The Functional Metabolism and Molecular Biology of Vitamin D Action

The evolution of our understanding of the biological impact of vitamin D is briefly reviewed, with a focus on the physiology and endocrinology of the vitamin D system. This chapter attempts to bring the molecular discoveries in vitamin D metabolism and mechanisms of action into focus on known physiology and endocrinology. The latest developments on metabolism of vitamin D, the enzymes involved, and the genes responsible are presented. The impact of the molecular discoveries on current views of the importance of vitamin D in public health is also presented.     

Vitamin D: metabolism

The biologically active metabolite of vitamin D, 1,25(OH)(2)D(3), affects mineral homeostasis and has numerous other diverse physiologic functions including effects on growth of cancer cells and protection against certain immune disorders. This article reviews the role of vitamin D hydroxylases in providing a tightly regulated supply of 1,25(OH)(2)D(3). The role of extrarenal 1α(OH)ase in placenta and macrophages is also discussed, as well as regulation of vitamin D hydroxylases in aging and chronic kidney disease. Understanding specific factors involved in regulating the hydroxylases may lead to the design of drugs that can selectively modulate the hydroxylases. The ability to alter levels of these enzymes would have therapeutic potential for the treatment of various diseases, including bone loss disorders and certain immune diseases.     

Vitamin D: extraskeletal health

Vitamin D deficiency is the most common nutritional deficiency and likely the most common medical condition in the world. There is a multitude of causes of vitamin D deficiency, but the major cause has been the lack of appreciation that the body requires 5- to 10-fold higher intakes than is currently recommended by the Institute of Medicine and other health agencies. It is likely that our hunter gatherer fore-fathers being exposed to sunlight on a daily basis were making several thousand IU of vitamin D a day. The fact that 100 IU of vitamin D prevented overt signs of rickets led to the false security that ingesting twice this amount was more than adequate to satisfy the body’s vitamin D requirement. Although this may be true for preventing overt skeletal deformities associated with rickets, there is now overwhelming and compelling scientific and epidemiologic data suggesting that the human body requires a blood level of 25(OH)D above 30 ng/mL for maximum health. The likely reason is that essentially every tissue and cell in the body has a VDR and thus, to have enough vitamin D to satisfy all of these cellular requirements, the blood level of 25(OH)D needs to be above 30 ng/mL. It has been estimated that for every 100 IU of vitamin D ingested that the blood level of 25(OH)D increases by 1 ng/mL. Thus to theoretically achieve a blood level above 30 ng/mL requires the ingestion of 3000 IU of vitamin D a day. There is evidence, however, that when the blood levels of 25(OH)D are less than 15 ng/mL, the body is able to more efficiently use vitamin D to raise the blood level to about 20 ng/mL. To raise the blood level of 25(OH)D above 20 ng/mL requires the ingestion of 100 IU of vitamin D for every 1-ng increase; therefore to increase the blood level to the minimum 30 ng/mL requires the ingestion of at least 1000 IU of vitamin D a day for adults. There is a great need to significantly increase the recommended adequate intakes of vitamin D. All neonates during the first year of life should take at least 400 IU/d of vitamin D, and increasing it to 1000 IU/d may provide additional health benefits. Children 1 year and older should take at least 400 IU/d of vitamin D as recently recommended by the American Academy of Pediatrics, but they should consider increasing intake up to 2000 IU/d derive maximum health benefits from vitamin D. Prepubertal and teenage girls who received 2000 IU of vitamin D per day for a year showed improvement in their musculoskeletal health with no untoward toxicity. All adults should be taking 2000 IU of vitamin D per day. A recent study reported that adults who took 50,000 IU of vitamin D once every 2 weeks, which is equivalent to taking 3000 IU of vitamin D a day, for up to 6 years was effective in maintaining blood levels of 25(OH)D of between 40 and 60 ng/mL without any toxicity. There is no downside to increasing either a child’s or adult’s vitamin D intake, with the exception of acquired disorders such as granulomatous diseases including sarcoidosis and tuberculosis, as well as some lymphomas with activated macrophages that produce 1,25(OH)2D3 in an unregulated fashion.     

