16.2: Metabolism of vitamin D (18b.2)

Vitamin D can be obtained in two ways: from skin synthesis of vitamin D3 (cholecalciferol) and from ingestion of the parent compounds (D2 (ergocalciferol) or D3) from foods or supplements. This situation creates problems in assessing vitamin D status as dietary intake alone is not sufficient to gauge risk for deficiency. Sun exposure along with behavioural and environmental factors affecting skin synthesis must also be taken into account.

18b.2.1 Skin syn­thesis of vitamin D₃ (cholecalciferol)

The require­ment for vitamin D can be met by skin syn­thesis alone provided UVB can reach the skin. The syn­thesis of vitamin D₃ in the skin involves two stages: the photochem­ical transform­ation of 7-dehydrochol­esterol to pre­vit­amin D₃ by UVB, followed by thermal isomerization of the pre­vit­amin to vitamin D₃ (cholecalciferol). Variables influ­enc­ing the form­ation of pre­vit­amin D₃ in the skin include skin pig­ment­ation, the intensity of the solar ultra­violet light, and envi­ron­mental factors such as clouds, smog, clothing and sunscreen use (Grant et al., 2016; Wacker and Holick, 2013). Over-expo­sure to UVB will not lead to excess skin syn­thesis of vitamin D, as pre­vit­amin D as well as vitamin D₃ are irreversibly con­verted to inactive meta­bolites(Wacker and Holick, 2013). In the absence of UVB expo­sure, the require­ment for vitamin D must be met from diet­ary sources. Mostly, the require­ment is met partially or fully by diet, even in equa­torial regions because people may embrace an urban or sun-avoiding lifestyle.

18b.2.2 Vitamin D₂ (ergocalciferol)

Vitamin D₂ (ergo­cal­ciferol) cannot be made by animals. The only source is ingestion of certain foods in the fungi king­dom. It is import­ant to note the fungi king­dom is separate from the other eukaryotic life king­doms of plants and animals and texts may erroneously refer to vitamin D₂ as a “plant” source. Sun-exposed mush­rooms naturally provide vitamin D₂, while UV-exposed yeast and mush­rooms added to the food supply enhance the vitamin D con­tent of foods (Wacker and Holick, 2013).

The major meta­bolic steps involved in the meta­bolism of vitamin D₂ are similar to those for the meta­bolism of vitamin D₃ (cholecalciferol). The evi­dence about efficacy of vitamin D₂ versus vitamin D₃ suggests that although vitamin D₃ is the more active (Logan et al., 2013), vitamin D₂ is a reasonable alter­nat­ive (Wacker and Holick, 2013). Hence, in the following dis­cussion and in figure 18b.2, the term “vitamin ” refers to either or both vitamin D₂ and vitamin D₃ and their meta­bolites.

18b.2.3 Production of 25‑hydroxy­vitamin D

Vitamin D enters the circu­lation from the skin or from the lymph via the thoracic duct, bound to a specific vitamin D-binding pro­tein. Vitamin D is trans­ported to adipose tissue where it is stored, or to the liver, where it is hydrox­yl­ated to 25‑hydroxy­vitamin D (25(OH)₂D [also called cal­cidiol when referring to 25(OH)₂D₃], the major circulating form of vitamin D (Figure 18b.2).

Figure 18b.2 Formation of vitamin D metabolites. Once the transport form 25(OH)D is made, the Endocrine pathway (section 18b.2.4) for synthesis of the active metabolite 1,25(OH)₂D is illustrated. Parathyroid hormone (PTH) directs synthesis of 1,25(OH)₂D in response to a need for calcium or phosphate. Plasma 1,25(OH)₂D stimulates intestinal calcium transport and bone calcium mobilization, then blunts PTH synthesis to turn cycle off (section 18b.13). Adapted from Holick, Kidney International 32: 912–929, 1987.

The plasma 25(OH)₂D meta­bolite has sev­eral fates. When there is a need for calcium (des­cribed below) then 25(OH)₂D is con­verted in the kidney by an en­zyme (25(OH)₂D-1-α-hy­droxy­lase) to pro­duce the bio­logi­cally active meta­bolite 1,25‑dihydroxy­vita­min D [1,25(OH)₂D] also called calcitriol. Circulating 25(OH)₂D can also be taken up by tissues and subsequently con­verted to 1,25(OH)₂D inside cells if the 1-hy­droxy­lase en­zyme has been activated. Finally, in the pathway for inactivation and excretion of vitamin D in bile, 25(OH)₂D is converted to 24,25‑dihydroxy­vitamin D by the enzyme 25‑hydroxy­vitamin D-24-hydroxy­lase (Wacker and Holick, 2013). The enzyme 25‑hydroxy­vitamin D-24-hydroxylase also inactivates 1,25(OH)₂D (calcitriol).

