- Email: [email protected]
CHANGING PREVALENCE OF JUVENILE-ONSET DIABETES MELLITUS
88
The AIDS necropsy rate in our study was 41%. It is possible that AIDS patients who underwent necropsy were not representative of all AIDS cases. Most of the studies showing the value of necropsy in a general population had similar necropsy rates (less than 50%),&10 which also leaves open the possibility that these cases were not representative. However, a Swedish study with a necropsy rate of 96% found essentially equal diagnostic error rates to that of other studies.8 Whether equal diagnostic error rates would be found if all AIDS patients underwent necropsy is unknown and should be investigated. The necropsy rate has declined both for general patients6 and for AIDS patients.5 Information about the mechanisms of human immunodeficiency virus transmission have underscored the hazards of handling this organism, which may be one factor in the tremendous decline in the necropsy
of AIDS demonstrated the
rate
Numerous studies have of necropsy in a general improved medical knowledge,
patients. value
population.’-" Despite experience, and diagnostic tools, clinically important diagnoses are missed and awareness of these diagnoses can only be established through postmortem examination. Our study suggests that even though the cause of death is undisputed, because of the important clinical, educational, and public health information obtained, clinicians should continue to request necropsies for AIDS patients. We thank Dr Daniel Alonso, Mr Troy Dr Richard Ratzan, Dr Stoneburner.
John Pearson,
Jacobs, Dr Mack Lipkin Jr, Dr Margaret Rea, and Dr Rand
Correspondence should be addressed to W. G. T., Bellevue Hospital IN-49, First Avenue and 27th Street, New York, NY10016, USA. REFERENCES 1 Peterman
Drotman
TA, DP, Curran JW Epidemiology of the acquired immunodeficiency syndrome (AIDS) Epidemiol Rev 1985; 7: 1-21 2 Gottlieb MS, Schroff R, Schanker HM, et al Pneumocystis carinii pneumonia and candidiasis in previously healthy homosexual men evidence of a new acquirted cellular immunodeficiency N Engl J Med 1981, 305: 1425-31. 3 Snider WD, Simpson DM. Aronyk KE, Nielson SL Primary lymphoma of the nervous system associated with acquired immune-deficiency syndrome N Engl J Med 1983, 309: 45 4 Sohn CC, Schoff RM, Kliewer KE, Lebel DM, Fligiel S Disseminated Mycobacteriion aviion intracellulare infection in homosexual men with acquired cell mediated immunodeficiency a histologic and immunologic study of two cases Am J Clin Pathol 1983, 79: 247-52 5 Wilkes MS, Jacobs TA, Milberg J, Stonebumer R Autopsy patterns m patients dying of AIDS in New York City. Arch Pathol Lab Med (in press) 6 Nemetz PN, Ludwig J, Kurland LT. Assessing the autopsy Am J Pathol 1987; 128: 362-79 7 Scottolini AG, Weinstein SR. The autopsy in clinical quality control JAMA 1983; 250: 1192-94 8 Button M Diagnostic errors discovered at autopsy Acta Med Scand 1974. 196: 203-10 9 Bauer EW, Robbins SL. An autopsy study of cancer patients: accuracy of the clinical diagnoses 1955 to 1965 Boston City Hospital JAMA 1972; 221: 1471-74 10 Cameron HM, McGoogan E A prospective study of 1152 hospital autopsies inaccuracies in death certification J Pathol 1981, 133: 273-83. 1 1 Goldman L, Sayson R, Robbins S, Cohn LH, Bettman M, Weisberg M The value of the autopsy in three medical eras. N Engl J Med 1983; 308: 1000-05. 12 Cameron HM, McGoogan E A prospective study of 1152 hospital autopsies analysis of inaccuracies in clinical diagnoses and their significance J Pathol 1981, 133: 285-300 13. Britton M Clinical diagnostics, experience from 383 autopsied cases Acta Med Scand
1974; 196: 211-19
17
18
19
CATHERINE S. PECKHAM ZARRINA KURTZ ANTHONY E. ADES
Department of Paediatric Epidemiology, Institute of Child Health, 30 Guilford Street, London WC1 1EH
Comparison of age-specific prevalence of juvenile-onset diabetes mellitus between 1946 and 1958 British cohort birth studies (up to the ages of 26 and 23, respectively) suggests that the overall prevalence of diabetes in young life has not increased, but the disease is manifest at an earlier age in susceptible individuals. Summary
INTRODUCTION
STUDIES in the UK,12continental Europe (cited in 3), and the US4 have suggested an increased prevalence of juvenileonset diabetes; further evidence came from preliminary analysis of British birth cohort studies. Stewart-Brown et aP compared the prevalence of diabetes up to 11 years of age: this was estimated to be 0-1per 1000 for children born in 1946; 0-6 per 1000 for those born in 1958; and 1-3 per 1000 for children born in 1970. We have compared the age of
G, McDonald RJ, Maniatis T. Oleske J, Kapila R, Reichman LB Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS) JAMA 1986; 256: 362-66. 21. Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72: 650-58. 22 Stevanovic G, Tucakovic G, Dotlic R, Kanjuh V Correlation of clinical diagnoses with autopsy findings Hum Pathol 1986, 17: 1225-30 23 Cohn J, Holzman RS Survival of patients with AIDS following M aviumintracellulare (MAI) infection: roles of rifabutin and prior duration of AIDS Program and Abstracts of the 26th Interscience Conference on Antimicrobials Agents and Chemotherapy, 1986: 178. 24 Centers for Disease Control, US Department of Health and Human Services Diagnosis and management of mycobacterial infection and disease in persons with human immunodeficiency virus infection. Ann Intern Med 1987; 106: 254-56. 25 Armstrong D, Gold JWM, Dryjanski J, et al Treatment of infections in patients with the acquired immunodeficiency. syndrome. Ann Intern Med 1985; 103: 738-43 26. Piala M, Cone LA, Chang CM, Mocarski ES. Cytomegalovirus viremia increases with progressive immune deficiency m patients infected with HTLV-III AIDS Res
20 Sunderam
1986; 2: 175-81 27 Godwin TA, Felix JC. The histopathology of the liver 105 cases. Lab Invest 1987, 56: 26A.
