Poorly controlled pediatric type 1 diabetes mellitus is a risk factor for metabolic dysfunction associated steatotic liver disease (MASLD): An observational study.

OBJECTIVES: Recent studies have suggested a link between type 1 diabetes mellitus (T1D) and metabolic dysfunction associated steatotic liver disease (MASLD) in children and adolescent, but longitudinal evidence is lacking. This study aimed to investigate the potential association between poorly controlled T1D and elevated alanine aminotransferase (ALT), serving as a proxy for MASLD in children and adolescents over time. METHODS: The study included 32,325 children aged 2-17 years with T1D from Germany, Austria, and Switzerland who had undergone at least one assessment of liver enzyme levels recorded in the Diabetes-Patienten- Verlaufsdokumentation registry. Multivariable logistic and Cox regression models were calculated to show possible associations between T1D and elevated ALT values (>26 U/L in males, >22 U/L in females) as a proxy for MASLD. RESULTS: Children with poorly controlled T1D (HbA1c > 11%) exhibited increased odds of elevated ALT values, after adjustment for age, sex, diabetes duration and overweight (odds ratio [OR] 2.54; 95% confidence interval [CI], 2.10-3.10; p < 0.01). This finding is substantiated by a longitudinal analysis, which reveals that inadequately controlled T1D was associated with a higher hazard ratio (HR) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 (HR: 1.54; 95% CI, 1.19-2.01; p < 0.01). CONCLUSION: In conclusion, the current study strongly links poorly controlled T1D in children and adolescents to MASLD irrespective of overweight. This association is not only present cross-sectionally but also increases over time. The study underscores the critical role of effective diabetes management in reducing the risk of MASLD in this population.

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

Background: To describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN. Methods: Survey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN. Results: Fifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria. Conclusion: The majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists.

2017 American Academy of Pediatrics Clinical Practice Guideline: Impact on Prevalence of Arterial Hypertension in Children and Adolescents With Type 1 Diabetes.

OBJECTIVE: In 2017, the American Academy of Pediatrics introduced a new guideline (2017 Clinical Practice Guideline of the American Academy of Pediatrics [AAP 2017]) to diagnose arterial hypertension (HTN) in children that included revised, lower normative blood pressure (BP) values and cut points for diagnosing high BP in adolescents. We studied the impact of the new AAP 2017 on prevalence of HTN in children with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: Up to September 2018, 1.4 million office BP measurements in 79,849 children and adolescents (aged 5-20 years) with T1DM were documented in the DPV (Diabetes Prospective Follow-up) registry. BP values of the most recent year were aggregated, and BP values of 74,677 patients without antihypertensive medication were analyzed (median age 16 years and diabetes duration 5.3 years, 52.8% boys). BP values were classified according to AAP 2017 and the references of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) (2011) and the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (fourth report) (2004). RESULTS: Of the patients, 44.1%, 29.5%, and 26.5% were hypertensive according to AAP 2017, KiGGS, and fourth report, respectively. Differences in prevalence of HTN were strongly age dependent: <10 years, AAP 2017 31.4%, KiGGS 30.7%, fourth report 19.6%; 10 to <15 years, AAP 2017 30.9%, KiGGS 31.2%, fourth report 22.4%; and ≥15 years, AAP 2017 53.2%, KiGGS 28.4%, fourth report 30.0%. Among teenagers ≥15 years, 59.1% of boys and only 46.3% of girls were classified as hypertensive by AAP 2017 but only 21.1%/26% of boys and 36.7%/34.4% of girls by KiGGS/fourth report, respectively. CONCLUSIONS: Classification of BP as hypertension depends strongly on the normative data used. Use of AAP 2017 results in a significant increase in HTN in teenagers ≥15 years with T1DM, particularly in boys. AAP 2017 enhances the awareness of elevated BP in children, particularly in patients with increased risk for cardiovascular disease.

Diabetes Mellitus and Autoimmune Hepatitis: Demographical and Clinical Description of a Relatively Rare Phenotype.

