Dr. Ron’s Research Review – July 29, 2020

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This week’s research review focuses on the boring story of boron and hypervitaminosis D.

Hypervitaminosis D

Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D).
Vitamin D toxicity and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally.
Many forms of exogenous (iatrogenic) and endogenous vitamin D toxicity exist.
Exogenous vitamin D toxicity is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of vitamin D toxicity due to vitamin D overdosing.
Endogenous vitamin D toxicity may develop from excessive production of an active vitamin D metabolite - 1,25(OH)|2|D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous vitamin D toxicity may also develop from an excessive production of 25(OH)D and 1,25(OH)|2|D in congenital disorders, such as Williams-Beuren syndrome.
Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism.
Researchers have proposed many processes to explain vitamin D toxicity. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. (Marcinowska-Suchowierska et al., 2018)

Vitamin D Metabolism

7-Dehydro-Cholesterol → Pre-D3 → D3 → 25OHD3 → 1,25OHD3 → calcitroic acid
cholecalciferol → calcidiol → calcitriol → calcitroic acid
Vitamin D 25-hydroxylase (cytochrome P450 2R1, CYP2R1) converts cholecalciferol (vitamin D3) into calcidiol (25OHD3).
1-alpha-hydroxylase (5-hydroxyvitamin D3 1-alpha-hydroxylase) converts calcidiol to calcitriol (1,25OHD3), the active form of vitamin D3.
Calcitriol 24-hydroxylase (CYP24A1) converts calcitriol into inactive 1,24,25-trihydroxyvitamin D, calcitroic acid.

Genetics

Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH)|2| D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B),
The case study describes very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)|2| D.
One index case presented with a partial improvement with 1alfa-hydroxyvitamin D|3| or alfacalcidol (1α-OH-D|3| ) treatment, and we observed a dramatic increase in the 1,25-(OH)|2| D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D|3| ), we documented normal 24-hydroxylase activity (CYP24A1). (Molin et al., 2017)

Boron

Nutritional boron can inhibit a range of microsomal enzymes that insert hydroxyl groups vicinal to existing hydroxyls in steroids, including the enzymes that catabolize estradiol and 25-hydroxyvitamin D. (Miljkovic et al., 2004)

Fructoborates

Sugar-borates (SBs) are mono- or di-sugar-borate esters (SBEs) comprised of one or two monosaccharide molecules linked to a boron (B) atom.
Sugar-borate esters occur naturally in commonly consumed herbs, vegetables, fruits, seeds, and nuts and, other than greatly varying levels of boron found in local drinking water, are the primary natural dietary sources of boron-containing molecules in humans.
To date, the most studied sugar-borate esters is calcium fructoborate (CaFB). (Hunter et al., 2019)

 

Dr. Ron

 


Articles

 

The Fructoborates: Part of a Family of Naturally Occurring Sugar-Borate Complexes-Biochemistry, Physiology, and Impact on Human Health: a Review.
            (Hunter et al., 2019)  Download
Sugar-borates (SBs) are mono- or di-sugar-borate esters (SBEs) comprised of one or two monosaccharide molecules linked to a boron (B) atom. SBEs occur naturally in commonly consumed herbs, vegetables, fruits, seeds, and nuts and, other than greatly varying levels of B found in local drinking water, are the primary natural dietary sources of B-containing molecules in humans. To date, the most studied SBE is calcium fructoborate (CaFB). CaFB represents an important example of how organic B-containing molecules are significantly distinct from their inorganic counterparts. During these past two decades, CaFB has been researched for its physical and biochemical characteristics, safety, and clinical outcomes. Results of these researches are presented and discussed herein. CaFB has been characterized using Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), high-performance thin-layer chromatography (HPTLC), nuclear magnetic resonance (NMR), liquid chromatography-multistage accurate mass spectrometry (LC-MSn), X-ray diffraction (XRD), Raman spectroscopy, and inductively coupled plasma (ICP) in non-biological and biological specimens. Potential health benefits of CaFB have been clinically investigated in pilot and efficacy studies demonstrating (i) significant reductions in knee discomfort and improved flexibility within 7, 14, and 90 days and (ii) significant effect on blood levels of inflammatory, cardiovascular, and other biomarkers. These studies support the use of CaFB as a dietary supplement for the management of joint discomfort. CaFB is presented here in order to illustrate how physiological benefits are imparted by distinct organic boron-containing molecules rather than solely by the element B itself. Considering recent National Health and Nutrition Examination Survey (NHANES) data reporting increases in age-related joint pain and an increasing elderly demographic, SBEs offer potential for safe, natural, and effective management of joint discomfort and improved mobility in human and animal health applications. Several of these studies may also open new opportunities for use of SBEs for health benefits beyond joint health.