definition for acquired immunodeficiency suppl no 1S) 3S-9S October 28, 1987) New York City Department of Health
AIDS:
an
autopsy
study of
50 patients. Ann Neurol 1983, 14: 403-18 30 Whelan MA, Kricheff IJ, Handler M, et al. Acquired immunodeficiency syndrome cerebral computed tomographic manifestations Radiology 1983, 149: 477-84 31 Rhodes RH Histopathology of the central nervous system in the acquired immunodeficiency syndrome Hum Pathol 1987; 18: 636-43 32 Elkin CM, Leon E, Grenell SL, Leeds NE Intracranial lesions in the acquired
case
AIDS Surveillance Unit Report Karsner HT, Rothchild L, Crump ES Clinical diagnosis as compared with necropsy findings in six hundred cases JAMA 1919, 73: 666-69 Wells HG Relation of clinical to necropsy diagnosis in cancer and value of existing cancer statistics. JAMA 1923, 80: 737-40 Hui AN, Koss MN, Meyer PR Necropsy findings in acquired immunodeficiency syndrome a comparison of premortem diagnoses with postmortem findings Hum Pathol 1984; 15: 670-76 Marchevsky A, Rosen MJ, Chrystal G, Kleinerman J. Pulmonary complications of the acquired immunodeficiency syndrome a clinicopathologic study of 70 cases Hum Pathol 1985, 16: 659-70
in
28. Morgello S, Cho E-S, Nielsen S, Devinsky O, Petito CK. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome an autopsy study of 30 cases and a review of the literature Hum Pathol 1987, 18: 289-97. 29 Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB Neurological complications of acquired immune deficiency syndrome analysis of
MMWR 1987, 46
15 AIDS Surveillance (Update 16
CHANGING PREVALENCE OF
JUVENILE-ONSET DIABETES MELLITUS
33
14. Revision of the CDC surveillance
syndrome
Child Health
34
35
immunodeficiency syndrome, radiological (computed tomographic) features JAMA 1985; 253: 393-96. Navia BA, Petito CK, Gold JWM, Cho E-K, Jordan BD, Price RW Cerebral tuxoplasmosis complicating the acquired immune deficiency syndrome, clinical and neuropathological findings in 27 patients Ann Neurol 1986; 19: 224-38 Ambros RA, Lee E-Y, Sharer LR, Khan MY, Robboy SJ The acquired immunodeficiency syndrome in intravenous drug abusers and patients with a sexual risk clinical and postmortem comparisons. Hum Pathol 1987, 18: 1109-14 Gold JWM, Brown AE, et al. Central-nervous-system toxoplasmosis in
Wong B,
homosexual
parenteral drug abusers Ann Intern Med 1984, 100: 36-42 MA, Walls KW Evaluation of cerebral-mass lesions in acquired immunodeficiency syndrome N Engl J Med 1983, 308: 1099 37 Roldan EO, Moskowitz L, Hensley GT. Pathology of the heart in acquired immunodeficincy symdrome. Arch Pathol Lab Med 1987, 111: 943-46. 38 Reilly JM, Cunnion RE, Andersen DW, Virmani R, O’Leary TJ, Parrillo JE Patients with the acquired immunodeficiency syndrome and histopathological myocarditis frequently manifest major clinical cardiac abnormalities. J Am Coll Cardiol 1987, 9: men
36 Pitchenik AE, Fischl
154A
and
89 AGE AT ONSET AND PREVALENCE OF JUVENILE ONSET DIABETES
18 cases had occurred by the age of 10, a cumulative incidence of 1-3 per 1000-reached by age 13 in the 1958 cohort, and by about age 18 in the 1946 cohort. In all three cohorts, the prevalence was higher in males than in females but the difference was not statistically significant except in the 1970 cohort, where the male:female ratio at 10 years was 3-5:1(p = 0-031, two-tailed test). No statistically significant social class differences were found but, in all three cohorts, there was a tendency for cases to occur in those from non-manual backgrounds: in the 1970 cohort, none of the 18 cases were children of men in semi-skilled and unskilled manual occupations.
cohort,
DISCUSSION
( ) Weighted case numbers in parentheses for 1946 cohort. *5 children reported for the first time at the 23 year follow-up, for whom no age of incidence is known. Cum prev cumulative prevalence/ =
and cumulative in the 1958 and 1946 years, respectively.
onset
1000.
