Assessment of thiol-disulfide and glutathione homeostasis after levothyroxine replacement in individuals with autoimmune or nonautoimmune hypothyroidism

Senat, Almila; Erinc, Osman; Yesilyurt, Soner; Gok, Gamze; Erel, Ozcan

doi:10.20945/2359-4292-2023-0197

Brasil

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Original Article • Arch. Endocrinol. Metab. 68 • 2024 • https://doi.org/10.20945/2359-4292-2023-0197 linkcopy

Assessment of thiol-disulfide and glutathione homeostasis after levothyroxine replacement in individuals with autoimmune or nonautoimmune hypothyroidism

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective Thyroid hormones are known to affect the biosynthesis and degradation of antioxidant compounds, suggesting a possible link between hypothyroidism and oxidative stress. However, there is no clear consensus in the literature regarding this association. The aim of this study was to evaluate oxidative stress markers (extracellular thiol-disulfide homeostasis and intracellular glutathione homeostasis) in patients with hypothyroidism due to autoimmune (Hashimoto’s thyroiditis) or nonautoimmune thyroid disease rendered euthyroid after levothyroxine replacement.

Subjects and methods The study included 116 patients admitted to the Taksim Training and Research Hospital (Istanbul, Türkiye). Of these, 50 had hypothyroidism due to Hashimoto’s thyroiditis (HT group), 30 had nonautoimmune hypothyroidism (NAIH group), and 36 were healthy controls (control group). All participants were women. Extracellular thiol-disulfide homeostasis and intracellular glutathione homeostasis tests were assessed as oxidative stress markers.

Results Thiol-disulfide homeostasis in both HT and NAIH groups was shifted toward the oxidative spectrum. Compared with the control group, the HT and NAIH groups had lower levels of native (p < 0.001 and p = 0.001, respectively) and total (p = 0.002 and p = 0.012, respectively) thiol, as well as a lower native thiol/total thiol ratio (p < 0.001 for both). The HT group also had higher disulfide levels than the control group (p = 0.027). Reduced glutathione (GSH) and oxidized glutathione (GSSG) values were comparable across all three groups, but the HT and NAIH groups had higher GSSG/GSH (p < 0.001 for both) and GSSG/(GSH+GSSG) ratios (p = 0.003 and p = 0.005, respectively), along with lower GSH/(GSH+GSSG) ratio (p = 0.001 and p = 0.002, respectively) than the control group.

Conclusion Levothyroxine replacement was ineffective in ameliorating oxidative stress in patients with hypothyroidism due to Hashimoto’s thyroiditis or nonautoimmune causes, as extracellular thiol-disulfide homeostasis was notably altered in these patients compared with healthy controls. The findings of this study suggest that oxidative stress remains a prevailing issue in patients with autoimmune or nonautoimmune hypothyroidism even after euthyroidism is restored.

Glutathione; Hashimoto’s thyroiditis; hypothyroidism; thiol-disulfide homeostasis; oxidative stress

