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Original Article

Hypovitaminosis D in Medical Inpatients

Melissa K. Thomas, M.D., Ph.D., Donald M. Lloyd-Jones, M.D., Ravi I. Thadhani, M.D., M.P.H., Albert C. Shaw, M.D., Ph.D., Donald J. Deraska, M.D., Barrett T. Kitch, M.D., Eleftherios C. Vamvakas, M.D., Ph.D., Ian M. Dick, M.Sc., Richard L. Prince, M.D., and Joel S. Finkelstein, M.D.

N Engl J Med 1998; 338:777-783March 19, 1998

Abstract

Background

Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown.

Methods

We assessed vitamin D intake, ultraviolet-light exposure, and risk factors for hypovitaminosis D and measured serum 25-hydroxyvitamin D, parathyroid hormone, and ionized calcium in 290 consecutive patients on a general medical ward.

Results

A total of 164 patients (57 percent) were considered vitamin D–deficient (serum concentration of 25-hydroxyvitamin D, <15 ng per milliliter), of whom 65 (22 percent) were considered severely vitamin D–deficient (serum concentration of 25-hydroxyvitamin D, <8 ng per milliliter). Serum 25-hydroxyvitamin D concentrations were related inversely to parathyroid hormone concentrations. Lower vitamin D intake, less exposure to ultraviolet light, anticonvulsant-drug therapy, renal dialysis, nephrotic syndrome, hypertension, diabetes mellitus, winter season, higher serum concentrations of parathyroid hormone and alkaline phosphatase, and lower serum concentrations of ionized calcium and albumin were significant univariate predictors of hypovitaminosis D. Sixty-six percent of the patients who consumed less than the recommended daily amount of vitamin D and 37 percent of the patients with intakes above the recommended daily amount were vitamin D–deficient. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of hypovitaminosis D in a multivariate model. In a subgroup of 77 patients less than 65 years of age without known risk factors for hypovitaminosis D, the prevalence of vitamin D deficiency was 42 percent.

Conclusions

Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily amount and those without apparent risk factors for vitamin D deficiency.

Media in This Article

Figure 2Relation between Serum 25-Hydroxyvitamin D Concentrations and Mean (±SE) Serum Concentrations of Parathyroid Hormone in the Study Patients.
Figure 1Prevalence of Hypovitaminosis D among 290 Medical Inpatients.
Article

Vitamin D deficiency is a risk factor for osteopenia and bone fractures.1-5 In ambulatory elderly people whose average serum concentration of 25-hydroxyvitamin D was slightly low, supplementation with 20 μg (800 IU) of vitamin D and with calcium substantially reduced the risk of osteoporotic fractures, including hip fractures.6,7 Multiple studies have estimated the prevalence of hypovitaminosis D in selected populations at particular risk for vitamin D deficiency, such as residents of nursing homes and people over the age of 65, to be between 25 and 54 percent.8-11 However, the prevalence of hypovitaminosis D in more diverse patient populations has not been well characterized. Conditions associated with hypovitaminosis D, such as poor dietary intake, inadequate sun exposure, and chronic liver and renal diseases, are common in general medical inpatients, as is therapy with drugs that impair vitamin D activation or accelerate its clearance, such as phenytoin, carbamazepine, and rifampin. Thus, such inpatients may be at risk for vitamin D deficiency. Because replacement therapy is simple and reduces the risk of fractures, an understanding of the prevalence of vitamin D deficiency may alter routine medical practice and have important public health implications.

Methods

Study Subjects

We studied 150 patients admitted consecutively in March 1994 and 140 patients admitted consecutively in September 1994 to general medical wards at Massachusetts General Hospital. The months of March and September were chosen to represent the seasonal nadir and peak, respectively, of serum vitamin D concentrations in Boston.12 The study was approved by the Subcommittee on Human Studies of Massachusetts General Hospital, and oral consent was obtained from the patients (3 of 293 declined to participate).

A subgroup of 77 patients with no known risk factors for hypovitaminosis D was defined by excluding patients who were more than 65 years of age, housebound or living in a nursing home, or taking anticonvulsant drugs, or who had a chronic debilitating illness (cancer, acquired immunodeficiency syndrome, congestive heart failure, or chronic obstructive pulmonary disease), renal disease (defined as a serum creatinine concentration >1.5 mg per deciliter [133 μmol per liter], the presence of the nephrotic syndrome, or the need for dialysis), liver disease (defined as a serum bilirubin concentration >2.0 mg per deciliter [34 μmol per liter] or the presence of hepatitis or cirrhosis), or a condition causing malabsorption of nutrients (inflammatory bowel disease, chronic pancreatitis, or gastric or small-bowel resection).

