Hyperthyroidism with reference to elevated serum FT3 and FT4 levels in patients with ischemic stroke

Introduction

Hyperthyroidism is a common endocrine metabolic condition and comprises a group of disorders whereby excessive hormones are produced and secreted by the thyroid gland. And the prevalence of overt hyperthyroidism in mainland China was 0.78% from 2015 to 2017 (1,2). The predominant cause of hyperthyroidism is diffuse toxic goiter (Graves' disease), which is caused by circulating immunoglobulin G autoantibodies binding with the thyrotrophin (TSH) receptor (3,4). Patients with hyperthyroidism have an increased risk for acute cardiovascular events, while the elevated TSH levels may improve motor functional outcome after ischemic stroke (5).

Patients with hyperthyroidism frequently present with clinical symptoms, such as tenseness, irascibility, tachycardia, hand tremors, anxiety and myasthenia, which are caused by high levels of thyroid hormones triiodothyronine (T3) and thyroxine (T4) (6). In almost all tissue of the body, thyroid dysfunction serves a vital role in a variety of metabolic processes, independent of hyperthyroidism (7,8).

A number of studies have reported that hyperthyroidism is associated with several metabolic disorders and cardiovascular events (9,10). There are numerous targets of thyroid hormone, such as the hypothalamus and hypophysis, in the cerebrovascular system, which are active in decreasing systemic vascular resistance, altering systolic and diastolic cardiac function to improve cardiac contractility (11,12). In addition, there is a direct association between cerebrovascular diseases (such as Moyamoya disease, carotid atheromatous plaques, spontaneous cervical artery dissection and cerebral venous thrombosis during therapy) and recovery (13).

Previous clinical studies have reported that patients with acute stroke also exhibit neuroendocrine dysfunction (14,15). In China, the primary cause of mortality within the older population is cerebrovascular disease, with 1,500,000-2,000,000 new cases diagnosed each year and a high morbidity rate; the prevalence of stroke is 116-219/100,000/year, and mortality is 58-142/100,000/year in 2010 in China (16,17). In 2020, the mortality rate of intracerebral hemorrhage and ischemic stroke was 3.3/100,000 and 0.9/100,000 among young adults (aged 15-49 years) in China (18). Prospective and retrospective studies have suggested that hyperthyroidism may aggravate or be used as a risk factor for predicting ischemic stroke (5,19). However, to the best of our knowledge, the mechanism underlying the association between hyperthyroidism and cerebrovascular disease remains to be fully elucidated. Therefore, in the present study, the risk of ischemic stroke in patients with hyperthyroidism was investigated.

Patients and methods

Patients

The present study was a case-control study, including 4,674 individuals [582 cases and 4,092 controls (2,947 males; median age, 65 years; age range, 21-100 years; 1,727 females; median age, 69 years; age range, 20-97 years)] at the Second Affiliated Hospital of Nanchang University and Kunshan Affiliated Hospital of Nanjing University of Chinese Medicine (both Nanjing, China) and Suzhou Affiliated Hospital of Medical School, Nanjing University (Suzhou, China) during the period of September 2007 to June 2024. Inclusion criteria were cerebral hemorrhage in adults as well as events and/or mortality recorded. Exclusion criteria were as follows: i) Overt thyroid diseases, ii) exclude patients with hypothyroidism or other thyroid diseases (including chronic thyroid autoimmune disorder. All patients gave written informed consent for participation in the study. The study was approved (approval no. IRB2025053) by the Ethics Committee of Suzhou Affiliated Hospital of Medical School, Nanjing University and (No. 2025[148] by the Ethics Committee of the Second Affiliated Hospital of Nanchang University.

Detailed information of each patient was extracted from the electronic medical records, including past medical history, age, sex and chemical and X-ray results. In the present study, initial hospitalization due to ischemic stroke was used as an indicator. All patients with ischemic stroke were confirmed by GE Revolution CT or GE Discovery MR750W 3.0T. Patients with cerebral hemorrhage based on physical and clinical symptoms and those with subarachnoid hemorrhage or other immunological disease were excluded. The case group was diagnosed with hyperthyroidism by laboratory examination, which could exclude patients with hypothyroidism or other thyroid diseases (including chronic thyroid autoimmune disorder; determined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. 3d edition); the control group excluded patients with hyperthyroidism history (20).

