Brief Critical Reviews

May 1992: 138-147

Vitamin D and Psoriasis Skin can serve as the source of vitamin D when exposed to sunlight so that cutaneous 7-dehydrocholesterol can be converted to the vitamin. Skin is also a target organ for the hormone form of vitamin D: 1,25-(OH)2D3. Both skin keratinocytes grown in tissue culture and samples of human skin have the nuclear receptor for 1,25(0H),D,. New results suggest that this hormone or its analogs may be effective in treating some forms of psoriasis.

Introduction

It has become established over the last two decades that the physiologically important molecule vitamin D, must be considered, for all practical purposes, to be biologically inactive. What has emerged as our current understanding of the mechanism of the action of vitamin D is a complex tale of steroid metabolism, endocrine intrigue involving receptors, and a myriad of target organs, both classic (e.g., intestine, bone, and kidney) and newly identified (e.g., bone marrow, pancreas B cells, skin cells, and a variety of tumor cells). In addition, there now exists a host of insights into diseases related to dysfunction of the many biologic processes related to vitamin D as well as the concurrent development of new clinical applications for drug forms of vitamin D metabolites. Thus, the parent vitamin D is now known to undergo an obligatory two-step metabolism to I ,25(OH),-vitamin D, [ 1,25(OH),D,], which involves two separate organs, the liver and kidney, which through two distinct cytochrome P-450 hydroxylases introduce hydroxyl moieties on carbon25 and carbon-I , respectively. The kidney is considered the endocrine gland responsible for production of the steroid hormone 1,25(OH),D3. In addition to 1 ,25(OH),D, and the intermediate 25(OH)D,, there are some 37 other known metabolites of vitamin D,.,

',,

This review was prepared by Karen E. Lowe, Ph.D., and Anthony W. Norman, Ph.D., at the Department of Biochemistry and Division of Biomedical Sciences, University of California, Riverside, CA 92521. 138

The secosteroid 1,25(OH),D, is then delivered systemically to a wide array of target tissues that contain protein receptors which possess a highly specific ligand-binding domain for this hormone. Currently, there is evidence that at least 30 tissues possess this nuclear localized receptor for 1,25(OH),D,.4 The 1,25(OH),D,, in conjunction with its receptor, then produces biologic responses both through regulation of gene tran~cription~.~ and through a nongenomic pathway that may involve the opening of CaZCchannels.6 For a recent comprehensive review of all aspects of vitamin D, see reference 7. The particular point of focus of this review concerns the skin. Skin can serve as the source of vitamin D when it receives suitable ultraviolet exposure (i.e., sunlight) so that the endogenous 7-dehydrocholesterol is converted photochemically to the parent vitamin D. In addition, skin is one of the newly discovered target organs of the hormone form of vitamin D, 1,25(OH),D,. Skin keratinocytes grown in tissue culture,8 as well as samples of human skin,' were found to possess the nuclear receptor for 1 ,25(OH),D,. This article will review the evidence that skin is a target organ for the action of 1,25(OH),D, and, in addition, will describe some new clinical results suggesting that 1,25(OH),D, or analogs thereof may be efficacious in treating certain forms of psoriasis. Vitamin D and Psoriasis

Several studies have documented the presence of the specific 1,25(OH),D, nuclear receptor (VDR) in human cultured epidermal keratinocytes, l 2 and dermal fibroblasts.8*'2Keratinocytes in all epidermal layers (except the outermost stratum corneum) of normal skin express the VDR.', Research has demonstrated that 1,25(OH),D, regulates the growth and differentiation of epidermal keratinocytes. l 4 Hosomi et a1.15reported the first evidence that 1,25(OH),D, brings about the terminal differentiation of cultured mouse epidermal cells. The hormone decreases the proliferation and stimulates the morphologic differentiation of cultured human keratinocytes. l 6 It is not yet clear in biochemical terms how 1,25(OH),D3 induces these changes in keratinocyte differentiation, although it is possible that other Nutrition Reviews, Vol. 50, No. 5