prevalence of juvenile-onset diabetes cohorts, up to the ages of 23 and 26 METHOD
In the Medical Research Council National Survey of Health and 1946 cohort), data were collected on all 13 687 births on March 3-9,1946 in England, Scotland, and Wales, with follow-up studies on a subsample of 5362 children.s The National Child Development Study (NCDS; 1958 cohort) has followed up all 17 733 births in England, Scotland, and Wales on March 3-9, 1958,6 and the Child Health and Education Study (CHES; 1970 cohort) has followed up all 16 015 births in England, Scotland, and Wales on April 5-11, 1970 up to age 10.3 A wide range of data have been collected at various ages in all cohorts, with high response rates (from 91-3% to 754%). Children with diabetes mellitus were identified and the diagnosis of insulin-dependent diabetes was validated from their medical records. Cumulative prevalence rates were calculated by standard survival methods. At each age, the denominator used was the number who had responded at the subsequent follow-up survey, less those who had already been identified as diabetic: this procedure resulted in only minor changes in prevalence rates from previously published data for the 1958 cohort, and in higher rates for the 1946 cohort. A weighting was applied to the observed data from the 1946 cohort, to compensate for the selection of the survey sample, which comprised all children born to non-manual and agricultural workers, but only a randomly selected 25% of children of manual workers.
Development (NSHD;
RESULTS
The accompanying table shows the age at diagnosis of children with diabetes and the prevalence at each age for the three cohorts. By age 26 in the 1946 cohort, the estimated cumulative incidence was 5-3 per 1000. In the 1958 cohort, 41 cases had occurred by the age of 23 years with a
cumulative incidence of 3-1per 1000, roughly equivalent to the prevalence at 20 years for the 1946 cohort. In the 1970
The reported increase in the prevalence of diabetes in children from the United States, Israel, Finland, and other areas of Europe was supported by data up to the age of 11 from the three British cohort studiesbut the increase found at earlier ages was not sustained into the mid-20s, by which age most cases of insulin-dependent diabetes should have been identified.7 An East German study likewise revealed little change in the incidence of diabetes under the age of 20 for the 20 years up to 1974.8 Juvenile-onset diabetes may not, therefore, have increased in prevalence, but may manifest at an earlier age in susceptible individuals. Jefferson et al9 found an increased incidence in children under 5 years old in whom the incidence of diabetes had risen from 7-4/100000 in 1969-73, and 8-9/100 000 in 1974-1978, to 13-6/100 000 children in 1979-83. Similar trends have been seen in Poland. 10 Damage to the islet cells may occur for several years before symptoms arise,11 and insidious onset of hyperglycaemia has been described.I2 Earlier recognition of clinical symptoms is unlikely to have influenced our figures because most cases in the 1946 cohort were discovered in symptom-free individuals at examinations for military service and pregnancy.5 In the 1958 and 1970 cohorts, first presentation was invariably because of acute symptoms: onset of diabetes in younger children may well be more acute. Neither a change in diagnostic criteria nor a change in case ascertainment is likely over the period studied, and no children have died from diabetes in the three cohorts, so a changed death rate could not account for any change in
prevalence. Juvenile-onset diabetes has an important genetic component and Irvine13 suggested that two genetically determined susceptibilities operate, one towards autoimmunity and the other towards viral infection of the islets. However, non-genetic factors must also be considered:14 the increased prevalence at a younger age in British children over a 24-year period is more likely to be due to changed environmental factors than to genetic factors. Suggested environmental factors include viral infection,ls toxins,16 and critical weight,17 although several such factorsl8 probably interact on a genetically susceptible individual. A seasonal variation in onset has been observed in some studies,5.19 but the three cohorts were all born at the same time of year and so a seasonal infection is less likely to explain the earlier incidence of diabetes. In the 1958 NCDS cohort, a higher proportion of children with diabetes reported a history of measles and mumps than the rest of the cohort, but the small number of diabetics makes interpretation difficult. Fleegler20 reported that the age of onset of insulin-dependent diabetes did not change after introduction of rubella vaccine into the US, and so rubella
90
acquired in pregnancy was unlikely to be a major factor in the aetiology of childhood diabetes. Similarly, in the UK, reduction in congenital rubella syndrome has coincided with an earlier onset of insulin-dependent diabetes. An increased incidence of diabetes was found in boys at the youngest ages in the 1970 birth cohort and other studies.921 Fleegler et al20 suggested a finite and equal number of susceptible males and females, and that the precipitating events that result in expression of the disease operate differently in the two sexes at different ages, although others have suggested that males inherit an increased susceptibility or differentially experience environmental triggers.2223 Dietary changes could explain an earlier onset of juvenileonset diabetes. The tendency for childhood diabetes to occur in socially advantaged families in the British cohorts has also been reported in other countries.24 Low prevalence rates have been found in primitive societies,25 but could be explained by various factors such as deaths from other causes, different genetic susceptibility, and absence of toxins in food additives, as well as low rates of obesity. Songer26 suggested that obesity may precipitate both accelerated growth and insulin-dependent diabetes, and circulating insulin levels are higher in rapidly growing children.27 When diagnosed as diabetic, children tend to be as tall or taller than their peers 1121 although cessation of growth is an early sign of diabetes.28 Increases in height and weight have occurred in primary school children in all social classes in the UK between 1972 and 1987.z9 In the 1958 cohort, the prevalence of obesity (weight at least 120% of expected weight for height and sex) in 7-year-old children was double that in the 1946 cohort, but by adolescence this difference had narrowed considerably. 3D Overweight was more common in children from lower social classes, whereas diabetes was more common in children from non-manual backgrounds, but factors that lead to higher rates of obesity in children from different socio-economic groups may also differ. 31 Our data suggest that the prevalence of juvenile-onset diabetes has not increased, but is manifest at an earlier age, probably due to changed environmental factors. We thank our colleagues Ken Fogelman and Peter Shepherd from the National Child Development Study, and Dr Michael Wadsworth and Dr Sarah Stewart-Brown for data from the 1946 and 1970 cohorts, respectively.
