RESUMEN
OBJECTIVES: To examine the exocrine pancreatic function in carriers of the hepatocyte nuclear factor 1ß gene (HNF1B) mutation by direct testing. METHODS: Patients with HNF1B mutations and control subjects were assessed using rapid endoscopic secretin tests and secretin-stimulated magnetic resonance imaging. Seven patients and 25 controls underwent endoscopy, while eight patients and 20 controls had magnetic resonance imaging. Ductal function was assessed according to peak bicarbonate concentrations and acinar function was assessed according to peak digestive enzyme activities in secretin-stimulated duodenal juice. The association of pancreatic exocrine function and diabetes status with pancreatic gland volume was examined. RESULTS: The mean increase in secretin-stimulated duodenal fluid was smaller in patients than controls (4.0 vs 6.4 ml/min; P = 0.003). We found lower ductal function in patients than controls (median peak bicarbonate concentration: 73 vs 116 mEq/L; P < 0.001) and lower acinar function (median peak lipase activity: 6.4 vs 33.5 kU/ml; P = 0.01; median peak elastase activity: 0.056 vs 0.130 U/ml; P = 0.01). Pancreatic fluid volume outputs correlated significantly with pancreatic gland volumes (r² = 0.71, P = 0.008) in patients. The total fluid output to pancreatic gland volume ratios were higher in patients than controls (4.5 vs 1.3 ml/cm³; P = 0.03), suggesting compensatory hypersecretion in the remaining gland. CONCLUSION: Carriers of the HNF1B mutation have lower exocrine pancreatic function involving both ductal and acinar cells. Compensatory hypersecretion suggests that the small pancreas of HNF1B mutation carriers is attributable to hypoplasia, not atrophy.
Asunto(s)
Células Acinares/metabolismo , Enfermedades del Sistema Nervioso Central/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Insuficiencia Pancreática Exocrina/etiología , Enfermedades Renales Quísticas/fisiopatología , Páncreas Exocrino/fisiopatología , Conductos Pancreáticos/fisiopatología , Jugo Pancreático/metabolismo , Regulación hacia Arriba , Células Acinares/patología , Adolescente , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/patología , Niño , Esmalte Dental/anomalías , Esmalte Dental/patología , Esmalte Dental/fisiopatología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Femenino , Factor Nuclear 1-beta del Hepatocito/genética , Humanos , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/patología , Masculino , Persona de Mediana Edad , Mutación , Tamaño de los Órganos , Páncreas Exocrino/metabolismo , Páncreas Exocrino/patología , Conductos Pancreáticos/metabolismo , Conductos Pancreáticos/patología , Jugo Pancreático/química , Linaje , SecretinaRESUMEN
AIMS/HYPOTHESIS: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. METHODS: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. RESULTS: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) ≥ 0.91, p ≤ 1 × 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. CONCLUSIONS/INTERPRETATION: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.
Asunto(s)
Proteína C-Reactiva/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Técnicas de Diagnóstico Molecular , Adulto , Edad de Inicio , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Europa (Continente) , Glucoquinasa/química , Glucoquinasa/genética , Factor Nuclear 1-alfa del Hepatocito/química , Factor Nuclear 4 del Hepatocito/química , Factor Nuclear 4 del Hepatocito/genética , Heterocigoto , Humanos , Metaanálisis como Asunto , Persona de Mediana Edad , Mutación , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
AIMS: To study incidence and risk factors of early neonatal dehydration in a Norwegian population based cohort. METHODS: Term neonates admitted to a paediatric department during 2002-2008 with a weight loss > or = 12% within three weeks of age were identified retrospectively through review of medical records. For each patient a sex-matched control group of two full-term infants was selected to assess risk factors for dehydration. RESULTS: A total of 38 of 37 321 infants (1.0 per thousand) were admitted at a median age of 6 (interquartile range 5-12) days, and the admission rate increased during the study period (p for trend = 0.008). Simultaneously, mean nursery stay decreased from 3.5 to 2.7 days (p = 0.022). Mean weight loss was 15.0% of birth weight and 17 of 29 (58.6%) had serum sodium above 145 mmol/L. The only significant difference between patients and controls was that mothers of patients were older (32.3 +/- 5.0 vs. 29.4 +/- 5.4 years, p = 0.005). CONCLUSION: Short nursery stay may be a risk factor for dehydration in newborn infants.