Patients with mild autonomous cortisol secretion (MACS) are at increased risk of cardiometabolic outcomes, such as hyperglycemia, metabolic syndrome, and cardiovascular diseases. Nonalcoholic fatty liver disease (NAFLD) is also associated with increased cardiometabolic risk. We aimed to investigate the prevalence and predictors of NAFLD in metabolically healthy subjects with MACS.

Forty patients with MACS and 60 patients with nonfunctioning adrenal incidentaloma (NFAI) matched for age, gender, and body mass index were included. We excluded various diseases that may lead to NAFLD, such as diabetes, cardiovascular diseases, and liver disorders. Non-alcoholic fatty liver disease was evaluated with unenhanced abdominal computed tomography and noninvasive fatty liver indices.

Patients with MACS had lower mean liver attenuation values (Hounsfield units, HU) than those with NFAI (p = 0.001). Visceral adiposity index, hepatic steatosis index, and fatty liver index were higher in the MACS group than in the NFAI group (p = 0.009, p = 0.002, p = 0.023, respectively). However, there was no significant association between the mean liver HU value and these indices. There was a significant association between serum cortisol level after the 1 mg dexamethasone suppression test (DST) and mean liver HU value independent of other traditional risk factors in various models performed in multivariable linear regression analysis.

Our findings suggest that MACS is associated with an increased risk of NAFLD, and serum cortisol level after 1 mg DST is an independent predictor of NAFLD in patients with MACS.

While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH.

Hypercortisolism may be considered as a continuum in terms of both hormonal and cardiometabolic abnormalities. It ranges from cases with "normal" hormonal profile and low to intermediate risk of comorbidity to florid cases with clear clinical and hormonal evidence of glucocorticoid excess and clearly increased cardiometabolic risk. Even in patients with nonfunctioning adrenal incidentaloma (NFAI), defined as adrenal incidentaloma with normal results on the currently available hormonal test for evaluation of hypercortisolism, cardiometabolic and mortality risk is higher than in the general population without adrenal lesions. Mild hypercortisolism or autonomous cortisol secretion (ACS) is a term used for patients with adrenal incidentaloma and pathological dexamethasone suppression test (DST) results, but without specific clinical signs of hypercortisolism. It is widely known that this condition is linked to higher prevalence of several cardiometabolic comorbidities, including diabetes, hypertension, osteoporosis and metabolic syndrome, than in patients with NFAI or without adrenal tumor. In case of overt Cushing's syndrome, cardiovascular risk is extremely high, and standard mortality ratio is high, cardiovascular disease being the leading cause of death. The present review summarizes the current evidence for a detrimental cardiometabolic profile in patients with possible (NFAI), probable (ACS) and certain hypercortisolism (overt Cushing's syndrome).

Mild autonomous cortisol secretion (mACS) is a state of cortisol excess usually associated with existence of adrenal incidentaloma. Because of the lack of symptoms of the disease, the biochemical evaluation is the most important to determine a diagnosis. However, scientific societies have different diagnostic criteria for mACS, which makes the treatment of this disease and using results of original papers in daily practice more difficult. Chronic hypercortisolemic state, even if mild, may lead to diseases that are mostly connected with overt Cushing's syndrome. Some of them can cause a higher mortality of patients with mACS and those problems need to be addressed. In this review we describe the comorbidities associated with mACS: cardiovascular disorders, arterial hypertension, diabetes mellitus, insulin resistance, dyslipidemia, obesity, metabolic syndrome, non-alcoholic fatty liver disease, vertebral fractures and osteoporosis. The point of this paper is to characterise them and determine if and how these conditions should be managed. Two databases - PubMed and Web of Science were searched. Even though the evidence are scarce, this is an attempt to lead clinicians through the problems associated with this enigmatic condition.

