1050
separate from peristaltic contractions. We would also point out that nutcracker oesophagus and spasm are not the same condition, although both could occur in the same patient.
University Department of Surgery, University of Wales College of Medicine, Cardiff CF4 4XN, UK, and Department of Gastroenterology, University Hospital of Wales, Cardiff
H. C. MCKIRDY R. LOWNDES G. L. SWIFT H. A. DAVIES D. LEWIS
J. RHODES
GL, Alban Davies H, McKirdy H, Lowndes R, Lewis D, Rhodes J. A long-term clinical review of patients with oesophageal pain. Q J Med 1991; 81:
1. Swift
937-44.
2. Benjamin SB, Richter JE, Cordova CM, Knuff TE, Castell DO. Prospective manometric evaluation with pharmacologic provocation of patients with suspected oeaophageal motility disfunction. Gastroenterology 1983; 84: 893-901.
SiR,—In your March 7 editorial you note that"... studies on the
aetiology of obscure chest pain tend to show abnormalities in the organ system that is the special interest of the researchers". It is unfortunate that you exemplify this statement by concentrating exclusively on ischaemic heart disease and oesophageal causes of chest pain. You do not mention chest wall pain, spinal arthritis, hyperventilation, or anxiety and panic, all of which are well described and
of chest discomfort.’ Your also preoccupation ignores the considerable evidence that persistent non-cardiac chest pain is often of multifactorial aetiology, in which misinterpretation of medically minor symptoms leads to the conclusion that pain is due to heart disease, which in turn leads to further anxiety and to repeated consultation and discomfort disability.z Oesophageal misinterpreted as evidence of heart disease is likely to be a more unpleasant and disabling symptom than oesophageal symptoms common
causes
with single
causes
accepted as indigestion. You also surprisingly conclude that the outlook for the sort of patients with persistent symptoms investigated in hospital clinics is good. This is only true for expectation of life: outcome with respect to relief of symptoms, disability, consultation, and other use of medical resources is poor.3,4 Clearly simple reassurance is not effective in such patients,showever effective it is for patients presenting with acutely unexplained chest pain in primary care. Reassurance and information are useful when the patient finds an explanation for symptoms acceptable, and when particular anxieties are dealt with. In a small proportion of patients an underlying depressive illness requires antidepressants, but in others advice about coping with the localised muscular tension, explanation about the link between anxiety and heightened awareness of bodily sensations, breathing exercises to prevent hyperventilation, and advice about graded return to normal activities are necessary. We have presented evidence from a controlled trial showing the benefits of such treatment in patients with chronic symptoms, which have persisted despite reassurance in the clinic.6 Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK
RICHARD MAYOU CHRISTOPHER BASS
Mayou RA. Atypical chest pain. J Psychosom Res 1989; 33: 373-406. Mayou RA. Patients’ fears of illness, chest pain and palpitations. In: Creed F, Mayou RA, Hopkins A, eds. Medical symptoms not explained by organic disease. London: Royal College of Psychiatrists and Royal College of Physicians, 1991: 25-33. 3. Bass C. Chest pain and breathlessness: relationship to psychiatric illness. Am J Med 1992; 92 (suppl IA): 12-17 4. Chambers J, Bass C. Chest pain with normal coronary anatomy: a review of natural history and possible etiologic factors. Prog Cardiovasc Dis 1990; 33: 161-84. 5. Charmer KS, James MA, Papouchado M, et al. Failure of a negative exercise test to reassure patients with chest pain. QJ Med 1987; 63: 315-22. 6. Klimes I, Mayou RA, Pearce MJ, et al Psychological treatment for atypical non-cardiac chest pain: a controlled evaluation. Psychol Med 1990; 20: 605-11.
