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Community and International Nutrition

Hypovitaminosis D Is Common among Pulmonary Tuberculosis Patients in Tanzania but Is Not Explained by the Acute Phase Response^1,2

³ Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, 1958 Frederiksberg, Denmark; ⁴ National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania; ⁵ National Institute for Medical Research, Mwanza Medical Research Centre, Mwanza, Tanzania; ⁶ Department of Clinical Biochemistry, Aalborg University Hospital, 9100 Aalborg, Denmark; ⁷ DBL–Centre for Health Research and Development, Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, 1958 Frederiksberg, Denmark; and ⁸ Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark

^* To whom correspondence should be addressed. E-mail: hfr{at}life.ku.dk.

	ABSTRACT

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
Vitamin D is essential to immune function, but little is known about the vitamin D status in equatorial populations. A cross-sectional study was conducted among pulmonary tuberculosis (PTB) patients in Mwanza, Tanzania to identify the predictors of their vitamin D status. Data on sociodemography, season, and intake of food, alcohol, tobacco, and soil were collected, anthropometric measurements taken, and serum ₁-antichymotrypsin (ACT), ferritin and soluble transferrin receptor (sTfR), and serum 25-hydroxy-(ergocalciferol+cholecalciferol) [25(OH)D] determined. Of the 655 patients studied, 79.7% (508/637) were culture-positive (PTB+) and 47.2% HIV infected. Mean serum ACT, an acute phase reactant, was 0.73 ± 0.25 g/L with 69.2% >0.6 g/L. Mean serum 25(OH)D was 86.6 ± 32.9 nmol/L, with 41.2% <75 nmol/L. Serum 25(OH)D was highest during the harvest season, May to July, compared with the remaining year. Single subjects had lower [10.4 (95% CI 4.0; 16.9) nmol/L] serum 25(OH)D concentrations than married subjects and PTB+ patients had concentrations lower [8.2 (95% CI 1.5; 14.9) nmol/L] than PTB– patients. Serum 25(OH)D increased with consumption of a large freshwater fish but not of small dried fish or other foods. BMI and serum TfR were positive predictors of serum 25(OH)D, whereas neither elevated serum ACT nor HIV were predictors. In conclusion, serum 25(OH)D is a valid measure of vitamin D status during the acute phase response. The lower concentrations in PTB+ patients may reflect lower sun exposure or increased utilization. The health consequences of hypovitaminosis D in low-income equatorial populations, at risk for both infectious and chronic diseases, should be studied.

	Introduction

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

There is evidence to suggest that vitamin D is a determinant of tuberculosis (TB).⁹ First, vitamin D binds to nuclear receptors resulting in the generation of the oxidative burst responsible for the intracellular antimycobacterial activity (2). Second, vitamin D receptor polymorphisms have been shown to provide differential protection toward TB, although a meta-analysis was inconclusive (3). Third, vitamin D supplementation has been shown to enhance immunity to mycobacteria among exposed adults (4). Fourth, a number of studies have demonstrated associations between low serum vitamin D and pulmonary TB (PTB) (5,6). However, an association between low serum vitamin D and TB based on case-control studies could reflect reverse causality, if TB infection impairs vitamin D status or if the accompanying acute phase response affects the validity of serum vitamin D as a marker of status.

Nevertheless, vitamin D is important to the immune system (7), and a recent prospective study among young Finnish men found that low serum 25-hydroxy-(ergocalciferol+cholecalciferol) [25(OH)D] was associated with increased risk of respiratory tract morbidity (8). Therefore, low vitamin D status in TB patients, whether cause or effect, might be an important determinant of treatment outcome and comorbidities.

As part of a trial among PTB patients in Tanzania (9,10), we collected baseline data on serum 25(OH)D. Here, we present data on the prevalence of hypovitaminosis D and on the role of sociodemographic characteristics, season, infections and the acute phase response, nutritional status, and dietary intake as predictors of serum 25(OH)D.

	Subjects and Methods

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Study area and population. The study was conducted in the Mwanza region, Tanzania, between August 2001 and July 2002. Mwanza City is at a latitude of 2.28 S, longitude 32.55 E, and an altitude of 1140 m (11). The rainfall per year is 700–1000 mm. The long rains last from February to April and the harvest occurs from May to July. Short rains may occur in November and January. In general, the study participants were unveiled, with their faces and often lower arms or lower legs exposed to the sun.

