Journal of the American College of Nutrition, Vol. 25, No. 1, 56-63 (2006)
Published by the American College of Nutrition
Is Chromium an Important Element in HIV-Positive Patients with Metabolic Abnormalities? An Hypothesis Generating Pilot Study
Elaheh Aghdassi, PhD,
Irving E. Salit, MD,
Lillia Fung, BSc,
Lavaniya Sreetharan, BSc,
Sharon Walmsley, MD and
Johane P. Allard, MD
Department of Medicine, The University Health Network, The Toronto General Hospital, Toronto, CANADA
Address reprint requests to: Dr. Johane P. Allard, The Toronto General Hospital, 200 Elizabeth St., Eaton Wing, 9th Floor, Room 217a, Toronto, Ontario, M5G-2C4, CANADA. E-mail johane.allard{at}uhn.on.ca
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ABSTRACT
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Background: Chromium plays a role in insulin sensitivity.
Objectives: To compare chromium measurements in HIV-positive patients with or without (N) antiretroviral therapy (ART) to that of healthy controls (HC) and, to determine if there is any association between chromium levels and abnormalities in body composition, glucose and lipid metabolism.
Design: A cross-sectional study in 91 HIV patients (75 HIV-ART, 16 HIV-N) and 13 HC. Chromium was assessed in the diet, plasma, toenails, and urine. Fasting blood glycemia and lipids, lipodystrophy score and body fat were also determined.
Results: Dietary intake of chromium was similar in the 3 groups. Plasma and toenail Cr were lower in HIV compared to HC, but urinary chromium was similar. However, when the HIV-positive patients on ART were compared to those who were naïve to therapies, urinary excretion of chromium was higher in HIV-ART. In addition, urinary excretion of chromium significantly and positively correlated with lipodystrophy score and negatively with various parameters of metabolic syndrome.
Conclusion: Despite a similar dietary intake, chromium levels were lower in HIV-positive patients and urinary chromium excretion correlated with some metabolic parameters. Low chromium levels may be due to increased chromium losses. These results support further studies on chromium in HIV patients.
Key words: chromium, HIV, glucose, lipid, lipodystrophy, body composition
Abbreviations: ART = antiretroviral therapy • BIA = bioelectric impedance analysis • Cr = chromium • HAART = highly active antiretroviral therapies • HC = healthy control subjects • HDL = high density lipoprotein • HIV = human immunodeficiency virus • IRI = insulin resistance index • LDL = low density lipoprotein • LS = lipodystrophy • N = HIV patient who is naïve to antiretroviral drugs • PI = protease inhibitors • TG = triglycerides
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INTRODUCTION
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Highly active antiretroviral therapy (HAART) became available in the mid-1990’s. Since then metabolic abnormalities have been noted in blood glucose, lipid metabolism, body fat distribution (lipohypertrophy, lipoatrophy, and mixed pattern) and insulin resistance [1–6]. Insulin resistance may be at the core of this metabolic syndrome. These abnormalities are associated with increased risk of cardiovascular disease and they may impact on the long-term prognosis of patients whose life expectancies are now significantly extended because of effective viral suppression by HAART.
Chromium (Cr) is a nutrient that potentiates insulin action and thus is an essential element for glucose and lipid metabolism [7–13]. A balanced diet will provide Cr with an availability of 1–2% [14–17]. Some of the best sources of chromium are processed meats, liver, whole grains, dried beans, broccoli, mushrooms, and spices [14,15]. Ingested Cr is absorbed from the jejunum and upper ileum [18,19], transported by transferrin and stored in the bones, spleen, liver, skeletal muscles and adipose tissue [16,17,20]. It is eliminated in a rapid phase (1–2 days) representing clearance from the blood and in a slower phase from tissues. Adipose and muscle tissues retain Cr for about 2 weeks, whereas liver and spleen may store Cr for as long as 12 months [16,20]. At least 80% of excreted Cr is eliminated in the urine. The remainder is eliminated in the feces, hair, sweat and bile [21].
