686
Journal of the Royal Society of Medicine Volume 85 November 1992
Cyanocobalamin- a
A G Freeman MD FRCP
case
for withdrawal: discussion paper
Meadow Rise, 3 Lakeside, Swindon SN3 IQE
Keywords: anaemia, pernicious; optic neuropathies; chronic cyanide intoxication; hydroxocobalamin; cyanocobalamin
It seems evident that controversy still surrounds the treatment of pernicious anaemia and other vitamin B12 deficiency disorders. The long quest for the 'antipernicious anaemia factor' in the liver seemed to have ended in 1948 when pure cyanocobalamin was isolated. This was found to be very active therapeutically when given by intramuscular injection and was non-toxic in extremely high doses'. Lederle, in a recent commentary2, advocates that patients with pernicious anaemia should now be treated with oral cyanocobalamin. He is not without support in that 40% of patients with pernicious anaemia in Sweden are being similarly treated3. He further states that such!- treatment is cheap and effective, produces clinical and haematological remissions, and that most patients would prefer it if given the choice. He considers that a wider appreciation of its effectiveness would be of value to physicians and that this is 'Medicine's best kept secret' and that 'it is time to let the secret out'. It is now known that there are at least four forms of vitamin B12 (cobalamin), ie cyanocobalamin, hydroxocobalamin and two coenzymes forms which are biochemically active, namely methylcobalamin and
adenosylo-cobalamin4. Evidence has been presented that oral treatment with vitamin B12 cannot replace body stores in patients with Addisonian pernicious anaemia where there is a lack of gastric intrinsic factor due to an autoimmune gastritis causing malabsorption of vitamin B12 or in those who have undergone total gastrectomyor ileal resection. Such patients will require life-long parenteral vitamin B12 therapy. In the United Kingdom, intramuscular hydroxocobalamin has replaced cyanocobalamin as it is retained in the body longer than cyanocobalamin and thus for maintenance therapy needs only be given at intervals of 3 months5-7. In strongly opposing any treatment for pernicious anaemia other than parenteral hydroxocobalamin on a life-time basis once the diagnosis has been confirmed I would emphasize that hydroxocobalamin is also a potent cyanide antagonist whereas cyanocobalamin is not. Thus oral or intramuscular cyanocobalamin is ineffective in the treatment of patients with tobacco amblyopia or retrobulbar neuritis in pernicious anaemia, examples of optic neuropathy due to chronic cyanide intoxication8. Healthy smokers with normal vision have raised cyanocobalamin levels and raised plasma and urinary thiocyanate levels, products of effective cyanide detoxication as compared with the levels in healthy non-smokers9. Patients with tobacco amblyopia, even if they smoke more than their healthy counterparts, have much lower levels of plasma cyanocobalamin and thiocynate in their body fluids indicative of a
reduced ability to detoxify the cyanide in the tobaccosmoke to which they are exposed'0. Patients with tobacco amblyopia who have normal serum vitamin B12 levels need not continue therapy with intramuscular hydroxocobalamin once their visual acuity and visual fields have returned to normal providing they abstain from further smoking. However, those patients who have low serum vitamin B12 levels or evidence of -defective vitamin B12 absorption will need to continue-indefinitely with hydroxocobalamin irrespective of their smoking habits as will all patients with pernicious anaemia and other vitamin B12 deficiency disorders who are at risk of developing- optic neuropathy if they are smokers. There is certainly no place for either oral or intramuscular cyanocobalamin in the treatment of such patients in that hydroxocobalamin and not cyanocobalamin, is a powerful cyanide antagonist. Because confusion still persisted among doctors over the various commercial forms of vitamin B12 available for therapeutic use and their adverse effects in neuro-ophthalmological disorders, we presented a case for withdrawal of cyanocobalamin in favour of hydroxocobalamin and submitted t-his in 1970 to the Committee on Safety of Medicines'2. As no action was taken by the manufacturers, we asked again in 1978 'Svhy has cyanocobalamin not been withdrawn?'. We laid particular emphasis on the fact- that some patients fail to respond to treatment because, although hydroxocobalamin had been prescnbed, cyanocobalamin had been administered instead. The, diagnosis may then be questioned, treatment stopped and the patient with tobacco amblyopia be condemned to a life of poor sight'3. In 1981, the Committee on Safety of Medicines drew attention to our thesis that hydroxocobalamin is effective in treatment of certain bptie neuropathies, of which tobacco amblyopia is an example, but cyanocobalamin is not. Since tobacco amblyopia may occur in patients with pernicious anaemia it is clearly preferable to use hydroxocobalamin routinely instead of cyanocobalamin'4. This view is supported by Linnell and co-workers who, in support of our contention, stated that there was no condition in which it has been claimed that cyanocobalamin was preferable to hydroxocobalamin and that there was no place for its continued use15. Despite these recommendations it appears that cyanocobalamin has not been withdrawn for therapeutic use'6. Even the World Health Organization's Committee on the selection of essential drugs listed only cyanocobalamin'7, thus placing an incalculable number of patients with tobacco and tropical amblyopia and optic neuropathy in pernicious anaemia at risk.
