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Silent thyroid dysfunction and nerve damage: Unraveling the association between subclinical hypothyroidism and diabetic peripheral neuropathy
*Corresponding author: Rahul Garg, Department of Medicine, Farukh Hussain Medical College, Agra, Uttar Pradesh, India. gargrahul27@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Garg R, Thakre A. Silent thyroid dysfunction and nerve damage: Unraveling the association between subclinical hypothyroidism and diabetic peripheral neuropathy. Glob J Health Sci Res. doi: 10.25259/GJHSR_32_2025
Abstract
Objectives:
While diabetic peripheral neuropathy (DPN) is traditionally linked to glycemic control, emerging evidence suggests other metabolic factors may play critical roles. This study investigates whether subclinical hypothyroidism (SCH), a frequently overlooked condition in type 2 diabetes mellitus (T2DM), might contribute to the development and progression of DPN.
Material and Methods:
We conducted a cross-sectional study of 384 T2DM patients at our hospital. Participants underwent comprehensive thyroid function testing (including thyroid-stimulating hormone, free T3, free T4, and anti-thyroid peroxidase [TPO] antibodies) and detailed peripheral nerve assessment (combining clinical examination, nerve conduction studies, and validated questionnaires). Statistical analysis examined the relationship between SCH and DPN while controlling for traditional risk factors.
Results:
Among our cohort, 12.5% (n = 48) presented with SCH and 80.2% (n = 308) were euthyroid. DPN prevalence was significantly higher in the SCH group (70.8%) compared to euthyroid patients (44.2%, P < 0.001). SCH patients with DPN demonstrated not only higher prevalence but significantly greater neuropathy severity (composite severity score 11.8 ± 3.6 vs. 7.9 ± 3.2, P < 0.001), with 58.8% presenting with severe neuropathy compared to 26.5% of euthyroid patients with DPN (P < 0.001). This association remained robust after multivariate adjustment for age, sex, diabetes duration, glycemic control, and other potential confounders (adjusted odds ratio 2.58, 95% confidence interval 1.31–5.08, P = 0.006). SCH patients with DPN demonstrated more severe neuropathic symptoms and poorer nerve conduction parameters than their euthyroid counterparts with DPN. Notably, TSH levels correlated positively with neuropathy severity scores (r = 0.365, P < 0.001), and anti-TPO antibody positivity was detected in 62.5% of SCH patients with DPN.
Conclusion:
Our findings reveal that SCH is independently associated with both the presence and severity of DPN in T2DM patients. This suggests that thyroid dysfunction may contribute to diabetic neuropathy pathogenesis through mechanisms beyond glycemic control. Routine thyroid screening may be valuable in the comprehensive management of diabetic neuropathy, and the potential therapeutic implications warrant further investigation.
Keywords
Diabetic peripheral neuropathy
Nerve conduction studies
Subclinical hypothyroidism
Thyroid-stimulating hormone
Type 2 diabetes mellitus
INTRODUCTION
Diabetic peripheral neuropathy (DPN) represents one of the most debilitating complications of diabetes mellitus, affecting approximately 6–51% of patients and substantially diminishing quality of life.[1-4] The pathogenesis of DPN is multifactorial, involving metabolic, vascular, and inflammatory mechanisms, with chronic hyperglycemia being the primary driver.[5,6] However, the variability in the development and progression of DPN among patients with similar glycemic control suggests the involvement of additional contributing factors.[5,6]
The interplay between diabetes and thyroid function has garnered increasing attention in recent years. Thyroid disorders occur more frequently in diabetic populations than in the general public,[7-9] with subclinical hypothyroidism (SCH) being particularly prevalent.[10-12] Characterized by elevated thyroid stimulating hormone (TSH) levels despite normal free thyroid hormone concentrations, SCH affects between 4.7–23% of type 2 diabetes mellitus (T2DM) patients, depending on the population studied.[11-14]
Recent evidence suggests a novel and potentially crucial pathophysiological link between thyroid function and peripheral nerve health that remains poorly understood. While DPN has traditionally been attributed primarily to glycemic dysregulation, the significant variability in neuropathy development among patients with similar glycemic profiles points to additional contributing mechanisms. SCH represents a compelling but underexplored metabolic factor that may significantly influence DPN development and progression. Preliminary studies indicate elevated TSH levels correlate with diabetic neuropathy severity[15-17] and diabetic complications occur more frequently in patients with thyroid dysfunction, even in subclinical states.[18-20] This relationship has strong biological plausibility, as thyroid hormones regulate critical processes essential for nerve integrity and function, including myelin formation, axonal transport, and mitochondrial activity – all potentially relevant to DPN pathogenesis.[21-26] Elucidating this relationship could reveal new therapeutic targets beyond glycemic control for this debilitating complication.