The metabolic abnormalities reported in patients with HIV are very similar to the abnormalities seen in patients with type 2 diabetes and in those with chromium deficiency. Type 2 diabetic patients have been shown to have low levels of plasma chromium and high levels of urinary chromium excretion [22]. In these patients, chromium supplementation resulted in an improvement in insulin sensitivity [23,24] and other metabolic parameters [25,26]. Therefore, the purpose of this pilot study was to determine whether chromium in plasma, urine, toenail and hair are similarly abnormal in antiretroviral (ART)-treated and untreated HIV-positive patients (HIV-N) compared to healthy control (HC) subjects. It was also important to determine if there is any association between the measured Cr levels and lipodystrophy or abnormalities in glucose and lipid metabolism.
HIV-infected patients have been reported to have deficiencies in several micronutrients such as selenium and zinc [27–31]. However, this is the first study evaluating chromium status of these patients. This study may lead to the generation of an hypothesis for a future trial of chromium supplementation in this patient population.
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MATERIAL & METHODS
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Patients
One hundred patients with HIV infection were recruited from the Immunodeficiency Clinic of the Toronto General Hospital, University Health Network from September 2000 to June 2002. They were English-speaking HIV-seropositive men and women aged >18 y and were clinically stable, without concomitant acute infection or malignancy. Seventy-five patients were on stable anti-retroviral therapy for at least 8 weeks; 16 HIV-seropositive subjects were on no anti-retroviral therapy. ART could include combinations of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Determination of no ART was made if the subject reported no ART use in the 6 months before entry into the study and remained ART-free through the date of assessments. Thirteen healthy controls (9 men and 4 women), in the same age group with a similar body mass index (BMI) without known abnormalities in blood glucose and/or blood lipid profile were also recruited from hospital workers. This protocol was approved by the Ethics Review Board of The University Health Network and all patients gave written informed consent.
Measurements
The subject’s medical history over the past 12 months was collected from the patients and by chart review. Subjects were advised to notify the study coordinator if there was any subsequent change in medication and health status. Study subjects had fasting blood glucose, triglycerides (TG), total cholesterol (HDL, LDL), HIV-RNA concentrations and CD4 lymphocytes measured as part of a routine clinical care. Blood was collected for measurements of insulin, C-peptide and chromium. Twenty-four hour urinary Cr excretion, and toenail Cr were also measured. Dietary intake of chromium was assessed by collecting a 7-day food record. Nutritional status was assessed by measuring body mass index (height and weight). Body fat was assessed by anthropometric measurements [32,33] and by bioelectrical impedance analysis (BIA) [34]. A lipodystrophy score was calculated based on a previously developed questionnaire [3]. The use of oral hypoglycemic drugs, insulin and lipid-lowering agents were also monitored.
Methods
Laboratory Assessment.
Blood glucose, insulin and C-peptide were measured in a fasting state. Surrogate measures of insulin resistance (homeostasis model for insulin resistance (HOMA), Bennetts index, insulin-to-glucose ratio) and quantitative insulin sensitivity check index (QUICKI), were calculated using fasting insulin, and glucose concentrations [35]. The calculation of these measures is summarized in Table 3.
Impaired glucose tolerance was defined according to 1998 American Diabetes Association [36], as a fasting blood glucose >6.1 mmol/l. Fasting insulin >161 pmol/L and fasting C-peptide >500 pmol/L were considered abnormal. Hypertriglyceridemia was defined as fasting concentrations above 2.0 mmol/L [37]. Hypercholesterolemia was defined as total cholesterol concentrations above 5.5 mmol/L and a low HDL-cholesterol concentration as less than 0.9 mmol/L [38,39].
Nutritional Assessment.
Body composition was assessed by BIA [34] that uses a tetra-polar device (Model Spectrum II, RJL Systems) and an excitation current of 800 uA at 50 kHz (34). The subjects were supine with arms and legs abducted and electrodes are placed just proximal to the right metacarpal and metatarsal joint III. Detector electrodes were placed between the distal prominences of the right radius and ulna and between the right medial and lateral right malleoli on the foot. BIA resistance and reactance are used to calculate fat mass and fat-free mass according to regression equations previously validated in different age groups [34].
