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High Frequency of Vitamin D Deficiency
in Ambulatory HIV-Positive Patients
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AIDS RESEARCH AND HUMAN RETROVIRUSES
Volume 25, Number 1, 2009
M. Rodriguez,1,2 B. Daniels,1 S. Gunawardene,3 and G.K. Robbins1
1Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
2University of Alabama at Birmingham-Montgomery Health Center, University of Alabama at Birmingham, Montgomery, Alabama
36116.
3Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.c
"As expected, low vitamin D intake was associated with severe 25-D deficiency. We also found a high frequency of secondary hyperparathyroidism, possibly from vitamin D deficiency. One unexpected finding was a possible association between concurrent antiretroviral use and elevated PTH levels."
"Subclinical vitamin D deficiency is common in the general population and has been shown to correlate with osteoporosis"..... "A high prevalence of 25-D deficiency has been reported in some HIV-infected cohorts.......in patients with HIV-associated lipodystrophy in the southeastern United States (92%)"..... The optimal 25-D concentration in serum is controversial . The current normal value for serum concentration is 20 ng/ml..... "Lower vitamin D intake was significantly associated with severe (< /=10 ng=ml) 25-D deficiency ( p=0.01) and tended to be associated with moderate 25-D deficiency ( p=0.08, both Wilcoxon rank-sum test). There was a suggestion that lower vitamin D intake (<250 IU) and lack of regular exercise were associated with moderate 25-D deficiency (OR 3.3; 95% CI 1.0, 10.3, p=0.05 and OR 3.1; 95% CI 0.9, 11.1, p=0.09, respectively)."....... "Elevated PTH serum levels (>60 pg=ml) were significantly associated with concurrent antiretroviral use ( p=0.01); of the subjects who were not taking antiretrovirals, none had elevated PTH levels, whereas 40% of those on antiretrovirals had elevated PTH. Elevated PTH levels were also significantly associated with low daily calcium intake (<1000 mg) (p=0.03) and tended to be associated with low daily vitamin D intake (<250 IU) (p=0.07, both Wilcoxon rank-sum test)."....... "All of our subjects were normocalcemic; however, low-normal serum calcium (8.5-8.9 vs. >/=9mg/dl) was associated with increased PTH levels (OR=13.85, CI 1.48, 129.9, p=0.0116). Similar to other reports, PTH levels were negatively correlated with 25-D levels (r= -0.48; p=0.0003).21,23"
"Serum 25-D levels of >32 ng/ml may be needed to maintain normal calcium absorption and PTH levels.37,42 As higher PTH levels tend to be seen only in individuals with low 25-D vitamin levels and low daily calcium intake (<800mg/day),23 a daily vitamin D intake of at least 700-800 IU taken with 1200-1500mg of calcium may be necessary for bone health.24,26,38,39,42"
Abstract
Several reports have suggested an increased prevalence of osteopenia and osteoporosis in HIV-infected individuals. Vitamin D deficiency may be a risk factor for osteoporosis and bone fractures. We aimed to determine the prevalence of vitamin D insufficiency in an outpatient HIV clinic in Boston. We collected serum levels of 25-OH vitamin D and evaluated calcium and vitamin D intake in adult HIV-positive outpatients during the winter and spring of 2005. Fifty-seven subjects were enrolled. The prevalence of moderate (< /=20 and>10
Ng/ml) and severe (< /=10 ng/ml) 25-OH vitamin D deficiency was 36.8% and 10.5%, respectively. Lower vitamin D intake was significantly associated with severe 25-OH vitamin D deficiency (p=0.01). Lactose intolerance tended to be associated with severe vitamin D deficiency (p=0.08). Antiretroviral use and low daily calcium intake were significantly associated with elevated parathyroid hormone levels ( p=0.01 and 0.03, respectively). Vitamin D deficiency was frequent in ambulatory HIV-positive patients. HIV-infected individuals living in areas with low exposure to ultraviolet light during winter may benefit from vitamin D supplementation.