	Control group (n = 36)	NAIH group (n = 30)	HT group (n = 50)	P values
Age (years)	38.9 ± 14.4	52.25 ± 14.7	46.7 ± 13.7	0.002
Smoking (packs/year)	0 (0-0)	0 (0-15)	0 (0-20)	0.058
Duration of hypothyroidism (months)	–	71.6 ± 24.6	69.3 ± 21.7	0.911
Systolic blood pressure (mmHg)	120 (100-130)	120 (110-138)	120 (100-130)	0.547
Diastolic blood pressure (mmHg)	80 (65-80)	80 (70-90)	80 (65-80)	0.744
Diabetes mellitus (%)	0 (0)	3 (¹⁰)	3 (6)	0.097
Hypertension (%)	2 (5.5)	8 (26.6)	14 (28)	0.010
Coronary artery disease (%)	1 (2.7)	0 (0)	0 (0)	0.359
Cerebrovascular disease (%)	0 (0)	0 (0)	1 (2)	0.563
Peripheral artery disease (%)	0 (0)	0 (0)	1 (2)	0.563
Weight (kg)	61.5 (55-76.5)	82.6 (74.1-88.5)	70.4 (62.2-79.5)	<0.001
Height (cm)	159 ± 0.07	157 ± 0.05	157 ± 0.08	0.201
Body mass index (kg/m2)	25.6 ± 5.93	29.3 ± 12.1	26.5 ± 8.45	0.279
Creatinine (mg/dL)	0.63 ± 0.09	0.69 ± 0.11	0.68 ± 0.10	0.027
eGFR (mL/min/1.73 m2)	113 ± 14.2	97.4 ± 17.6	102 ± 17.7	0.001
Aspartate aminotransferase (U/L)	16 (14-19.7)	17.5 (16-22.2)	17 (15-22.5)	0.174
Alanine aminotransferase (U/L)	13 (9-19)	20.5 (14.5-25)	14.5 (10.7-21.2)	0.013
C-reactive protein (mg/dL)	2.16 ± 2.88	4.41 ± 5.54	3.61 ± 5.02	0.157
ESR (mm/hour)	7.02 ± 6.70	12.3 ± 7.39	14.4 ± 15.1	0.018
Free triiodothyronine (ng/dL)	3.17 ± 0.45	2.64 ± 0.29	2.86 ± 0.48	<0.001
Free thyroxine (ng/dL)	11.6 ± 1.21	11.03 ± 2.91	11.9 ± 2.44	0.237
TSH (mIU/L)	1.84 (1.29-2.83)	2.66 (1.90-3.88)	3.10 (2.13-4.03)	0.001
Anti-TG (kU/L)	14.3 (12.3-17.7)	14.3 (12.6-16.7)	196 (54.1-398)	<0.001
Anti-TPO (kU/L)	9.84 (9-13.7)	9 (9-9.36)	180 (55.7-307)	<0.001
Hemoglobin (g/L)	128 (117-133)	136 (129-141)	128 (114-134)	0.007

	Control group (n = 36)	NAIH group (n = 30)	HT group (n = 50)	P values
Native thiol (µmol/L)	382 ± 48.8	325 ± 58.7	338 ± 58	* <0.001 = 0.001 * = 0.717
Total thiol (µmol/L)	423 ± 52.5	369 ± 63.4	385 ± 61.1	* = 0.002 = 0.012 * = 0.497
Disulfide (µmol/L)	20.4 ± 3.44	23.6 ± 5.37	23.7 ± 6.95	* = 0.094 = 0.027 * = 0.997
Disulfide/native thiol (%)	5.37 ± 0.85	7.51 ± 1.98	7.17 ± 2.28	* <0.001 <0.001 * = 0.741
Disulfide/total thiol (%)	4.84 ± 0.69	6.48 ± 1.48	6.20 ± 1.71	* < 0.001 < 0.001 * = 0.707
Native/total thiol (%)	90.3 ± 1.38	87.1 ± 2.97	87.5 ± 3.43	* < 0.001 < 0.001 * = 0.709

	Control group (n = 36)	NAIH group (n = 30)	HT group (n = 50)	P values
GSH (µmol/L)	613 (560-650)	613 (598-753)	613 (550-732)	* = 0.334 = 0.355 * = 0.949
GSH+GSSG (µmol/L)	139 ± 44.1	156 ± 35.7	153 ± 45.2	* = 0.334 = 0.355 * = 0.949
GSSG (µmol/L)	42.2 ± 18.1	53.2 ± 16.3	51.1 ± 19.2	* = 0.095 = 0.106 * = 0.896
GSSG/GSH (%)	60.4 (53.9-78.2)	133 (85.5-140)	108 (83.6-130)	* < 0.001 < 0.001 * = 0.149
GSSG/(GSH+GSSG) (%)	29.4 ± 4.41	33.3. ± 3.86	32.5 ± 3.87	* = 0.003 = 0.005 * = 0.698
GSH/(GSH+GSSG) (%)	41.1 ± 8.82	33.2 ± 7.73	34.9 ± 7.75	* = 0.001 = 0.002 * = 0.421