Evaluation of Clinical Characteristics

Within 24 hours after admission, each patient's record was reviewed. The data collected included age, sex, race, and diagnoses, with emphasis on any history of liver disease, renal disease, gastric or small-bowel surgery, inflammatory bowel disease, pancreatitis, malabsorption, and therapy with anticonvulsant agents (phenytoin, phenobarbital, and carbamazepine), rifampin, or glucocorticoids. Each patient was classified as ambulatory, housebound, living in a nursing home, or homeless. The patients were not followed during the hospitalization, except to determine mortality during the incident admission.

Dietary and Sun-Exposure Interviews

Study physicians were trained by a research dietitian to obtain standardized histories of dietary vitamin D intake. A questionnaire was developed that included a list of foods containing vitamin D in amounts of at least 1.25 μg (50 IU) per serving,13 and average daily and weekly consumption of these foods was assessed. Regular use of multivitamins, vitamin D, or calcium supplements was noted. Exposure to the sun was rated with the use of a previously validated nine-point scale,14 which measured the degree and extent of recent sun exposure, the use of sunscreens, and recent travel to southern locations. Two hundred six patients completed both the dietary and sun-exposure interviews. The remaining 84 patients were unable to provide complete dietary and sun-exposure information because of impaired mental status and were excluded from the multivariate analyses.

Laboratory Studies

Morning blood samples were obtained from the patients after an overnight fast within 24 hours after admission. Serum parathyroid hormone was measured by a two-site immunoradiometric assay.15 Serum 25-hydroxyvitamin D was measured by competitive protein-binding assay (Nichols Institute, San Juan Capistrano, Calif.). Serum vitamin D–binding protein was measured by radioimmunoassay.16 Routine chemistries were measured by a Hitachi multichannel analyzer, and serum ionized calcium was measured by a gas analyzer (Nova Biomedical, Waltham, Mass.). The samples were analyzed in multiple assays; the interassay coefficients of variation were less than 6 percent for the measurements of parathyroid hormone and 8 to 14 percent for 25-hydroxyvitamin D.

Definition of Hypovitaminosis D

The patients were divided into three diagnostic categories according to their serum 25-hydroxyvitamin D concentrations: those with severe hypovitaminosis D (serum 25-hydroxyvitamin D concentration, less than 8 ng per milliliter [20 nmol per liter]), those with moderate hypovitaminosis D (serum 25-hydroxyvitamin D concentration, 8 to 15 ng per milliliter [20 to 37 nmol per liter]), and those with adequate vitamin D stores (serum 25-hydroxyvitamin D concentration, more than 15 ng per milliliter). The definition of severe hypovitaminosis D was based on the lower limit of normal of 9 ng per milliliter (22 nmol per liter) for serum 25-hydroxyvitamin D concentrations in New England as measured by chromatography in the reference laboratory (Nichols Institute). The definition of moderate hypovitaminosis D was determined according to the Nichols Institute's norms for serum 25-hydroxyvitamin D of 16 to 74 ng per milliliter (40 to 185 nmol per liter) in a competitive protein-binding assay (mean ±2 SD calculated from measurements in 208 normal adult subjects in Southern California, Virginia, and New England in the summer and early fall) and from published data demonstrating that serum parathyroid hormone concentrations are increased in patients who have serum 25-hydroxyvitamin D concentrations that are less than or equal to 15 ng per milliliter.11,17,18

Statistical Analysis

There were no differences between the characteristics of the patients studied in March and those of the patients studied in September, and the results were therefore combined. Associations between categorical variables and categories of serum 25-hydroxyvitamin D concentrations were examined by using Pearson's chi-square tests. Kruskal–Wallis nonparametric analysis of variance was used to examine associations between continuous variables and categories of serum 25-hydroxyvitamin D concentrations. For multivariate analyses, vitamin D deficiency was defined as a serum 25-hydroxyvitamin D concentration less than or equal to 15 ng per milliliter. Associations with categorical variables were examined with the use of two-tailed Fisher's exact tests, and associations with continuous variables were examined with Mann–Whitney rank-sum tests.