"The majority of patients were receiving antiretroviral treatment and had CD4 cell counts >350 cells=ml with undetectable viral loads....
....We found a high frequency of vitamin D deficiency in HIV-infected outpatients followed in the northeastern United States during and immediately after the winter months, when ambient sunlight is too weak for adequate vitamin D synthesis. As expected, low vitamin D intake was associated with severe 25-D deficiency. We also found a high frequency of secondary hyperparathyroidism, possibly from vitamin D deficiency. One unexpected finding was a possible association between concurrent antiretroviral use and elevated PTH levels.....
....a daily vitamin D intake of at least 700-800 IU taken with 1200-1500mg of calcium may be necessary for bone health.....
....We found a tendency for higher frequency of moderate 25-D deficiency in subjects receiving NNRTI. The use of efavirenz was associated with vitamin D deficiency in a case report; this association may be explained by hydroxylation and inactivation of vitamin D through the induction of CYP3A4 and CYP24, respectively.34 While none of our patients had frank hypocalcemia, other studies have reported significant rates of hypocalcemia in HIV-infected individuals.....
.....A recent report found improved 25-D and PTH levels after supplementation was given to HIV-infected patients with vitamin D deficiency.43.....
.....Our study had several limitations. First, the study was cross-sectional and limited to the winter and spring of 2005. In addition, the number of subjects was small and limited to a single clinic in Boston...... We did not include institutionalized or nonambulatory patients who may be at higher risks for vitamin D deficiency.....exposure to ultraviolet light and bone mineral density were not measured.....
.....In conclusion, we found a high frequency of vitamin D deficiency in ambulatory HIV-infected patients seen in a Boston HIV clinic during mid-winter and spring months. The association of vitamin D deficiency with elevated blood PTH suggests that the vitamin D deficiency is physiologically significant, and this vitamin D deficiency's inverse association with supplemental vitamin D intake suggests that HIV-infected individuals living in this and geographically similar regions may benefit from vitamin D supplementation, at least during the winter season. Interventional studies are warranted to define the effects of vitamin D and calcium supplements on serum PTH, bone health, and innate immune
defenses in HIV-infected patients."
Introduction
In recent years there have been several reports suggesting an increased prevalence of osteopenia and osteoporosis in HIV-infected patients.1-9 Possible explanations include abnormalities in bone turnover caused by HIV infection itself; abnormalities in osteoclast activity induced by cytokines such as tumor necrosis factor (TNF-a) and interleukin-6 or by alterations in the nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) system; impaired bone mineralization; and an increased prevalence of risk factors for reduced bone mineral density, such as hypogonadism, androgen and=or estrogen deficiency, low body weight, malnutrition, malabsorption, opiate use, cigarette smoking, lactic acidemia, and glucocorticoid and alcohol use.8-16 The association of antiretroviral therapy with osteopenia and osteoporosis, particularly with protease
inhibitors and some nucleoside=nucleotide reverse transcriptase inhibitors, has been proposed but remains controversial. 4-6,8,9,11,12,14,17,18 Until recently, data to suggest an increased prevalence of fractures in HIV-infected patients were lacking. However, a recent study reported a higher prevalence of fractures in HIV-infected individuals compared with uninfected individuals, including vertebral, hip, and wrist fractures. There is concern that osteoporosis and osteoporotic fractures will become frequent comorbidities in HIV-infected patients as they age.19
Vitamin D can be ingested either through diet or supplements, or synthesized in the skin following exposure to ultraviolet radiation. In the liver, vitamin D is hydroxylated to 25-hydroxyvitaminD(calcidiol, 25-D). Some of the circulating 25-D is further 1a-hydroxylized in the kidneys and other tissues to 1,25-OH vitamin D (calcitriol, 1,25-hydroxyvitamin D, 1,25-D), which is the active form of vitamin D. Vitamin D is deposited in adipose tissue, but the depot is not large enough to prevent seasonal variations in plasma concentrations. Vitamin D stores can be estimated by measuring serum 25-D concentrations due to its half-life of approximately 2 weeks. Serum vitamin D and=or serum 1,25-D do not reliably