	Anti-TG	Anti-TPO	TSH	fT3	fT4
Native thiol (µmol/L)	r = -0.230 p = 0.017	r = -0.108 p = 0.267	r = -0.280 p = 0.004	r = 0.415 p < 0.001	r = -0.027 p = 0.786
Total thiol (µmol/L)	r = -0.242 p = 0.011	r = -0.101 p = 0.297	r = -0.253 p = 0.009	r = 0.397 p < 0.001	r = 0.061 p = 0.533
Disulfide (µmol/L)	r = 0.150 p = 0.119	r = -0.043 p = 0.654	r = 0.122 p = 0.212	r = -0.046 p = 0.636	r = -0.023 p = 0.812
GSH (µmol/L)	r = -0.043 p = 0.676	r = -0.028 p = 0.785	r = 0.100 p = 0.337	r = 0.135 p = 0.195	r = -0.081 p = 0.439
GSH+GSSG (µmol/L)	r = 0.023 p = 0.823	r = 0.091 p = 0.380	r = 0.088 p = 0.398	r = -0.095 p = 0.360	r = -0.141 p = 0.174
GSSG (µmol/L)	r = 0.050 p = 0.629	r = 0.190 p = 0.291	r = 0.061 p = 0.556	r = -0.143 p = 0.169	r = -0.136 p = 0.191

	uSt. B	95% confidence intervals	P values
Native thiol
Age (years)	-2.643	(-3.30) – (-1.98)	<0.001
Hypertension (%)	-15.1	(-39.05) – (8.71)	0.211
Body mass index (kg/m²)	-0.767	(-1.99) – (0.454)	0.216
Weight (kg)	-0.048	(-0.191) – (0.095)	0.507
Adjusted R2 0.560, p < 0.001
Total thiol
Age (years)	-2.78	(-3.50) – (-2.06)	<0.001
Hypertension (%)	-7.96	(-33.6) – (17.7)	0.540
Body mass index (kg/m²)	-0.979	(-2.27) – (0.318)	0.137
Weight (kg)	-0.059	(-0.213) – (0.096)	0.452
Adjusted R2 0.523, p < 0.001
Disulfide
Age (years)	-0.045	(-0.143) – (0.053)	0.366
Hypertension (%)	1.88	(-1.62) – (5.38)	0.289
Body mass index (kg/m²)	0.016	(-0.161) – (0.193)	0.857
Weight (kg)	0.003	(-0.018) – (0.024)	0.809
Adjusted R² 0.024, p = 0.823
GSSG/GSH ratio
Age (years)	-0.200	(-0.785) – (0.385)	0.499
Hypertension (%)	25.2	(3.79) – (46.6)	0.022
Body mass index (kg/m²)	-0.150	(-1.15) – (0.855)	0.767
Weight (kg)	0.068	(-0.05) – (0.188)	0.262
Adjusted R² 0.058, p = 0.055
GSSG/(GSH+GSSG) ratio
Age (years)	-0.031	(-0.105) – (0.043)	0.412
Hypertension (%)	3.31	(0.590) – (6.04)	0.018
Body mass index (kg/m²)	-0.027	(-0.155) – (0.101)	0.676
Weight (kg)	0.005	(-0.011) – (0.020)	0.548
Adjusted R² 0.042, p = 0.099
GSH/(GSH+GSSG) ratio
Age (years)	0.062	(-0.087) – (0.210)	0.412
Hypertension (%)	-6.62	(-12.1) – (-1.18)	0.018
Body mass index (kg/m²)	0.054	(-0.202) – (0.309)	0.418
Weight (kg)	-0.009	(-0.04) – (0.021)	0.677
Adjusted R² 0.042, p = 0.099

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[TFN1] Values are shown as mean ± standard deviation or median (interquartile range). Abbreviations: anti-TG, antithyroglobulin antibodies; anti-TPO, antithyroperoxidase antibodies; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate; TSH, thyroid-stimulating hormone.