Association between serum ferritin level and fibromyalgia ... - Nature

European Journal of Clinical Nutrition (2010) 64, 308–312

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ORIGINAL ARTICLE

Association between serum ferritin level and fibromyalgia syndrome O Ortancil1, A Sanli1, R Eryuksel2, A Basaran1 and H Ankarali3 1

Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak,Turkey; Department of Physical Medicine and Rehabilitation, Ministry of Health Zonguldak State Hospital, Zonguldak, Turkey and 3 Department of Biostatistics, Faculty of Medicine, Zonguldak Karaelmas University, Zonguldak,Turkey 2

Background/Objectives: Iron is essential for a number of enzymes involved in neurotransmitter synthesis. Analysis of cerebrospinal fluid in fibromyalgia syndrome (FMS) has shown a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin. This study aimed to investigate the association of ferritin with FMS. Subjects/Methods: A total of 46 patients with primary FMS participated in this case–control study, and 46 healthy females who were age matched to the patients were used as the control group. Venous blood samples collected from all subjects were used to evaluate serum ferritin, vitamin B12 and folic acid levels. Results: The mean serum ferritin levels in the fibromyalgia (FM) and control groups were 27.3±20.9 and 43.8±30.8 ng/ml, respectively, and the difference was statistically significant (P ¼ 0.003). Binary multiple logistic regression analysis with age, body mass index, smoking status and vitamin B12, as well as folic acid and ferritin levels showed that having a serum ferritin level o50 ng/ml caused a 6.5-fold increased risk for FMS. Conclusions: Our study implicates a possible association between FM and decreased ferritin level, even for ferritin in normal ranges. We suggest that iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS.

European Journal of Clinical Nutrition (2010) 64, 308–312; doi:10.1038/ejcn.2009.149; published online 20 January 2010 Keywords: fibromyalgia; pathophysiology; ferritin; iron deficiency

Introduction Iron deficiency with or without concurrent anemia is the most widespread nutrient deficiency affecting 30% of the global population (DeMaeyer and Adiels-Tegman, 1985). Iron is used in the generation of energy by the cytochrome oxidase enzyme system. Iron deficiency results in fatigue, poor endurance and even causes muscle pain (Gerwin, 2005). Recently, it has been shown in a mouse model that nutritional iron deficiency leads to a reduced pain threshold, which then increases pain sensation (Dowling et al., 2009). Iron is essential for a number of enzymes involved in neurotransmitter synthesis (Beard et al., 1993), including Correspondence: Dr O Ortancil, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Zonguldak Karaelmas University, Zonguldak, Turkey. E-mail: [email protected] This article was presented as a poster (P-051) in National Rheumatic Diseases Congress, 14–18 May 2008, Antalya, Turkey. Received 10 April 2009; revised 6 November 2009; accepted 6 November 2009; published online 20 January 2010

tryptophan hydroxylase (serotonin) and tyrosine hydroxylase (norepinephrine and dopamine). Iron deficiency anemia presents with multiple mood and behavioral signs that are similar to the signs of depressed individuals. Notably, the onset of most of these signs and symptoms is in initial stages, when the serum ferritin level has decreased but frank anemia has not yet occurred (Vahdat Shariatpanaahi et al., 2007). Iron supplementation therapy can resolve many of the symptoms of depression in patients with iron deficiency anemia before any improvement in red blood cell counts or indices is achieved. This may result from the recovery of neurotransmitters and enzyme levels dependent on iron and unrelated to hemoglobin concentration (Kathlen and Escott-Stump, 2004). It has been shown that patients with fibromyalgia syndrome (FMS) experience pain differently from that of the general population because of dysfunctional pain processing in the central nervous system. Several mechanisms including central sensitization, blunting of inhibitory pain pathways, alterations in neurotransmitters and psychiatric comorbid conditions may be responsible for

