Vitamin D Metabolism

Abnormalities of vitamin D metabolism play a major role in the development of the secondary hyperparathyroidism characteristic of chronic kidney disease (as a result of impaired production of calcitriol from the diseased kidney as renal mass decreases [42]).

From: Dynamics of Bone and Cartilage Metabolism (Second Edition) , 2006

INTRODUCTION

RONALD L. HORST , ... G. SATYANARAYANA REDDY , in Vitamin D (Second Edition), 2005

IV. SPECIES VARIATION IN VITAMIN D METABOLISM AND ACTION

Most concepts of vitamin D metabolism and function have been developed with the rat and/or chick as experimental models. Studying vitamin D metabolism is hampered by the paucity of data on the normal circulating levels of vitamin D metabolites in birds, mammals, and reptiles under normal conditions. Most recent research has focused on the analysis of 25OHD and 1,25(OH) 2D as indicators of vitamin D status or aberrant physiological states. Table I summarizes the concentrations of the two metabolites that have been reported for several species by various laboratories. Close inspection of the information suggests that some mammals (mole rat, wild wood vole, horse, and wild wood mouse) and aquatic species (lamprey, carp, halibut, and bullfrog) appear to have very low or undetectable concentrations of 25OHD, and yet these animals appeared to be normal with no evidence of vitamin D deficiency. It is questionable whether some of these species have a requirement for vitamin D. The damara mole rat, for example, is a subterranean herbivore that in its natural habitat has no access to any obvious source of vitamin D and consumes a diet of roots and tubers [213]. These animals exhibit a high apparent calcium absorption efficiency (91%) and, like the horse and rabbit, actually use renal calcium excretion as the major regulator of calcium homeostasis [214, 215]. In studies with rabbits consuming adequate amounts of calcium, it is very difficult to develop any overt or histological signs of vitamin D deficiency, and vitamin D may play a minor, if any, role in normal day-to-day functions in these animals [216].

TABLE I. Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations in Several Species of Animals

Concentration
Species 25OHD (ng/ml) 1,25(OH)2D (pg/ml) Ref.
Human 32 31 [162]
Rhesus monkey 188 207 [231]
Rhesus monkey 50 95 [232]
Marmoset 90 400 [232]
Marmoset 64 640 [233]
Wild woodmouse <5 <10 [234]
Wild bank vole <5 <5 [234]
Mole rat <2 17 [213]
Lamprey ND a 274 [235]
Shark ND 87 [235]
Leopard shark 56 3 [236]
Horned shark 33 6 [236]
Carp ND 174 [235]
Bastard halibut ND 192 [235]
Atlantic cod <2 59 [237]
Bullfrog (mature) 2 21 [235]
Soft-shelled turtle 16 12 [235]
Turkey 26 52 [141]
Chicken 27 21 [141]
Cow 43 38 [141]
Sheep 27 36 [141]
Pig 76 60 [141]
Horse 6 19 [238]
a
ND, Not done.

In the wild, most animals do not have a dietary need for vitamin D, as sufficient vitamin D3 can be synthesized in the skin on irradiation by sunlight. However, indoor confinement of humans and other animals has resulted in the diet becoming the main source of vitamin D, leading to considerable research to determine the amount of dietary vitamin D required to substitute for lack of exposure to sunlight. Photochemically produced vitamin D3 enters the circulation and becomes immediately available, whereas dietary vitamin D3 may undergo modifications prior to becoming available for use by the body. One species where significant modification of vitamin D occurs before absorption is the ruminant. Within 24 hr, as much as 80% of vitamin D can undergo metabolism in vitro in rumen incubation media [217]. At least four metabolites are produced by the rumen microbes [217, 218]. Two of these metabolites have been identified as the cis (5Z) and trans (5E) isomers of 10-keto-19-norvitamin D3 (Fig. 2) [207]. The trans isomer has also been identified in cow plasma (R. L. Horst, unpublished data, 1983). Neither compound has agonistic activity with regard to promoting bone calcium resorption [219] or intestinal calcium absorption [207]. Rather, this novel metabolism is likely a detoxification process, as evidenced by the ability of ruminants to tolerate large oral doses of vitamin D3 that would be toxic if given parenterally. The presence of the rumen, therefore, represents a major control point in vitamin D metabolism that may differ from monogastrics. Such a control point may have survival value, because the ruminant evolved as a grazing animal with the opportunity for long periods of sunlight exposure, as well as consumption of large quantities of irradiated plants. If left uncontrolled, such a combination might result in vitamin D toxicity.

