The clinical review of vitamin B12 deficiency by Hunt et al was concise and informative. However, it did not mention autonomic dysfunction caused by vitamin B12 deficiency. Urinary incontinence, impotence and orthostatic hypotension are well-recognized autonomic manifestations of vitamin B12 deficiency (1) .
I have seen patients with long-standing drenching night sweats responding dramatically to intramuscular vitamin B12. Physiologically it is not surprising since changes in the peripheral autonomic nervous system may be the earliest manifestations of small-fiber neuropathy and hyperhidrosis frequently accompanies small-fiber peripheral neuropathy (2) . Episodic hyperhidrosis also occurs commonly in patients with familial dysautonomia, a hereditary sensory and autonomic neuropathy (3) . Autonomic dysfunction resulting in long- and short-term heart rate variability has been found to be significantly lower in vitamin-B12 deficient subjects compared to controls (4,5). Beitzke et al found major hemodynamic and autonomic impairment in patients with vitamin-B12 deficiency (6) . Defective sympathetic activation and decreased catecholamine release has been postulated as pathogenic mechanisms. Reduction of sudomotor sympathetic unmyelinated fibers has been described in patients with vitamin-B12 deficiency and orthostatic hypotension (7) .
The exact mechanism of excessive sweating in vitamin-B12 deficiency is a matter of speculation and will require further studies. Spinal sympathetic over-activity is one plausible explanation.
As the authors state, using serum cobalamin assay to diagnosis vitamin B12 deficiency has its limitations. “Functional” vitamin B12 deficiency is a syndrome where a wide variety of symptoms in the presence of “normal” serum levels of the vitamin respond to vitamin B12 therapy. Megaloblastic anemia and sub-acute combined degeneration of spinal cord are only the extreme manifestations observed at the far end of the spectrum with severe deficiency. On the other hand, non-specific symptoms like fatigue are the earliest manifestations. Autonomic dysfunction, it seems, is a common manifestation of functional vitamin B12 deficiency and seems to occur early in the course of disease process. This spectrum of disease usually presents in the absence of any changes in red blood cell indices and is easily misdiagnosed since serum levels of vitamin are in the “normal” range. Indeed, short-term fluctuations in HCy and MMA levels may also result in normal levels of these metabolites, thus obscuring the deficiency. This has been described previously in a patient who had total absence of vibratory sensation in the iliac crest, knees and ankles and normal levels of vitamin and metabolites, which resolved completely after 2 months of vitamin B12 therapy (8) . In this study, only 16% of patients with clinical response to cobalamin therapy had low serum levels of the vitamin and values were above 300pg/mL in 54% of cases. In addition, HCy and MMA values were in the normal range in 49% and 23% of cases respectively. Both metabolite levels were normal in 21% of cases.
The preferred route of administration of vitamin B12 has also been debated for a long time. Majority of cobalamin in the circulation is bound to haptocorrin and is unavailable for cellular uptake. Only cobalamin bound to transcobalamin is taken up by endocytosis mediated by the cell surface transcobalamin receptor. Only 6-20% of total plasma vitamin B12 is in the active form, bound to transcobalamin II (9) . Most of the studies of oral vitamin B12 therapy used serum levels of vitamin and its metabolites as the markers of response to therapy. However, correction of an abnormal laboratory value does not mean successful outcome. An objective improvement in health outcome is only meaningful if accompanied by a clinical response. For example, in a study of 80 patients over a 3-month period, although 80-90% of patients achieved normal serum cobalamin levels on an oral dose of 650 to 1000mcg daily, clinical improvement was observed only in 20 - 30% of patients (10) . Similarly, in an open study of vitamin B12 deficiency related to food-cobalamin malabsorption in 10 patients, oral crystalline cobalamin was prescribed at a dose of 650mcg per day for at least 3 months. Normalization of vitamin levels was seen in 80% of patients, along with significant increase in hemoglobin levels and decrease in mean corpuscular volume but clinical improvement occurred only in 20% of patients (11) . We can only speculate the reasons behind lack of response to oral vitamin B12 and it may be that cobalamin somehow undergoes a transformation in the portal circulation so is made less able to be internalized by the cells and only when cobalamin is able to bypass portal circulation, the cells internalize it. This seems to be a saturable process since a minority of patients responds clinically to oral therapy.
1- Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Med Baltimore1991;70:229-45.
2- Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006;34:57-61.
3- Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001;68:598-605.
4- Sözen AB, Demirel S, Akkaya V, Kudat H, Tükek T, Yeneral M, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998;71:25-7.
5- Aytemir K, Aksoyek S, Buyukasik Y, haznedaroglu I, Atalar E, Ozer N, et al. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 2000;23:975-8.
6- Beitzke M, Pfister P, Fortin J, Skrabal F. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic and Clin 2002;97:45-54.
7- Toru S, Yokota T, Inaba A, Yamawaki M, Yamada M, Mizusawa H, et al. Autonomic dysfunction and orthostatic hypotension caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry 1999;66:804-5.
8- Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978-85.
9- Hall CA. The carriers of native vitamin B12 in normal human serum. Clin Sci Mol Med 1977;53:453-7.
10- Andrès E, Perrin AE, Demangeat C, et al. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med 2003;14:221-6.
11- Andrès E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med 2001;111:126-9.