Definitions and biochemical biomarkers

Patients with hypermetabolic symptoms and thyroid storm, diagnosed as having high levels of thyroid hormones and low thyrotrophin (TSH) levels in serum, were recorded as hyperthyroidism. The TSH reference range was 0.55-4.78 mIU/l. The FT3 reference range was 2.3-4.2 pg/ml. The FT4 reference range was 0.89-1.8 ng/dl. The diagnosis of hypertension was past medical history of hypertension, currently receiving antihypertensive medication or blood pressure ≥140/90 mmHg at three different times without receiving antihypertensive medications (21). Patients with typical diabetic symptoms, including random venous blood glucose ≥11.1 mmol/l, fasting plasma glucose ≥7.0 mmol/l or oral glucose tolerance test 2-h plasma glucose levels ≥11.1 mmol/l, were defined as diabetes mellitus (22). Atrial fibrillation was defined previous history of atrial fibrillation or if electrocardiogram monitoring revealed atrial fibrillation following hospitalization (23). The definition of coronary heart disease was coronary angiography showing lumen diameter stenosis ≥50% in at least one coronary vessels (24).

Statistical analysis

SPSS (version 26.0; IBM Corp.) was used to perform the χ2 and two-sample unpaired t-tests to examine the differences in patient clinical features and the levels of TSH, FT3, FT4 and other metabolic indices. All data are presented as median (25% Percentile, 75% Percentile). Odds ratios (ORs) and 95% CI were calculated using logistic regression to estimate the association between the hyperthyroidism and ischemic stroke. P<0.05 was considered to indicate a statistically significant difference.

Results

Patient clinical characteristics

A total of 582 patients with ischemic stroke and hyperthyroidism were incorporated into the case group, whereas 4,092 patients were allocated into the control group. There were significant differences in sex distribution, smoking status and alcohol consumption status (Table I). The mean age of the case group was 65.52±12.48 years, similar to 65.12±12.50 years in the control group. History of stroke, CHD, hypertension, AF, heart disease and current hypertension and heart disease may influence patients with hyperthyroidism group. In total, 91.99% patients in the control group demonstrated favorable recovery, compared with 66.5% in the patient group.

Table I Patient clinical characteristics.

Table I

Patient clinical characteristics.

Characteristic	Control (n=4092)	Cases (n=582)	P-value
Mean age, years	65.52±12.48	65.12±12.50	0.459
Sex (%)			<0.001
Male	2,624 (64.13)	323 (55.50)
Female	1,468 (35.87)	259 (44.50)
Smoker (%)			0.085
Yes	917 (22.24)	112 (19.24)
No	3,175 (77.59)	470 (80.75)
Alcohol consumption (%)			<0.001
Yes	818 (19.99)	80 (13.70)
No	3,274 (80.01)	502 (86.25)
History of stroke (%)			<0.001
Yes	460 (11.24)	115 (19.80)
No	3,632 (88.81)	467 (80.24)
History of CHD (%)			0.047
Yes	172 (4.20)	35 (6.00)
No	3,920 (95.80)	547 (93.99)
History of diabetes (%)			0.807
I (type 1 diabetes mellitus	56 (1.37)	10 (1.70)
Type 2 diabetes mellitus	577 (14.10)	75 (12.90)
III (composite diabetes mellitus)	6 (0.15)	1 (0.17)
IV (diabetes mellitus in pregnancy)	3 (0.73)	1 (0.17)
No	3,450 (84.31)	495 (85.05)
History of hypertension (%)			<0.001
Grade 1	2,206 (53.91)	250 (42.96)
II (Grade 2 hypertension)	66 (1.61)	22 (3.78)
III (Grade 3 hypertension)	7 (0.17)	3 (0.52)
No	1,813 (44.31)	308 (52.92)
History of AF (%)			0.013
I (long-standing persistent AF)	10 (0.24)	4 (0.69)
II (persistent AF)	13 (0.32)	6 (1.03)
III (paroxysmal AF)	138 (3.37)	24 (4.12)
No	3,931 (96.07)	548 (94.16)
History of heart disease (%)			<0.001
Yes	34 (0.83)	14 (2.41)
No	4,058 (99.17)	568 (97.59)
Current diabetes (%)			0.474
Yes	669 (16.35)	102 (17.53)
No	3,423 (83.65)	480 (82.47)
Current hypertension (%)			<0.001
Yes	2,176 (53.18)	243 (41.75)
No	1,916 (46.82)	339 (58.25)
Current hyperlipemia (%)			0.477
Yes	256 (6.26)	32 (5.50)
No	3,836 (93.74)	550 (94.50)
Current CHD (%)			0.077
Yes	191 (4.67)	37 (6.36)
No	3,901 (95.33)	545 (93.64)
Current AF (%)			0.069
Yes	539 (13.17)	61 (10.48)
No	3,553 (86.83)	521 (89.52)
Current heart disease (%)			<0.001
Yes	336 (8.21)	94 (16.15)
No	3,756 (91.79)	488 (83.85)
Length of hospital stay (range), days	10 (8-13)	10 (7-14)	0.543
Outcome			<0.001
Cured	491 (12.00)	60 (10.31)
Improved	3,273 (79.99)	327 (56.19)
Dead	61 (1.49)	5 (0.86)
Other	267 (6.52)	190 (32.64)

