Cystic fibrosis-related diabetes and lung disease: an update.

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Pericardial Effusion Associated with Diazoxide Treatment for Congenital Hyperinsulinism.

BACKGROUND: Diazoxide is widely used to manage congenital hyperinsulinism and is generally well tolerated. Pericardial effusion is not a recognized side effect of diazoxide, apart from 2 single case reports. CASE DESCRIPTION: Three patients with congenital hyperinsulinism developed pericardial effusion at the ages of 7 weeks, 8 months, and 17 years. The duration of diazoxide treatment (10-15 mg/kg/day) was 6.5 weeks, 5 months, and 17 years, respectively. There was no evidence of fluid overload or significant other cardiac anomaly. The 7-week-old patient presented with signs of cardiac failure, was treated with diuretics, and the effusion resolved after cessation of diazoxide. The 8-month-old patient required emergency subxiphoid drainage of the effusion due to hemodynamic compromise. The pericardial fluid had high numbers of polymorphonuclear cells, but did not grow any organisms, and histology showed non-specific chronic reactive changes; the effusion did not recur after cessation of diazoxide. The 17-year-old patient presented with atrial fibrillation, was treated with beta blockade and colchicine, and continues on diazoxide with monitoring of the effusion by ultrasound. CONCLUSION: Patients on long-term diazoxide treatment may be at risk of pericardial effusion, the timing and significance of which is unpredictable. The duration of diazoxide treatment before presentation of pericardial effusion varied in our patients from weeks to years. We advise serial echocardiography 1-2 months after commencement of diazoxide and annually thereafter.

Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis.

BACKGROUND: Screening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old. METHODS: We analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG120min), peak BG (BGmax) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants. RESULTS: The BGmax was higher than the BG120min in 25/27 (93%) participants. There was a significant inverse correlation between BGmax and weight z-score (rs = -0.56, p = .002) and between BGmax and FEV1 (rs = -0.54, p = .014) that was not present for BG120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (rs = - 0.69, p = .027) or as % time > 7.8 (rs = - 0.76, p = .011). CONCLUSIONS: Children with CF < 10 years of age with higher BGmax on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG120min. CGM also identifies glucose excursions in young children with CF.

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis.

BACKGROUND: Children with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation. METHODS: We assessed 18 children (5 females) with median age of 3.2 years (range 0·9-5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level. RESULTS: Peak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG rs = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, ß = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015). CONCLUSION: Children with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development.

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.

Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens.

OBJECTIVE: Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5mg/m2/week) in very young children with Prader-Willi Syndrome (PWS). DESIGN: Prospective longitudinal clinical intervention. METHODS: We evaluated 31 infants (aged 2-12months) and 42 toddlers (13-24months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDSWHO) and PWS specific BMI (SDSPWS), bone age, insulin-like growth factor 1 (IGF-I) levels and adverse events over 3years of GHT. RESULTS: At commencement of GHT infants had a lower BMI SDSWHO (-0.88 vs 0.40) than toddlers, while toddlers had a lower height SDSWHO (-1.44 vs -2.09) (both P<0.05). All increased height SDSWHO (2year delta height infants +1.26 SDS, toddlers+1.21 SDS), but infants normalised height sooner, achieving a height SDS of -0.56 within 1year, while toddlers achieved a height SDS of -0.88 in two years. BMI SDSWHO increased, while BMI SDSPWS decreased (both P<0.0001) and remained negative. The GHT response did not differ with gestation (preterm 23%) or genetic subtype (deletion vs maternal uniparental disomy). Bone age advancement paralleled chronological age. All children had low serum IGF-I at baseline which increased, but remained within the age-based reference range during GHT (for 81% in first year). Four children had spinal curvature at baseline; two improved, two progressed to a brace and two developed an abnormal curve over the observation period. Mild to severe central and/or obstructive sleep apnoea were observed in 40% of children prior to GHT initiation; 11% commenced GHT on positive airway pressure (PAP), oxygen or both. Eight children ceased GHT due to onset or worsening of sleep apnoea: 2 infants in the first few months and 6 children after 6-24months. Seven resumed GHT usually after adjusting PAP but five had adenotonsillectomy. One child ceased GHT temporarily due to respiratory illness. No other adverse events were reported. Two children substantially improved their breathing shortly after GHT initiation. CONCLUSION: Initiation of GHT in infants with 4.5mg/m2/week was beneficial and comparable in terms of auxological response to a dose of 7mg/m2/week. Regular monitoring pre and post GH initiation assisted in early detection of adverse events. IGF-I levels increased with the lower dose but not excessively, which may lower potential long-term risks.

Diagnosing cystic fibrosis-related diabetes: current methods and challenges.