However, substantial knowledge gaps remain regarding the prevalence and clinical significance of SCH specifically in patients with established DPN. Previous investigations often relied on limited sample sizes or employed less comprehensive neuropathy assessment methods. Moreover, it remains unclear whether the relationship between SCH and DPN operates independently of established risk factors such as age, diabetes duration, and glycemic control.
Our study therefore aims to address three key questions: First, what is the prevalence of SCH in patients with DPN? Second, does SCH associate with DPN presence and severity independent of traditional risk factors? And third, what potential mechanisms might connect subclinical thyroid dysfunction with diabetic neuropathy? By exploring these questions, we hope to provide insights that could enhance the understanding and management of diabetic neuropathy.
MATERIAL AND METHODS
Study design and participants
Between June 2023 and December 2024, we enrolled 384 patients with established T2DM in this cross-sectional study conducted at our tertiary care hospital. Our Institutional Ethics Committee approved the study protocol, and we obtained written informed consent from all participants.
We included patients who: (1) had a confirmed T2DM diagnosis according to American Diabetes Association criteria; (2) were between 30 and 75 years of age; and (3) were willing to participate fully in the study. We excluded individuals with: (1) known thyroid disorders or current thyroid medication use; (2) other potential causes of peripheral neuropathy (alcohol abuse, vitamin B12 deficiency, uremia, and paraneoplastic syndrome); (3) severe cardiac, hepatic, or renal disease; (4) acute illness or infection; (5) pregnancy or lactation; or (6) current use of medications known to affect thyroid function or peripheral nerve assessment.
Clinical assessment and data collection
Each participant underwent a thorough clinical evaluation including medical history review, physical examination, and anthropometric measurements. Using a standardized questionnaire, we documented diabetes duration, current treatments, presence of other diabetic complications, and concomitant medications.
We calculated body mass index (BMI) as weight in kilograms divided by height in meters squared. After 5 min of rest, we measured blood pressure with patients seated. We defined hypertension as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or current antihypertensive medication use.
Laboratory investigations
Following an overnight fast of at least 8 h, we collected blood samples from all participants. Glycemic assessments included fasting plasma glucose, 2-h postprandial glucose, and glycated hemoglobin (HbA1c). We measured a complete lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]) using standard laboratory protocols.
For thyroid function assessment, we measured serum TSH, free triiodothyronine, and free thyroxine (FT4) through electrochemiluminescence immunoassay. We defined SCH as serum TSH above the upper reference limit (>4.5 μIU/mL) with normal FT4 levels (0.9–1.7 ng/dL). We also measured anti-thyroid peroxidase (anti-TPO) antibodies to evaluate potential autoimmune etiology, considering values >35 IU/mL as positive.
We assessed renal function by measuring serum creatinine and calculating estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula. From morning spot urine samples, we determined urinary albumin-to-creatinine ratio, with values ≥30 mg/g indicating albuminuria.
DPN assessment
Our approach to DPN evaluation combined clinical assessment, electrophysiological testing, and validated questionnaires for a comprehensive picture of nerve function.
The clinical assessment included detailed neurological examination focusing on sensory perception (using 10-g Semmes-Weinstein monofilament, 128-Hz tuning fork, and pinprick testing), muscle strength evaluation, deep tendon reflex testing, and foot examination for deformities or ulceration. We employed the Michigan Neuropathy Screening Instrument for standardized clinical evaluation, considering scores ≥2.5 positive for neuropathy.
