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Thyroid function and lipid profile in bipolar I patients
Asian Journal of Psychiatry 4 (2011) 139–143
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Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Review
Thyroid function and lipid profile in bipolar I patients Asma Ezzaher a,*, Dhouha Haj Mouhamed a, Anwar Mechri b, Fadoua Neffati a, Wahiba Douki a, Lotfi Gaha b, Mohamed Fadhel Najjar a a b
Laboratory of Biochemistry-Toxicology, Monastir University Hospital, Tunisia Research Laboratory ‘Vulnerability to Psychotic Disorders LR 05 ES 10’, Department of Psychiatry, Monastir University Hospital, Tunisia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 June 2010 Received in revised form 5 February 2011 Accepted 8 February 2011
Objective: This study aims to evaluate the prevalence of thyroid dysfunctions and to explore their association with perturbations in lipid profile in bipolar I patients. Patients and methods: Our study included 130 bipolar I patients diagnosed according to the DSM IV, and 124 control subjects aged respectively 37.9 12.1 and 37.6 13.2 years. TSH and FT4 were determined using electrochemiluminescence. Total cholesterol, triglycerides, c-LDL and c-HDL were determined by enzymatic colorimetric methods and ApoA1, ApoB and Lp(a) by immunoturbidimetric techniques on Kone´lab 30TM. Results: Patients had significantly higher TSH values than controls and had perturbations in lipid profile. 0.7% and 28.5% of patients had respectively hyperthyroidism and hypothyroidism. Hypothyroidism was associated with obesity and perturbations in lipid profile particularly increase in total cholesterol, c-LDL, ApoB, ApoB/ApoA1 and Lp(a) and decrease in ApoA1 and c-HDL. Moreover, it was associated with lithium and valproic acid treatment. Conclusions: Hypothyroidism was frequent in bipolar patients. It was significantly associated with obesity and perturbations in lipid profile. Therefore, bipolar patients require specific care, particularly for thyroid, lipid profile and weight; the effectiveness of this care will be evaluated during follow-up period. ß 2011 Elsevier B.V. All rights reserved.
Keywords: Bipolar I disorder Hypothyroidism Lipid profile Obesity
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . 2.1. Subjects . . . . . . . . . . . 2.2. Samples . . . . . . . . . . . 2.3. Biochemical analysis. 2.4. Clinical evaluations . . 2.5. Statistical analysis. . . Results . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . Acknowledgements . . . . . . . References . . . . . . . . . . . . . .
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1. Introduction Bipolar disorder is a major psychiatric disorder that affects 1–3% of the worldwide population and is characterised by mood alteration
* Corresponding author at: Research Laboratory ‘Vulnerability to Psychotic Disorders LR 05 ES 10’, Department of Psychiatry, Monastir University Hospital, Tunisia. Tel.: +216 73 461 144; fax: +216 73 460 678. E-mail address: [email protected] (A. Ezzaher). 1876-2018/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ajp.2011.02.002
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139 140 140 140 140 140 140 141 142 142 142
associated with recurrent depression and mania in lifetime separated by periods of normal behaviour or euthymia (Marmol, 2008). Medical disease and medical risk factors are common in bipolar disorder, affect the course and severity of the disease and its treatment, and lead to even greater morbidity, mortality, and disability. Many medical problems have been documented in this population, the most common of which are cardiovascular disease, diabetes, obesity, dyslipidemia and thyroid disease (Soreca et al., 2008). Disorders of the thyroid gland are frequently associated with several mental disturbances. Thyroid hormones have a profound
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
140
Table 1 Sociodemographic and clinical characteristics of the sample population.
Gender: men/women (ratio) Age (years)
Bipolar I patients (n = 130)
Control group (n = 124)
p
85/45 (1.89) 37.9 12.1
81/43 (1.88) 37.6 13.2
1 0.84
Bipolar I patients (n = 130) Number Cigarette smoking Smokers Non-smokers Alcoholic beverage Consumers Non-consumers Episode of illness Depressive (D) Euthymic (E) Manic (M) Treatment Valproic acid Lithium Carbamazepine Antipsychotiques Lithium/valproic acid
Control group (n = 124) %
Number
p %
68 62
52.3 47.7
63 61
50.8 49.2
0.90
17 113
13.0 87.0
14 110
11.3 88.7
0.70
21 73 36
16.2 56.1 27.7
– – –
– – –
– – –
64 12 10 38 6
49.2 9.2 7.7 29.3 4.6
– – – – –
– – – – –
– – – – –
influence on behaviour and mood, and appear to be able to modulate the phenotypic expression of major affective illness (Bauer et al., 2002). This intimate association between the thyroid system and behaviour has been the impetus for exploring the effects of thyroid hormones in modulating affective illness, and the role of the hypothalamic–pituitary–thyroid axis in the pathophysiology of mood disorders. On the other hand, relations between thyroid function and lipid status remain controversial. Some investigators have suggested that subjects with hypothyroidism have an increased risk of coronary artery disease. These effects may, in part, be related to atherogenic change in lipid profile (Cappola and Ladenson, 2003). This study aims to evaluate the prevalence of thyroid dysfunctions and to explore their association with perturbations in lipid profile in bipolar I patients. 2. Methods 2.1. Subjects This study was approved by the local ethical committee and all subjects were of Tunisian origin. Our sample included 130 bipolar I patients from the psychiatry department of the University Hospital of Monastir. The mean age was 37.9 12.1 years, 85 men (38.1 11.4 years) and 45 women (37.53 13.41 years). Consensus on the diagnosis, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria (American Psychiatric Association, 2004), was made by psychiatrists. The exclusion criteria were age (<18 years), other psychiatric illnesses, epilepsy or mental retardation. The control group consisted of 124 volunteer subjects without psychiatric or endocrinological diagnoses and matched for age and gender with bipolar patients. The mean age was 37.6 13.2 years, and there were 81 men (36.9 12.6 years) and 43 women (38.8 14.1 years). All subjects were questioned about their age, gender, cigarette and alcohol consumption habits and clinical and therapeutic history. Whether any of the patients were treated with replacement thyroxine and their use of lipid-lowering medications (i.e. statins, niacin, fish oil, etc.) was not determined. Participants with biochemical signs of overt thyroid dysfunction or dyslipidemia were advised to consult their general physician for checking. The sociodemographic and clinical characteristics are shown in Table 1.