INTRODUCTION: Cystic fibrosis-related diabetes (CFRD) is the end-point of a spectrum of glucose abnormalities in cystic fibrosis that begins with early insulin deficiency and ultimately results in accelerated nutritional decline and loss of lung function. Current diagnostic and management regimens are unable to entirely reverse this clinical decline. AREAS COVERED: This review summarises the current understanding of the pathophysiology of CFRD, the issues associated with using oral glucose tolerance tests in CF and the challenges faced in making the diagnosis of CFRD. Medline database searches were conducted using search terms "Cystic Fibrosis Related Diabetes", "Cystic Fibrosis" AND "glucose", "Cystic Fibrosis" AND "insulin", "Cystic Fibrosis" AND "Diabetes". Additionally, reference lists were studied. Expert commentary: Increasing evidence points to early glucose abnormalities being clinically relevant in cystic fibrosis and as such novel diagnostic methods such as continuous glucose monitoring or 30 minute sampled oral glucose tolerance test (OGTT) may play a key role in the future in the screening and diagnosis of early glucose abnormalities in CF.

Advances in the detection and management of cystic fibrosis related diabetes.

PURPOSE OF REVIEW: This review will outline the screening, diagnosis and management of cystic fibrosis related diabetes (CFRD). It will also discuss advances in the detection of early glucose abnormalities, their clinical significance and the emerging role for early insulin therapy. RECENT FINDINGS: Before the onset of diabetes (as currently defined), patients with cystic fibrosis (CF) display glucose abnormalities, detectable either by 30-minutely sampled oral glucose tolerance testing (OGTT), or by continuous ambulatory interstitial glucose monitoring (CGM). These early glucose abnormalities are associated with the presence of glucose in airway fluid, potentially promoting the growth of airway pathogens and contributing to the progression of respiratory disease. Progressive insulin deficiency underlies these glucose abnormalities, and insulin deficiency also causes catabolism. Pilot studies of once-daily insulin therapy in the early stages of insulin deficiency show improved lung function and weight gain (important predictors of survival in CF). SUMMARY: Early stages of insulin deficiency may be contributing to catabolism and deteriorating lung function in CF. It is plausible that early insulin therapy may prevent this deterioration, a view supported by pilot studies. Randomized controlled trials of early insulin therapy will now determine whether insulin therapy should be commenced earlier than current practice in CF.

Markers of pancreatic function in the breath.

Exhaled breath analysis is able to identify biomarkers of respiratory and systemic diseases. It was hypothesized that markers of pancreatic function would be identified in the breath of those with diabetes mellitus and cystic fibrosis. Children aged 6-18 years old with diabetes mellitus (DM), cystic fibrosis (CF), cystic fibrosis related diabetes (CFRD) and healthy controls (C) contributed exhaled breath condensate (EBC), with concurrent blood glucose measurements taken from a subset. EBC C-peptide, glucose, sodium concentrations and conductivity were subsequently measured.A total of 104 children were recruited (DM = 56, CF = 26, CFRD = 5, C = 17). C-peptide was detected in EBC: CF 19.6 ± 11.7 pmol L(-1); DM: 9.66 ± 8.27 pmol L(-1); CFRD: 11.9 ± 9.23 pmol L(-1) which was significantly higher than in the control group (0.987 ± 2.26 pmol L(-1)) (p < 0.0001). No statistically significant difference was seen between the three groups for glucose, conductivity or sodium concentration.Glucose was not reliably found in EBC, but C-peptide was found to be higher in CF EBC. This may represent inflammation and a change in airway integrity, rather than increased secretion of this peptide.

Hypothalamic-pituitary-adrenal axis recovery following prolonged prednisolone therapy in infants.

CONTEXT: The duration of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid treatment is uncertain. OBJECTIVE: We aimed to determine the duration of HPA axis suppression in prednisolone-treated infants and the age at which circadian variation in salivary cortisol is established in healthy infants. DESIGN, SETTING, AND PARTICIPANTS: Before the adoption of propranolol treatment by the Vascular Birthmarks Clinic, 12 infants with infantile hemangioma received high-dose prednisolone for 12 to 25 weeks' duration, weaned over 4 to 6 weeks, and ceased at age 21 to 31 weeks. Parents collected serial salivary samples at two time points per day (before first and last feed) until circadian variation in salivary cortisol (measured by radioimmunoassay) was observed, when a confirmatory 1 µg Synacthen test was performed. Ten healthy control infants had serial salivary cortisol measurements to determine the age at which circadian variation is established. MAIN OUTCOME MEASURE: We defined circadian variation as evening salivary cortisol <50% of the early morning level on two consecutive sampling weeks. RESULTS: Circadian variation appeared within 6 weeks (median 2.7, range 1.4-5.4) of prednisolone cessation. All confirmatory Synacthen tests were normal (peak serum cortisol >600 nmol/L) and were performed within 12 weeks of prednisolone cessation. Healthy controls developed circadian variation at median 16 weeks of age (range 8-24). CONCLUSION: HPA recovery occurred within 6 to 12 weeks, shorter than empirical recommendations, to give stress cover for 6 to 12 months. Reduced duration of stress-cover precautions may reduce parental anxiety and side effects from unnecessary glucocorticoid use. Healthy control infants established circadian variation in salivary cortisol between 2 and 6 months of age.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