Vitamin D Toxicity-A Clinical Perspective.
            (Marcinowska-Suchowierska et al., 2018)  Download
Confusion, apathy, recurrent vomiting, abdominal pain, polyuria, polydipsia, and dehydration are the most often noted clinical symptoms of vitamin D toxicity (VDT; also called vitamin D intoxication or hypervitaminosis D). VDT and its clinical manifestation, severe hypercalcemia, are related to excessive long-term intake of vitamin D, malfunctions of the vitamin D metabolic pathway, or the existence of coincident disease that produces the active vitamin D metabolite locally. Although VDT is rare, the health effects can be serious if it is not promptly identified. Many forms of exogenous (iatrogenic) and endogenous VDT exist. Exogenous VDT is usually caused by the inadvertent or improper intake of extremely high doses of pharmacological preparations of vitamin D and is associated with hypercalcemia. Serum 25-hydroxyvitamin D [25(OH)D] concentrations higher than 150 ng/ml (375 nmol/l) are the hallmark of VDT due to vitamin D overdosing. Endogenous VDT may develop from excessive production of an active vitamin D metabolite - 1,25(OH)|2|D in granulomatous disorders and in some lymphomas or from the reduced degradation of that metabolite in idiopathic infantile hypercalcemia. Endogenous VDT may also develop from an excessive production of 25(OH)D and 1,25(OH)|2|D in congenital disorders, such as Williams-Beuren syndrome. Laboratory testing during routine clinical examinations may reveal asymptomatic hypercalcemia caused by the intake of vitamin D even in doses recommended for the general population and considered safe. That phenomenon, called hypersensitivity to vitamin D, reflects dysregulated vitamin D metabolism. Researchers have proposed many processes to explain VDT. Those processes include elevated activity of 1α-hydroxylase or inhibited activity of 24-hydroxylase, both leading to increased concentration of 1,25(OH)D; increased number of vitamin D receptors; and saturation of the capacity of vitamin D binding protein. Increased public awareness of vitamin D-related health benefits might increase the risk of VDT due to self-administration of vitamin D in doses higher then recommended for age and body weight or even higher than the established upper limit intake values. Consequently, the incidence of hypercalcemia due to hypervitaminosis D might increase.

Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition
            (Molin et al., 2017) Download
Vitamin D requires a two-step activation by hydroxylation: The first step is catalyzed by hepatic 25-hydroxylase (CYP2R1, 11p15.2) and the second one is catalyzed by renal 1α-hydroxylase (CYP27B1, 12q13.1), which produces the active hormonal form of 1,25-(OH)|2| D. Mutations of CYP2R1 have been associated with vitamin D-dependent rickets type 1B (VDDR1B), a very rare condition that has only been reported to affect 4 families to date. We describe 7 patients from 2 unrelated families who presented with homozygous loss-of-function mutations of CYP2R1. Heterozygous mutations were present in their normal parents. We identified a new c.124_138delinsCGG (p.Gly42_Leu46delinsArg) variation and the previously published c.296T>C (p.Leu99Pro) mutation. Functional in vitro studies confirmed loss-of-function enzymatic activity in both cases. We discuss the difficulties in establishing the correct diagnosis and the specific biochemical pattern, namely, very low 25-OH-D suggestive of classical vitamin D deficiency, in the face of normal/high concentrations of 1,25-(OH)|2| D. Siblings exhibited the three stages of rickets based on biochemical and radiographic findings. Interestingly, adult patients were able to maintain normal mineral metabolism without vitamin D supplementation. One index case presented with a partial improvement with 1alfa-hydroxyvitamin D|3| or alfacalcidol (1α-OH-D|3| ) treatment, and we observed a dramatic increase in the 1,25-(OH)|2| D serum concentration, which indicated the role of accessory 25-hydroxylase enzymes. Lastly, in patients who received calcifediol (25-OH-D|3| ), we documented normal 24-hydroxylase activity (CYP24A1). For the first time, and according to the concept of personalized medicine, we demonstrate dramatic improvements in patients who were given 25-OH-D therapy (clinical symptoms, biochemical data, and bone densitometry). In conclusion, the current study further expands the CYP2R1 mutation spectrum. We note that VDDR1B could be easily mistaken for classical vitamin D deficiency. © 2017 American Society for Bone and Mineral Research.

 

References

Hunter, JM, et al. (2019), ‘The Fructoborates: Part of a Family of Naturally Occurring Sugar-Borate Complexes-Biochemistry, Physiology, and Impact on Human Health: a Review.’, Biol Trace Elem Res, 188 (1), 11-25. PubMed: 30343480
Marcinowska-Suchowierska, E, et al. (2018), ‘Vitamin D Toxicity-A Clinical Perspective.’, Front Endocrinol (Lausanne), 9 550. PubMed: 30294301
Miljkovic, D, N Miljkovic, and MF McCarty (2004), ‘Up-regulatory impact of boron on vitamin D function -- does it reflect inhibition of 24-hydroxylase’, Med Hypotheses, 63 (6), 1054-56. PubMed: 15504575
Molin, A, et al. (2017), ‘Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition’, J Bone Miner Res, 32 (9), 1893-99. PubMed: 28548312