Anthropometric measurements included circumferences at mid-arm, waist and hip. Skin folds at the triceps, biceps, subscapular, suprailiac and thigh were measured to the nearest 0.1 mm with Lange skin fold calipers (Cambridge Scientific Instruments, Inc, Cambridge, MD) by using standard techniques [32,33]. Body mass index was calculated by dividing the weight in kg by height in meter squared. In addition, lipodystrophy was documented clinically as described by Carr et al [3] where patients self-report peripheral fat wasting (face, arms, buttocks, or legs) or abdominal fat accumulation, by answering a questionnaire. The scores ranged from 0–32 with 1–8 classified as very mild, 9–15 as mild, 16–24 as moderate and 25–32 as severe lipodystrophy.
Chromium Assessment.
a) Dietary intake: Subjects were instructed to record their dietary intake for a Period of 7 days to estimate the frequency of the food groups consumed based on excellent, good and poor sources of chromium. Food items were categorized by calculating the amount of Cr supplied in a typical serving size defined in the Canada Food Guide. Cr sources offering >5 ug/serving were deemed as "excellent," sources between 1–5 ug/serving were "good" and anything <1 ug/serving was deemed as "low" source. Total numbers of "excellent" and "good" sources over a 7 days period were tallied [15,40–44] and reported as the number of servings per 1000 kcal of energy intake.
b) Plasma Cr: Blood was collected in a trace element free-vacutainer, centrifuged at 2400 rpm for 10 min. Plasma was analyzed for chromium following the method described by Hill [45] and modified by Anderson [46] using atomic absorption spectrophotometer, equipped with a graphite furnace. Depending on the concentration of the sample, chromium concentration was determined using either the method of standard additions or standard curve procedures. National Institute of Standards and Technology (NIST, Gaithersburg, MD) Bovine Powder Reference Material (RM) 8414 was analyzed as a check for the method.
c) Urinary Cr: Twenty-four hr urinary output was collected in a 4L plastic container on one occasion. Urinary Cr concentration was determined by method of standard additions on 1:5 diluted samples by atomic absorption spectrophotometer, as described [47]. Serum creatinine was measured by routine laboratory technique and creatinine clearance was calculated using gender specific formula: {[(140-age) x wt (kg)]/serum creatinin (umol/l)} x 1.2 x (0.85 if female)} to assess renal function. Urinary chromium was expressed as umol of Cr per umol of creatinine cleared per minute.
d) Toenail Cr: Toenail samples were weighed and washed sequentially in Hexane, Ethanol and rinsed thrice with de-ionized water and left to dry overnight loosely covered at room temperature. Samples were digested in a nitric acid solution over a hot plate, centrifuged at 2400 rpm for 10 minutes and the supernatants were diluted with de-ionized water and analyzed by atomic absorption spectrophotometer using graphite furnace [48].
Statistical Analyses
One-way ANOVA was used to compare the 3 groups. Statistical significance was defined as P < 0.05. If significant, Bonferroni’s post hoc test was used to compare any two groups. When normality failed, non-parametric tests were used to compare the 3 groups. Spearman correlation was used to evaluate the association between chromium status and various parameters. SPSS software (version 11) was used for the statistical analysis.
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RESULTS
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Clinical Features
Of the 100 patients, 9 were lost to follow-up (due to inability to keep their appointments) and 91 completed the study. Seventy-six men and 15 women with HIV infection, and 9 men and 4 women who were HIV-negative healthy control subjects were included in this analysis. Characteristics of the subjects are reported in Table 1. Among the HIV patients, 75 were on ART and 16 were not on ART. There were no differences in weight and BMI among the groups. However, patients on ART were older than the other two groups. Mean CD4 count and viral load did not differ significantly by anti-retroviral use. The range for CD4 count was 20–1321 cells/mm3 for patients on ART and 66–743 cells/mm3 for patients who were not on ART. The median for HIV-RNA (copies/ml) were 93 and 10,887 respectively.