Drug Safety BLOOD DISORDERS AND SUICIDE IN PATIENTS TAKING MIANSERIN OR AMITRIPTYLINE WILLIAM H. W. INMAN
Drug Safety Research Unit, North Croft House, Winchester Road, Botley, Southampton SO3 2BX
Summary amitriptyline addressed
to
26 781 patients who had been prescribed 42 082 mianserin and prescribed were followed up by means of a questionnaire their general practitioners. No patient had
aplastic anaemia, agranulocytosis, or leucopenia severe enough to endanger life, and in only 2 patients in each group was a causal association likely. If either drug does cause leucopenia, the incidence is likely to be in the range of 1 in 10 000 to 1 in 100 000 patients. Among patients who were reported to have attempted suicide, 56 of 246 survivors of amitriptyline overdoses required intensive care, compared with none of 92 patients who overdosed with mianserin. 4 patients who overdosed with amitriptyline alone died, compared with none of the patients who overdosed with mianserin alone. Both drugs are associated with a low risk of blood disorders, but mianserin is appreciably safer than amitriptyline because of its low toxicity in overdosage. INTRODUCTION
BECAUSE of concern about reports of agranulocytosis and other blood disorders associated with mianserin received by the Committee on Safety of Medicines (CSM) and other
regulatory agencies, a study using prescription-event monitoring (PEM) was undertaken at the Drug Safety Research Unit to measure the risk and to compare it with the
Seto Y Viruses and the pathogenesis of diabetes mellitus. Diabetes 1978, 27: 1126-42 16 Helgason T, Jonasson MR. Evidence for a food additive as a cause of ketosis-prone diabetes Lancet 1981, ii 716-20 17 Edelstem AD, Hughes IA, Oakes S, Gordon IRS, Savage DCL Height and skeletal maturity in children with newly-diagnosed juvenile-onset diabetes Arch Dis Child 15
Rayfield EJ,
1981, 56: 40-44 Epidemiology Research
International Preventing insulin dependent diabetes mellitus the environmental challenge Br Med J 1987; 295: 479-81 19 Gamble DR, Taylor KW Seasonal incidence of diabetes mellitus Br Med J 1969; in
18 Diabetes
REFERENCES 1 Calnan M. Peckham CS Incidence of insulin-dependent diabetes years of life. Lancet
1977;
ii:
m
the first
sixteen
589-90
CC, Thorogood M, Smith PG, Heasman MA, Clarke JA, Mann JI Epidemiology of type 1 insulin-dependent diabetes in Scotland 1968-1976. evidence of an increasing incidence Diabetologia 1983; 24: 238-43 Stewart-Brown S, Haslum M, Butler N Evidence for increasing prevalence of diabetes mellitus in childhood Br Med J 1983; 286: 1855-57 North AF, Gorwitz K, Sultz HA. A secular increase in the incidence of juvenile diabetes mellitus J Pediatr 1977; 91: 706-10 Wadsworth MEJ, Jarrett RJ. Incidence of diabetes in the first 26 years of life Lancet 1974, ii: 1172-74 Fogelman K, ed. Britain’s sixteen year-olds. London National Children’s Bureau,
631-33. 20
2 Patterson
3 4.
5 6.
