Michael Kerstens

Incidence of Venous Thromboembolism in Patients with Cushing's Syndrome: A Multicenter Cohort Study

CONTEXT Venous thrombosis has frequently been reported in patients with endogenous Cushings syndrome (CS). OBJECTIVE The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Lack of relationship between 11β-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients

OBJECTIVES To test whether insulin resistance in type 2 diabetes mellitus is associated with an altered overall setpoint of the 11β‐hydroxysteroid dehydrogenase (11βHSD) mediated cortisol to cortisone Inter‐conversion towards cortisol, and to evaluate whether changes in insulin sensitivity induced by antecedent hyperinsulinaemia are related to changes in the 11βHSD setpoint.

Determination of urinary 18β-glycyrrhetinic acid by gas chromatography and its clinical application in man

A sensitive and quantitative gas chromatographic assay for the determination of 18 beta-glycyrrhetinic acid (18 beta-GA), the main metabolite of glycyrrhizin after oral licorice consumption in human urine, has been developed and validated. For the extraction of 18 beta-GA from urine two Sep-Pak C18 extractions, hydrolysis with Helix pomatia and three liquid-liquid extractions were performed, using 18 alpha-glycyrrhetinic acid (18 alpha-GA) as internal standard. Both 18 beta-GA and internal standard were converted into their pentafluorobenzyl-ester/trimethylsilyl-ether derivatives and detected by flame ionization detection using a WCOT-fused-silica capillary column. Good quality control data were obtained in precision and accuracy tests. The detection limit of the gas chromatographic method was 10 micrograms/l with a urine volume of 10 ml. A detection limit of 3 micrograms/l was obtained by performing GC-MS. The GC method was used to monitor the urinary excretion of 18 beta-GA after licorice consumption by two healthy volunteers and a patient suspected of licorice abuse. Furthermore, it was shown that this GC assay enables to detect other metabolites related to licorice consumption.

Gas chromatographic–mass spectrometric analysis of urinary glycyrrhetinic acid: an aid in diagnosing liquorice abuse

Abstract. Kerstens MN, Guillaume CPF, Wolthers BG, Dullaart RPF (University Hospital Groningen, Groningen, The Netherlands). Gas chromatographic–mass spectrometric analysis of urinary glycyrrhetinic acid: an aid in diagnosing liquorice abuse. J Intern Med 1999; 246: 539–547.

Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation.

Background  Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity and plasma aldosterone in uncomplicated type 1 diabetes mellitus by evaluating the effects of endogenous (sodium restriction) and exogenous (angiotensin I infusion) stimulation.

11b-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockade

Background It has been suggested that an altered setpoint of the 11βHSD‐mediated cortisol to cortisone interconversion towards cortisol contributes to sodium retention in nephrotic syndrome patients. We studied the parameters of 11βHSD activity in proteinuric patients, in particular its activity at the kidney level. We also studied the effect of angiotensin‐II receptor blockade on the parameters of 11βHSD activity.

Effects of growth hormone replacement on cortisol metabolism in hypopituitary patients treated with cortisone acetate

Growth hormone (GH) replacement may inhibit 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) activity, resulting in diminished conversion of cortisone to cortisol. Moreover, GH replacement may lower bioavailability of hydrocortisone tablets. Therefore, substitution therapy with cortisone acetate could be disadvantageous during GH replacement. We conducted a randomized, placebo-controlled GH replacement (1 to 2 U GH/day) study during 6 months, followed by a 6-month open extension study (2U GH/day). Twelve men and 12 women with GH deficiency, of whom 17 received cortisone acetate (25 to 37.5 mg/day), participated. Eight patients were randomized to placebo initially. At baseline, after 6 and 12 months, urinary cortisol and cortisone metabolites were measured. No changes in urinary cortisol metabolites were observed after 6 months placebo (n=8). After 6 months GH the urinary (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortison ratio ((THF+alloTHF)/THE ratio) was unaltered in cortisone acetate treated patients (n = 17) and in patients with intact adrenal function (n = 7), whereas after 12 months GH the (THF + alloTHF)/THE ratio decreased only in cortisone acetate treated patients (1 dropout, n=9). Urinary THF and alloTHF were higher in cortisone acetate treated patients than in patients with intact adrenal function before GH and remained so after 12 months GH (p < 0.05 to p < 0.01). The sum of cortisol + cortisone metabolites did not change after GH in either group. The urinary free cortisol/free cortisone ratio, presumably reflecting renal 11betaHSD2 activity, tended to decrease in cortisone acetate treated patients (p<0.07 and p<0.05 after 6 and 12 months GH, respectively), as well as in patients with intact adrenal function (p<0.05 and a decrease in five/six patients after 6 and 12 months GH, respectively). In conclusion, these results suggest that GH replacement decreases 11betaHSD1 activity, which becomes manifest in patients receiving cortisone acetate substitution therapy. 11betaHSD2 activity is unaltered or may even be increased. It is unlikely that the bioavailability of conventional doses of cortisone acetate is impaired after GH replacement.