Shortly after the discovery of vitamin D, it seemed apparent that vitamins D2 and D3 had similar biological activities in most mammals and that birds and New World monkeys discriminated against vitamin D2 in favor of vitamin D3 [220, 221]. More recent research, fostered by the discovery of sensitive analytical techniques and the availability of high specific activity 3H-labeled vitamin D species, indicated that differences in the metabolism of vitamins D2 and D3 in mammals are perhaps widespread. Most notable were the apparent discrimination against vitamin D2 by pigs [222], cows [218], and humans [223] and the apparent preference for vitamin D2 by rats [222, 224].

Vitamin D and its metabolites are transported in the blood of vertebrates attached to a specific protein commonly known as the vitamin D binding protein or DBP [225]. Baird et al. [226] have shown that protein binding increases the solubility of steroids and that the metabolic clearance rate of steroids is in part dependent on their binding to specific plasma proteins. Affinity of metabolites to the plasma transport proteins may, therefore, provide a means for determining which species would utilize vitamin D2 poorly. For example, if the binding protein showed lower affinity toward 25OHD2 relative to 25OHD3, then one would predict that 25OHD2 would be removed from the circulation faster than 25OHD3. This is indeed the case for the chick. Hoy et al. [227] showed that chick discrimination against vitamin D2 was probably a result of enhanced clearance of the vitamin D2 metabolites 25OHD2 and 1,25(OH)2D2, and that the enhanced clearance was associated with weaker binding of these vitamin D2 metabolites (relative to the vitamin D3 forms) to DBP.

In one of the most comprehensive studies reported to date, Hay and Watson [228] studied the affinities of DBP for 25OHD2 and 25OHD3 in 63 vertebrate species. They found that the DBP in fish, reptiles, and birds discriminated against 25OHD2 in favor of 25OHD3, which is consistent (at least in birds) with the discrimination against vitamin D2. One notable exception to this hypothesis, however, is the New World monkey. Hay and Watson [228] found that in New World monkeys, the plasma transport protein has equal affinity for 25OHD2 and 25OHD3, which is inconsistent with the well-documented discrimination against vitamin D2. Factors other than affinity of the binding protein for 25OHD are, therefore, important in determining how efficiently the different forms of vitamin D can be utilized by animals.

Another example of species discrimination against the different vitamin D forms is in the rat. However, in this species, discrimination is against vitamin D3 in favor of vitamin D2 [222]. The rat DBP is known to have equal affinity for 25OHD2 and 25OHD3, but a lower affinity for vitamin D2 relative to vitamin D3 [229]. Reddy et al. [230] suggested that the lower affinity for vitamin D2 resulted in its enhanced availability for liver 25-hydroxylation. Hence, in the presence of DBP, more 25OHD2 was made relative to 25OHD3 when equal amounts of vitamin D2 or vitamin D3 substrate were perfused into rat livers. This observation is consistent with the higher circulating concentrations of 25OHD2 observed in acute experiments with vitamin D–deficient rats dosed with equal amounts of vitamins D2 and D3 [222]. In the experiments conducted by Reddy et al. [230], if binding protein was eliminated from the perfusion media, equal amounts of 25OHD2 and 25OHD3 were synthesized. Collectively, these data suggest that discrimination against the different forms of vitamin D could likely result from variations in the affinity of DBP for the parent compound and/or one or more of their metabolites. Regardless of the mechanism for discrimination, it appears that these differences are present to afford animals the most efficient utilization of the most abundant antirachitic agents available in their environment.