1976
7 Catling W, Houston AC, Hill RD The prevalence of diabetes mellitus in a typical English community. J R Coll Physicians Lond 1985, 19: 248-54. 8 Schliack V 9th Annual Meeting of the European Study Group for the Epidemiology of Diabetes. Lund ESGED, 1974 9. Jefferson IG, Smith MA, Baum JD Insulin dependent diabetes in under 5 year olds. Arch Dis Child 1985, 60: 1144-48 M, La Porte RE, Walczak M, Dmochowski K, Bogaczynska E Apparent epidemic of insulin-dependent diabetes mellitus in midwestern Poland Diabetes 1987; 36: 106-13. Woodrow JC Update on insulin dependent diabetes Br Med J 1983; 286: 1683 Tarn AC, Smith CP, Spencer KM, Bottazzo GF, Gale EAM Type 1 insulin dependent) diabetes. a disease of slow clinical onset? Br Med J 1987, 294: 342-45 Irvine WJ Classification of idiopathic diabetes. Lancet 1977, i: 638-42 Leslie RDG Causes of insulin dependent diabetes Br Med J 1983; 287: 5-6
10 Rewers
11. 12 13 14
21 22 23
Fleegler FM, Rogers KD, Drash A, Rosenbloom AL, Travis LB, Court JM. Age, sex and season of onset of juvenile diabetes in different geographic areas. Pediatrics 1979; 63 (3) 374-79 Bloom A, Hayes ’I’M, Gamble DR. Register of newly diagnosed diabetic children Br Med J1975, iii 580-83 Editorial Sex and juvenile diabetes. Br Med J 1977; i: 594-95. Michaels R, Rogers KD A sex difference in immunologic responsiveness. Pediatrics
1971; 47: 120. 24 Editorial Diabetes mellitus and socioeconomic factors Lancet
1982; ii: 530-31 25 West KM Epidemiology of diabetes and its vascular lesions New York. Elsevier, 1978 26 Songer TJ, Laporte RE, Tajima N, et al. Height at diagnosis of insulin dependent diabetes in patients and their non-diabetic family members. Br Med J 1986; 292: 1419-22 27 Hindmarsh PC, Matthews DR, De Silvio L, Kurtz AB, Brook CGD Relationship between height velocity and fasting insulin concentration in children Arch Dis Child 1988, 63: 665-66 28. Hoskins PJ, Leslie RDG, Pyke DA. Height at diagnosis of diabetes in children; a study in identical twins Br Med J 1985, 290: 278-80 29 Rona RJ, Chinn S. The National Study of Health and Growth: nutritional surveillance of primary school children from 1972 to 1981 with special reference to unemployment and social class Ann Human Biol 1984, 11 (1) 17-28. 30 Peckham CS, Stark O, Simonite V, Wolff OH. Prevalence of obesity in British children born in 1946 and 1958. Br Med J 1983, 286: 1237-42 31 Rolland-Cachera MF, Deheeger M, Pequignot F, Guilloud-Bataille M, Vinit H Adiposity and food intake in young children: the environmental challenge to individual susceptibility Br Med J 1988; 296: 1037-38.
The AIDS necropsy rate in our study was 41%. It is possible that AIDS patients who underwent necropsy were not representative of all AIDS cases. Most of the studies showing the value of necropsy in a general population had similar necropsy rates (less than 50%),&10 which also leaves open the possibility that these cases were not representative. However, a Swedish study with a necropsy rate of 96% found essentially equal diagnostic error rates to that of other studies.8 Whether equal diagnostic error rates would be found if all AIDS patients underwent necropsy is unknown and should be investigated. The necropsy rate has declined both for general patients6 and for AIDS patients.5 Information about the mechanisms of human immunodeficiency virus transmission have underscored the hazards of handling this organism, which may be one factor in the tremendous decline in the necropsy
of AIDS demonstrated the
rate
Numerous studies have of necropsy in a general improved medical knowledge,
patients. value
population.’-" Despite experience, and diagnostic tools, clinically important diagnoses are missed and awareness of these diagnoses can only be established through postmortem examination. Our study suggests that even though the cause of death is undisputed, because of the important clinical, educational, and public health information obtained, clinicians should continue to request necropsies for AIDS patients. We thank Dr Daniel Alonso, Mr Troy Dr Richard Ratzan, Dr Stoneburner.
John Pearson,
Jacobs, Dr Mack Lipkin Jr, Dr Margaret Rea, and Dr Rand
Correspondence should be addressed to W. G. T., Bellevue Hospital IN-49, First Avenue and 27th Street, New York, NY10016, USA. REFERENCES 1 Peterman
Drotman
TA, DP, Curran JW Epidemiology of the acquired immunodeficiency syndrome (AIDS) Epidemiol Rev 1985; 7: 1-21 2 Gottlieb MS, Schroff R, Schanker HM, et al Pneumocystis carinii pneumonia and candidiasis in previously healthy homosexual men evidence of a new acquirted cellular immunodeficiency N Engl J Med 1981, 305: 1425-31. 3 Snider WD, Simpson DM. Aronyk KE, Nielson SL Primary lymphoma of the nervous system associated with acquired immune-deficiency syndrome N Engl J Med 1983, 309: 45 4 Sohn CC, Schoff RM, Kliewer KE, Lebel DM, Fligiel S Disseminated Mycobacteriion aviion intracellulare infection in homosexual men with acquired cell mediated immunodeficiency a histologic and immunologic study of two cases Am J Clin Pathol 1983, 79: 247-52 5 Wilkes MS, Jacobs TA, Milberg J, Stonebumer R Autopsy patterns m patients dying of AIDS in New York City. Arch Pathol Lab Med (in press) 6 Nemetz PN, Ludwig J, Kurland LT. Assessing the autopsy Am J Pathol 1987; 128: 362-79 7 Scottolini AG, Weinstein SR. The autopsy in clinical quality control JAMA 1983; 250: 1192-94 8 Button M Diagnostic errors discovered at autopsy Acta Med Scand 1974. 196: 203-10 9 Bauer EW, Robbins SL. An autopsy study of cancer patients: accuracy of the clinical diagnoses 1955 to 1965 Boston City Hospital JAMA 1972; 221: 1471-74 10 Cameron HM, McGoogan E A prospective study of 1152 hospital autopsies inaccuracies in death certification J Pathol 1981, 133: 273-83. 1 1 Goldman L, Sayson R, Robbins S, Cohn LH, Bettman M, Weisberg M The value of the autopsy in three medical eras. N Engl J Med 1983; 308: 1000-05. 12 Cameron HM, McGoogan E A prospective study of 1152 hospital autopsies analysis of inaccuracies in clinical diagnoses and their significance J Pathol 1981, 133: 285-300 13. Britton M Clinical diagnostics, experience from 383 autopsied cases Acta Med Scand
