Vitamin D and the Parenteral Nutrition Patient Hector F. DeLuca  Gastroenterology  Volume 137, Issue 5, Pages S79-S91 (November 2009) DOI: 10.1053/j.gastro.2009.07.075 Copyright © 2009 AGA Institute Terms and Conditions

Figure 1 The production of vitamin D in skin and its conversion through the liver to the major circulating form, 25-OH-D3, and its conversion to the final vitamin D hormone, 1,25-(OH)2D3, in the proximal convoluted tubule cells of the kidney. Gastroenterology 2009 137, S79-S91DOI: (10.1053/j.gastro.2009.07.075) Copyright © 2009 AGA Institute Terms and Conditions

Figure 2 Regulation of serum calcium by the calciotropic hormones, parathyroid hormone (PTH), and 1,25-(OH)2D3. Plasma calcium is kept constant at 10 mg% in normal animals and man. This level is required to prevent hypocalcemic tetany on the one hand and to ensure mineralization of newly formed collagen fibrils of bone. 1,25-(OH)2D3 accomplishes this by activating the enterocyte to transport calcium against electrochemical potential gradient in the small intestine to the plasma compartment. If calcium is not available from that source, continued stimulation of the parathyroid results in high levels of PTH and 1,25-(OH)2D3 causes mobilization of calcium. Both hormones are required in vivo for this result. Furthermore, the reabsorption of the final 1% of the filtered load of calcium in the kidney is under the influence of 1,25-(OH)2D3 and the PTH. Both are also required for this function. These elevated plasma calcium levels result in the mineralization of the skeleton and prevention of hypocalcemic tetany. Gastroenterology 2009 137, S79-S91DOI: (10.1053/j.gastro.2009.07.075) Copyright © 2009 AGA Institute Terms and Conditions

Figure 3 Diagrammatic representation of the regulation of serum calcium by 1,25-(OH)2D3. Plasma level of calcium is shown as a thermometer. Very slight movements of calcium in the low range activate a calcium-sensing protein in the parathyroids that cause immediate secretion of the PTH. PTH activates the 1α-hydroxylase in the proximal convoluted tubule cells that causes a synthesis 1,25-(OH)2D3. 1,25-(OH)2D3 then acts on the intestine, bone, and kidney as described in Figure 2 to raise plasma calcium. When calcium rises above the normal range, secretion of PTH is shut off. Higher than normal calcium levels also activate a calcium-sensing protein in the parafollicular cells of the thyroid, which secretes calcitonin. Calcitonin then blocks bone resorption, bringing calcium into the normal range. Calcitonin also activates small amounts of the 1α-hydroxylase to produce a sustaining amount of 1,25-(OH)2D3 for its functions other than in calcium homeostasis. 1,25-(OH)2D3 feedback regulates the biosynthesis of PTH and parathyroid proliferation. Gastroenterology 2009 137, S79-S91DOI: (10.1053/j.gastro.2009.07.075) Copyright © 2009 AGA Institute Terms and Conditions

Figure 4 The molecular mechanism whereby 1,25-(OH)2D3 is believed to regulate gene transcription. The VDR changes configuration on binding of 1,25-(OH)2D3, which then causes rejection of the co-repressor. The liganded VDR then binds to the vitamin D-responsive element (VDRE) usually in the promoter region of a target gene. There it forms a heterodimer with retinoid X receptor. This resulting complex then binds several proteins that in turn cause transacetylation of the histones of chromatin loosening the structure. This is followed by the leaving of those proteins and attachment of a new group of transcription factors that then either stimulate transcription or, in the case of parathyroid, inhibit transcription. Gastroenterology 2009 137, S79-S91DOI: (10.1053/j.gastro.2009.07.075) Copyright © 2009 AGA Institute Terms and Conditions

Figure 5 The mechanism whereby 1,25-(OH)2D3 and PTH cause bone resorption. These 2 hormones stimulate the secretion of RANKL which binds to a receptor encoded by nuclear factor RANK. This then facilitates the differentiation of the myelocytes to form precursor osteoclasts. These early osteoclasts are stimulated further to become active osteoclasts. Furthermore, RANKL also stimulates inactive osteoclasts to become active. This results in the resorption of bone and the return of bone calcium into the plasma compartment. (Courtesy of Dr Jackie A. Fretz [J.W. Pike Lab]). Gastroenterology 2009 137, S79-S91DOI: (10.1053/j.gastro.2009.07.075) Copyright © 2009 AGA Institute Terms and Conditions