reflect vitamin D body stores.20
Subclinical vitamin D deficiency is common in the general population and has been shown to correlate with osteoporosis. 20 In temperate latitudes near sea level, cutaneous production of vitamin D almost ceases in winter. In previous studies from the northeastern United States, vitamin D deficiency has been reported in over half of individuals.21-23 Vitamin D supplementation may be beneficial for patients at risk for osteoporosis and osteopenia, particularly when used together with calcium supplements.24-26
A high prevalence of 25-D deficiency has been reported in some HIV-infected cohorts: in treated and untreated patients in Spain (86%), in heavily pretreated patients in Italy (81.25%), in patients with HIV-associated lipodystrophy in the southeastern United States (92%), in adolescents and young adult patients in the United States (87%), and in infected children from New York City (23%), among others. 6,27-31 Other studies have reported lower 25-D levels in HIV-infected patients compared to uninfected controls.30 The frequency of 25-D deficiency has also been reported to be higher in HIV-infected African-Americans.29 A number of studies have reported low levels of 1,25-D in patients with advanced HIV infection.3,15,30,32,33 Proinflammatory cytokines such as TNF-a may cause a defect in renal 1ahydroxylation of 25-D to 1,25-D.30 The role of highly active antiretroviral therapy (HAART) in vitamin D deficiency is not clear; protease inhibitors may impair the bioactivation of 25-D to 1,2-D,32 and a case report has described severe 25-D deficiency after starting efavirenz.34 However, a recent study from Spain found higher 25-D levels in patients receiving HAART compared to untreated patients.35 A small study of HIV-infected patients reported an association between low 1,25-D levels and mortality.32 There are limited published data on vitamin D levels in HIV-infected adults in the northeastern United States. Therefore, as patients are living healthier and longer on current antiretroviral therapy, we set out to define the prevalence of and correlates for vitamin D deficiency in our outpatient population.
Materials and Methods
Adult HIV-positive outpatients were recruited from the Infectious Disease Clinic at Massachusetts General Hospital (MGH) during the winter and spring. Patients with conditions known to be associated with vitamin D deficiency were excluded: recent hospitalization, chronic renal failure (serum creatinine>1.5mg/dl), nephrotic syndrome, pancreatic insufficiency, chronic severe liver disease (direct bilirubin>2mg/dl), active hepatitis or cirrhosis, active inflammatory bowel disease, gastric or small-bowel resection, active malignancy, and active or recent use (within 3 months) of carbamazepine, systemic glucocorticoids, growth hormone, isoniazid, phenobarbital, phenytoin, or rifampin. All subjects signed an informed consent. The study was approved by the Partners Institutional Review Board.
Subjects were asked to verify their current medications and were asked about exercise, vitamin use, and lactose intolerance. Daily intake of calcium and vitamin D was assessed using a previously validated questionnaire administered by a research assistant.21 Medications, medical problems, and most recent laboratory values were extracted from the medical records (CD4 cell count, viral load, and albumin). Serum 25-D and 1,25-D levels were measured by Immunoassay IRA (DiaSorin, Stillwater, MN) at the MGH clinical laboratory or at Quest Laboratory. Serum total calcium, intact parathyroid hormone (PTH), and inorganic phosphate were measured by the MGH clinical laboratory.36
A 25-OH vitamin D deficiency was defined as moderate if the serum concentration was < /=20 ng/ml and > 10 ng/ml, or as severe if the concentration was < /=10 ng/ml. Medians and interquartile ranges were calculated. Fisher's exact test was used to calculate odds ratios and 95% confidence intervals (95% CI) for categorical indicators. Bivariate and multivariate analyses were performed, and multivariate linear regression and logistic regression models were created. Analyses were conducted using SAS version 8 (SAS Institute, Cary, NC).