[i] CHD, coronary heart disease; AF, atrial fibrillation.

Serum metabolic biochemical biomarkers

The median levels of serum TSH in the case group was found to be lower compared with those in control group, but the difference in mean levels was not significant (Table II). FT3 and FT4 levels in the case group were significantly higher compared with those in the control group. Compared with that in the control group, the level of serum cholesterol (CHO) in the hyperthyroidism group was lower (4.45 vs. 4.17 mmol/l). Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in both groups were lower than the reference range. However, the case group had lower levels of both compared with those in the control group. The serum levels of lipoprotein A (LPa) in each group fell within the reference range (<30 mg/dl), but the serum level of LPa in the hyperthyroidism group was significantly lower compared with that in the control group.

Table II Levels of serum metabolic biochemical biomarkers.

Table II

Levels of serum metabolic biochemical biomarkers.

A, Age <40 years
	Cases (n=18)		Controls (n=83)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	0.02	0.09, 1.87	1.50	0.90, 2.15	0.025
FT3, pg/ml	4.23	2.55, 13.46	3.06	2.80, 3.36	<0.001
FT4, ng/ml	2.18	1.10, 4.96	1.23	1.14, 1.39	<0.001
LDH, IU/l	170.80	152.40, 230.90	179.00	155.80, 220.70	0.596
CK, IU/l	45.29	32.05, 86.43	111.70	75.70, 151.00	0.281
CHO, mmol/l	3.68	2.77, 4.90	4.35	3.84, 5.00	0.097
TG, mmol/l	1.00	0.70, 1.57	1.46	1.01, 2.13	0.057
LDL, mmol/l	1.76	1.41, 3.25	2.75	2.09, 3.24	0.112
HDL, mmol/l	1.02	0.78, 1.25	0.95	0.82, 1.12	0.869
LPa, mg/dl	18.84	8.01, 45.24	14.52	8.97, 26.91	0.362
TG/HDL ratio	1.01	0.64, 1.99	1.59	0.95, 2.46	0.335
B, Age, 40-49 years
	Cases (n=42)		Controls (n=366)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	0.31	0.01, 1.80	1.40	0.87, 2.19	0.023
FT3, pg/ml	3.22	2.59, 4.10	2.95	2.63, 3.21	<0.001
FT4, ng/ml	1.26	1.14, 1.83	1.23	1.12, 1.37	<0.001
LDH, IU/l	162.40	140.20, 207.20	173.40	145.50, 210.30	0.874
CK, IU/l	73.45	47.02, 109.90	91.75	68.25, 140.60	0.151
CHO, mmol/l	4.20	3.13, 4.87	4.49	3.77, 5.35	0.001
TG, mmol/l	1.32	0.96, 1.96	1.47	1.06, 2.19	0.220
LDL, mmol/l	2.56	1.61, 3.15	2.75	2.17, 3.41	0.007
HDL, mmol/l	0.89	0.75, 1.05	1.01	0.89, 1.19	0.003
LPa, mg/dl	17.27	7.31, 29.33	19.14	9.60, 37.96	0.343
TG/HDL ratio	1.49	0.95, 2.46	1.48	0.93, 2.37	0.825
C, Age, 50-59 years
	Cases (n=121)		Controls (n=809)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	1.06	0.02, 2.23	1.59	1.05, 2.41	0.890
FT3, pg/ml	3.14	2.81, 3.99	2.94	2.66, 3.21	<0.001
FT4, ng/ml	1.32	1.11, 1.68	1.25	1.12, 1.37	<0.001
LDH, IU/l	178.60	150.30, 220.40	174.60	151.60, 206.90	0.011
CK, IU/l	81.03	47.78, 131.00	94.34	66.25, 135.80	0.048
CHO, mmol/l	4.23	3.51, 4.84	4.55	3.84, 5.25	0.049
TG, mmol/l	1.32	0.98, 1.87	1.47	1.05, 2.07	0.198
