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1.
JAMA Netw Open ; 3(3): e200663, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32154887

RESUMO

Importance: Inflammation is a key driver of malnutrition during illness and is often accompanied by metabolic effects, including insulin resistance and reduction of appetite. However, it still remains unclear if inflammation influences the response to nutritional support among patients with disease-related malnutrition. Objective: To examine whether patients' baseline inflammatory status is associated with the effect of nutritional support on 30-day mortality. Design, Setting, and Participants: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized clinical trial conducted in 8 Swiss hospitals from April 2014 to February 2018. A total of 1950 participants who had C-reactive protein measurements at the time of admission were included in this secondary analysis. Data analysis was conducted between June and July 2019. Interventions: Hospitalized patients at risk for malnutrition were randomly assigned to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or standard hospital food (control group). Main Outcomes and Measures: The primary end point was 30-day mortality. Based on C-reactive protein levels at admission, patients were stratified into groups with low, moderate, or high inflammation (<10 mg/L, 10-100 mg/L, and >100 mg/L, respectively). Results: A total of 1950 patients (median [interquartile range] age, 75 [65-83] years; 1025 [52.6%] men) were included; 533 (27.3%) had low levels of inflammation, 894 (45.9%) had moderate levels of inflammation, and 523 (26.8%) had high levels of inflammation. Compared with the control group, patients receiving nutritional support showed a significant reduction in 30-day mortality, regardless of C-reactive protein level (adjusted odds ratio, 0.61; 95% CI, 0.43-0.86; P = .005). In the subgroup of patients with high inflammation, there was no beneficial effect of nutritional support (adjusted odds ratio, 1.32; 95% CI, 0.70-2.50; P = .39), providing evidence that inflammation has a significant modifying association (P for interaction = .005). Conclusions and Relevance: Based on this secondary analysis of a multicenter randomized trial, a patient's admission inflammatory status was associated with their response to nutritional support. If validated in future clinical trials, nutritional support may need to be individualized based on a patient's initial presentation and markers of inflammation. These results may also help to explain some of the heterogeneity in treatment effects of nutrition seen in previous critical care trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02517476.

2.
Obes Surg ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221822

RESUMO

BACKGROUND: Iron deficiency is a common finding in patients with previous bariatric surgery, and parenteral supplementation is frequently required. Ferric carboxymaltose (FCM) is among the preferred compounds used but may be associated with new-onset hypophosphatemia. This study was undertaken to study the prevalence of hypophosphatemia following FCM in patients with previous bariatric surgery, a population that may be at particular risk due to highly prevalent secondary hyperparathyroidism. METHODS: Patients with previous bariatric surgery and iron depletion scheduled for FCM infusion were prospectively studied before and one week after FCM application. The primary endpoint was new-onset hypophosphatemia. Patients were followed until plasma phosphate had normalized without replacement. RESULTS: Fifty-two patients (40 females) following Roux-en-Y gastric bypass (n = 50) or sleeve gastrectomy (n = 2), with a median age of 46 years (range 22-68) and a BMI of 32.2 kg/m2 (27.5-37.3), were analyzed. Fifteen patients (29%) developed new-onset hypophosphatemia, with 11 (21%) requiring oral phosphate supplementation for a median duration of 14 days (14-25). The plasma phosphate decreased by 0.3 mmol/l (-0.5--0.2; p < 0.001) secondary to a 56% increase in the fractional urinary phosphate excretion (p < 0.001). This was associated with a significant increase in serum intact FGF23 (+30%; p < 0.001) and a decrease in serum 1,25(OH)2 vitamin D3 concentrations (-37.6%; p < 0.001). CONCLUSION: Patients with previous bariatric surgery receiving FCM are at considerable risk of developing significant hypophosphatemia secondary to increased renal phosphate wasting through a mechanism involving FGF23. Monitoring plasma phosphate should be considered following FCM in patients with previous bariatric surgery. CLINICAL TRIAL REGISTRATION: ISRCTN registry, ISRCTN12291677, https://www.isrctn.com.

