European Journal of Cardiovascular Medicine

Hypothyroidism is a common endocrine condition that impacts various organ systems, including the central nervous system (CNS). It manifests a range of neuropsychiatric and neuromuscular symptoms, including somnolence, lethargy, generalised weakness, and postural instability, all of which can profoundly affect quality of life.^[1] The manifestations mostly result from the diminished availability of thyroid hormones, which are crucial for sustaining neuronal metabolism, synaptic transmission, and general neurophysiological integrity.^[2] Clinically, hypothyroidism is classified into two categories: overt hypothyroidism (OH), marked by increased thyroid-stimulating hormone (TSH) and diminished levels of circulating thyroid hormones (T3 and T4), and subclinical hypothyroidism (SH), in which TSH is elevated while thyroid hormone levels are maintained within normal ranges. SH frequently remains asymptomatic or manifests with nonspecific symptoms, complicating diagnosis.^[3] The global frequency varies from 1% to 10% in the general population, with 2% to 5% of SH cases advancing to OH each year. The illness is more common in women and tends to escalate with age, impacting approximately 20% of women over 60 years old. This demographic trend highlights the significance of early detection and surveillance.^[4,5] Thyroid Function Tests (TFTs), which encompass the assessment of TSH, free T3 (FT3), and free T4 (FT4), are critical diagnostic instruments for appraising thyroid function. TSH is notably sensitive and frequently the initial test to exhibit abnormalities in thyroid dysfunction. TFTs facilitate the observation of illness progression and therapeutic response.^[6] Significantly, variations in TFT levels, especially increased TSH and reduced FT4, have been linked to modifications in central nervous system function, but the degree to which these alterations influence specific neuronal pathways is still being explored.^[7] Visual evoked potentials (VEPs) provide a non-invasive technique to evaluate the functional integrity of the visual system, encompassing the retina, optic nerve, and visual cortex. VEP exhibit greater susceptibility to demyelination and conduction delays, rendering them an essential instrument for identifying subclinical neurological involvement in systemic conditions such as hypothyroidism. Numerous studies have examined VEP alterations in hypothyroid individuals, yielding inconsistent outcomes.^[8,9] The discrepancies in findings underscore the necessity for more study to ascertain if VEP modifications consistently correlate with thyroid dysfunction as evaluated by TFTs. The current study is unusual since it examines the relationship between particular TFT parameters (TSH, FT3, FT4) and variations in VEP. Comprehending this link may enhance our understanding of the neurophysiological effects of thyroid malfunction and facilitate the utilisation of VEPs as a prospective early indicator for neurological involvement in both subclinical and overt hypothyroidism.

 Aims and objectives

• To assess the correlation between thyroid function tests and VEP parameters in patients with hypothyroidism.

Present study was a descriptive study conducted in Department of physiology in association with Endocrinology and General Medicine OPD and Department of Neurology in Government Medical College, Kottayam. The study was conducted over a period of 18 months. Participants were selected from patients attending the endocrinology or neurology outpatient clinics and controls were matched for age and sex. A total of 51 hypothyroid patients and 51 controls were included.

Inclusion criteria

• Age between 18 and 70 years
• Hypothyroid group: TSH > 5 mIU/L or Serum free T4 less than 0.7ng/dL.¹⁰
• Control group: Normal TSH [ 0.4 – 5μU/mL], FT3 [0.2- 0.5 ng/dL] and FT4 [ 0.7 – 2.5 ng/dL] values.¹⁰
• No history of neurological or visual disorders

Exclusion criteria

• Diabetes mellitus, hypertension, or other systemic diseases
• History of optic neuritis, glaucoma, or any other ocular pathology
• Use of medications affecting CNS or thyroid function
• Uncorrected visual acuity < 6/9 in either eye
• Drug history
• History of Smoking or alcoholism.

