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Issues In kwashiorkor
Table: Outcome after at least 5 years of follow-up of nephrotic patients with membranous nephropathy, treated with
supportive or immunosuppressive (methylprednisolone plus chlorambucil) therapy In the table these results are compared with those obtained after 5 years by Ponticelli2 with both supportive and immunosuppressive therapy. We conclude that the true outcome, a reduced renal function in nephrotic patients, was similar and had a poor prognosis in both untreated groups. Although remission of proteinuria was similar in Schieppati’s supportive group (which, however, included 13/37 [35%] patients with subnephrotic proteinuria), compared with Ponticelli’s immunosuppressive treatment group, a ten-fold reduction of progression to renal failure with treatment, despite wide confidence intervals (low statistical power) of both studies, cannot be discounted. Antonio Piccoli, Luana Pillon Institute of Internal Medicine, Division of 35128 Padova, Italy
Nephrology, University of Padova,
Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med
1
2
1993; 329: 85-89. Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989; 320: 8-13.
Issues In kwashiorkor SIR-Baily (Dec 11, p 1490) criticises Mayatepek and colleagues (Oct 16, p 958) for investigating leucotriene excretion in children with kwashiorkor on the grounds that it is "a starkly simple and thoroughly understood" problem for which "we already know largely what needs to be done". We already know what needs to be done for most illnesses: for AIDS we merely prevent promiscuity; for malaria we eliminate mosquitoes; and so on. There are no simple solutions; to assert that we can eliminate poverty, the harbinger of malnutrition, and that therefore research on malnutrition is a "disinterested search for knowledge", is mischievous. A societal component to a disease is not an argument to cease clinical research. Children admitted with kwashiorkor have an acute mortality rate of between 10% and 50% in different centres-which is higher than for almost any other paediatric disease. Baily’s contention implies either that the attending physicians are incompetent or that this mortality is acceptable and should not be improved by scientific methods. A clear indictment of the lack of scientific effort is the fact that the mortality rate has not changed for 40 years. Doctor’s struggling to treat these patients do their best in isolation, and cry out for help that Baily would deny. The perception that malnutrition is simple accepts the status quo, denies investigative funds, and discourages the scientific community from addressing important unsolved
problems. To say that kwashiorkor is a "political and economic rather than a laboratory problem" is a defence that allows the scientific community to ignore the difficulties and shirk responsibility. The political and economic realities are
problem
292
such that the present situation, where up to half the world’s children are malnourished, will continue for the foreseeable future. The only way to make progress is for many more scientists to stop "fiddling while children starve" and start to investigate the malnourished children, not the reverse. Only clinical scientists can most usefully contribute this expertise. Why is there so little global scientific effort going into malnutrition research? Why do we remain so ignorant about the pathophysiology of malnutrition?’ Criticism of the very few who try to help malnourished children scientifically is monstrous. Dickensian charity was never a solution for the diseases of poverty. We do not know the aetiology or pathogenesis of kwashiorkor.2,3 The hypothesis that kwashiorkor is due to protein deficiency is wrong. The misconception led genetic engineers to develop new varieties of crops, to support livestock and fish farming rather than crop production, even to methods to produce single-cell protein from oil. We remain ignorant about kwashiorkor because simplistic and naive concepts of aetiology fill the text books, after publication of which it ceased to be seen as a scientific problem. How wrong can we be? Investigation of kwashiorkor is resisted because it might put the reputations of senior workers, technological investment, soya processing plants, exports to the developing world and other commercial interests at risk. In fact, far from being "the minutiae of reductionist knowledge", Mayatepek and colleagues’ demonstration of a high leucotriene excretion is of practical importance in the management of these children because attempts to increase glutathione, known to be depleted in these children,’ may lead to their death if Wendel’s resuhs,5 which show that endotoxin/tumour-necrosis-factor induced hepatic necrosis in galactosamine-sensitised mice is mediated by the leucotrienes and stimulated by glutathione, are applicable to children with kwashiorkor. Michael H N Golden Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, UK
1
2
3 4 5
Golden MH. The importance of doing medical research in the Commonwealth Caribbean. West Indian Med J 1988; 37: 193-200. Golden MH. The consequences of protein deficiency in man and its relationship to the clinical features of kwashiorkor. In: Blaxter KL, Waterlow JC, eds. Nutritional adaptation in man. London: John Libbey, 1985: 169-87. Waterlow JC. Protein-energy malnutrition. London: Edward Arnold, 1992: 1-407. Golden WH, Ramdath DD. Free radicals in the pathogenesis of kwashiorkor. Proc Nutr Soc 1987; 46: 53-68. Wendel A. The role of glutathione and its eicosanoid adduct in experimental hepatitis in mice. In: Taniguchi N, Higashi T, Sakamoto Y, Meister A, eds. Glutathione centennial. San Diego: Academic Press, 1989: 333-42.