2.2. Samples After a 12 hour overnight fasting, venous blood for each patient was drawn in tubes containing lithium heparinate and immediately centrifuged. The plasma samples were stored at 20 8C until the biochemical analysis. 2.3. Biochemical analysis Thyroid-stimulating hormone (TSH) and FT4 were determined by chemiluminescence (Elecsys 2010TM Roche diagnostics). Concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol (c-LDL) and high-density lipoprotein cholesterol (c-HDL) were determined by enzymatic colorimetric methods, and apolipoprotein (ApoA1, ApoB) and lipoprotein(a) (Lp(a)) levels by immunoturbidimetric techniques using Kone´lab 30 equipment (Thermo Electron Corporation, Ruukintie, Finland). 2.4. Clinical evaluations Body mass index (BMI) was calculated as weight (kg) divided by height (m2). Obesity was defined when BMI 30 kg/m2 (World Health Organization, 1997). 2.5. Statistical analysis Statistical analyses were performed using SPSS v. 13.0 (SPSS, Chicago, IL, USA). Quantitative variables were presented as Table 2 Comparisons of biological and clinical variables between bipolar I patients and control group. Biological and clinical variables
Patients (n = 130)
Controls (n = 124)
p
TSH (mIU/L) FT4 (ng/L) BMI (kg/m2) Cholesterol (mmol/L) c-HDL (mmol/L) c-LDL (mmol/L) Triglycerides (mmol/L) ApoA1 (g/L) ApoB (g/L) ApoB/ApoA1 Lipoprotein(a) (mg/L)
2.73 1.80 12.69 2.64 27.13 4.57 4.42 0.99 0.98 0.28 2.14 1.10 1.95 1.15 1.20 0.23 0.82 0.28 0.70 0.26 243 223
1.62 0.72 12.87 1.70 25.30 3.81 3.90 0.99 1.09 0.36 1.29 0.56 1.61 0.96 1.29 0.45 0.77 0.23 0.62 0.26 156 120
<0.001 0.5 <0.001 <0.001 0.01 <0.001 0.04 0.04 0.03 0.01 <0.001
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
141
Table 3 Repartition of patients according to thyroid parameters. Thyroid parameters
TSH (mIU/L) FT4 (ng/L) * a
Bipolar patients (n = 130) Hyperthyroid patientsa TSH < 0.18 (n = 1)
Euthyroid patients 0.18 TSH 3.06 (n = 92)
Hypothyroid patients TSH > 3.06 (n = 37)
0.067 12.58
1.93 0.70 12.88 2.52
4.84 1.97* 12.23 2.99
Hypothyroid patients vs euthyroid patients: p < 0.001. Because of small effective (n = 1) hyperthyroid patient was excluded for this study.
Table 4 Comparisons between euthyroid patients, hypothyroid patients and control group by demographic and biological variables. Demographic and biological variables
Age (years) BMI (kg/m2) Cholesterol (mmol/L) c-HDL (mmol/L) c-LDL (mmol/L) Triglycerides (mmol/L) ApoA1 (g/L) ApoB (g/L) ApoB/ApoA1 Lipoprotein(a) (mg/L)
Control group (n = 124)
Bipolar patients (n = 129) 0.18 TSH 3.06 (n = 92)
TSH > 3.06 (n = 37)
p
37.6 13.2 25.30 3.81
37.45 11.2 26.80 4.42a
38.70 14.2 27.99 5.02b
<0.001 0.21
3.90 0.99 1.09 0.36 1.29 0.56 1.61 0.96 1.29 0.45 0.77 0.23 0.62 0.26 156 120
4.36 1.02a 0.99 0.28a 2.12 1.07a 1.79 1.30 1.19 0.22a 0.83 0.30a 0.71 0.25a 256 245a
4.56 0.95b 0.97 0.23b 2.17 1.22b 2.37 2.03b 1.21 0.24 0.80 0.23 0.70 0.30 212 163b
0.29 0.90 0.80 0.11 0.69 0.60 0.86 0.23
p: statistical analysis between euthyroid and hypothyroid patients. a Euthyroid patients vs control group: p < 0.05. b Hypothyroid patients vs control group: p < 0.05.
mean SD and comparisons were performed using the Student’s t test. Qualitative variable comparisons were performed using the chisquare (x2) test. The statistical significance level was set at p < 0.05.