Stepwise discriminant analyses were used to identify the variables that best predicted vitamin D deficiency and to calculate the accuracy of those predictors.19 The accuracy of the computed discriminant function was estimated by a jackknifed classification matrix.20 Variables associated with serum 25-hydroxyvitamin D concentrations in univariate analyses (P<0.10) were eligible for inclusion in the multivariate models.

Results

Clinical Characteristics

The characteristics of the patients are shown in Table 1Table 1Base-Line Clinical Characteristics of the 290 Patients.. Few patients had conditions often associated with hypovitaminosis D or were taking medications known to alter vitamin D metabolism (Table 2Table 2Prevalence of Conditions Often Associated with Hypovitaminosis D in the 290 Patients.). Three patients with serum 25-hydroxyvitamin D concentrations of less than 8 ng per milliliter, two patients with concentrations between 8 and 15 ng per milliliter, and three patients with values greater than 15 ng per milliliter died while in the hospital.

Prevalence of Hypovitaminosis D

The prevalence of hypovitaminosis D in the 290 patients was 57 percent (164 patients) (Figure 1Figure 1Prevalence of Hypovitaminosis D among 290 Medical Inpatients.). Sixty-five patients (22 percent) had severe hypovitaminosis D, and an additional 99 patients (34 percent) had moderate hypovitaminosis D. Sixty-three percent of the patients studied in March and 49 percent of those studied in September had serum 25-hydroxyvitamin D concentrations of 15 ng per milliliter or less. The mean (±SD) serum 25-hydroxyvitamin D concentration for all 290 patients was 15±9 ng per milliliter. Serum parathyroid hormone concentrations rose steeply as serum 25-hydroxyvitamin D concentrations declined below 15 ng per milliliter (Figure 2Figure 2Relation between Serum 25-Hydroxyvitamin D Concentrations and Mean (±SE) Serum Concentrations of Parathyroid Hormone in the Study Patients.), indicating a physiologic response, presumably through hypocalcemia, to the low serum 25-hydroxyvitamin D concentrations.

Variables Associated with Hypovitaminosis D

Anticonvulsant-drug therapy (P = 0.04), renal dialysis (P = 0.007), nephrotic syndrome (P = 0.04), and winter season (P = 0.04) were significantly associated with hypovitaminosis D. There were trends toward associations with housebound status (P = 0.07) and female sex (P = 0.08). Of the 60 housebound patients, 42 (70 percent) had serum 25-hydroxyvitamin D concentrations of 15 ng per milliliter or less. Of the 18 most frequently noted diagnoses (each affecting at least 20 patients), only hypertension (P = 0.009) and diabetes mellitus (P = 0.04) were significantly associated with hypovitaminosis D.

Lower vitamin D intake, exposure to ultraviolet light, and serum concentrations of ionized calcium and albumin, and higher serum concentrations of parathyroid hormone and alkaline phosphatase were associated with lower 25-hydroxyvitamin D concentrations. There was no association between serum concentrations of vitamin D–binding protein and 25-hydroxyvitamin D (Table 3Table 3Association of Continuous Variables with Vitamin D Deficiency.).

Vitamin D Intake and Sun Exposure

Serum 25-hydroxyvitamin D concentrations were higher in the patients with higher vitamin D intakes (Figure 3AFigure 3Relation between Daily Vitamin D Intake (Panel A) and Ultraviolet-Light Exposure (Panel B) and Mean (±SE) Serum 25-Hydroxyvitamin D Concentrations in the Study Patients. and Figure 3B). The mean (±SD) daily vitamin D intake reported was 7.5±7.3 μg (300±292 IU). Sixty-seven percent of the patients reported vitamin D intakes less than the recommended daily amount for their age (5 μg for adults 19 to 50 years old, 10 μg for adults 51 to 70 years old, and 15 μg for adults 71 or older21). Moderate or severe hypovitaminosis D was present in 66 percent of the patients reporting daily vitamin D intakes less than the recommended amount for their age and in 37 percent of the patients reporting daily vitamin D intakes in excess of the recommended amount for their age. Forty-six percent of the patients who reported taking multivitamins and 60 percent of those who reported not taking multivitamins had hypovitaminosis D. Increasing exposure to ultraviolet light was also associated with higher serum 25-hydroxyvitamin D concentrations (Figure 3A and Figure 3B).

