Severe multisystem organ dysfunction in an adolescent with simultaneous presentation of Addison's and Graves' disease.

OBJECTIVES: To report an unusual case of simultaneous presentation of Addison's and Graves' disease in an adolescent female previously diagnosed with type 1 diabetes (T1D) and Hashimoto's. CASE PRESENTATION: A 15-year-old female with T1D and hypothyroidism presented to the emergency department with altered mental state, fever, and left arm weakness for one day. Clinical work-up revealed coexistent new-onset adrenal insufficiency and hyperthyroidism. Her clinical course was complicated by severe, life-threating multisystem organ dysfunction including neurologic deficits, acute kidney injury, and fluid overload. Thyroidectomy was ultimately performed in the setting of persistent signs of adrenal crises and resulted in rapid clinical improvement. CONCLUSIONS: Endocrinopathy should be included in the differential diagnosis of altered mental status. This case additionally illustrates the challenges of managing adrenal insufficiency in the setting of hyperthyroidism and supports the use of thyroidectomy in this situation.

Hormonal and metabolic effects of carbohydrate restriction in children with Prader-Willi syndrome.

OBJECTIVE: Macronutrient regulation of hyperphagia and adiposity in Prader-Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9-18 years) fed, in random order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate (LF, 65% carb, 15% fat, 20% protein) diets matched for calories and protein. METHODS: Participants were randomized to consume either the LC or LF diet during a first hospital admission and the second diet during a subsequent admission. Blood samples were obtained after overnight fasting and 1 hour after a mixed meal. RESULTS: Relative to subjects consuming the LF diet, subjects consuming the LC diet had: lower postprandial insulin concentrations (P = 0.02); higher fasting GLP-1 AND GIP concentrations and increased postprandial GLP-1 (P < 0.02); reduced ratio of fasting ghrelin to GLP-1 (P = 0.0078); increased FFA and fatty acid oxidation, as assessed by concentrations of even-chain acylcarnitines (P < 0.001); lower fasting TG and TG/HDL ratio (P < 0.01); and higher concentrations of branch chain amino acids (P < 0.01). There were no changes in glucose, PYY, or adiponectin. CRP, AST and ALT were all higher (P < 0.01) on the LC diet. CONCLUSIONS: Increases in GLP-1 with low carbohydrate feeding and reductions in the ratio of ghrelin to GLP-1 might limit food intake and improve glycaemic control in PWS. Other potential benefits of carbohydrate restriction may include fat mobilization and oxidation and reductions in the TG/HDL ratio, a marker of insulin resistance. However, increases in CRP, AST and ALT necessitate longer-term studies of low carbohydrate efficacy and safety.

Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone.

OBJECTIVES: To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. METHODS: We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated with ghrelin, peptide YY and markers of insulin sensitivity (adiponectin and HOMA-IR). RESULTS: Compared with obese controls (OC), children with PWS had fasting hyperghrelinaemia, hyperadiponectinaemia, hypoinsulinaemia and increased ghrelin/PYY. Hyperghrelinaemia, hyperadiponectinaemia and hypoinsulinaemia were more striking in PWS females than males, and decreases in BCAA were detected only in PWS females. GH-treated PWS subjects had lower leptin and higher IGF-1 and adiponectin than untreated subjects; fasting ghrelin, PYY and insulin levels were comparable. Ghrelin correlated inversely with BCAA in PWS but not OC. Adiponectin correlated negatively with BMIz and HOMA-IR in PWS; in contrast, adiponectin correlated more strongly with BCAA than BMIz or HOMA-IR in OC. CONCLUSIONS: BCAA levels were lower in PWS females than OC females and correlated inversely with ghrelin. Low BCAA in PWS females may promote hyperghrelinaemia and hyperphagia, while hyperadiponectinaemia may maintain insulin sensitivity despite excess weight gain. GH treatment may reduce leptin and increase adiponectin, but does not affect fasting ghrelin or PYY.

Sex differences in biomarkers associated with insulin resistance in obese adolescents: metabolomic profiling and principal components analysis.

OBJECTIVE: Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens. RESEARCH DESIGN AND METHODS: Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio. RESULTS: Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R(2) = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R(2) = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males. CONCLUSIONS: BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.

Screening for metabolic and reproductive complications in obese children and adolescents.

Childhood obesity is associated with a number of metabolic comorbidities. These include glucose intolerance and type 2 diabetes mellitus, hyperlipidemia, fatty liver disease, and reproductive complications, such as polycystic ovary syndrome. The occurrence of these complications in a child or adolescent may result in progressive health decline at an early age. We, therefore, advocate screening and early diagnosis. This purpose of this review is to outline a rational, evidence-based approach to screening obese children and adolescents for metabolic and reproductive complications. In each section, the aim is to provide the primary care provider with a review of the literature supporting current screening practices. As such, this review is designed to assist the primary care provider in the selection and interpretation of screening tests and to make recommendations regarding the referral of patients for subspecialty care.