There was no difference in hypothyroidism prevalence between antipsychotic and mood stabilizers treatment, while hypothyroidism was more frequent in patients treated with valproic acid and lithium (Table 5).
3. Results Bipolar patients had significantly higher TSH values than controls, while no significant change in FT4 values was observed. Moreover, they had significantly higher values for total cholesterol, c-LDL, triglycerides, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significantly lower values for c-HDL and ApoA1 than the control subjects (Table 2). According to TSH values, patients were subdivided in three groups: euthyroid group (70.8%), hypothyroid group (28.5%) and hyperthyroid group (0.7%) (Table 3). Hypothyroid patients had significantly higher levels of TSH, total cholesterol, triglycerides, c-LDL, Lp(a) and BMI and significantly lower levels of c-HDL than control group. Additionally, euthyroid patients had significantly higher levels of TSH, total cholesterol, c-LDL, ApoA1, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI, and significantly lower levels of c-HDL and ApoA1 than control group, while no significant change between hypothyroid and euthyroid patients was observed (Table 4). Comparisons between hypothyroid patients and control group by demographic and clinical variables noted that there was no significant difference among gender, age, cigarette smoking and alcoholic beverage. In patients, the highest prevalence of hypothyroidism was found in women and patients aged more than 60 years. Cigarette smoking and alcoholic beverage were not significantly associated with hypothyroidism but 20.6% of smoker patients and 11.8% of alcoholic consumer patients had hypothyroidism (Table 5). We noted that there is no significant variation in hypothyroid patients among episode and duration of illness, while the highest prevalence of hypothyroidism was found in depressive patients and when duration of illness was less than 10 years (Table 5).
Table 5 Comparisons between hypothyroid patients and control subjects by demographic and clinical variables. Demographic and clinical variables
Gender Men Women Age 39 years 40–59 years 60 years Cigarette smoking Yes No Alcoholic beverage Yes No Duration of illness 10 >10 Episode of illness Depressive Euthymic Manic Treatment Antipsychotiques Mood stabilizers Valproic acid Carbamazepine Lithium/valproic acid Lithium
Hypothyroid patients (n = 37)
Controls (n = 124)
Statistical analysis
Number
%
Number
23/85 14/45
27 31.1
81 43
65.3 34.7
0.84
19/74 14/49 4/7
25.7 28.6 57.2
79 37 8
63.7 29.8 6.5
0.15
14/68 23/62
20.6 37.1
61 63
49.2 50.8
0.19
2/17 35/113
11.8 40
14 110
11.3 88.7
0.36
21/59 16/71
35.6 22.5
– –
– –
8/21 18/73 11/36
39 24.7 30.6
– – –
– – –
11/38 26/92 20/64 2/10 3/6 1/12
28.9 28.3 31.3 20 50 8.4
–
–
– – – –
– – – –
%
142
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
4. Discussion Bipolar patients had significant increase in TSH and slight decrease in FT4 than control subjects. It has been suggested that the thyroid system may have different roles in the pathophysiological process of bipolar disorders. Indeed, thyroid hormones have been shown to possess mood regulating properties via their modulation of multiple central transmission systems (e.g., serotonin and norepinephrine) and the increase in availability of thyroid hormones has been hypothesized to be therapeutic for mood disorders (Bauer et al., 2003). Patients had significantly higher levels of total cholesterol, cLDL, triglycerides, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significant lower levels of c-HDL and ApoA1 than control subjects. This may explain the high risk of cardiovascular disease and the high prevalence of metabolic syndrome (Garcia-Portilla et al., 2009; Fagiolini et al., 2005; Sicras et al., 2008) in bipolar patients. The underlying mechanism for the altered lipid status and obesity in bipolar patients is unclear. A possible explanation might be found in the patient’s nutritional status, the decrease in physical activity and the medications used (Ezzaher et al., 2010). Additionally, Chung et al. (2007) reported that bipolar disorder is associated with perturbations in the lipid profile which playa an important role in the pathophysiology of mood disorders, particularly in bipolar disorders. Our data showed that 38 patients had thyroid dysfunction: one with hyperthyroidism (0.7%) and 37 (28.5%) with hypothyroidism. A patient with hyperthyroidism was excluded from this study because of small effective number. Compared to other populations, the prevalence of hypothyroidism in our patients was 3-fold higher than that reported in Spanish patients by Valle et al. (1999) (9.2%) and similar to that reported in Italian patients by Bartalena et al. (1990) (32%). These differences could be due to ethnicity and eating habits. Euthyroid patients had significantly higher levels of total cholesterol, c-LDL, ApoA1, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significantly lower levels of c-HDL and ApoA1 than control group, while no significant change between hypothyroid and euthyroid patients was observed. This could confirm the effect of bipolar disorder on perturbations