PRIMARY ALDOSTERONISM STUDIES ON SCREENING, OUTCOME OF ADRENALECTOMY AND FUNCTIONAL PATHOLOGY

This thesis comprises four studies with the general aim to improve the management of patients with primary aldosteronism (PA). PA is a hypertensive disorder due to autonomous secretion of aldosterone from one or both adrenal glands. PA exerts negative effects on the cardiovascular system beyond the negative effects of the elevated blood pressure, why it is important to detect PA among patients with hypertension and provide specific treatment. In PA, aldosterone is raised, leading to reduced renin levels. An elevated aldosterone to renin ratio (ARR) can be used as a screening tool to detect PA. The overall prevalence of PA is 5-15 % among patients with hypertension. In primary care, the frequency is lower, but displays a wide range and is therefore uncertain. In this thesis, the prevalence of PA was studied in a primary care setting by screening with the ARR among 178 patients with hypertension with continued antihypertensive medication. The prevalence was 1.6-3.3 %, why screening among the general hypertensive population would not be awarding. Antihypertensive medication, especially angiotensin-receptor blockers, ACE-inhibitors and thiazide diuretics were found to lower the ARR in patients with essential hypertension. Different cut-off levels for the ARR when screening with or without antihypertensive medication may be of value. Unilateral PA is usually due to an adrenal adenoma while bilateral PA most often is due to hyperplasia. Unilateral disease can be cured by adrenalectomy, while bilateral disease is treated pharmacologically. Some patients are not cured by adrenalectomy or recur at long-term followup, because they have bilateral PA, and will need specific medical treatment. At histopathology evaluation it is sometimes difficult to distinguish between adenoma and hyperplasia. Methods for functional pathology would serve in the postoperative evaluation. Functional pathology was used to detect the site of aldosterone and cortisol synthesis in adrenal glands from patients operated for PA. The results were related to clinical outcome and longterm follow-up. With situ hybridization mRNA, expressing enzymes for aldosterone and cortisol synthesis, was detected. With immunohistochemistry, specific antibodies against these enzymes were applied. Results from the two methods were never conflicting. Adenomas typically demonstrated evidence of aldosterone synthesis and sometimes also cortisol synthesis. In some adrenals, there were several nodules with demonstration of aldosterone synthesis, suggestive of hyperplasia. A consecutive series of 120 patients with PA were operated 1985-2010 due to unilateral aldosterone hypersecretion. Adrenalectomy led to cure of PA in 91 % with a median follow-up of 5 years. Also patients not cured benefitted from the operation, as their blood pressure improved. Functional pathology changed the diagnosis in 7 %. All adenoma patients were cured. Their preoperative 24 haldosterone values were higher compared to patients with hyperplasia. Among hyperplasia patients, 61 % were cured. Their preoperative aldosterone values were lower than in those not cured. It remains to be seen if they recur in the future. Conclusions: The low detection rate of PA among hypertensive patients in primary care does not favor general screening. With functional pathology, the site of aldosterone synthesis in adrenals from patients operated for PA was for the first time demonstrated in a clinical setting with a large series of patients. It is suggested that immunohistochemistry with specific antibodies be used in routine postoperative evaluation as an adjunct to routine histopathology. LIST OF PUBLICATIONS This thesis is based on the following original studies, referred to in the text by their Roman numerals: I. Volpe C, Wahrenberg H, Hamberger B, Thoren M. Screening for primary aldosteronism in a primary care unit. Journal of the Renin-AngiotensinAldosterone system 2013; 14(3):212-219. II. Enberg U, Volpe C, Hoog A, Wedell A, Farnebo LO, Thoren M, Hamberger B. Postoperative differentiation between unilateral adrenal adenoma and bilateral adrenal hyperplasia in primary aldosteronism by mRNA expression of the gene CYP11B2. Eur J Endocrinol. 2004 Jul; 151(1):73-85. III. Volpe C, Hoog A, Ogishima T, Mukai K, Lu M, Thoren M, Hamberger B. Immunohistochemistry improves histopathologic diagnosis in primary aldosteronism. J Clin Pathol 2013; 66:351-354. IV. Volpe C, Hamberger B, Hoog A, Mukai K, Calissendorff J, Wahrenberg H, Zedenius J, Thoren M. Primary aldosteronism; long-term follow-up after adrenalectomy and diagnostic value of immunohistochemistry. Manuscript.