Pseudohypoparathyroidism

Although vitamin D was recognized as early as 1932 as the nutrient essential for normal bone and tooth development in early life, it has only been in the last decade that its importance in maintaining the integrity of the skeleton in the elderly has been studied. This article presents evidence that the vitamin D available to regulate calcium and bone metabolism in the older population is often inadequate.

Less than 100 years ago, vitamin D was found to prevent rickets, a bone disease then widespread in children. Now, almost a century later, investigators continue to clarify its role in the prevention of bone loss, or osteoporosis, in the older adult. Vitamin D is an essential factor in the regulation of calcium and mineral homeostasis and functions as a hormone along with calcitonin . and parathyroid hormone to maintain normal serum levels of calcium and phosphorus. For excellent historical perspectives on vitamin D, see DeLuca[1] and Holick.[2]

Because the elderly are at risk for vitamin D deficiency, a thorough understanding of the role of this substance in health and disease is important to professionals working with this group.3

BIOCHEMISTRY

The general term "vitamin D" actually includes multiple compounds with different degrees of physiological activity, compounds that can be characterized chemically as ring-shaped alcohols or secosteroids. Figure 1 provides the names, abbreviations, and structures for major compounds in vitamin D metabolism. In addition to the three key forms of vitamin D--[25(OH)D.sub.3] (calcidiol); [[1,25(OH).sub.2][D.sub.3]] (calcitriol); and 24R, [[25(OH).sub.2][D.sub.3]],(24R,25 dihydroxy vitamin [D.sub.3])--at least 35 other vitamin [D.sub.3] metabolites have been isolated and chemically characterized.

Sources of Vitamin D. Vitamin D can be consumed in the diet or synthesized within the body. It can be ingested in the form of vitamin [D.sub.2], ergocalciferol from plant sources, and vitamin [D.sub.3], calciferol, from animal sources. Both forms are transported to the liver for further utilization. In vitamin D synthesis, the initial step in the production of physiologically active vitamin D is the conversion of 7-dehydrocholesterol to pre-vitamin [D.sub.3]. This occurs in the skin through a reaction which requires the presence of ultraviolet light. Pre-vitamin [D.sub.3] then undergoes a temperature-dependent spontaneous conversion to vitamin [D.sub.3]. Vitamin [D.sub.3] is bound to vitamin-D-binding protein and transported to the liver, where a 25-hydroxylase enzyme metabolizes it to [25(OH)D.sub.3] (calcidiol). The next step, which is rate limiting (output controlling), occurs in the kidney. There, a mitochondrial enzyme converts [25(OH)D.sub.3] to [[1,25(OH).sub.2][D.sub.3]] (calcitriol), which is approximately 5 to 10 times as potent as the original calciferol vitamin D3. Subsequent degradation of both 1,25 and 24,25(0H)2D3 results in over 25 metabolic degradation products. Two features of this process which are especially relevant clinically are the dependence of the first step on ultraviolet light (sun-exposed skin) and the fact that the rate of converting the precursor to the most active form of the vitamin is dependent on the amount of available functional kidney tissue.[4]

Function and Regulation. The understanding of the role of vitamin D in the human body has increased greatly since the 1960s, when a preparation of radioactive vitamin D became available. In many ways, vitamin D is best thought of as a steroidal hormone and a part of the endocrine system. It is a compound which can be produced by the body, regulates multiple metabolic processes in different organs, and has a feedback control mechanism.[1] It binds to various carrier proteins and activates specific receptor sites in a manner similar to that of other steroid hormones. It differs primarily in its unique synthetic process within the body as described above. The production of [[1,25(OH).sub.2][D.sub.3]] can be modulated according to the calcium needs of the body. The chief regulatory factors are [[1,25(OH).sub.2][D.sub.3]] itself, parathyroid hormone (PTH), and the serum levels of calcium and phosphate. When serum calcium levels fall, the production of parathyroid hormone is stimulated. PTH acts on the renal proximal tubule to increase the synthesis of [[1,25(OH).sub.2][D.sub.3]]. There is a negative feedback loop to this system such that elevated levels of [[1,25(OH).sub.2][D.sub.3]] decrease synthesis of PTH by an inhibitory action on the preproparathyroid hormone gene. The increased level of calcitriol then acts to raise the calcium level through increased intestinal absorption of calcium, apparently through at least two mechanisms. One of these is a genomic-mediated up-regulation which increases the amount of calbindin-D, a calcium-binding protein. The other is a rapid increase in calcium transport through the mucosa.[4]