3.
Clin Nutr ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882232

RESUMO

INTRODUCTION: The Nutritional Risk Screening 2002 (NRS 2002) identifies patients at risk of malnutrition. We studied the prognostic implications of this score with regard to short-term and long-term clinical outcomes in a well-characterised cohort of medical inpatients from a previous trial. METHODS: This is a secondary analysis of an investigator-initiated, prospective randomised controlled multicenter trial in Switzerland (EFFORT) that compared the effects of an individualised nutritional support intervention with standard of care. We investigated associations between admission NRS and several short-term and long-term outcomes using multivariable regression analyses. RESULTS: Of the 2028 patients, 31% had an NRS of 3, 38% of 4 and 31% of ≥5 points, and 477 (24%) died during the 180 days of follow-up. For each point increase in NRS, we found a stepwise increase in risk of 30-day mortality (adjusted Hazard Ratio (HR) 1.22 (95% CI 1.00 to 1.48), p = 0.048) and 180-day mortality (adjusted HR 1.37 (95% CI 1.22 to 1.55), p < 0.001). NRS was associated with length of hospital stay (adjusted difference of 0.60 days per NRS point increase, 95%CI 0.23 to 0.97, p = 0.002) and functional outcomes at 180 days (adjusted decrease in Barthel index of -4.49 points per NRS point increase, 95%CI -6.54 to -2.45, p < 0.001). In a subgroup analysis, associations of NRS and short-term adverse outcomes were less pronounced in patients receiving nutritional support (intervention group) compared to control group patients (adjusted HR for 30-day mortality 1.12 [95%CI 0.83 to 1.52, p = 0.454] vs. 1.33 [95%CI 1.02 to 1.72, p = 0.032]). CONCLUSION: The NRS is a strong and independent risk score for malnutrition-associated mortality and adverse outcomes over 180 days. Our data provide strong evidence that the nutritional risk, however, is modifiable and can be reduced by the provision of adequate nutritional support.

4.
Medicine (Baltimore) ; 98(48): e18113, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770235

RESUMO

The impact of vitamin D deficiency on the recovery of patients with malnutrition remains undefined. Our aim was to study the prevalence of vitamin D deficiency in a well-characterized cohort of patients with malnutrition and its association with outcomes.Within this secondary analysis of a randomized controlled trial, we examined the association of vitamin D deficiency and adverse clinical outcomes over a follow-up of 180 days in hospitalized patients at risk for malnutrition. We measured 25-hydroxyvitamin D levels upon admission and defined Vitamin D deficiency when levels were <50nmol/l. The primary endpoint was 180-day mortality.The prevalence of vitamin D deficiency in our cohort of 828 patients was 58.2% (n = 482). Patients with vitamin D deficiency had increased 180-day mortality rates from 23.1% to 29.9% (odds ratio 1.42, 95% confidence interval [CI] 1.03-1.94, P = .03). When adjusting the analysis for demographics, comorbidities, and randomization, this association remained significant for the subgroup of patients not receiving vitamin D treatment (adjusted odds ratio 1.63, 95% CI 1.01-2.62, P = .04). There was no significantly lower risk for mortality in the subgroup of vitamin D deficient patients receiving vitamin D treatment compared to not receiving treatment (adjusted odds ratio 0.74, 95% CI 0.48-1.13, P = .15).Vitamin D deficiency is highly prevalent in the population of malnourished inpatients and is negatively associated with long-term mortality particularly when patients are not receiving vitamin D treatment. Our findings suggest that malnourished patients might benefit from vitamin D screening and treatment in case of deficiency.


Assuntos
Idoso Fragilizado/estatística & dados numéricos , Fragilidade/mortalidade , Desnutrição/mortalidade , Deficiência de Vitamina D/mortalidade , Deficiência de Vitamina D/terapia , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Feminino , Fragilidade/sangue , Fragilidade/complicações , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Desnutrição/sangue , Desnutrição/complicações , Prevalência , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Vitaminas/uso terapêutico
5.
Praxis (Bern 1994) ; 108(9): 599-608, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31288663