1974; 196: 211-19
17
18
19
CATHERINE S. PECKHAM ZARRINA KURTZ ANTHONY E. ADES
Department of Paediatric Epidemiology, Institute of Child Health, 30 Guilford Street, London WC1 1EH
Comparison of age-specific prevalence of juvenile-onset diabetes mellitus between 1946 and 1958 British cohort birth studies (up to the ages of 26 and 23, respectively) suggests that the overall prevalence of diabetes in young life has not increased, but the disease is manifest at an earlier age in susceptible individuals. Summary
INTRODUCTION
STUDIES in the UK,12continental Europe (cited in 3), and the US4 have suggested an increased prevalence of juvenileonset diabetes; further evidence came from preliminary analysis of British birth cohort studies. Stewart-Brown et aP compared the prevalence of diabetes up to 11 years of age: this was estimated to be 0-1per 1000 for children born in 1946; 0-6 per 1000 for those born in 1958; and 1-3 per 1000 for children born in 1970. We have compared the age of
G, McDonald RJ, Maniatis T. Oleske J, Kapila R, Reichman LB Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS) JAMA 1986; 256: 362-66. 21. Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72: 650-58. 22 Stevanovic G, Tucakovic G, Dotlic R, Kanjuh V Correlation of clinical diagnoses with autopsy findings Hum Pathol 1986, 17: 1225-30 23 Cohn J, Holzman RS Survival of patients with AIDS following M aviumintracellulare (MAI) infection: roles of rifabutin and prior duration of AIDS Program and Abstracts of the 26th Interscience Conference on Antimicrobials Agents and Chemotherapy, 1986: 178. 24 Centers for Disease Control, US Department of Health and Human Services Diagnosis and management of mycobacterial infection and disease in persons with human immunodeficiency virus infection. Ann Intern Med 1987; 106: 254-56. 25 Armstrong D, Gold JWM, Dryjanski J, et al Treatment of infections in patients with the acquired immunodeficiency. syndrome. Ann Intern Med 1985; 103: 738-43 26. Piala M, Cone LA, Chang CM, Mocarski ES. Cytomegalovirus viremia increases with progressive immune deficiency m patients infected with HTLV-III AIDS Res
20 Sunderam
1986; 2: 175-81 27 Godwin TA, Felix JC. The histopathology of the liver 105 cases. Lab Invest 1987, 56: 26A.
definition for acquired immunodeficiency suppl no 1S) 3S-9S October 28, 1987) New York City Department of Health
AIDS:
an
autopsy
study of
50 patients. Ann Neurol 1983, 14: 403-18 30 Whelan MA, Kricheff IJ, Handler M, et al. Acquired immunodeficiency syndrome cerebral computed tomographic manifestations Radiology 1983, 149: 477-84 31 Rhodes RH Histopathology of the central nervous system in the acquired immunodeficiency syndrome Hum Pathol 1987; 18: 636-43 32 Elkin CM, Leon E, Grenell SL, Leeds NE Intracranial lesions in the acquired
case
AIDS Surveillance Unit Report Karsner HT, Rothchild L, Crump ES Clinical diagnosis as compared with necropsy findings in six hundred cases JAMA 1919, 73: 666-69 Wells HG Relation of clinical to necropsy diagnosis in cancer and value of existing cancer statistics. JAMA 1923, 80: 737-40 Hui AN, Koss MN, Meyer PR Necropsy findings in acquired immunodeficiency syndrome a comparison of premortem diagnoses with postmortem findings Hum Pathol 1984; 15: 670-76 Marchevsky A, Rosen MJ, Chrystal G, Kleinerman J. Pulmonary complications of the acquired immunodeficiency syndrome a clinicopathologic study of 70 cases Hum Pathol 1985, 16: 659-70
in
28. Morgello S, Cho E-S, Nielsen S, Devinsky O, Petito CK. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome an autopsy study of 30 cases and a review of the literature Hum Pathol 1987, 18: 289-97. 29 Snider WD, Simpson DM, Nielsen S, Gold JWM, Metroka CE, Posner JB Neurological complications of acquired immune deficiency syndrome analysis of
MMWR 1987, 46
15 AIDS Surveillance (Update 16
CHANGING PREVALENCE OF
JUVENILE-ONSET DIABETES MELLITUS
33
14. Revision of the CDC surveillance
syndrome
Child Health
34
35
immunodeficiency syndrome, radiological (computed tomographic) features JAMA 1985; 253: 393-96. Navia BA, Petito CK, Gold JWM, Cho E-K, Jordan BD, Price RW Cerebral tuxoplasmosis complicating the acquired immune deficiency syndrome, clinical and neuropathological findings in 27 patients Ann Neurol 1986; 19: 224-38 Ambros RA, Lee E-Y, Sharer LR, Khan MY, Robboy SJ The acquired immunodeficiency syndrome in intravenous drug abusers and patients with a sexual risk clinical and postmortem comparisons. Hum Pathol 1987, 18: 1109-14 Gold JWM, Brown AE, et al. Central-nervous-system toxoplasmosis in
Wong B,
homosexual
parenteral drug abusers Ann Intern Med 1984, 100: 36-42 MA, Walls KW Evaluation of cerebral-mass lesions in acquired immunodeficiency syndrome N Engl J Med 1983, 308: 1099 37 Roldan EO, Moskowitz L, Hensley GT. Pathology of the heart in acquired immunodeficincy symdrome. Arch Pathol Lab Med 1987, 111: 943-46. 38 Reilly JM, Cunnion RE, Andersen DW, Virmani R, O’Leary TJ, Parrillo JE Patients with the acquired immunodeficiency syndrome and histopathological myocarditis frequently manifest major clinical cardiac abnormalities. J Am Coll Cardiol 1987, 9: men
36 Pitchenik AE, Fischl
154A
and
89 AGE AT ONSET AND PREVALENCE OF JUVENILE ONSET DIABETES
18 cases had occurred by the age of 10, a cumulative incidence of 1-3 per 1000-reached by age 13 in the 1958 cohort, and by about age 18 in the 1946 cohort. In all three cohorts, the prevalence was higher in males than in females but the difference was not statistically significant except in the 1970 cohort, where the male:female ratio at 10 years was 3-5:1(p = 0-031, two-tailed test). No statistically significant social class differences were found but, in all three cohorts, there was a tendency for cases to occur in those from non-manual backgrounds: in the 1970 cohort, none of the 18 cases were children of men in semi-skilled and unskilled manual occupations.