Procedure

A proforma was filled on demographic and anthropometric characteristics such as height, weight, BMI. Volunteers were familiarized with the procedures to be carried out. Pulse, Blood pressure were measured after making the individual relaxed for 5minutes. General, systemic and ophthalmic examination (including visual acuity using snellen chart) were done. Venous blood samples were collected from each participant after overnight fasting. Serum levels of TSH, free T3 (FT3), and free T4 (FT4) were measured using a chemiluminescent immunoassay (CLIA) technique. VEPs were recorded using scalp electrodes placed according to the 10–20 International System, with Oz (2 cm above the inion) as the active electrode, Fz as the reference, and Cz as the ground. Each eye was tested separately while the other was patched, as subjects fixated on a central point. A checkerboard pattern reversed at a fixed rate without brightness change. Responses were amplified, averaged, and showed typical N75, P100, and N145 peaks. The P100 wave, generated in the occipital cortex, consistently reflected CNS activity with a latency of 84–105 ms (mean 96 ± 4 ms).

Statistical analysis

Data were entered in MS Excel Spreadsheet. The analysis was done using SPSS Software version 20.0. Latency of P100, N75 and N145 of VEP waveform were described as mean and standard deviation’ for both groups. Correlation of the serum levels of TSH, free T4 and freeT3 with the continuous variables (VEP latency) were assessed by Pearson correlation coefficient. A p value < 0.05 was taken as statistically significant.

The mean age of hypothyroid patients was 32.92 ± 6.35 years, compared to 31.29 ± 5.15 years in the control (euthyroid) group. Of the 51 individuals diagnosed with hypothyroidism, 35 were female and 16 were male indicating a higher prevalence of hypothyroidism among women. Mean weight of hypothyroid patients was 69.51 ± 9.326 and of control group was 62.76± 6.976. mean weight is more in hypothyroid patients. The mean BMI in the hypothyroid group was 25.98 ± 2.82, while the euthyroid group had a significantly lower mean BMI of 22.23±1.33. This difference was highly significant, with a t-value of 7.979 and a p-value of less than 0.0001, indicating that individuals with hypothyroidism tend to have a higher BMI. The mean heart rate in the hypothyroid group was 66.20 ± 3.93 beats per minute, while the euthyroid group had a significantly higher mean heart rate of 83.16 ± 6.40 beats per minute. Statistical analysis yielded a t-value of -16.138, with a mean difference of -16.96 beats per minute. The mean systolic blood pressure (SBP) was 126.67±7.23 mmHg in hypothyroid patients and 126.59 ± 6.44 mmHg in euthyroid individuals. In contrast, diastolic blood pressure (DBP) was slightly lower in hypothyroid patients (77.41 ± 6.74 mmHg) compared to euthyroid individuals (80.00 ± 6.44 mmHg). The comparison of SBP and DBP between hypothyroid patients and euthyroid subjects revealed no significant difference. (Table-1) There was a significant positive correlation between serum TSH and P100 and N75 latency. But there was no significant correlation with N145 latency in hypothyroid patients. (Table 2) There was a significant positive correlation between Free T4 and N75 and N145 latency. But there was no significant correlation with P100 latency in hypothyroid patients. (Table 3) There was no significant correlation between Serum Free T3 and VEP parameters. (Table 4).

Table 1:  Comparison of TFT in hypothyroid patients and euthyroid patients

Table 2:  Comparison of TSH with P100, N75 and N145 latency in hypothyroid patients

Table 3:  Comparison of Free T4 with P100, N75 and N145 latency in hypothyroid patients

Table 4:  Comparison of Free T3 with P100, N75 and N145 latency in hypothyroid patients