Toxicity of dothiepin In overdose SiR-Buckley and colleagues (Jan 15, p 159) draw attention to the well-known potential for all tricyclic antidepressants to cause seizures and arrhythmias when taken in overdose. They state that there are no previous studies on the toxicity of tricyclics, including dothiepin; this is not so, and indeed the results of their study are at odds with previous findings. A study undertaken by the poisons unit of Guy’s Hospital’ of 489 overdose patients, 70 of whom took dothiepin, did not show any significant differences in the frequency of convulsions or cardiac arrhythmias with various antidepressants. The frequency of seizures was 0-25% for individual drugs. Dothiepin was in the middle of the range, and did not differ significantly from any other tricyclic antidepressant. In addition, Jick and co-workers2 showed, in a population of 42 000 depressed patients receiving tricyclic
supportive or immunosuppressive (methylprednisolone plus chlorambucil) therapy In the table these results are compared with those obtained after 5 years by Ponticelli2 with both supportive and immunosuppressive therapy. We conclude that the true outcome, a reduced renal function in nephrotic patients, was similar and had a poor prognosis in both untreated groups. Although remission of proteinuria was similar in Schieppati’s supportive group (which, however, included 13/37 [35%] patients with subnephrotic proteinuria), compared with Ponticelli’s immunosuppressive treatment group, a ten-fold reduction of progression to renal failure with treatment, despite wide confidence intervals (low statistical power) of both studies, cannot be discounted. Antonio Piccoli, Luana Pillon Institute of Internal Medicine, Division of 35128 Padova, Italy
Nephrology, University of Padova,
Schieppati A, Mosconi L, Perna A, et al. Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med
1
2
1993; 329: 85-89. Ponticelli C, Zucchelli P, Passerini P, et al. A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989; 320: 8-13.
Issues In kwashiorkor SIR-Baily (Dec 11, p 1490) criticises Mayatepek and colleagues (Oct 16, p 958) for investigating leucotriene excretion in children with kwashiorkor on the grounds that it is "a starkly simple and thoroughly understood" problem for which "we already know largely what needs to be done". We already know what needs to be done for most illnesses: for AIDS we merely prevent promiscuity; for malaria we eliminate mosquitoes; and so on. There are no simple solutions; to assert that we can eliminate poverty, the harbinger of malnutrition, and that therefore research on malnutrition is a "disinterested search for knowledge", is mischievous. A societal component to a disease is not an argument to cease clinical research. Children admitted with kwashiorkor have an acute mortality rate of between 10% and 50% in different centres-which is higher than for almost any other paediatric disease. Baily’s contention implies either that the attending physicians are incompetent or that this mortality is acceptable and should not be improved by scientific methods. A clear indictment of the lack of scientific effort is the fact that the mortality rate has not changed for 40 years. Doctor’s struggling to treat these patients do their best in isolation, and cry out for help that Baily would deny. The perception that malnutrition is simple accepts the status quo, denies investigative funds, and discourages the scientific community from addressing important unsolved
problems. To say that kwashiorkor is a "political and economic rather than a laboratory problem" is a defence that allows the scientific community to ignore the difficulties and shirk responsibility. The political and economic realities are
problem
292
such that the present situation, where up to half the world’s children are malnourished, will continue for the foreseeable future. The only way to make progress is for many more scientists to stop "fiddling while children starve" and start to investigate the malnourished children, not the reverse. Only clinical scientists can most usefully contribute this expertise. Why is there so little global scientific effort going into malnutrition research? Why do we remain so ignorant about the pathophysiology of malnutrition?’ Criticism of the very few who try to help malnourished children scientifically is monstrous. Dickensian charity was never a solution for the diseases of poverty. We do not know the aetiology or pathogenesis of kwashiorkor.2,3 The hypothesis that kwashiorkor is due to protein deficiency is wrong. The misconception led genetic engineers to develop new varieties of crops, to support livestock and fish farming rather than crop production, even to methods to produce single-cell protein from oil. We remain ignorant about kwashiorkor because simplistic and naive concepts of aetiology fill the text books, after publication of which it ceased to be seen as a scientific problem. How wrong can we be? Investigation of kwashiorkor is resisted because it might put the reputations of senior workers, technological investment, soya processing plants, exports to the developing world and other commercial interests at risk. In fact, far from being "the minutiae of reductionist knowledge", Mayatepek and colleagues’ demonstration of a high leucotriene excretion is of practical importance in the management of these children because attempts to increase glutathione, known to be depleted in these children,’ may lead to their death if Wendel’s resuhs,5 which show that endotoxin/tumour-necrosis-factor induced hepatic necrosis in galactosamine-sensitised mice is mediated by the leucotrienes and stimulated by glutathione, are applicable to children with kwashiorkor. Michael H N Golden Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, UK
1
2
3 4 5
Golden MH. The importance of doing medical research in the Commonwealth Caribbean. West Indian Med J 1988; 37: 193-200. Golden MH. The consequences of protein deficiency in man and its relationship to the clinical features of kwashiorkor. In: Blaxter KL, Waterlow JC, eds. Nutritional adaptation in man. London: John Libbey, 1985: 169-87. Waterlow JC. Protein-energy malnutrition. London: Edward Arnold, 1992: 1-407. Golden WH, Ramdath DD. Free radicals in the pathogenesis of kwashiorkor. Proc Nutr Soc 1987; 46: 53-68. Wendel A. The role of glutathione and its eicosanoid adduct in experimental hepatitis in mice. In: Taniguchi N, Higashi T, Sakamoto Y, Meister A, eds. Glutathione centennial. San Diego: Academic Press, 1989: 333-42.
Toxicity of dothiepin In overdose SiR-Buckley and colleagues (Jan 15, p 159) draw attention to the well-known potential for all tricyclic antidepressants to cause seizures and arrhythmias when taken in overdose. They state that there are no previous studies on the toxicity of tricyclics, including dothiepin; this is not so, and indeed the results of their study are at odds with previous findings. A study undertaken by the poisons unit of Guy’s Hospital’ of 489 overdose patients, 70 of whom took dothiepin, did not show any significant differences in the frequency of convulsions or cardiac arrhythmias with various antidepressants. The frequency of seizures was 0-25% for individual drugs. Dothiepin was in the middle of the range, and did not differ significantly from any other tricyclic antidepressant. In addition, Jick and co-workers2 showed, in a population of 42 000 depressed patients receiving tricyclic