Serum Amyloid A, Paraoxonase-1 Activity, and Apolipoprotein Concentrations as Biomarkers of Subclinical Atherosclerosis Risk in Adrenal Incidentaloma Patients

Background

Adrenal incidentalomas (AIs), particularly subclinical hypercortisolism (SH), are related to an increased risk of atherosclerosis. The anti-oxidative enzyme paraoxonase-1 (PON1) and the acute phase reactant serum amyloid A (SAA) are transported by highdensity lipoprotein and reciprocally regulated in acute inflammatory response. Our aim was to investigate serum SAA, PON1, and apolipoprotein levels as indicators of subclinical atherosclerosis in patients with nonfunctioning AI (NFAI) and SH.

Methods

The study group consisted of 60 controls, 14 SH, and 86 NFAI subjects. Serum amyloid A (SAA), PON1 activity, lipid profiles, apoA and B, lipoprotein A (LpA), hsCRP, and HOMA-IR levels were compared in all groups.

Results

Serum insulin, triglyceride, SAA, SAA/PON1 ratio, LpA, apoB, hsCRP, and morning cortisol levels were found to be higher while PON1 and apoAI levels were lower in the SH and NFAI groups compared with the controls, and these parameters were found to be more impaired in SH group than NFAI group (p <0.001). HOMA-IR was higher and DHEAS was lower in the SH group than in the other groups. The SAA/PON1 ratio was positively correlated with LpA (r = 0.460; p <0.001), apoB (r = 0.515; p <0.001), insulin (r = 0.275; p = 0.026), triglyceride (r = 0.248; p = 0.002), morning cortisol (r = 0.259; p = 0.045), and UFC (r = 0.274; p <0.001) and negatively correlated with apoAI (r = 0.329; p <0.001), ACTH (r = −0.384; p <0.001), and DHEAS (r = −0.521, p <0.001) levels. The cut-off value of the SAA/PON1 ratio for NFAI was >0.23, and for SH it was >1.33.

Conclusion

The serum SAA/PON1 ratio was high in both the NFAI and SH groups and also exhibited higher levels in SH group. An increased SAA/PON1 ratio and low DHEAS could be attributable to subclinical atherosclerosis risk in SH patients.

Introduction

Adrenal incidentalomas (AI) are lesions that are detected during routine imaging for nonadrenal gland-related complaints or physical examination findings. In the general population, 95% of AIs are found to be nonmalignant tumors at the time of diagnosis (1). Although most of them are nonfunctioning AIs (NFAI), cortisol hypersecretion is the most likely disorder that may ensue. Hypercortisolism persists throughout follow-up and may become clinically apparent in some cases of NFAI (2). Subclinical hypercortisolism (SH) is defined as a state of impaired hypothalamic–pituitary–adrenal axis cortisol secretion in the absence of the classical signs or symptoms of hypercortisolism, and it is estimated to appear in 9% of patients with AI 1, 3. In studies reporting on follow-ups of patients with AI, <1% of patients with “autonomous cortisol secretion” progressed to overt Cushing's syndrome 4, 5. Emerging evidence indicates the increased prevalence of arterial hypertension, insulin resistance, metabolic syndrome, hyperlipidemia, hyperuricemia, obesity, diabetes mellitus (DM), cardiovascular disease (CVD), and related mortality in AI and SH patients 6, 7, 8, 9, 10. Recently, we found NFAI to be associated with higher epicardial fat thickness, increased left ventricular mass index, carotid intima–media thickness (CIMT), and hypertension prevalence 11, 12.

Serum paraoxonase 1 (PON1) activity is thought to be a potential biomarker for the severity of CVD (13). In addition, elevated serum PON1 activity levels are thought to be protective against cardiac diseases in the general population (14). In the course of inflammation, the serum amyloid A (SAA) content of high-density lipoprotein cholesterol (HDL-C) increases, whereas apolipoprotein AI (apoAI) and PON1 decrease (15). Serum PON1 activity seems to be regulated by inflammation and oxidative stress-related molecules associated with SAA regulation in humans (16). The combined use of SAA and PON1 may serve as an index that plays the role of a surrogate marker of dysfunctional HDL-C in inflammation and oxidative stress conditions. Apolipoproteins bind lipids to form the lipoproteins that transport the lipids through the lymphatic and circulatory systems. Apolipoprotein B (apoB) is the primary apolipoprotein in low-density lipoprotein cholesterol (LDL-C), which is responsible for transporting cholesterol to tissues. Apolipoprotein AI, the major protein component of HDL-C, expresses its anti-atherogenic properties by transporting cholesterol from the tissues to the liver (17). It has been suggested that the anti-atherogenic and anti-inflammatory properties of apoAI are due to inhibiting the production of cytokines by monocytes and macrophages (18). Elevated lipoprotein A (LpA) levels are considered to be a causal risk factor for atherosclerosis and CVD 19, 20, 21.

Dehydroepiandrosterone sulfate (DHEAS) is an androgen precursor hormone secreted in the adrenal glands under the dominant regulation of adrenocorticotrophic hormone (ACTH). It is thought that low DHEAS levels in SH are due to the chronic suppression of ACTH (22). Indeed, low serum DHEAS levels are usually found in chronic inflammatory and atherosclerotic diseases. The underlying biological pathway through which DHEAS plays a direct role in the pathogenesis of subclinical vascular disease remains unclear, but it is believed that DHEAS inhibits the migration and proliferation of cells inside the vascular wall, causing vascular smooth muscle cell apoptosis and thus reducing vascular remodeling after injury (23). Some studies have described potent inverse relations between DHEAS levels and insulin resistance and carotid intima–media thickness 24, 25. In a women's health study, low DHEAS levels were related to an increased risk (>two fold) of CVD mortality (26).

Metabolic disorders accompanying subclinical atherosclerosis are common in the general population; therefore, it is difficult to conclude whether is there any contributory relationship between AI and metabolic disorders. In this study, we aimed to investigate markers of chronic inflammation, such as serum SAA, PON1 activity, apoAI, apoB, LpA levels, lipid profile, and DHEAS levels, in NFAI and SH patients to determine the potential subclinical atherosclerosis risk in these patients.