LDL, mmol/l	2.62	1.92, 3.10	2.72	2.14, 3.32	0.049
HDL, mmol/l	0.97	0.78, 1.14	1.03	0.86, 1.24	0.001
LPa, mg/dl	18.12	8.80, 26.50	20.89	11.31, 39.92	0.017
TG/HDL ratio	1.45	0.93, 2.39	1.42	0.93, 2.20	0.825
D, Age 60-69 years
	Cases (n=165)		Controls (n=1,190)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	1.14	0.15, 2.06	1.59	0.99, 2.58	0.227
FT3, pg/ml	3.00	2.61, 3.49	2.87	2.57, 3.14	<0.001
FT4, ng/ml	1.28	1.14, 1.48	1.23	1.11, 1.34	<0.001
LDH, IU/l	173.80	149.20, 219.50	178.60	156.50, 217.60	0.998
CK, IU/l	86.90	60.30, 126.70	89.62	62.37, 133.30	0.352
CHO, mmol/l	4.15	3.44, 4.74	4.47	3.77, 5.17	0.001
TG, mmol/l	1.27	0.83, 1.78	1.33	1.00, 1.89	0.103
LDL, mmol/l	2.53	1.90, 3.01	2.64	2.12, 3.29	0.003
HDL, mmol/l	0.97	0.80, 1.22	1.05	0.88, 1.25	0.027
LPa, mg/dl	17.85	9.14, 32.30	20.60	11.51, 38.48	0.139
TG/HDL ratio	1.31	0.84, 2.07	1.30	0.86, 1.95	0.816
E, Age, 70-79 years
	Cases (n=175)		Controls (n=1,077)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	1.02	0.23, 2.23	1.54	0.86, 2.53	0.085
FT3, pg/ml	2.85	2.51, 3.17	2.73	2.40, 2.99	<0.001
FT4, ng/ml	1.30	1.13, 1.54	1.22	1.10, 1.33	<0.001
LDH, IU/l	189.40	161.60, 229.50	185.20	161.00, 223.50	0.777
CK, IU/l	88.50	62.09, 124.30	89.20	63.18, 131.40	0.211
CHO, mmol/l	4.39	3.69, 5.15	4.39	3.71, 5.16	0.832
TG, mmol/l	1.22	0.90, 1.66	1.15	0.89, 1.55	0.279
LDL, mmol/l	2.61	2.11, 3.38	2.59	2.03, 3.20	0.425
HDL, mmol/l	1.04	0.91, 1.25	1.11	0.94, 1.30	0.017
LPa, mg/dl	18.76	11.37, 34.64	19.11	10.62, 37.56	0.173
TG/HDL ratio	1.20	0.77, 1.70	1.06	0.74, 1.55	0.079
F, Age, ≥80 years
	Cases (n=61)		Controls (n=567)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	1.13	0.33, 1.88	1.57	0.92, 2.46	0.521
FT3, pg/ml	2.71	2.23, 3.00	2.54	2.20, 2.83	<0.001
FT4, ng/ml	1.22	1.07, 1.40	1.22	1.10, 1.34	0.055
LDH, IU/l	179.80	150.00, 217.90	191.40	165.70, 227.60	0.513
CK, IU/l	87.70	46.00, 128.50	83.46	56.85, 128.10	0.670
CHO, mmol/l	4.05	3.37, 4.61	4.36	3.69, 5.12	0.003
TG, mmol/l	1.06	0.68, 1.39	1.06	0.80, 1.38	0.996
LDL, mmol/l	2.31	1.92, 2.85	2.57	2.05, 3.14	0.056
HDL, mmol/l	1.04	0.88, 1.23	1.13	0.95, 1.34	0.003
LPa, mg/dl	23.71	11.06, 38.01	20.71	11.16, 34.70	0.656
TG/HDL ratio	0.84	0.68, 1.65	0.91	0.66, 1.38	0.034
G, Total
	Cases (n=582)		Controls (n=4,092)
Biomarker	Median	25-75th percentile	Median	25, 75th percentile	P-value
TSH, mIU/l	1.01	0.10, 2.12	1.57	0.93, 2.45	0.215
FT3, pg/ml	2.98	2.55, 3.42	2.82	2.49, 3.10	<0.001
FT4, ng/ml	1.29	1.13, 1.59	1.23	1.11, 1.35	<0.001
LDH, IU/l	179.10	153.20, 222.30	180.70	156.80, 217.70	0.261
CK, IU/l	84.05	55.98, 124.00	90.23	62.95, 133.40	0.060
CHO, mmol/l	4.17	3.47, 4.88	4.45	3.76, 5.18	<0.001
TG, mmol/l	1.24	0.88, 1.72	1.27	0.95, 1.11	0.076
LDL, mmol/l	2.55	2.94, 3.11	2.64	2.09, 3.26	<0.001
HDL, mmol/l	0.99	0.83, 1.19	1.07	0.90, 1.27	<0.001
LPa, mg/dl	18.36	9.40, 32.01	19.99	10.99, 38.06	0.006
TG/HDL ratio	1.21	0.80, 1.83	1.25	0.80, 1.98	0.431

