European Journal of Neurology 2014, 21: 996–1001
doi:10.1111/ene.12425
Association of moyamoya disease with thyroid autoantibodies and thyroid function: a case control study and meta-analysis C. Leia, B. Wua,b, Z. Maa, S. Zhanga and M. Liua,b a
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Sichuan; and bState Key Laboratory of Human Disease Biotherapy and Ministry of Education, West China Hospital, Sichuan University, Sichuan, China
Keywords:
meta-analysis, moyamoya disease, thyroid autoantibody, thyroid function Received 4 November 2013 Accepted 24 February 2014
Background and purpose: Evidence suggests that elevated thyroid function and elevated levels of thyroid autoantibodies are associated with risk of moyamoya disease (MMD). Therefore a meta-analysis of all available evidence was performed, including unpublished data from our own center, in order to assess this association. Methods: Major literature databases were reviewed without language restrictions to identify studies examining the association between MMD and thyroid function or thyroid autoantibodies. These data were combined with those from our own prospective study. This study involved consecutively recruited patients with MMD and two groups of age-matched control patients: patients with non-MMD stroke and healthy individuals. The groups were compared in terms of serum triiodothyronine (T3), thyroxine (T4), free T4, free T3, thyroid stimulating hormone, antithyroperoxidase antibody and anti-thyroglobulin antibody. Results: Our prospective study involved 28 patients with MMD, 28 age-matched patients with non-MMD stroke and 28 age-matched healthy control participants. The results showed an association between risk of MMD and elevated thyroid autoantibodies [odds ratio (OR) 9.00, 95% confidence interval (CI) 1.03–78.94] but not between risk of MMD and elevated thyroid function (OR 5.87, 95% CI 0.64–53.93). Meta-analysis of our data with findings from the literature further supported the association with elevated thyroid autoantibodies (OR 8.77, 95% CI 4.45–17.29) and indicated an association with elevated thyroid function (OR 9.74, 95% CI 2.18–43.49). Conclusions: Evidence strongly suggests that elevated thyroid autoantibodies and elevated thyroid function are independently associated with MMD. These clinical variables may require regular monitoring in patients with MMD.
Introduction Moyamoya disease (MMD) is a rare cerebrovascular condition characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, giving rise to a network of collateral vessels resembling a puff of smoke on angiograms [1,2]. The disease has been observed around the world, although it is thought to occur more often in Asians [3–6]. Large studies have investigated the clinicoepidemiological features of MMD [3], but little is known about its etiology and progression. Recent studies Correspondence: B. Wu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China (tel.: +86 18 980602142; fax: +86 28 85423551; e-mail: dragonwbtxf@hotmail. com). or M. Liu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China (tel.: +86 18 980601671; fax: +86 28 85423551; e-mail: [email protected]).
996
suggest that the disease is associated with elevated levels of thyroid autoantibodies and elevated thyroid function [7,8]. Since this finding may provide a valuable starting point for basic and applied research into the disease, it was important to verify it with as much statistical power as possible. Therefore a comprehensive review of the literature was carried out and data extracted from carefully selected studies were combined together with data from our own prospective, controlled study. Our goal was to establish whether risk of MMD is associated with levels of thyroid autoantibodies and/or levels of thyroid function.