Etiology. Vitamin D deficiency in the elderly is more prevalent than once believed. There are two major factors contributing to this problem.[3] First, vitamin D production declines in the elderly. Cause of this decline is a reduction in sun-exposed skin. This can result both from decreased time in the sun and from decreased exposed skin caused by clothing preferences. A second factor is the decreased renal mass seen in most older adults. The reduction in renal mass leads to a corresponding decrease in production of the [[1,25(OH).sub.2][D.sub.3]], the most active form of the hormone. In patients with renal disease, there is often impaired conversion of 25-hydroxyvitamin D to [[1,25(OH).sub.2][D.sub.3]]. Renal diseases can also have an impact on levels of 25-hydroxyvitamin D in patients with nephrotic syndrome. Heavy proteinuria may result in loss of vitamin-D-binding protein with associated loss of 25-hydroxyvitamin D. Vitamin D has a close interrelationship with PTH. The cause of hypocalcemia in patients with hypoparathyroidism (idiopathic or surgical) is at least partly due to lack of [[1,25(OH).sub.2][D.sub.3]]. The missing hormone, PTH, normally would be responsible for exerting a positive influence on the biosynthesis of [[1,25(OH).sub.2][D.sub.3]] from [25(OH)D.sub.3]. Therefore, exogenous supplementation with vitamin D3 may help correct the hypocalcemia. Pseudohypoparathyroidism (a syndrome in which the PTH is normal or even elevated and accompanied by hypocalcemia) usually results in an inadequate plasma level of [[1,25(OH).sub.2][D.sub.3]. This syndrome is related to the inability of the kidneys to recognize PTH, which results in both excessive loss of calcium and phosphorous in the urine and also inadequate conversion of calcidiol to calcitriol. Hypocalcemia associated with pseudohypoparathyroidism is often correctable with oral [[1,25(OH).sub.2][D.sub.3]] (1 to 3 [micro]g/day) or large doses of [25(OH)D.sub.3].

In addition to reduced production of the vitamin, older people take in less exogenous vitamin D. The major dietary source of vitamin D is fortified dairy products, which many elders forego because of lactase deficiency, a fairly common condition in the older adult, or because they limit either calorie or saturated fat intake. The combination of reduced production and reduced exogenous intake places the elderly at significantly greater risk for vitamin D deficiency.[6] A variety of drugs interfere with the metabolism, absorption, and utilization of vitamin D. Laxatives, particularly mineral oil, interfere with the absorption of exogenous vitamin D in the gut.[7] Cholestyramine may bind vitamin D in the gut and may also interfere with absorption. A variety of anticonvulsive medications, including carbamazepine, phenytoin, and phenobarbital, have been shown to interfere with vitamin D metabolism. A list of possible causes of vitamin D deficiency in the elderly is given in Table 1.

Vitamin D has a role in the etiology of osteoporosis, a generalized reduction in bone mass which is a major cause of disability in the elderly. Osteoporosis is, in fact, a group of disorders with heterogeneous etiologies. Osteoporosis may occur in a primary or secondary form. The primary form is evidenced by a marked reduction in histologically normal bone. In the secondary form, the bone may or may not be morphologically normal.[4] The cause of primary osteoporosis is not easily identified. Loss of bone appears to be the consequence of aging, and this may begin as early as the third decade of life. The loss includes cortical and trabecular bone and often results in hip and vertebral fractures. Secondary osteoporosis occurs in association with well-defined inherited or acquired disorders and with the use of certain drugs.[8] This form accounts for 10% to 15% of cases of osteoporosis. The difficulty in investigating osteoporosis results from the facts that

* the pathophysiology is not

clearly understood

* guidelines for diagnosis are not

clearly defined

* equipment necessary for a diagnosis

is not widely available

* treatment is not simple or rapidly

effective.