Vitamin D

Vitamin D evolved for the development and maintenance of a healthy vertebrate skeleton. Vitamin D (1,25-dihydroxyvitamin D) maintains serum calcium and phosphorus levels in a physiologic range for skeleton mineralization. Vitamin D increases intestinal calcium absorption, stimulating osteoblast function and mobilizing osteoclast precursor cells to enhance bone calcium mobilization. Most vitamin D for the human requirement comes from exposure to sunlight. Sunscreen use, aging, and an increase in latitude or skin pigmentation dramatically reduce the cutaneous synthesis of vitamin D₃. Vitamin D deficiency has been linked to increased risk of many chronic diseases, including diabetes, cancer, hypertension, and heart disease. There is strong evidence that vitamin D plays a role in immunomodulation, cellular proliferative activity regulation, and renin production downregulation. Thus, vigilance to prevent vitamin D deficiency by the measurement of serum 25-hydroxyvitamin D is important for overall health and well-being. Although the recommended adequate intake for vitamin D is 200, 400, and 600 international units (IUs) for ages 0–50, 51–70, and 71+ yr, respectively, in the absence of exposure to adequate sunlight, the requirement is at least 1000 IUs of vitamin D. Responsible sun exposure will guarantee vitamin D sufficiency. Eating and drinking foods fortified with vitamin D, such as milk and orange juice, also provides some of the vitamin D requirement.     

Deranged Vitamin D Metabolism but Normal Bone Mineral Density in Finnish Noncirrhotic Male Alcoholics

To study the effect of prolonged ethanol consumption on calcium metabolism and on the prevalence of osteoporosis we examined 38 Finnish noncirrhotic male alcoholics (30-55 years of age) with dietary interviews and biochemical measurements and by measuring the bone mineral content of the forearm using single photon absorptiometry (SPA) and the bone mineral density of the spine, humerus and proximal femur using nonquantified computer tomography (CT) and dual-energy x-ray absorptiometry (DEXA). In comparison two groups of healthy controls were studied. The mean daily dietary intake of calcium was 1.3 g in the patients and 1.2 g in the controls. The dietary intake of vitamin D was equal in the study groups, too. The serum levels of calcium, phosphate and parathyroid hormone did not show any difference between the patients and controls but in the alcoholics the urinary excretion of calcium was reduced by 42% (p less than 0.0001) as compared to the controls. The serum levels of 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and 24,25-dihydroxyvitamin D3 were reduced in the alcoholics by 40% (p less than 0.0001), 23% (p less than 0.01), and 48% (p less than 0.0001), respectively, as compared to the controls. The alcoholic men had normal levels of serum testosterone and they did not have hypercortisolism. The bone mineral content of the dominant forearm measured by SPA was similar in the study groups as were the bone mineral densities (BMD) of the lumbar and humeral areas measured by CT. The BMD at the lumbar, femoral neck, Ward's triangle and trochanter sites measured by DEXA did not differ, either.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic Alcohol Treatment Results in Disturbed Vitamin D Metabolism and Skeletal Abnormalities in Rats

The effect of chronic alcohol consumption on the skeleton was investigated in rats. The treated group received ethanol administered as 38% of caloric intake in a liquid diet (Sustacal) for 10 months. The control rats were pair weighted to the ethanol-treated animals throughout the study; the growth curves of the two groups were the same. The controls were given the same liquid diet except that dextrin:maltose (3:1) was substituted isocalorically for ethanol. Ethanol-treated rats did not differ from the pair-weighted controls in mean serum calcium, phosphorous, or creatinine. In contrast, serum magnesium was reduced (p less than 0.02) in alcohol-treated rats. Ethanol treatment also resulted in changes in the serum concentrations of vitamin D metabolites; serum 25-hydroxyvitamin D3 was increased (p less than 0.001), while serum 1,25-dihydroxyvitamin D3 was decreased (p less than 0.01). Tibial length was reduced in ethanol-treated rats (p less than 0.05) but there was no change in femoral length. Medullary area was increased in tibial diaphyses from alcohol-treated rats compared to weight matched control animals (p less than 0.01), indicating a net increase in resorption. The cross-sectional area of the tibial diaphysis of ethanol-treated rats was the same as the matched controls. Trabecular bone was decreased in the tibial metaphysis of ethanol-treated rats compared to the matched controls (p less than 0.05) indicating a net loss of trabecular bone. Ethanol treatment did not have an effect on the organic weight of the femur but the ash weight was reduced (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

