Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis

Abstract

BackgroundVitamin D deficiency, determined by blood levels of 25-hydroxyvitamin D [25(OH) D, i.e. the major vitamin D form in blood], has been shown to associate with all-cause mortalities. We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)2D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)2D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)2D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)2D deficiency, disorders leading to the 1,25(OH)2D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)2D deficiency.MethodsWe studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1α-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)2D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function.ResultsWe demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)2D deficiency could not be overcome by increased production of PTH which stimulates 1α-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)2D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver.ConclusionsBecause FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1α-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)2D deficiency and for the improvement of survival among sepsis patients.

The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19

“…Additionally, we recently demonstrated that serum levels of 1,25(OH) 2 D 3 were significantly lower in non-survivors compared to survivors among sepsis patients, and that complex mechanisms underlie low 1,25(OH) 2 D 3 in critically ill patients [27].…”

“…Vitamin D sufficiency is widely defined as a serum 25-hydroxyvitamin D (25(OH)D) level greater than or equal to 30 ng/ ml (75 nmol/L), while insufficiency is defined as 20 to 30 ng/ml (50-75 nmol/L), and deficiency is a level lower than 20 ng/ml (50 nmol/L) [25]. A low level of vitamin D is common in the elderly and has been associated with all-cause mortality including sepsis, and that supplementation of vitamin D could significantly reduce overall mortality [26,27]. Besides geographic and climate factors, vitamin D deficiency is also more prevalent among individuals with darker skin than those with a lighter skin color due to the fact that heavy pigmentation reduces vitamin D production in the skin [28].…”

The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury

“…To treat LPS-induced ALI, we elected to utilize the following two therapeutic agents: insulin-like growth factor-I (IGF-I) and the store-operated calcium channel inhibitor (BTP-2). IGF-I therapy was selected, because we observed a reduction in the serum IGF-I in our past sepsis studies [ 9 ]. Previously, we found that the decrease in serum IGF-I during sepsis was associated with the depression of growth hormone receptor (GHR) expression in the liver and increased circulating inflammatory cytokines [ 9 ].…”

“…IGF-I therapy was selected, because we observed a reduction in the serum IGF-I in our past sepsis studies [ 9 ]. Previously, we found that the decrease in serum IGF-I during sepsis was associated with the depression of growth hormone receptor (GHR) expression in the liver and increased circulating inflammatory cytokines [ 9 ]. Since inflammatory cytokines were known to suppress GHR expression in the liver, which was the primary source of circulating IGF-I, we reasoned that the suppressed liver GHR expression accounted for the low-serum IGF-I under systemic inflammatory conditions.…”

Is the vitamin D status of patients with COVID-19 associated with reduced mortality?

“…Therefore, a possible hypothesis that could explain our findings would be that tissue damage in the kidneys and to a lesser extent in the lung caused by SARS-CoV2 may lead to an active decrease of 1,25(OH)D, responsible for the majority of biological actions of Vitamin D, but not in the form usually determined in plasma, Calcifediol. Previous studies showed that blood 25(OH)D levels may not correlate with blood 1,25(OH) 2 D levels in some clinical conditions [63–65].…”