is high.2 Swift et aP have shown that this pattern of low mortality but high morbidity at follow-up also applies to patients with negative cardiac investigations but positive evidence of oesophageal
dysmotility. Furthermore, although
reassurance
after
negative cardiological
may be beneficial for many patients, for some it is neither safe nor effective. Lantinga et al4 found that one year after patients with chest pain had angiographically normal coronary
investigations
to believe that they had heart disease and 42% remained unsure. I have completed twelve years’follow-up of patients who underwent coronary angiography for chest pain in 1979-80.5 Of 31 patients who were explicitly reassured that their coronary arteries were normal, 13 % believed they had heart disease one year later and 6% remained unsure.6 Furthermore, of those who said they had been reassured by their cardiologist’s statements, 60% were still receiving medical attention for continuing chest pain. 29 of these patients were re-interviewed in 1991, none of whom showed evidence of clinically significant coronary artery disease during follow-up. Nevertheless, 10 of 29 (34%) said they believed they had heart disease, and 5 (17%) remained unsure. 11of these 15 (73%) continued to complain of pain, as did a similar proportion (64%) of the 14 who did not believe that they had heart disease. These findings suggest that for substantial number of such patients reassurance is ineffective in both the short and long term. Furthermore, according to a model of hypochondriasis proposed by Warwick and Salkovskis,7 reassurance is in fact counterproductive, since it increases morbidity by perpetuating a cycle of health-related anxiety (which it only temporarily allays), followed by repeated medical consultation, and further costly investigation, with negative results and attendant iatrogenic risks. A psychological approach that specifically excludes reassurance has been used with benefit in patients with chest pain of uncertain cause.8 The challenge therefore is to separate, in advance, those patients who will respond positively to reassurance from those who will not: it is only in the former group that reassurance is safe and effective, and the outlook good.
arteries, 25% continued
University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
S. G. POTTS
AVG, Sones FM. Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: 10-year follow-up of 521 patients. Circulation 1980; 62: 712-17. 2. Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries Am J Cardiol 1986; 58: 1181-87. 3 Swift GL, Alban-Davies H, McKurdy H, Lowndes R, Lewis D, Rhodes J A long-term clinical review of patients with oesophageal pain. Q J Med 1991; 81: 1. Proudfit WL, Bruschke
937-44.
Lantinga LJ, Sprafkin RP, McCroskery JH, Baker MT, Warner RA, Hill NE. One-year psychosocial follow-up of patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 1988; 62: 209-13. 5. Bass C, Cawley R, Wade C, et al. Unexplained breathlessness and psychiatric morbidity in patients with normal and abnormal coronary arteries Lancet 1983; i:
4
605-09. 6. Bass C. Unexplained chest pain: clinical and psychosocial studies in patients with presumptive angina. MD, thesis, University of London, 1984 7 Warwick HM, Salkovskis PM. Hypochondriasis. Behav Res Ther 1990; 28: 105-17. 8. Klimes I, Mayou RA, Pearce MJ, Coles L, Fagg JR. Psychological treatment for atypical non-cardiac chest pain: a controlled evaluation. Psychol Med 1990; 20: 605-11.
1. 2.
SiR,—Your March 7 editorial is welcome, but your conclusion that "outlook is good and reassurance is a safe and effective remedy", cannot go unchallenged. It is true that the mortality associated with chest pain of uncertain origin is low,’ but long-term morbidity in respect of continuing pain, associated psychological symptoms, functional disability, and reliance on medical resources ...