Subjects and methods Clinical study
Study participants with MMD were consecutively recruited in the Department of Neurology, West © 2014 The Author(s) European Journal of Neurology © 2014 EAN
MMD and thyroid autoantibodies and thyroid function
China Hospital, between 1 January 2009 and 31 May 2013. This study was approved by the Scientific Research Department of West China Hospital and it was designed in accordance with local ethics criteria for human research. Informed consent was obtained from subjects or their guardians. The diagnosis for MMD was made by use of digital subtraction angiography and/or magnetic resonance angiography, based on Japanese guidelines [9]. MMD is a chronic cerebrovasculopathy of uncertain etiology, characterized by progressive stenosis of the terminal portion of the internal carotid arteries and their main branches. This stenosis triggers compensatory development of collateral vasculature by small vessels near the apex of the carotid artery, on the cortical surface, leptomeninges, and branches of the external carotid artery supplying the dura and base of the skull. Moyamoya syndrome was diagnosed when radiographic features similar to those of idiopathic MMD coexisted with other medical conditions that might explain the vasculopathy, such as sickle cell disease and tuberculous meningitis. Age-matched patients with non-MMD stroke were consecutively recruited from the same department over the same period as a control group. Patients were excluded if they had moyamoya syndrome or if the available data on serum levels of thyroid hormones and autoantibodies were incomplete. To provide a second control group, age-matched healthy participants from our hospital who came for routine check-ups were recruited. Neither these individuals nor their immediate family had a history of cardiovascular disease or MMD based on interviews and medical records at the health control. Baseline information was collected at admission on age, gender and stroke risk factors (hypertension, diabetes mellitus, hypercholesterolemia, history of cerebral infarction, current smoking, alcohol intake). Hypertension was defined as current use of antihypertensive medications, or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Diabetes mellitus was defined as the use of antidiabetic medication or a fasting serum glucose level ≥7.0 mmol/l. Hypercholesterolemia was defined as fasting serum total cholesterol level ≥220 mg/dl or use of lipid-lowering agents. Patients who had smoked ≥1 cigarette/day for at least 1 year were classified as current smoking. Patients who had consumed ≥50 ml of alcohol/day for more than 1 year were defined as positive for alcohol intake [10]. Data were also collected on serum levels of triiodothyronine (T3), thyroxine (T4), free T4, free T3, thyroid stimulating hormone (TSH), anti-thyroperoxidase antibody (TPOAb) and anti-thyroglobulin antibody (TGAb). © 2014 The Author(s) European Journal of Neurology © 2014 EAN
997
Baseline levels of thyroid hormones were used to classify patients as having elevated thyroid function, decreased thyroid function or euthyroidism [8,11]. Elevated thyroid function was biochemically defined as a serum TSH level below the lower limit of the assay manufacturer’s reference range (0.27–4.2 mU/l). Similarly, decreased thyroid function was biochemically defined as a serum TSH level above the upper limit of the manufacturer’s reference range. Patients were defined as having elevated TPOAb when the serum TPOAb level was above the manufacturer’s reference range (
doi:10.1111/ene.12425
Association of moyamoya disease with thyroid autoantibodies and thyroid function: a case control study and meta-analysis C. Leia, B. Wua,b, Z. Maa, S. Zhanga and M. Liua,b a
Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, Sichuan; and bState Key Laboratory of Human Disease Biotherapy and Ministry of Education, West China Hospital, Sichuan University, Sichuan, China
Keywords:
meta-analysis, moyamoya disease, thyroid autoantibody, thyroid function Received 4 November 2013 Accepted 24 February 2014
Background and purpose: Evidence suggests that elevated thyroid function and elevated levels of thyroid autoantibodies are associated with risk of moyamoya disease (MMD). Therefore a meta-analysis of all available evidence was performed, including unpublished data from our own center, in order to assess this association. Methods: Major literature databases were reviewed without language restrictions to identify studies examining the association between MMD and thyroid function or thyroid autoantibodies. These data were combined with those from our own prospective study. This study involved consecutively recruited patients with MMD and two groups of age-matched control patients: patients with non-MMD stroke and healthy individuals. The groups were compared in terms of serum triiodothyronine (T3), thyroxine (T4), free T4, free T3, thyroid stimulating hormone, antithyroperoxidase antibody and anti-thyroglobulin antibody. Results: Our prospective study involved 28 patients with MMD, 28 age-matched patients with non-MMD stroke and 28 age-matched healthy control participants. The results showed an association between risk of MMD and elevated thyroid autoantibodies [odds ratio (OR) 9.00, 95% confidence interval (CI) 1.03–78.94] but not between risk of MMD and elevated thyroid function (OR 5.87, 95% CI 0.64–53.93). Meta-analysis of our data with findings from the literature further supported the association with elevated thyroid autoantibodies (OR 8.77, 95% CI 4.45–17.29) and indicated an association with elevated thyroid function (OR 9.74, 95% CI 2.18–43.49). Conclusions: Evidence strongly suggests that elevated thyroid autoantibodies and elevated thyroid function are independently associated with MMD. These clinical variables may require regular monitoring in patients with MMD.
