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Insulin-dependent diabetes mellitus and coeliac disease
THE LANCET
Viewpoint
Insulin-dependent diabetes mellitus and coeliac disease Cornelius C Cronin, Fergus Shanahan The sensitive and specific tests now available to screen for coeliac disease have shown that the prevalence of this condition in the general population is higher than previously supposed.1 The prevalence of coeliac disease as determined by screening among patients with insulindependent diabetes mellitus (IDDM) is also higher than suspected—with rates of 1·0–7·8% (table).2–18 The likely explanation for the frequent simultaneous occurrence of these two disorders is a similar genetic background. In particular, both coeliac disease and IDDM are associated with a high frequency of HLA-DR3 genotypes.19 Class-II HLA genes in the HLA-D region code for cell-surface molecules which bind and present antigenic peptides to T cells and have a major role in the pathogenesis of many autoimmune disorders. We propose that the clinical implication of this association is that IDDM patients should be screened and treated for coeliac disease. IgA endomysial antibody is the most sensitive and specific screening test for coeliac disease.20 The diagnosis is confirmed by small-bowel biopsy. The rates given in the table are probably underestimates. Many patients with positive antibody tests do not agree to small-bowel biopsy. Some patients who are antibody negative at diagnosis of IDDM may later test positive.14,16 Also some patients with positive antibodies but negative small-bowel biopsies may have latent coeliac disease. We have found that almost one in 20 IDDM patients in our clinic have coeliac disease.18 As in other similar studies, most patients were symptom-free and all were clinically undetected. There is, therefore, a strong association between IDDM and coeliac disease. By contrast, among patients with non-insulin-dependent diabetes mellitus, the frequency of coeliac disease is similar to that of the general population.11,21 Before screening tests were available, reports of coeliac disease in IDDM patients found that most patients19,21 were underweight and had diarrhoea—typical symptoms of coeliac disease. Anaemia was common, caused by iron or folic-acid deficiency. In nearly all patients, diabetes was diagnosed first. Many patients had poor metabolic control and hypoglycaemia was frequent, which suggests that “brittle diabetes” may be a manifestation of coeliac disease. Patients in general complied with dietary gluten restriction and an improvement in symptoms and weight gain was found. An increase in insulin requirements, improved metabolic control, and fewer hypoglycaemic episodes followed treatment in most cases.19,21 By contrast, studies in IDDM populations with coeliac disease detected by screening, have found these patients to have few or no symptoms or consequences of malabsorption.3,6,8,10 Patients are predominantly female and have an earlier age of onset of IDDM.4,5,7 There is a Department of Medicine, Cork University Hospital and University College Cork, Wilton, Cork, Ireland (C C Cronin MD, F Shanahan MD) Correspondence to: Dr Cornelius C Cronin
1096
tendency to think of coeliac disease as a childhood disorder. However, coeliac disease may present at any age, and reported frequencies among IDDM patients are generally higher in adults (table). Gastrointestinal symptoms may be present, but are often mild and appreciated only in retrospect.6,7,10,11 Failure to grow is a concern in diabetic children with coeliac disease and has been found in some7 but not in other8 studies. Iron deficiency is the most common laboratory abnormality,11 and anaemia may be present or absent.6,7,13 Folic-acid concentrations tend to be in the low-normal range.11 Glucose control in most patients is not adversely affected by subclinical coeliac disease.4,7 Page and colleagues11 found better metabolic control in patients with coeliac disease than in those without. Similarly, troublesome hypoglycaemia is not a feature—presumably a reflection of the limited damage to the mucosa of the small intestine in subclinical coeliac disease. Many clinicians recommend that all IDDM patients should be screened for coeliac disease. Some physicians recommend regular screening every few years for patients whose initial test is negative—particularly if the tests were done at the time diabetes was diagnosed, since the tests may later become positive.14,16 If these guidelines are followed, a large number of IDDM patients with subclinical coeliac disease will be detected. The combined figures from several studies show that only 21 of 144 coeliac-disease patients had been diagnosed before screening.2–8,10–16,18 Standard dietary guidelines for IDDM recommend large amounts of long-acting, gluten-rich carbohydrate, and the additional restrictions imposed by a gluten-free diet are difficult. Patients may also have problems coming to terms with the diagnosis of a second chronic disease, with adverse consequences on patient morale. Patients without symptoms tend to be less motivated and less
Ref
Country
2 3
Finland Finland
4 5
Italy Germany and Switzerland Finland Italy Australia USA Sweden UK Australia Italy Finland USA Finland Italy Ireland
6 7 8 9 10 11 12 13 14 15 16 17 18
Number of patients 215 children 201 children 146 children 1032 children 195 adults 498 children 180 children 211 children 436 children 767 adults 273 children 383 adults 238 children 47 adults 776 children 639 adults 101 adults
Test
Frequency (%)
ARA Jejunal biopsy, ARA, AGA AGA AGA
2·3 3·5 3·4 1·1–1·3
ARA AGA AGA EmA AGA, ARA AGA AGA, EmA EmA ARA EmA ARA, AGA EmA, AGA EmA
4·1 3·2 2·2 1·4 4·6 2·0 1·8 2·6 3·8 6·4 2·4 7·8 4·9
ARA=antireticulin antibody; AGA=antigliadin antibody; EmA=endomysial antibody.