BACKGROUND/AIMS: Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. METHODS: A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. RESULTS: After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. CONCLUSION: This practical regimen improved sodium control, parental independence, and allowed discharge home.

Once daily insulin detemir in cystic fibrosis with insulin deficiency.

The aim of this study was to determine if once daily insulin detemir reverses decline in weight and lung function in patients with cystic fibrosis (CF). 12 patients with early insulin deficiency and six with CF related diabetes (aged 7.2-18.1 years) were treated for a median of 0.8 years. Changes in weight and lung function following treatment were compared to pretreatment changes. Before treatment, the change in weight SD score (ΔWtSDS), percentage of predicted forced expiratory volume in 1 s (Δ%FEV(1)) and percentage of predicted forced vital capacity (Δ%FVC) declined in the whole study population (-0.45±0.38, -7.9±12.8%, -5.8±14.3%) and in the subgroup with early insulin deficiency (-0.41±0.43, -9.8±9.3%, -6.8±10.3%). Following treatment with insulin ΔWtSDS, Δ%FEV(1) and Δ%FVC significantly improved in the whole study population (+0.18±0.29 SDS, p=0.0001; +3.7±10.6%, p=0.007; +5.2±12.7%, p=0.013) and in patients with early insulin deficiency (+0.22±0.31 SDS, p=0.003; +5.3±11.5%, p=0.004; +5.8±13.4%, p=0.024). Randomised controlled trials are now needed.

Cystic fibrosis related diabetes (CFRD)--the end stage of progressive insulin deficiency.

In cystic fibrosis, gradual pancreatic destruction causes progressive insulin deficiency, culminating in cystic fibrosis related diabetes (CFRD). As a consequence of insulin deficiency, elevated glucose levels can be detected (well before the diagnosis of CFRD), by continuous ambulatory subcutaneous interstitial fluid glucose monitoring or 30-min sampled oral glucose tolerance test (OGTT). Current diagnostic criteria for CFRD (based on 0 and 120-min OGTT blood glucose levels) were originally designed to forecast microvascular disease in type 2 diabetes, rather than CF-specific outcomes such as declining weight or lung function. In CF, decline in either weight or lung function predicts early mortality. Both may precede the diagnosis of CFRD by several years. Insulin, a potent anabolic hormone, is recommended treatment for CFRD, but use in earlier stages of insulin deficiency is not established. Conventional dosing (with four or more insulin injections per day) is burdensome and carries substantial risk of hypoglycemia. However, recent uncontrolled trials suggest that once-daily injection of intermediate or long-acting insulin improves weight and lung function, with minimal hypoglycemia risk, in CFRD and also in early insulin deficiency. It is plausible that insulin may be of greater benefit to respiratory function when given prior to the diagnosis of CFRD, after which structural lung disease may be irreversible. It is also plausible that early insulin treatment may prolong the lifespan of the remaining insulin-secreting ß-cells. Randomized controlled trials are now needed to determine whether or not current clinical practice should be altered toward the earlier commencement of insulin in CF.

Increased detection of cystic-fibrosis-related diabetes in Australia.

OBJECTIVES: To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis. METHODS: Incident cases of CFRD in young people aged ≤ 18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register. RESULTS: CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2-8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007-2008 compared with previous years (61% vs 6%, p<0.001). CONCLUSIONS: CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation.

Three cases of osteoma cutis occurring in infancy. A brief overview of osteoma cutis and its association with pseudo-pseudohypoparathyroidism.

We report three cases of primary osteoma cutis in children, two of whom (siblings) were associated with Albright's hereditary osteodystrophy (AHO), manifesting as short stature with autosomal dominant inheritance from the father, but no dysmorphic features and no parathyroid hormone (PTH) resistance. Osteoma cutis can manifest as an isolated skin disease, a secondary condition to other skin diseases (such as acne), or in association with several syndromes, including AHO, which in turn may be associated with PTH resistance. The management and prognosis of patients diagnosed with osteoma cutis is determined by whether the skin manifestation has occurred in isolation, in association with a syndrome, or as a secondary skin disease. These three paediatric cases highlight the importance of understanding the aetiology and associations of osteoma cutis in order to appropriately investigate and manage patients who present with this rare skin disease.

