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ANEMIAS: Macrocytic

If LOW RBC, Hgb, or Hct
Then evaluate MCV & MCHC to determine if anemia is:
-microcytic hypochromic (MCV < 82 fL, MCHC < 30 g/dL)
Iron deficiency anemia
Sideroblastic anemia
Anemia of chronic disease (some cases)
Pyridoxine Responsive anemia (B6 deficiency)
Chronic blood loss
Lead poisoning
-normocytic normochromic (MCV 82-97 fL, MCHC 32-36 g/dL)
Acute blood loss
Early stage Iron deficiency anemia
Hemolytic anemia from any cause
Anemia of Chronic Disease (ACD)
Hereditary spherocytosis – osmotic fragility test
Aplastic Anemia
-macrocytic (MCV > 97 fL) (remember theoretical upper limit of 37 g/dL for MCHC)
B12 deficiency
Folate deficiency
Myelodysplastic Syndrome
Cancer chemotherapy
Alcohol abuse
Liver disease

--TYPES: B12/folate deficiency, myelodysplastic syndrome, hypothyroidism, cancer chemotherapy, alcohol abuse, liver disease
--ETIO: B12/folate deficiency, cytotoxic drugs-->defective DNA syn w/ normal RNA synthesis-->cytoplasm grows but nucleus doesn't
--ETIO: hyperthyroidism, pregnancy, disseminated cancer (dt increased requirement)
--ETIO: impaired DNA syn, alcoholism, VEGAN diet (all B12/folate)
--Dx: MCV > 95-100, macrocytes tend to be round not oval
--Dx: aniso, poik, high RDW, Howell Jolly bodies
--Dx: with alcoholism/liver dz see Target cells
--Dx: BM is markedly hypercellular dt increased numbers of all myeloid precursors
--Dx: hypersegs (neuts & eos)-->neutropenia
--Dx: retics may be elevated if BM is overstimulated in response to hemolysis
--Dx: consider thyroid testing
--Tx: B12 supplementation may not succeed if poor absorption dt no gastric parietal cells or intrinsic factor, due to autoimmune destruction of those cells

MEGALOBLASTIC VS MACROCYTIC is there a difference? the notes are confusing.
--megaloblastic: B12/folate deficient, drugs (dilantin), inborn errors of metabolism
--macrocytic: alcoholism, liver dz, hypothyroidism, myelodysplastic syndrome, chemotherapy
--megaloblastic = impaired DNA synthesis-->delayed division of rapidly proliferating cells (skin, GI, mucosa, hematopoietic cells)-->cellular gigantism "megaloblastosis"...so maturation asynchrony with cytoplsm growing at normal rate but nucleus retarded-->hemolysis in blood-->pancytopenia in severe cases
--common LAB features of (Macrocytic) Megaloblastic anemia: varying degrees of anemia, increased bilirubin dt hemolysis, macro-ovalocytes on blood smear, HOWELL-JOLLY BODIES in RBC's, hypersegmented neutrophils on smear, BM exam shows megaloblastic changes

--chronic dz<-impaired absorbtion of B12<-lack of intrinsic factor in gastic secretions
--cobalamin = vitamin B12
--most in Celts and Scandinavians (10-12/100,000)
--damage to gastric mucosa mbdt an autoreactive T-cell response leading to Abs against parietal cells (in 90% of pts with PA but only 5% of healthy adults)
--3 types of Abs found in pernicious anemia: 1) type I blocks binding of B12 to IF, 2) type II prevents binding of IF-B12 complex to ileal receptor, 3) type III not specific to PA but found in up to 50% of elders with chronic gastritis
--neurological complications B12 deficient and unTx: myelin loss in nerves of posterior column, megaloblastic madness: delusions, hallucinations, outbursts, paranoid schoziphrenic ideation
--in elderly: Alzheimers, memory loss, irritability, personality change
--pt may have neuro Sx w/o anemia when taking folate/high folate diet but still B12 deficient
--foods containing much cobalamin: meat and milk
--possible association between PA and H. pylori infx
--definite association between PA and other autoimmune dz
--people with pernicious anemia might also have H. pylori because they have a 2-3x risk of gastric carcinoma
--PA in adults assoc w/ gastric atrophy and achlorhydria-->iron deficiency; without acid dietary ferric is not solubized from foodstuffs
--Dx: gold standard of diagnosis for pernicious anemia: endoscopic biopsy of gastric mucosa showing depleted parietal cells, gastric "intestinalization" (stomach has goblet cells like intestine)
--S/Sx: oral: atrophic glossitis
--best way to test for B12 deficiency: serum < 180pg/mL (insurance pays for this test) or more reliable, RBC levels (insurance not pay)
--other findings that may indicate B12 deficiency: increased serum homocysteine and methylmalonic acid
--risks assoc w/ increased homocysteine and methymalonic a.: atherosclerosis and thrombosis

FOLATE = pteroylmonoglutamic acid
--folate stores last weeks to 4 months, daily requirement is 50-100 micrograms
--dietary sources of folate: green leafy veggies (foliage), lemons, bananas and melons, yeast and liver
--meds that interfere with folate absorbtion: dilantin, oral contraceptives, phenytoin
--not much stored in body: a continuous dietary supply is needed
--reasons for folate deficiency besides poor diet: overcooking food, alcoholism, malabsorption (bact overgrowth), increased requirements: pregnancy, disseminated cancer, hemolytic anemias, dialysis
--drugs impair the body's use of folate: methotrexate (chemo)
--serum folate test measures methylfolate, mb increased in 1/3 of B12 pts dt B12 needed to transfer methyl group to form tetrahydrofolate (metabolically active form)
--decreased serum folate mb unreliable dt recent low folate diet, or absorption probs
--BEST method to assess folate levels in tissues: RBC folate
--serum findings in folate deficiency: megalocytes in blood (megaloblasts in marrow), multinucleated neuts (hypersegs), decreased folate level, elevated homocysteine
--folate deficiency in pregnant women leads to babies with neural tube defects (spina bifida), low birtyh weight, cleft lip and palate
--enzyme impaired by cobalamin/folate deficiency: thymidine synthase--/-->DNA synthesis

--usu a 2-5 year store in liver
--irreversible neuro damage can result from deficiency
--3 common causes: malabsorption (low/lack IF, pernicious anemia), B12 degradation (bact overgrowth, worms), low dietary intake (relatively rare)
--B12 assays using intrinsic factor as only binding prot give true values for serum B12
--serum B12 decreased in 30% of pts with folate deficiency
--urine methymalonic acid assay (MMA): excretion is increased in 95% of pts with B12 deficiency
--MMA conversion to succinic acid requires B12 cofactor

--anemia in 30-50% of pts
--morphology ranges from macro to microcytic
--decreased thyroid hormone has a direct effect on erythropoiesis since hormone administration corrects both anemia and hypothyroid condition



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