Most people in the study population ate several types of staple foods such as maize, cassava, sweet potato, rice, and millet. Fish was most common animal food eaten. Of the 3 commercial fish species in Lake Victoria, the Nile perch (Lates niloticus) is mainly exported, whereas the Nile tilapia (Oreochromis niloticus) and dagaa (Rastrineobola argentea) are consumed locally (12). Tilapia is a large fish of which the fillet is eaten, whereas dagaa is a sardine-like fish eaten whole after solar drying.

The study was carried out within the framework of the National TB and Leprosy Program (13), with diagnosis and treatment of PTB patients conducted in accordance with recommended standard procedures (14).

In brief, at each of the recruitment centers, in- and out-patients with suspected TB were asked to submit 3 sputum specimens (spot, morning, spot) for examination of acid-fast bacilli using the Ziehl-Neelsen staining technique. Newly diagnosed and relapse PTB patients aged 15 y were recruited. After informed consent, those who were sputum microscopy-positive were requested to submit a morning sputum specimen in a sterile universal bottle for confirmation at the Zonal TB Reference Laboratory at the Bugando Medical Centre, using microscopy after flourochrome (Auramine O) staining and culture on Lowenstein Jensen solid media (15).

Patients found microscopy-positive by Ziehl-Neelsen staining at the 5 recruitment centers and patients found sputum-negative but with a history, clinical manifestations, and X-ray indicative of TB according to WHO guidelines (14), provided an additional sputum sample that was examined by Auramine O staining and by culture at the Zonal TB Reference Laboratory. For the purpose of this study, patients were categorized as sputum culture-positive (PTB+) or culture-negative (PTB–) pulmonary TB patients.

Prior to TB treatment, questionnaire data on sociodemography, smoking, alcohol, and soil consumption were obtained from each patient. Marital status was categorized as married, single, and separated/widowed, where married included cohabiting and singles included never-married. In addition, data on the frequency of intake of tilapia and dagaa, beef, goat, chicken, fruits, and vegetables within the past 3 mo was recorded based on the categories: never, <1 d/wk, 1–3 d/wk, 4–6 d/wk, or daily.

    Anthropometric measurements. Height, weight, mid-upper arm circumference (UAC), and triceps skin-fold thickness were measured. From weight and height measurements, BMI was calculated as weight (kg)/height (m)². Arm muscle area (AMA) and arm fat area (AFA) were calculated by using the formulae AMA = [UAC – (triceps skin-fold thickness x )]²/(4 x ) and AFA = [UAC²/(4 x )] – AMA (16).

    Examination for infections. Stool and urine samples were also collected on 2 consecutive days and examined for eggs of geohelminths or Schistosoma spp, and blood smears were examined for malaria parasites, as previously described (17). HIV testing was conducted using 2 enzyme immunological assays and samples found positive were then tested for HIV-1 viral load using a RT-PCR (18).

    Biochemical measurements. Serum was separated and kept at –70°C for analyses at the Department of Human Nutrition, University of Copenhagen, Denmark. Serum ferritin was measured by a fluoroimmunoassay kit (DELFIA Ferritin; Wallac). The detection limit of the method was 0.5 µg/L and inter-run variation was 5% CV. Serum ₁-antichymotrypsin (ACT) was measured by automated turbidimetry (Cobas Mira Plus; Roche) using rabbit antihuman ACT (catalog no. Q 0367, DAKO). The inter-run variation was 3% CV. Serum soluble transferrin receptors (sTfR) was measured by an automated turbidimetry kit (IdeA sTfR-IT, catalog no. 67968, Orion Diagnostica) analyzed with Cobas Mira Plus, Roche. Inter-run variation was 8% CV.

We measured total serum 25(OH)D by a RIA with ¹²⁵I-labeled 25(OH)D [¹²⁵I-25(OH)D] as tracer using a kit from IDS (Immunodiagnostic-Systems) by Capio Diagnostics. Prior to analysis, the serum samples were precipitated and extracted. After centrifugation, an aliquot of the supernatant was incubated with ¹²⁵I-25(OH)D and a specific antibody against 25(OH)D for 1.5 h. The antibody-bound 25(OH)D and ¹²⁵I-25(OH)D were separated from the free by an incubation with anti-IgG bound to cellulose. After centrifugation, the supernatant was decanted and the radioactivity was measured on a -counter. The interassay CV was 10.8% at 25.9 nmol/L and 11.9% at 87.8 nmol/L.