Predictors of Hypovitaminosis D

Independent predictors of hypovitaminosis D were identified by stepwise multivariate discriminant analysis in which risk factors for vitamin D deficiency that had a univariate association (P<0.10) with vitamin D deficiency were included in the model. These factors were inadequate vitamin D intake, insufficient sun exposure, winter season, older age, female sex, anticonvulsant-drug therapy, dialysis, nephrotic syndrome, and being housebound. Inadequate vitamin D intake, winter season, and being housebound were significant independent predictors of hypovitaminosis D and could correctly classify 59 percent of the patients (P<0.001). The addition of the other six variables to the model increased the accuracy of the classification to 68 percent.

Prevalence of Hypovitaminosis D in the Patients with No Known Risk Factors

The mean age of the 77 patients in the subgroup with no known risk factors for vitamin D deficiency was 44±14 years. Forty-eight (62 percent) were men and 29 (38 percent) were women. The most common diagnoses in this subgroup were coronary artery disease (39 percent), hypertension (29 percent), diabetes mellitus (17 percent), hypercholesterolemia (16 percent), substance abuse (16 percent), asthma (16 percent), atrial fibrillation (8 percent), and syncope (8 percent). Among these patients, 32 (42 percent) were vitamin D–deficient, of whom 11 had serum 25-hydroxyvitamin D concentrations of less than 8 ng per milliliter and 21 had values between 8 and 15 ng per milliliter (Figure 1).

Discussion

We found a high prevalence (57 percent) of hypovitaminosis D in unselected general medical inpatients. In previous studies of elderly housebound people and nursing home residents, one quarter to one half were vitamin D–deficient.8-11 The patients we studied were younger than those in many previous studies, and only a minority were housebound or residents of a nursing home. Thus, our patients may have been more representative of the general population than those reported on previously.

It is unclear why the prevalence of vitamin D deficiency was so high. Low levels of ultraviolet-light exposure and vitamin D intake are probably important factors. The definition of vitamin D deficiency may also affect estimates of its prevalence. We defined categories of severe and moderate hypovitaminosis D on the basis of a series of observations in the literature.11,17,18,22 Serum parathyroid hormone concentrations have been found to increase when serum 25-hydroxyvitamin D concentrations fall below 15 ng per milliliter in elderly housebound people,11 and we found a similar relation in the patients we studied. In postmenopausal women, bone density is lower in those who have serum 25-hydroxyvitamin D concentrations of 15 ng per milliliter or less.23 Thus, there is strong physiologic evidence that serum 25-hydroxyvitamin D concentrations of 15 ng per milliliter or less are insufficient to maintain adequate skeletal integrity.

In fact, other investigators have reported that serum 25-hydroxyvitamin D concentrations above 15 ng per milliliter may not be sufficient to exclude hypovitaminosis D. There are seasonal changes in both serum parathyroid hormone concentrations and bone density in patients with serum 25-hydroxyvitamin D concentrations of 37 ng per milliliter (92 nmol per liter) or less.24,25 Increasing patients' serum 25-hydroxyvitamin D concentrations to 20 ng per milliliter (50 nmol per liter) through supplementation with vitamin D increases serum 1,25-dihydroxyvitamin D concentrations,26 and some experts have suggested that serum 25-hydroxyvitamin D concentrations should exceed 30 ng per milliliter (75 nmol per liter). Had we used such a definition of vitamin D deficiency to categorize our patients, 93 percent of them would have been considered vitamin D–deficient.

Previous estimates of the prevalence of hypovitaminosis D in outpatients were substantially lower than in our study.9,27 The higher prevalence of vitamin D deficiency in this study may be related in part to the relatively low solar intensity in New England12 or to the nature of our patients. Medical inpatients are more likely than outpatients to have conditions associated with vitamin D deficiency. However, 42 percent of our healthy subgroup were vitamin D–deficient, providing evidence that these results are not attributable to severity of illness.

