Cornelius C. Cronin

Insulin-dependent diabetes mellitus and coeliac disease

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

Anemia in patients with chronic inflammatory bowel disease

1. Targan S, Hanauer SB, van Deventer SJ, et al. A short term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. N Engl J Med 1997;337: 1029–35. 2. Rutgeerts P, D’Haens G, Targan S, et. al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (Infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–9. 3. Present DH, Rutgeerts P, Targan S, et. al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–1405. 4. Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn’s disease. First anniversary clinical experience. Am J Gastroenterol 2000;95:3469–77. 5. Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with Infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000;95:3490–7. 6. Ricart E, Panaccione R, Loftus EV, et al. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic. The first 100 patients. Gastroenterol 2000;118:A568. 7. Chey WY, Hussain A, Ryan C, et al. Infliximab for refractory ulcerative colitis. Am J Gastroenterol 2001;96:2373–81. 8. Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporin in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 1994;330:1841–5. 9. Bickston SJ, Lichtenstein GR, Arseneau KO, et al. The relationship between Infliximab treatment and lymphoma in Crohn’s disease. Gastroenterology 1999;117:1433–7.

Celiac disease and the transition from childhood to adulthood: a 28-year follow-up.

OBJECTIVES:Follow-up of celiac disease diagnosed in childhood is variable or nonexistent after transition to adulthood. Outcome, continuity of care, and adherence to a gluten-free diet are poorly documented. We report a 28-yr follow-up of 50 adults in whom the original childhood diagnosis could be confirmed.METHODS:Original pediatric charts were reviewed, and subjects were invited to undergo dietary evaluation, measurement of bone mineral density, and quality-of-life assessment. The mean duration of celiac was 28.5 yr, median 28.7 yr (range 22–45 yr). The mean and median age of the group was 35 yr.RESULTS:Only 22% of patients were enrolled in an adult gastroenterology clinic. Fifty percent were fully compliant with a gluten-free diet; 18% were partially compliant; and 32% were not adhering to diet. The main motivating factor for dietary compliance was avoidance of symptoms rather than avoidance of complications. Eighty-six percent of the females and 21% of the males had iron deficiency. Bone mineral density was subnormal in 32%; 28.9% were osteopenic and 2.6% were osteoporotic. Quality-of-life scores were normal.CONCLUSIONS:Most patients diagnosed with celiac in childhood receive no medical or dietary supervision after transition to adulthood. One-third are not compliant with diet; the primary motivating factor for those who do comply is avoidance of symptoms rather than fear of complications. The prevalence of preventable and treatable disorders in these young adults highlights a failure of health services after transition from pediatric to adult health care.

Microalbuminuria in Patients with Non-Insulin-dependent Diabetes Mellitus Relates to Nocturnal Systolic Blood Pressure

PURPOSE Microalbuminuria predicts early mortality in non-insulin-dependent-diabetes mellitus patients (NIDDM). Our objective in the present study was to compare and assess the relationship between 24-hour, day and nocturnal ambulatory blood pressure (BP) and urinary albumin excretion rate (UAE) in microalbuminuric and normoalbuminuric NIDDM and in normal control subjects. PATIENTS AND METHODS In the present cross-sectional study, 24 hour ambulatory BP (daytime BP and nocturnal BP) and HbA1c were compared in microalbuminuric (n = 10) and nonmicroalbuminuric NIDDM patients (n = 10) and in nondiabetic controls (n = 9). None of the patients were taking antihypertensive agents. RESULTS In the microlbuminuric group, whereas 24 hour and daytime systolic BP differed significantly from control values (P < 0.025 and P < 0.05 respectively), there was no difference between diabetic groups. However, nocturnal systolic BP in the microalbuminuric group was significantly higher than in the normoalbuminuric diabetic patients (139 vs. 125) (P < 0.05) and a significant difference was also found between the NIDDM patients and the control group (139, 125 vs. 114) (P < 0.025). In multiple regression analysis, only nocturnal systolic BP showed a significant relationship with UAE (P < 0.05). CONCLUSIONS We suggest that the higher nocturnal systolic blood pressure seen in our microalbuminuric NIDDM patients may contribute to the increased morbidity in this group.

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases

Introduction Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma.

The prevalence of coeliac disease among female subjects having bone densitometry

BackgroundOsteoporosis frequently complicates coeliac disease but most studies focus on symptomatic patients at the time of diagnosis. Screening tests have revealed that many individuals with coeliac disease have mild, atypical, or absent symptoms.AimTo evaluate the relationship between coeliac disease and osteopenia or osteoporosis in female subjects attending for bone densitometry.MethodsWe studied 371 female subjects attending for bone densitometry, without secondary causes of osteoporosis and included those with normal and with reduced bone mineral density. Mineral density was measured by dual energy X-ray absorptiometry. Screening for coeliac disease was by measurement of anti-endomysial antibody by indirect immunofluorescence.ResultsTwo of 115 (1.7%) female subjects with normal bone density and five of 256 (1.9%) female subjects with sub-normal bone density were positive for endomysial antibody. Five subjects who underwent small bowel biopsy had histological changes suggestive of coeliac disease.ConclusionsIn females referred for bone densitometry, endomysial antibody positivity was not more prevalent among those with reduced bone mineral density. Examining only patients with clinically detected coeliac disease may overestimate the frequency of complications. This study does not support population screening for coeliac disease in an area with a high frequency of the condition.