Serum 25(OH)D <75 nmol/L was used to define hypovitaminosis, and serum 25(OH)D <25, 25–50, and 50–75 nmol/L defined severe vitamin D deficiency, mild vitamin D deficiency, and vitamin D insufficiency, respectively (6).

    Ethical consideration. The Ethics Committee of the National Institute for Medical Research in Tanzania granted permission to conduct the study and the National Committee on Biomedical Research Ethics in Denmark recommended it. Oral informed consent was obtained from all study participants before inclusion. Patients diagnosed with helminth infections were treated and those with malaria were referred for further evaluation. Pre-HIV test counseling was given to all participants and post-test counseling was offered to those who wanted to know their HIV test results.

    Statistical analysis. Normal probability plots were used to assess the distribution of continuous variables. Values in the text are means ± SD or means (95% CI) unless otherwise indicated. The 2-sample t test or 1-way ANOVA was used to test for differences in means between 2 or more groups and the chi-square test was used to test for differences in proportions. Post hoc tests were not conducted.

Multiple linear regression analysis was used to identify predictors of serum 25(OH)D. The variables assessed were age, sex, religion, ethnicity, marital status, occupation, smoking, consumption of alcohol and soil, season, PTB and HIV status, Schistosoma mansoni and hookworm infections, nutritional status including markers of iron status, and intake of fish. Variables with P-values < 0.10 were kept in the model and those with a P-value < 0.05 were considered significant. We examined normal and residual-vs.-fitted plots to assess normality and homoscedasticity of residuals. Stata version 10.0 (StataCorp) was used for all analyses.

	Results

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
The age (range) was 36.1 (15–87) y and most of the 655 patients were males (58.6%), Christians (73.4%), and of Wasukuma ethnicity (50.2%). Of the 655 patients, culture data were available for 637 (97.3%), 508 (79.7%) of whom were PTB+.

The prevalence of HIV coinfection was 47.2%, 43.6% among PTB+ and 62.6% among PTB- patients. The prevalence of S. mansoni was 34.4% and 18.0% had hookworm. Other helminth infections as well as malaria parasitaemia were less common, with prevalences <5% (18). The mean serum ACT was 0.73 ± 0.25 g/L, with 69.2% >0.6 g/L. Due to the acute phase response to TB, serum ferritin was also considerably elevated, with a geometric mean of 206 µg/L (interquartile range 95.5; 549.5; H. Friis, N. Range, C. B. Kristensen, P. Kæstel, J. Changalucha, W. Malenganisho, H. Krarup, P. Magnussen, and A. B. Andersen, unpublished data). The BMI was low, due to loss of both lean and fat mass, with a mean of 18.5 ± 2.8 kg/m² and 29% <17.0 kg/m² (N. S. Range, W. Malenganisho, M. M. Temu, J. Changalucha, P. Magnussen, H. Krarup, A. B. Andersen, and H. Friis, unpublished data).

The intake of vegetables and fruits was modest, whereas the intake of fish was high, with 27.9% reporting consumption of tilapia >4 d/wk and 21.4% eating dagaa >4 d/wk.

    Serum vitamin 25(OH)D. The mean serum 25(OH)D was 86.6 ± 32.9 nmol/L. Hypovitaminosis D was present in 41.2%; 0.8% had severe vitamin D deficiency (<25 nmol/L), 9.8% had mild vitamin D deficiency (25–50 nmol/L), and 30.6% had vitamin D insufficiency (50–75 nmol/L). Serum 25(OH)D concentration did not differ between women (87.3 ± 31.1 nmol/L) and men (86.1 ± 34.2 nmol/L) nor did the proportion with hypovitaminosis D, which was 40.7% and 41.5%, respectively.

There was considerable variation by season and marital status in serum 25(OH)D concentrations (Fig. 1; Table 1). Categories of sex, age, religion, ethnicity, and occupation did not differ. Similarly, subjects who did not and those who did consume alcohol did not differ.

View larger version (18K): [in this window] [in a new window]   FIGURE 1  Serum 25(OH)D concentrations in 653 PTB patients by month of recruitment.

Frequency of intake of tilapia was a strong predictor; intakes of 4–6 and 7 d/wk were associated with 11.6 (95% CI: 1.0; 22.1) and 15.8 (95% CI: 4.6; 27.0) nmol/L higher serum 25(OH)D compared with an intake <1 d/wk. In contrast, intake of dagaa and other foods were not predictors.