RESUMO

Interdisciplinary Management of Sellar Masses Abstract. Sellar masses may present with an impairment of pituitary function (hypopituitarism), hormone hypersecretion (prolactinoma, acromegaly, glucocorticoid excess) or neurological symptoms (visual impairment, headache). An increasing number of them is discovered as an incidentaloma. Among the various entities, benign pituitary adenomas and cystic lesions are most frequently encountered. The work-up includes a laboratory evaluation for hormone hyper- or hyposecretion and an MRI of the pituitary gland. If the optic chiasm is compromised, a visual field examination is mandatory. Except for prolactinomas, symptomatic sellar masses are usually resected via an endoscopic transsphenoidal approach. If a total resection is not feasible because of the invasion of surrounding structures, debulking to relieve pressure from the optic chiasm is the primary goal and radiotherapy may be considered. Residual hormone excess can be treated medically. In the early postoperative period special attention to the development and treatment of disordered body water homeostasis and hypopituitarism is crucial. Interdisciplinary work-up and decision making are of utmost importance and will offer the best management.


Assuntos
Adenoma , Hipopituitarismo , Neoplasias Hipofisárias , Adenoma/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Hipófise , Neoplasias Hipofisárias/diagnóstico por imagem
6.
Lancet ; 393(10188): 2312-2321, 2019 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-31030981

RESUMO

BACKGROUND: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. METHODS: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. FINDINGS: 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). INTERPRETATION: In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. FUNDING: The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.


Assuntos
Desnutrição/prevenção & controle , Apoio Nutricional/métodos , Assistência Centrada no Paciente/métodos , Doença Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica/epidemiologia , Comorbidade , Ingestão de Energia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Medição de Risco
8.
Praxis (Bern 1994) ; 107(24): 1345-1353, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30482120

RESUMO

Diagnosis and Treatment of Familial Hypercholesterolemia Abstract. Familial hypercholesterolemia secondary to heterozygous mutations in the LDL receptor, Apolipoprotein B or PCSK9 gene is characterized by 2- to 3-fold elevated LDL cholesterol levels, premature atherosclerosis and extravascular cholesterol deposits (tendon xanthomata, corneal arcus). The same phenotype may occur if a person carries several LDL cholesterol rising polymorphisms (polygenic FH). Primary prevention with statins has been shown to dramatically reduce the cardiovascular burden in patients with the disease. However, it is estimated that less than 10 % of affected subjects in Switzerland have received the diagnosis, and undertreatment is frequent. Thus, clinical cardiovascular events are still the first manifestation of the disease in many cases. A correct diagnosis in index patients and cascade screening of families are mandatory to identify and treat patients before they suffer the sequelae of untreated severe hypercholesterolemia. In patients with clinical cardiovascular disease combination lipid lowering treatment with potent statins, ezetimibe and the newly available PCSK9 inhibitors will successfully lower LDL cholesterol to normal or even target levels.


Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Apolipoproteínas B/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/terapia , Análise Mutacional de DNA , Ezetimiba/uso terapêutico , Triagem de Portadores Genéticos , Testes Genéticos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética
9.
N Engl J Med ; 379(5): 428-439, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30067922

RESUMO

BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).


Assuntos
Diabetes Insípido/diagnóstico , Glicopeptídeos/sangue , Polidipsia/diagnóstico , Poliúria/etiologia , Solução Salina Hipertônica/administração & dosagem , Privação de Água/fisiologia , Adulto , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/efeitos adversos , Diabetes Insípido/sangue , Diabetes Insípido/complicações , Diabetes Insípido/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Hiponatremia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Polidipsia/sangue , Polidipsia/complicações , Curva ROC , Sensibilidade e Especificidade , Urina/química
10.
PLoS One ; 13(8): e0202007, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30114246

