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

Disclosures

Clin Endocrinol. 2020;92(6):509-517. 

In This Article

Discussion

Vitamin D status is well known to be inversely associated with blood pressure along with its classic role in calcium homeostasis and bone metabolism. It has also been shown to be inversely associated with metabolic syndrome and cardiovascular diseases. In many countries throughout all continents, low vitamin D exists in approximately 50% of the population.[23] Our study showed similarly high prevalence of low vitamin D levels among PA subjects. This finding is consistent with those reported in the western countries as confirmed by Petramala et al demonstrating 65% of PA subjects have low vitamin D levels. This relationship between low vitamin D and aldosterone excess could be synergistic with the onset and progression of cardiovascular complications and chronic kidney disease.

This study demonstrated significant reduction in the systolic blood pressure 3 months following vitamin D treatment. The effect was more pronounced in subjects with vitamin D deficient and insufficient as compared to PA subjects with normal vitamin D levels at baseline. Vitamin D deficient subgroup benefited the most with significant and greater magnitude in the systolic blood pressure reduction following treatment. This relationship can be explained at a cellular level where vitamin D exerts its antihypertensive effects through improved endothelial function. Improvement of the systolic blood pressure in this study is consistent with other previous study that showed significant decreased in the systolic blood pressure by 14 mm Hg and improvement in the flow-mediated vasodilatation of the brachial artery following increment of vitamin D level by 6.12 ng/mL in a vitamin D deficient subjects.[24] Additionally, further studies demonstrated that vitamin D acts as a direct transcriptional regulator of endothelial nitric oxide synthase.[25] Reduced expression of the endothelial nitric oxide synthase in turn leads to endothelial dysfunction, increased arterial stiffness and blood pressure levels.

Other mechanisms likely to involve in the protective effects of vitamin D in hypertensive subjects include anti-inflammatory and suppressive effect on the renin-angiotensin-aldosterone system.[26] Grubbler and collaborators have evaluated the effect of short-term vitamin D supplementation on the plasma aldosterone levels in non-PA hypertensive patients with vitamin D insufficiency, and it has been shown that vitamin D supplementation decreases plasma aldosterone levels.[20]

In this study, the vitamin D deficient group had the largest drop in blood pressure but the vitamin D insufficient and replete groups had the larger drop in aldosterone levels. It is important to highlight that this subgroup analysis is a post hoc analysis rather than the predefined study objective. The sample size calculation was based on its primary objective. As such the interpretation of these results should be taken in light of its inherent limitation. The inconsistencies observed between the results could possibly be due to smaller sample size as the sample size has never been powered to look at the effects between these subgroups. This incongruity also might suggest that the blood pressure reduction seen with vitamin D treatment is not solely due to its relationship with aldosterone levels but there might be other possible effects such as improvement in the endothelial function[24,27] or reduction in the cytokines or inflammatory cells[28] which has been shown to result in blood pressure reduction.

Up-to-date, this is the first study that demonstrates significant reduction in the plasma aldosterone concentration following vitamin D treatment in PA subjects. The reduction in aldosterone concentration is important as high plasma aldosterone concentration has been shown to be deleterious to the cardiovascular and kidney function independent of the blood pressure levels. PA itself, a condition with excessive autonomous aldosterone production has been shown to increase the risk of myocardial infarction, stroke and chronic kidney disease. Hence, the reduction in the aldosterone levels following vitamin D treatment hopefully will translate into an improvement in the hard end-points and this will require further studies.

PA is associated with constellation of diseases such as cardiovascular, renal, metabolic and more recently osteoporosis. In a 2004 animal study, rats given aldosterone and salt were found to have a reduction in bone mineral density (BMD) and cortical bone strength.[29] These findings led to several subsequent human studies, which found the association between PA and secondary hyperparathyroidism with subsequent low bone mineral density and a higher prevalence of vertebral osteoporotic fractures.[12–14] Previously, we have demonstrated that bone loss and potential fracture risk among PA patients are likely a result of aldosterone-mediated secondary hyperparathyroidism. PA-directed treatment leads to improvement in hyperparathyroidism, bone markers, as well as BMD.[15] Hence, it is essential to detect PA early in the course of the disease in order to prevent any possible complications related to this potentially curable condition.

Another important finding in this study includes the strong association between aldosterone levels and the eGFR. Aldosterone may contribute to renal impairment via direct and indirect effects. Direct effects are probably mediated through the mineralocorticoid receptor by causing tubulointerstitial inflammation and subsequent fibrosis.[30] Indirectly, higher circulating aldosterone predisposes a person to an increased risk of hypertension. High systolic blood pressure, in turn, results in an increased rate of renal function loss. Another deleterious effects of hyperaldosteronism on the kidney include functional changes (glomerular hyperfiltration) followed by structural changes that induce glomerular ischaemia and renal insufficiency.[31] Improvement in the eGFR from this study is strongly associated with reduction of aldosterone levels and improvement in the systolic blood pressure following an increased in the vitamin D levels. These findings may suggest an interrelationship between aldosterone, vitamin D, mineralocorticoid receptor (MR), and vitamin D receptor (VDR) as both MR and VDR belong to the same nuclear receptors and a possible interaction between these receptors could be hypothesized.

Normal level of PTH, serum calcium and 24-hour urinary calcium was observed despite majority of the subjects are vitamin D insufficient. These findings are in keeping with previous reports that suggest not all individuals who are vitamin D insufficient have an increased PTH levels.[32] Possible suggested explanation for normal PTH response to a low level of vitamin D includes the preservation and improvement of the glomerular filtration rate which acts as an important factor in maintaining the PTH levels.[33]

This study has its own limitations. Firstly, our study did not have a control or placebo group. Including essential hypertension as another control group would add another dimension to the study. Such an endeavour would highly be advocated for future studies. Secondly, there was no assessment on subjects dietary vitamin D intake. Thirdly, the small number of subjects in each vitamin D categories might have mask the actual impact of vitamin D treatment on the biochemical and clinical parameters assessed in these subgroups.

Despite the above limitations, this is the first-ever study performed assessing the impact of vitamin D treatment on the blood pressure and aldosterone levels in PA population. The results of this study shared some insights into the potential role of vitamin D in the pathophysiology of PA with regards to its clinical and biochemical effects.

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