2,8-dihydroxyadenine urolithiasis, an underdiagnosed disease SIR,-Adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) catalyses the formation of adenosine monophosphate (AMP) from adenine. Homozygosity for deficiency of this enzyme results in the accumulation of adenine and its oxidation product 2,8dihydroxyadenine (2,8-DHA). Because 2,8-DHA is insoluble over a large urinary pH range, individuals with complete APRT deficiency (type I or APRT* QO) often present with 2,8-DHA urolithiasis, which may lead to severe renal failure. The frequency of heterozygosity at the APRT locus has been estimated to be O’4-l’ 1 % in healthy white populations, suggesting a homozygosity of 1 in 50 000 to 1 in 100000.2 However, a surprisingly small number (33 cases) of such patients were recorded in a thorough review in 1989.3 This suggests either that many people who are
1051
homozygous for APRT deficiency remain symptom-free throughout their lives or, more plausibly, that they are unrecognised ormisdiagnosed. This is important because an effective treatment is available if the condition is diagnosed early and the prognosis depends on renal function remaining at the time of diagnosis. Since the first description of the disease in our laboratory’ only 21 cases of homozygous APRT type I deficiency (from nineteen families) have been identified in France (17 in Necker-Paris and 4 in Debrousse-Lyon). The diagnosis was usually made by detailed analysis of urinary calculi or crystals by infrared spectroscopy with confinmtion by assay of APRT activity in erythrocytes. 19 of the homozygotes had 2,8-DHA urolithiasis; the other 2 were healthy siblings diagnosed in family studies. Apart from 1 Canadian patient, all were French, and all were white; and two-thirds were males.3 62% of cases were adults, suggesting that 2,8-DHA is not essentially a disease of children as was once thought. However, the time from onset to correct diagnosis was usually much longer in adults. In all instances, the calculi were first considered to be uric acid because uric acid calculi and 2,8-DHA calculi are radiolucent and have the same reactivity in non-specific tests (murexide test, colorimetry reactions, thermogravimetric analysis). In children, the rarity of urolithiasis at this age, together with the absence of the expected uric acid overproduction, prompted some physicians to ask for physical analysis of the calculi or crystals, which led to the correct diagnosis. On the other hand, when the first symptoms appeared in adults a diagnosis of uric acid urolithiasis was erroneously maintained for years, supported by the mistaken detection of "uric acid" or "urate" crystals in urine. The request for detailed analysis seems, regrettably, to depend mainly on the curiosity of the physician. In two cases, 2,8-DHA crystals were first detected on renal biopsy-at the stage of terminal renal insufficiency in a 73-year-old woman with a history of renal colic and after the rejection of a renal allograft in a 51-year-old man with an unexplored history of recurrent urolithiasis. The diagnosis in our laboratories was made on 14 out of 10 000 urinary stones analysed (7 out of 700 in children) during the period 1976-91. From this proportion and the prevalence of urolithiasis in France (put at L5%’’) the number of French patients with 2,8-DHA urolithiasis can be estinated at 1000, a figure consistent with the calculated frequency of homozygous APRT deficiency mentioned above. Absence of symptoms and difficulties in diagnosis may have contributed to lack of adequate recognition. On the other hand, this series is large when set beside the 33 reported in the world,3 and only 4 cases have been reported from the United States with a population five times that of France. Our patients came from all regions of France, and we have no indication of any genetic bias to explain this discrepancy. An influence of diet cannot be excluded. Also, therapeutic custom may influence the apparent frequency of the disease: the erroneous diagnosis of uric acid urolithiasis may promptly lead to allopurinol therapy, which is quite efficient in preventing 2,8-DHA lithiasis, so many patients may be being successfully treated albeit without the correct diagnosis. 2,8-DHA accumulation is not a rare cause of urolithiasis but it is often missed. The defect should be suspected in any patient with radiolucent stones and/or a history of recurrent urinary-tract infection, haematuria, proteinuria, crystalluria, abdominal pain, dysuria, or renal colic. Better knowledge of the disease could shorten the time from recognition of urolithiasis to diagnosis of APRT deficiency and thus prevent renal complications. 2,8-DHA excretion can be prevented by allopurinol 5-10 mg/kg, and a low purine diet and increased fluid intake are also advised. With greater use of infrared or X-ray diffraction analysis of calculi coupled with erythrocyte APRT activity assay, the disorder may be diagnosed more often. Moreover, crystals should be analysed in patients with radiolucent urolithiasis but who have not excreted urinary stones.