Coeliac disease found by screening of IDDM patients
Vol 349 • April 12, 1997
THE LANCET
compliant with gluten restriction. Few studies of IDDM patients with coeliac disease diagnosed on screening have post-treatment follow-up data.3,6,8,10,11,13 The long-term prognosis of coeliac disease in this setting is not known, although gluten restriction does not seem to result in improved metabolic control.3,8,10,11 Is it worthwhile to diagnose subclinical coeliac disease in IDDM patients? An increased risk of various malignant diseases, such as squamous-cell carcinoma of the pharynx and oesophagus, adenocarcinoma of the small intestine, and in particular, small-bowel lymphoma, is a feature of coeliac disease that has received much attention. Malignancy may be the first manifestation of subclinical coeliac disease.22 Coeliac disease is associated with infertility in both men and women.23 Subclinical coeliac disease in women may be an unsuspected cause of delayed menarche, amenorrhoea, premature menopause, recurrent abortions, and a low pregnancy rate.23 Osteoporosis is a well-recognised manifestation of gluten-sensitive enteropathy—whether or not symptoms have been present.24 Attention has been drawn to an association with epilepsy25 and other neurological syndromes.26 The benefits of treatment can be difficult to quantify, but evidence suggests that gluten restriction reverses, or at least decreases the risk of complications and associated conditions.23,24,27,28 There is no reason to believe that the benefits of a gluten-free diet in IDDM patients would differ from those achieved in non-diabetic patients. Screening will detect both the undiagnosed patient with symptoms and the patient who is symptom-free. Many individuals without apparent symptoms who are found to have coeliac disease remark on a new-found vitality and sense of well-being when started on a gluten-free diet. In individual patients, an improvement in glycaemic control may be seen. An unanswered question is whether gluten restriction in IDDM patients with coeliac disease, with or without symptoms, alters the rate and progression of diabetic complications. There should be a high index of suspicion of coeliac disease in all IDDM patients. IDDM patients with any gastrointestinal symptom—no matter how mild or nonspecific—evidence of malabsorption, or unexplained constitutional symptoms should be investigated for coeliac disease. Patients in whom the diagnosis is confirmed should be strongly advised to adhere to a gluten-free diet throughout life. However, even an increase in the awareness of this diagnosis will not lead to the detection of all cases. Should all IDDM patients, irrespective of symptoms, be screened by tests for IgA endomysial antibodies, the preferred screening test? Coeliac disease, associated with substantial morbidity and increased mortality,29 is probably unique among immunological disorders in that a safe and effective treatment is available. We believe that coeliac disease is sufficiently prevalent and that the benefits of diagnosis and treatment are such that this disorder should be actively sought in all IDDM patients. Even in patients who cannot or will not restrict gluten intake, care can be taken to ensure adequate repletion of iron, folic acid, and fat-soluble vitamins, and to detect complications as early as possible. Whether the benefits that accrue from this recommendation will balance the use of resources and the difficulties many IDDM patients with this additional diagnosis will experience, can be ascertained only by controlled clinical trials.