Rapid Response:
The clinical review of vitamin B12 deficiency by Hunt et al was concise and informative. However, it did not mention autonomic dysfunction caused by vitamin B12 deficiency. Urinary incontinence, impotence and orthostatic hypotension are well-recognized autonomic manifestations of vitamin B12 deficiency (1) .
I have seen patients with long-standing drenching night sweats responding dramatically to intramuscular vitamin B12. Physiologically it is not surprising since changes in the peripheral autonomic nervous system may be the earliest manifestations of small-fiber neuropathy and hyperhidrosis frequently accompanies small-fiber peripheral neuropathy (2) . Episodic hyperhidrosis also occurs commonly in patients with familial dysautonomia, a hereditary sensory and autonomic neuropathy (3) . Autonomic dysfunction resulting in long- and short-term heart rate variability has been found to be significantly lower in vitamin-B12 deficient subjects compared to controls (4,5). Beitzke et al found major hemodynamic and autonomic impairment in patients with vitamin-B12 deficiency (6) . Defective sympathetic activation and decreased catecholamine release has been postulated as pathogenic mechanisms. Reduction of sudomotor sympathetic unmyelinated fibers has been described in patients with vitamin-B12 deficiency and orthostatic hypotension (7) .
The exact mechanism of excessive sweating in vitamin-B12 deficiency is a matter of speculation and will require further studies. Spinal sympathetic over-activity is one plausible explanation.
As the authors state, using serum cobalamin assay to diagnosis vitamin B12 deficiency has its limitations. “Functional” vitamin B12 deficiency is a syndrome where a wide variety of symptoms in the presence of “normal” serum levels of the vitamin respond to vitamin B12 therapy. Megaloblastic anemia and sub-acute combined degeneration of spinal cord are only the extreme manifestations observed at the far end of the spectrum with severe deficiency. On the other hand, non-specific symptoms like fatigue are the earliest manifestations. Autonomic dysfunction, it seems, is a common manifestation of functional vitamin B12 deficiency and seems to occur early in the course of disease process. This spectrum of disease usually presents in the absence of any changes in red blood cell indices and is easily misdiagnosed since serum levels of vitamin are in the “normal” range. Indeed, short-term fluctuations in HCy and MMA levels may also result in normal levels of these metabolites, thus obscuring the deficiency. This has been described previously in a patient who had total absence of vibratory sensation in the iliac crest, knees and ankles and normal levels of vitamin and metabolites, which resolved completely after 2 months of vitamin B12 therapy (8) . In this study, only 16% of patients with clinical response to cobalamin therapy had low serum levels of the vitamin and values were above 300pg/mL in 54% of cases. In addition, HCy and MMA values were in the normal range in 49% and 23% of cases respectively. Both metabolite levels were normal in 21% of cases.
The preferred route of administration of vitamin B12 has also been debated for a long time. Majority of cobalamin in the circulation is bound to haptocorrin and is unavailable for cellular uptake. Only cobalamin bound to transcobalamin is taken up by endocytosis mediated by the cell surface transcobalamin receptor. Only 6-20% of total plasma vitamin B12 is in the active form, bound to transcobalamin II (9) . Most of the studies of oral vitamin B12 therapy used serum levels of vitamin and its metabolites as the markers of response to therapy. However, correction of an abnormal laboratory value does not mean successful outcome. An objective improvement in health outcome is only meaningful if accompanied by a clinical response. For example, in a study of 80 patients over a 3-month period, although 80-90% of patients achieved normal serum cobalamin levels on an oral dose of 650 to 1000mcg daily, clinical improvement was observed only in 20 - 30% of patients (10) . Similarly, in an open study of vitamin B12 deficiency related to food-cobalamin malabsorption in 10 patients, oral crystalline cobalamin was prescribed at a dose of 650mcg per day for at least 3 months. Normalization of vitamin levels was seen in 80% of patients, along with significant increase in hemoglobin levels and decrease in mean corpuscular volume but clinical improvement occurred only in 20% of patients (11) . We can only speculate the reasons behind lack of response to oral vitamin B12 and it may be that cobalamin somehow undergoes a transformation in the portal circulation so is made less able to be internalized by the cells and only when cobalamin is able to bypass portal circulation, the cells internalize it. This seems to be a saturable process since a minority of patients responds clinically to oral therapy.
1- Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Med Baltimore1991;70:229-45.
2- Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006;34:57-61.
3- Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001;68:598-605.
4- Sözen AB, Demirel S, Akkaya V, Kudat H, Tükek T, Yeneral M, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998;71:25-7.
5- Aytemir K, Aksoyek S, Buyukasik Y, haznedaroglu I, Atalar E, Ozer N, et al. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 2000;23:975-8.
6- Beitzke M, Pfister P, Fortin J, Skrabal F. Autonomic dysfunction and hemodynamics in vitamin B12 deficiency. Autonomic Neurosci: Basic and Clin 2002;97:45-54.
7- Toru S, Yokota T, Inaba A, Yamawaki M, Yamada M, Mizusawa H, et al. Autonomic dysfunction and orthostatic hypotension caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry 1999;66:804-5.
8- Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood 2005;105:978-85.
9- Hall CA. The carriers of native vitamin B12 in normal human serum. Clin Sci Mol Med 1977;53:453-7.
10- Andrès E, Perrin AE, Demangeat C, et al. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med 2003;14:221-6.
11- Andrès E, Kurtz JE, Perrin AE, et al. Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption. Am J Med 2001;111:126-9.
Competing interests: No competing interests