Laboratory of Biochemistry
B,
I. CEBALLOS-PICOT
Hôpital Necker-Enfants Malades,
J. L. PERIGNON
75015 Paris, France
M. HAMET
Laboratory of Biochemistry A and
Crystal Laboratory,
Hôpital Necker-Enfants Malades
M. DAUDON
Laboratory of Biochemistry B, Hôpital Necker-Enfants
Malades
P. KAMOUN
Johnson LA, Gordon RB, Emmerson BT Adenine phosphonbosyltransferase: a simple spectrophotometric assay and the incidence of mutation in the normal population. Biochem Genet 1977; 15: 265-72. 2. Simmonds HA. 2,8-dihydroxyadenine lithiasis. Clin Chim Acta 1986; 160: 103-08. 3. Simmonds HA, Sahota AS, Van Acker KJ. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1989: 1029-44. 4. Carrier MP, Hamet M, Hamburger J. Une nouvelle maladie metabolique: le deficit complet en adenine phosphoribosyltransferase avec lithiase de 2,8dihydroxyadenine. C R Acad Sci III 1974; 279: 883-86. 5. Ang KS, Mignard JP, Cam G, Cloup C, Carlier M, Simon P. Epidemiologie de la lithiase urinaire dans la région de Saint-Brieuc. Etude prospective sur 4 ans (1986-1989). Inform Sci Biol 1990; 16: 30. 1.
Nicotinamide and
prevention of diabetes
SiR,—The process affecting pancreatic beta-cells in insulindependent diabetes mellitus (IDDM) can be arrested by immunosuppression. This finding, and the demonstration that the onset of IDDM in first-degree relatives of patients with the disease can be predicted, led the American Diabetes Association1 and other organisations to promote clinical trials designed to test the efficacy and safety of preventive interventions. Nicotinamide is likely to be the first such experimental therapy to be tried on a wide scale, and randomised trials are at an advanced stage of preparation. These trials will involve the screening of very many first-degree relatives to identify sufficient numbers at high risk of IDDM. Representatives of several groups committed to trials with nicotinamide met in Toronto on Jan 8 and 9,1992, to agree on a collaboration that would permit valid analysis of pooled data from separate studies. Nicotinamide inhibits activated macrophage killing of beta cells in vitro, and reduces induction of class IMHC protein on mouse beta cells. Both processes may have central roles in the pathogenesis of insulitis in man. The drug prevents diabetes in murine models of diabetes and, in combination with desferrioxamine, it prevents islet-cell allograft rejection in mice. (A complete list of references covering the biological evidence is available from J. D.) In man some but not all of the short-term trials with pharmacological doses of nicotinamide have suggested retardation of beta-cell loss in overt IDDM,2 and of progression in the preclinical stage.7-99 The potential risks of this therapy seem low but the safety of long-term nicotinamide in high dosage has not been established. High dosage nicotinamide has been asociated with liver dysfunction in man 10 and it can induce insulin-secreting tumours of the pancreas in rats after exposure to streptozotocin. However, in the limited experience in patients with beta-cell damage major irreversible adverse effects have not been reported.2-9 At the Toronto meeting there was agreement that first-degree relatives of patients with IDDM should be studied in randomised, double-blind and placebo-controlled trials to test the null hypothesis that "Nicotinamide does not prevent onset of IDDM in high-risk first-degree relatives". The entry criteria should include at least two positive tests for islet-cell antibody (ICA) one or both being 20 Juvenile Diabetes Foundation units or more. A reference laboratory for each trial should meet the proficiency standards of the International Diabetes Workshop and an additional ICA measurement will be done at baseline by a common external reference laboratory for all those entered in the trials. A second inclusion criterion will be the performance of an intravenous glucose-tolerance test to determine the first-phase insulin response (FPIR), on a standard protocol. The FPIR may not determine eligibility but will be used in the overview analysis to evaluate the efficacy of nicotinamide in preventing IDDM according to the degree of beta-cell dysfunction at entry. Exclusion criteria will include a two-point oral glucose-tolerance test diagnostic for diabetes by World Health Organisation (WHO) critera. The dose of nicotinamide will be standardised and comparable formulations will be used. The primary outcome measure will be diabetes mellitus defined by WHO criteria. A mechanism was established for monitoring adverse effects and information on safety will be regularly submitted to a common database for review. Should important adverse effects to nicotinamide be identified, the data centre will report back to the safety monitoring committee of each trial for further action as
required.
separate from peristaltic contractions. We would also point out that nutcracker oesophagus and spasm are not the same condition, although both could occur in the same patient.
