Anton Luger

Zusammenfassung Akute Stoffwechselentgleisungen können für Erwachsene in Abhängigkeit von ihrem Ausmaß lebensbedrohlich sein. Dementsprechend sind eine rasche umfassende Diagnostik und Therapie sowie eine enge Überwachung der Vitalparameter und Laborbefunde erforderlich. Bei der Therapie, die sich bei der ketoazidotischen (DKA) und hyperglykämisch-hyperosmolaren (HHS) Form nicht wesentlich unterscheidet, kommt dem Ausgleich des meist beträchtlichen Flüssigkeitsdefizits mit mehreren Litern einer physiologischen kristalloiden Lösung eine vorrangige Rolle zu. Bei den Elektrolyten ist insbesondere auf eine ausgeglichene Serum-Kalium-Konzentration zu achten. Normal-Insulin oder rasch wirksame Analoga können initial als i.v.-Bolus verabreicht werden, in der Folge jedoch kontinuierlich über einen Perfusor. Die Umstellung auf eine subkutane Insulintherapie soll erst bei ausgeglichenem Säure-Basen-Haushalt und zufriedenstellender Glykämie erfolgen.

Pituitary hormone axes modulate glucose metabolism and exert direct or indirect effects on insulin secretion and function. Cortisol and growth hormone are potent insulin-antagonistic hormones. Therefore impaired glucose tolerance, elevated fasting glucose concentrations and diabetes mellitus are frequent in Cushing’s disease and acromegaly. Also prolactinomas, growth hormone (GH) deficiency, hypogonadism and hypothyroidism might be associated with impaired glucose homeostasis but usually to a lesser extent. Therefore glucose metabolism needs to be closely monitored and treated in patients with pituitary adenomas. Correction of the pituitary dysfunction is frequently followed by improvement of glucose homeostasis.

Zusammenfassung: Akute Stoffwechselentgleisungen können für Erwachsene in Abhängigkeit von ihrem Ausmaß lebensbedrohlich sein. Dementsprechend sind eine rasche umfassende Diagnostik und Therapie sowie eine enge Überwachung der Vitalparameter und Laborbefunde erforderlich. Bei der Therapie, die sich bei der ketoazidotischen (DKA) und hyperglykämisch-hyperosmolaren (HHS) Form nicht wesentlich unterscheidet, kommt dem Ausgleich des meist beträchtlichen Flüssigkeitsdefizits mit mehreren Litern einer physiologischen kristalloiden Lösung eine vorrangige Rolle zu. Bei den Elektrolyten ist insbesondere auf eine ausgeglichene Serum-Kalium-Konzentration zu achten. Normal-Insulin oder rasch wirksame Analoga können initial als i.v.-Bolus verabreicht werden, in der Folge jedoch kontinuierlich über einen Perfusor. Die Umstellung auf eine subkutane Insulintherapie soll erst bei ausgeglichenem Säure-Basen-Haushalt und zufriedenstellender Glykämie erfolgen.

Introduction: In patients with cured Cushing’s syndrome, comorbidities often persist after remission of glucocorticoid excess. Here we investigate long-term comorbidities in patients with Cushing’s syndrome in remission, and their relationship to metabolic and hormonal markers at the initial diagnosis of the disease. Methods/design: We evaluated 118 patients with cured Cushing’s syndrome (55 Cushing’s disease, 55 adrenal Cushing’s syndrome and 8 ectopic Cushing’s syndrome) 10 years (range 2–29) after the last surgery. Anthropometric, metabolic, hormonal parameters and comorbidities (obesity, diabetes, hyperlipidaemia, hypertension, osteoporosis, depression) at the last follow-up visit were obtained; baseline data on parameters at diagnosis of Cushing’s syndrome were extracted from hospital records. Uni- and multivariate regression analysis was performed for testing the relationship between baseline factors and long-term comorbidities. Results: Inpatients with manifest comorbidities at diagnosis, Cushing’s remission resolved diabetes in 54% of cases, hypertension in 34% of cases, hyperlipidaemia in 28% and depression in 48% of cases. Ten (range 2-29) years after the last surgery the prevalences of comorbidities in cured patients were: obesity 16%, diabetes 12%, hypertension 58%, hyperlipidaemia 62%, depression 16% and osteoporosis 21%. In a multivariate regression analysis, age, fasting glucose and depression at Cushing’s diagnosis, were positive predictors of the number of long-term comorbidities, while baseline urinary free cortisol secretion negatively correlated with the persistence of comorbidities in the long-term. The negative relationship between baseline 24-h urinary cortisol secretion and long-term comorbidities was also found when pituitary and adrenal Cushing’s cases were analysed separately. Conclusions: Long-term comorbidities after remission of Cushing’s syndrome depend not only on the presence of classical cardiovascular risk factors such as age and hyperglycaemia at diagnosis, but also on the amount of glucocorticoid excess. Lower baseline urinary cortisol levels are associated with more long-term comorbidities, possibly due to the delayed diagnosis in milder Cushing’s syndrome leading to a longer exposure to excess glucocorticoids.