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Molecular basis of bone diseases

Emanuela Galliera , Massimiliano M. Corsi Romanelli , in Essential Concepts in Molecular Pathology (Second Edition), 2020

Vitamin D metabolism

Vitamin D metabolism is illustrated in Fig. 28.2. The major sources of vitamin D are synthesis in the skin under the influence of UV, and a small portion is derived from the diet. Calcitrol binds specific vitamin D receptors (VDR) at the target organ, activating transcription factors that regulate calcium metabolism and bone metabolism. VDRs are expressed by all three major bone cell types: osteoclasts, osteoblasts, and osteocytes. VDRs are essential regulators of vitamin D metabolism. Hence, defects in the VDR gene results in hereditary vitamin D-resistant rickets, characterized by an impairment of a bone matrix mineralization. In addition to the catabolic effect of vitamin D in bone, VDRs mediate anabolic function in osteoblasts. The overexpression of VDR in mature osteoblast cell lines result in increased mineral formation and decreased bone resorption.

Figure 28.2. Vitamin D metabolism. In the skin, 7-dehydrocholesterol is converted into pre-vitamin D3 by UV light and then modified into vitamin D3 (cholecalciferol). The dietary source of vitamin D is in the form of ergocalciferol (vitamin D2). Vitamin D2 and D3 are prohormones transported into the blood by means of specific binding proteins and are hydroxylated in the liver into 25-hydroxyvitamin D (calcidiol). Calciferol is further hydroxylated in the renal tubule into 1,25 dihydroxyvitamin D (calcitrol), which is the active form of the hormone. The production of calcitrol is stimulated by increased levels of parathyroid hormone (PTH) and decreased level of phosphate (PO4).

Vitamin D deficiencies lead to impaired mineralization of bone mass and present with disease in the form of rickets during growth and osteomalacia in the adult age. Beyond insufficient dietary vitamin D intake, vitamin D-deficiency results from malabsorption in gastrointestinal, pancreatic, and hepatobiliary diseases. In addition, some drugs and toxins, such as anticonvulsants and bisphosphonates, can impair vitamin D metabolism.

Several genetic disorders cause heritable forms of rickets and osteomalacia. X-linked hypophosphatemia, also called vitamin D-resistant rickets, is the most common form of hereditary rickets and osteomalacia resulting from inactivating mutations of the PHEX genes that encode endopeptidases. Autosomal dominant hypophosphatemic rickets is a rare form of renal phosphate loss caused by a gain-of-function mutation of the gene encoding FGF23 (fibroblast growth factor 23), which has recently described as a marker of fracture risk. Autosomal recessive hypophosphatemic rickets is a rare form caused by mutation is the DMP1, ENPP1, and FAM20C genes, encoding for different proteins involved in vitamin D metabolism. Additional forms of hereditary rickets or osteomalacia are vitamin D-dependent rickets type I and II, characterized by reduced vitamin D biosynthesis, and hypophophatasia which is rare and due to deficient activity of tissue nonspecific enzyme alkaline phosphatase.

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Molecular Basis of Bone Diseases

Emanuela Galliera PhD , Massimiliano M. Corsi Romanelli MD, PhD , in Molecular Pathology (Second Edition), 2018

Vitamin D Metabolism

Vitamin D metabolism is illustrated in Fig. 28.2. The major sources of vitamin D are synthesis in the skin under the influence of UV, and a small portion is derived from the diet. In the skin, 7-dehydrocholesterol is converted into previtamin D3 by UV light and then modified into vitamin D3 (cholecalciferol). The dietary source of vitamin D is in the form of ergocalciferol (vitamin D2). Vitamins D2 and D3 are prohormones transported into the blood by means of specific binding proteins, followed by hydroxylation in the liver to produce 25-hydroxyvitamin D (calcidiol). Calciferol is further hydroxylated in the renal tubule into 1,25 dihydroxyvitami D (calcitrol), which is the active form of the hormone. Increased levels of PTH and decreased level of phosphate (PO4) stimulate the production of calcitrol.