University Department of Surgery, University of Wales College of Medicine, Cardiff CF4 4XN, UK, and Department of Gastroenterology, University Hospital of Wales, Cardiff
H. C. MCKIRDY R. LOWNDES G. L. SWIFT H. A. DAVIES D. LEWIS
J. RHODES
GL, Alban Davies H, McKirdy H, Lowndes R, Lewis D, Rhodes J. A long-term clinical review of patients with oesophageal pain. Q J Med 1991; 81:
1. Swift
937-44.
2. Benjamin SB, Richter JE, Cordova CM, Knuff TE, Castell DO. Prospective manometric evaluation with pharmacologic provocation of patients with suspected oeaophageal motility disfunction. Gastroenterology 1983; 84: 893-901.
SiR,—In your March 7 editorial you note that"... studies on the
aetiology of obscure chest pain tend to show abnormalities in the organ system that is the special interest of the researchers". It is unfortunate that you exemplify this statement by concentrating exclusively on ischaemic heart disease and oesophageal causes of chest pain. You do not mention chest wall pain, spinal arthritis, hyperventilation, or anxiety and panic, all of which are well described and
of chest discomfort.’ Your also preoccupation ignores the considerable evidence that persistent non-cardiac chest pain is often of multifactorial aetiology, in which misinterpretation of medically minor symptoms leads to the conclusion that pain is due to heart disease, which in turn leads to further anxiety and to repeated consultation and discomfort disability.z Oesophageal misinterpreted as evidence of heart disease is likely to be a more unpleasant and disabling symptom than oesophageal symptoms common
causes
with single
causes
accepted as indigestion. You also surprisingly conclude that the outlook for the sort of patients with persistent symptoms investigated in hospital clinics is good. This is only true for expectation of life: outcome with respect to relief of symptoms, disability, consultation, and other use of medical resources is poor.3,4 Clearly simple reassurance is not effective in such patients,showever effective it is for patients presenting with acutely unexplained chest pain in primary care. Reassurance and information are useful when the patient finds an explanation for symptoms acceptable, and when particular anxieties are dealt with. In a small proportion of patients an underlying depressive illness requires antidepressants, but in others advice about coping with the localised muscular tension, explanation about the link between anxiety and heightened awareness of bodily sensations, breathing exercises to prevent hyperventilation, and advice about graded return to normal activities are necessary. We have presented evidence from a controlled trial showing the benefits of such treatment in patients with chronic symptoms, which have persisted despite reassurance in the clinic.6 Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK
RICHARD MAYOU CHRISTOPHER BASS
Mayou RA. Atypical chest pain. J Psychosom Res 1989; 33: 373-406. Mayou RA. Patients’ fears of illness, chest pain and palpitations. In: Creed F, Mayou RA, Hopkins A, eds. Medical symptoms not explained by organic disease. London: Royal College of Psychiatrists and Royal College of Physicians, 1991: 25-33. 3. Bass C. Chest pain and breathlessness: relationship to psychiatric illness. Am J Med 1992; 92 (suppl IA): 12-17 4. Chambers J, Bass C. Chest pain with normal coronary anatomy: a review of natural history and possible etiologic factors. Prog Cardiovasc Dis 1990; 33: 161-84. 5. Charmer KS, James MA, Papouchado M, et al. Failure of a negative exercise test to reassure patients with chest pain. QJ Med 1987; 63: 315-22. 6. Klimes I, Mayou RA, Pearce MJ, et al Psychological treatment for atypical non-cardiac chest pain: a controlled evaluation. Psychol Med 1990; 20: 605-11.