[i] TSH, thyrotrophin; FT3, free thyroxine; FT4, triiodothyronine; LDH, Lactate Dehydrogenase; CK, creatine kinase; CHO, cholesterol; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LPa, lipoprotein A.

In patients aged <40 years, the difference in the median level of serum TSH, FT3 and FT4 was significant in cases than the control group. In patients aged 40-49 years, there were statistically significant differences in the median levels of serum thyroid hormones (TSH, FT3 and FT4), CHO, LDL and HDL. The median levels of serum FT3, FT4, LDH, creatine kinase (CK), CHO, LDL, HDL and LPa in the case and control groups were significant in those aged 50-59 years. The median levels of FT3, FT4, CHO, LDL and HDL in those aged 60-69 years were significantly different. In addition, there was a marked difference in the median levels of serum FT3, FT4 and HDL in the 70-79 years group. In the ≥80 years group, serum FT3, CHO and HDL had significantly different median levels. However, there was only a significant difference in the TG/HDL ratio between the case and control group in the ≥80 years category. These results suggest that thyroid hormones may serve various roles in different age groups, which may aggregate the cerebral infarction injury and worsen the prognosis of patients with hyperthyroidism.

Elevated serum FT3 and FT4 are associated with ischemic stroke

Age, sex, FT3 (OR, 2.097; 95% CI, 1.795-2.449), FT4 (OR, 1.503; 95% CI, 1.101-2.051), LDH (OR, 1.002; 95% CI, 1.001-1.003) and HDL (OR, 0.330; 95% CI, 0.194-0.561) were associated with ischemic stroke according to multivariate analysis (Table III). The results suggested that the increase of thyroid hormone FT3 and FT4 increased the risk of cerebral infarction by 1.5-2.0 times. However, increases in HDL levels were a marker of reduced risk of cerebral infarction.

Table III Multivariate analysis of clinical parameters.

Table III

Multivariate analysis of clinical parameters.

							95% C.I. for EXP(B)
Characteristic	B	S.E	Wals	df	Sig.	Exp (B)	Lower	Upper
Sex	-0.546	0.101	29.022	1	0.000	0.579	0.475	0.706
Age	0.010	0.004	6.170	1	0.013	1.010	1.002	1.018
TSH	0.010	0.009	1.104	1	0.293	1.010	0.991	1.029
FT3	0.740	0.079	87.414	1	0.000	2.097	1.795	2.449
FT4	0.407	0.159	6.587	1	0.010	1.503	1.101	2.051
LDH	0.002	0.001	11.245	1	0.001	1.002	1.001	1.003
CK	0.000	0.000	1.770	1	0.183	1.000	0.999	1.000
CHO	-0.200	0.170	1.390	1	0.238	0.818	0.587	1.142
TG	-0.091	0.083	1.225	1	0.268	0.913	0.776	1.073
LDL	0.203	0.177	1.324	1	0.250	1.225	0.867	1.733
HDL	-1.109	0.271	16.760	1	0.000	0.330	0.194	0.561
LPa	-0.003	0.002	2.331	1	0.127	0.997	0.993	1.001

[i] TSH, thyrotrophin; FT3, free thyroxine; FT4, triiodothyronine; LDH, lactate dehydrogenase; CK, creatine kinase; CHO, cholesterol; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LPa, lipoprotein A; B, partial regression coefficient; S.E, standard error; Wals, Wald Chi-squared test; df, degree of freedom; Sig., significance probability; Exp(B), odds ratio; C.I., confidence interval.