In the present study, the mean age of hypothyroid patients was 32.92 ± 6.35 years, closely comparable to the euthyroid control group (31.29 ± 5.15 years), indicating that both groups were age-matched. A notable gender disparity was observed, with a higher prevalence of hypothyroidism among females which aligns with existing literature suggesting that hypothyroidism was more common in women, particularly during reproductive and perimenopausal ages. Unnikrishnan AG et al.^[11] did a multi‑center study across eight major cities reported that females had a significantly higher prevalence than males—15.86% vs 5.02%—and the odds of hypothyroidism increased significantly with age: individuals aged 36‑45 and above had approximately 1.5‑fold higher risk compared to the 18‑35 age group. Similarly, the population-based study done by Khosravi M et al.^[12] documented that women had five folds more chance of hypothyroidism (adjusted OR=5.31, 95% CI=3.06-9.19 vs. unadjusted OR=6.28, 95% CI=3.90-10.12), and they usually developed it between the ages of 30 and 39. Anthropometric analysis revealed significantly higher body weight (69.51 ± 9.33 kg) and BMI (25.98 ± 2.82) in hypothyroid patients compared to euthyroid controls (62.76 ± 6.98 kg and 22.23 ± 1.33, respectively; p < 0.0001), supporting the link between hypothyroidism and weight gain due to reduced metabolic rate. Compared to the present study, research done by Dubey N et al.¹³ the mean BMI in hypothyroid group was 28.60 ± 4.61 while it was 25.93± 3.17 in euthyroid group.

Cardiovascular findings showed a significantly lower mean heart rate in the hypothyroid group (66.20 ± 3.93 bpm) versus controls (83.16 ± 6.40 bpm; p < 0.0001), indicating bradycardia. However, no significant differences were found in systolic or diastolic blood pressure, suggesting thyroid dysfunction primarily affects cardiac rhythm rather than blood pressure regulation. In contrast, subclinical hypothyroid cohorts have sometimes displayed raised diastolic pressure and dyslipidemia in the study done by Kc R et al.^[14] Jiang L et al.^[15] noted that no metabolic risk factor was significantly linked to SH in males, but that age (OR = 0.568, p = 0.004), BMI (OR = 5.029, p < 0.001), and systolic/diastolic blood pressure (SBP/DBP) (OR = 5.243, p < 0.001) were independent predictors of SH in females. Thyroid function test results confirmed the biochemical diagnosis, with significantly elevated TSH and reduced free T4 levels in hypothyroid patients compared to controls (TSH: 10.785 ± 5.97 µU/mL vs. 2.021 ± 0.72 µU/mL; Free T4: 0.526 ± 0.164 ng/dL vs. 1.744 ± 0.465 ng/dL). Interestingly, Free T3 levels were relatively similar between groups, indicating that peripheral conversion might be maintained in some patients.

VEP analysis showed a significant correlation between elevated TSH and delayed P100 and N75 latencies, indicating slowed visual conduction in hypothyroidism. Free T4 was negatively correlated with N75 and N145 latencies. No significant correlations were found with Free T3 or TSH and N145, suggesting selective sensitivity of early visual pathways. Azimi A et al.^[16] noted that hypothyroid individuals exhibited prolonged P100 delay and diminished PVEP amplitude compared to control groups. Sharma G et al.^[17] reported that VEP latencies were prolonged, with a subsequent reduction observed after hormone replacement therapy. The P100 (ms) waveform was shown to be very significant (p < 0.001). The amplitude (P100-N75 mV), which was decreased in hypothyroid individuals, exhibited enhancement upon the attainment of euthyroidism. A substantial positive connection was identified between P100, N75 delay and pretreatment blood TSH levels. The study conducted by Gautam V et al.^[18] revealed a positive association of 0.335, 0.338, and 0.301 between the amplitudes of the N75, P100, and N145 waves and the fT3 hormone, respectively. Additionally, fT4 exhibited a positive correlation of 0.186 and 0.185 with the wave amplitudes of N75 and N145 waves, respectively, and a negative correlation of TSH levels of -0.492, -0.280, and -0.397 with the amplitudes of N75, P100, and N145 waves, respectively. The hypothyroid group exhibited a greater VEP latency in the N75 wave compared to the euthyroid group (72.12±6.34 vs. 68.54±4.32).

The notable changes in BMI, heart rate, and VEP latencies in hypothyroid patients emphasise the necessity for early identification and intervention. The strong association between TSH and VEP components indicates that visual evoked potentials may function as an effective non-invasive method to assess neurophysiological alterations in persons with hypothyroidism. Subsequent research employing bigger sample numbers and longitudinal methodologies may elucidate the use of VEPs in clinical thyroidology.