Introduction Moyamoya disease (MMD) is a rare cerebrovascular condition characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, giving rise to a network of collateral vessels resembling a puff of smoke on angiograms [1,2]. The disease has been observed around the world, although it is thought to occur more often in Asians [3–6]. Large studies have investigated the clinicoepidemiological features of MMD [3], but little is known about its etiology and progression. Recent studies Correspondence: B. Wu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China (tel.: +86 18 980602142; fax: +86 28 85423551; e-mail: dragonwbtxf@hotmail. com). or M. Liu, Stroke Clinical Research Unit, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China (tel.: +86 18 980601671; fax: +86 28 85423551; e-mail: [email protected]).
996
suggest that the disease is associated with elevated levels of thyroid autoantibodies and elevated thyroid function [7,8]. Since this finding may provide a valuable starting point for basic and applied research into the disease, it was important to verify it with as much statistical power as possible. Therefore a comprehensive review of the literature was carried out and data extracted from carefully selected studies were combined together with data from our own prospective, controlled study. Our goal was to establish whether risk of MMD is associated with levels of thyroid autoantibodies and/or levels of thyroid function.
Subjects and methods Clinical study
Study participants with MMD were consecutively recruited in the Department of Neurology, West © 2014 The Author(s) European Journal of Neurology © 2014 EAN
MMD and thyroid autoantibodies and thyroid function
China Hospital, between 1 January 2009 and 31 May 2013. This study was approved by the Scientific Research Department of West China Hospital and it was designed in accordance with local ethics criteria for human research. Informed consent was obtained from subjects or their guardians. The diagnosis for MMD was made by use of digital subtraction angiography and/or magnetic resonance angiography, based on Japanese guidelines [9]. MMD is a chronic cerebrovasculopathy of uncertain etiology, characterized by progressive stenosis of the terminal portion of the internal carotid arteries and their main branches. This stenosis triggers compensatory development of collateral vasculature by small vessels near the apex of the carotid artery, on the cortical surface, leptomeninges, and branches of the external carotid artery supplying the dura and base of the skull. Moyamoya syndrome was diagnosed when radiographic features similar to those of idiopathic MMD coexisted with other medical conditions that might explain the vasculopathy, such as sickle cell disease and tuberculous meningitis. Age-matched patients with non-MMD stroke were consecutively recruited from the same department over the same period as a control group. Patients were excluded if they had moyamoya syndrome or if the available data on serum levels of thyroid hormones and autoantibodies were incomplete. To provide a second control group, age-matched healthy participants from our hospital who came for routine check-ups were recruited. Neither these individuals nor their immediate family had a history of cardiovascular disease or MMD based on interviews and medical records at the health control. Baseline information was collected at admission on age, gender and stroke risk factors (hypertension, diabetes mellitus, hypercholesterolemia, history of cerebral infarction, current smoking, alcohol intake). Hypertension was defined as current use of antihypertensive medications, or systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Diabetes mellitus was defined as the use of antidiabetic medication or a fasting serum glucose level ≥7.0 mmol/l. Hypercholesterolemia was defined as fasting serum total cholesterol level ≥220 mg/dl or use of lipid-lowering agents. Patients who had smoked ≥1 cigarette/day for at least 1 year were classified as current smoking. Patients who had consumed ≥50 ml of alcohol/day for more than 1 year were defined as positive for alcohol intake [10]. Data were also collected on serum levels of triiodothyronine (T3), thyroxine (T4), free T4, free T3, thyroid stimulating hormone (TSH), anti-thyroperoxidase antibody (TPOAb) and anti-thyroglobulin antibody (TGAb). © 2014 The Author(s) European Journal of Neurology © 2014 EAN
997
Baseline levels of thyroid hormones were used to classify patients as having elevated thyroid function, decreased thyroid function or euthyroidism [8,11]. Elevated thyroid function was biochemically defined as a serum TSH level below the lower limit of the assay manufacturer’s reference range (0.27–4.2 mU/l). Similarly, decreased thyroid function was biochemically defined as a serum TSH level above the upper limit of the manufacturer’s reference range. Patients were defined as having elevated TPOAb when the serum TPOAb level was above the manufacturer’s reference range (