We studied demographic, metabolic, and clinical characteristics of patients with diabetes and autoimmune hepatitis (AIH) from the German/Austrian DPV registry. A total of 139 patients with diabetes and AIH were analyzed and compared to 437 728 patients with diabetes without AIH. The prevalence of AIH in patients with T1DM (44.8/100 000) seems higher than in the general population, the prevalence of AIH in patients with T2DM (23.6/100 000) does not seem to be increased. Patients with T2DM and AIH had a shorter duration of diabetes (p=0.007) and a higher proportion of females (p<0.001) compared to T2DM without AIH. Patients with diabetes (T1DM or T2DM) and AIH required higher insulin doses (p<0.001 and p=0.03, respectively) and showed increased liver enzymes (aspartate transaminase, alanine transaminase, gamma-glutamyltransferase) compared to diabetes patients without (all p<0.001). We detected a lower percentage of patients treated with oral antidiabetic drugs (p=0.01) and a higher percentage of patients treated by insulin in patients with T2DM and AIH (p<0.001) compared to patients with T2DM alone. We observed a higher incidence of autoimmune thyroid disease (AIT) in patients with diabetes (T1DM or T2DM) and AIH (p<0.001) compared to diabetes patients without AIH. AIH seems more frequent in patients with T1DM. Patients with diabetes and AIH require intensification of antidiabetic therapy and seem to have a higher prevalence of AIT.

Detection of obstructive uropathy and assessment of differential renal function using two functional magnetic resonance urography tools. A comparison with diuretic renal scintigraphy in infants and children.

AIM: After detection of obstructive uropathy (OU), the indication for or against surgery is primarily based on the differential renal function (DRF). This is to compare functional magnetic resonance urography (fMRU) with dynamic renal scintigraphy (DRS) to assess OU and DRF in infants and children. PATIENTS, METHODS: Retrospective analysis in 30 patients (female: 16; male: 14; median age: 5.5 years [0.2-16.5]), divided into subgroup A (age: 0-2 years; n = 16) and B (> 2-17 years; n = 14). fMRU was assessed by measuring renal transit time (RTT) and volumetric DRF with CHOP fMRU tool (CT) and ImageJ MRU plug-in (IJ). OU detection by fMRU was compared with DRS (standard of reference) using areas under the curves (AUC) in ROC analyses. Concordant DRF was assumed if absolute deviation between fMRU and DRS was ≤ 5 %. RESULTS: DRS confirmed fixed OU in 4/31 kidneys (12.9 %) in subgroup A. AUC of CT was 0.94 compared with 0.93 by IJ. Subgroup B showed fixed OU in 1/21 kidneys (4.8 %) with AUCs of 0.98 each. RTT measured neither by CT nor by IJ in confirmed fixed OU was < 1200 s - resulting in negative predictive values of 1.0 each. In subgroup A, DRF was concordant in 81.3 % of the kidneys for CT and DRS compared with 75.0 % for IJ and DRS. In subgroup B, CT and DRS were concordant in 91.7 %, and IJ and DRS in 45.8 % of the kidneys. CONCLUSION: fMRU accurately excluded fixed OU in infants and children, independent from the software used for quantification. However, assessment of DRF with fMRU deviated from DRS especially in infants who may profit most from early intervention. Thus, fMRU cannot fully replace DRS as primary functional examination. If, for clinical reasons, fMRU is performed in first place and it cannot exclude fixed OU, it should be followed by DRS for validation and DRF quantification.

Does ß-Cell Autoimmunity Play a Role in Cystic Fibrosis-Related Diabetes? Analysis Based on the German/Austrian Diabetes Patienten Verlaufsdokumentation Registry.