Results
Patients were recruited during their regularly scheduled ambulatory care visits at the MGH HIV Clinic. No inpatients were included in the study. Fifty-seven subjects were enrolled between 2/25/05 and 6/8/05. One subject did not complete the dietary questionnaire. All patients were ambulatory; none was bedridden. Serum inorganic phosphate and PTH levels were not measured in one and two subjects, respectively.
Table 1 shows demographic and treatment characteristics of the subjects. The median age was 46 (range 26-66 years) and 77% were male. The majority of patients were receiving antiretroviral treatment and had CD4 cell counts >350 cells/ul with undetectable viral loads. Table 2 shows dietary and lifestyle characteristics.
The prevalence of moderate or severe (< /=20 ngml) and severe (< /=10 ngml) 25-D deficiency in this cohort was 36.8% and 10.5%, respectively. Using a definition of 25D deficiency that has been proposed by some authors (#< /=2 ng=ml), 74.4% of this cohort was deficient.37-39 Table 3 shows median and interquartile laboratory results and proportion of subjects with abnormal values. All subjects had normal serum albumin levels and none had hypercalcemia.
Lower vitamin D intake was significantly associated with severe (< /=10 ng=ml) 25-D deficiency ( p=0.01) and tended to be associated with moderate 25-D deficiency ( p1/40.08, both Wilcoxon rank-sum test). There was a suggestion that lower vitamin D intake (<250 IU) and lack of regular exercise were associated with moderate 25-D deficiency (OR 3.3; 95% CI 1.0, 10.3, p=0.05 and OR 3.1; 95% CI 0.9, 11.1, p=0.09, respectively).
Subjects reporting lactose intolerance tended to have severe 25-D deficiency; however, this was not statistically significant (OR 7.8; 95% CI 1.0, 61.5, p=0.08).
Moderate 25-D deficiency tended to be more likely in the subjects on HAART receiving nonnucleoside reverse transcriptase inhibitors (NNRTIs) (OR 3.03; 95% CI 0.99, 9.27, p=0.06). Multivariate modeling did not significantly alter the results of the bivariate analysis.
Elevated PTH serum levels (>60 pg=ml) were significantly associated with concurrent antiretroviral use ( p=0.01); of the subjects who were not taking antiretrovirals, none had elevated PTH levels, whereas 40% of those on antiretrovirals had elevated PTH. Elevated PTH levels were also significantly
associated with low daily calcium intake (<1000 mg) (p=0.03) and tended to be associated with low daily vitamin D intake (<250 IU) ( p=0.07, both Wilcoxon rank-sum test). Serum calcium analyzed as a continuous variable was not significantly associated with higher PTH levels ( p=0.12). All of our subjects were normocalcemic; however, low-normal serum calcium (8.5-8.9 vs. >/=9mg/dl) was associated with increased PTH levels (OR=13.85, CI 1.48, 129.9, p=0.0116).