growth factors and proto-oncogene products may be involved. The 1,25(OH),D, might decrease target cell sensitivity to growth factors that are mediated by epidermal growth factor (EGF) receptor. l7 In cultured human keratinocytes, 1,25(OH),D, increases the transcription of transforming growth factor p1 (TGF-PI), and thus enhances the antiproliferative effect of this factor. l 8 Furthermore, 1,25(OH),D, rapidly decreases the synthesis of c-myc proto-oncogene mRNA,19 concomitant with an inhibition of DNA synthesis in cultured human keratinocytes. It has also been noted that 1 ,25(OH),D, can stimulate keratinocyte differentiation via a rapid increase of intracellular calcium concentration.20 Yada et al.,' showed that the addition of either 12 nmol/L 1,25(OH),D,, la(OH)D,, 25(OH)D,, or 24,25(OH),D, to cultured keratinocytes increased the production of 1,2-diacylglycerol and inositol 1,4,5-triphosphate, and enhanced the translocation of protein kinase C (PKC) from the cytosol to the membrane. Of these vitamin D, derivatives, only 1,25(OH),D, induced the formation of cornified envelopes, a morphologic marker of terminal keratinocyte differentiation. Pretreatment of the keratinocytes with the PKC down-regulator phorbol12,13-dibutyrate, or with the PKC inhibitor H-7, blocked the induction of cellular differentiation by 1,25(OH),D,. These results suggest that PKC activation is a necessary but insufficient step for the induction of keratinocyte differentiation. Although experiments have indicated that 1,25(OH),D, at concentrations higher than lop8 mollL regulates the growth and differentiation of normal human keratinocytes,'' the in vivo role of 1,25(OH),D, in keratinocyte development has been unclear because normal human serum 1,25(OH),D, concentrations range from lo-" to lo-" mol/L. Since the concentration of 25(OH)D, in normal human serum is 10-8-10-7 mol/L, Matsumoto et al.,' examined the possibility that a significant amount of 1,25(OH),D, in keratinocytes might be produced endogenously from 25(OH)D,. The results indicated that cultured keratinocytes from normal human adult skin rapidly convert 25(OH)D3 to 1,25(OH),D,, which is retained within the cells and not released into the medium. The treatment with 1 0 - ~moYL 25(OH)D3 was nearly as effective as moVL 1,25(OH),D3 in suppressing the proliferation and inducing the differentiation of keratinocytes. The data support the idea that the 1,25(OH),D, derived endogenously from the precursor 25(OH)D,, rather than the circulating 1,25(OH),D3, may regulate epidermal keratinocytes in vivo. Precedent for 1,25(0H),D,-regulated paracrine systems already exists. Activated macrophages, particularly those present in the bone marNutrition Reviews, Vol. 50,No. 5

row, are definitely capable of producing small quantities of 1,25(OH),D,, which is then utilized locally to promote selective hematopoietic cell differentiati~n.~~.~~ The skin immune system may be another target for 1,25(OH),D,. Evidence suggests that the hormone may regulate a cytokine cascade involved in the accumulation of leukocytes during skin inflammation. Interleukin-8 (IL-g), a proinflammatory neutrophil-activating peptide, is not present in normal human epidermis but can be isolated from the skin of patients with psoriasis or other conditions, such as allergic dermatitis. The hormone 1,25(OH),D, causes a dose-dependent inhibition of IL-8 mRNA expression in IL-la-stimulated cultured human keratinocytes, dermal fibroblasts, and mon~cytes.~~ Psoriasis is a common, chronic skin disease characterized by hyperproliferation and incomplete differentiation of the epidermal keratinocytes. Conflicting data have been obtained on the vitamin D metabolism in psoriasis patients. Normal serum 1,25(OH),D, concentrations were observed in patients with moderate to extensive psoriasis,2s*26 while lower circulating 1,25(OH),D3 levels,27 hypoparathyroidism,28and h y p ~ c a l c e m i ahave ~ ~ been reported in patients with severe psoriasis. Studies using larger groups of psoriasis patients reported normal parameters of 1,25(OH),D,, calcium, and bone m e t a b ~ l i s m . ~From ' * ~ ~ the available results it has been concluded that psoriasis does not appear to arise from deranged vitamin D metabolism. Current Status of Clinical Applications