For nerve conduction studies (NCS), we examined the median, ulnar, peroneal, tibial, and sural nerves bilaterally, measuring conduction velocity, amplitude, and latency according to standardized techniques. We considered electrophysiological diagnosis of DPN present when abnormalities appeared in at least two different nerves, with at least one being a lower extremity nerve.
To assess neuropathic symptoms, we used the diabetic neuropathy symptom (DNS) score (range 0–4, with ≥1 indicating symptomatic neuropathy) and the neuropathic pain symptom inventory (NPSI) to characterize pain quality and severity.
Based on our combined assessment approach, we classified participants as having confirmed DPN if they demonstrated both abnormal NCS results and clinical signs/symptoms of neuropathy.
Neuropathy severity quantification and clinical relevance
To comprehensively quantify neuropathy severity, we employed a multi-dimensional approach integrating both objective physiological parameters and patient-reported symptoms. We calculated a composite neuropathy severity score by combining:
Sensory deficit quantification: The number of abnormal sensory modalities (0–3) based on monofilament, vibration, and pinprick testing, providing objective measurement of large and small fiber sensory loss
Motor function assessment: Graded muscle strength evaluation (0–5 scale) for distal lower extremity muscle groups, capturing the degree of motor involvement
Reflex abnormalities: Ankle reflex scoring (0 = absent, 1 = present with reinforcement, 2 = normal), reflecting the integrity of large fiber function and spinal reflexes
Symptom burden: DNS score (0–4) and NPSI score (0–100), quantifying both the presence and intensity of neuropathic symptoms that impact quality of life
Electrophysiological severity: Calculated as the number of abnormal parameters across tested nerves, with greater weight assigned to amplitude reductions (which indicate axonal loss) versus velocity slowing (indicating demyelination).
This multi-parameter approach allows for clinically meaningful stratification of neuropathy severity that correlates with functional impairment and complication risk. Mild neuropathy (composite score <5) typically presents with minimal functional limitations, moderate neuropathy (score 5–10) associates with gait alterations and increased fall risk, while severe neuropathy (score >10) significantly impairs daily activities and substantially increases foot ulceration risk. This detailed severity quantification enables more nuanced analysis of the relationship between thyroid dysfunction and neuropathic impairment beyond simple binary classification.
Statistical analysis
We performed all statistical analyses using the Statistical Package for the Social Sciences version 26.0. For continuous variables, we presented data as mean ± standard deviation or median with interquartile range, depending on distribution normality as assessed by the Kolmogorov–Smirnov test. For categorical variables, we reported frequencies and percentages. We compared differences between groups using Student’s t-test or Mann–Whitney U-test for continuous variables and chi-square or Fisher’s exact test for categorical variables, as appropriate. We evaluated correlations between variables using Pearson’s or Spearman’s correlation coefficient based on data distribution. To assess the association between SCH and DPN while controlling for potential confounding factors, we conducted logistic regression analysis, adjusting for age, sex, BMI, diabetes duration, HbA1c, lipid profile, hypertension, and albuminuria. We expressed results as odds ratios with 95% confidence intervals (CIs). In addition, we used linear regression models to evaluate the relationship between TSH levels and neuropathy severity scores. We considered p-values <0.05 statistically significant for all analyses.
RESULTS
Baseline characteristics
Among our 384 T2DM patients, 48 (12.5%) had SCH, 308 (80.2%) were euthyroid, and 28 (7.3%) presented with other thyroid abnormalities, including overt hypothyroidism (3.9%), overt hyperthyroidism (1.6%), subclinical hyperthyroidism (1%), and unclassified thyroid dysfunction (0.8%), as illustrated in Figure 1.
- Distribution of thyroid status among patients with type 2 diabetes mellitus.