The goals in the management of osteoporosis include prevention of the disease and reduction of the loss of bone mass as the adult ages. The risk factors for the development of the loss of bone mass are listed in Table 2. Numerous researchers have attempted to use vitamin D as a therapy, and conflicting results have been reported in the literature.[6] Fujita[9] reviewed the results of 23 studies that investigated the possible benefits of vitamin D therapy. The majority of the studies found positive results. Higher doses, longer duration of use, and more sensitive methods of measuring bone mass were associated with the positive outcomes. An increase in bone density was the greatest benefit reported. Negative effects included hypercalcemia and kidney stones. All of the researchers agreed that dietary calcium intake should be monitored and correlated with vitamin D use.[10] Empirical supplementation is not recommended unless the diet is deficient and serum vitamin D levels are abnormally low.[9]

Vitamin D deficiency was reported in 1981 by Brooks[11] to be a cause of bilateral cochlear deafness. He reported that biochemical osteomalacia resolutions in deafness were the result of an inadequate intake of vitamin D. Brooks reported a total of 10 cases of deafness, and, in the cases where the serum [25(OH)D.sub.3] was <5.0 ng/ml, 3000 to 6000 IU/d of calciferol (vitamin [D.sub.3]) were used to correct the deficiency. Careful monitoring of calcium levels is suggested. Replacement therapy did result in unilateral hearing improvement in two of the subjects.

Hypervitaminosis. In hyperparathyroidism, there is an overproduction of PTH, resulting in hypercalcemia secondary to increased intestinal mucosa calcium absorption and reduced renal calcium clearance as well as increased bone calcium exchange. Because of the elevated PTH, there is increased synthesis of [[1,25(OH).sub.2][D.sub.3]. Although excessive amounts of vitamin D are not easily obtained from dietary sources, vitamin D intoxication has been diagnosed in patients treated with vitamin D or its analogs for hypoparathyroidism, renal osteodystrophy or osteoporosis, psoriasis and in other people who ingest excessive amounts of vitamin D supplements. Numerous studies have shown that the elderly are more likely to use vitamin supplements. Koplan et al.[12] reported that the use of vitamin supplementation was associated with greater age, higher income, higher education level, and the white race. In the 1990s, a New England dairy accidentally added excessive amounts of vitamin D their milk, and numerous cases of hypervitaminosis were reported.[13] The clinical syndrome included hypercalcemia, hypercalciuria, anorexia, vomiting, polydipsia, polyuria, muscular weakness, joint pain, demineralization of the bone, and in severe cases even stupor and death. The threshold level for adverse effects appears to be 10,000 IU/d, but toxic levels have not been established, because the range varies from one individual to another depending on the amount previously stored in the liver.

EVALUATION OF VITAMIN D STATUS

Severe vitamin D deficiency in the young causes definitive symptoms, but marginal deficiencies in the elderly are more difficult to diagnose. Radiolabled vitamin D assays are available to assess the vitamin D status of a patient; however, most researchers believe that the circulating level of [25(OH)D.sub.3] provides a less expensive and more widely available assay. Normal plasma levels range from 10 to 80 ng/ml. A level of <5 ng/ml is regarded as an indicator for vitamin therapy. In the elderly person with renal insufficiency, the circulation level of [[1,25(OH).sub.2][D.sub.3]] should be evaluated, because the 25(0H)D3 levels may be normal even in deficiency states.[14] Measurement of calcium and phosphorus contributes to the assessment of clinical severity of deficiency or excess states (Table 3). [TABULAR DATA 3 OMITTED]

NUTRIENT REQUIREMENTS

The requirement for vitamin D is known to be dependent on the concentration of calcium and phosphorous in the diet, the physiological state of development, age, sex, degree of exposure to the sun, and the amount of skin pigmentation. Very dark skin can prevent up to 95% of ultraviolet light rays from the sun from reaching the layers of the skin where the conversion of 7-dehydrocholesterol to the active form of vitamin D occurs.[15] Wearing protective clothing outside also prevents the conversion in the skin.