Undiagnosed maternal celiac disease in pregnancy and an increased risk of fetal growth restriction.

To the Editor: The reported risk of fetal growth restriction (FGR) associated with undiagnosed celiac disease varies significantly with odds ratios (ORs) in referenced papers varying between 2.6 and 6. FGR is a major pregnancy complication responsible for a 5 to 20fold increase in perinatal mortality and for considerable perinatal morbidity. FGR may also have lifelong consequences ranging from neurodevelopmental delay to an increased risk of developing hypertension, heart disease, and diabetes later in life. The prevalence of celiac disease varies widely depending on ethnicity and occurs at rates greater then 1% in the Irish population. To clarify the risk of low-birth weight in babies of mothers with undiagnosed celiac disease we performed a study in the high prevalence Irish population using, for the first time, individualized birth ratios (IBRs). The use of IBRs allows us take into account factors omitted in other studies, such as the influence of maternal height and weight on the birth weight of babies. We performed a retrospective cohort study to assess the magnitude of low-birth weight babies defined as an IBR less than the 10th centile in women with undiagnosed celiac disease. The study was approved by the Cork University Teaching Hospitals Clinical Research Ethics Committee. A search of the Cork University Hospital database between the years 2000 and 2005 was performed and 270 female patients, in whom a primary diagnosis of celiac disease (confirmed by small bowel mucosal biopsy) was made during the study period, were identified. Patients were classified as having a primary diagnosis of celiac disease based on the World Health Organization International Classification of Diseases (ICD10). These women were contacted and asked to complete a structured postal questionnaire regarding their reproductive and medical history before and after their diagnosis of celiac disease. Nonrespondents were followed up via a telephone survey. One hundred and seventy of the 270 women contacted responded (response rate 63%). Fifty-two women with celiac disease were excluded owing to nulliparity and incomplete data. One hundred and eighteen women had one or more pregnancies at least 2 years before being diagnosed with celiac disease and all of these 118 women were included in our analysis. To establish a non-celiac comparator group, we invited 250 women attending gynecology clinics and two general practitioners clinics in Cork between March and June 2008 to participate. Two hundred and fourteen of these women completed the questionnaire (response rate 86%). Sixty-two women were excluded owing to nulliparity and incomplete data. The data from 152 women, none with known celiac disease, were used in our analysis and are referred to as the reference group. The following maternal characteristics were recorded: maternal age, ethnicity, prepregnancy weight, height, and medical history including hypertension, diabetes, preeclampsia, kidney problems, and thyroid disease. We also recorded gestation, sex, and birth weight of all infants born, parity, miscarriages, terminations, stillbirths, and the occurrence of any fertility problems. To ensure the observations were independent of each other, the data were restricted to the first born child of each patient. Using maternal height and weight and infant gestation, sex, and weight we calculated IBRs using the centile calculator provided by the Gestation Network (www.gestation.net). Statistical analysis was performed using STATA 10 statistical software. Linear regression analysis was used to determine the association between maternal celiac disease and offspring birth weight. The model was adjusted for maternal age, gestational age, body mass index, infant sex, and year of birth. All potential confounders were categorical. Logistic regression was used to calculate the OR and their 95% confidence intervals (CI) for each fetal outcome in relation to the presence of maternal celiac disease. The logistic regression model was adjusted for maternal age, body mass index, infant sex, and year of birth. Data from 118 women with undiagnosed celiac disease and 152 women in the reference group was available for the analysis. There was no important difference in mean maternal age or mean gestational age at delivery in women with undiagnosed celiac disease and the reference group. The adjusted mean difference in birth weight between offspring of women with undiagnosed celiac disease and the offspring of our reference group was 151 g (95% CI: 284, 18). Using multiple logistic regression we were able to demonstrate that women with undiagnosed celiac disease had a significantly increased risk of delivering a baby with a birth weight less than the 10th [adjusted OR 2.19, (95% CI: 1.04, 4.57)]. Risk of birth weight less than the fifth centile in offspring of celiac women was, nonsignificantly, increased compared with offspring of women in the reference group [adjusted OR 2.45, (95% CI: 0.98, 6.10)]. There was a trend toward women with undiagnosed celiac disease having a baby with a birth weight less than third centile but these results and those demonstrating the OR of a birth weight less than the fifth centile were not statistically significant. This study, the first to use IBRs, demonstrates that women with undiagnosed celiac disease have a significantly increased risk of delivering a baby with a birth weight less than the 10th centile compared with women in our reference group. IBRs take into account factors omitted in other studies, such as the influence of maternal height and weight on the birth weight of babies. The magnitude of the effect of undiagnosed celiac disease on low-birth weight correlates well with previous studies. Our results may underestimate the true effect of FGR in women with undiagnosed celiac disease as we did not take into account the fact that potentially 1% of our reference group may also have undiagnosed celiac disease. The study is retrospective and our response rate of 63% reflected the wide age spectrum (18 to 80 y old) which we targeted. This response rate rose to 76% when we narrowed our age range from 29 to 76 years. No funding was received for the production of this paper. This work was carried out in Cork University Maternity Hospital and Cork University Hospital. The authors declare that they have no conflict of interest.