Vol 349 • April 12, 1997
References 1 2
3
4
5
6
7
8
9
10
11 12
13
14
15
16
17
18
19
20
21 22 23
24 25 26
27 28 29
Catassi C, Ratsch IM, Fabiani E, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 200–03. Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK. Increased prevalence of coeliac disease in diabetes. Arch Dis Child 1984; 59: 739–42. Savilahti E, Simell O, Koskimies S, Rilva A, Akerblom HK. Celiac disease in insulin-dependent diabetes mellitus. J Pediatr 1986; 108: 690–93. Cacciari E, Salardi S, Volta U, et al. Prevalence and characteristics of coeliac disease in type 1 diabetes mellitus. Acta Paediatr Scand 1987; 76: 671–72. Koletzko S, Burgin-Wolff A, Koletzko B, et al. Prevalence of coeliac disease in diabetic children and adolescents: a multicentre study. Eur J Pediatr 1988; 148: 113–17. Collin P, Salmi J, Hallstrom O, et al. High frequency of coeliac disease in adult patients with type I diabetes. Scand J Gastroenterol 1989; 24: 81–84. Barera G, Bianchi C, Calisti L, et al. Screening of diabetic children for coeliac disease with antigliadin antibodies and HLA typing. Arch Dis Child 1991; 66: 491–94. Gadd S, Kamath KR, Silink M, Skerritt JH. Co-existence of coeliac disease and insulin-dependent diabetes mellitus in children: screening sera using an ELISA test for gliadin antibody. Aust NZ J Med 1992; 22: 256–60. Rossi TM, Albini CH, Kumar V. Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus. J Pediatr 1993; 123: 262–64. Sigurs N, Johansson C, Elfstrand PO, Viander M, Lanner A. Prevalence of coeliac disease in diabetic children and adolescents in Sweden. Acta Paediatr 1993; 82: 748–51. Page SR, Lloyd CA, Hill PG, Peacock I, Holmes GK. The prevalence of coeliac disease in adult diabetes mellitus. QJM 1994; 87: 631–37. Verge CF, Howard NJ, Rowley MJ, et al. Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM: a populationbased study. Diabetologia 1994; 37: 1113–20. Sategna-Guidetti C, Grosso S, Pulitano R, Benaduce E, Dani F, Carta Q. Celiac disease and insulin-dependent diabetes mellitus. Dig Dis Sci 1994; 39: 1633–37. Maki M, Huupponen T, Holm K, Hallstrom O. Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut 1995; 36: 239–42. Rensch MJ, Merenich JA, Lieberman M, Long BD, Davis DR, McNally PR. Gluten-sensitive enteropathy in patients with insulindependent diabetes mellitus. Ann Intern Med 1996; 124: 564–67. Saukkonen T, Savilahti E, Reijonen H, Ilonen J, Tuomilehto-Wolf E, Akerblom HK. Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus. Diabet Med 1996; 13: 464–70. De Vitis I, D’Addesa S, Ghirlanda G, Gasbarrini G. Celiac disease (CD) and insulin dependent diabetes mellitus (IDDM): a multicentre study. Gastroenterology 1996; 110 (suppl): A13 (abstr). Cronin CC, Shanahan F, Liddy G, Feighery A, Ferriss JB, Feighery C. High prevalence of coeliac disease in patients with insulin-dependent (type 1) diabetes mellitus. Ir J Med Sci 1996; 165 (suppl 4): 2 (abstr). Shanahan F, Mckenna R, McCarthy CF, Drury MI. Coeliac disease and diabetes mellitus: a study of 24 patients with HLA typing. QJM 1982; 51: 329–35. Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P. Endomysial antibody: is it the best screening test for coeliac disease? Gut 1992; 33: 1633–37. Walsh CH, Cooper BT, Wright AD, Malins JM, Cooke WT. Diabetes mellitus and coeliac disease: a clinical study. QJM 1978; 47: 89–100. Cooper BT, Read AE. Coeliac disease and lymphoma. QJM 1987; 63: 269–74. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis 1994; 12: 186–90. Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322–27. Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy, and cerebral calcifications. Lancet 1992; 340: 439–43. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989; 30: 333–38. Bardella MT, Molteni N, Prampolini L, et al. Need for follow-up in coeliac disease. Arch Dis Child 1994; 70: 211–13. Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterology 1989; 97: 265–71.
