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VITAMIN B12 ASSOCAIETED NEUROLOGICAL Vitamin B-12 role in bone marrow function

DISEASE -In the cytoplasm, methylcobalamin serves as cofactor

Pathophysiology: for methionine synthesis by allowing transfer of a methyl
Vitamin B-12 structure (cobalamin) group from 5-methyl-tetrahydrofolate (5-methyl-THF) to
Is a complex molecule in which a cobalt atom is homocysteine (HC), forming methionine and
contained in a corrin ring. demethylated tetrahydrofolate (THF).
Vitamin B-12 is available in animal protein; strict -This results in reduction in serum homocysteine, which
vegetarians may obtain it from legumes(poor source) appears to be toxic to endothelial cells. Methionine is
Body stores further metabolized to S-adenosylmethionine (SAM).
Total body stores are 2-5 mg, of which half is stored in -THF is used for DNA synthesis. After conversion to its
the liver. polyglutamate form, THF participates in purine synthesis
The recommended daily intake is 2 mcg/d in adults; and the conversion of deoxyuridylate (dUTP) to
pregnant and lactating women require 2.6 mcg/d. deoxythymidine monophosphate (dTMP), which is then
Children require 0.7 mcg/d and, in adolescence, 2 mcg/d. phosphorylated to deoxythymidine triphosphate (dTTP).
Because vitamin B-12 is highly conserved through the dTTP is required for DNA synthesis
enterohepatic circulation, cobalamin deficiency from - In vitamin B-12 deficiency, formation of dTTP is
malabsorption develops after 2-5 years and deficiency impaired and accumulation of 5-methyl-THF is occurs,
from dietary inadequacy in vegetarians develops after 10- trapping folate in its unusable form and leading to
20 years. retarded DNA synthesis.
Deficiency causes are mainly nutritional and -RNA contains dUTP (deoxyuracil triphosphate) instead
malabsorptive, Pernicious anemia being most common. of dTTP, allowing for protein synthesis to proceed
Physiology of absorption uninterrupted and resulting in macrocytosis and
After ingestion, the low stomach pH cleaves cobalamin cytonuclear dissociation.
from other dietary protein. The free cobalamin binds to -Both deficiencies lead to megaloblastic anemia and
gastric R binder, a glycoprotein in saliva, and the disordered maturation in granulocytic lineages; therefore,
complex travels to the duodenum and jejunum, where folate supplementation can reverse the hematologic
pancreatic peptidases digest the complex and release abnormalities of vitamin B-12 deficiency but has no
cobalamin. impact on the neurologic abnormalities of vitamin B-12
-Free cobalamin can then bind with gastric intrinsic deficiency, indicating both result from different
factor (IF), a 50-kd glycoprotein produced by the gastric mechanisms.
parietal cells, the secretion of which parallels that of Vitamin B-12 role in the peripheral and central
hydrochloric acid. Hence, in states of achlorhydria, IF nervous systems
secretion is reduced, leading to cobalamin deficiency. -CNS demyelination may play a role, but how cobalamin
-Importantly, up to 99% of ingested cobalamin requires deficiency leads to demyelination remains unclear.
IF for absorption. only 1% of free cobalamin is absorbed Reduced SAM or elevated methylmalonic acid (MMA)
passively in the terminal ileum. Thus Oral replacement may be involved.
with large vitamin B-12 doses is appropriate for PA. -SAM is required as the methyl donor in polyamine
-Once bound with IF, vitamin B-12 is resistant to further synthesis and transmethylation reactions. Methylation
digestion. The complex travels to the distal ileum and reactions are needed for myelin maintenance and
binds to a specific mucosal brush border receptor, cublin, synthesis. SAM deficiency results in abnormal
which facilitates the internalization of cobalamin-IF methylated phospholipids such as phosphatidylcholine,
complex in an energy-dependent process. and it is linked to central myelin defects and abnormal
-Once internalized, IF is removed and cobalamin is neuronal conduction, which may account for the
transferred to other transport proteins, transcobalamin I, encephalopathy and myelopathy.
II, and III (TCI, TCII, TCIII). -In addition, SAM influences serotonin, norepinephrine,
and dopamine synthesis. This suggests that, in addition to
-Eighty percent of cobalamin is bound to TCI/III, whose structural consequences of vitamin B-12 deficiency,
role in cobalamin metabolism is unknown. The other functional effects on neurotransmitter synthesis that may
20% binds with TCII, the physiologic transport protein be relevant to mental status changes may occur.
produced by endothelial cells. Its half-life is 6-9 min,
thus delivery to target tissues is rapid. -Another possible cause of neurologic manifestations
-The cobalamin-TCII complex is secreted into the portal involves the other metabolically active form of
blood where it is taken up mainly in the liver and bone cobalamin, adenosylcobalamin, a mitochondrial cofactor
marrow as well as other tissues. in the conversion of L-methylmalonyl CoA to succinyl
-Once in the cytoplasm, cobalamin is liberated from the CoA. Vitamin B-12 deficiency leads to an increase in L-
complex by lysosomal degradation. methylmalonyl-CoA, which is converted to D-
An enzyme-mediated reduction of the cobalt occurs by methylmalonyl CoA and hydrolyzed to MMA. Elevated
cytoplasm methylation to form methylcobalamin or by MMA results in abnormal odd chain and branched chain
mitochondrial adenosylation to form adenosylcobalamin, fatty acids with subsequent abnormal myelination,
the 2 metabolically active forms of cobalamin. possibly leading to defective nerve transmission.

NO pathomechanisms in vitamin B-12 deficiency Physical Examination

NO can oxidize the cobalt core of vitamin B-12 from a 1+ Most patients exhibit signs of peripheral nervous system
to 3+ valance state, rendering methylcobalamin inactive, (PNS)-neuropathy or spinal cord involvement
inhibiting Homocysteine conversion to methionine and (myelopathy). Or combination of both.
depleting the supply of SAM. -Objective sensory abnormalities usually result from
Patients with sufficient vitamin B-12 body stores can posterior column involvement and less often from PNS
maintain cellular functions after NO exposure, but in disease.
patients with borderline or low vitamin B-12 stores, this -Early in the course, poor joint position and vibration
oxidation may be sufficient to precipitate clinical sense predominate. Typically, the legs are affected before
manifestations. the arms. A Romberg sign is commonly found. The gait
Causes of B12 deficiency may be wide based.
Check -Absent ankle reflexes with relative hyperreflexia at the
Clinical presentation- knees. Plantars are initially flexor and later extensor. A
History: Hoffman sign may be found (mixture of upper motor and