Chromium Assessment
Plasma Cr was significantly lower and often below the normal range (<2 umol/l) in both HIV groups (43 patients in HIV-ART (57%) and 12 patients in HIV-N (80%)) when compared to HC (Table 2). There was no difference between HIV-N and HIV-ART. Similarly, toenail Cr was significantly lower in HIV compared to HC. Twenty-four hour urinary Cr excretion corrected for creatinine clearance was significantly higher in HIV patients on ART compared to HIV-N. In both HIV groups, Cr excretion was similar to HC despite lower plasma Cr. There was no significant difference in chromium status comparing patients with undetectable viral load to those who had >50 RNA copies/ml (data not shown).
Metabolic Features
The results of blood biochemistry are reported in Table 3. Serum C-peptide was significantly higher in patients on ART when compared to the other two groups. Although serum glucose and insulin levels were also higher in patients on ART, these differences did not reach statistical significance. With respect to the surrogate measures of insulin resistance and insulin sensitivity, there was a trend toward a higher HOMA and insulin to glucose ratio in patients on ART when compared to HIV-N and healthy controls. However, serum TG and total cholesterol were significantly higher and HDL cholesterol was significantly lower in patients on ART compared to HIV-N and healthy controls. Serum LDL-cholesterol was similar among the groups.
Body Composition
The results of body composition are reported in Table 4. Total body fat estimated by BIA and by anthropometry was significantly lower in HIV-ART compared to HIV-N. Anthropometric measurements also revealed a significantly lower skin fold thickness at triceps, suprailiac and thighs in HIV-ART compared to HC or to HIV-N patients. There was no difference between HC and HIV-N patients. On the other hand, patients on ART had a significantly higher waist-to-hip ratio compared to the other two groups. In addition, lipodystrophy score was significantly higher in HIV-ART compared to HIV-N.
Associations between Chromium Parameters & Metabolic/Body Composition Measurements
In patients with HIV, there was a significantly positive correlation between the 24 hr urinary Cr excretion and lipodystrophy score (r = 0.267, P = 0.004) and; a negative correlation with BMI (r = –0.309, P = 0.004), sum of skinfold thicknesses (r = –0.229, P = 0.045), body fat mass measured by BIA (r = –0.272, P = 0.011) and by anthropometry (r = –0.234, P = 0.020) and waist circumference (r = –0.263, P = 0.014). Correlations between plasma or toenail chromium and glucose, lipid and body composition parameters were not statistically significant.
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DISCUSSION
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This study is the first to evaluate chromium parameters in patients with HIV infection. The results of this pilot study demonstrated that despite a similar dietary intake of chromium, patients with HIV (with or without ART) had lower plasma and toenail chromium when compared to healthy control individuals. Despite lower plasma Cr, HIV patients had similar urinary Cr excretion compared to HC. This suggests an inappropriately increased urinary excretion. This may be drug-related as HIV patients on ART had a significantly higher chromium excretion compared to those who were not on ART. In addition, urinary excretion of chromium correlated with some of the metabolic abnormalities reported in HIV.
Abnormal glucose and lipid parameters as well as lipodystrophy have been reported with ART [1–6,49] and was confirmed in this study. These abnormalities are similar to those reported in patients with type 2 diabetes and chromium deficiency [50–53] that have insulin resistance at the core of this metabolic syndrome. Because of this association we decided to investigate Cr in HIV patients with or without ART.
The impact of Cr on glucose and lipid metabolism may be due to its effect on insulin sensitivity by increasing insulin receptor numbers [7]. Cr also up-regulates tyrosine kinase (involved in the translocation of GLUT4 to the plasma membrane for glucose uptake) and down-regulates tyrosine phosphatase of the insulin receptor and thus increases the phosphorylation of beta-subunits that is directly associated with insulin sensitivity [8–13,54,55]. Some anti-retroviral drugs such as protease inhibitors are reported to block the transport capability of GLUT4 [56]. Therefore, the inhibition of GLUT4 by ART or Cr deficiency [56–58] can contribute to insulin resistance and lead to metabolic abnormalities such as higher triglycerides and total cholesterol reported in HIV patients on ART [1–3] and also observed in this study.