Based on the ability of 1,25(OH),D3 to suppress keratinocyte proliferation and to promote epidermal differentiation, several studies have examined the effects on psoriasis patients of the oral or topical administration of 1,25(OH),D3 and its analogs. 2.5,26,32-34 Open, uncontrolled clinical trials have reported the improvement of psori;itic skin lesions after the oral administration of 1,25(OH),D3" and after the topical application of 1,24(OH),D335 and 1,25(OH)2D3.25However, a double-blind placebo-controlled study found that 0.5 pg of 1,25(OH),D, applied topically twice daily did not significantly improve psoriatic lesions.32 This conflicting result was attributed to the 1,25(OH),D3 dosage and to the topical treatment vehicle (medium chain triglycerides), which may have affected the bioavailability of the hormone. Previous studies had reported a clinical improvement in psoriasis patients using topical l ,25(OH),D3 prepared with petrolatum as the vehicle.,' Researchers have been concerned that clinical use of 1,25(OH),D3 may not provide a safe therapy 139

for psoriasis because of the potent effects of this hormone on calcium m e t a b o l i ~ mSerious .~~ clinical side effects of excessive 1,25(OH),D3 administration can include hypercalcemia, hypercalciuria, soft tissue calcification, kidney stones, and bone resorption. In leukemia patients, oral doses of 1,25(OH),D3 higher than a few micrograms daily were found to induce hyper~alcemia.~’ Also, transdermal absorption of topically applied 1,25(OH),D3 (15 pg/g ointment, applied twice daily to a skin surface area of 600-1200 cm2) caused an increase in urinary calcium excretion, although the parameter remained within the normal range.38Because of the concern for potential health risks to psoriasis patients on long-term l ,25(OH),D3 treatment, synthetic vitamin D analogs have been designed and screened selectively for keratinocyte-regulating properties accompanied by less potent effects on calcium metabolism. Calcipotriol (MC903) (see Figure 1) is a synthetic analog of ~ c x , ~ ~ ( O containing H~D, a C2TC23 double bond and a cyclopropane ring in the modified side chain. Calcipotriol is rapidly converted in vivo to inactive metabolites and has been found to be about 200-fold less potent than 1,25(OH),D3 in causing hypercalcemia and hypercalciuria in rats.39 Experiments conducted in vitro showed that calcipotriol and 1,25(OH),D3 were equipotent in their binding affinity for the VDR and in their regulatory effect on epidermal keratinocytes.” Double-blind, placebo-controlled studies found that topically applied calcipotriol significantly improved psoriatic The optimal dosage of 50 pg/g ointment, applied twice daily (maximum of 100 g of ointment per week), produced the greatest improvement within six weeks. Parameters of vitamin D and calcium metabolism remained in the normal range. Local skin irritation was an adverse effect reported by less than 5% of the patients treated with topical c a l c i p ~ t r i o l .After ~ ~ calcipotriol treatment was ended, the psoriatic lesions tended to recur. Longer-term studies (six to 12 months) on the safety and effectiveness of calcipotriol indicate that calci-

OH 1

HO’“

&

OH

HO”H O‘ Figure 1. Structural formulas of 1,25(OH),D, and calcipotriol . 140

potriol ointment may become an appropriate maintenance therapy for psoriasis. Prospects for the Future