18b.2.4 Renal production of circulating 1,25‑dihydroxy­vita­min D (calcitriol)

The active form of vitamin D, 1,25(OH)₂D (calcitriol) that circulates in plasma is made in the kidney in the Endocrine Pathway as shown in Figure 18b.2. This syn­thesis of 1,25(OH)₂D is homeo­statically con­trolled, mainly by the action of para­thyroid hor­mone (PTH) in res­ponse to serum calcium levels, and fibro­blast growth factor 23 (FGF-23) related to serum phos­phate levels (Wacker and Holick, 2013), that regulate the activ­ity of renal (25(OH)D-1-α-hy­droxy­lase). For exam­ple, a de­crease in plasma calcium prompts an inc­rease in para­thyroid hor­mone secretion from the para­thyroid gland that acts to mobilize calcium stores from the bone. Parathyroid hor­mone also promotes the syn­thesis of 1,25(OH)₂D in the kidney which, in turn, stimulates the mobilization of calcium from the bone and inc­reased in­test­inal calcium absorption (Figure 18b.2). Once plasma calcium levels are normal, the need for circulating 1,25(OH)₂D diminishes and there is no stimulation of the en­zyme 25(OH)D-1-α-hy­droxy­lase. Thus, circulating levels of 1,25(OH)₂D are not related to vitamin D status as in de­fi­ciency low levels of 1,25(OH)₂D may reflect lack of the precursor meta­bolite 25(OH)D. However, as vitamin D de­fi­ciency leads to sec­ond­ary hyper­para­thyroid­ism with PTH-enhanced 1,25(OH)₂D production, vitamin D deficiency can be assoc­iated with normal to high 1,25(OH)₂D (calcitriol) levels.

Another reason why the level of 1,25(OH)₂D is not useful in assess­ing vitamin D status is because 1,25(OH)₂D is a very short-lived meta­bolite causing its own destruc­tion by rapidly inducing synthesis of the enzyme 25‑hydroxy­vitamin D-24-hy­droxy­lase (Wacker and Holick, 2013).

18b.2.5 Extrarenal production of 1,25‑dihydroxy­vita­min D (calcitriol)

The extrarenal pathway of 1,25(OH)₂D (calcitriol) is locally pro­duced in almost every tissue in the body (Norman, 2008). As 1,25(OH)₂D acts locally, this syn­thesis pathway is called Paracrine / Autocrine. Activity of extra-renal 25(OH)D-1-α-hy­droxy­lase is not regul­ated by the hor­mones that con­trol renal 25(OH)D-1-α-hy­droxy­lase (i.e., PTH and FGF-23). The activity of the enzyme must be induced in the cell. The diverse actions of 1,25(OH)₂D, when acting locally as a trans­crip­tion factor in many differ­ent cell types, are called “non-calcemic” or “non-skel­etal” and include immuno-modulatory and cell-differ­entiating properties. It is these properties that have led re­searchers to inves­tigate vitamin D and its derivatives in the patho­gen­esis of cancer, respiratory dis­eases, and immune res­ponses. For further details of these noncalcemic func­tions see (Norman, 2008) and (Wacker and Holick, 2013).

18b.2.6 Serum 25(OH)D

Serum 25(OH)D is a biomarker of vitamin D exposure and status. Both meta­bolites 25(OH)D and 1,25(OH)₂D circulate in plasma. The former, 25(OH)D, reflects the sum of vitamin D from diet­ary intake and sunlight expo­sure, whereas plasma 1,25(OH)₂D con­cen­trations reflect the immediate physio­logical need and are under homeo­static con­trol in the kidney. Concentrations of 1,25(OH)₂D in plasma are about 0.1% of those of 25(OH)D. In vitamin D de­fi­ciency, serum 1,25(OH)₂D levels may be normal or even ele­vated, as a result of inc­reased renal production of 1,25(OH)₂D in res­ponse to the rise in serum para­thyroid levels (Wacker and Holick, 2013). In con­trast, plasma 25(OH)D con­cent­rations remain low until a reserve accumulates. As a result, the plasma 25(OH)D con­cent­ration reflects medium to long-term vitamin D availability from both diet­ary and endog­enous sources, thus making it the best biomarker of vitamin D exposure and status.