RESUMO

BACKGROUND: Despite their widespread use in this population, data on the pharmacodynamic (PD) properties of the insulin analogs detemir and glargine in severely obese patients with type 2 diabetes are lacking. METHODS: The primary objective of the study was to compare the PD properties of two different doses of the basal insulin analogs detemir and glargine in patients with type 2 diabetes and a BMI > 35 kg/m2. PD data were derived from euglycemic clamp studies over 30 hours and each subject was studied for four times after the subcutaneous injection of a lower (0.8 U/kg body weight) and higher (1.6 U/kg body weight) dose of both detemir and glargine using a single-blind, randomised cross-over design. RESULTS: Six male and four female patients with type 2 diabetes and a mean BMI of 43.2±5.1 kg/m2 (mean age 55.7±2 years, mean HbA1c 7.2±0.3%) completed the study. The total GIRAUC0-30 (mean difference 1224 mg/kg, 95%CI 810-1637, p = 0.00001), GIRAUC0-24 (mean difference 1040 mg/kg, 95%CI 657-1423; p = 0.00001), GIRAUC24-30 (mean difference 181 mg/kg, 95%CI 64-298; p = 0.004), GIRmax (mean difference 0.93 mg/kg/min, 95%CI 0.22-1.64, p = 0.01) and time to GIRmax (+1.9 hours, 95%CI 0.5-3.2; p = 0.009) were higher after the higher doses of both insulins, without significant differences between detemir and glargine. However, during the last 6 hours of the clamp the GIRAUC24-30 was significantly increased with glargine (mean difference 122 mg/kg, 95%CI 6-237, p = 0.043), reflecting a more pronounced late glucose lowering effect. CONCLUSIONS: A clear dose-response relationship can be demonstrated for both insulin analogs, even at very high doses in severely obese patients with type 2 diabetes. Compared to detemir, glargine has a more pronounced late glucose lowering effect 24-30 h after its injection. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN57547229.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Detemir/farmacocinética , Insulina Glargina/farmacocinética , Obesidade/complicações , Adulto , Biomarcadores , Glicemia/efeitos dos fármacos , Peptídeo C , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Técnica Clamp de Glucose , Humanos , Insulina Detemir/administração & dosagem , Insulina Glargina/administração & dosagem , Masculino , Pessoa de Meia-Idade
11.
Mol Genet Metab ; 125(1-2): 73-78, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30037504

RESUMO

BACKGROUND: 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). METHODS: In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. RESULTS: 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ±â€¯129 vs 35 ±â€¯14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ±â€¯182 vs 398 ±â€¯90 µmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ±â€¯22 vs 110 ±â€¯18 µmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. CONCLUSION: In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.


Assuntos
Doença de Depósito de Glicogênio Tipo I/sangue , Metabolismo dos Lipídeos/genética , Esfingolipídeos/sangue , Adolescente , Adulto , Alanina/sangue , Feminino , Glucose/metabolismo , Doença de Depósito de Glicogênio Tipo I/genética , Doença de Depósito de Glicogênio Tipo I/patologia , Humanos , Masculino , Serina/sangue , Serina C-Palmitoiltransferase/genética , Esfingolipídeos/genética , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-28680643

RESUMO

Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing's syndrome and only a few cases have been reported in the literature. Differentiating between Cushing's disease and ectopic Cushing's syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing's disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing's syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing's disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing's disease. LEARNING POINTS: The discrimination between a Cushing's disease and ectopic Cushing's syndrome is challenging and has many caveats.Ectopic ACTH/CRH co-secreting tumors are very rare.Dynamic tests as well as BIPSS may be compatible with Cushing's disease in ectopic CRH-secretion.High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing's syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing's syndrome and lead to further investigations.

13.
J Clin Endocrinol Metab ; 102(5): 1451-1453, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323955

RESUMO

Context: Diabetic ketoacidosis has been described as a rare complication of acromegaly and may be observed in 1% of affected patients. The well-described direct lipolytic effect of growth hormone results in increased availability of free fatty acids (FFAs) for hepatic ketogenesis and is an important pathogenic event. More recently, ketoacidosis has been identified as an important complication of sodium-glucose-transport-protein 2 inhibitors (SGLT2i). Increased pancreatic glucagon secretion, impaired renal ketone body clearance, and an increase in FFA concentrations secondary to decreased insulin concentrations are likely precipitating factors. Case Description: We report a case of rapid-onset severe ketoacidosis within 2 days after adding empagliflozin to metformin, sitagliptin, and gliclazide in a presumably type 2 diabetic patient with unrecognized acromegaly and chronic hyperglycemia. Transsphenoidal resection of the growth-hormone secreting macroadenoma restored normal growth-hormone and insulinlike growth factor 1 concentrations and the diabetes was well controlled thereafter. Conclusion: We hypothesize that SGLT2i, through their intrinsic effects on ketone body metabolism, may possibly precipitate ketoacidosis in patients with active acromegaly and diabetes mellitus.