of lipid profile and obesity. Furthermore, hypothyroid patients had significantly higher levels of total cholesterol, triglycerides, c-LDL, Lp(a) and BMI and significantly lower levels of c-HDL than control group. The relationship between the hypothalamic–pituitary–thyroid axis and obesity and lipid profile had been investigated. Many reports suggest that leptin may modify hypothalamic production of TSH. Leptin and TSH have almost identical circadian rhythms, and leptin deficiency is closely associated with dysregulated patterns of pulsatile and circadian rhythms of TSH secretion, suggesting a possible role of leptin in regulating TSH secretion (Reinehr, 2010). Additionally, many studies suggest that thyroid hormones appear to regulate hepatic lipase, which alters c-HDL subfractions. The activity of lipoprotein lipase, which lowers triglyceride levels through hydrolysis of triglyceride-enriched lipoproteins and facilitation of cholesterol transfer from these lipoproteins to cHDL, is increased by thyroid hormone (Pearce et al., 2007). Comparisons between hypothyroid patients and controls by demographic variables noted that there was no significant difference among gender, age, cigarette smoking and alcoholic beverage. This can confirm the effect of mood disorders in the hypothalamic–pituitary–thyroid axis. In patients, the highest prevalence of hypothyroidism was found in women and patients aged more than 60 years. This is in line with results reported by Carle´ et al. (2006). Among clinical characteristics, we found that there was no significant association between hypothyroidism and illness dura-
tion, as reported by Valle et al. (1999). Furthermore, hypothyroidism was not significantly associated with illness episodes; however, depressive patients had the highest prevalence of this dysfunction. Many studies suggested that the alterations in the hypothalamic–pituitary–thyroid axis in depression might be associated with a deficiency in serotonin and/or noradrenalin levels. It has been hypothesized that reduced serotoninergic input could increase thyrotropin-releasing hormone (TRH) secretion which may lead to the down regulation of pituitary TRH receptors in euthyroid depressed patients (Eker et al., 2008). Our study failed to show any significant association between hypothyroidism and treatment, while it was more frequent in patients taking valproic acid and lithium. These results are in agreement with those reported by Gau et al. (2010). The mechanism by which valproic acid may cause hypothyroidism is not clear. It has been reported that patients treated chronically with valproic acid have secondary zinc and selenium deficiencies. The thyroid gland has a group of selenoproteins including glutathione peroxidase, 50 -deiodinase, and thioredoxine reductase that are important in thyroid hormone synthesis. Nutritional selenium deficiency has been reported to cause hypothyroidism and the suggested pathophysiology is a malfunction of the human 50 -deiodinases. Moreover, hypothyroidism has been reported to result from low zinc levels in patients with Down syndrome (Mikati et al., 2007). Furthermore, lithium therapy can cause alternations in thyroid status by blocking iodothyronine formation and inhibiting thyroid hormone release with a compensatory increase in TSH level (Baumgartner et al., 1997; Lombardi et al., 1993). Several methodological limitations should be considered when interpreting these findings. First, larger sample sizes of groups would be beneficial. Second, our work is a cross-sectional study that does not permit to follow up biological parameters. Third, the sample of bipolar patients may not be representative of more heterogeneous populations. Finally, the diagnosis of controls was made by psychiatrists but without formal use of structured instruments to exclude psychiatric disorders in controls. In conclusion, hypothyroidism in bipolar patients is the most frequent thyroid dysfunction. It is significantly associated with obesity and perturbations in lipid profile. It is also associated with treatment by valproic acid and lithium. However, no significant association was found between hypothyroidism and sociodemographic or clinical characteristics. This thyroid dysfunction can increase the risk to develop coronary artery disease in patients. Therefore, they should undergo regular testing of thyroid and lipid profile testing as well as body weight checks. Clinicians should track the effects of treatment on physical and biological parameters, and should facilitate access to appropriate medical care. Conflict of interest statement The authors stated that there are no conflicts of interest regarding the publication of this article. Acknowledgements We would like to thank the patients and control subjects for their assistance in this study. References American Psychiatric Association, 2004. Diagnostic and Statistical Manual of Mental Disorders, 4th edition. American Psychiatric Association, Washington, DC. Bartalena, L., Pellegrini, L., Meschi, M., Antonangeli, L., Bogazzi, F., Dell’osso, L., 1990. Evaluation of thyroid function in patients with rapid-cycling and non-rapidcycling bipolar disorder. Psychiatry Res. 34, 13–17.
