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602 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 603

evidence of cobalamin malabsorption. The cause of the malabsorp-
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tion may be intestinal or gastric or a combination of both. 310, 311
Pancreatic Disease Some degree of cobalamin malabsorption has
been demonstrated in 50 to 70 percent of patients with exocrine pan-
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creatic insufficiency. Cobalamin malabsorption in pancreatic insuf-
ficiency is caused by a deficiency in pancreatic proteases, resulting in a
partial failure to destroy HC–Cbl complexes whose destruction is a pre-
requisite for the transfer of cobalamin to intrinsic factor. Pancreatic
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insufficiency rarely causes clinically significant cobalamin deficiency. 314
Dietary Cobalamin Deficiency Dietary cobalamin deficiency was
previously considered very unusual and restricted largely to complete
vegetarians who also do not consume dairy products and eggs (veg-
ans). Low serum cobalamin levels occur in 50 to 60 percent of individ-
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uals in this group. The onset of cobalamin deficiency in vegans is slower
than in conditions associated with cobalamin malabsorption. Thus it
may take 10 to 20 years for an individual consuming a vegan diet to man- Figure 41–15. Degeneration of spinal cord in combined system dis-
ifest features of cobalamin deficiency. This is because the enterohepatic ease. (Reproduced with permission from JW Harris, RW Kellermeyer: The Red
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pathway for biliary cobalamin absorption remains intact, thus conserv- Cell: Production, Metabolism, Destruction: Normal and Abnormal, rev ed.
ing body cobalamin stores. Breastfed infants of vegan mothers also Harvard University Press, Cambridge, 1970.)
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may develop cobalamin deficiency. Cobalamin deficiency in vegans
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presents with mild megaloblastic anemia, glossitis, and neurologic dis- in cobalamin deficiency. 328,329 Cobalamin deficiency may also contrib-
turbances. In addition to vegans, however, there is mounting evidence of ute to the risk of vascular disease through elevation of homocysteine
cobalamin inadequacy in children and young adults in developing coun- levels. Other disease associations with cobalamin deficiency have been
tries that cannot be explained on the basis of cobalamin malabsorption, described. These include a possible increase in breast cancer risk in
and has therefore been attributed to inadequate dietary intake. 318 premenopausal women and in osteoporosis. 331,332 Because cobalamin
330
Cobalamin deficiency may occur in severe general malnutrition. A reserves are large, years may pass between the cessation of cobalamin
megaloblastic anemia not related to cobalamin deficiency may accom- absorption and the appearance of deficiency symptoms.
pany kwashiorkor or marasmus. 319
Neurologic Abnormalities
Neurologic Effects of Cobalamin Deficiency Cobalamin deficiency causes a neurologic syndrome that is particularly
Previously, the neurologic abnormalities of cobalamin deficiency were dangerous because the syndrome can develop in isolation, with no
333
attributed to disordered metabolism of myelin lipids caused by an megaloblastic anemia to suggest a lack of cobalamin, 294,334 and because
320
impaired methylmalonyl CoA mutase reaction. Similar neurologic the syndrome cannot be reversed by treatment when it is sufficiently far
abnormalities do not, however, occur in patients with inherited methyl- advanced. The syndrome usually begins with paresthesias in feet and
malonyl CoA mutase deficiency. 260,321 Authentic combined system dis- fingers as a result of early peripheral neuropathy and disturbances of
ease has occurred in a patient with nutritional folate deficiency and vibratory sense and proprioception. The earliest signs, which precede
322
323
in a patient with MTHFR deficiency. The latter reports suggest the other neurologic findings by months, are loss of position sense in the
neurologic lesions of cobalamin deficiency result from deranged methyl second toe and loss of vibration sense for a 256-Hz but not a 128-Hz tun-
335
group metabolism. Animal studies support this hypothesis. Neuro- ing fork. Left untreated, the neurologic disorder progresses to spastic
logic disorders closely resembling combined system disease develop ataxia resulting from demyelination of the dorsal and lateral columns of
in cobalamin-deficient fruit bats, pigs, and monkeys. The devel- the spinal cord, so-called combined system disease (Fig. 41–15). 336
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325
opment of these disorders is prevented by methionine, which is pro- The peripheral nerves, the spinal cord, and the brain are affected by
duced in a cobalamin-dependent reaction and is the precursor of the cobalamin deficiency. Somnolence and perversion of taste, smell, and
biologic methylating reagent SAMe. A finding that further supports a vision with occasional optic atrophy are accompanied by slow waves on
methylation defect is that brains from cobalamin-deficient pigs contain the electroencephalogram. A dementia mimicking Alzheimer disease
337
increased levels of SAH, a powerful methylation inhibitor produced can develop. There is recent evidence linking low cobalamin status
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in SAMe-dependent methylation reactions: with brain volume loss and cerebral white matter lesions. 338,339 Psycho-
logical derangements, including psychotic depression and paranoid
SAMe + RH → SAH + RCH 3 schizophrenia, can occur. Frank psychosis in cobalamin deficiency
340
where RH is any unmethylated compound and RCH is its methylated has been given the sobriquet megaloblastic madness. 341
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form. Against the methylation defect hypothesis is the finding that The neurologic lesions of cobalamin deficiency can be detected
cobalamin deficiency had no effect on SAMe, SAH, or methylation of by magnetic resonance imaging (MRI). Demyelination appears as
342
327
phospholipids or myelin basic protein in the brains of fruit bats. T2-weighted hyperintensity of the white matter. MRI is particularly
useful for confirming the diagnosis of a neurologic disorder result-
ing from cobalamin deficiency. MRI also has been used to follow the
CLINICAL FEATURES progress of neurologic abnormalities during treatment of cobalamin-
The more typical clinical picture of cobalamin deficiency includes the deficient patients. 342
nonspecific manifestations of megaloblastosis, such as anemia, throm-
bocytopenia, neutropenia, smooth tongue, cardiomyopathy, pale yel- Subtle Cobalamin Deficiency
low skin and/or weight loss, plus specific features caused by the lack Some observations suggest the existence of a large group of patients
of cobalamin, chiefly neurologic abnormalities. Disturbances in either who are hematologically normal, with a normal hematocrit and MCV,
or both cellular and hormonal immune functions have been reported but who have cobalamin-responsive neuropsychiatric disease.
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