cohort,
DISCUSSION
( ) Weighted case numbers in parentheses for 1946 cohort. *5 children reported for the first time at the 23 year follow-up, for whom no age of incidence is known. Cum prev cumulative prevalence/ =
and cumulative in the 1958 and 1946 years, respectively.
onset
1000.
prevalence of juvenile-onset diabetes cohorts, up to the ages of 23 and 26 METHOD
In the Medical Research Council National Survey of Health and 1946 cohort), data were collected on all 13 687 births on March 3-9,1946 in England, Scotland, and Wales, with follow-up studies on a subsample of 5362 children.s The National Child Development Study (NCDS; 1958 cohort) has followed up all 17 733 births in England, Scotland, and Wales on March 3-9, 1958,6 and the Child Health and Education Study (CHES; 1970 cohort) has followed up all 16 015 births in England, Scotland, and Wales on April 5-11, 1970 up to age 10.3 A wide range of data have been collected at various ages in all cohorts, with high response rates (from 91-3% to 754%). Children with diabetes mellitus were identified and the diagnosis of insulin-dependent diabetes was validated from their medical records. Cumulative prevalence rates were calculated by standard survival methods. At each age, the denominator used was the number who had responded at the subsequent follow-up survey, less those who had already been identified as diabetic: this procedure resulted in only minor changes in prevalence rates from previously published data for the 1958 cohort, and in higher rates for the 1946 cohort. A weighting was applied to the observed data from the 1946 cohort, to compensate for the selection of the survey sample, which comprised all children born to non-manual and agricultural workers, but only a randomly selected 25% of children of manual workers.
Development (NSHD;
RESULTS
The accompanying table shows the age at diagnosis of children with diabetes and the prevalence at each age for the three cohorts. By age 26 in the 1946 cohort, the estimated cumulative incidence was 5-3 per 1000. In the 1958 cohort, 41 cases had occurred by the age of 23 years with a
cumulative incidence of 3-1per 1000, roughly equivalent to the prevalence at 20 years for the 1946 cohort. In the 1970
The reported increase in the prevalence of diabetes in children from the United States, Israel, Finland, and other areas of Europe was supported by data up to the age of 11 from the three British cohort studiesbut the increase found at earlier ages was not sustained into the mid-20s, by which age most cases of insulin-dependent diabetes should have been identified.7 An East German study likewise revealed little change in the incidence of diabetes under the age of 20 for the 20 years up to 1974.8 Juvenile-onset diabetes may not, therefore, have increased in prevalence, but may manifest at an earlier age in susceptible individuals. Jefferson et al9 found an increased incidence in children under 5 years old in whom the incidence of diabetes had risen from 7-4/100000 in 1969-73, and 8-9/100 000 in 1974-1978, to 13-6/100 000 children in 1979-83. Similar trends have been seen in Poland. 10 Damage to the islet cells may occur for several years before symptoms arise,11 and insidious onset of hyperglycaemia has been described.I2 Earlier recognition of clinical symptoms is unlikely to have influenced our figures because most cases in the 1946 cohort were discovered in symptom-free individuals at examinations for military service and pregnancy.5 In the 1958 and 1970 cohorts, first presentation was invariably because of acute symptoms: onset of diabetes in younger children may well be more acute. Neither a change in diagnostic criteria nor a change in case ascertainment is likely over the period studied, and no children have died from diabetes in the three cohorts, so a changed death rate could not account for any change in
prevalence. Juvenile-onset diabetes has an important genetic component and Irvine13 suggested that two genetically determined susceptibilities operate, one towards autoimmunity and the other towards viral infection of the islets. However, non-genetic factors must also be considered:14 the increased prevalence at a younger age in British children over a 24-year period is more likely to be due to changed environmental factors than to genetic factors. Suggested environmental factors include viral infection,ls toxins,16 and critical weight,17 although several such factorsl8 probably interact on a genetically susceptible individual. A seasonal variation in onset has been observed in some studies,5.19 but the three cohorts were all born at the same time of year and so a seasonal infection is less likely to explain the earlier incidence of diabetes. In the 1958 NCDS cohort, a higher proportion of children with diabetes reported a history of measles and mumps than the rest of the cohort, but the small number of diabetics makes interpretation difficult. Fleegler20 reported that the age of onset of insulin-dependent diabetes did not change after introduction of rubella vaccine into the US, and so rubella
90