Assuntos
Adenoma/complicações , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Glucosídeos/efeitos adversos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Hipoglicemiantes/efeitos adversos , Adenoma/cirurgia , Diabetes Mellitus Tipo 2/complicações , Cetoacidose Diabética/etiologia , Quimioterapia Combinada , Ácidos Graxos não Esterificados/metabolismo , Gliclazida/uso terapêutico , Glucagon/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Corpos Cetônicos/metabolismo , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fosfato de Sitagliptina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose
15.
PLoS One ; 10(5): e0125426, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25946206

RESUMO

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine ß-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.


Assuntos
Catecolaminas/metabolismo , Epinefrina/biossíntese , Norepinefrina/metabolismo , Paraganglioma/metabolismo , Feocromocitoma/metabolismo , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Criança , Dexametasona/farmacologia , Dopamina beta-Hidroxilase/biossíntese , Dopamina beta-Hidroxilase/genética , Feminino , Humanos , Masculino , Metanefrina/metabolismo , Pessoa de Meia-Idade , Paraganglioma/genética , Feniletanolamina N-Metiltransferase/biossíntese , Feniletanolamina N-Metiltransferase/genética , Feocromocitoma/genética , RNA Mensageiro/biossíntese , Células Tumorais Cultivadas , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética , Adulto Jovem
16.
Surgery ; 157(1): 119-25, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25482468

RESUMO

BACKGROUND: To evaluate the relationship between the BRAF V600E mutation and clinicopathologic parameters and to assess the impact of the BRAF V600E mutation and established risk scores on survival in patients with papillary thyroid carcinoma (PTC). METHODS: Retrospective analysis of a consecutive, single-institutional cohort of patients with PTC larger than 1 cm. Clinical risk scores according to the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS), European Organisation for Research and Treatment of Cancer (EORTC), and tumor, node, metastases (TNM) scoring systems were determined. BRAF exon 15 mutation analysis was performed by polymerase chain reaction and Sanger sequencing. RESULTS: BRAF V600E mutations were found in 75/116 (65%) PTC. The rates for 5- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 92% and 87%, 98% and 96%, and 96% and 94%, respectively. Low MACIS scores were associated with longer OS (10 y 95% vs 75%, P = .008), DSS (10 y 100% vs 89%, P = .02) and RFS (100% vs 85%, P = .006). Comparable survival advantages were observed for patients with early EORTC scores and low TNM stage. BRAF V600E mutation status was not associated with clinicopathologic characteristics of aggressive behavior such as extrathyroidal extension, lymph node metastases, higher T-categories, male sex, and greater age. Furthermore, BRAF V600E mutation status was not correlated with clinical risk scores and decreased survival. CONCLUSION: In concordance with other studies, we did not find a negative prognostic impact of a positive BRAF V600E mutation status on survival. In contrast, the risk algorithms MACIS, EORTC score, and TNM stage were associated with impaired prognosis. Therefore, clinical staging systems represent better tools for risk stratification than BRAF V600E mutation status.


Assuntos
Carcinoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma Papilar , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Medição de Risco , Suíça/epidemiologia , Câncer Papilífero da Tireoide , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
17.
PLoS One ; 8(8): e72876, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24023652

