The Effect of Vitamin D Treatment on Clinical and Biochemical Outcomes of Primary Aldosteronism

Noor Ashikin Ismail; Nor Azmi Kamaruddin; Shamsul Azhar Shah; Norlela Sukor


Clin Endocrinol. 2020;92(6):509-517. 

In This Article

Abstract and Introduction


Introduction: Primary aldosteronism (PA) contributed to the cardiovascular disease and metabolic alterations independent of the blood pressure level. Evidence exists that aldosterone excess also affects calcium and mineral homeostasis. PA subjects have been shown to have greater prevalence of vitamin D deficiency. However, the impact of vitamin D treatment in this population has never been assessed.

Objective: This study aimed to evaluate the effect of vitamin D treatment on clinical and biochemical outcomes of PA patients.

Methods: Two hundred forty hypertensive subjects were screened, 31 had positive ARR, and 17 patients with newly confirmed PA following positive confirmatory test that has not been subjected for definitive treatment were enrolled. Clinical parameter (blood pressure) and biochemical parameters (renal profile, plasma aldosterone concentration, plasma renin activity, serum calcium, vitamin D, intact parathyroid hormone, 24-hour urinary calcium) were measured at baseline and 3 months of treatment with Bio-D3 capsule. Primary outcomes were the changes in the blood pressure and biochemical parameters.

Results: About 70% of our PA subjects have low vitamin D levels at baseline. Three months following treatment, there were significant: (a) improvement in 25(OH)D levels; (b) reduction in systolic blood pressure and plasma aldosterone concentration; and (c) improvement in the eGFR. The vitamin D deficient subgroup has the greatest magnitude of the systolic blood pressure reduction following treatment.

Conclusions: This study demonstrated significant proportion of PA patients has vitamin D insufficiency. Vitamin D treatment improves these interrelated parameters possibly suggesting interplay between vitamin D, aldosterone, renal function and the blood pressure.


Primary aldosteronism (PA) is a condition caused by overproduction of aldosterone and is a major cause of secondary hypertension accounting for 5%-13% of all hypertensive subjects.[1] The main subtypes of PA are idiopathic aldosteronism (IHA) accounting 60% of patients which caused by bilateral adrenal hyperplasia (BAH) and unilateral aldosterone producing adenoma (APA) in approximately 30% of cases.[2] In the past, it had been documented that PA contributed to the development of cardiovascular disease and the metabolic alterations caused by inappropriate secretion of aldosterone. Long-term exposure to elevated aldosterone concentrations can result in cardiovascular and metabolic sequelae as well as lower quality of life that occur independent of the blood pressure level.[3–5]

A markedly increased rate of cardiovascular events in patients with primary hyperaldosteronism as compared to patients with essential hypertension was reported by Milliez et al with striking increase risk of stroke, myocardial infarction and atrial fibrillation. These deleterious effects on cardiometabolic profile appear to be involved with variable aldosterone-mediated mechanisms including activation of inflammatory cells and circulatory cytokines and activation of collagen synthesis on the vessels wall leading into intimal thickening.[6]

Apart from various harmful aldosterone effects on the heart and vessels, evidence exists that aldosterone may also impact the calcium and mineral homeostasis exceeding its classic effect on the water and electrolyte balance.[7–9]

Almost 30 years ago Resnick et al[10] had observed a remarkable lower serum calcium and marked elevation of parathyroid hormone (PTH) levels in patients with PA. Serum PTH was consistently elevated suggesting secondary hyperparathyroidism due to the calciuretic effect of aldosterone excess on the parathyroid gland. Elevated PTH, beyond its well known effects on the bone and calcium metabolism, is also considered as a cardiovascular risk factor.

In a cross-sectional and interventional data from the Graz Endocrine Causes of Hypertension (GECOH) study, PTH levels were significantly higher in PA patients compared to essential hypertension with no significant difference in the vitamin D level. The authors hypothesized that PA contributes to the secondary hyperparathyroidism independent of vitamin D level.[11] These findings were all echoed in other studies which showed a positive association between PTH levels with aldosterone excess which was not affected by vitamin D status.[12,13]

In a recent finding discovered by Petramala et al,[14] PA subjects have been shown to have greater prevalence of vitamin D insufficiency (65% versus 25%) as compared to essential hypertension. Higher prevalence of osteopenia and osteoporosis was also seen among PA patients. Additionally, patients with early PA may already exhibit increased bone turnover marker (CTX and P1NP) despite no significant changes in the bone mineral density.[15] These observations support that bone loss and potentially fracture risk in PA patients were potentially the result of aldosterone-mediated hypercalciuria and the consecutive secondary hyperparathyroidism in addition to low vitamin D levels.

Vitamin D insufficiency, as defined by 25-hydroxyvitamin D concentration less than 30 ng/mL, is a well known established risk factor for cardiovascular events and mortality. The physiological effects of vitamin D receptor (VDR) activation in experimental studies include the suppression of neurohumoral activation and improvements in endothelial and vascular function. A direct effect of vitamin D insufficiency on aldosterone secretion was proved by in vitro studies showing that treatment of cultured adrenocortical cells of hypertensive rats with calcitriol decreases aldosterone levels.[16] Previous studies also suggest that calcitriol, through the VDR, has a negative regulatory role on renin gene transcription, inducing cardioprotective effects.[17] Other authors report an activation of the renin-angiotensin-aldosterone system in vitamin D deficient patients. These studies confirm the interrelationship between renin, aldosterone, vitamin D, mineralocorticoid receptor (MR) and vitamin D receptor (VDR). Both MR and VDR belong to the same superfamily of nuclear receptors and a possible interaction between these receptors could be hypothesized. A relationship between vitamin D deficiency and aldosterone increase could be synergistic in the onset and progression of cardiovascular complications and of chronic kidney disease.[18,19]

In PA subjects, up-to-date, there are no studies done to evaluate the impact of vitamin D treatment on the aldosterone and blood pressure levels. One randomized clinical trial conducted by Grübler et al[20] in Styrian Vitamin D Hypertension trial demonstrated a significant difference in the plasma aldosterone concentration between placebo and the intervention arm receiving 2800IU of vitamin D3 for 8 weeks in 187 non–PA-related hypertension. However, no clinical parameters were assessed. On the basis of this statement, we embarked on this study to evaluate the effect of vitamin D treatment on the clinical and biochemical outcomes of PA patients.