OBJECTIVE: Research on ß-cell autoimmunity in cystic fibrosis (CF)-related diabetes (CFRD) is still rare. We aimed to analyze the frequency of ß-cell autoimmunity and the influence on age at diabetes onset, insulin requirement, type of insulin therapy, and hypoglycemic or ketoacidotic events in patients with CFRD compared with antibody-negative patients with CFRD in the Diabetes Patienten Verlaufsdokumentation (DPV) registry. RESEARCH DESIGN AND METHODS: We analyzed data of 837 patients with CFRD in the German/Austrian DPV database by multivariable mixed-regression modeling. RESULTS: In our cohort, 8.5% of patients with CFRD (n = 72) were found to be ß-cell antibody positive. There was a female preponderance in this patient group: 65.3 vs. 57.6%. Diabetes onset (median [interquartile range]) was earlier (14.00 [10.15-15.90] vs. 16.10 [13.50-21.20] years; P < 0.005), and insulin dose/kg body weight was higher (0.95 [0.61-1.15] vs. 0.67 [0.33-1.04] IU/kg; P < 0.05). There were also differences in the type of insulin treatment. Insulin pump therapy was used significantly more often in patients with CFRD with ß-cell autoimmunity (18.2 vs. 6.4%; P < 0.05). The differences for multiple daily injections (ICT) and conventional therapy (CT) were not significant (ICT: 67.7 vs. 79.0%; CT: 15.2 vs. 14.6). Oral antidiabetic agents were rarely used in both groups. Rate of severe hypoglycemia with coma and rate of ketoacidosis were higher in antibody-positive patients (hypoglycemia with coma: 8.0 vs. 1.4, P < 0.05; ketoacidosis: 9.3 vs. 0.9, P < 0.05). CONCLUSIONS: Presence of ß-cell autoantibodies in our cohort of patients with CFRD (8.5%) appeared to be greater than in the general population and was associated with female sex, earlier onset of diabetes, and higher insulin requirement. Insulin pump therapy was used significantly more often in patients with ß-cell antibodies. Severe hypoglycemia and ketoacidosis were significantly more frequent in CFRD with ß-cell autoimmunity compared with ß-cell antibody-negative patients with CFRD.

Why is insulin pump treatment rarely used in adolescents and young adults with cystic fibrosis-related diabetes?

BACKGROUND: In type 1 diabetes (T1D), the use of continuous subcutaneous insulin infusion (CSII) has increased steadily in the last years. Compared with conventional insulin injection regimes, major advantages might be a nearly physiological insulin secretion, lower rates of hypoglycemia, higher flexibility in daily life, and increased quality of life. Data on CSII in cystic fibrosis-related diabetes (CFRD) are scarce. OBJECTIVE: To analyze current use of insulin pumps in CFRD and compare demographics of pump-treated patients between CFRD and T1D. METHODS: Data from the prospective German/Austrian diabetes patient registry on insulin-treated patients with either CFRD (n = 515) or T1D (n = 43 165) aged >10 yr at manifestation of diabetes were analyzed. RESULTS: A total of 4.1% (n = 21) of CFRD and 17.7% (n = 7647) of T1D patients received insulin pump treatment within the recent year of care (p < 0.001). Pump-treated patients with CFRD had a significantly shorter duration of diabetes [median (Q1 ; Q3 ): 5.8 (2.9; 9.5) vs. 7.8 (4.3; 20.4) yr, p = 0.026] and tended to be younger [22.0 (18.2; 30.1) vs. 24.9 (17.3; 45.9) yr] than pump-treated T1D patients. Age at initiation of CSII seemed to be lower in CFRD [19.2 (16.5; 29.2) vs. 23.3 (14.8; 43.5) yr]. Insulin pump therapy was used slightly more often in male CFRD patients than females (4.7 vs. 3.6%), whereas in T1D the opposite was observed (14.9 vs. 21.2%, p < 0.001). Discontinuation rate of CSII was higher in CFRD than T1D (30.0 vs. 12.7%, p = 0.005). CONCLUSIONS: Despite potential advantages, insulin pump therapy was rarely used among adolescent and young adult CFRD patients.

Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: a multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database.

OBJECTIVE: To investigate diabetes-specific autoantibodies and additional autoimmune phenomena in a large cohort of young patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data from 28,671 patients <30 years with type 1 diabetes from 242 specialized centers in Germany and Austria were analyzed. RESULTS: At least one beta-cell antibody was present in 81.6% of patients. beta-cell-Ab-negative patients were significantly younger at diabetes onset (P < 0.0001). A total of 19.6% had positive thyroid antibodies with female predominance (62%, P < 0.0001). Antibodies to tissue transglutaminase were present in 10.7%, with a significantly longer duration of diabetes (P < 0.0001). Parietal cell antibodies were found in 283 patients, associated with older age (P < 0.001), and adrenal antibodies were present in 94 patients. In 575 patients, at least three different autoimmune phenomena were present. CONCLUSIONS: Thyroid autoimmunity and antibodies suggestive for celiac disease are the most prevalent additional immune phenomena in type 1 diabetes. Parietal/adrenal antibodies are rare.

Influence of food intake, age, gender, HbA1c, and BMI levels on plasma cholesterol in 29,979 children and adolescents with type 1 diabetes--reference data from the German diabetes documentation and quality management system (DPV).

