[CME/Answers: Hypocalcemia and Hypoparathyroidism]. / CME/Antworten: Hypokalzämie und Hypoparathyreoidismus.

CME/Answers: Hypocalcemia and Hypoparathyroidism Abstract. Dyselectrolytemias are common, but not immediately clearly assignable. In addition to hyponatremia, hypercalcemia plays an important role in clinical practice. Clinically no less relevant are hypocalcemias and a frequently underlying primary hypoparathyroidism, which in most cases is iatrogenic - caused by thyroid surgery. The therapeutic goal includes not only adequate calcium control but also the detection and treatment of secondary complications in cases of chronic hypoparathyroidism.

[CME: Hypocalcemia and Hypoparathyroidism]. / CME: Hypokalzämie und Hypoparathyreoidismus CME-Fragen.

CME: Hypocalcemia and Hypoparathyroidism Abstract. Dyselectrolytemias are common, but not immediately clearly assignable. In addition to hyponatremia, hypercalcemia plays an important role in clinical practice. Clinically no less relevant are hypocalcemias and a frequently underlying primary hypoparathyroidism, which in most cases is iatrogenic - caused by thyroid surgery. The therapeutic goal includes not only adequate calcium control but also the detection and treatment of secondary complications in cases of chronic hypoparathyroidism.

A rare cause of primary adrenal insufficiency due to a homozygous Arg188Cys mutation in the STAR gene.

Steroidogenic acute regulatory protein (STAR) is a key protein for the intracellular transport of cholesterol to the mitochondrium in endocrine organs (e.g. adrenal gland, ovaries, testes) and essential for the synthesis of all steroid hormones. Several mutations have been described and the clinical phenotype varies strongly and may be grouped into classic lipoid congenital adrenal hyperplasia (LCAH), in which all steroidogenesis is disrupted, and non-classic LCAH, which resembles familial glucocorticoid deficiency (FGD), which affects predominantly adrenal functions. Classic LCAH is characterized by early and potentially life-threatening manifestation of primary adrenal insufficiency (PAI) with electrolyte disturbances and 46,XY disorder of sex development (DSD) in males as well as lack of pubertal development in both sexes. Non-classic LCAH manifests usually later in life with PAI. Nevertheless, life-long follow-up of gonadal function is warranted. We describe a 26-year-old female patient who was diagnosed with PAI early in life without detailed diagnostic work-up. At the age of 14 months, she presented with hyperpigmentation, elevated ACTH and low cortisol levels. As her older brother was diagnosed with PAI two years earlier, she was put on hydrocortisone and fludrocortisone replacement therapy before an Addisonian crisis occurred. Upon review of her case in adulthood, consanguinity was noted in the family. Genetic analysis for PAI revealed a homozygous mutation in the STAR gene (c.562C>T, p.Arg188Cys) in both siblings. This mutation has been previously described in non-classic LCAH. This case illustrates that early onset, familial PAI is likely due to autosomal recessive genetic mutations in known genes causing PAI. LEARNING POINTS: In childhood-onset PAI, a genetic cause is most likely, especially in families with consanguinity.Adult patients with an etiologically unsolved PAI should be reviewed repeatedly and genetic work-up should be considered.Knowing the exact genetic diagnosis in PAI is essential for genetic counselling and may allow disease-specific treatment.Young men and women with NCLAH due to homozygous STAR Arg188Cys mutation should be investigated for their gonadal function as hypogonadism and infertility might occur during puberty or in early adulthood.

Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study".

BACKGROUND: Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. METHODS: In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. RESULTS: The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97-1.00), and a cut-off value ≤ 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96-1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively). CONCLUSIONS: Copeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01456533 . Registered on 20 October 2011.

Low-carbohydrate high-fat diets in combination with daily exercise in rats: effects on body weight regulation, body composition and exercise capacity.

BACKGROUND: The aim of the current investigation was to examine the effects of consuming a low-carbohydrate high-fat diet (LC-HFD) in combination with daily exercise on body weight, body composition, endocrine control of the energy balance system and exercise capacity in adolescent and mature rats. METHOD: Adolescent (n=23) and mature rats (n=16) were maintained on either a standard chow diet (CH) or a LC-HFD for a period of ten days prior to daily exercise training for 21 days in forced running wheel system. At the end of the 21 day training sessions all rats took part in an exercise performance test where time to exhaustion was measured. RESULTS: Rats maintained on the LC-HFD demonstrated a significant lack of body weight gain (p<0.05) compared to CH maintained rats, despite equicaloric intake and performing identical amounts of daily exercise. Body composition was significantly altered in the LC-HFD rats (p<0.05) with increased body fat (p<0.01). Leptin concentrations were higher (p<0.05) and IGF-I concentrations were lower (p<0.01) in the LC-HFD fed rats. Exercise performance was not diminished in the LC-HFD group despite the higher fat mass. Both groups irrespective of age performed equally as well in the time to exhaustion test (p>0.05). CONCLUSION: Maintenance on the LC-HFD in combination with forced daily exercise did not impact exercise capacity (total distance and meters per minute). Additionally consumption of an extreme LC-HFD in combination with daily exercise resulted in significantly less body weight gain but increased fat mass. When combined with daily exercise this diet clearly had a negative impact on body composition, but did not affect exercise capacity.

Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity.

Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut-brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3-36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation.

Low-carbohydrate high-fat diets: regulation of energy balance and body weight regain in rats.

The aim of the current investigations was to examine the effects of a low-carbohydrate high-fat diet (LC-HFD) on body weight, body composition, growth hormone (GH), IGF-I, and body weight regain after stopping the dietary intervention and returning the diet back to standard laboratory chow (CH). In study one, both adolescent and mature male Wistar rats were maintained on either an isocaloric LC-HFD or CH for 16 days before having their diet switched. In study two, mature rats were maintained on either LC-HFD or CH for 16 days to determine the effects of the LC-HFD on fat pad weight. LC-HFD leads to body weight loss in mature rats (P < 0.01) and lack of body weight gain in adolescent rats (P < 0.01). Despite less body weight, increased body fat was observed in rats maintained on LC-HFD (P < 0.05). Leptin concentrations were higher (P < 0.05), and IGF-I (P < 0.01) concentrations were reduced in the LC-HFD rats. When the diet was returned to CH following LC-HFD, body weight regain was above and beyond that which was lost (P < 0.01). The LC-HFD resulted in increased body fat and had a negative effect upon both GH and IGF-I concentrations, which might have implications for the accretion and maintenance of lean body mass (LBM), normal growth rate and overall metabolic health. Moreover, when the LC-HFD ceases and a high-carbohydrate diet follows, more body weight is regained as compared to when the LC-HFD is consumed, in the absence of increased energy intake.

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

Gastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy.

BACKGROUND: A 14-year-old boy presented with daytime somnolence, intermittent emesis and hypothyroidism. Neuroimaging revealed a calcified suprasellar intracranial mass, suspected to be a craniopharyngioma. Subtotal resection of the tumor confirmed the diagnosis. Extreme obesity (BMI >60 kg/m(2)) and hyperinsulinemia followed tumor resection and cranial irradiation. Dietary interventions were unsuccessful, and pharmacologic intervention (i.e. octreotide) only slowed the rate of weight gain. INVESTIGATIONS: Radiography documented the suprasellar mass. Following surgical resection and radiotherapy, hypothalamic-pituitary deficiencies were found. Preprandial and postprandial excursions of insulin, active ghrelin and leptin were measured before and after gastric bypass surgery. DIAGNOSIS: Panhypopituitarism, hypothalamic obesity and hyperinsulinemia following craniopharyngioma therapy. MANAGEMENT: Severe caloric restriction, octreotide, and pituitary hormone replacement did not produce weight loss. Gastric bypass surgery led to reduced food cravings, significant weight loss, and amelioration of obesity-related comorbidities. Correction of fasting hyperinsulinemia, normalization of postprandial insulin responses, and reductions in active ghrelin and leptin concentrations were also observed.

Increased acylated plasma ghrelin, but improved lipid profiles 24-h after consumption of carob pulp preparation rich in dietary fibre and polyphenols.

We have recently shown that a polyphenol-rich insoluble dietary fibre preparation from carob pulp (Ceratonia siliqua L; carob fibre) decreased postprandial acylated ghrelin, TAG and NEFA during an acute liquid meal challenge test. However, delayed effects of carob fibre consumption are unknown. Therefore, a randomized controlled crossover study in nineteen healthy volunteers consuming foods with or without 50 g carob fibre was conducted. On the subsequent day (day 2), glucose, TAG, total and acylated ghrelin as well as insulin, NEFA and leptin were assessed at baseline and at timed intervals for 300 min after ingestion of standardized bread. Consumption of carob fibre-enriched foods did not affect fasting concentrations of glucose, TAG, total ghrelin, NEFA, insulin and leptin. Fasting acylated ghrelin was increased on the day subsequent to carob fibre consumption compared with control (P = 0.046). After consumption of the standard bread on day 2, glucose response (P = 0.029) was increased, and TAG (P = 0.033) and NEFA (P < 0.001) responses were decreased compared with control. Postprandial responses of total and acylated ghrelin, insulin and leptin on day 2 were unaffected by carob fibre consumption the previous day. In conclusion, an increase in total and acylated plasma ghrelin accompanied by enhanced lipid metabolism after carob fibre consumption suggests higher lipid utilization and suppressed lipolysis on the day subsequent to carob fibre consumption. However, elevated glucose levels after carob fibre consumption need to be addressed in future studies.