Figure 28.2. Vitamin D metabolism.

In the skin, 7-dehydrocholesterol is converted into pre-vitamin D3 by UV light and then modified into vitamin D3 (cholecalciferol). The dietary source of vitamin D is in the form of ergocalciferol (vitamin D2). Vitamin D2 and D3 are prohormones transported into the blood by means of specific binding proteins and are hydroxylated in the liver into 25-hydroxyvitamin D (calcidiol). Calciferol is further hydroxylated in the renal tubule into 1,25 dihydroxyvitamin D (calcitrol), which is the active form of the hormone. The production of calcitrol is stimulated by increased levels of parathyroid hormone (PTH) and decreased level of phosphate (PO4).

Calcitrol binds specific vitamin D receptors (VDR) at the target organ, activating transcription factors that regulate calcium metabolism and bone metabolism. VDRs are expressed by all three major bone cell types: osteoclasts, osteoblasts, and osteocytes. VDRs are essential regulators of vitamin D metabolism. Hence, defects in the VDR gene results in hereditary vitamin D-resistant rickets, characterized by an impairment of a bone matrix mineralization [93]. VDR influences RANKL production by osteoblasts. A recently developed mouse knockout model was developed. In this model, osteoblast-specific RANKL expression is deregulated providing mechanistic insights into the essential role of VDR in the regulation of osteoclastogenesis [94]. In addition to the catabolic effect of vitamin D in bone, VDRs mediate anabolic function in osteoblasts. The overexpression of VDR in mature osteoblast cell lines result in increased mineral formation and decreased bone resorption [95].

Vitamin D deficiencies lead to impaired mineralization of bone mass and presenting with disease in the form of rickets during growth and osteomalacia in the adult age [96]. Beyond insufficient dietary vitamin D intake, vitamin D-deficiency results from malabsorption in gastrointestinal, pancreatic, and hepatobiliary diseases. In addition, some drugs and toxins, such as anticonvulsants and bisphosphonates, can impair vitamin D metabolism [97].

Several genetic disorders cause heritable forms of rickets and osteomalacia. X-linked hypophosphatemia, also called vitamin D-resistant rickets, is the most common form of hereditary rickets and osteomalacia resulting from inactivating mutations of the PHEX genes that encode endopeptidases [98]. Autosomal dominant hypophosphatemic rickets is a rare form of renal phosphate loss caused by a gain-of-function mutation of the gene encoding FGF23 (fibroblast growth factor 23), which has recently described as a marker of fracture risk [99]. Autosomal recessive hypophosphatemic rickets is a rare form caused by mutation is the DMP1, ENPP1, and FAM20C genes, encoding for different proteins involved in vitamin D metabolism. Additional forms of hereditary rickets or osteomalacia are vitamin D-dependent rickets type I and II, characterized by reduced vitamin D biosynthesis (hypophophatasia) due to deficient activity of tissue nonspecific enzyme alkaline phosphatase.

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Clinical Assessment and Management of Chronic Kidney Disease Across Its Stages

Ashte' K. Collins , ... Paul L. Kimmel , in Chronic Renal Disease (Second Edition), 2020

Vitamin D

Vitamin D metabolism becomes impaired in CKD, primarily due to decreased conversion of 25-hydroxyvitamin D 3 to 1,25-dihydroxyvitamin D3 by the kidneys. 100,101 It has been proposed that vitamin D supplementation can inhibit the RAAS and attenuate podocyte injury, and vitamin D supplementation has been associated with reduction in proteinuria. 102 De Zeeuw and colleagues showed in the VITAL study that high-dose paracalcitol supplementation was associated with a significant decline in proteinuria in patients with type 2 diabetes with CKD compared to placebo, but there was no significant slowing of CKD progression. 103 As more information is developed regarding circulating fibroblast growth factor-23 (FGF-23) and phosphate levels, and their interrelationships with CKD progression and mortality, the role of vitamin D supplementation in preserving residual renal function will become clearer. 104