In this study chromium was measured in plasma, toenail and urine. Absorbed Cr is eliminated from the body in a rapid phase (1–2 days) representing clearance from the blood, and in a slower phase from tissues. At least 80% of excreted Cr is eliminated in the urine; the remainder is eliminated in the feces, hair, nails, sweat and bile. Although Cr levels in blood, urine, and toenails can be accurately assessed, none of these levels accurately reflects body Cr stores [18,20]. This was a limitation in our study as the body store in tissues such as muscles and adipose tissue could not be measured. However, urine and blood Cr values are a gauge of Cr status. Elevated circulating plasma Cr, that is not lost from the body, is a reflection of increased availability of Cr. A lower Cr in the blood and toenail with a decrease in urinary Cr excretion may indicate a low chromium status as a consequence of HIV infection. It may also indicate that a homeostatic mechanism is in place to maintain a certain tissue level of Cr and that is only maintained at a decreased level of serum and urinary Cr. On the other hand a lower plasma level and a higher excretion of urinary Cr in patients on ART, observed in this study, may indicate an increased mobilization of Cr from the tissues that is subsequently excreted in the urine and lost. This may have been triggered by an increased circulating insulin or high blood glucose level [21,47,59]. While fasting glucose levels were similar among the three groups, insulin and C-peptide levels were higher in patients on ART. This may result in a compromised tissue level. The question remains whether it is the high levels of circulating insulin and glucose that are present first and thus responsible for increased Cr loss in patients on ART or, is it a low Cr status in these patients that contribute to ART-related metabolic abnormalities such as hyperglycemia and lipid abnormalities. ART may also increase Cr losses if associated with gastrointestinal side effects such as diarrhea, nausea and vomiting. To date, the best way to assess chromium status is by supplementation followed by examination for clinical response. Thus investigating the effect of Cr supplementation in HIV patients especially those on ART may help answer some of these questions.
In this study, we selected the healthy control subjects to be comparable with regards to age and BMI as both can affect chromium status [60,61]. Although the mean BMI and age for all HIV subjects were similar to healthy controls, when divided into subgroups, those on ART were slightly older. Chromium concentration in various tissues decreases by 42–49% over a 75 year-plus age range [60]. However, we feel that the small difference in age between the HIV-ART and healthy controls in this study is not of clinical significance in terms of the chromium levels measured.
Dietary Cr intake was also assessed. Chromium content of foods is not available in food composition tables or in any of the nutrient software programs and thus we relied on several published papers [15,40–44] to categorize dietary intake of patients into poor, good and excellent sources. Processed meats; liver; whole-grains, some legumes, such as dried beans; some vegetables, including broccoli and mushrooms; and spices are some of the best sources of Cr. Dairy products, and most fruits and vegetables, contain low amounts of Cr. Rice and sugar are poor sources. In our study, dietary intake of chromium when corrected for daily caloric intake was similar among the three groups.
In summary, plasma and toenail chromium is decreased in patients with HIV. In addition, patients on ART have an increase in their urinary chromium excretion. The alteration in urinary chromium excretion was associated with some of the metabolic abnormalities seen in patients with HIV. These findings are very similar to what is reported with chromium deficiency and also in patients with type 2 diabetes. In both, chromium supplementation resulted in an improvement in insulin sensitivity and in metabolic parameters [23–26,62–67]. Therefore, the study of chromium supplementation in patients with HIV is warranted.
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FOOTNOTES
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Dr. Sharon Walmsley is supported by a Career Scientist Award from the Ontario HIV Treatment Network.
Received November 30, 2004.
Revised August 12, 2005.
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ABSTRACT
INTRODUCTION