is high.2 Swift et aP have shown that this pattern of low mortality but high morbidity at follow-up also applies to patients with negative cardiac investigations but positive evidence of oesophageal
dysmotility. Furthermore, although
reassurance
after
negative cardiological
may be beneficial for many patients, for some it is neither safe nor effective. Lantinga et al4 found that one year after patients with chest pain had angiographically normal coronary
investigations
to believe that they had heart disease and 42% remained unsure. I have completed twelve years’follow-up of patients who underwent coronary angiography for chest pain in 1979-80.5 Of 31 patients who were explicitly reassured that their coronary arteries were normal, 13 % believed they had heart disease one year later and 6% remained unsure.6 Furthermore, of those who said they had been reassured by their cardiologist’s statements, 60% were still receiving medical attention for continuing chest pain. 29 of these patients were re-interviewed in 1991, none of whom showed evidence of clinically significant coronary artery disease during follow-up. Nevertheless, 10 of 29 (34%) said they believed they had heart disease, and 5 (17%) remained unsure. 11of these 15 (73%) continued to complain of pain, as did a similar proportion (64%) of the 14 who did not believe that they had heart disease. These findings suggest that for substantial number of such patients reassurance is ineffective in both the short and long term. Furthermore, according to a model of hypochondriasis proposed by Warwick and Salkovskis,7 reassurance is in fact counterproductive, since it increases morbidity by perpetuating a cycle of health-related anxiety (which it only temporarily allays), followed by repeated medical consultation, and further costly investigation, with negative results and attendant iatrogenic risks. A psychological approach that specifically excludes reassurance has been used with benefit in patients with chest pain of uncertain cause.8 The challenge therefore is to separate, in advance, those patients who will respond positively to reassurance from those who will not: it is only in the former group that reassurance is safe and effective, and the outlook good.
arteries, 25% continued
University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK
S. G. POTTS
AVG, Sones FM. Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: 10-year follow-up of 521 patients. Circulation 1980; 62: 712-17. 2. Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries Am J Cardiol 1986; 58: 1181-87. 3 Swift GL, Alban-Davies H, McKurdy H, Lowndes R, Lewis D, Rhodes J A long-term clinical review of patients with oesophageal pain. Q J Med 1991; 81: 1. Proudfit WL, Bruschke
937-44.
Lantinga LJ, Sprafkin RP, McCroskery JH, Baker MT, Warner RA, Hill NE. One-year psychosocial follow-up of patients with chest pain and angiographically normal coronary arteries. Am J Cardiol 1988; 62: 209-13. 5. Bass C, Cawley R, Wade C, et al. Unexplained breathlessness and psychiatric morbidity in patients with normal and abnormal coronary arteries Lancet 1983; i:
4
605-09. 6. Bass C. Unexplained chest pain: clinical and psychosocial studies in patients with presumptive angina. MD, thesis, University of London, 1984 7 Warwick HM, Salkovskis PM. Hypochondriasis. Behav Res Ther 1990; 28: 105-17. 8. Klimes I, Mayou RA, Pearce MJ, Coles L, Fagg JR. Psychological treatment for atypical non-cardiac chest pain: a controlled evaluation. Psychol Med 1990; 20: 605-11.
1. 2.
SiR,—Your March 7 editorial is welcome, but your conclusion that "outlook is good and reassurance is a safe and effective remedy", cannot go unchallenged. It is true that the mortality associated with chest pain of uncertain origin is low,’ but long-term morbidity in respect of continuing pain, associated psychological symptoms, functional disability, and reliance on medical resources ...