Journal of the Royal Society of Medicine Volume 85 November 1992
Since our original work on the aetiology of tobacco amblyopia'8 and retrobulbar neuritis in Addisonian pernicious anaemia19 more than 30 years ago, I have been particularly concerned with the neuro-ophthalmological manifestations of deficiency diseases and degenerative neuropathies. Clinical and laboratory studies on the pathogenesis of such disorders have been continued in many centres and the precise role ofchronic cyanide intoxication has merited plarticular attention. As a result of the development and application of the chromo-bioautographic method of estimating individual plasma-cobalamins in neuroophthalmological disorders, it may in the future be possible to identify patients at risk in genetically determined disorders, such as Leber's optic atrophy, and thus initiate effective prophylactic measuresIsuch as stopping smoking and giving hydroxocobalamin' intramuscularly before the onset of irreversible visual failure8.' Besides being present in tobacco-smoke and alcohol, cyanide has a world-wide distribution in the plant kingdom. Optic neuropathy, often afsdciated with nerve deafness, my6lopathy -with yramidal tract involvement, and sensory ataxia, is particuiilAiy prone to occur in tropical and subtropical counthes where nutrition is poor and the indigenouds population suffers from a low protein and sulphurcontaining amino acid intake ind high cyanide exposure from a dietary source such as unprocessed cassava roots20. If the indiscriminate dumping of industrial cyanide waste continues unchecked with the inherent risk of pollution of food and water supplies there' may well come a time when more widespread chronic cyanide neurotoxicity occurs in the'Western hemfsphere from a dietary source in persons with-a genetic or acquired error of cyanide or vitamin B12 metabolism2l. Looking to the future, it is possible that other cyanide antagonists, with the obvious advantage 'of oral administration, will becbme available. In this event, all patients with tobacco and nutritional amblyopia and optic neuropathy, myelopathy or neuropathy of obscure origin, should be very carefully screened for evidence of vitamin B12 deficiency before embarking on any therapy other than intramuscular hydroxocobalamin22.