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Vitamin D and Multiple Sclerosis

Colleen E. Hayes , Faye E. Nashold , in Vitamin D (Fourth Edition), 2018

Enzymes of Vitamin D Activation

Vitamin D metabolism has been well described previously [71,87–90], and the action of key enzymes is detailed in Chapter 5 (vol. 1 of this book) and Chapter 6 (vol. 1 of this book). Two hydroxylation reactions convert biologically inactive vitamin D3 into the biologically active hormone, 1,25(OH)2D3. The CYP2R1-encoded vitamin D-25-hydroxylase produces 25-OHD3 from vitamin D3, and the CYP27B1-encoded 25-hydroxyvitaminD-1α-hydroxylase converts 25-OHD3 into 1,25(OH)2D3. There is an important feedback inhibition loop to limit excessive exposure to 1,25(OH)2D3 in hormone-responsive tissues. The 1,25(OH)2D3 induces transcription of the CYP24A1 gene encoding the 24-hydroxylase enzyme that degrades the hormone into biologically inactive calcitroic acid. The hydroxylases are cytochrome P450 enzymes encoded in nuclear DNA but resident in the mitochondrial membrane [87,88].

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Vitamin D Disorders in Chronic Kidney Disease

Michelle Denburg MD, MS , Ian de Boer MD, MS , in Chronic Kidney Disease, Dialysis, and Transplantation (Fourth Edition), 2019

Disturbances in Chronic Kidney Disease

Vitamin D metabolism is profoundly disordered in CKD. Abnormalities begin during early CKD stages (i.e., before stage 3) and progress as renal function declines. 55,56 The central feature of this process is a decline in circulating calcitriol, which occurs early and is due to diminished 1-α hydroxylase substrate, mass, and activity (Fig. 11.4, Box 11.1). 56-58 25(OH)D and calcitriol concentrations are directly correlated in CKD, in contrast to persons with normal kidney function, suggesting that calcitriol synthesis may be more substrate-dependent in the setting of CKD. 59-62 Still, diminished 1-α hydroxylase activity is probably the most important cause of declining calcitriol levels in CKD. Hyperphosphatemia, hyperuricemia, metabolic acidosis, and diabetes are associated with decreased 1-α hydroxylase activity. 35,56,58,63,64 Elevated levels of FGF-23, which act to maintain serum phosphorous concentration as GFR falls, potently suppress 1-α hydroxylase activity. 36,37 This is part of a negative feedback loop, whereby calcitriol stimulates FGF-23 release from osteocytes and osteoblasts, and FGF-23 downregulates further calcitriol production. Hyperparathyroidism secondary to calcitriol deficiency is a common complication of CKD (see Fig. 11.4, see Chapter 8). 65

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Osteoporosis Associated with Illnesses and Medications

HYESOO LOWE , ELIZABETH SHANE , in Osteoporosis (Third Edition), 2008

6. VITAMIN D

Vitamin D metabolism may play a role in the pathogenesis of diabetes, particularly in the regulation of insulin secretion. Calcitriol receptors have been found on pancreatic islet cells, and vitamin D deficiency appears to be associated with impaired insulin secretion [ 82]. Epidemiologic studies also suggest a link between vitamin D deficiency and diabetes. Several large population-based studies revealed a decreased risk of developing T1DM in patients who had received vitamin D supplementation in early childhood [83, 84]. A study of 88 patients reported significantly lower serum concentrations of 25(OH)vitamin D and 1,25(OH)2 vitamin D in newly diagnosed type 1 diabetics as compared with healthy controls [85]. Regarding T2DM, epidemiologic data suggest an association between T2DM or metabolic syndrome with calcium intake, but no clear association with intake of vitamin D alone [86, 87]. However, in a study of 753 healthy postmenopausal women, low vitamin D levels have been correlated with increased serum fasting glucose concentrations, possibly mediated by insulin resistance [88, 89]. A prospective study of 142 elderly Dutch men found an inverse association between serum 25(OH)vitamin D and glucose concentrations following oral glucose tolerance testing [90]. Another study using hyperglycemic clamps on 126 nondiabetic adults showed that 25(OH)vitamin D levels are associated with insulin sensitivity, but not with first or second phase insulin secretion [91]. This is an area that warrants further investigation.