2,8-dihydroxyadenine urolithiasis, an underdiagnosed disease SIR,-Adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) catalyses the formation of adenosine monophosphate (AMP) from adenine. Homozygosity for deficiency of this enzyme results in the accumulation of adenine and its oxidation product 2,8dihydroxyadenine (2,8-DHA). Because 2,8-DHA is insoluble over a large urinary pH range, individuals with complete APRT deficiency (type I or APRT* QO) often present with 2,8-DHA urolithiasis, which may lead to severe renal failure. The frequency of heterozygosity at the APRT locus has been estimated to be O’4-l’ 1 % in healthy white populations, suggesting a homozygosity of 1 in 50 000 to 1 in 100000.2 However, a surprisingly small number (33 cases) of such patients were recorded in a thorough review in 1989.3 This suggests either that many people who are
1051
homozygous for APRT deficiency remain symptom-free throughout their lives or, more plausibly, that they are unrecognised ormisdiagnosed. This is important because an effective treatment is available if the condition is diagnosed early and the prognosis depends on renal function remaining at the time of diagnosis. Since the first description of the disease in our laboratory’ only 21 cases of homozygous APRT type I deficiency (from nineteen families) have been identified in France (17 in Necker-Paris and 4 in Debrousse-Lyon). The diagnosis was usually made by detailed analysis of urinary calculi or crystals by infrared spectroscopy with confinmtion by assay of APRT activity in erythrocytes. 19 of the homozygotes had 2,8-DHA urolithiasis; the other 2 were healthy siblings diagnosed in family studies. Apart from 1 Canadian patient, all were French, and all were white; and two-thirds were males.3 62% of cases were adults, suggesting that 2,8-DHA is not essentially a disease of children as was once thought. However, the time from onset to correct diagnosis was usually much longer in adults. In all instances, the calculi were first considered to be uric acid because uric acid calculi and 2,8-DHA calculi are radiolucent and have the same reactivity in non-specific tests (murexide test, colorimetry reactions, thermogravimetric analysis). In children, the rarity of urolithiasis at this age, together with the absence of the expected uric acid overproduction, prompted some physicians to ask for physical analysis of the calculi or crystals, which led to the correct diagnosis. On the other hand, when the first symptoms appeared in adults a diagnosis of uric acid urolithiasis was erroneously maintained for years, supported by the mistaken detection of "uric acid" or "urate" crystals in urine. The request for detailed analysis seems, regrettably, to depend mainly on the curiosity of the physician. In two cases, 2,8-DHA crystals were first detected on renal biopsy-at the stage of terminal renal insufficiency in a 73-year-old woman with a history of renal colic and after the rejection of a renal allograft in a 51-year-old man with an unexplored history of recurrent urolithiasis. The diagnosis in our laboratories was made on 14 out of 10 000 urinary stones analysed (7 out of 700 in children) during the period 1976-91. From this proportion and the prevalence of urolithiasis in France (put at L5%’’) the number of French patients with 2,8-DHA urolithiasis can be estinated at 1000, a figure consistent with the calculated frequency of homozygous APRT deficiency mentioned above. Absence of symptoms and difficulties in diagnosis may have contributed to lack of adequate recognition. On the other hand, this series is large when set beside the 33 reported in the world,3 and only 4 cases have been reported from the United States with a population five times that of France. Our patients came from all regions of France, and we have no indication of any genetic bias to explain this discrepancy. An influence of diet cannot be excluded. Also, therapeutic custom may influence the apparent frequency of the disease: the erroneous diagnosis of uric acid urolithiasis may promptly lead to allopurinol therapy, which is quite efficient in preventing 2,8-DHA lithiasis, so many patients may be being successfully treated albeit without the correct diagnosis. 2,8-DHA accumulation is not a rare cause of urolithiasis but it is often missed. The defect should be suspected in any patient with radiolucent stones and/or a history of recurrent urinary-tract infection, haematuria, proteinuria, crystalluria, abdominal pain, dysuria, or renal colic. Better knowledge of the disease could shorten the time from recognition of urolithiasis to diagnosis of APRT deficiency and thus prevent renal complications. 2,8-DHA excretion can be prevented by allopurinol 5-10 mg/kg, and a low purine diet and increased fluid intake are also advised. With greater use of infrared or X-ray diffraction analysis of calculi coupled with erythrocyte APRT activity assay, the disorder may be diagnosed more often. Moreover, crystals should be analysed in patients with radiolucent urolithiasis but who have not excreted urinary stones.