Overgrowth.

Overgrowth presenting at birth requires blood glucose monitoring while a cause is sought. Among older children presenting with tall stature, common causes such as familial tall stature and simple obesity must be distinguished from rarer endocrine and genetic causes. Several genetic overgrowth syndromes carry increased risk of malignancy and regular screening is recommended. The use of high-dose oestrogen or testosterone in an attempt to limit final stature has limited efficacy and carries a significant risk of side effects. Endocrine and genetic assessment ought to be considered for cases of unexplained overgrowth.

Early glucose abnormalities in cystic fibrosis are preceded by poor weight gain.

OBJECTIVE: Progressive beta-cell loss causes catabolism in cystic fibrosis. Existing diagnostic criteria for diabetes were based on microvascular complications rather than on cystic fibrosis-specific outcomes. We aimed to relate glycemic status in cystic fibrosis to weight and lung function changes. RESEARCH DESIGN AND METHODS: We determined peak blood glucose (BG(max)) during oral glucose tolerance tests (OGTTs) with samples every 30 min for 33 consecutive children (aged 10.2-18 years). Twenty-five also agreed to undergo continuous glucose monitoring (CGM) (Medtronic). Outcome measures were change in weight standard deviation score (wtSDS), percent forced expiratory volume in 1 s (%FEV1), and percent forced vital capacity (%FVC) in the year preceding the OGTT. RESULTS: Declining wtSDS and %FVC were associated with higher BG(max) (both P = 0.02) and with CGM time >7.8 mmol/l (P = 0.006 and P = 0.02, respectively) but not with BG(120 min). A decline in %FEV1 was related to CGM time >7.8 mmol/l (P = 0.02). Using receiver operating characteristic (ROC) analysis to determine optimal glycemic cutoffs, CGM time above 7.8 mmol/l > or =4.5% detected declining wtSDS with 89% sensitivity and 86% specificity (area under the ROC curve 0.89, P = 0.003). BG(max) > or =8.2 mmol/l gave 87% sensitivity and 70% specificity (0.76, P = 0.02). BG(120 min) did not detect declining wtSDS (0.59, P = 0.41). After exclusion of two patients with BG(120 min) > or =11.1 mmol/l, the decline in wtSDS was worse if BG(max) was > or =8.2 mmol/l (-0.3 +/- 0.4 vs. 0.0 +/- 0.4 for BG(max) <8.2 mmol/l, P = 0.04) or if CGM time above 7.8 mmol/l was > or =4.5% (-0.3 +/- 0.4 vs. 0.1 +/- 0.2 for time <4.5%, P = 0.01). CONCLUSIONS: BG(max) > or =8.2 mmol/l on an OGTT and CGM time above 7.8 mmol/l > or =4.5% are associated with declining wtSDS and lung function in the preceding 12 months.

The role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications.

OBJECTIVE: The purpose of this study was to explore whether the presence of thyroid and endomysial autoantibodies at diagnosis of type 1 diabetes in children predicts development of thyroid and celiac disease, respectively, and whether diabetes-associated autoantibodies at diagnosis predict development of microvascular complications up to 13 years later. RESEARCH DESIGN AND METHODS: Autoantibodies were measured at diagnosis of type 1 diabetes in 173 children aged 0-15 years and included thyroperoxidase antibody (TPOA), endomysial antibody (EMA), islet cell autoantibody, GAD antibody (GADA), and insulin autoantibody. Thyroid disease was defined as thyroid stimulating hormone level > or = 5 microU/ml. Celiac disease was confirmed by small-bowel biopsy. Assessment of microvascular complications included stereoscopic fundal photography, pupillometry, thermal threshold, and albumin excretion rate (AER). RESULTS: The incidence rates for thyroid and celiac disease were 0.9 and 0.7 per 100 patient-years, respectively. Within 13 years, 6 of 13 children with positive TPOA tests at diagnosis developed thyroid disease compared with 5 of 139 children with negative TPOA tests (P < 0.001). All four patients with positive EMA titers at diagnosis had biopsy-proven celiac disease. Five of 11 patients who developed thyroid disease and 4 of 8 who developed celiac disease had negative TPOA and EMA tests at diagnosis, respectively. Retinopathy was detected in 39% and elevated AER in 36%. The presence of diabetes-associated autoantibodies at diagnosis did not predict microvascular complications though GADA titer levels predicted pupillary abnormality. CONCLUSIONS: Elevated TPOA and EMA levels at diagnosis of type 1 diabetes predict the development of thyroid and celiac disease, respectively. In children with negative antibody titers at diagnosis, screening at 2-year intervals is recommended.