A large number of patients with vitamin D intakes above the recommended daily amount were vitamin D–deficient. Because milk products contain variable amounts of vitamin D,28 vitamin D intake may have been overestimated. Multivitamin therapy was not protective. This finding might reflect inaccurate self-reporting, because the majority of multivitamin supplements contain 10 μg of vitamin D. Our data support the conclusion that the current recommended daily intakes of vitamin D, which were recently revised upward,21 may be insufficient. For example, a daily intake of 5 μg of vitamin D was less effective in preventing bone loss than a daily intake of 20 μg in postmenopausal women.29 Moreover, daily administration of 10 μg of vitamin D in patients with high dietary calcium intakes did not protect against fractures,30 whereas 20 μg of vitamin D per day plus calcium decreased the risk of fractures in elderly women with lower dietary calcium intakes.6,7

Our multivariate models could predict vitamin D deficiency with an accuracy of 59 to 68 percent, making them only slightly more accurate than predictions that would have occurred by chance. Because the assessment of common clinical risk factors failed to identify many patients with hypovitaminosis D, screening by using serum 25-hydroxyvitamin D concentrations may be required to identify patients with vitamin D deficiency.

The importance of vitamin D deficiency is related primarily to bone integrity. Because vitamin D is required for calcium homeostasis, secondary hyperparathyroidism may develop in patients with vitamin D deficiency. With increasing severity of hypovitaminosis D and secondary hyperparathyroidism, patients progress from states of increased bone turnover and decreased bone mass to states of impaired, and ultimately absent, mineralization with generalized osteomalacia.1 Many patients with osteoporotic fractures have low serum 25-hydroxyvitamin D concentrations.4,5 Because treatment with vitamin D and calcium increases bone mass and substantially reduces the risk of fractures,3,6,7,31 the diagnosis of vitamin D deficiency warrants attention. In addition to its effect on the skeleton, hypovitaminosis D may affect other organ systems adversely, resulting in muscle weakness and pain,2 progression of osteoarthritis,32 or impaired macrophage activation.33

Our study had several limitations. Many patients were acutely ill. Although it is possible that acute illness could have suppressed cutaneous vitamin D synthesis, the half-life of serum 25-hydroxyvitamin D is approximately three weeks,34 so an arrest of synthesis should not have affected serum 25-hydroxyvitamin D concentrations rapidly. Substantial reductions in serum concentrations of vitamin D–binding protein are needed to lower serum 25-hydroxyvitamin D concentrations. Such reductions occur in only a few clinical conditions, such as severe hepatic failure, nephrotic syndrome, and severe malnutrition,2,35 which were rare in our patients. Furthermore, we found no relation between serum concentrations of 25-hydroxyvitamin D and those of vitamin D–binding protein in our patients. Thus, it seems unlikely that changes in concentrations of serum vitamin D–binding protein due to acute illness can explain our findings. Finally, the higher serum parathyroid hormone concentrations in the patients with low serum 25-hydroxyvitamin D concentrations attest to the physiologic importance of the latter. In fact, we may have underestimated the prevalence of hypovitaminosis D by not identifying patients with low serum 1,25-dihydroxyvitamin D concentrations despite adequate serum 25-hydroxyvitamin D concentrations.

In conclusion, we found a high prevalence of hypovitaminosis D in unselected medical inpatients in the United States. Standard clinical risk factors were poor predictors of vitamin D deficiency. Maintaining vitamin D intake at the level of the current recommended daily amount or using multivitamins may not be sufficient to ensure adequate vitamin D stores. Because of the potential adverse effects of vitamin D deficiency on the skeleton and other organ systems, widespread screening for vitamin D deficiency or routine vitamin D supplementation should be considered.

Supported by grants from the National Institutes of Health (RR-1066, R29-DK43341, DK07028, and DK02476) and the American Kidney Fund.

We are indebted to the nursing staff of the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital for processing patient samples; to the resident physicians and staff of the Bigelow medical services for facilitating patient participation; to Deborah Lentz, R.D., Ellen Anderson, R.D., and Jane Hubbard, R.D., for conducting dietary analyses; to Dr. Gino Segre of the endocrine laboratory for assisting with measurements of serum parathyroid hormone and 25-hydroxyvitamin D; to Dr. Roger Bouillon for providing vitamin D–binding protein antiserum; to Dr. John T. Potts, Jr., for encouraging and supporting research by house staff; and to Dr. Robert Neer for providing scholarly advice.

Source Information

From the Endocrine Unit (M.K.T., D.J.D., J.S.F.), Department of Medicine (D.M.L.-J., R.I.T., A.C.S., B.T.K.), and the Department of Pathology (E.C.V.), Massachusetts General Hospital and Harvard Medical School, Boston; and the Department of Medicine, University of Western Australia, Perth (I.M.D.), and the Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands (R.L.P.) — both in Australia.

Address reprint requests to Dr. Finkelstein at the Endocrine Unit, Bulfinch 327, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

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