Thus, with the understanding that skin cells, particularly keratinocytes, possess specific receptors for the hormone form of vitamin D, and that psoriasis is a chronic hyperproliferative skin disease that involves both immunologic and inflammatory processes, it is possible to understand and appreciate the remarkable recent clinical advances. Because 1,25(OH),D3 inhibits epidermal proliferation and promotes epidermal differentiation, the appropriate administration (both intravenously and topically) of 1,25(OH),D3 or several related analogs provides dramatic clinical improvement of some forms of psoriasis that heretofore had proven very difficult to manage. However, since 1,25(OH),D, itself is so hypercalcemic, one looks forward with anticipation to the continued development of additional analogs of 1,25(OH),D3 like calcipotriol, which are devoid of inappropriate side effects but are still highly potent in inhibiting proliferation and in promoting differentiation of skin cells. This, then, will allow initiation of long-term trials of the clinical efficacy of 1,25(OH),D3 analogs in psoriasis. 1. Reichel H, Koeffler HP, Norman AW. The role of the vitamin D endocrine system in health and disease. N Engl J Med 1989;320:980-91 2. Haussler MR. Vitamin D receptors: nature and function. Annu Rev Nutr 1986;6:527-62 3. Henry HL, Norman AW. Vitamin D: metabolism and biological actions. Annu Rev Nutr 1984;4: 493-520 4. Minghetti PP, Norman AW, 1,25(OH),-vitamin D, receptors:gene regulation and genetic circuitry. FASEB J 1988;2:3043-53 5. Lowe KE, Maiyar A, Norman AW. Vitamin D-mediated gene expression. Crit Rev Eukaryotic Gene Express 1992;2:6!%109 6. Anonymous. Nongenomic effects of vitamin D. Nutr Rev 1991;49:306-7 7. Norman AW, Bouillon R, Thomasset M, eds. Vitamin D: Gene regulation, structure-function analysis and clinical application. Berlin: Walter de Gruyter, 1991:991 pp 8. E i l C, Marx SJ, Nuclear uptake of 1,25dihydr~xy[~H]-cholecalciferol in dispersed fibroblasts cultured from normal human skin. Proc Natl Acad Sci USA 1981;78:2652-6 9. Bikle DD, Nemanic MK, Gee E, Elis P. 1,25dihydroxyvitamin D, production by human keratinocytes: kinetics and regulation. J Clin Invest 1986;78:557-66 10. Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target-cells for 1,25-dihydroxyvitamin-D3in intestinal-tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979;206:1188-90 Nutrition Reviews, Vol. 50, No. 5

11. Feldman D, Chen T, Hirst M, Colston K, Karasek M, Cone C. Demonstration of 1,25-dihydroxyvitamin D, receptors in human skin biopsies. J Clin Endocrinol Metab 1980;51:1463-5 12. Clernens TL, Adams JS, Horiuchi N, et al. Interaction of 1,25-dihydroxyvitamin-D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin D-dependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D., J Clin Endocrinol Metab 1983;56:824-30 13. Milde P, Hauser U, Simon T, et al. Expression of 1,25-dihydroxyvitamin D, receptors in normal and psoriatic skin. J Invest Dermatol 1991;97:23G9 14. Suda T, Miyaura C, Abe E,et al. Modulation of cell differentiation, immune responses and tumor production by vitamin D compounds. In: Peck WA, ed. Bone and mineral research. Amsterdam: Elsevier, 1986:vol 4, 1-48 15. Hosomi J, Hosoi J, Abe E, Suda T, Kuroki T. Regulation of terminal differentiation of cultured mouse epidermal cells by 1,alpha,25-dihydroxyvitamin D., Endocrinology 1983;113:1950-7 16. Smith EL, Walworth NC, Holick MF. Effect of 1,alpha,25-dihydroxyvitamin D, on the morphological and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions. J Invest Dermatol 1986;86:709-14 17. Koga M, Eisman JA, Sutherland RL. Regulation of epidermal growth factor receptor levels by 1,25dihydroxyvitamin D, in human breast cancer cells. Cancer Res 1988;48:2734-9 18. McLane JA, Kim H-J, Abdelkader N, et al. 1,25(OH),D, enhances anti-proliferative effect and transcription of TGF-P on human keratinocytes in culture. In: Norman AW, Bouillon R, Thomasset M, eds. Vitamin D: gene regulation, structurefunction analysis, and clinical application. Berlin: Walter de Gruyter, 1991:426-7 19. Matsumoto K, Hashimoto K, Nishida Y, Hashiro M, Yoshikawa K. Growth-inhibitory effects of 1,25dihydroxyvitamin D, on normal human keratinocytes cultured in serum-free medium. Biochem Biophys Res Commun 1990;166:916-23 20. Yada Y, Ozeki T, Meguro S, Mori S, Nozawa Y. Signal transduction i n the onset of terminal keratinocyte differentiation induced by 1a,25dihydroxyvitamin D,: role of protein kinase C translocation. Biochem Biophys Res Commun 1989;163:1517-22 21. Matsurnoto K, Azuma Y, Kiyoki M, Okumura H, Hashimoto K, Yoshikawa K. Involvement of endogenously produced 1,25-dihydroxyvitamin D, in the growth and differentiation of human keratinocytes. Biochim Biophys Acta 1991;1092:311-8 22. Reichel H, Koeffler HP, Norman AW. Synthesis in vitro of 1,25-dihydroxyvitarnin D, and 24,25dihydroxyvitamin D, by interferon-7-stimulated normal human bone marrow and alveolar macrophages. J Biol Chem 1987;262:10931-7 23. Reichel H, Norman AW. Systemic effects of vitamin D. Annu Rev Med 1989;40:71-8 Nutrition Reviews, Vol. 50, No. 5

