Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin–antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.
Andrea M Isidori, Marianna Minnetti, Emilia Sbardella, Chiara Graziadio, and Ashley B Grossman
Emilia Sbardella, Marianna Minnetti, Denise D’Aluisio, Laura Rizza, Maria Rosaria Di Giorgio, Fabio Vinci, Riccardo Pofi, Elisa Giannetta, Mary Anna Venneri, Annarita Vestri, Sergio Morelli, Andrea Lenzi, and Andrea M Isidori
Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas – recently defined as possible autonomous cortisol secretion (pACS) – has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking.
Subjects and methods
Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind.
According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 non-functioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P = 0.006) and mildly correlated to the post-DST cortisol level (rho = 0.347; P = 0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSA variance (P = 0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P = 0.001) and worse arterial stiffness assessed by pulse wave velocity (P = 0.033).
In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition.
Alessia Cozzolino, Tiziana Feola, Ilaria Simonelli, Giulia Puliani, Valeria Hasenmajer, Marianna Minnetti, Elisa Giannetta, Daniele Gianfrilli, Patrizio Pasqualetti, Andrea Lenzi, and Andrea M Isidori
Neurosurgery is the first-line treatment for acromegaly. Whether metabolic disorders are reversible after neurosurgery is still debated. The meta-analysis aimed to address the following questions: (i) Does neurosurgery affect glycolipid metabolism? (ii) Are these effects related to disease control or follow-up length?
A meta-analysis and systematic review of the literature.
Three reviewers searched databases until August 2019 for prospective trials reporting glycometabolic outcomes after neurosurgery. Three other extracted outcomes, all assessed the risk of bias.
Twenty studies were included. Neurosurgery significantly reduced fasting plasma glucose (FPG) (effect size (ES): −0.57 mmol/L, 95% CI: −0.82 to −0.31; P < 0.001), glucose load (ES: −1.10 mmol/L, 95% CI: −1.66 to −0.53; P < 0.001), glycosylated haemoglobin (HbA1c) (ES: −0.28%, 95% CI: −0.42 to −0.14; P < 0.001), fasting plasma insulin (FPI) (ES: −10.53 mU/L, 95% CI: −14.54 to −6.51; P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (ES: −1.98, 95% CI: −3.24 to −0.72; P = 0.002), triglycerides (TGDs) (ES: −0.28 mmol/L, 95% CI: −0.36 to −0.20; P < 0.001) and LDL-cholesterol (LDLC) (ES: −0.23 mmol/L, 95% CI: −0.45 to −0.02 mmol/L); P = 0.030) and increased HDL-cholesterol (HDLC) (ES: 0.21 mmol/L, 95% CI: 0.14 to 0.28; P < 0.001). Meta-regression analysis showed that follow-up length – not disease control – had a significant effect on FPG, with the greatest reduction in the shortest follow-up (beta = 0.012, s.e. = 0.003; P = 0.001).
Neurosurgery improves metabolism with a significant decrease in FPG, glucose load, HbA1c, FPI, HOMA-IR, TGDs, and LDLC and increase in HDLC. The effect on FPG seems to be more related to follow-up length than to disease control.