BMI was a strong predictor of serum 25(OH)D. AMA, but not AFA, was a predictor when assessed in a model without BMI but not in a model with BMI.

Both serum ferritin and TfR were predictors, but when included in the same model, only serum TfR was a predictor. Compared with concentrations <1.9 mg/L, elevated serum TfR, which reflects peripheral iron deficiency, was associated with increasing serum 25(OH)D. If included instead of TfR, serum ferritin concentrations >500 µg/L were associated with 15.6 nmol/L lower serum 25(OH)D compared with concentrations <24 µg/L.

The intercept, reflecting the mean serum 25(OH)D of individuals falling into the reference category of all the variables in the model, was 66.3 (95% CI: 48.1; 85.3) nmol/L. If variables were recoded so that the reference categories were harvest season, married status, culture positivity, intake of tilapia 4–6 d/wk, and BMI and serum TfR in normal ranges, then the intercept increased to 103.1 (95% CI: 84.7; 121.4) nmol/L.

	Discussion

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
The 44% prevalence of hypovitaminosis D was similar to that reported from a study among TB patients in Guinea-Bissau (6). In that study, the prevalence of hypovitaminosis D was higher (46 vs. 39%) and the mean serum 25(OH)D was lower (78 vs. 85 nmol/L) in TB patients compared with controls. We did not study individuals without TB for comparison. Although this was a limitation, we were able to compare vitamin D status between PTB+ and PTB– patients and to assess if serum 25(OH)D was associated with the acute phase response. Such comparisons within the group of TB patients are likely to be less susceptible to confounding and selection bias than comparison with healthy controls.

Infections eliciting an acute phase response or affecting the intestinal tract may impair micronutrient status, mediated via reduced intake or absorption of nutrients or increased utilization or loss. The validity of the markers of micronutrient status may also be affected. Vitamin D is unique among vitamins in that it is generated in the skin by sun exposure. Thus, effects of infection on intake or absorption are of limited importance to vitamin D status, but infection may affect utilization and loss of vitamin D. It may also affect the validity of serum 25(OH)D as a marker of vitamin D status. The active metabolite is carried by a serum protein, vitamin D-binding protein, and serum proteins often decline during the acute phase response. In addition, an infection may influence the time spent exposed to the sun.

The PTB+ group had 8 nmol/L lower serum 25(OH)D than the PTB– patients, The difference was not explained by the higher serum ACT in the PTB+ patients. In fact, serum ACT and 25(OH)D were not associated. This is in accordance with the finding from a small study among patients with malaria (19). Although no acute phase reactants were determined, plasma 25(OH)D did not change over the course of the infection. It is, therefore, likely that the lower serum 25(OH)D in PTB+ patients reflects less sun exposure due to longer or more severe disease and a greater consumption of vitamin D by macrophages needed for the intracellular antimycobacterial activity may contribute (2).

Only a few small studies have reported data on the possible relationship between vitamin D status and HIV infection, and none are from low-income countries (20). A study from Germany reported lower serum 25(OH)D and 1,25(OH)₂D among asymptomatic HIV patients receiving treatment compared with uninfected controls (21), whereas a similar study from Norway found lower serum 1,25(OH)₂D, but not serum 25(OH)D, among HIV-infected patients (22). We found no difference in serum 25(OH)D with HIV coinfection among TB patients. The strength of our study, in terms of assessing the relationship between vitamin D status and HIV status, was that no subjects were receiving antiretroviral treatment at the start of TB treatment and that selection bias was less of a concern, because both cases and controls were recruited because of TB. The lack of difference by HIV status in our study may strengthen the argument that the lower serum 1,25(OH)₂D in the studies among European patients receiving antiretroviral treatment could be due to an effect of antiretroviral drugs rather than HIV infection per se (20). This is supported by an in vitro study, showing that protease inhibitors impaired the enzyme converting 25(OH)D to 1,25(OH)₂D (23).

    Season. Although well-known at higher latitudes, the seasonal variation in serum 25(OH)D, with concentrations rising from March to July, was surprising. Only brief daily sun exposure is needed to produce adequate vitamin D and excess sun exposure converts cholecalciferol to inactive metabolites. Hence, seasonal variation is not expected in countries around the equator, such as Puerto-Rico (24) and Guinea-Bissau (6).