In the vast majority of cases adrenal incidentalomas (AI) are benign adrenocortical adenomas. They are present in up to 10% of the population over 70 years, with incidence increasing with age. Mild cortisol excess (MCE) in the context of AI is defined as autonomous cortisol secretion (ACS) in the absence of the classical clinical features of Cushing's syndrome. MCE has been reported in up to at least one third of patients with AI. Numerous studies have shown that MCE in AI is associated with increased cardiovascular events and mortality, likely to be consequent upon both hemodynamic changes and inflammatory pathways, and a worse metabolic phenotype characterized by: pancreatic β-cell dysfunction, insulin resistance, visceral obesity and dyslipidemia. There is currently no level 3 evidence from large intervention randomized controlled trials to guide management of MCE in AI, and there is a lack of predictive tools to allow stratification to intervention of only those patients who would benefit in terms of improved metabolic and cardiovascular end-points. Here, we describe the mal-effects of cortisol on cardiovascular and metabolic tissues and discuss management strategies based on current largely observational data.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

In current practice, an adrenal adenoma usually comes as an unexpected byproduct of an imaging study performed for unrelated reasons, without any prior suspect of adrenal disease. Therefore, these tumors currently represent a public health challenge because they are increasingly recognized due to the widespread use of high-resolution cross-sectional imaging for diagnostic purposes. In radiology series, the prevalence of adrenal adenomas increases steeply with age, from around 3% below the age of 50 years up to 10% in the ageing population. These tumors may have clinical relevance because they are able to secrete cortisol autonomously, independently from the pituitary control, in up to 20-30% of patients. In most of the cases the resulting cortisol excess is insufficient to produce a typical Cushing phenotype but may have clinical consequences, such as hypertension, diabetes, obesity, dyslipidemia and osteoporosis. Despite some controversy on the most effective diagnostic algorithm to define this subtle hypercortisolism, there is mounting evidence that a simple approach by using the 1-mg overnight dexamethasone suppression test (DST) may stratify patients for their cardiovascular risk. Cross-sectional, retrospective studies showed that patients with increasingly higher cortisol following DST have an adverse cardiovascular risk profile and are at increased risk of death. Therefore, also a subtle autonomous cortisol excess is associated with increased morbidity and mortality, mainly of cardiovascular origin.

Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up.

Prospective study in a tertiary hospital.

Seventy-one patients with AI [51 nonfunctioning (NFAI) and 20 ACS] and 5·54 ± 1·7 years follow-up underwent testing for ACS and oral glucose tolerance test to determine IR indices and adrenal imaging.

At follow-up, 16/51 (31%) NFAI patients converted to ACS, while two with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary-free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9·8% NFAI and 15% ACS, respectively) and 14 IR (17·6% NFAI and 25% ACS, respectively). Adenoma size increased from 2·1 ± 0·8 to 2·3 ± 0·8 cm, whereas IR correlated with postdexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Ν-UFC), to H-UFC, C-ACS and ACS patients.

New-onset ACS developed in 31% patients with NFAI, whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.

Subclinical hypercortisolism (SH), defined as alterations of the hypothalamus-pituitary-adrenal axis in the absence of clinical signs or symptoms related to cortisol secretion, is a common finding in patients with adrenal incidentalomas. The clinical correlates of this pathological condition have become clearer over the last few years. The aim of this review is to summarize the co-morbidities and the clinical outcomes of patients with SH. According to the analysis of the results of the studies published within the last 15 years, hypertension and type 2 diabetes are a common finding in patients with SH, occurring roughly in 2/3 and 1/3 of the patients respectively. Moreover, several additional cardiovascular and metabolic complications, like endothelial damage, increased visceral fat accumulation and impaired lipid metabolism have been shown to increase the cardiovascular risk of those patients. Accordingly, recent independent reports investigating the natural history of the disease in a long-term follow-up setting have shown that patients with SH have a higher incidence of cardiovascular events and related mortality. Moreover, longitudinal studies have also shown increased incidence of osteoporotic vertebral fractures. Future research is needed to improve the diagnostic performance of hormonal tests, by assessment of the complete steroid profile with more accurate assays, and to define the efficacy of surgical vs medical treatment in a randomized-controlled setting.