Abnormal rate of serum metabolic biochemical biomarkers

There was a difference in the abnormal rate of serum metabolic biochemical biomarkers in the different age groups (Table IV). There were significance differences for the abnormal rate of serum TSH, FT4, FT3, CK and CHO between the case and control groups in the <40 and 40-49 years age categories. In addition, a significant difference was found in the abnormal rates of serum TSH, FT4, FT3, LDH, CK, TG, HDL and LPa amongst patients in the 50-59 years category. Significant differences were also found in the abnormal rates of serum TSH, FT4, FT3, CHO and LPa in patients aged 60-69 years and 70-79 years and of serum TSH, FT4 and FT3 in patients aged ≥80 years. In total, the abnormal rate of serum TSH, FT4, FT3, CK, CHO, HDL and LPa were significantly different between the case and control groups.

Table IV Abnormal levels of serum metabolic biochemical biomarkers.

Table IV

Abnormal levels of serum metabolic biochemical biomarkers.

A, Age, <40 years
	Cases (n=18)			Controls (n=83)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	13	4	1	6	75	2	<0.001
FT3	2	7	9	11	70	2	<0.001
FT4	1	7	10	2	79	2	<0.001
LDH	1	13	4	5	64	14	0.865
CK	10	7	1	9	68	6	<0.001
CHO	0	15	3	0	68	15	0.020
TG	0	14	4	0	49	34	0.137
LDL	0	16	2	0	75	8	0.850
HDL	16	2	0	80	3	0	0.184
LPa	0	12	6	0	65	18	0.293
B, Age, 40-49 years
	Cases (n=42)			Controls (n=366)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	24	15	3	38	317	11	<0.001
FT3	6	26	10	30	335	1	<0.001
FT4	2	30	10	8	357	1	<0.001
LDH	1	36	5	20	305	41	0.691
CK	12	30	0	46	306	14	0.011
CHO	0	38	4	0	259	107	0.007
TG	0	25	17	0	224	142	0.833
LDL	0	39	3	0	296	70	0.055
HDL	41	1	0	329	37	0	0.104
LPa	0	34	8	0	247	119	0.074
C, Age, 50-59 years
	Cases (n=121)			Controls (n=809)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	50	63	8	51	722	36	<0.001
FT3	11	82	28	78	726	5	<0.001
FT4	7	91	23	21	786	2	<0.001
LDH	3	97	21	33	699	77	0.026
CK	34	85	2	81	696	32	<0.001
CHO	0	97	24	0	595	214	0.120
TG	0	86	35	0	498	311	0.043
LDL	0	107	14	0	693	116	0.413
HDL	114	7	0	708	101	0	0.032
LPa	0	94	27	0	518	291	0.003
D, Age, 60-69 years
	Cases (n=165)			Controls (n=1,190)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	61	94	10	95	1017	78	<0.001
FT3	17	117	31	145	1042	3	<0.001
FT4	7	127	31	33	1147	10	<0.001
LDH	6	139	20	36	980	174	0.648
CK	27	129	9	156	968	66	0.517
CHO	0	144	21	0	894	296	0.001
TG	0	115	50	0	822	368	0.871
LDL	0	150	15	0	1021	169	0.073
HDL	147	18	0	1041	149	0	0.555
LPa	0	121	44	0	774	416	0.035
E, Age, 70-79 years
	Cases (n=175)			Controls (n=1,077)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	66	96	13	116	894	67	<0.001
FT3	23	136	16	209	865	3	<0.001
FT4	5	145	25	34	1036	7	<0.001
LDH	1	147	27	19	896	162	0.505
CK	20	145	10	136	827	114	0.106
CHO	0	136	39	0	814	263	0.541
TG	0	134	41	0	869	208	0.206
LDL	0	142	33	0	940	137	0.028
HDL	155	20	0	909	168	0	0.152
LPa	0	124	51	0	711	366	0.208
F, Age, ≥80 years
	Cases (n=61)			Controls (n=567)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	21	34	6	48	474	45	<0.001
FT3	18	38	5	175	391	1	<0.001
FT4	3	52	6	20	543	4	<0.001
LDH	3	51	7	10	453	104	0.122
CK	18	41	2	101	434	32	0.075
CHO	0	53	8	0	436	131	0.074
TG	0	53	8	0	495	72	0.926
LDL	0	55	6	0	489	78	0.393
HDL	55	6	0	462	105	0	0.091
LPa	0	388	179	0	42	19	0.946
G, Total
	Cases (n=582)			Controls (n=4,092)
Biomarker	Low	Normal	High	Low	Normal	High	P-value
TSH	235	306	41	354	3499	239	<0.001
FT3	77	406	99	648	3429	15	<0.001
FT4	25	452	105	118	3948	26	<0.001
LDH	15	483	84	123	3397	572	0.822
CK	121	437	24	529	3299	264	<0.001
CHO	0	483	99	0	3066	1026	<0.001
TG	0	427	155	0	2957	1135	0.577
LDL	0	509	73	0	3514	578	0.302
HDL	528	54	0	3529	563	0	0.003
LPa	0	427	155	0	2703	1389	<0.001