References 1 Matthews DM, Linnell JC. Vitamin B12: an area of darknss BAM 1979ii:5333-5 2 Lederle FA. Oral cobalamin for pernicious anaemia. JAMA 199426b94-53 Berlin R. Written communication, Nov. 1989 (cited by Lederle FA, JAMA 1991;265:94-5) 4 Matthews DM. Distribution of cobalamins in the animal body. In: Zagalak B, Friedrich W, eds. Vitamin B12: Proceedings ofthe 3rd European Symposium. Berlin: De Gruyter, 1979:681-94 5 Drugs and Therapeutics Bulletin 1984;22:43-4 6 Chipping PM. Vitamin B12 deficiency. Prescribers' J 1988;28:117-24 7 British National Formulary. March 1991:296-7 8 Freeman AG. Optic neuropathy and chronic cyanide intoxication: a review. J R Soc Med 1988;18:103-6 9 Wilson J, Linnell JC, Matthews DM. Plaacqbalmin in neuro-ophthalmelogal diseases. Lancet 1971i:777-8 10 Wilson J, Matthews D)4. Metabolic inter-relationships between cyanide, thiocyanate and vitamin B12 in smokerse and non-smokers. Cltn Sci 1966;#31:1-7 11 k'6ulds WS, Bronte-Stewart JM, ChiAolm IA. Serum
thiocyahate concentrstions intobaccb amblyoia. Nature (A,tnd) 1968;218:586 12 Foulds WS, Freeman AG,- Phillips CI, Wilson J. Cyanocobalamin: a casefor withdrawal. Lancet 1970;:35 13 Freeman AG, Wilson J, F'ou1ds WS, Phillips CI. Why has cyanocobalamin, not been withdrawn? Lancet 1978;i:777-8 14 Commitee pn Safety of Medicines, Current problems, July 1981:6 15 Linnell JC, Matthews DM, England JM Therapeutic
misuse of cyanocobalamin. Lancet 1978ii:1053-4
16 Monthly Index ofMedical Specialities, January 1991:178 17 Terry SI, Nicholson GD. Survival of cyanocobalamin. Lancet 1978i-:848 18 Heaton JM, McCormick AJA, Freeman AG. Tobacco amblyopia: a clinical. manifestation of vitamin B12
deficiency.-Lancet 1958ji:286-90 19 Freeman AG, Heaton JM. The aetiology of retrobulbar neuritis in Addisonian pernicious anaemia. Lancet 196i1i:908-11 20 Osuntokum BO, Osuntokun 0. Tropical amblyopia. Am J Ophthalmol
1971;72:708-16
21 Freenan AG. Chronic cyanide intoxication. BZM 1981;282:1321 22 Freeman AG. Food and cyanide. BMJ 1972ii:49
(Accepted 18 November- 1991)
687
Journal of the Royal Society of Medicine Volume 85 November 1992
Cyanocobalamin- a
A G Freeman MD FRCP
case
for withdrawal: discussion paper
Meadow Rise, 3 Lakeside, Swindon SN3 IQE
Keywords: anaemia, pernicious; optic neuropathies; chronic cyanide intoxication; hydroxocobalamin; cyanocobalamin
It seems evident that controversy still surrounds the treatment of pernicious anaemia and other vitamin B12 deficiency disorders. The long quest for the 'antipernicious anaemia factor' in the liver seemed to have ended in 1948 when pure cyanocobalamin was isolated. This was found to be very active therapeutically when given by intramuscular injection and was non-toxic in extremely high doses'. Lederle, in a recent commentary2, advocates that patients with pernicious anaemia should now be treated with oral cyanocobalamin. He is not without support in that 40% of patients with pernicious anaemia in Sweden are being similarly treated3. He further states that such!- treatment is cheap and effective, produces clinical and haematological remissions, and that most patients would prefer it if given the choice. He considers that a wider appreciation of its effectiveness would be of value to physicians and that this is 'Medicine's best kept secret' and that 'it is time to let the secret out'. It is now known that there are at least four forms of vitamin B12 (cobalamin), ie cyanocobalamin, hydroxocobalamin and two coenzymes forms which are biochemically active, namely methylcobalamin and