acquired in pregnancy was unlikely to be a major factor in the aetiology of childhood diabetes. Similarly, in the UK, reduction in congenital rubella syndrome has coincided with an earlier onset of insulin-dependent diabetes. An increased incidence of diabetes was found in boys at the youngest ages in the 1970 birth cohort and other studies.921 Fleegler et al20 suggested a finite and equal number of susceptible males and females, and that the precipitating events that result in expression of the disease operate differently in the two sexes at different ages, although others have suggested that males inherit an increased susceptibility or differentially experience environmental triggers.2223 Dietary changes could explain an earlier onset of juvenileonset diabetes. The tendency for childhood diabetes to occur in socially advantaged families in the British cohorts has also been reported in other countries.24 Low prevalence rates have been found in primitive societies,25 but could be explained by various factors such as deaths from other causes, different genetic susceptibility, and absence of toxins in food additives, as well as low rates of obesity. Songer26 suggested that obesity may precipitate both accelerated growth and insulin-dependent diabetes, and circulating insulin levels are higher in rapidly growing children.27 When diagnosed as diabetic, children tend to be as tall or taller than their peers 1121 although cessation of growth is an early sign of diabetes.28 Increases in height and weight have occurred in primary school children in all social classes in the UK between 1972 and 1987.z9 In the 1958 cohort, the prevalence of obesity (weight at least 120% of expected weight for height and sex) in 7-year-old children was double that in the 1946 cohort, but by adolescence this difference had narrowed considerably. 3D Overweight was more common in children from lower social classes, whereas diabetes was more common in children from non-manual backgrounds, but factors that lead to higher rates of obesity in children from different socio-economic groups may also differ. 31 Our data suggest that the prevalence of juvenile-onset diabetes has not increased, but is manifest at an earlier age, probably due to changed environmental factors. We thank our colleagues Ken Fogelman and Peter Shepherd from the National Child Development Study, and Dr Michael Wadsworth and Dr Sarah Stewart-Brown for data from the 1946 and 1970 cohorts, respectively.
Drug Safety BLOOD DISORDERS AND SUICIDE IN PATIENTS TAKING MIANSERIN OR AMITRIPTYLINE WILLIAM H. W. INMAN
Drug Safety Research Unit, North Croft House, Winchester Road, Botley, Southampton SO3 2BX
Summary amitriptyline addressed
to
26 781 patients who had been prescribed 42 082 mianserin and prescribed were followed up by means of a questionnaire their general practitioners. No patient had
aplastic anaemia, agranulocytosis, or leucopenia severe enough to endanger life, and in only 2 patients in each group was a causal association likely. If either drug does cause leucopenia, the incidence is likely to be in the range of 1 in 10 000 to 1 in 100 000 patients. Among patients who were reported to have attempted suicide, 56 of 246 survivors of amitriptyline overdoses required intensive care, compared with none of 92 patients who overdosed with mianserin. 4 patients who overdosed with amitriptyline alone died, compared with none of the patients who overdosed with mianserin alone. Both drugs are associated with a low risk of blood disorders, but mianserin is appreciably safer than amitriptyline because of its low toxicity in overdosage. INTRODUCTION
BECAUSE of concern about reports of agranulocytosis and other blood disorders associated with mianserin received by the Committee on Safety of Medicines (CSM) and other
regulatory agencies, a study using prescription-event monitoring (PEM) was undertaken at the Drug Safety Research Unit to measure the risk and to compare it with the
Seto Y Viruses and the pathogenesis of diabetes mellitus. Diabetes 1978, 27: 1126-42 16 Helgason T, Jonasson MR. Evidence for a food additive as a cause of ketosis-prone diabetes Lancet 1981, ii 716-20 17 Edelstem AD, Hughes IA, Oakes S, Gordon IRS, Savage DCL Height and skeletal maturity in children with newly-diagnosed juvenile-onset diabetes Arch Dis Child 15
Rayfield EJ,
1981, 56: 40-44 Epidemiology Research
International Preventing insulin dependent diabetes mellitus the environmental challenge Br Med J 1987; 295: 479-81 19 Gamble DR, Taylor KW Seasonal incidence of diabetes mellitus Br Med J 1969; in
18 Diabetes
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Fleegler FM, Rogers KD, Drash A, Rosenbloom AL, Travis LB, Court JM. Age, sex and season of onset of juvenile diabetes in different geographic areas. Pediatrics 1979; 63 (3) 374-79 Bloom A, Hayes ’I’M, Gamble DR. Register of newly diagnosed diabetic children Br Med J1975, iii 580-83 Editorial Sex and juvenile diabetes. Br Med J 1977; i: 594-95. Michaels R, Rogers KD A sex difference in immunologic responsiveness. Pediatrics
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