[i] Reference ranges are as follows: TSH, 0.55-4.78 mIU/l; FT3, 2.30-4.21 pg/ml; FT4, 0.89-1.80 ng/ml; LDH, 120-250 IU/l; CK, 50-310 IU/l; CHO, <5.18 mmol/l; TG, <1.70 mmol/l; LDL, <3.63 mmol/l; HDL, >1.42 mmol/l and LPa, <30 mg/dl. TSH, thyrotrophin; FT3, free thyroxine; FT4, triiodothyronine; LDH, lactate Dehydrogenase; CK, creatine kinase; CHO, cholesterol; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LPa, lipoprotein A.

Abnormal rate of serum FT3 and FT4 is associated with ischemic stroke

Multivariate statistical analysis was performed for the abnormal rate of serum metabolic biochemical biomarkers (Table V). An association with the abnormal rate of serum TSH, FT3, FT4, CK, CHO, LDL, HDL and LPa was found between the case and control groups. The abnormal rate of serum FT3 (OR, 2.105; 95% CI, 1.607-2.757), FT4 (OR, 3.278; 95% CI, 2.171-4.947) was associated with ischemic stroke. These results suggest that the increase in the abnormal rate of thyroid hormones FT3 and FT4 can increase the risk of cerebral infarction by 2-3 times.

Table V Multivariate analysis of abnormal rate of clinical parameters.

Table V

Multivariate analysis of abnormal rate of clinical parameters.

							95% CI for EXP(B)
Characteristic	B	S.E	Wals	df	Sig.	Exp (B)	Lower	Upper
Age	0.006	0.004	2.712	1	0.100	1.006	0.999	1.014
TSH	-1.280	0.109	137.099	1	0.000	0.278	0.224	0.344
FT3	0.744	0.138	29.215	1	0.000	2.105	1.607	2.757
FT4	1.187	0.210	31.938	1	0.000	3.278	2.171	4.947
LDH	0.228	0.123	3.460	1	0.063	1.256	0.988	1.597
CK	-0.339	0.111	9.311	1	0.002	0.712	0.573	0.886
CHO	-0.583	0.173	11.333	1	0.001	0.558	0.398	0.784
TG	0.155	0.112	1.925	1	0.165	1.168	0.938	1.455
LDL	0.477	0.194	6.027	1	0.014	1.611	1.101	2.358
HDL	-0.448	0.165	7.353	1	0.007	0.639	0.462	0.883
LPa	-0.280	0.106	6.923	1	0.009	0.756	0.614	0.931

[i] TSH, thyrotrophin; FT3, free thyroxine; FT4, triiodothyronine; LDH, lactate dehydrogenase; CK, creatine kinase; CHO, cholesterol; TG, triglyceride; LDL, low-density lipoprotein; HDL, high-density lipoprotein; LPa, lipoprotein A; B, partial regression coefficient; S.E., standard error; Wals, Wald Chi-squared test; df, degree of freedom; Sig., significance probability; Exp(B), Odds Ratio; C.I., confidence interval

Discussion

In the present case-control study, data from 582 patients with hyperthyroidism and 4,092 controls were analyzed. Hyperthyroidism was associated with ischemic stroke, where elevated levels of serum FT3 and FT4 were indicators. During the development of brains in mammals, thyroid hormones are key (25). By binding intracellular and membranous receptors, such as Na+-K+-activated ATPase, voltage-gated K+ channel, thyroid hormones influence brain cell activity, including sarcoplasmic reticulum proteins and intracellular calcium handling, which serve a key role in the regulation of the cytosolic calcium concentration and the excitation-contraction coupling in muscle (26).