Ferritin in FMS O Ortancil et al

309 aberrant pain processing, which may result in chronic pain and associated symptoms (Abeles et al., 2007). Reduced concentration of biogenic amine metabolites including dopamine, norepinephrine and serotonin has been shown by the analysis of cerebrospinal fluid (CSF) of FMS patients (Russell et al., 1992; Legangneux et al., 2001). The aim of this study was to investigate the possible association of iron reserve,that is, serum ferritin level, with FM. As iron is essential for neurotransmitter synthesis, we believed that decreased iron stores might lead to reduced production of biogenic amines, which in turn might have a role in the pathophysiology of FMS. Restless legs syndrome (RLS) is another disease, in which the dopaminergic system is involved (Gamaldo and Earley, 2006). Iron and dopamine are also believed to be linked in producing RLS symptoms (Allen, 2004). A previously reported association of ‘low normal’ ferritin levels with RLS (Allen, 2004; Mizuno et al., 2005; Gamaldo and Earley, 2006) also prompted us to investigate the association of ‘low normal’ ferritin levels with FMS.

Materials and methods In this case–control study, 57 consecutive patients with fibromyalgia (FM) who were referred to the Department of Physical Medicine and Rehabilitation between January 2007 and September 2007 were recruited. The study was approved by the local ethics committee of the Zonguldak Karaelmas University. The American College of Rheumatology criteria for FMS were used to establish the diagnosis of FMS (Wolfe et al., 1990). Demographic characteristics and smoking status were collected by a self-reported questionnaire. To evaluate the clinical severity of the disease, the Fibromyalgia Impact Questionnaire (FIQ) was used. The FIQ is a self-reported instrument, which consists of 10 items (Burckhardt et al., 1991). A high total value (maximum 100) indicates severe effects on daily activities. The questionnaire has been proved to be valid and reliable in Turkish FMS patients (Sarmer et al., 2000). The presence of depression was evaluated using the Beck questionnaire, which is a 21-item self-reported questionnaire assessing both the presence and the severity of depression. The scores of each item range between 0 and 3 (0 ¼ least, 3 ¼ most). The total score is the sum of all items with a maximum of 63. A score of X10 was considered as an indication for clinically significant depressive symptoms (Beck et al., 1961). The Turkish version of the BDI (Beck Depression Inventory) has been reported to be valid and reliable by Hisli (1988). The RLS was diagnosed on the basis of standard clinical criteria developed by the International Restless Legs Syndrome Study Group (Allen et al., 2003). Venous blood samples were obtained from all participants. The samples were used to evaluate the serum ferritin (ECLIA, Roche E-170, Osaka, Japan), vitamin B12 (ECLIA, Roche E170), folic acid levels (ECLIA, Roche E-170), complete blood count (Beckman Coulter Inc., Model Coulter LH 750

Analyzer, Bohemia, NY, USA), and C-reactive protein (immunonephelometry, Dade Behring, Marburg, Germany) and erythrocyte sedimentation rate (Westergren, Electa Lab Monitor 100, Forli, Italy). A total of 54 healthy females among the hospital staff and some of their relatives who were age matched to the patients were used as the control group. Subjects were excluded if they were receiving iron supplements, and had a history of physical disease that was accompanied by mood disorders, such as multiple sclerosis, Parkinson’s disease and/or hypothyroidism. Participants with a hemoglobin level o12 g/dl (n ¼ 1 in the FM group and n ¼ 4 in the control group) were also excluded. As ferritin is one of the acutephase reactants, patients with inflammatory disorders were excluded from the study, and subjects who had high erythrocyte sedimentation rate (420 mm per h) or Creactive protein (45 mg/l) were disqualified (n ¼ 10 in the FM group and n ¼ 4 in control group). Finally, among the 57 patients attending our outpatient clinic with the diagnosis of FMS, 46 were included, and among the 54 healthy individuals, 46 subjects were included in the study. The SPSS (version 11.5, SPSS, Chicago, IL, USA) program was used for all statistical calculations. Independent samples Student’s t-test was used for comparison of means of age, body mass index, as well as serum levels of vitamin B12, folic acid and ferritin in the FM group and controls. Both w2 test and Fisher’s exact test were used for comparisons of categorical variables. For evaluation of related risk factors of FM, binary multiple logistic regression analysis with enter method was performed. The relationship between ferritin and FIQ scores was explored with Pearson’s correlation analysis. Po0.05 was considered statistically significant.