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Contents lists available at ScienceDirect
Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp
Review
Thyroid function and lipid profile in bipolar I patients Asma Ezzaher a,*, Dhouha Haj Mouhamed a, Anwar Mechri b, Fadoua Neffati a, Wahiba Douki a, Lotfi Gaha b, Mohamed Fadhel Najjar a a b
Laboratory of Biochemistry-Toxicology, Monastir University Hospital, Tunisia Research Laboratory ‘Vulnerability to Psychotic Disorders LR 05 ES 10’, Department of Psychiatry, Monastir University Hospital, Tunisia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 3 June 2010 Received in revised form 5 February 2011 Accepted 8 February 2011
Objective: This study aims to evaluate the prevalence of thyroid dysfunctions and to explore their association with perturbations in lipid profile in bipolar I patients. Patients and methods: Our study included 130 bipolar I patients diagnosed according to the DSM IV, and 124 control subjects aged respectively 37.9 12.1 and 37.6 13.2 years. TSH and FT4 were determined using electrochemiluminescence. Total cholesterol, triglycerides, c-LDL and c-HDL were determined by enzymatic colorimetric methods and ApoA1, ApoB and Lp(a) by immunoturbidimetric techniques on Kone´lab 30TM. Results: Patients had significantly higher TSH values than controls and had perturbations in lipid profile. 0.7% and 28.5% of patients had respectively hyperthyroidism and hypothyroidism. Hypothyroidism was associated with obesity and perturbations in lipid profile particularly increase in total cholesterol, c-LDL, ApoB, ApoB/ApoA1 and Lp(a) and decrease in ApoA1 and c-HDL. Moreover, it was associated with lithium and valproic acid treatment. Conclusions: Hypothyroidism was frequent in bipolar patients. It was significantly associated with obesity and perturbations in lipid profile. Therefore, bipolar patients require specific care, particularly for thyroid, lipid profile and weight; the effectiveness of this care will be evaluated during follow-up period. ß 2011 Elsevier B.V. All rights reserved.
Keywords: Bipolar I disorder Hypothyroidism Lipid profile Obesity
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . 2.1. Subjects . . . . . . . . . . . 2.2. Samples . . . . . . . . . . . 2.3. Biochemical analysis. 2.4. Clinical evaluations . . 2.5. Statistical analysis. . . Results . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . Acknowledgements . . . . . . . References . . . . . . . . . . . . . .
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1. Introduction Bipolar disorder is a major psychiatric disorder that affects 1–3% of the worldwide population and is characterised by mood alteration
* Corresponding author at: Research Laboratory ‘Vulnerability to Psychotic Disorders LR 05 ES 10’, Department of Psychiatry, Monastir University Hospital, Tunisia. Tel.: +216 73 461 144; fax: +216 73 460 678. E-mail address: [email protected] (A. Ezzaher). 1876-2018/$ – see front matter ß 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ajp.2011.02.002
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139 140 140 140 140 140 140 141 142 142 142
associated with recurrent depression and mania in lifetime separated by periods of normal behaviour or euthymia (Marmol, 2008). Medical disease and medical risk factors are common in bipolar disorder, affect the course and severity of the disease and its treatment, and lead to even greater morbidity, mortality, and disability. Many medical problems have been documented in this population, the most common of which are cardiovascular disease, diabetes, obesity, dyslipidemia and thyroid disease (Soreca et al., 2008). Disorders of the thyroid gland are frequently associated with several mental disturbances. Thyroid hormones have a profound
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
140
Table 1 Sociodemographic and clinical characteristics of the sample population.
Gender: men/women (ratio) Age (years)
Bipolar I patients (n = 130)
Control group (n = 124)
p
85/45 (1.89) 37.9 12.1
81/43 (1.88) 37.6 13.2
1 0.84
Bipolar I patients (n = 130) Number Cigarette smoking Smokers Non-smokers Alcoholic beverage Consumers Non-consumers Episode of illness Depressive (D) Euthymic (E) Manic (M) Treatment Valproic acid Lithium Carbamazepine Antipsychotiques Lithium/valproic acid
Control group (n = 124) %
Number
p %
68 62
52.3 47.7
63 61
50.8 49.2
0.90
17 113
13.0 87.0
14 110
11.3 88.7
0.70
21 73 36
16.2 56.1 27.7
– – –
– – –
– – –
64 12 10 38 6
49.2 9.2 7.7 29.3 4.6
– – – – –
– – – – –
– – – – –
influence on behaviour and mood, and appear to be able to modulate the phenotypic expression of major affective illness (Bauer et al., 2002). This intimate association between the thyroid system and behaviour has been the impetus for exploring the effects of thyroid hormones in modulating affective illness, and the role of the hypothalamic–pituitary–thyroid axis in the pathophysiology of mood disorders. On the other hand, relations between thyroid function and lipid status remain controversial. Some investigators have suggested that subjects with hypothyroidism have an increased risk of coronary artery disease. These effects may, in part, be related to atherogenic change in lipid profile (Cappola and Ladenson, 2003). This study aims to evaluate the prevalence of thyroid dysfunctions and to explore their association with perturbations in lipid profile in bipolar I patients. 2. Methods 2.1. Subjects This study was approved by the local ethical committee and all subjects were of Tunisian origin. Our sample included 130 bipolar I patients from the psychiatry department of the University Hospital of Monastir. The mean age was 37.9 12.1 years, 85 men (38.1 11.4 years) and 45 women (37.53 13.41 years). Consensus on the diagnosis, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria (American Psychiatric Association, 2004), was made by psychiatrists. The exclusion criteria were age (<18 years), other psychiatric illnesses, epilepsy or mental retardation. The control group consisted of 124 volunteer subjects without psychiatric or endocrinological diagnoses and matched for age and gender with bipolar patients. The mean age was 37.6 13.2 years, and there were 81 men (36.9 12.6 years) and 43 women (38.8 14.1 years). All subjects were questioned about their age, gender, cigarette and alcohol consumption habits and clinical and therapeutic history. Whether any of the patients were treated with replacement thyroxine and their use of lipid-lowering medications (i.e. statins, niacin, fish oil, etc.) was not determined. Participants with biochemical signs of overt thyroid dysfunction or dyslipidemia were advised to consult their general physician for checking. The sociodemographic and clinical characteristics are shown in Table 1.