Background: Despite adequate hormone replacement therapy, evidence suggests that mortality is increased in patients suffering from primary adrenal insufficiency (AI), mainly because of cardiovascular diseases. Since activation of the renin-angiotensin-aldosteron system (RAAS) plays an important role in the development of hypertension and cardiovascular disease we aimed to investigate, if there are differences in AI compared to healthy controls. Methods: Eight patients with AI (female n=5; male n=3; age 56±21; BMI 22,8±2,8 kg/m²; mean blood pressure 140/83 mmHg)) and eight matched healthy volunteers (female n=5; male n=3; age 52±21; BMI 25,2±4,3 kg/m²; mean blood pressure 135/84 mmHg) were included. Blood was drawn in the morning in the fasting state to measure serum electrolytes, renin-, aldosterone, cortisol and ACTH concentrations. Assessment of physiologically active angiotensin concentrations and equilibrium analysis was performed by RAS fingerprint measurements. Results: In patients suffering from AI RAAS activity was increased with significantly elevated concentrations of renin (P=0.027), angiotensin-1 (P=0.022), angiotensin-2 (P=0.032), angiotensin-1-7 (P=0.03) and angiotensin-1-5 (P=0.03), as well as in a reduction in aldosteron-angiotensin-2 ratio (AA2-Ratio, P=0.003) compared to controls, resulting in a characteristic RAAS fingerprint. Plasma renin activity was strongly correlated with the sum of angiotensin-1+ angiotensin-2 (r=0.983; P< 0.01). Conclusions: AI is associated with a unique RAAS fingerprint. Physiologically active angiotensin concentrations are highly elevated, despite adequate hormone replacement therapy. This might contribute to the reported increased cardiovascular risk and should be investigated in future trials.

Background: Altered hepatic mitochondrial activity plays a key role in the development of non-alcoholic fatty liver disease (NAFLD). GH has been shown to stimulate mitochondrial function in skeletal muscle. Therefore we hypothesize that the time course of serum GH concentrations during an oral glucose tolerance test might be related to hepatic mitochondrial energy metabolism in vivo in humans. Methods: 15 volunteers (male/female: 7/8; 55±8 years; BMI 25±4 kg/m²) were investigated on two study days; i) oral glucose tolerance tests were performed to assess dynamics of glucose, insulin, C-peptide and GH concentrations and ii) hepatic lipid content was measured by 1H/31P magnetic resonance spectroscopy (MRS). Saturation transfer technique was applied to assess ATP synthesis rate (k). Results: Basal GH concentrations and GH dynamics strongly correlated with hepatic mitochondrial activity (GH_baseline&k_liver:r=0.783; PAUC& k_liver: r=0.676; P=0.008). There was no association between HCL and GH, as well as between HCL and k_liver. Six subjects fulfilled criteria for NAFLD (HCL≥5.5%). They presented significantly higher glucose levels and insulin resistance. The strong relationship between GH and k_liver did not differ between patients with and without NAFLD. Discussion: Our data indicate that basal as well as postprandial (oGTT) GH concentrations are directly related to hepatic energy metabolism in insulin sensitive and insulin resistant humans.

Introduction: Hypertension (HTN) is a major cardiovascular (CV) risk factor and independent predictor of the increased mortality in patients with acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure (BP) levels, however little is known on the effect of pegvisomant (PEGV) treatment on HTN. Methods/design: ACROSTUDY is an open-label, international, prospective, non-interventional study monitoring the long-term safety of PEGV. After informed consent, study patients were enrolled on an ongoing basis. Data were analysed to identify the clinical characteristics and evolution of HTN in patients with acromegaly treated with PEGV. Results: As of May 31, 2016, data from 2090 patients (15 countries) were available. At ACROSTUDY start, 1038 patients (49.7%, 51% male) had diagnosed HTN (96.4% were on anti-HTN medications). Most HTN patients were Caucasian (95%) and 75.8% was treated with PEGV before ACROSTUDY start. Modifiable CV risk factors that were reported besides HTN were BMI >25 (87.2%), diabetes (72.2%), dyslipidemia (10.2%), sleep apnoea (71.8%), and 17.7% had history of CVD. In the HTN group, the mean age at diagnosis of acromegaly was 48 years (S.D. 12.7) and the mean age at the start of PEGV (Baseline) was 56 years (S.D. 12.1) vs 36.3 years (S.D.11.7) and 43 years (S.D. 12.7) for non-HTN group. Time from diagnosis to PEGV treatment was 8.4 years (S.D. 8.5) vs 6.5(S.D. 7.2) in HTN and non-HTN group respectively. At baseline systolic BP(SBP) was 138.3 and diastolic BP(DBP) 85 mmHg. Follow up at year 5 showed SBP 134.5 and DBP 82.5 mmHg. Average IGF-1 level at baseline was 488.9 and 218 ng/ml at year 5. Conclusions: HTN is a common comorbidity in acromegaly. Patients with HTN tend to be older at diagnosis and start of PEGV and have multiple CV risk factors. With PEGV treatment, blood pressure levels remain stable over time.