adenosylo-cobalamin4. Evidence has been presented that oral treatment with vitamin B12 cannot replace body stores in patients with Addisonian pernicious anaemia where there is a lack of gastric intrinsic factor due to an autoimmune gastritis causing malabsorption of vitamin B12 or in those who have undergone total gastrectomyor ileal resection. Such patients will require life-long parenteral vitamin B12 therapy. In the United Kingdom, intramuscular hydroxocobalamin has replaced cyanocobalamin as it is retained in the body longer than cyanocobalamin and thus for maintenance therapy needs only be given at intervals of 3 months5-7. In strongly opposing any treatment for pernicious anaemia other than parenteral hydroxocobalamin on a life-time basis once the diagnosis has been confirmed I would emphasize that hydroxocobalamin is also a potent cyanide antagonist whereas cyanocobalamin is not. Thus oral or intramuscular cyanocobalamin is ineffective in the treatment of patients with tobacco amblyopia or retrobulbar neuritis in pernicious anaemia, examples of optic neuropathy due to chronic cyanide intoxication8. Healthy smokers with normal vision have raised cyanocobalamin levels and raised plasma and urinary thiocyanate levels, products of effective cyanide detoxication as compared with the levels in healthy non-smokers9. Patients with tobacco amblyopia, even if they smoke more than their healthy counterparts, have much lower levels of plasma cyanocobalamin and thiocynate in their body fluids indicative of a
reduced ability to detoxify the cyanide in the tobaccosmoke to which they are exposed'0. Patients with tobacco amblyopia who have normal serum vitamin B12 levels need not continue therapy with intramuscular hydroxocobalamin once their visual acuity and visual fields have returned to normal providing they abstain from further smoking. However, those patients who have low serum vitamin B12 levels or evidence of -defective vitamin B12 absorption will need to continue-indefinitely with hydroxocobalamin irrespective of their smoking habits as will all patients with pernicious anaemia and other vitamin B12 deficiency disorders who are at risk of developing- optic neuropathy if they are smokers. There is certainly no place for either oral or intramuscular cyanocobalamin in the treatment of such patients in that hydroxocobalamin and not cyanocobalamin, is a powerful cyanide antagonist. Because confusion still persisted among doctors over the various commercial forms of vitamin B12 available for therapeutic use and their adverse effects in neuro-ophthalmological disorders, we presented a case for withdrawal of cyanocobalamin in favour of hydroxocobalamin and submitted t-his in 1970 to the Committee on Safety of Medicines'2. As no action was taken by the manufacturers, we asked again in 1978 'Svhy has cyanocobalamin not been withdrawn?'. We laid particular emphasis on the fact- that some patients fail to respond to treatment because, although hydroxocobalamin had been prescnbed, cyanocobalamin had been administered instead. The, diagnosis may then be questioned, treatment stopped and the patient with tobacco amblyopia be condemned to a life of poor sight'3. In 1981, the Committee on Safety of Medicines drew attention to our thesis that hydroxocobalamin is effective in treatment of certain bptie neuropathies, of which tobacco amblyopia is an example, but cyanocobalamin is not. Since tobacco amblyopia may occur in patients with pernicious anaemia it is clearly preferable to use hydroxocobalamin routinely instead of cyanocobalamin'4. This view is supported by Linnell and co-workers who, in support of our contention, stated that there was no condition in which it has been claimed that cyanocobalamin was preferable to hydroxocobalamin and that there was no place for its continued use15. Despite these recommendations it appears that cyanocobalamin has not been withdrawn for therapeutic use'6. Even the World Health Organization's Committee on the selection of essential drugs listed only cyanocobalamin'7, thus placing an incalculable number of patients with tobacco and tropical amblyopia and optic neuropathy in pernicious anaemia at risk.