In Mwanza, the mean number of daily sunshine hours per day over the last 20 y ranges from 7.0 to 9.0 h/d (W. Timiza, Tanzania Meteorological Agency, 2008, personal communication). It was lowest in October to April with 7.0–7.4 h/d and peaked in June and July with 9.0 h/d. The increased vitamin D status through the harvest season from May to the peak in June and July coincides with the peak in sunshine hours. The increase may be explained by a combination of slightly more sun hours, more outdoor activities, and more sun exposure during the cooler days of June and July.

    Socioeconomics. The lower serum 25(OH)D in single compared with married patients is likely due to behavioral differences leading to work-related differences in sun exposure, because season and dietary intake were controlled for. Smoking and serum 25(OH)D were not associated. This is in accordance with data from the NHANES III (25) but not with other studies finding either positive (26) or negative (27) relationships between smoking and serum 25(OH)D.

    Dietary intake. Intake of tilapia, but not dagaa, was associated with vitamin D status. Dietary vitamin D is found in fatty fish such as salmon, mackerel, and herring, and several studies have demonstrated that frequency of fish intake is a predictor of vitamin D status (28–31). The Nile tilapia has a low fat content, with total lipid content <1 g/100 g (32). The vitamin D content of fish, however, is not proportional to the amount of fat but also depends on the content in the food chain (33). Yet, it is surprising that tilapia intake was such a strong predictor of vitamin D status in our study and it may suggest that vitamin D may be present in lean tissue. Consumption of alcohol and soil, common in the study area and predictors of iron status and hemoglobin (34), were not predictors.

    Nutritional status. The positive association between BMI and serum 25(OH)D in our study is in contrast to negative associations found in studies from western countries, explained by sequestration of the fat-soluble vitamin D in fat tissue (28,29,35). In our study population, BMI is a measure of underweight. Although the magnitude of the acute phase response is a strong predictor of loss of lean as well as fat body mass in TB patients (N. S. Range, W. Malenganisho, M. M. Temu, J. Changalucha, P. Magnussen, H. Krarup, A. B. Andersen, and H. Friis, unpublished data), elevated serum ACT did not explain the positive association between BMI and serum 25(OH)D. We suggest that the association is due to the fact that low BMI in this population reflects a longer period of reduced sun exposure and, hence, lower vitamin D status.

We also found that serum ferritin was a negative predictor and sTfR a positive predictor of serum 25(OH)D, although in the final model, only the latter was included. Serum ferritin is a measure of iron stores and serum sTfR is a measure of tissue iron deficiency; hence, serum ferritin and sTfR are inversely associated. Although serum ferritin increases considerably during TB and other infections precipitating an acute phase response, it does so in a predictable way (H. Friis, N. Range, C. B. Kristensen, P. Kæstel, J. Changalucha, W. Malenganisho, H. Krarup, P. Magnussen, and A. B. Andersen, unpublished data). Therefore, our findings may reflect an inverse association between iron status and serum 25(OH)D, i.e. subjects with higher iron status (high serum ferritin and low sTfR) have low serum 25(OH)D. This is in contrast to speculations that iron deficiency may impair vitamin D status due to impaired handling of vitamin D in the skin and gut (36), although the evidence for this is weak (37,38).

Hypovitaminosis D is common among TB patients, even in populations near the equator. Serum 25(OH)D seems to be a valid measure of vitamin D during the acute phase response. Studies on the health effects of hypovitaminosis D in low-income, equatorial populations at risk of both infectious and chronic diseases are needed.

	FOOTNOTES

 
¹ Supported by the DBL Centre for Health Research and Development and DANIDA (grant no. 91072).

² Author disclosures: H. Friis, N. Range, M. Pedersen, C. Mølgaard, J. Changalucha, H. Krarup, P. Magnussen, C. Søborg, and Å. Andersen, no conflicts of interest.

⁹ Abbreviations used: ACT, -1 antichymotrypsin; AFA, arm fat area; AMA, arm muscle area; pulmonary tuberculosis; ¹²⁵I-25(OH)D, ¹²⁵I-labeled 25-hydroxy-(ergocalciferol+cholecalciferol); 25(OH)D, 25-hydroxy-(ergocalciferol+cholecalciferol); PTB, pulmonary tuberculosis; PTB–, culture-negative pulmonary tuberculosis; PTB+, culture-positive pulmonary tuberculosis; sTfR, soluble transferrin receptor; TB, tuberculosis; UAC, upper arm circumference.

Manuscript received 8 July 2008. Initial review completed 16 August 2008. Revision accepted 2 October 2008.

	LITERATURE CITED

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 

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