Megaloblastic Anemias

First Things First (assess & treat for the following)

• Although not considered a typical ICU disease, there are acute processes that megaloblastic anemia (MA) contributes to or directly affects.
• Source control for SIRS/sepsis as these patients usually present with decompensated disease
• Acute MA
  • Acute leukopenia with/without thrombocytopenia with minimal change in anemia
  • Can occur 5-6 hrs post N2O anesthesia in pts with borderline folate deficiency, severe catastrophic illness in conjunction with multiple transfusions, CRRT, TPN, meds (trimethoprim)
  • Similar to immune cytopenia but marrow extremely megaloblastic 12-24 hours after inciting event
  • Prevention with folinic acid 30 mg prior to surgery and repeated with cobalamin
  • Will not see laboratory stigmata of MA because of the rapidity with which it develops (hypersegmented PMN may not occur for 5 days)
  • Rapid response with folate (5 mg) and B12 (1 mg) is expected.
• B12-related deficiency occurs:
  • 3-5 years following total gastrectomy and 10-12 years following partial, except in cases where rapid cellular turnover occurs
• Pernicious anemia (PA)
  • Indolent, occurring usually age >40, blood group A especially
  • Can develop into acute crisis
  • Associated with autoimmune disorders, hypogammaglobulinemia
  • Look for premature graying or blueing of eyes
  • Can have signs and symptoms of MA but usually worse
• Insidious diseases can progress to acute disease when nutritional depletion is combined with rapid cell turnover.
• Generalized systemic disorder of impaired DNA synthesis from dysfunction of pyrimidine (B12) and purine (folate) pathways
  • Inappropriate concentrations of these substrates or drugs that impair their function
  • Rapidly dividing cells most affected: marrow, GI/GU mucosa
• All share an ineffective synthesis or availability in precursors of DNA production (deoxyribonucleoside triphosphates): cytosine, guanine/purine, adenine, thymine foundations, which then affect cells dependent on their production
  • Eventually, the basic cellular folate deficiency affects maturation phases of rapid growth cells with resultant enlargement (without maturity) and retention of normal transcription of DNA to RNA (maturation without development).
  • The final result is thwarted DNA repair, which fragments from mechanistic frustration of “S” phase division, leading to shortened, dysfunctional and irregular life spans of erythroid, leukoid and mucosal cell lines, ultimately ending in premature death.
• Folate deficiency most often is result of poor nutrition or rapid loss from exaggerated cell growth (reticulocytosis of hemolytic anemia).
  • EtOH abuse, elderly, hyperalimentation, hemodialysis, pregnancy
  • Poor/impaired absorption in sprue, anatomical/functional GI tract changes
  • Minimal daily requirement ~100 mcg
  • Average total body store (TBS) 10 mg
  • Storage sufficient for about 3-4 months if no rapid turnover exists
  • 33% of folate is bound to albumin, rest is free
  • 60-90 mcg enters bile and excreted daily in small bowel
  • This loss is worsened when intestinal cell sloughing is accelerated in malabsorptive diseases.
• B12 deficiency is most commonly caused by pernicious anemia, which is created by loss of intrinsic factor (IF) from anatomical and/or functional parietal cell loss (gastric surgery, blind loops, loss of terminal ileum).
  • Intrinsic factor is required for B12 absorption.
  • Body reserves are higher than folate and daily requirement is ~5 mcg.
  • 1-5 mcg is absorbed daily from a diet of 5-30 mcg/d.
  • Source is via animal sources, synthesis by microorganisms
  • Average TBS 2-5 mg
  • Daily obligatory loss ~1-5 mcg (0.1% TBS) irrespective of TBS
  • In pts with deficiency, 15 mcg/d is sufficient for restoration of body stores unless ongoing loss exists
  • Storage sufficient for ~3-4 years if no rapid turnover exists
  • Other causes: vegan diet, medications, congenital inborn errors
  • Crisis states of myelodysplastic syndromes and acute myelogenous leukemia (subtype M6)