Funding: Self  

Conflicts of interest: Nil

1. Beck-Peccoz P, Rodari G, Giavoli C, Lania A. Central hypothyroidism—a neglected thyroid disorder. Nature reviews endocrinology. 2017 Oct;13(10):588-98.
2. Salazar P, Cisternas P, Martinez M, Inestrosa NC. Hypothyroidism and cognitive disorders during development and adulthood: implications in the central nervous system. Molecular Neurobiology. 2019 Apr;56(4):2952-63.
3. Khandelwal D, Tandon N. Overt and subclinical hypothyroidism: who to treat and how. Drugs. 2012 Jan;72(1):17-33.
4. Taylor PN, Albrecht D, Scholz A, Gutierrez-Buey G, Lazarus JH, Dayan CM et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews Endocrinology. 2018 May;14(5):301-16.
5. Singh SK, Singh R, Singh SK, Pandey AK, Jaiswal S, Rai PK. Thyroid dysfunction in India: What is different. Int J Adv Med. 2024 May;11:286-90.
6. Yazdaan HE, Jaya F, Sanjna F, Junaid M, Rasool S, Baig A et al. Advances in thyroid function tests: precision diagnostics and clinical implications. Cureus. 2023 Nov 17;15(11).
7. Garg MK, Mahalle N, Kumar KH. Laboratory evaluation of thyroid function: Dilemmas and pitfalls. Medical Journal of Dr. DY Patil Vidyapeeth. 2016 Jul 1;9(4):430-6.
8. Phurailatpam J. Evoked potentials: Visual evoked potentials (VEPs): Clinical uses, origin, and confounding parameters. Journal of Medical Society. 2014 Sep 1;28(3):140-4.
9. Sio SW, Chan BK, Aljufairi FM, Sebastian JU, Lai KK, Tham CC et al. Diagnostic methods for dysthyroid optic neuropathy: A systematic review and analysis. Survey of Ophthalmology. 2024 May 1;69(3):403-10.
10. Shlomo M, Polonsky KS, Larsen PR. Williams Textbook of Endocrinology. 12th ed. Philadelphia: Saunders; 2012. p. 350-51.
11. Unnikrishnan AG, Kalra S, Sahay RK, Bantwal G, John M, Tewari N. Prevalence of hypothyroidism in adults: An epidemiological study in eight cities of India. Indian journal of endocrinology and metabolism. 2013 Jul 1;17(4):647-52.
12. Khosravi M, Azizi R, Fallahzadeh H, Mirzaei M. Prevalence, Incidence, and Risk Factors of Hypothyroidism in Adult Residents of Yazd Greater Area, 2015–2021: Results of Yazd Health Study. Iranian Journal of Medical Sciences. 2024 Oct 1;49(10):623.
13. Dubey N, Rai P, Arora J, Rai N, Budholia PK. A comparative study on visual evoked potential (VEP) wave P100 latency in hypothyroid and euthyroid individuals. International journal of health sciences. 2022;6(S3):3800-10.
14. Kc R, Khatiwada S, Deo Mehta K, Pandey P, Lamsal M, Majhi S. Cardiovascular risk factors in subclinical hypothyroidism: A case control study in Nepalese population. Journal of thyroid research. 2015;2015(1):305241.
15. Jiang L, Du J, Wu W, Fang J, Wang J, Ding J. Sex differences in subclinical hypothyroidism and associations with metabolic risk factors: a health examination-based study in mainland China. BMC Endocrine Disorders. 2020 Dec;20:1-8.
16. Azimi A, Bonakdaran S, Heravian J, Layegh P, Yazdani N, Alborzi M. Pattern visual evoked potential in hypothyroid patients. Documenta Ophthalmologica. 2019 Apr 15;138:77-84.
17. Sharma G, Aggarwal S. Visual evoked potentials in overt hypothyroid patients before and after achievement of euthyroidism. Indian Journal of Endocrinology and Metabolism. 2017 May 1;21(3):419-23.
18. Gautam V, Paudel BH, Lamsal M, Agrawal K, Jha MK, Maharjan S et al. Visual evoked potentials’ responses in hypothyroidism and hyperthyroidism. Int J Res Med Sci. 2019 May;7:1589-93.