RESUMO

OBJECTIVE: Copeptin, a marker for stress mirroring vasopressin concentrations, has been shown to increase upon insulin-induced hypoglycaemia in patients after transsphenoidal surgery of pituitary adenomas. Patients with type 1 diabetes mellitus are prone to hypoglycaemia, but no data about copeptin levels upon hypoglycaemia are available. Furthermore, the perception of hypoglycaemia can vary from total unawareness to disabling episodes. The aim of this study was to investigate whether copeptin increases upon hypoglycaemia in patients with type 1 diabetes mellitus and is associated with the degree of hypoglycaemia awareness. MATERIALS AND METHODS: In this prospective observational study, 17 patients with type 1 diabetes underwent a standardized insulin infusion test. Blood sampling for glucose and copeptin was performed at baseline and after 60 minutes (min). To assess hypoglycaemia associated symptoms the Mood and Symptom Questionnaire (MSQ) was conducted at baseline and after 60 min. RESULTS: During insulin infusion, blood glucose decreased from 5.1 (SD±0.2) to 3.0 (±0.5) mmol/L at 60 min (p<0.001). Copeptin concentrations increased from 3.2 (±1.7) to 3.8 (±1.9) pmol/L (p = 0.03). Mood and Symptoms Questionnaire scores increased from 14 (±3.0) to 18 (±5.8), (p = 0.006). Patients with good hypoglycaemia awareness had an increase in copeptin from 3.0 (±1.8) to 4.2 (±2.4) pmol/L (p = 0.03) in contrast to patients more unaware of hypoglycaemia who only showed an increase in copeptin from 3.3 (±1.6) to 3.6 (±1.4) pmol/L (p = 0.4). There was a trend to a larger copeptin increase in patients aware of hypoglycemia compared to patients unaware of hypoglycemia (p = 0.074). CONCLUSION: Copeptin increases in patients with type 1 diabetes upon insulin induced hypoglycaemia. Interestingly, the copeptin increase seems associated with the degree of hypoglycaemia awareness. This hypothesis warrants further verification. TRIAL REGISTRATION: ClinicalTrials.gov NCT00515801.


Assuntos
Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Glicopeptídeos/sangue , Conhecimentos, Atitudes e Prática em Saúde , Hipoglicemia/sangue , Hipoglicemia/complicações , Adulto , Feminino , Humanos , Masculino
18.
PLoS One ; 8(4): e61780, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593497

RESUMO

OBJECTIVES: To investigate the relation between primary chronic insomnia and insulin sensitivity, visceral adiposity, non alcoholic fatty liver disease and neuroendocrine hormones. MATERIALS AND METHODS: In a case-controlled, prospective clinical trial 13 women with primary chronic insomnia according to DSM-IV criteria were compared to 12 healthy controls matched for age, sex, BMI, body composition and menopausal status. All participants had a sleep assessment including polysomnographic studies and neuropsychiatric evaluation. Insulin sensitivity was evaluated using the euglycaemic hyperinsulinemic clamp. Hepatic fat content, visceral adipose tissue and intramyocellular lipid accumulation were assessed using magnetic resonance imaging and spectroscopy. The hormonal stress axis was evaluated by measurements of midnight and early morning salivary cortisol, urinary catecholamines and plasma metanephrines. Body composition was determined using body impedance analysis and indirect calorimetry. RESULTS: Although the diagnosis of primary chronic insomnia was made by established clinical criteria, standard polysomongraphic studies failed to identify altered sleep continuity and architecture when compared to matched controls. However, women with primary chronic insomnia showed significantly higher midnight salivary cortisol concentrations (1.46 vs. 0.76 nmol/l, p = 0.02), indicating dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Plasma glucose and lipid concentrations, insulin sensitivity, hepatic and intramyocellular fat content, visceral adipose tissue mass and body composition did not differ between the two groups. CONCLUSION: Healthy women with clinically diagnosed primary chronic insomnia demonstrate a dysregulation of circadian cortisol secretion despite normal sleep continuity and architecture. Increased midnight cortisol levels, however, were not associated with impaired metabolism of glucose and lipids.


Assuntos
Glucose/metabolismo , Metabolismo dos Lipídeos , Sistemas Neurossecretores/metabolismo , Distúrbios do Início e da Manutenção do Sono/metabolismo , Composição Corporal , Estudos de Casos e Controles , Catecolaminas/urina , Impedância Elétrica , Metabolismo Energético , Feminino , Técnica Clamp de Glucose , Humanos , Hidrocortisona/metabolismo , Hiperinsulinismo/complicações , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Metanefrina/sangue , Pessoa de Meia-Idade , Músculos/metabolismo , Polissonografia , Estudos Prospectivos , Descanso , Sono , Distúrbios do Início e da Manutenção do Sono/sangue , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/urina
19.
J Clin Endocrinol Metab ; 97(8): 2773-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22569243

