Research report
Lower serum zinc in Chronic Fatigue Syndrome (CFS): Relationships to immune dysfunctions and relevance for the oxidative stress status in CFS

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Abstract

The present study examines serum zinc concentrations in patients with chronic fatigue syndrome (CFS) versus normal volunteers. Serum zinc levels were determined by means of an atomic absorption method. We found that serum zinc was significantly lower in the CFS patients than in the normal controls. There was a trend toward a significant negative correlation between serum zinc and the severity of CFS and there was a significant and negative correlation between serum zinc and the subjective experience of infection. We found that serum zinc was significantly and negatively correlated to the increase in the alpha2 protein fraction and positively correlated to decreases in the expression of mitogen-induced CD69+ (a T cell activation marker) on CD3+ as well as CD3+CD8+ T cells. These results show that CFS is accompanied by a low serum zinc status and that the latter is related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong anti-oxidant, the present results further support the findings that CFS is accompanied by increased oxidative stress. The results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements.

Introduction

Chronic fatigue syndrome (CFS) is defined as a debilitating fatigue lasting at least six months with the presence of four of the following symptoms: sore throat, tender cervical and axillary lymph nodes, difficulties concentrating, muscle or joint pain, unrefreshing sleep, sleep disorders, headache, and post-exertion malaise (Fukuda et al., 1994, National Institute of Allergy and Infectious Diseases, 1996, Maes, 2005). The onset of CFS is associated with a number of trigger factors, such as viral or bacterial infections, stressful life events, type IV allergies, exposure to toxins (e.g. heavy metals), and the leaky gut syndrome (Maes, 2005).

There are now some studies which indicate that the pathophysiology of CFS is related to disturbances in the immune system (Klimas et al., 1990, Visser et al., 1998, Patarca et al., 1994, Linde et al., 1992, Lloyd et al., 1992, Barker et al., 1994, Maes, 2005). Thus, some results indicate activation of the inflammatory response system (IRS) with, for example, an elevated number and percentage of T Lymfocyte subtypes (Klimas et al., 1990) and changes in the levels of cytokines (Patarca et al., 1994, Linde et al., 1992). Recently, we found that the mitogen-induced expression of the CD69 molecule on the T and natural killer cell surface was significantly reduced in patients with CFS (Mihaylova et al., in press), suggesting severe disorders in the early activation of T cells. An earlier review, however, concluded that no persistent pattern of immunological abnormalities could be identified in CFS (Lyall et al., 2003).

There is a strong degree of comorbidity between CFS and major depression (Maes, 2005). Fatigue is one of the key symptoms of depression (Maes et al., 1990a, Maes et al., 1990b). Treatment with cytokines, such as interferon-alpha, induces fatigue in almost all subjects and the degree of fatigue one week after starting interferon-alpha treatment predicts the severity of the cognitive symptoms of depression (Wichers et al., 2005). In addition, IRS activation and an increased production of pro-inflammatory cytokines play a role in the pathophysiology of major depression (Maes et al., 1990a, Maes et al., 1990b, Maes, 1995). This suggests that both CFS and major depression are related to IRS activation.

Decreased concentrations of serum zinc are one of the biochemical characteristics of fatigue, depression and IRS activation. Firstly, early clinical manifestations of lowered zinc status comprise fatigue, depression, cognitive disorders and dysphoria, symptoms which also occur in CFS (Solomons, 1988, Prasad et al., 1993). However, in CFS few studies have examined serum zinc. Ostrom (2003) argues that zinc deficiency can contribute to CFS. For example, leukonychia (white spots on finger nails) is one of those characteristics for CFS pointing towards lowered zinc. van Rensburg et al. (2001) did not find any difference in serum zinc between 15 CFS patients and 15 normal controls. Secondly, some studies show that depression is accompanied by lower serum zinc (Maes et al., 1994, Maes et al., 1997) and that zinc can be used in the treatment of depression (Nowak et al., 2000, Nowak et al., 2003a). Thirdly, lowered serum zinc is a sensitive marker of immune activation and inflammation (Maes et al., 1997). In the latter, lowered zinc is caused by an increased production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) (Bremner and Beattie, 1995). Moreover, zinc deficiency may impair cell-mediated and humoral immunity and thus may contribute to immunological findings in CFS and major depression (Solomons, 1988, Good et al., 1982, Fraker et al., 1986, Prasad et al., 1993, Maes, 1995).

The aim of the present study was to examine whether serum zinc is significantly lower in CFS and whether lowered serum zinc is related to symptoms of CFS (e.g. depressed mood, fatigue or concentration disorders), or to the immune and inflammatory disorders in that illness.

Section snippets

Subjects and methods

Thirty-three subjects participated in the present study, 21 patients with CFS and 12 unrelated controls (staff or their family members). The patients were consecutively admitted to the M-Care4U Outpatient Clinics, Belgium. The study period extended from October 2003 until October 2004. The diagnosis of CFS was made using the diagnostic criteria of the Centers for Disease Control and Prevention (Fukuda et al., 1994), i.e. in order to receive a diagnosis of chronic fatigue syndrome, a patient

Methods

Serum zinc levels were determined by means of an atomic absorption method (PerkinElmer Analyst 200, Brussels, Belgium). The analytical inter-assay CV value of our assay was < 10%. Serum albumin and the alpha-2 protein fraction, which were used as inflammatory markers, were measured by means of serum protein electrophoresis (SEBIA Benelux, Raketstraat, Brussels). The inter-assay CV values for the fractions were < 2.0%. We also measured the CD69 expression on CD3+ and CD3+CD8+ T cells after mitogen

Statistics

Group mean differences were examined by means of analysis of variance (ANOVA) or covariance (ANCOVA). Relationships between variables were assessed by means of Pearson's product moment or Spearman's rank order correlation coefficients or by means of multiple regression analysis. The diagnostic performance of serum zinc for CFS was checked by means of ROC (receiver operating characteristics) analysis with computation of the area under the ROC curve, sensitivity, specificity and predictive value

Results

There were no significant differences in age (mean ± SD: 41.9 ± 13.2 versus 42.1 ± 8.2 years; F = 0.2, df = 1/31, p = 0.9) or gender (male / female ratio: 7 / 14 versus 4 / 8, χ2 = 0.0, df = 1, p = 1.0) between CFS patients and normal controls. There were no significant relationships between age and serum zinc (F = 0.3, p = 0.6). Serum zinc was not significantly different between females and males (F = 0.7, df = 1/28, p = 0.6).

Fig. 1 shows the mean (± SEM) values for serum zinc in the CFS patients and in the normal controls.

Discussion

The main findings of this study are that CFS is accompanied by lower serum zinc and that the latter is significantly related to markers of inflammation and immune activation. Our results are in agreement with the hypothesis of Ostrom (2003) who argued that zinc deficiency can contribute to CFS. For example, Ostrom argued that leukonychia (white spots on finger nails) is one of those characteristics of CFS, which points towards lowered zinc. On the other hand, van Rensburg et al. (2001) did not

Acknowledgments

The research reported was supported by a NARSAD Distinguished researcher award to M. Maes and by M-CARE4U and CRC-MH, Antwerp, Belgium. The authors thank Dr. J.-L. Rummens, M.D., Ph.D., for his valuable help in performing this study. The secretarial assistance of Indra Corten is greatly appreciated.

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