Mika Tsuiki

Histopathological Diagnosis of Primary Aldosteronism Using CYP11B2 Immunohistochemistry

CONTEXT Although primary aldosteronism (PA) is the most common cause of endocrine hypertension, histopathological methods to reveal the presence and sites of aldosterone overproduction remain to be established. OBJECTIVE The objective of the study was to investigate the significance of immunohistochemical staining to detect CYP11B2 and CYP11B1 in adrenal tissue of patients with PA. DESIGN AND PATIENTS Thirty-two patients with PA who underwent unilateral adrenalectomy were studied. Immunohistochemical staining was performed using anti-CYP11B2 and anti-CYP11B1 antibodies on paraffin-embedded sections. We analyzed the expression of each enzyme semiquantitatively by scoring staining intensity and correlating it with clinical findings. RESULTS Twenty-two patients showed positive CYP11B2 immunostaining in their tumors (aldosterone producing adenoma, APA). Four patients with CYP11B2-negative unilateral adenomas and 4 patients without tumors on computed tomography showed aldosterone-producing cell clusters (APCCs) with CYP11B2 immunostaining in the zona glomerulosa (multiple APCCs). The remaining 2 patients had unilateral multiple adrenocortical micronodules and diffuse adrenocortical hyperplasia, respectively. In APA, CYP11B2 score adjusted for tumor volume was positively correlated with plasma aldosterone and negatively correlated with serum potassium. The APA group was divided into 3 subgroups based on relative CYP11B2 and CYP11B1 immunostaining levels. The CYP11B2/CYP11B1-equivalent and CYP11B1-dominant APA groups showed significantly higher serum cortisol after 1 mg dexamethasone and larger tumor size than the CYP11B2-dominant APA group. CONCLUSIONS The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia.

Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism

Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut‐off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut‐off of <4 without sufficient evidence for its diagnostic accuracy.

Chronic kidney disease score for predicting postoperative masked renal insufficiency in patients with primary aldosteronism.

Chronic kidney disease (CKD) is sometimes unmasked after unilateral adrenalectomy in patients with primary aldosteronism (PA) without expectation.

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154–69 920) in the higher side and 12 953 (range, 1866–36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4–66.0] versus 17.3 [4.0–59.0] pg/mL per &mgr;g/dL; P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

A subtype prediction score for primary aldosteronism.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Although adrenal venous sampling (AVS) is recommended as the gold standard procedure for subtype classification in PA, it is a specialized technique with limited availability. The objective of this study was to develop a scoring system that predicted PA subtype using clinical characteristics. Seventy-one patients with PA were studied. The subjects were diagnosed as having either unilateral (n=32) or bilateral disease (n=39) based on AVS, surgery and/or the postoperative clinical course. Variables associated with laterality in the univariate analysis were entered into multivariable logistic regression models and the regression coefficients were used to construct a subtype prediction score. The diagnostic significance of the score was then evaluated using receiver operating characteristic (ROC) curve analysis. The subtype prediction score was calculated as follows: serum potassium ⩽3.4 mEq l–1, 2 points; plasma aldosterone concentration ⩾165 pg ml–1, 3 points; and aldosterone to renin ratio ⩾1000 in a post-captopril challenge test (plasma renin activity in ng ml–1 h–1), 3 points. ROC curve analysis for the ability to discriminate between unilateral and bilateral PA showed that a score of 5 points had 75% sensitivity and 95% specificity, and a score of 3 points had a sensitivity of 97% and a specificity of 59%. The area under the ROC curve was 0.920 (95% confidence interval, 0.859–0.979). Our subtype prediction score could discriminate between unilateral and bilateral PA and is useful for selecting patients who should undergo AVS before surgery.

Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism

Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized.

Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism

The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature.

Prevalence of Cardiovascular Disease and Its Risk Factors in Primary AldosteronismNovelty and Significance: A Multicenter Study in Japan

There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K+ ⩽3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study

In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS).

Shortened saline infusion test for subtype prediction in primary aldosteronism

Primary aldosteronism (PA) is a common cause of endocrine hypertension [1, 2]. Since hyperaldosteronism induces various complications [3–5], early diagnosis and treatment is important in clinical practice. Aldosteroneproducing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are the major subtypes of PA [6]. Since APA is surgically curable and IHA is not subjected to adrenal surgery but to medical treatment, subtype classification is essential in selecting the type of treatment for PA. Several guidelines have been proposed for the clinical practice of PA [2, 7, 8]. Adrenal vein sampling (AVS) is considered as the reference test to distinguish between unilateral and bilateral hypersecretion of aldosterone. However, it is relatively invasive, costly, and scarcely available even in developed countries. Moreover, its true diagnostic value is unknown and has been called into question. More convenient means to make subtype diagnoses are awaited. Saline infusion test (SIT) is one of the most commonly used and inexpensive confirmatory tests. It was also demonstrated to be useful for predicting PA subtypes [9]. It can be of great help in abbreviating the diagnostic procedure if the confirmatory test is also useful for subtype diagnosis. However, there is still little evidence to support the significance of SIT for subtype classification. In addition, the test requires 2 l of saline loading over 4 h, which is a physical burden to patients and can cause potential adverse effects on cardiovascular function. Another adverse effect of the SIT is that it lowers serum potassium and is therefore dangerous for patients with uncorrected hypokalemia. Considering the limited availability of AVS compared to the high prevalence of PA, it would be helpful if we could gain additional information from routine clinical practice to select patients who should undergo AVS before surgery. The aim of the present study was to assess the value of the standard SIT and a shortened version thereof in predicting unilateral aldosterone hypersecretion in patients with PA.