Journal of the Royal Society of Medicine Volume 85 November 1992
Since our original work on the aetiology of tobacco amblyopia'8 and retrobulbar neuritis in Addisonian pernicious anaemia19 more than 30 years ago, I have been particularly concerned with the neuro-ophthalmological manifestations of deficiency diseases and degenerative neuropathies. Clinical and laboratory studies on the pathogenesis of such disorders have been continued in many centres and the precise role ofchronic cyanide intoxication has merited plarticular attention. As a result of the development and application of the chromo-bioautographic method of estimating individual plasma-cobalamins in neuroophthalmological disorders, it may in the future be possible to identify patients at risk in genetically determined disorders, such as Leber's optic atrophy, and thus initiate effective prophylactic measuresIsuch as stopping smoking and giving hydroxocobalamin' intramuscularly before the onset of irreversible visual failure8.' Besides being present in tobacco-smoke and alcohol, cyanide has a world-wide distribution in the plant kingdom. Optic neuropathy, often afsdciated with nerve deafness, my6lopathy -with yramidal tract involvement, and sensory ataxia, is particuiilAiy prone to occur in tropical and subtropical counthes where nutrition is poor and the indigenouds population suffers from a low protein and sulphurcontaining amino acid intake ind high cyanide exposure from a dietary source such as unprocessed cassava roots20. If the indiscriminate dumping of industrial cyanide waste continues unchecked with the inherent risk of pollution of food and water supplies there' may well come a time when more widespread chronic cyanide neurotoxicity occurs in the'Western hemfsphere from a dietary source in persons with-a genetic or acquired error of cyanide or vitamin B12 metabolism2l. Looking to the future, it is possible that other cyanide antagonists, with the obvious advantage 'of oral administration, will becbme available. In this event, all patients with tobacco and nutritional amblyopia and optic neuropathy, myelopathy or neuropathy of obscure origin, should be very carefully screened for evidence of vitamin B12 deficiency before embarking on any therapy other than intramuscular hydroxocobalamin22.
References 1 Matthews DM, Linnell JC. Vitamin B12: an area of darknss BAM 1979ii:5333-5 2 Lederle FA. Oral cobalamin for pernicious anaemia. JAMA 199426b94-53 Berlin R. Written communication, Nov. 1989 (cited by Lederle FA, JAMA 1991;265:94-5) 4 Matthews DM. Distribution of cobalamins in the animal body. In: Zagalak B, Friedrich W, eds. Vitamin B12: Proceedings ofthe 3rd European Symposium. Berlin: De Gruyter, 1979:681-94 5 Drugs and Therapeutics Bulletin 1984;22:43-4 6 Chipping PM. Vitamin B12 deficiency. Prescribers' J 1988;28:117-24 7 British National Formulary. March 1991:296-7 8 Freeman AG. Optic neuropathy and chronic cyanide intoxication: a review. J R Soc Med 1988;18:103-6 9 Wilson J, Linnell JC, Matthews DM. Plaacqbalmin in neuro-ophthalmelogal diseases. Lancet 1971i:777-8 10 Wilson J, Matthews D)4. Metabolic inter-relationships between cyanide, thiocyanate and vitamin B12 in smokerse and non-smokers. Cltn Sci 1966;#31:1-7 11 k'6ulds WS, Bronte-Stewart JM, ChiAolm IA. Serum
thiocyahate concentrstions intobaccb amblyoia. Nature (A,tnd) 1968;218:586 12 Foulds WS, Freeman AG,- Phillips CI, Wilson J. Cyanocobalamin: a casefor withdrawal. Lancet 1970;:35 13 Freeman AG, Wilson J, F'ou1ds WS, Phillips CI. Why has cyanocobalamin, not been withdrawn? Lancet 1978;i:777-8 14 Commitee pn Safety of Medicines, Current problems, July 1981:6 15 Linnell JC, Matthews DM, England JM Therapeutic
misuse of cyanocobalamin. Lancet 1978ii:1053-4
16 Monthly Index ofMedical Specialities, January 1991:178 17 Terry SI, Nicholson GD. Survival of cyanocobalamin. Lancet 1978i-:848 18 Heaton JM, McCormick AJA, Freeman AG. Tobacco amblyopia: a clinical. manifestation of vitamin B12
deficiency.-Lancet 1958ji:286-90 19 Freeman AG, Heaton JM. The aetiology of retrobulbar neuritis in Addisonian pernicious anaemia. Lancet 196i1i:908-11 20 Osuntokum BO, Osuntokun 0. Tropical amblyopia. Am J Ophthalmol
1971;72:708-16
21 Freenan AG. Chronic cyanide intoxication. BZM 1981;282:1321 22 Freeman AG. Food and cyanide. BMJ 1972ii:49
(Accepted 18 November- 1991)
687
