B₁₂ Deficiency Anemia

Nejm 1997;337:1441; 1966;275:978

Cause:

• S/p gastric resection, even yrs later may develop, probably the most common cause now (Ann IM 1996;124:469), or post-gastric bypass or even plication
• Pernicious anemia (PA) with no intrinsic factor (IF): congenital juvenile type (Nejm 1972;287:425), and adult autosomal-dominant, atrophic gastritis type; both genetic but unrelated (Ann IM 1974;81:372)
• Diphylobothrium latumcompetition for gut B₁₂
• Dietary deficiency, very rare, perhaps only in strict non–ovolacto-vegetarians (Nejm 1978;299:317)
• Distal small bowel absorptive defect, limited to as little as 10-20 cm in some patients
• Blind loop bacterial consumption (Ann IM 1977;87:546)
• Drugs: PAS, neomycin, colchicine (Nejm 1968;279:845)
• "Pancreatic intrinsic factor" deficiency of enzyme to break down salivary protein-B₁₂ complex so can bind IF in stomach (Nejm 1971;284:627)
• Malabsorption of food/protein-bound B₁₂ very common (15% prevalence) in elderly (Am J Clin Nutr 1994;60:2)

Pathophys:B₁₂ is a crucial coenzyme for ribonucleotide reductase (RNA to DNA) and propionic catabolism, lack of which may cause CNS demyelination 1st in posterior, then in lateral columns. In PA, antigastric parietal cell (where IF made), as well as H⁺/K+-ATPase antibodies

PA increased in Scandinavians and blood group A people; prevalence in all races in US ~0.1% (Nejm 1978;298:647; Ann IM 1971;74:448), 1.9% over age 60 yr

Sx:of anemia, sore mouth; mean age of onset of PA = 60 yr; 20% of PA pts have pos family hx; diarrhea and other malabsorptions sx

Si:Anemia, glossitis, stomatitis, fair complexion, vitiligo

Sx onset after 2 yr of total deficiency

CHF due to profound anemia; thrombocytopenic purpura; stomach cancer with adult PA; subacute combined degeneration (case—Nejm 2003;348:2204) of cortex and posterior and lateral (corticospinal) columns of spinal cord w sx of distal paresthesias and numbness, paraplegia, vibratory sense and position sense loss, pos Rhomberg, psychiatric sx and dementia, and peripheral neuropathy, seen even without macrocytosis (Nejm 1988;318:17,20, 1752); carcinoid-secreting tumor due to chronic gastrin stimulation (Nejm 1997;336:866)

r/o (Nejm 1973;288:764) other macrocytic anemias: folate deficiency, orotic aciduria (Nejm 1990;322:1641, 1652), Di Guglielmo's syndrome, anti-DNA drugs

Lab:

Chem:Gastrin levels sky high (no acid inhibition since acid-secreting cells hit harder than gastrin secretors—Nejm 1970;282:358). Hgb F and A₂ increased; B₁₂ by RIA <100 pgm/cc, but levels <300 may be significant if elevated MMA levels too; increased LDH, Fe, bilirubin, serum methylmalonic acid (MMA) (>271 nM/L), and homocysteine levels elevated before overt B₁₂ deficiency (Ann IM 1996;124:469)

Gastric:Aspirate shows no acid, no false negatives?

Hem:Macrocytic anemia, neutropenia, and hypersegmented polys, normal or sometimes low platelets (ineffective production) unlike Fe deficiency; r/o myelodysplastic syndromes. Retics increased in 1st week of rx

Path:Marrow is megaloblastic with red cell precursor nuclei still open, ie, not pyknotic in late normoblastic stage, Howell-Jolly bodies, giant "C" metamyelocytes. In PA, stomach shows lymphatic infiltration early; CNS shows multifocal myelin degeneration with microcavities and glial scar

Serol:Elevated intrinsic factor antibodies in PA

Schilling test:Rarely done anymore; 1st load with im B₁₂, then 3 h later give hot B₁₂ po and measure excretion in 24-48 h urine sample, normal >15%; then repeat with intrinsic factor to see if corrects

Rx:

(Jags 2002;50:1789)

Preventive: avoid unnecessary folate replacement, which helps anemia but masks subacute combined degneration (Nejm 2003;348:2204)

B₁₂ 1000-2000 µgm qd loading dose × 7 d im or weeks po, or q 3 d × 4, or nasal spray (Nascobal) 500 µgm q 1 wk (8 doses/bottle); po as good as im even if no intrinsic factor (Acta Med Scand 1968;184:247; Nejm 1959;260:361); then 500-1000 µgm/mo po/im/nasal maintenance. Recheck retics or MMA level after 1 wk of rx, esp if po

Consider gastroscopy at least at diagnosis, maybe regularly to pick up cancer in situ, which has an 85% 5-yr survival