Laboratory of Biochemistry
B,
I. CEBALLOS-PICOT
Hôpital Necker-Enfants Malades,
J. L. PERIGNON
75015 Paris, France
M. HAMET
Laboratory of Biochemistry A and
Crystal Laboratory,
Hôpital Necker-Enfants Malades
M. DAUDON
Laboratory of Biochemistry B, Hôpital Necker-Enfants
Malades
P. KAMOUN
Johnson LA, Gordon RB, Emmerson BT Adenine phosphonbosyltransferase: a simple spectrophotometric assay and the incidence of mutation in the normal population. Biochem Genet 1977; 15: 265-72. 2. Simmonds HA. 2,8-dihydroxyadenine lithiasis. Clin Chim Acta 1986; 160: 103-08. 3. Simmonds HA, Sahota AS, Van Acker KJ. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1989: 1029-44. 4. Carrier MP, Hamet M, Hamburger J. Une nouvelle maladie metabolique: le deficit complet en adenine phosphoribosyltransferase avec lithiase de 2,8dihydroxyadenine. C R Acad Sci III 1974; 279: 883-86. 5. Ang KS, Mignard JP, Cam G, Cloup C, Carlier M, Simon P. Epidemiologie de la lithiase urinaire dans la région de Saint-Brieuc. Etude prospective sur 4 ans (1986-1989). Inform Sci Biol 1990; 16: 30. 1.
Nicotinamide and
prevention of diabetes
SiR,—The process affecting pancreatic beta-cells in insulindependent diabetes mellitus (IDDM) can be arrested by immunosuppression. This finding, and the demonstration that the onset of IDDM in first-degree relatives of patients with the disease can be predicted, led the American Diabetes Association1 and other organisations to promote clinical trials designed to test the efficacy and safety of preventive interventions. Nicotinamide is likely to be the first such experimental therapy to be tried on a wide scale, and randomised trials are at an advanced stage of preparation. These trials will involve the screening of very many first-degree relatives to identify sufficient numbers at high risk of IDDM. Representatives of several groups committed to trials with nicotinamide met in Toronto on Jan 8 and 9,1992, to agree on a collaboration that would permit valid analysis of pooled data from separate studies. Nicotinamide inhibits activated macrophage killing of beta cells in vitro, and reduces induction of class IMHC protein on mouse beta cells. Both processes may have central roles in the pathogenesis of insulitis in man. The drug prevents diabetes in murine models of diabetes and, in combination with desferrioxamine, it prevents islet-cell allograft rejection in mice. (A complete list of references covering the biological evidence is available from J. D.) In man some but not all of the short-term trials with pharmacological doses of nicotinamide have suggested retardation of beta-cell loss in overt IDDM,2 and of progression in the preclinical stage.7-99 The potential risks of this therapy seem low but the safety of long-term nicotinamide in high dosage has not been established. High dosage nicotinamide has been asociated with liver dysfunction in man 10 and it can induce insulin-secreting tumours of the pancreas in rats after exposure to streptozotocin. However, in the limited experience in patients with beta-cell damage major irreversible adverse effects have not been reported.2-9 At the Toronto meeting there was agreement that first-degree relatives of patients with IDDM should be studied in randomised, double-blind and placebo-controlled trials to test the null hypothesis that "Nicotinamide does not prevent onset of IDDM in high-risk first-degree relatives". The entry criteria should include at least two positive tests for islet-cell antibody (ICA) one or both being 20 Juvenile Diabetes Foundation units or more. A reference laboratory for each trial should meet the proficiency standards of the International Diabetes Workshop and an additional ICA measurement will be done at baseline by a common external reference laboratory for all those entered in the trials. A second inclusion criterion will be the performance of an intravenous glucose-tolerance test to determine the first-phase insulin response (FPIR), on a standard protocol. The FPIR may not determine eligibility but will be used in the overview analysis to evaluate the efficacy of nicotinamide in preventing IDDM according to the degree of beta-cell dysfunction at entry. Exclusion criteria will include a two-point oral glucose-tolerance test diagnostic for diabetes by World Health Organisation (WHO) critera. The dose of nicotinamide will be standardised and comparable formulations will be used. The primary outcome measure will be diabetes mellitus defined by WHO criteria. A mechanism was established for monitoring adverse effects and information on safety will be regularly submitted to a common database for review. Should important adverse effects to nicotinamide be identified, the data centre will report back to the safety monitoring committee of each trial for further action as
required.