A low‐saturated‐fat, low‐cholesterol diet decreases plasma CETP activity and pre β‐HDL formation but does not affect cellular cholesterol efflux to plasma from type 1 diabetic patients

The aim of this study was to evaluate the effect of a low‐saturated‐fat, low‐cholesterol diet on plasma lipopoproteins, pre β‐high density lipoprotein (HDL) formation, lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities, as well as on the ability of plasma to stimulate cellular cholesterol efflux. Twelve male type 1 diabetic patients with plasma cholesterol >5.0 mmol/L were studied while consuming their usual diet and after 6 weeks of a low‐fat, low‐cholesterol diet. Pre β‐HDL formation was measured using crossed immuno‐electrophoresis. Plasma LCAT, CETP and PLTP activities were assayed by exogenous substrate methods. The ability of plasma to promote cellular cholesterol efflux out of Fu5AH rat hepatoma cells and out of human skin fibroblasts was also determined. Saturated fat intake was lowered (p = 0.001) due to replacement with carbohydrates, while mono‐ and polyunsaturated fat intake remained unchanged. Cholesterol intake decreased as well (p = 0.003). The changes in plasma total cholesterol, very low and low‐density lipoprotein (VLDL+LDL) cholesterol, HDL cholesterol, HDL phospholipids, apolipoprotein (apo) A‐I, plasma LCAT activity and PLTP activity were not significant. Plasma CETP activity (p = 0.008) and pre β‐HDL formation (p = 0.008) decreased. The ability of plasma to promote cholesterol efflux out of fibroblasts and Fu5AH cells remained unchanged. Reduction in dietary saturated fat and cholesterol intake does not adversely affect cellular cholesterol efflux to plasma from type 1 diabetic patients, despite a drop in pre β‐HDL formation.

Multiple skeletal lesions on FDG PET in severe primary hyperparathyroidism

A 55-year-old man presented with weight loss and diffuse bone pain. Strongly elevated concentrations of calcium (3.49 mmol/L, with normoalbuminuria) and parathyroid hormone (260 pmol/L) indicated primary hyperparathyroidism.F-FDG PET/CT scanning demonstrated uptake in the right upper and right lower pole of the thyroid region but also multiple F-FDG-avid osteolytic lesions, including the 7th cervical and 3rd lumbar vertebrae (a). Histopathological examination of a vertebral bone biopsy revealed a brown tumour. An enlarged left upper and right upper parathyroid gland were resected using a sestamibi gamma probe. In addition, a left-sided hemithyroidectomy with ipsilateral paratracheal nodal dissectionwas performed because of a suspected mass in the left thyroid lobe and enlarged lymph nodes [1]. Pathological examination demonstrated a parathyroid adenoma but no carcinoma. Postoperative recovery was complicated by a severe hungry bone syndrome. Repeat FFDG PET/CT scanning 4 months after surgery showed a marked reduction in the number of F-FDG-avid lesions in the skeleton (b). Also the intensity of F-FDG uptake in the remaining lesions was significantly lower. Severe parathyroid bone disease is nowadays rarely encountered [2]. Brown tumours are osteolytic lesions which may mimic skeletal metastasis [3–5]. Microscopically, excessive osteoclast resorption is seen with destruction of cortical bone and formation of fibrous cysts. The marrow may be replaced by vascularized fibrous tissue and osteoclast-like giant cells. Haemosiderin deposits give these tumours their characteristic brown colour. Reduction in abnormal F-FDG uptake paralleled resolution of the hungry bone syndrome in our patient. Indeed, brown tumours may disappear after successful parathyroidectomy [5].

Plasma normetanephrine concentrations are affected by dietary sodium intake

Fig. 1. Effect of sodium loading on plasma normetanephrine andmetanephrine concentrations in healthy subjects (n=98). Scatter dot plots demonstrating individual values of plasma normetanephrine (NMN; panel A) and plasma metanephrine (MN; panel B) at baseline and after sodium loading test (SLT). Concentrations are presented on the left y-axis, and relative changes (%) on the right y-axis. Horizontal lines present median values. Plasma normetanephrine concentrations are affected by dietary sodium intake