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Management of Bone Disease in Candidates for Organ Transplant

Susan M. Ott MD , in Bone Disease of Organ Transplantation, 2005

E Vitamin D and PTH

Vitamin D metabolism is usually normal in mild to moderate liver failure, but in end-stage disease (as is seen in many transplant candidates) the 25-hydroxylation of vitamin D may become impaired. Patients with liver disease frequently have low serum levels of 25(OH)D, but reported levels vary widely, partly because of differences in sunlight exposure and dietary factors, as shown in Table 4 [77, 81, 89, 92, 93, 97, 105, 112, 118–124]. These levels can be low because of reduced exposure to sunlight, malabsorption, increased vitamin D catabolism, higher excretion of polar metabolites, or reduced levels of D-binding protein [125]. D-binding protein and albumin both bind vitamin D, and in chronic liver disease these two proteins are reduced in parallel, so that the free levels of 25(OH)D are higher than suggested by the ordinary serum levels [126]. When serum 25(OH)D is very low, osteomalacia can be seen, but with current medical practice severe vitamin D deficiency is uncommon.

TABLE 4. Vitamin D levels in patients with cirrhosis

Author Date Location N Patients Mean serum 25(OH)D ng/mL
Matloff 1982 Boston 10 PBC 19
Hodgson 1985 Minnesota 15 PBC 18
Stellon 1986 England 36 PBC 18
Diamond 1989 Australia 54 Cirrhosis 17
Kirch 1990 Germany 22 Cirrhosis 31
Rabinovitz 1992 Pittsburgh 30 Pre-Transplant 11
Hodgson 1993 Minnesota 24 PBC 16
Compston 1996 England 27 Pre-Transplant 6
Bagur 1998 Argentina 23 PBC 27
Crosbie 1999 Ireland 12 Pre-Transplant 6
Hay 2001 Minnesota 63 Pre-Transplant 15
Monegal 2001 Spain 45 Pre-Transplant 9
Floreani 2001 Italy 23 Pre-Transplant 9
Guanabens 2003 Spain 32 PBC 55
Guichelaar 2003 Minnesota 33 Pre-Transplant 17

Most studies also show normal or decreased serum PTH levels in liver transplant candidates [77, 89, 95, 105, 112, 119, 123, 124, 127, 128]. The mechanism for this is unclear; with poor calcium absorption and low vitamin D, PTH would be expected to increase. One study found increased PTH levels when using an assay that detected midregion PTH, but normal levels when a different assay which detected the whole sequence was used [119].

After transplantation, the PTH and 25(OH)D levels increase significantly For example, in one study mean serum PTH level was 26.6 pg/ml at baseline and increased to 61.2 pg/ml in 2 years. Serum 25(OH)D levels were low at baseline and returned to the normal range after 2 years [77].

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INTRODUCTION

MEHRDAD RAHMANIYAN , NORMAN H. BELL , in Vitamin D (Second Edition), 2005

I. INTRODUCTION

Vitamin D metabolism is influenced by a number of factors. These include race, geographic location, diet, body habitus, and exercise. To understand how these factors exert their influence, it is useful to briefly review the metabolism of vitamin D and vitamin D–endocrine system. These subjects are discussed in greater detail in Chapter 2 of this book. A list of populations at risk for developing rickets and osteomalacia and factors involved is shown in Table I.

TABLE I. Causes and Consequences of Vitamin D Deficiency in Various Races and Populations

Population Increased skin pigment Diminished exposure to sunshine Inadequate intake of vitamin D Rickets Osteomalacia
Asian Indians + + + + +
Blacks + + + + −
Caucasians − − + + −
Chinese − − + + −
Egyptians + + + + −
Hispanics + − − − −
Jordanians + + + + −
Libyans + + + + −
Moroccans + + + + −
Pakistanis + + + + +
Polynesians + − − − −
Saudi Arabians + + + + −
Lebanese − + + + −
Turkish + + + + −
Iranians + + + + −
Other Arabs + + + + −

Newborn infants of any race or population are prone to develop rickets when breast-fed and kept indoors.