2.2. Samples After a 12 hour overnight fasting, venous blood for each patient was drawn in tubes containing lithium heparinate and immediately centrifuged. The plasma samples were stored at 20 8C until the biochemical analysis. 2.3. Biochemical analysis Thyroid-stimulating hormone (TSH) and FT4 were determined by chemiluminescence (Elecsys 2010TM Roche diagnostics). Concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol (c-LDL) and high-density lipoprotein cholesterol (c-HDL) were determined by enzymatic colorimetric methods, and apolipoprotein (ApoA1, ApoB) and lipoprotein(a) (Lp(a)) levels by immunoturbidimetric techniques using Kone´lab 30 equipment (Thermo Electron Corporation, Ruukintie, Finland). 2.4. Clinical evaluations Body mass index (BMI) was calculated as weight (kg) divided by height (m2). Obesity was defined when BMI 30 kg/m2 (World Health Organization, 1997). 2.5. Statistical analysis Statistical analyses were performed using SPSS v. 13.0 (SPSS, Chicago, IL, USA). Quantitative variables were presented as Table 2 Comparisons of biological and clinical variables between bipolar I patients and control group. Biological and clinical variables
Patients (n = 130)
Controls (n = 124)
p
TSH (mIU/L) FT4 (ng/L) BMI (kg/m2) Cholesterol (mmol/L) c-HDL (mmol/L) c-LDL (mmol/L) Triglycerides (mmol/L) ApoA1 (g/L) ApoB (g/L) ApoB/ApoA1 Lipoprotein(a) (mg/L)
2.73 1.80 12.69 2.64 27.13 4.57 4.42 0.99 0.98 0.28 2.14 1.10 1.95 1.15 1.20 0.23 0.82 0.28 0.70 0.26 243 223
1.62 0.72 12.87 1.70 25.30 3.81 3.90 0.99 1.09 0.36 1.29 0.56 1.61 0.96 1.29 0.45 0.77 0.23 0.62 0.26 156 120
<0.001 0.5 <0.001 <0.001 0.01 <0.001 0.04 0.04 0.03 0.01 <0.001
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
141
Table 3 Repartition of patients according to thyroid parameters. Thyroid parameters
TSH (mIU/L) FT4 (ng/L) * a
Bipolar patients (n = 130) Hyperthyroid patientsa TSH < 0.18 (n = 1)
Euthyroid patients 0.18 TSH 3.06 (n = 92)
Hypothyroid patients TSH > 3.06 (n = 37)
0.067 12.58
1.93 0.70 12.88 2.52
4.84 1.97* 12.23 2.99
Hypothyroid patients vs euthyroid patients: p < 0.001. Because of small effective (n = 1) hyperthyroid patient was excluded for this study.
Table 4 Comparisons between euthyroid patients, hypothyroid patients and control group by demographic and biological variables. Demographic and biological variables
Age (years) BMI (kg/m2) Cholesterol (mmol/L) c-HDL (mmol/L) c-LDL (mmol/L) Triglycerides (mmol/L) ApoA1 (g/L) ApoB (g/L) ApoB/ApoA1 Lipoprotein(a) (mg/L)
Control group (n = 124)
Bipolar patients (n = 129) 0.18 TSH 3.06 (n = 92)
TSH > 3.06 (n = 37)
p
37.6 13.2 25.30 3.81
37.45 11.2 26.80 4.42a
38.70 14.2 27.99 5.02b
<0.001 0.21
3.90 0.99 1.09 0.36 1.29 0.56 1.61 0.96 1.29 0.45 0.77 0.23 0.62 0.26 156 120
4.36 1.02a 0.99 0.28a 2.12 1.07a 1.79 1.30 1.19 0.22a 0.83 0.30a 0.71 0.25a 256 245a
4.56 0.95b 0.97 0.23b 2.17 1.22b 2.37 2.03b 1.21 0.24 0.80 0.23 0.70 0.30 212 163b
0.29 0.90 0.80 0.11 0.69 0.60 0.86 0.23
p: statistical analysis between euthyroid and hypothyroid patients. a Euthyroid patients vs control group: p < 0.05. b Hypothyroid patients vs control group: p < 0.05.
mean SD and comparisons were performed using the Student’s t test. Qualitative variable comparisons were performed using the chisquare (x2) test. The statistical significance level was set at p < 0.05.
