Answer 5

• Folate-poor diet (rare in US)
  
  • Alcoholism
  • Severe poverty
• Increased folate requirement
  
  • Pregnancy
  • Severe hemolytic anemia (↑RBC turnover)
  • Severe psoriasis (↑skin cell turnover)
• Drug therapy
• Malabsorption
  
  • Tropical sprue (Carribbean)
  • Celiac disease

Question 6

Manifestations of folate deficiency

Answer 6

• Megaloblastic anemia
• Glossitis/stomatitis (denuding of tongue papillae [have rapid turnover])
• GI malabsorption 2/2 impaired GI epithelium (rare)
• Labs: ↑homocysteine, nl methylmalonic acid

Question 7

Cobalamin (Vitamin B₁₂)
FUNCTIONS

Answer 7

• Folate metabolism: required for demethylation of methyl-THF
• Conversion of methylmalonyl CoA to succinyl CoA
  
  • ​↑methylmalonyl CoA suggests B₁₂ deficiency
• Methylation of myelin

Question 8

Cobalmin absorption

Answer 8

• Ingested and binds to R protein in stomach.
• Intrinsic factor (IF) (produced by parietal cells in stomach) replaces R protein in the duodenum because of alkalinazation.
• Complex travels to terminal ileum where B₁₂ absorbed.

Question 9

Causes of cobalamin deficiency

Answer 9

• Gastric failure
  
  • Pernicious anemia
  • Total gastrectomy (e.g., from cancer surgery)
• Ileal failure
  
  • Regional enteritis (Crohn’s disease)
  • Ileal resection
  • Tropical sprue
  • Celiac disease
• Competing organisms
  
  • Bacterial overgrowth (blind loop) - consumes B₁₂
  • Diphyllobothrium latum (fish parasite)

Question 10

Pernicious anemia

Answer 10

• Autoimmune destruction of parietal cells
• Antibodies vs. parietal cells and intrinsic factor
• Achlorhydria (low stomach acid)
• Increased incidence of gastric cancer
• Increased incidence in AAs, northern Europeans
• Often associated with other immune diseases (e.g., Hashimoto’s thyroiditis)

Question 11

Cause of peripheral folate depletion

Answer 11

Cobalamin deficiency (necessary to convert methyl-THF to THF)

Question 12

Peripheral manifestations of cobalamin deficency

Answer 12

• Megaloblastic anemia: indistinguishable from folate deficiency; due to intracellular folate deficiency
• Stomatitis/glossitis
• GI mucosa alterations
• Could correct the above with high-dose folate, but do not do this: must treat B₁₂ deficiency (necessary for neuro development)

Question 13

Central manifestations of cobalamin deficiency

Answer 13

• Brain: dementia, psychological disturbances
• Spinal cord: demyelinating disease, loss of posterior & lateral columns (subacute combined degeneration/combined system disease)
• Neurological disease stabliized but not reversed with treatment
• Labs: ↑homocysteine and methylmalonic acid

Question 14

Sequence of events in cobalamin deficiency

Answer 14

1. ↑ serum homocysteine & methylmalonic acid
2. ↓serum cobalamin
3. ↑MCV; neutrophil hypersegmentation
4. MCV rises above normal
5. Anemia
6. Symptoms (precede above in 30-40% of patients)

Question 15

Diagnosis/therapy of megaloblastic anemia

Answer 15

• Draw levels at first suspicion of problem, before any therapy.
• Once levels drawn, begin treatment with both B₁₂ and folate.
• Once levels back, discontinue one or the other depending on levels.
• Transfusions are to be avoided unless if hemodynamic compromise present or patient having angina.