24. Larsen CG, Kristensen M, Paludan K, et al. 1,25(OH),D, is a potent regulator of interleukin-1 induced interleukin-8 expression and production. Biochem Biophys Res Comrnun 1991;176:102&6. 25. Morimoto S, Yoshikawa K, Kozuka T, et al. An open study of vitamin D, treatment in psoriasis vulgaris. Br J Dermatol 1986;115:421-9 26. Smith EL, Pincus SH, Donovan L, Holick MF. A novel approach for the evaluation and treatment of psoriasis. J Am Acad Dermatol 1988;19:516-28 27. Staberg 8, Oxholm A, Klemp P, Christiansen C. Abnormal vitamin D metabolism in patients with psoriasis. Acta Derm Venereol (Stockh) 1987;67: 65-8 28. Risum G. Psoriasis exacerbated by hypoparathyroidism with hypocalcemia. Br J Dermatol 1973; 89:309-12 29. Stewart AF, Battaaglini-Sabetta J, Millstone L. Hypocalcemia-induced pustular psoriasis of von Zumbusch. New experience with an old syndrome. Ann Intern Med 1984;100:677-80 30. Mortensen L, Kragballe K, Charles P. Effect of calcipotriol on psoriasis: a double blind placebo controlled study of calcipotriol (MC903) and calcium metabolism. In: Norman AW, Bouillon R, Thomasset M, eds. Vitamin D: gene regulation, structurefunction analysis, and clinical application. Berlin: Walter de Gruyter, 1991:443-4 31. Kragballe K. Efficacy and tolerability of calcipotriol in psoriasis. In: Norman AW, Bouillon R, Thomasset M, eds. Vitamin D: gene regulation, structure-function analysis, and clinical application. Berlin: Walter de Gruyter, 1991:417-23 32. Van De Kerkhof PCM, Van Bokhoven M, Zultak M, Czarnetzki BM. A double-blind study of topical la,25-dihydroxyvitamin D, in psoriasis. Br J Derrnatol 1989;120:661-4 33. Kragballe K, Beck HI, Sorgaard H. Improvement of psoriasis by a topical vitamin D, analogue (MC903) in a double-blind study. Br J Derrnatol 1988;119:223-30 34. Henderson CA, Papworth-Smith J, Cunliffe WJ, Highet AS, Shamy HK, Czarnetzki BM. A doubleblind, placebo-controlled trial of topical 1,25dihydroxycholecalciferol in psoriasis. Br J Dermato1 1989;121:493-6 35. Kato T, Rokugo M, Terui T, Tagarni H. Successful treatment of psoriasis with topical application of active vitamin D, analogue, la,24-dihydroxycholecalciferol. Br J Dermatol 1986;115:431-3 36. Kragballe K, Gjertsen BT, De Hoop D, et al. Double-blind, rightheft comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991;337:193-6 37. Koeffler HP, Hirjik K, ltri L. 1,25-Dihydroxyvitarnin D:, in vivo and in vitro effects on human preleukernic and leukemic cells. Cancer Treat Rep 1985; 69:1399-407 38. Langner A, Verjans H, Stapor V, et al. Treatment of chronic plaque psoriasis by 1a,25-dihydroxyvitamin D, ointment. In: Norman AW, Bouillon R, 141

Thomasset M, eds. Vitamin D: gene regulation, structure-function analysis, and clinical application. Berlin: Walter de Gruyter, 1991:430-1 39. Binderup L, Bramm E. Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988;37:889-95

40. Staberg B, Roed-Petersen J, Menne T. Efficacy of topical treatment in psoriasis with MC903, a new vitamin D, analogue. Acta Dermatol Venereol (Stockh) 1989;69:147-50 41. Kragballe K. Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol. Arch Dermatol 1989;125:1647-52

Acetyl-Carnitine and Alzheimer’s Disease In a double-blind, randomized, controlled clinical trial, progression of Alzheimer’s disease was significantly reduced in patients who received acetyl-carnitine (2 glday) for one year.