Results All of the 46 patients in the FM group were women with a mean age of 46.9±10.6 years and 46 healthy women age matched to the patients (47.7±9.4) were used as the control group. There were no significant differences between both the groups in terms of age, body mass index, hemoglobin, serum vitamin B12 and folic acid levels (P40.05) (Table 1). The prevalence rates of smoking in the FM and control groups were 21.7 and 10.9%, respectively, and the difference was not significant (Fisher’s P ¼ 0.259). All subjects in the study and control groups were alcohol abstainers. There was only one participant regularly exercising in the FM group, whereas no individuals in the control group followed a regular exercising habit. None of the participants in the control group had a BDI score 410. On the other hand, 13 patients with FMS had BDI scores 410. There were no participants with RLS in the control group, whereas six patients in the FM group had RLS. The normal range of serum ferritin levels in our laboratory was 13–150 ng/ml. The mean serum ferritin levels in the FM and control groups were 27.3±20.9 and 43.8±30.8 ng/ml, European Journal of Clinical Nutrition


310 Table 1 Descriptive statistics of characteristics in each group FM (n ¼ 46) mean±s.d.

Controls (n ¼ 46) mean±s.d.

Age (years) BMI (kg/m2) Hgb (g/dl) Ferritin (ng/ml)

46.9±10.6 28.5±5.8 13.4±1.0 27.3±20.9

47.7±9.4 27.4±5.0 13.5±0.9 43.8±30.8

Ferritin o50 ng/ml 450 ng/ml

40 (87.0%) 6 (13.0%)

26 (56.5%) 20 (43.5%)

297.6±120.7 9.2±3.1

295.7±113.0 8.9±2.5

Group

B12 (pg/ml) Folic acid (ng/ml)

Abbreviations: BMI, body mass index; FM, fibromyalgia.

respectively; the difference was statistically significant (P ¼ 0.003) (Table 1). As RLS and depression was previously shown to be associated with iron deficiency, 13 patients who had BDI scores 410 and 6 patients who had RLS in the FM group were excluded, and the statistical analysis was repeated. The mean ferritin levels in the FM and control groups were 30.8±20.9 and 43.8±30.8 ng/ml, respectively, and the difference between patients and controls was statistically significant (P ¼ 0.035) after these patients were excluded. For the logistic regression model, a cutoff level of 50 ng/ml was used as this level was reported to be the critical point below which clinical symptoms of RLS patients were found to be exaggerated, although ferritin levels were within normal ranges (Sun et al., 1998). Binary multiple logistic regression analysis with age, body mass index, smoking status, as well as vitamin B12, folic acid and ferritin levels showed that having a serum ferritin level o50 ng/ml caused a 6.5-fold increased risk for FMS (Table 2). When the statistical analysis was repeated after excluding patients with RLS and depression, having a serum ferritin level o50 ng/ml caused a 5.9-fold increased risk for FMS (P ¼ 0.011). Among the 46 patients, the rate of those who had ferritin levels o50 ng/ml was significantly higher than that of the control group (87 versus 56.5%, P ¼ 0.001). The difference was also statistically significant when patients with RLS and depression were excluded (85.2 versus 56.5%, P ¼ 0.012). The mean FIQ score of the FM group was 60.0±10.9, and there was no significant correlation between ferritin and FIQ scores (P ¼ 0.226, rho ¼ 0.182) in the FM group.

Discussion Iron is known to be essential for a number of enzymes involved in serotonin and dopamine synthesis (Beard et al., 1993). Deficiency in serotonergic neuronal functioning might be related to the pathophysiology of FMS (Moldofsky and Warsh, 1978; Yunus et al., 1992; Neeck, 2002). A dysregulation of dopaminergic neurotransmission in the European Journal of Clinical Nutrition

Table 2 Results of evaluation of risk factors for fibromyalgia with logistic regression analysis b-Coefficient

Age (years) BMI (kg/m2) Smoking B12 (pg/ml) Folic acid (ng/ml) Ferritin 50 ng/ml Constant