There was no difference in hypothyroidism prevalence between antipsychotic and mood stabilizers treatment, while hypothyroidism was more frequent in patients treated with valproic acid and lithium (Table 5).
3. Results Bipolar patients had significantly higher TSH values than controls, while no significant change in FT4 values was observed. Moreover, they had significantly higher values for total cholesterol, c-LDL, triglycerides, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significantly lower values for c-HDL and ApoA1 than the control subjects (Table 2). According to TSH values, patients were subdivided in three groups: euthyroid group (70.8%), hypothyroid group (28.5%) and hyperthyroid group (0.7%) (Table 3). Hypothyroid patients had significantly higher levels of TSH, total cholesterol, triglycerides, c-LDL, Lp(a) and BMI and significantly lower levels of c-HDL than control group. Additionally, euthyroid patients had significantly higher levels of TSH, total cholesterol, c-LDL, ApoA1, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI, and significantly lower levels of c-HDL and ApoA1 than control group, while no significant change between hypothyroid and euthyroid patients was observed (Table 4). Comparisons between hypothyroid patients and control group by demographic and clinical variables noted that there was no significant difference among gender, age, cigarette smoking and alcoholic beverage. In patients, the highest prevalence of hypothyroidism was found in women and patients aged more than 60 years. Cigarette smoking and alcoholic beverage were not significantly associated with hypothyroidism but 20.6% of smoker patients and 11.8% of alcoholic consumer patients had hypothyroidism (Table 5). We noted that there is no significant variation in hypothyroid patients among episode and duration of illness, while the highest prevalence of hypothyroidism was found in depressive patients and when duration of illness was less than 10 years (Table 5).
Table 5 Comparisons between hypothyroid patients and control subjects by demographic and clinical variables. Demographic and clinical variables
Gender Men Women Age 39 years 40–59 years 60 years Cigarette smoking Yes No Alcoholic beverage Yes No Duration of illness 10 >10 Episode of illness Depressive Euthymic Manic Treatment Antipsychotiques Mood stabilizers Valproic acid Carbamazepine Lithium/valproic acid Lithium
Hypothyroid patients (n = 37)
Controls (n = 124)
Statistical analysis
Number
%
Number
23/85 14/45
27 31.1
81 43
65.3 34.7
0.84
19/74 14/49 4/7
25.7 28.6 57.2
79 37 8
63.7 29.8 6.5
0.15
14/68 23/62
20.6 37.1
61 63
49.2 50.8
0.19
2/17 35/113
11.8 40
14 110
11.3 88.7
0.36
21/59 16/71
35.6 22.5
– –
– –
8/21 18/73 11/36
39 24.7 30.6
– – –
– – –
11/38 26/92 20/64 2/10 3/6 1/12
28.9 28.3 31.3 20 50 8.4
–
–
– – – –
– – – –
%
142
A. Ezzaher et al. / Asian Journal of Psychiatry 4 (2011) 139–143
4. Discussion Bipolar patients had significant increase in TSH and slight decrease in FT4 than control subjects. It has been suggested that the thyroid system may have different roles in the pathophysiological process of bipolar disorders. Indeed, thyroid hormones have been shown to possess mood regulating properties via their modulation of multiple central transmission systems (e.g., serotonin and norepinephrine) and the increase in availability of thyroid hormones has been hypothesized to be therapeutic for mood disorders (Bauer et al., 2003). Patients had significantly higher levels of total cholesterol, cLDL, triglycerides, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significant lower levels of c-HDL and ApoA1 than control subjects. This may explain the high risk of cardiovascular disease and the high prevalence of metabolic syndrome (Garcia-Portilla et al., 2009; Fagiolini et al., 2005; Sicras et al., 2008) in bipolar patients. The underlying mechanism for the altered lipid status and obesity in bipolar patients is unclear. A possible explanation might be found in the patient’s nutritional status, the decrease in physical activity and the medications used (Ezzaher et al., 2010). Additionally, Chung et al. (2007) reported that bipolar disorder is associated with perturbations in the lipid profile which playa an important role in the pathophysiology of mood disorders, particularly in bipolar disorders. Our data showed that 38 patients had thyroid dysfunction: one with hyperthyroidism (0.7%) and 37 (28.5%) with hypothyroidism. A patient with hyperthyroidism was excluded from this study because of small effective number. Compared to other populations, the prevalence of hypothyroidism in our patients was 3-fold higher than that reported in Spanish patients by Valle et al. (1999) (9.2%) and similar to that reported in Italian patients by Bartalena et al. (1990) (32%). These differences could be due to ethnicity and eating habits. Euthyroid patients had significantly higher levels of total cholesterol, c-LDL, ApoA1, ApoB, ApoB/ApoA1 ratio, Lp(a) and BMI and significantly lower levels of c-HDL and ApoA1 than control group, while no significant change between hypothyroid and euthyroid patients was observed. This could confirm the effect of bipolar disorder on perturbations of lipid profile and