1097
Viewpoint
Insulin-dependent diabetes mellitus and coeliac disease Cornelius C Cronin, Fergus Shanahan The sensitive and specific tests now available to screen for coeliac disease have shown that the prevalence of this condition in the general population is higher than previously supposed.1 The prevalence of coeliac disease as determined by screening among patients with insulindependent diabetes mellitus (IDDM) is also higher than suspected—with rates of 1·0–7·8% (table).2–18 The likely explanation for the frequent simultaneous occurrence of these two disorders is a similar genetic background. In particular, both coeliac disease and IDDM are associated with a high frequency of HLA-DR3 genotypes.19 Class-II HLA genes in the HLA-D region code for cell-surface molecules which bind and present antigenic peptides to T cells and have a major role in the pathogenesis of many autoimmune disorders. We propose that the clinical implication of this association is that IDDM patients should be screened and treated for coeliac disease. IgA endomysial antibody is the most sensitive and specific screening test for coeliac disease.20 The diagnosis is confirmed by small-bowel biopsy. The rates given in the table are probably underestimates. Many patients with positive antibody tests do not agree to small-bowel biopsy. Some patients who are antibody negative at diagnosis of IDDM may later test positive.14,16 Also some patients with positive antibodies but negative small-bowel biopsies may have latent coeliac disease. We have found that almost one in 20 IDDM patients in our clinic have coeliac disease.18 As in other similar studies, most patients were symptom-free and all were clinically undetected. There is, therefore, a strong association between IDDM and coeliac disease. By contrast, among patients with non-insulin-dependent diabetes mellitus, the frequency of coeliac disease is similar to that of the general population.11,21 Before screening tests were available, reports of coeliac disease in IDDM patients found that most patients19,21 were underweight and had diarrhoea—typical symptoms of coeliac disease. Anaemia was common, caused by iron or folic-acid deficiency. In nearly all patients, diabetes was diagnosed first. Many patients had poor metabolic control and hypoglycaemia was frequent, which suggests that “brittle diabetes” may be a manifestation of coeliac disease. Patients in general complied with dietary gluten restriction and an improvement in symptoms and weight gain was found. An increase in insulin requirements, improved metabolic control, and fewer hypoglycaemic episodes followed treatment in most cases.19,21 By contrast, studies in IDDM populations with coeliac disease detected by screening, have found these patients to have few or no symptoms or consequences of malabsorption.3,6,8,10 Patients are predominantly female and have an earlier age of onset of IDDM.4,5,7 There is a Department of Medicine, Cork University Hospital and University College Cork, Wilton, Cork, Ireland (C C Cronin MD, F Shanahan MD) Correspondence to: Dr Cornelius C Cronin
1096
tendency to think of coeliac disease as a childhood disorder. However, coeliac disease may present at any age, and reported frequencies among IDDM patients are generally higher in adults (table). Gastrointestinal symptoms may be present, but are often mild and appreciated only in retrospect.6,7,10,11 Failure to grow is a concern in diabetic children with coeliac disease and has been found in some7 but not in other8 studies. Iron deficiency is the most common laboratory abnormality,11 and anaemia may be present or absent.6,7,13 Folic-acid concentrations tend to be in the low-normal range.11 Glucose control in most patients is not adversely affected by subclinical coeliac disease.4,7 Page and colleagues11 found better metabolic control in patients with coeliac disease than in those without. Similarly, troublesome hypoglycaemia is not a feature—presumably a reflection of the limited damage to the mucosa of the small intestine in subclinical coeliac disease. Many clinicians recommend that all IDDM patients should be screened for coeliac disease. Some physicians recommend regular screening every few years for patients whose initial test is negative—particularly if the tests were done at the time diabetes was diagnosed, since the tests may later become positive.14,16 If these guidelines are followed, a large number of IDDM patients with subclinical coeliac disease will be detected. The combined figures from several studies show that only 21 of 144 coeliac-disease patients had been diagnosed before screening.2–8,10–16,18 Standard dietary guidelines for IDDM recommend large amounts of long-acting, gluten-rich carbohydrate, and the additional restrictions imposed by a gluten-free diet are difficult. Patients may also have problems coming to terms with the diagnosis of a second chronic disease, with adverse consequences on patient morale. Patients without symptoms tend to be less motivated and less
Ref
Country
2 3
Finland Finland
4 5
Italy Germany and Switzerland Finland Italy Australia USA Sweden UK Australia Italy Finland USA Finland Italy Ireland
6 7 8 9 10 11 12 13 14 15 16 17 18
Number of patients 215 children 201 children 146 children 1032 children 195 adults 498 children 180 children 211 children 436 children 767 adults 273 children 383 adults 238 children 47 adults 776 children 639 adults 101 adults
Test
Frequency (%)
ARA Jejunal biopsy, ARA, AGA AGA AGA
2·3 3·5 3·4 1·1–1·3
ARA AGA AGA EmA AGA, ARA AGA AGA, EmA EmA ARA EmA ARA, AGA EmA, AGA EmA
4·1 3·2 2·2 1·4 4·6 2·0 1·8 2·6 3·8 6·4 2·4 7·8 4·9
ARA=antireticulin antibody; AGA=antigliadin antibody; EmA=endomysial antibody.