0.00499 0.09531 1.15247 0.00100 0.15871 1.86934 5.52146

Odds ratio

1.005 1.100 3.166 0.999 1.172 6.484 0.004

95, 0% C.I. for odds ratio Lower

Upper

0.955 0.994 0.821 0.995 0.982 2.031

1.058 1.218 12.206 1.003 1.399 20.694

P-value

0.836 0.065 0.094 0.658 0.078 0.002 0.008

Abbreviations: BMI, body mass index; C.I., confidence interval. Variable(s) entered in step 1: Age, BMI, smoking, B12, folic acid, ferritin (50 ng/ml).

pathophysiology of FMS has also been suggested (Wood et al., 2007a). Both serotonin (Otto et al., 2008) and dopamine (Wood et al., 2007b) have been reported to have a function in pain modulation. CSF in FMS patients has been shown to have a reduction in the concentration of biogenic amine metabolites, including dopamine, norepinephrine and serotonin (Russell et al., 1992; Legangneux et al., 2001; Bazzichi et al., 2006). We suggest that, iron as a cofactor in serotonin and dopamine production may have a role in the etiology of FMS. Moreover, patients with FMS have been shown to have fewer serotonin transporters expressed on the cellular membrane (Bazzichi et al., 2006). The serotonin transporter density was significantly lower in the brains of iron-deficient mice (Morse et al., 1999). Thus, iron deficiency may contribute to the pathophysiology of FMS by leading to a decrease in serotonin transporter density. To the best of our knowledge, our study is the first to investigate the relationship between serum ferritin level and FMS. Although the mean serum ferritin level of our patients was within normal limits, the mean ferritin level of patients with FMS was lower than that of healthy individuals. Our results showed a 5.9-fold increased risk of FMS in patients with serum ferritin levels o50 ng/ml, which suggests that a relative decrease in iron reserve might be associated with FMS. However, at present, it is not very clear whether such a relative reduction in iron stores would cause overt clinical problems. Such an association has been shown in patients with RLS, in the pathology of which dopaminergic system takes part (Gamaldo and Earley, 2006). Two separate studies have shown that RLS severity is correlated with serum ferritin levels, even for ferritin in normal ranges (O’Keeffe et al., 1994; Sun et al., 1998). In one of these studies, oral iron supplements were shown to decrease RLS symptoms in elderly patients who had initial serum ferritin levels o45 mg/l (O’Keeffe et al., 1994). On the other hand, Sun et al. (1998) reported that serum ferritin levels o50 ng/ml are correlated with increased symptom severity despite the ferritin levels within normal limits.


311 Ferritin levels decrease in the initial stage of iron deficiency, and anemia develops subsequently. In a recent study, the prevalence of FMS was found to be significantly higher in patients with iron deficiency anemia than in healthy controls (Pamuk et al., 2008). They reported that ferritin levels of iron deficiency anemia patients with or without FMS (4.5±2.9 and 3.7±2.2, respectively) did not differ. In our study, patients with iron deficiency anemia were excluded because the aim of our study was to evaluate the possible association of serum ferritin levels with FM. Vahdat Shariatpanaahi et al. investigated ferritin levels in female medical students with or without depression and excluded those who had a hemoglobin level o12 g/dl. Although the mean ferritin levels were within the normal range in both groups, they reported that students with depression had significantly lower ferritin levels than did controls and attributed the development of depressed mood to this finding, which indicated the possible role of iron in brain function. They concluded that their study implied a possible association between depression and decreased ferritin level before the occurrence of anemia (Vahdat Shariatpanaahi et al., 2007). We have also shown an association between decreased ferritin and FMS in our patient group without anemia. The lack of determination of ferritin levels in CSF was a limitation of our study. Identifying CSF ferritin levels might lead to a better understanding of the pathogenesis of the disease; however, this invasive procedure was not included in the study design. In conclusion, iron as a cofactor in serotonin and dopamine production might have a role in the etiology of FMS. Prescribing iron supplementation in these patients may create a new pathway in the treatment of FMS. Further clinical trials are required to evaluate the CSF ferritin level and the effectiveness of iron supplementation in treating symptoms of FMS.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements This study was approved by the Hospital Ethics Committee of Zonguldak Karaelmas University.

References Abeles AM, Pillinger MH, Solitar BM, Abeles M (2007). Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med 146, 726–734. Allen R (2004). Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 5, 385–391.

Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J (2003). Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4, 101–119. Bazzichi L, Giannaccini G, Betti L, Mascia G, Fabbrini L, Italiani P et al. (2006). Alteration of serotonin transporter density and activity in fibromyalgia. Arthritis Res Ther 8, R99. Beard JL, Connor JR, Jones BC (1993). Iron in the brain. Nutr Rev 51, 157–170. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961). An inventory for measuring depression. Arch Gen Psychiatry 4, 561–571. Burckhardt CS, Clark SR, Bennett RM (1991). The Fibromyalgia Impact Questionnaire: development and validation. J Rheumatol 18, 728–733. DeMaeyer E, Adiels-Tegman M (1985). The prevalence of anaemia in the world. World Health Stat Q 38, 302–316. Dowling P, Klinker F, Amaya F, Paulus W, Liebetanz D (2009). Irondeficiency sensitizes mice to acute pain stimuli and formalininduced nociception. J Nutr 139, 2087–2092. Gamaldo CE, Earley CJ (2006). Restless legs syndrome: a clinical update. Chest 130, 1596–1604. Gerwin R (2005). A review of myofascial pain and fibromyalgia–– factors that promote their persistence. Acupunct Med 23, 121–134. Hisli N (1988). The reliability and validity study of the Beck Depression Inventory in a Turkish sample. Turk J Psychol(in Turkish) 6, 118–122. Kathlen ML, Escott-Stump S (2004). Krauses Food Nutrition and Diet Therapy, 10th edn Chapman and Hall: Philadelphia, PA. Legangneux E, Mora JJ, Spreux-Varoquaux O, Thorin I, Herrou M, Alvado G et al. (2001). Cerebrospinal fluid biogenic amine metabolites, plasma-rich platelet serotonin and [3H]imipramine reuptake in the primary fibromyalgia syndrome. Rheumatology (Oxford) 40, 290–296. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005). CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14, 43–47. Moldofsky H, Warsh JJ (1978). Plasma tryptophan and musculoskeletal pain in non-articular rheumatism (‘fibrositis syndrome’). Pain 5, 65–71. Morse AC, Beard JL, Jones BC (1999). A genetic developmental model of iron deficiency: biological aspects. Proc Soc Exp Biol Med 220, 147–152. Neeck G (2002). Pathogenic mechanisms of fibromyalgia. Ageing Res Rev 1, 243–255. O’Keeffe ST, Gavin K, Lavan JN (1994). Iron status and restless legs syndrome in the elderly. Age Ageing 23, 200–203. Otto M, Bach FW, Jensen TS, Brosen K, Sindrup SH (2008). Escitalopram in painful polyneuropathy: a randomized, placebocontrolled, cross-over trial. Pain 139, 275–283. Pamuk GE, Pamuk ON, Set T, Harmandar O, Yesil N (2008). An increased prevalence of fibromyalgia in iron deficiency anemia and thalassemia minor and associated factors. Clin Rheumatol 27, 1103–1108. Russell IJ, Vaeroy H, Javors M, Nyberg F (1992). Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis. Arthritis Rheum 35, 550–556. Sarmer S, Ergin S, Yavuzer G (2000). The validity and reliability of the Turkish version of the Fibromyalgia Impact Questionnaire. Rheumatol Int 20, 9–12. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP (1998). Iron and the restless legs syndrome. Sleep 21, 371–377. Vahdat Shariatpanaahi M, Vahdat Shariatpanaahi Z, Moshtaaghi M, Shahbaazi SH, Abadi A (2007). The relationship between depression and serum ferritin level. Eur J Clin Nutr 61, 532–535. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL et al. (1990). The American College of Rheumatology

European Journal of Clinical Nutrition


312 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33, 160–172. Wood PB, Patterson II JC, Sunderland JJ, Tainter KH, Glabus MF, Lilien DL (2007a). Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain 8, 51–58.

European Journal of Clinical Nutrition

Wood PB, Schweinhardt P, Jaeger E, Dagher A, Hakyemez H, Rabiner EA et al. (2007b). Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci 25, 3576–3582. Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC (1992). Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol 19, 90–94.