Asians and Pakistanis are at risk to develop vitamin D deficiency and osteomalacia, particularly when they reside away from the equator. Despite knowledge of prevention of these diseases, they are widespread throughout the world.

Vitamin D metabolism can be summarized as follows (see Chapter 3 for details). In skin, vitamin D3 is synthesized from dermally produced 7-dehydrocholesterol. Previtamin D3 is converted from 7-dehydrocholesterol by absorption of one photon of ultraviolet sunlight, and the further conversion of previtamin D3 to vitamin D3 is regulated by body heat, a process that takes place over a period of several days and is temperature dependent [1, 2]. The vitamin is carried from capillaries in skin by vitamin D–binding protein to the liver, where it is converted to 25-hydroxyvitamin D (25OHD) by vitamin D-25-hydroxylase (CYP2R1), the newly discovered hepatic microsomal enzyme [3, 4]. 25OHD is further converted to 1,25-dihydroxyvitamin D [1,25(OH)2D] in the proximal tubule of the kidney by the mitochondrial enzyme 25OHD-1α-hydroxylase (1α-hydroxylase) (CYP27B1). The enzyme is stimulated directly by parathyroid hormone a reaction that is mediated by its messenger cyclic AMP [5–7], and indirectly by growth hormone, through stimulation of insulin-like growth factor-I [9, 10] and is inhibited by calcium [8, 11, 12] and inorganic phosphate [13, 14]. In states of vitamin D excess, 25OHD is converted to 24,25-dihydroxyvitamin D [24,25(OH)2D] by the mitochondrial enzyme 25OHD-24-hydroxylase (24-hydroxylase) (CYP24A1), which is present in the kidney and other organs [15–17], and less 1,25(OH)2D is produced. Conversely, in states of vitamin D deficiency, less 24,25(OH)2D and more 1,25(OH)2D is produced. The two metabolites undergo additional hydroxylation to form 1,24,25-trihydroxyvitamin D, before being converted to calcitroic acid. This degradative pathway is similar to the classic and alternative pathways that are involved in the transformation of cholesterol to bile acids. CYP24A1 is induced by 1,25(OH)2D by two vitamin D receptor (VDR) response elements in the gene promoter. Thus, 1,25(OH)2D regulates not only its own rate of degradation but that of 25OHD as well [18]. The regulation of degradation of 25OHD by 1,25(OH)2D is underscored by studies in rats which showed that 1,25(OH)2D increases the metabolic clearance rate of 25OHD [19] and by studies in human subjects which showed that the increase in serum 25OHD produced by pharmacologic doses of vitamin D was prevented by the simultaneous administration of 1,25(OH)2D3 [20].

Calcium metabolism is modulated by a negative feedback control system that includes the parathyroids, skeleton, kidneys, and intestine. Serum calcium is kept within a very narrow range by parathyroid hormone (PTH) and 1,25(OH)2D by stimulating osteoclastic bone resorption [21], the reabsorption of calcium by the renal tubules [22], and the intestinal absorption of calcium, a biochemical event mediated by 1,25(OH)2D via the VDR [23, 24]. Secretion of PTH by the parathyroid glands is stimulated by phosphate [25] and is inhibited by both calcium and 1,25(OH)2D. Inhibition by calcium is mediated via a calcium-sensing receptor [26] and inhibition by 1,25(OH)2D is mediated via the VDR [27, 28]. The inhibition of PTH secretion by 1,25(OH)2D in enhanced by up-regulation of the VDR in the parathyroids [29].