Coeliac disease found by screening of IDDM patients
Vol 349 • April 12, 1997
THE LANCET
compliant with gluten restriction. Few studies of IDDM patients with coeliac disease diagnosed on screening have post-treatment follow-up data.3,6,8,10,11,13 The long-term prognosis of coeliac disease in this setting is not known, although gluten restriction does not seem to result in improved metabolic control.3,8,10,11 Is it worthwhile to diagnose subclinical coeliac disease in IDDM patients? An increased risk of various malignant diseases, such as squamous-cell carcinoma of the pharynx and oesophagus, adenocarcinoma of the small intestine, and in particular, small-bowel lymphoma, is a feature of coeliac disease that has received much attention. Malignancy may be the first manifestation of subclinical coeliac disease.22 Coeliac disease is associated with infertility in both men and women.23 Subclinical coeliac disease in women may be an unsuspected cause of delayed menarche, amenorrhoea, premature menopause, recurrent abortions, and a low pregnancy rate.23 Osteoporosis is a well-recognised manifestation of gluten-sensitive enteropathy—whether or not symptoms have been present.24 Attention has been drawn to an association with epilepsy25 and other neurological syndromes.26 The benefits of treatment can be difficult to quantify, but evidence suggests that gluten restriction reverses, or at least decreases the risk of complications and associated conditions.23,24,27,28 There is no reason to believe that the benefits of a gluten-free diet in IDDM patients would differ from those achieved in non-diabetic patients. Screening will detect both the undiagnosed patient with symptoms and the patient who is symptom-free. Many individuals without apparent symptoms who are found to have coeliac disease remark on a new-found vitality and sense of well-being when started on a gluten-free diet. In individual patients, an improvement in glycaemic control may be seen. An unanswered question is whether gluten restriction in IDDM patients with coeliac disease, with or without symptoms, alters the rate and progression of diabetic complications. There should be a high index of suspicion of coeliac disease in all IDDM patients. IDDM patients with any gastrointestinal symptom—no matter how mild or nonspecific—evidence of malabsorption, or unexplained constitutional symptoms should be investigated for coeliac disease. Patients in whom the diagnosis is confirmed should be strongly advised to adhere to a gluten-free diet throughout life. However, even an increase in the awareness of this diagnosis will not lead to the detection of all cases. Should all IDDM patients, irrespective of symptoms, be screened by tests for IgA endomysial antibodies, the preferred screening test? Coeliac disease, associated with substantial morbidity and increased mortality,29 is probably unique among immunological disorders in that a safe and effective treatment is available. We believe that coeliac disease is sufficiently prevalent and that the benefits of diagnosis and treatment are such that this disorder should be actively sought in all IDDM patients. Even in patients who cannot or will not restrict gluten intake, care can be taken to ensure adequate repletion of iron, folic acid, and fat-soluble vitamins, and to detect complications as early as possible. Whether the benefits that accrue from this recommendation will balance the use of resources and the difficulties many IDDM patients with this additional diagnosis will experience, can be ascertained only by controlled clinical trials.