Similar to other reports, PTH levels were negatively correlated with 25-D levels (r= -0.48; p=0.0003).21,23
Discussion
The primary role of vitamin D is to maintain bone integrity. Individuals deficient in 25-D commonly develop secondary hyperparathyroidism, increased bone turnover, and reduced bone mineralization.21 The effects of vitamin D extend beyond bone metabolism. Vitamin D appears to have an effect in innate immune responses, T lymphocyte and monocyte/macrophage activation, and proposed associations with tuberculosis, diarrhea, and respiratory infections.30,40,41 Vitamin D deficiency may also adversely affect other organ systems, impair normal cell growth, lead to muscle weakness and pain, recurrent falls, and progression of osteoarthritis, and has been associated with colon cancer, insulin resistance, higher levels of hemoglobin A1C, and higher risk of nursing home admissions. 21,37,42,43 A recent report also linked vitamin D deficiency to increased cardiovascular disease.44
The optimal 25-D concentration in serum is controversial. The current normal value for serum concentration is 20 ng/ml, and the recommended dietary allowances (RDA) of vitamin D in the United States are 200 IU for children, adolescents, and adults up to age 50 years, 400 IU for adults aged 51-70 years, and 600 IU for those aged 71 years and older; however, some experts believe that the current recommendations for 25-D levels fall far short of levels for optimum health and long-term disease prevention.37-39,42 In our study,
almost half of the patients had a daily vitamin D intake below the RDA, and 76% had a daily intake below 400 IU. Serum 25-D levels of >32 ng/ml may be needed to maintain normal calcium absorption and PTH levels.37,42 As higher PTH
levels tend to be seen only in individuals with low 25-D vitamin levels and low daily calcium intake (<800mg/day),23 a daily vitamin D intake of at least 700-800 IU taken with 1200-1500mg of calcium may be necessary for bone health.24,26,38,39,42
We found a high frequency of vitamin D deficiency in HIV-infected outpatients followed in the northeastern United States during and immediately after the winter months, when ambient sunlight is too weak for adequate vitamin D synthesis. As expected, low vitamin D intake was associated with severe 25-D deficiency. We also found a high frequency of secondary hyperparathyroidism, possibly from vitamin D deficiency. One unexpected finding was a possible association between concurrent antiretroviral use and elevated PTH levels.
Secondary hyperparathyroidism was uncommon in a study of hypocalcemic HIV-infected patients with more advanced disease in pre-HAART.45 The authors of that study proposed an inadequate response of parathyroid cells in the setting of hypocalcemia in AIDS as a mechanism to explain their findings. Our patients had less advanced immunosuppression and the majority were taking HAART, so perhaps they were able to develop a state of normocalcemic secondary hyperparathyroidism from vitamin D deficiency that sicker patients with HIV infection could not develop. However, the etiology for this association remains unclear and should be explored further. The frequency of 1,25-D
deficiency in our study was low; other studies have reported a higher prevalence of 1,25-D deficiency in patients with more advanced HIV disease, and some authors have suggested an association with advanced immune suppression.
3,15,30,32,33 We found a tendency for higher frequency of moderate 25-D deficiency in subjects receiving NNRTI. The use of efavirenz was associated with vitamin D deficiency in a case report; this association may be explained by hydroxylation and inactivation of vitamin D through the induction of CYP3A4 and CYP24, respectively.34 While none of our patients had frank hypocalcemia, other studies have reported significant rates of hypocalcemia in HIV-infected individuals, 45,46 perhaps explained by more advanced disease, malnutrition,
hypoalbuminemia, and 25-D deficiency. A recent report found improved 25-D and PTH levels after supplementation was given to HIV-infected patients with vitamin D deficiency.43
Our study had several limitations. First, the study was cross-sectional and limited to the winter and spring of 2005. In addition, the number of subjects was small and limited to a single clinic in Boston. The small sample size may have reduced
our power to demonstrate significant associates with vitamin D deficiency. In the majority of our patients, HIV infection was well-controlled and they had relatively preserved CD4 counts, which could have affected the results. We did not measure ionized calcium. The diagnosis of lactose intolerance was based on self-reports and was not confirmed with standardized tests. We did not include institutionalized or nonambulatory patients who may be at higher risks for vitamin D deficiency. Finally, exposure to ultraviolet light and bone mineral density were not measured.
In conclusion, we found a high frequency of vitamin D deficiency in ambulatory HIV-infected patients seen in a Boston HIV clinic during mid-winter and spring months. The association of vitamin D deficiency with elevated blood PTH suggests that the vitamin D deficiency is physiologically significant, and this vitamin D deficiency's inverse association with supplemental vitamin D intake suggests that HIV-infected individuals living in this and geographically similar
regions may benefit from vitamin D supplementation, at least during the winter season. Interventional studies are warranted to define the effects of vitamin D and calcium supplements on serum PTH, bone health, and innate immune defenses in HIV-infected patients.
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