According to a previous study, ~28% patients with ischemic stroke have thyroid hormone levels outside of the reference range (27). Younger patients with stroke and hyperthyroidism have higher risk of subsequent CVD compared with that patients without hyperthyroidism (6,28). In addition, other previous studies have reported that low TSH levels may lead to poor prognosis in patients with ischemic stroke (29,30).

The present study suggested that metabolism of lipoproteins is dysfunctional in thyroid disease, as evidenced by the lower levels of CHO, LDL, HDL and LPa in patients with ischemic stroke and hyperthyroidism compared with those in patients with normal thyroid function. CHO had a positive association with ischemic stroke, where patients had higher risk of hemorrhagic stroke at CHO <50 mg/dl (31). Furthermore, for every 1 mmol/l increase in serum total CHO, the relative risk of hemorrhagic stroke is 0.85(32). Patients with hyperthyroidism may have increased CHO excretion and LDL turnover, resulting in low CHO levels (33). However, there is not enough evidence to support the potential association between ischemic stroke and HDL levels (34). A systematic review found that hyperthyroidism is associated with low LPa, suggesting that hyperthyroidism may mask dyslipidemia of patients and it is necessary to re-evaluate lipid parameters (35). Abnormal thyroid function may affect lipid biosynthesis and degradation, in addition to activity of enzymes in various lipid metabolic pathways, which may increase the risk of ischemic stroke.

Patients with ischemic stroke and hyperthyroidism may have a higher risk of intravenous thrombolysis compared with other patients (36,37). Excessive thyroid hormones lead to increased energy metabolism and oxygen demand in the body, which may damage the ischemic tolerance of the brain, increasing the risk of cerebral infarction (38,39). A previous study found that thyroid peroxidase autoantibody levels are elevated in patients with stroke and intracranial stenosis compared with those in patients without stenosis (40,41). These results suggest that the immune response may lead to endothelial cell dysfunction, which may aggravate cerebral infarction. A cohort study also revealed that during radioiodine treatment, patients with thyroid disease have higher risk of mortality than in the general population, especially in the first year (42).

Age, sex, FT3, FT4, LDH and HDL were associated with ischemic stroke. Elevated levels of thyroid hormone FT3 and FT4 increased the risk of patients with ischemic stroke 1.5-2 times, whilst the risk of cerebral infarction decreased with increasing HDL. In addition, the abnormal rate of serum FT3 and FT4 may increase the risk of ischemic stroke by 2-3 times. Therefore, regular monitoring of thyroid hormones FT3 and FT4 is key to prevent the occurrence of cerebral infarction.

The present study has limitations. Various risk factors, including age, heart disease, diabetes mellitus, smoking and drinking, may contribute to biased results, which cannot be eliminated. In addition, the number of participants and clinical index selected in the present study was relatively small.

In conclusion, the present study suggested that hyperthyroidism is a risk factor for aggravating the degree of cerebral infarction injury and high levels of FT3 and FT4 are associated with increased risk for ischemic stroke. Further research should assess the association between hyperthyroidism and ischemic stroke.

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Open Project of Key Laboratory of Functional Genomics and Molecular Diagnosis of Gansu Province (grant no. 2021BYGT-002).

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to the Chinese government's confidentiality policy on health data but are available from the corresponding author on reasonable request.

Authors' contributions

XZ and HW confirm the authenticity of all the raw data. XZ performed experiments and wrote the manuscript. ChaZ conceived the study. HW analyzed data, GW designed and concepted and BC performed experiments. CheZ performed experiments. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

The study protocol was conducted in accordance with the amended Declaration of Helsinki and approved by the local independent Ethic Committee of the Suzhou Affiliated Hospital of Medical School, Nanjing University, Suzhou city, China (approval no. IRB2025053) and the Ethics Committee of the Second Affiliated Hospital of Nanchang University [approval no. 2025(148)]. All patients gave written informed consent for participation in the study.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References