Alzheimer’s disease is the most common cause of dementia in developed countries. Its economic and social burden on families and society is well documented, as is the profound personal tragedy of Alzheimer’s patients who experience progressive loss of memory and cognitive ability. The prevalence of Alzheimer’s disease increases with age; it affects about 3 4 million Americans-approximately 10% of those older than age 65 and nearly half of those older than age 85.’32 In 1986 US health care costs attributable to Alzheimer’s disease were estimated at $50 billion a n n ~ a l l yBecause .~ of the increase in older age cohorts projected for the next century (as the baby boom ages), the future societal impact of Alzheimer’s disease will be even more substantial. The etiology of Alzheimer’s disease is unknown; the neuropathology includes nerve cell loss, neurofibrillary tangles and neuritic plaques, and decreased brain content of acetylcholine and other neurotransmitters. Treatment with acetylcholine or precursors has been generally unsuccessful. L-Carnitine is required for mitochondria1 transport of long-chain fatty acids for P - ~ x i d a t i o n .It~ . ~ may also have a role in metabolism of mediumchain fatty acids., Carnitine occurs naturally in the diet, particularly in animal products, and can also be synthesized endogenously from two .essential amino acids, lysine and methionine. Carnitine biosynthesis takes place in the liver and kidney and requires several other nutrients, including ascorCarnitine apbate, niacin, vitamin B,, and pears to be a conditionally essential nutrient in malnutrition and in newborns, pregnant and lactating This review was prepared by Barbara A.B. Bowman, Ph.D., at the Department of Nutrition and Dietetics, Georgia State University, University Plaza, Atlanta, GA 30303-3083. 142

women, patients receiving dialysis or total parenteral nutrition, and patients with liver d i ~ e a s e . ~ . ~ Carnitine and choline are related structurally; results from a recent clinical trial7 conducted in Italy imply a functional relationship as well. From 1987 to 1989 Spagnoli et al.7 conducted a multicenter randomized clinical trial to determine whether acetyl-carnitine (2 g/day for one year) affected the progression of cognitive and functional impairment in Alzheimer’s disease. The study was placebo-controlled and double-blind, and the investigators met regularly for monitoring and quality control. Patient selection criteria included those over 40 years old and a clinical diagnosis of Alzheimer’s disease for at least six months. Eligible subjects were screened for dementia using a previously validated instrument, then diagnosed using the DSM-111 diagnostic criteria for dementia. Subjects who were severely demented or who had serious systemic diseases were excluded, as were those with depression or non-Alzheimer’s dementia. Patients on antidepressant medication were also excluded. Some patients were receiving benzodiazepines or neuroleptics, but other “cerebroactive” drugs were discontinued in all but two subjects. Patients were randomized to control or treatment groups in blocks of four after relatives gave informed consent. All patients took four tablets daily (acetyl-carnitine or placebo), two after breakfast and two after lunch. Compliance was assessed by pill counts. The dose of 2 g acetyl-carnitine was based on preliminary studies in which 1-2 g orally was “usually well-tolerated, with agitation (i.e., restlessness and motor overactivity) being the only noteworthy adverse effect’ (p. 1726).” For comparison, this dose is equivalent to 1.6 glday of carnitine; dietary intakes of US nonvegetarians average about 100-300 mg/day . Progression of Alzheimer’s disease was evaluated at baseline and at 12 months using 14 different standardized instruments that assessed behavior, disability, and cognitive performance. Some tests were also repeated after three and six months. Data analyses included both univariate analysis of each Nutrition Reviews, Vol. 50, No. 5