Vitamin D requirements have been stated in international units (IU), a term defined by the World Health Organization. An IU of vitamin D is 0.025 [micro]g, which is equivalent to 65.0 pmol. When the discovery of the metabolites of [[1,25(OH).sub.2][D.sub.3]] occurred, it was proposed that 1.0 IU 1,25(OH)2D3 be set equivalent in molar terms to that of the parent vitamin [D.sub.3]. Thus, 1.0 IU of [[1,25(OH).sub.2][D.sub.3]] is equivalent to 65 pmol.

The vitamin D requirement for healthy adults has never been well defined. The adult does not have a requirement for a dietary intake, because vitamin D is produced in the skin when it is exposed to sunlight. Under normal conditions, human skin synthesizes up to 6 IU vitamin D/[cm.sup.2]/hr. The effect of seasonal sun exposure has been examined in numerous studies which conclude that the serum vitamin D levels were lowest in the autumn and winter and highest in the summer. Thus, a moderate exposure to the summer sun can provide adequate amounts of the vitamin. In northern latitudes during the winter, it is believed that over 2 hours of ultraviolet light would be required for adequate vitamin D synthesis, assuming that only part of the face is exposed to the winter cold. Exposure to the sun is often not adequate for vitamin D synthesis in the older adult.[16] Several researchers who investigated older adults, ability to photoproduce vitamin D found that older adults are not exposed to adequate amounts of ultraviolet rays either due to climate, living arrangements, or the fact that aging skin is less efficient in producing the vitamin subcutaneously.[17] It was found that an 80year-old requires almost twice as much time in the sun to produce the same amount of the vitamin as a 20-year-old. This increase in solar exposure would also increase the risk of skin cancer, negating the benefit of the vitamins, production. It has been found that increasing vitamin D intakes from 100 IU to 500 IU daily prevented wintertime bone loss and improved net bone mass.[18] When the adult is not exposed to the sun, there is a dietary requirement that the National Research Council's Food and Nutrition Board recommends to be [micro]g (200 IU) per day.[19] The Recommended Dietary Allowance (RDA) is too low for the homebound and institutionalized elderly. Hypovitaminosis D was found in the elderly African-American population, and intake of vitamin D was far below the RDA in older female subjects.[15] In the United States, milk is the major food source fortified with vitamin D. Processed cow's milk contains 10 [micro]g of cholecalciferol (400 IU) per quart and contributes a significant amount of the nutrient to the adult who consumes milk. However, lactose intolerance is a common problem in the older adult and often results in reduced milk consumption. Butter, egg yolk, fish liver oils, and fortified margarine are other dietary sources of the vitamin. The institutionalized elderly may need vitamin D supplementation to assure adequate intake.[14]

CONCLUSION

Vitamin D is essential for the overall well-being of the elderly, but its role is often neglected, resulting in disturbed calcium balance and bone homeostasis. Although risk factor for both deficiencies and excess may be present, deficiency status appears more common. The current RDA for vitamin D does not adequately cover the requirement of the nutrient as the body ages.[20] The RDA needs to be reassessed and probably increased to compensate for the related changes in the synthesis and metabolism of the nutrient that occur in the elderly. In assessing dietary adequacy of vitamin D intake, it is important not to assume that the older adult is consuming milk products. The need for supplementation must be accurately determined and the appropriate amount to ingest carefully considered. The fact that this nutrient can be toxic if ingested in large amounts must be thoroughly understood by the patient and by health care providers.