RESUMO

CONTEXT: The high diagnostic performance of plasma-free metanephrines (metanephrine and normetanephrine) (MN) for pheochromocytoma (PHEO) results from the tumoral expression of catechol-O-methyltransferase (COMT), the enzyme involved in O-methylation of catecholamines (CAT). Intriguingly, metanephrine, in contrast to epinephrine, is not remarkably secreted during a stress in hypertensive or normotensive subjects, whereas in PHEO patients CAT and MN are both raised to high levels. Because epinephrine and metanephrine are almost exclusively produced by the adrenal medulla, this suggests distinct CAT metabolism in chromaffin cells and pheochromocytes. OBJECTIVE: The objective of the study was to compare CAT metabolism between adrenal medulla and PHEO tissue regarding related enzyme expression including monoamine oxidases (MAO) and COMT. DESIGN: A multicenter comparative study was conducted. STUDY PARTICIPANTS: The study included 21 patients with a histologically confirmed PHEO and eight adrenal glands as control. MAIN OUTCOME MEASURES: CAT, dihydroxyphenol-glycol, 3,4-dihydroxyphenylacetic acid, and MN were measured in adrenal medulla and PHEO tissue. Western blot, quantitative RT-PCR and immunofluorescence studies for MAOA, MAOB, tyrosine hydroxylase, dopamine ß-hydroxylase, L-amino acid decarboxylase, and COMT were applied on tissue homogenates and cell preparations. RESULTS: At both the protein and mRNA levels, MAOA and COMT are detected less often in PHEO compared with adrenal medulla, conversely to tyrosine hydroxylase, L-amino acid decarboxylase, and dopamine ß-hydroxylase, much more expressed in tumor tissue. MAOB protein is detected less often in tumor but not differently expressed at the mRNA level. Dihydroxyphenol-glycol is virtually absent from tumor, whereas MN, produced by COMT, rises to 4.6-fold compared with adrenal medulla tissue. MAOA down-regulation was observed in 100% of tumors studied, irrespectively of genetic alteration identified; on the other hand, MAOA was strongly expressed in all adrenal medulla collected independently of age, gender, or late sympathetic activation of the deceased donor. CONCLUSION: High concentrations of MN in tumor do not only arise from CAT overproduction but also from low MAOA expression, resulting in higher substrate availability for COMT.


Assuntos
Neoplasias das Glândulas Suprarrenais/metabolismo , Metanefrina/metabolismo , Monoaminoxidase/fisiologia , Feocromocitoma/metabolismo , Adolescente , Medula Suprarrenal/metabolismo , Adulto , Idoso , Catecol O-Metiltransferase/análise , Catecol O-Metiltransferase/fisiologia , Catecolaminas/metabolismo , Regulação para Baixo , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Metanefrina/análise , Pessoa de Meia-Idade , Monoaminoxidase/análise , Monoaminoxidase/genética
20.
Diabetes ; 57(10): 2644-51, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18633112

RESUMO

OBJECTIVE: Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo. RESEARCH DESIGN AND METHODS: To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated muscle-specific IRS-1 Ser(302), Ser(307), and Ser(612) mutated to alanine (Tg IRS-1 Ser-->Ala) and IRS-1 wild-type (Tg IRS-1 WT) transgenic mice and examined insulin signaling and insulin action in skeletal muscle in vivo. RESULTS: Tg IRS-1 Ser-->Ala mice were protected from fat-induced insulin resistance, as reflected by lower plasma glucose concentrations during a glucose tolerance test and increased insulin-stimulated muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. In contrast, Tg IRS-1 WT mice exhibited no improvement in glucose tolerance after high-fat feeding. Furthermore, Tg IRS-1 Ser-->Ala mice displayed a significant increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity and Akt phosphorylation in skeletal muscle in vivo compared with WT control littermates. CONCLUSIONS: These data demonstrate that serine phosphorylation of IRS-1 plays an important role in mediating fat-induced insulin resistance in skeletal muscle in vivo.


Assuntos
Substituição de Aminoácidos , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Alanina/genética , Alanina/metabolismo , Animais , Western Blotting , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/farmacologia , Feminino , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Imunoprecipitação , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Serina/genética , Serina/metabolismo , Triglicerídeos/metabolismo
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