obesity. Furthermore, hypothyroid patients had significantly higher levels of total cholesterol, triglycerides, c-LDL, Lp(a) and BMI and significantly lower levels of c-HDL than control group. The relationship between the hypothalamic–pituitary–thyroid axis and obesity and lipid profile had been investigated. Many reports suggest that leptin may modify hypothalamic production of TSH. Leptin and TSH have almost identical circadian rhythms, and leptin deficiency is closely associated with dysregulated patterns of pulsatile and circadian rhythms of TSH secretion, suggesting a possible role of leptin in regulating TSH secretion (Reinehr, 2010). Additionally, many studies suggest that thyroid hormones appear to regulate hepatic lipase, which alters c-HDL subfractions. The activity of lipoprotein lipase, which lowers triglyceride levels through hydrolysis of triglyceride-enriched lipoproteins and facilitation of cholesterol transfer from these lipoproteins to cHDL, is increased by thyroid hormone (Pearce et al., 2007). Comparisons between hypothyroid patients and controls by demographic variables noted that there was no significant difference among gender, age, cigarette smoking and alcoholic beverage. This can confirm the effect of mood disorders in the hypothalamic–pituitary–thyroid axis. In patients, the highest prevalence of hypothyroidism was found in women and patients aged more than 60 years. This is in line with results reported by Carle´ et al. (2006). Among clinical characteristics, we found that there was no significant association between hypothyroidism and illness dura-
tion, as reported by Valle et al. (1999). Furthermore, hypothyroidism was not significantly associated with illness episodes; however, depressive patients had the highest prevalence of this dysfunction. Many studies suggested that the alterations in the hypothalamic–pituitary–thyroid axis in depression might be associated with a deficiency in serotonin and/or noradrenalin levels. It has been hypothesized that reduced serotoninergic input could increase thyrotropin-releasing hormone (TRH) secretion which may lead to the down regulation of pituitary TRH receptors in euthyroid depressed patients (Eker et al., 2008). Our study failed to show any significant association between hypothyroidism and treatment, while it was more frequent in patients taking valproic acid and lithium. These results are in agreement with those reported by Gau et al. (2010). The mechanism by which valproic acid may cause hypothyroidism is not clear. It has been reported that patients treated chronically with valproic acid have secondary zinc and selenium deficiencies. The thyroid gland has a group of selenoproteins including glutathione peroxidase, 50 -deiodinase, and thioredoxine reductase that are important in thyroid hormone synthesis. Nutritional selenium deficiency has been reported to cause hypothyroidism and the suggested pathophysiology is a malfunction of the human 50 -deiodinases. Moreover, hypothyroidism has been reported to result from low zinc levels in patients with Down syndrome (Mikati et al., 2007). Furthermore, lithium therapy can cause alternations in thyroid status by blocking iodothyronine formation and inhibiting thyroid hormone release with a compensatory increase in TSH level (Baumgartner et al., 1997; Lombardi et al., 1993). Several methodological limitations should be considered when interpreting these findings. First, larger sample sizes of groups would be beneficial. Second, our work is a cross-sectional study that does not permit to follow up biological parameters. Third, the sample of bipolar patients may not be representative of more heterogeneous populations. Finally, the diagnosis of controls was made by psychiatrists but without formal use of structured instruments to exclude psychiatric disorders in controls. In conclusion, hypothyroidism in bipolar patients is the most frequent thyroid dysfunction. It is significantly associated with obesity and perturbations in lipid profile. It is also associated with treatment by valproic acid and lithium. However, no significant association was found between hypothyroidism and sociodemographic or clinical characteristics. This thyroid dysfunction can increase the risk to develop coronary artery disease in patients. Therefore, they should undergo regular testing of thyroid and lipid profile testing as well as body weight checks. Clinicians should track the effects of treatment on physical and biological parameters, and should facilitate access to appropriate medical care. Conflict of interest statement The authors stated that there are no conflicts of interest regarding the publication of this article. Acknowledgements We would like to thank the patients and control subjects for their assistance in this study. References American Psychiatric Association, 2004. Diagnostic and Statistical Manual of Mental Disorders, 4th edition. American Psychiatric Association, Washington, DC. Bartalena, L., Pellegrini, L., Meschi, M., Antonangeli, L., Bogazzi, F., Dell’osso, L., 1990. Evaluation of thyroid function in patients with rapid-cycling and non-rapidcycling bipolar disorder. Psychiatry Res. 34, 13–17.
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