REFERENCES

[1] DeLuca HD. Vitamin D: 1993. Nutr Today 1993; 28(6):6 -11 . [2] Holick MF. Vitamin D: new horizons for the 21st century. Am J Clin Nutr 1994;60:619-30. [3] Holmes RP, Kummerow FA. The Vitamin D status of elderly Americans. Am J Clin Nutr 1988;38:335 6. [4] 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. [5] Gallagher JC. Vitamin D metabolism and therapy in elderly subjects. South Med 1 1992;85: (2S)43-7. [6] Chapuy MC et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-42. [7] Caniggia A, Gennari, C, Bianchi, V, Guideri R. Intestinal absorption of 45Ca in senile osteoporosis. Acta Med Scand 1963;173:613-17. [8] Schwartzman MS, Franck WA. Vitamin D toxicity complicating the treatment of senile, postmenopausal, and glucocorticoid-induced osteoporosis. Am I Med 1987j82:224-30. [9] Fujiti T. Vitamin D in the treatment of osteoporosis. Publ Soc Exp Biol Med 1992;199:394-9. [10] Reid IR, Ames RW, Evans MC, Gamble GD, Sharpe SJ. Effects of calcium supplementation on bone loss in postmenopausal women. N Engl J Med 1993;328:460-4. [11] Brooks GB. Vitamin D and deafness. Br Med 1981;283:273-4. [12] Koplan JP, Annest JL, Layde PM, Rubin GL. Nutrient intake and supplementation in the United States (NHANES). Am J Publ Health 1986;76:287-9. [13] Jacobus CH et al. Hypervitaminosis associated with drinking milk. N Engl I Med 1992;326: 1173-37. [14] McMurtry CT, Young SE, Downs RW, Adler RA. Mild vitamin D deficiency and secondary hyperparathyroidism in nursing home patients receiving adequate dietary vitamin D. J Am Geriatr Soc 1992;40:343 7. [15] Perry HM et al. A preliminary report of vitamin D and calcium metabolism in older African Americans. J Am Geriatr Soc 1993;41:61216. [16] Morley JE. A place in the sun does not guarantee adequate vitamin D. J Am Geriatr Soc 1989;37:663-4. [17] Webb AE, Pilbeam C, Hanafin N, Holick MF. An evaluation of the relative contributions of exposure to sunlight and the diet to the circulating concentrations of 25-hydroxyvitamin D in the elderly nursing home population. Am Clin Nutr 1990;51:1075-81. [18] Thomson SP, Wilton TJ, Hoskinf DJ, White DA, Pawley E. Is vitamin D necessary for skeletal integrity in the elderly? J Bone Joint Surg 1990;72B:1053-6. [19] Food and Nutrition Board. Recommended Dietary Allowance. 10th ed. Washington DC: National Academy of Sciences, 1989. [20] Gloth FM, Tobin JD, Sherman SS, Hollis BW. Is the recommended dietary allowance for Vitamin D too low for the homebound elderly? J Am Geriatr Soc 1991;39:137-41. Cass Ryan is an associate professor and Elva James Mann Eminent Scholar Chair. She is a registered dietitian and earned her doctorate in nutrition from Texas Tech University. Please send correspondence to Dr. Ryan at Louisiana Tech University, College of Human Ecology, Ruston, LA 71272. Paul Eleazer is an associate professor and the director of the Division of Geriatrics in the Department of Internal Medicine at the University of South Carolina, School of Medicine. He is board certified in internal medicine and geriatrics. John Egbert is an assistant clinical professor in the Division of Geriatrics, Department of Internal Medicine at the University of South Carolina, School of Medicine. He is also the director of Primary Care at Palmetto Senior Care, a Program of All Inclusive Care for the Elderly (PACE) at Richland Memorial Hospital in Columbia, South Carolina.

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