Medial arterial calcification, calcific aortic stenosis and mitral annular calcification in a diabetic patient with severe autonomic neuropathy.

Medial arterial calcification (Mönckebergs arteriosclerosis) is well described in diabetic patients with autonomic neuropathy. There is also a high prevalence of diabetes mellitus among subjects with calcific aortic stenosis and mitral annular calcification. We describe a diabetic patient with autonomic neuropathy and extensive medial arterial calcification who also had calcification of the aortic valve and of the mitral valve annulus. We propose that autonomic neuropathy may play a role in calcification of these structures at the base of the heart.

Charles Sugrue, M.D., of Cork (1775–1816) and the first description of a classical medical condition: phaeochromocytoma

The appearances after death observed in the following case are I think worthy of being preserved in your valuable publication, particularly as nothing similar are to be found in the writings of De Haen, Morgagni or Dr Baillie. I shall barely enumerate such particulars of the case as may serve to shew how easily the cause and seat of the disease may be misconceived. Richard Mountjoy, aged 8 years a thin sprightly boy of a fair complexion with blue eyes delicate skin and fair hair was attacked in the month of June of the year 1796 with a severe pain under the stomach. As most of the disease of children in this as well as in other countries are ascribed to worms, some worm powders were procured from an apothecary in this city which operated strongly. No mitigation of the pain having however ensued, I was sent for and found the boy apparently in great agony; he complained of excruciating and unremitting pain about the lower part of the stomach, shooting across the abdomen; his countenance was pale and languid and his pulse feeble. The pain was neither increased nor diminished on pressure; and as the bowels were free there was no reason to suspect an inflammation of any part of the intestinal canal. Different means were tried with a view of giving temporary ease but no material relief was experienced from any, except from laudanum in fairly large doses; he continued several weeks in this state, taking very little nourishment, and complaining of constant pain. On being questioned relative to the cause of his complaint, he could assign none, but recollected having received a severe blow of a rattan across the loins from his school-master. About the commencement of the following winter, after he had renounced the aid of medicine as useless, his health began suddenly to mend and he experienced temporary cessation of pain. Those symptoms became gradually more favourable, until he at length entirely recovered. From the winter of 1796 until the month of August 1799, he continued in perfect health. About the end of this month, the pain about the stomach returned, without any apparent cause, and precisely in the same situation as before; it was slight at first but increased daily. His appetite was at first very bad, but afterwards became voracious; on taking food however the pain was much aggravated, but he felt relief from bending his body forwards. He was often attacked with diarrhoea, of the appearance of blood and pus; at other times the bowels were constipated. He was blistered and took a variety of medicines without any benefit. Though during the last three or four months of his illness, he took a considerable quantity of nourishment, he visibly became more emaciated and feeble. His pulse was during this time about 120. His countenance resembled that of a person in the last stage of a pulmonary consumption; it was pale, and the hectic flush was distinctly marked on each cheek; he had constant profuse and universal perspiration; the C. Cronin (&) Mallow General Hospital, Mallow, Co Cork, Ireland e-mail: cccronin@eircom.net

Appropriateness of laboratory tests: requests for atypical pneumonia serology in a teaching hospital.

The cost of providing medical care is ever-increasing but the resources available are at best static. Major savings can be made by reducing inappropriate investigations. Using serological testing for organisms causing atypical pneumonia as an example, we examined the appropriateness of requests and also physicians’ understanding of the test. Of 119 patients tested, only 3 had titres indicative of acute infection. Most patients were tested within 2 days of hospital admission, before receipt of results excluding more likely diagnoses. Forty-five patients had no current or recent respiratory symptoms, in whom infection was highly unlikely. Titres were most often requested by the least experienced members of the clinical team. Of 70 patients with an acute illness in whom a definitive diagnosis, bacteriological or otherwise, was not made, in only 9 was a convalescent specimen sent for follow-up titres. Most requests for serology for organisms causing atypical pneumonia were inappropriate. Furthermore, in the majority of cases the test was incorrectly used.