Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome

Abstract

Primary aldosteronism (PA) is characterized by autonomous aldosterone hypersecretion from adrenal gland, resulting in low-renin hypertension often accompanied by hypokalemia and metabolic alkarosis. Recent epidemiologic studies have revealed that PA is more common cause of secondary hypertension than previously thought with its higher prevalence (5-15 %) in patients with hypertension [1][2][3][4][5]. Subclinical Cushing's syndrome (SCS) is characterized as subtle cortisol hypersecretion from adrenal tumor but lack of specific signs or symptoms of overt abstract. Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3β-HSD, P450 C17 ) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

Plasma Metanephrine for Assessing the Selectivity of Adrenal Venous Sampling

“…In agreement with emerging findings from other groups, 5,6,13,14 the above considerations conversely imply that cortisol provides a less than optimal parameter to establish selective catheterization in nonstimulated sequential AVS procedures. This conclusion is reinforced by our findings that metanephrine to normetanephrine and epinephrine to norepinephrine ratios in most nonstimulated AV samples designated nonselective, based on a cortisol-derived selectivity index of 3.0, were well above the range for ratios in PV samples and within the range for the AV samples designated as selective.…”

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism?

“…Second, the measurement and interpretation of steroid levels in both sampling approaches may have been biased. Immunoassays have inherent limitations; thus, in light of the endogenous differences in the laterality of cortisol secretion, the use of cortisol in the denominator of the SI and LI could have prevented accurate subtyping of PA, as previously reported (20,21). Because the common denominator of both SI and LI determined by C-AVS is cortisol level, the endogenous difference in laterality of cortisol secretion could lead to misinterpretation of S-AVS findings and affect subsequent sub-typing of PA determined by SI and LI, as reported in previous studies (20,21).…”

“…Immunoassays have inherent limitations; thus, in light of the endogenous differences in the laterality of cortisol secretion, the use of cortisol in the denominator of the SI and LI could have prevented accurate subtyping of PA, as previously reported (20,21). Because the common denominator of both SI and LI determined by C-AVS is cortisol level, the endogenous difference in laterality of cortisol secretion could lead to misinterpretation of S-AVS findings and affect subsequent sub-typing of PA determined by SI and LI, as reported in previous studies (20,21). Therefore, only the absolute concentrations of aldosterone and cortisol obtained by S-AVS could enable us to evaluate the precise intra-adrenal steroidogenic distribution, i.e., which tumor or intra-adrenal segment is responsible for hyperaldosteronism or autonomous cortisol production.…”

KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas [Rapid Communication]

“…However, the mRNA levels of steroidogenic enzymes of 3 APAs with co-secretion of cortisol did not show any specific profile. Hiraishi et al also reported that in a histopathological and immunohistochemical study of 3β-HSD and CYP17, CYP11B2 mRNA levels in APAs with subclinical Cushing's syndrome diagnosed with the guideline of a Research Committee for Adrenal Diseases supported by the Japanese Ministry of Health, Labor and Welfare did not show any difference from those in APAs [18].…”

“…Piaditis et al have reported that PA with hypercortisolism was observed in 12.1% of 83 adrenal incidentalomas [26]. In Japan, the prevalence was reported to be 15~30% [9,18,27]. Although the reason for the high prevalence of an association with autonomous cortisol secretion in APAs remains unclear, many cases have been described by Japanese investigators and this may have led to greater awareness in Japan [22].…”