OBJECTIVE: We investigated influences of a 12-h fast, age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) to provide reference percentiles for TC, LDL-C, and HDL-C of patients with good diabetes control (HbA1c < 7.5%) and normal weight (BMI < 90th percentile). METHOD: A cross-sectional analysis of the diabetes documentation and quality management system using the diabetes data acquisition system for prospective surveillance (DPV) software included 29 979 patients with type 1 diabetes mellitus (T1DM) aged 1-20 yr (52.4% male) from 253 diabetes centers in Germany and Austria. RESULTS: Fasting had no relevant influence on TC, LDL-C, and HDL-C. Multivariate regression analysis revealed strongest dependences of cholesterol on gender and HbA1c followed by BMI and age. Reference cholesterol percentiles of well-controlled and normal weight patients showed TC >or=4.40 mmol/L (170 mg/dL) corresponding to the 50th percentile in females and the 75th percentile in males. LDL-C >or=2.59 mmol/L (100 mg/dL) corresponded to the 50th-75th percentile in females and the 75th percentile in males. CONCLUSIONS: (i) Fasting is no precondition for the determination of TC, LDL-C, and HDL-C; (ii) TC, LDL-C, and HDL-C are strongest associated with gender and HbA1c followed by BMI and age; (iii) Gender- and age-adjusted cholesterol percentiles of well-controlled and normal weight patients with T1DM may serve as reference values and are similar to healthy German children; and (iv) Single target values for TC, LDL-C, and HDL-C based on healthy individuals' data do not sufficiently characterize abnormal cholesterol levels in young patients with T1DM.

Increased blood plasma concentrations of TGF-beta1 and TGF-beta2 after treatment with intravenous immunoglobulins in childhood autoimmune diseases.

Transforming growth factor-beta (TGF-beta), a multifunctional, immunosuppressive cytokine, is shown to be present in substantial amounts in commercially available intravenous immunoglobulin (IVIG) preparations. To assess whether TGF-beta isoforms are changed in the plasma of paediatric patients with childhood autoimmune diseases after IVIG infusion, 17 patients who received over a period of 12 months overall 56 IVIG infusions (Endobulin) were enrolled in a study. High levels of TGF-beta1 (16.95 +/- 8.16 ng/ml) as well as TGF-beta2 (62.71 +/- 9.50 ng/ml) were detected in the used 56 IVIG probes. TGF-beta1 and TGF-beta2 plasma concentrations were measured prior and 120 min after IVIG infusions by specific TGF-beta ELISA. Interestingly, significant increased TGF-beta1 and TGF-beta2 plasma levels were found in patients after treatment with IVIG. This data suggest that a TGF-beta-mediated mechanism of action may accompany other molecular effects of IVIG therapy. The amount of the potent anti-inflammatory TGF-beta isoforms within the IVIG preparations may exert a differentiated view regarding the manifold indications of IVIG therapy.

Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV).

OBJECTIVE: The aim of this data analysis was to ascertain the type and prevalence rate as well as age and sex distribution of cardiovascular risk factors in type 1 diabetic patients up to 26 years of age. RESEARCH DESIGN AND METHODS: Cardiovascular risk factors such as obesity, hypertension, dyslipidemia, poor glycemic control, and smoking were analyzed in 27,358 patients who were divided into three groups (prepubertal, pubertal, and adult) using specifically designed diabetes software for prospective disease documentation. RESULTS: More than half of the patients per age-group had at least one cardiovascular risk factor. Two risk factors were age dependently found in 6.2-21.7% and three or four risk factors in 0.5-4.7%. Elevated values of HbA(1c), total cholesterol, and BMI were found most frequently. Hypertension, smoking, and HDL cholesterol were observed more frequently in males, and elevated BMI, total cholesterol, and LDL cholesterol more often in females. Although 28.6% of the patients had dyslipidemia, merely 0.4% of them received medical treatment, and of the 8.1% of the patients with hypertension, only 2.1% of them were given antihypertensive medication. CONCLUSIONS: With increasing age, a greater number of patients with cardiovascular risk factors were observed. Significant sex differences were seen in the majority of risk factors. Despite the high prevalence of risk factors, only a small minority of patients received antihypertensive or lipid-lowering treatment. Early identification, prevention, and treatment of additional risk factors seem to be necessary, particularly in light of the high incidence of future cardiovascular disease.