Pathophysiology of Dyslipidemia in Cushing’s Syndrome

Abstract

Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing’s syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing’s syndrome. In Cushing’s syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing’s syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, very-low-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing’s syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.

Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease

“…Glucocorticoids have complex, still not fully elucidated effects on lipid metabolism, including direct and indirect actions on lipolysis, free fatty acid production and turnover, very-low density lipoproteins synthesis and fatty accumulation in liver [29]. Our data are supported by previous studies performed in patients with secondary hypoadrenalism, suggesting that long-term glucocorticoid replacement therapy can cause dyslipidemia, with a clear relation between glucocorticoid dose and levels of total cholesterol and LDL-cholesterol [14,30].…”

“…Plasma ACTH concentrations have not been usually considered for the definition of the adequacy of glucocorticoid replacement therapy. More recently, it has been suggested that ACTH profiles could be useful to assess the variable sensitivity to glucocorticoid activity in patients with Addison's disease [29] and, therefore, should be used as additional parameter for the monitoring of glucocorticoid replacement [30]. The evaluation of 24-hours urinary free cortisol or salivary cortisol could add further information on cortisol exposure during the day.…”

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry

“…Diabetes mellitus (DM) was diagnosed as a need for antidiabetic drug therapy or a diabetic pattern on a 75-g oral glucose tolerance test. Hyperlipidemia was defined as the need for antilipidemic drug therapy, low-density lipoprotein cholesterol levels ≥140 mg/dL as calculated using Friedewald's formula [14], or triglyceride levels ≥150 mg/dL [15]. Patients with body mass index (BMI) ≥25 kg/m 2 were defined as obese.…”

Urine protein electrophoresis study in dogs with pituitary dependent hyperadrenocorticism during therapy with trilostane

“…Although still not completely defined the mechanism by which glucocorticoids cause liver damage, Abdou et al (2013) revealed that dogs with liver vacuolation secondary to excess of glucocorticoids, hepatomegaly and changes in echogenicity of the hepatic parenchyma, throughout the study the serum values of total protein and albumin remained constant, within the reference value. Glucocorticoids regulate the differentiation, function and distribution of adipose tissue, and its effects are controversial and involve the stimulation of lipolysis in peripheral fat and lipogenesis in central fat (Arnaldi et al 2010). The pathogenic mechanisms are multifactorial, including indirect and direct actions in lipolysis, production and degradation of free fatty acids, very low density lipoprotein synthesis and accumulation of intrahepatic fat (Arnaldi et al 2010).…”

“…Glucocorticoids regulate the differentiation, function and distribution of adipose tissue, and its effects are controversial and involve the stimulation of lipolysis in peripheral fat and lipogenesis in central fat (Arnaldi et al 2010). The pathogenic mechanisms are multifactorial, including indirect and direct actions in lipolysis, production and degradation of free fatty acids, very low density lipoprotein synthesis and accumulation of intrahepatic fat (Arnaldi et al 2010). Therefore, is expected that the lipid metabolism is altered in dogs with HAC, and the animals of the present study showed significantly higher serum concentrations of cholesterol and triglycerides than the control group.…”