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Sarcoidosis

Nadera J. Sweiss , Robert P. Baughman , in Kelley's Textbook of Rheumatology (Ninth Edition), 2013

Managing Sarcoidosis: Focusing on Sarcoid Arthritis

No treatments have been U.S. Food and Drug Administration (FDA)-approved for sarcoidosis or for any of its manifestations, including sarcoid arthritis. Furthermore, no randomized trials have been conducted that can guide clinical decision making. To help guide clinicians in management, we have proposed a treatment algorithm, which is shown in Figure 117-2. 2 Nonsteroidal anti-inflammatory drugs, methotrexate, and local or low-dose systemic corticosteroids are our preferred first-line therapies. Alternatively, hydroxychloroquine may be used. Using information obtained from the diagnostic evaluation, the clinician usually makes treatment decisions after carefully considering the disease severity and its probable clinical course, as revealed by its radiographic progression.

The proposed algorithm requires regular patient visits to monitor disease activity and therapeutic efficacy and tolerability. Responders remain on first-line agents until disease resolution or, alternatively, treatment failure. Before nonresponders are prescribed second-line therapies, higher doses of corticosteroids may be used, depending on tolerability and manifest toxicity. If patients do require second-line medications, two options are available: (1) methotrexate may be given to methotrexate-naïve patients, or (2) biologic therapies consisting of nonmethotrexate disease-modifying antirheumatic drugs (e.g., sulfasalazine, hydroxychloroquine, azathioprine), monotherapy, or combinations thereof may be prescribed to patients who inadequately respond to first-line methotrexate.

For patients for whom this treatment approach fails, one can consider an alternative biologic therapy or an aggressive course of systemic corticosteroids with careful toxicity monitoring. Alternatively, participating in a clinical trial may be appropriate for some patients.

Vitamin D metabolism represents a complex issue in sarcoidosis. Up to 10% of sarcoidosis patients will have hypercalcemia or hypercalciuria. 52 The mechanism usually attributed has been increased production of 1,25-dihydroxyvitamin D (1,25-OH2D) by epithelioid cells in the granuloma. In one study, elevated 1,25-OH2D was associated with prolonged need for treatment. 53 However, this same group of patients often requires treatment for osteoporosis. 54 Bisphosphonates alone may be adequate to treat corticosteroid-induced osteoporosis. 55 Because of the disassociation between 25-hydroxyvitamin D (25-OHD) and 1,25-OH2D in sarcoidosis, it seems reasonable to measure both levels to ascertain which patients should receive vitamin D supplements.

Future Directions

Much remains to be learned about sarcoidosis. Its causes remain unclear, and no medications have been FDA-approved for its treatment. Although increasing attention has been paid to the underlying mechanisms of granuloma formation, full details of sarcoidosis immunopathogenesis have yet to be determined. Appropriate animal models and candidate genes are needed to help advance our understanding of this disease.

Large clinical trials are warranted. We have presented an algorithm for use in treating patients with an established diagnosis of sarcoidosis. However, treatment approaches vary by institution and by individual clinician owing to a myriad of conflicting studies that have been published about sarcoidosis management. Furthermore, therapeutic choices will likely differ according to the type and extent of organ system involvement observed in individual patients.

For relapsed and refractory disease, steroid-sparing agents including cytotoxic drugs and novel biologic therapies such as anti-TNF treatments have been used increasingly. Anti-TNF agents have been investigated in numerous sarcoidosis studies because of the potential role of TNF and other proinflammatory factors in sarcoidosis pathogenesis. Limiting their usefulness in this setting are mounting reports of granulomatous reactions to anti-TNF therapies in patients treated with these agents for nonsarcoidosis indications. Simply put, TNF inhibitors may help treat and may cause sarcoidosis. 56-59 With this point in mind, it is relevant to our discussion that the presentation of anti-TNF–induced sarcoidosis, similar to all phenotypes of sarcoidosis, is a unique entity, but it does overlap with that of other autoimmune diseases. Furthermore, anti-TNF agents have been reported to induce autoimmune diseases other than sarcoidosis, including systemic lupus erythematosus (SLE), vasculitis, and interstitial lung disease. Diagnosing these conditions in patients with anti-TNF–induced sequelae is critical.

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