Vitamin B12 and Folate Deficiency
Patients deficient in B12 (Cobalmin) or folate have elevated homocysteine levels.
Both are required for DNA synthesis. Vitamin B12 is also required for conversion of methylmalonic Co-A to succinyl Co-A. Excess methylmalonic acid precursors can be misincorporated into fatty acids and lipids during myelin sheath formation. This may explain the neurologic deficits seen with B12 deficiency.
Vitamin B12 Deficiency
Dietary sources: meats, milk products, and egg yolks. There are large stores of B12 in the liver, so dietary deficiency of B12 requires years of low intake and is rarely seen.
Absorption: Low pH in the stomach is needed to dissociate B12 from proteins Þ B12 binds to R protein in the stomach Þ intrinsic factor is made by the parietal cells, this binds to the R-B12complex Þ Pancreatic enzymes degrade R protein off B12 (this is required for ileal reabsorption) Þ B12 is absorbed and IF is broken off Þ B12 binds to transcobalamin II to be transported by the blood into tissues. Achlorohydria (from autoimmune disease or long term H2-blocker use) can thus lead to B12 malabsorption.
Causes: Pernicious anemia, gastrectomy, pancreatic insufficiency, intestinal overutilization of B12 (blind loop syndrome and fish tapeworm, diphyllobothrium), abnormal ileal mucosa (Crohn’s, ileal resection), B12 metabolism deficiency (rare).
Clinical manifestations of Deficiency :
- Pernicious anemia – autoimmune disorder resulting in atrophic gastritis and absent intrinsic factor production. Associated with other autoimmune disorders like Graves disease, Hashimoto’s thyroiditis, Addison’s disease and vitiligo. Clinical findings can include premature gray hair and vitiligo.
Diagnosis: Serum B12. About 5-10% have low normal B12 levels but, at the tissue level, are functionally B12 deficient. High serum homocysteine and methylmalonic acid. If high clinical suspicion of deficiency, work-up should be done.
Work-up (figuring out the cause of B12 deficiency): Perncious anemia is the most common cause. Anti-parietal cell antibody serum level is very sensitive but not specific. Anti-intrinsic factor antibody serum level is not as sensitive but very specific. If both tests come back negative and there is still some suspicion a Schilling Test can be performed. Schilling test: 1st part: Give oral, radiolabelled B12 and an intramuscular dose of non-radioactive B12 to saturate the receptors. Measure 24 hr. urine B12 level – low level indicates malabsorption. 2nd part: Test is repeated but with intrinsic factor added. (24 hr. urine level should correct itself if pernicious anemia, if not, there is an intestinal source of malabsorption). 3rd part: Test is repeated again, but after a course of antibiotics (will correct in cases of bacterial overgrowth). Problems with the Schilling test: Obtaining an accurate 24 hr. urine collection, the results are dependent upon normal renal function, and does not assess for ileal abnormalities.
Treatment: Generally parenteral B12. One regimen is 1 mg/day (IM) for one week, then 1 mg twice/week (week 2), then 1 mg/week for 4 weeks, then 1 mg/month for life (in PA). The response is rapid, first with the reversal of megaloblastosis and later the neurologic deficits (although not all will be totally reversible). If need blood transfusion, do it slowly.
- Hematologic (identical to folate deficiency) – Pateints present with symptoms of anemia (fatigue, weakness, dyspnea on exertion). Ineffective erythropoiesis (intermedullary RBC destruction), nuclear/cytoplasm dysynchrony (megablastosis), anemia (macrocytic then microcytic, opposite in iron deficiency); oval macrocytosis (elevated MCVs); poikylocytosis (RBC shape is distorted); elevated LDH and indirect bilirubin, low retic; hypersegmented neutrophils; leukopenia; and thrombocytopenia are characteristics of this deficiency.
- Non-hematologic manifestations – glossitis, angular cheilosis, diarrhea, abnormal pap smear.
- Neurologic manifestations (seen with B12 deficiency, and not folate deficiency) - 30% with neurologic findings have normal MCV and Hct. A lack of B12 can lead to patchy demyelination, spinal cord damage (subacute combined degeneration – begins in dorsal columns and proceeds to corticospinal tracts), paresthesias, numbness, leg weakness, ataxia, bowel or bladder incontinence, and impotence. Loss of joint position and vibratory sensation are early signs, sometimes with a broad based, ataxic gait. Cerebral manifestations include depression, dementia, and changes in personality.
Dietary sources: leafy vegetables, fruits, and animal proteins. Very limited stores, dietary deficiency commonly leads to clinical manifestations. Often seen in alcoholics whose diet is poor.
Absorption: Most folate compounds are in polyglutamate form. Hydrolysis by small intestinal brush border cells Þ absorption of monoglutamated folate forms. This process can be inhibited by brush border dysfunction (as seen in tropical sprue).
Causes: poor diet, alcohol (can also diminish folate absorption), anticonvulsants (particularly phenytoin), other meds (methotrexate, trimethoprim, sulfasalazine). Any disease with excess cell turnover (chronic hemolysis, psoriasis, pregnancy), and small bowel disorders (with extensive involvement).
Clinical Manifestations of Deficiency: See above.
Diagnosis: Serum folate level is very sensitive to folate intake – a single meal can normalize a patient with true folate deficiency. The RBC folate level correlates better with hepatic folate stores and reduced levels can be more reflective of tissue folate deficiency. RBC folate level can be decreased in both folate and B12 deficiency whereas the serum folate level will be normal in B12 deficiency. Elevated homocysteine only (normal meythylmalonic acid).
Treatment: 1 mg/day folate (usually orally, but can be given IV) is generally sufficient replacement (rare cases with excessive hemolysis will need 2-5 mg/day.)