Vol 349 • April 12, 1997
References 1 2
3
4
5
6
7
8
9
10
11 12
13
14
15
16
17
18
19
20
21 22 23
24 25 26
27 28 29
Catassi C, Ratsch IM, Fabiani E, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994; 343: 200–03. Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK. Increased prevalence of coeliac disease in diabetes. Arch Dis Child 1984; 59: 739–42. Savilahti E, Simell O, Koskimies S, Rilva A, Akerblom HK. Celiac disease in insulin-dependent diabetes mellitus. J Pediatr 1986; 108: 690–93. Cacciari E, Salardi S, Volta U, et al. Prevalence and characteristics of coeliac disease in type 1 diabetes mellitus. Acta Paediatr Scand 1987; 76: 671–72. Koletzko S, Burgin-Wolff A, Koletzko B, et al. Prevalence of coeliac disease in diabetic children and adolescents: a multicentre study. Eur J Pediatr 1988; 148: 113–17. Collin P, Salmi J, Hallstrom O, et al. High frequency of coeliac disease in adult patients with type I diabetes. Scand J Gastroenterol 1989; 24: 81–84. Barera G, Bianchi C, Calisti L, et al. Screening of diabetic children for coeliac disease with antigliadin antibodies and HLA typing. Arch Dis Child 1991; 66: 491–94. Gadd S, Kamath KR, Silink M, Skerritt JH. Co-existence of coeliac disease and insulin-dependent diabetes mellitus in children: screening sera using an ELISA test for gliadin antibody. Aust NZ J Med 1992; 22: 256–60. Rossi TM, Albini CH, Kumar V. Incidence of celiac disease identified by the presence of serum endomysial antibodies in children with chronic diarrhea, short stature, or insulin-dependent diabetes mellitus. J Pediatr 1993; 123: 262–64. Sigurs N, Johansson C, Elfstrand PO, Viander M, Lanner A. Prevalence of coeliac disease in diabetic children and adolescents in Sweden. Acta Paediatr 1993; 82: 748–51. Page SR, Lloyd CA, Hill PG, Peacock I, Holmes GK. The prevalence of coeliac disease in adult diabetes mellitus. QJM 1994; 87: 631–37. Verge CF, Howard NJ, Rowley MJ, et al. Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM: a populationbased study. Diabetologia 1994; 37: 1113–20. Sategna-Guidetti C, Grosso S, Pulitano R, Benaduce E, Dani F, Carta Q. Celiac disease and insulin-dependent diabetes mellitus. Dig Dis Sci 1994; 39: 1633–37. Maki M, Huupponen T, Holm K, Hallstrom O. Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut 1995; 36: 239–42. Rensch MJ, Merenich JA, Lieberman M, Long BD, Davis DR, McNally PR. Gluten-sensitive enteropathy in patients with insulindependent diabetes mellitus. Ann Intern Med 1996; 124: 564–67. Saukkonen T, Savilahti E, Reijonen H, Ilonen J, Tuomilehto-Wolf E, Akerblom HK. Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus. Diabet Med 1996; 13: 464–70. De Vitis I, D’Addesa S, Ghirlanda G, Gasbarrini G. Celiac disease (CD) and insulin dependent diabetes mellitus (IDDM): a multicentre study. Gastroenterology 1996; 110 (suppl): A13 (abstr). Cronin CC, Shanahan F, Liddy G, Feighery A, Ferriss JB, Feighery C. High prevalence of coeliac disease in patients with insulin-dependent (type 1) diabetes mellitus. Ir J Med Sci 1996; 165 (suppl 4): 2 (abstr). Shanahan F, Mckenna R, McCarthy CF, Drury MI. Coeliac disease and diabetes mellitus: a study of 24 patients with HLA typing. QJM 1982; 51: 329–35. Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P. Endomysial antibody: is it the best screening test for coeliac disease? Gut 1992; 33: 1633–37. Walsh CH, Cooper BT, Wright AD, Malins JM, Cooke WT. Diabetes mellitus and coeliac disease: a clinical study. QJM 1978; 47: 89–100. Cooper BT, Read AE. Coeliac disease and lymphoma. QJM 1987; 63: 269–74. Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF. Infertility, obstetric and gynaecological problems in coeliac sprue. Dig Dis 1994; 12: 186–90. Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322–27. Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy, and cerebral calcifications. Lancet 1992; 340: 439–43. Hadjivassiliou M, Gibson A, Davies-Jones GA, Lobo AJ, Stephenson TJ, Milford-Ward A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996; 347: 369–71. Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989; 30: 333–38. Bardella MT, Molteni N, Prampolini L, et al. Need for follow-up in coeliac disease. Arch Dis Child 1994; 70: 211–13. Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterology 1989; 97: 265–71.
1097