维生素D水平与糖代谢调节状态关系研究

目的探讨维生素D水平与糖代谢调节状态的相关性。方法选取2018年1—12月在该院初诊为2型糖尿病患者98例(A组),同期门诊查体空腹血糖受损/糖耐量受损者40例(B组)以及正常人群40名(C组)作为研究对象。比较3组人口学和临床指标差异,分析血清25-(OH)D与人口学、临床指标以及糖代谢调节状态评价指标胰岛B细胞功能指数(Homa-B)、胰岛素分泌指数(IAI)、胰岛素敏感性指数(IS)和胰岛素抵抗指数(Homa-IR)的相关性。结果3组在BMI、HDL、肌酐、空腹血糖、空腹胰岛素和糖化血红蛋白上差异有统计学意义(P<0.05),A组的BMI、HDL、空腹血糖和糖化血红蛋白较B、C组高,肌酐、血清25-(OH)D和空腹胰岛素较B、C组低;血清25-(OH)D与BMI、总胆固醇、甘油三酯、HDL、空腹血糖和糖化血红蛋白均具有负相关(P<0.05);血清25-(OH)D与Homa-B、IAI和IS具有正相关(P<0.05)。结论糖尿病患者的维生素D水平较空腹血糖受损/糖耐量受损和正常人群低,缺乏维生素D可影响胰岛B细胞的功能和敏感性,应适当补充维生素D。     

Vitamin D recommendations: beyond deficiency

Vitamin D plays an important role in regular bone growth and in adequate function of the innate immune system, including barrier functions of mucous membranes. A sufficient supply during pregnancy and lactation protects the child from infectious diseases. Clinical symptoms of severe vitamin D deficiency (rickets) are well known and can be easily detected. Signs and symptoms beyond deficiency, however, remain to be elucidated. Based on clinical and observational data, the plasma level of 25(OH)D may serve as a 'marker' to detect or define a subclinical deficiency. Levels below 50 nmol/l might be insufficient to maintain the non-bone-related activities of vitamin D. Finally, it has to be considered that all of the nonbone activities of vitamin D are in concert with vitamin A (9-cis retinoic acid). Studies combining both vitamins in sufficient amounts (cod liver oil) demonstrated a beneficial effect on the prevention of respiratory tract infections. Consequently, it should be strongly recommended to increase the intake of vitamin D and to ensure a daily intake of vitamin A as counseled.     

Vitamin B12 Metabolism in Myelomatosis

In 38 patients with myelomatosis the serum cobalamin varied from 34 pmol/l to 404 pmol/l, median 181.5 pmol/l, which is significantly lower than the levels in 22 control persons with range 173–535 pmol/l, median 265 pmol/l. In spite of low serum cobalamin no symptoms of vitamin B₁₂ deficiency could be demonstrated in any of the patients, except for the one patient who had a serum cobalamin of 34 pmol/l. Mean values for Hb, MCV, PCV, serum lactate-dehydrogenase, adjusted red cell folate and nucleated neutrophil count were similar in a group of patients with a serum cobalamin below 160 pmol/l and a group of patients with higher serum cobalamin values. The decrease in serum cobalamin is due in part to a reduction in the major cobalamin binder (TC-I) in serum. Measuring serum cobalamin in relationship to gastric acid secretion, we found a significantly higher frequency of hypo- and achlorhydria in patients with serum cobalamin below 160 pmol/l although the intestinal absorption of vitamin B₁₂ was normal by a Schilling test. Although our finding of low saturation of TC-I in serum seems to demonstrate decreased vitamin B₁₂ content in the body in myelomatosis, the lack of evidence for a functional vitamin B₁₂ deficiency speaks against giving a supplement to patients with myelomatosis.     

Vitamin D analogs

Vitamin D has gone through a renaissance with the association of vitamin D deficiency with a wide array of common diseases including breast, colorectal and prostate cancers, cardio-vascular disease, autoimmune conditions and infections. Vitamin D analogs constitute a valuable group of compounds which can be used to regulate gene expression in functions as varied as calcium and phosphate homeostasis, as well as cell growth regulation and cell differentiation of a wide spectrum of cell types. This review will discuss the full range of vitamin D compounds currently available, some of their possible uses, and potential mechanisms of action.