When comparing SCH and euthyroid patients, several significant differences emerged in baseline characteristics, as presented in Table 1. SCH patients were older (64.3 ± 8.7 vs. 56.8 ± 10.9 years, P < 0.001) and more frequently female (75.0% vs. 46.4%, P < 0.001). They also had higher BMI (30.1 ± 4.7 vs. 27.9 ± 4.5 kg/m2, P = 0.002) and longer diabetes duration (11.7 ± 7.5 vs. 9.3 ± 6.8 years, P = 0.026). The SCH group displayed a more atherogenic lipid profile, with elevated total cholesterol and LDL-C, and reduced HDL-C levels.
| Characteristic | All patients (n=384) | Euthyroid (n=308) | SCH (n=48) | P-value |
|---|---|---|---|---|
| Age (years) | 57.9±10.8 | 56.8±10.9 | 64.3±8.7 | <0.001 |
| Female, n(%) | 196 (51.0) | 143 (46.4) | 36 (75.0) | <0.001 |
| BMI (kg/m2) | 28.3±4.6 | 27.9±4.5 | 30.1±4.7 | 0.002 |
| Duration of diabetes (years) | 9.6±7.0 | 9.3±6.8 | 11.7±7.5 | 0.026 |
| HbA1c (%) | 7.8±1.6 | 7.7±1.5 | 8.2±1.7 | 0.042 |
| FPG (mg/dL) | 151.8±48.9 | 150.8±48.5 | 157.2±50.3 | 0.408 |
| PPG (mg/dL) | 228.5±76.1 | 227.3±74.8 | 236.4±80.2 | 0.455 |
| Total cholesterol (mg/dL) | 178.6±42.1 | 175.8±41.3 | 190.4±43.2 | 0.024 |
| Triglycerides (mg/dL) | 154.7±87.5 | 151.3±86.2 | 172.8±94.7 | 0.120 |
| HDL-C (mg/dL) | 42.8±10.7 | 43.2±11.1 | 38.9±8.6 | 0.014 |
| LDL-C (mg/dL) | 104.9±34.2 | 102.4±33.2 | 116.9±35.4 | 0.007 |
| TSH (μIU/mL) | 3.14±2.08 | 2.21±0.91 | 7.42±1.64 | <0.001 |
| FT4 (ng/dL) | 1.23±0.22 | 1.24±0.22 | 1.15±0.24 | 0.016 |
| FT3 (pg/mL) | 3.20±0.57 | 3.24±0.55 | 2.98±0.62 | 0.003 |
| Anti-TPO positive, n(%) | 76 (19.8) | 46 (14.9) | 30 (62.5) | <0.001 |
| Hypertension, n(%) | 217 (56.5) | 168 (54.5) | 30 (62.5) | 0.305 |
| Dyslipidemia, n(%) | 240 (62.5) | 187 (60.7) | 33 (68.8) | 0.288 |
| Diabetes treatment, n(%) | 0.365 | |||
| Oral agents only | 212 (55.2) | 175 (56.8) | 24 (50.0) | |
| Insulin only | 45 (11.7) | 33 (10.7) | 8 (16.7) | |
| Insulin+oral agents | 127 (33.1) | 100 (32.5) | 16 (33.3) |
Data are presented as mean±SD or number (percentage). SCH: Subclinical hypothyroidism, BMI: Body mass index, HbA1c: Glycated hemoglobin, FPG: Fasting plasma glucose, PPG: Postprandial glucose, HDL-C: High-density lipoprotein cholesterol, LDL-C: Low-density lipoprotein cholesterol, TSH: Thyroid stimulating hormone, FT4: Free thyroxine, FT3: Free triiodothyronine, Anti-TPO: Anti-thyroid peroxidase antibodies
Among patients with SCH, 62.5% tested positive for anti-TPO antibodies, indicating autoimmune thyroid disease as the predominant etiology. Mean TSH levels in the SCH group were significantly elevated at 7.42 ± 1.64 μIU/mL compared to 2.21 ± 0.91 μIU/mL in euthyroid patients.
DPN prevalence and characteristics
Overall, 47.4% of our cohort (182 patients) met the criteria for DPN diagnosis based on our combined clinical and electrophysiological assessment. The prevalence of DPN differed markedly between thyroid function groups, affecting 70.8% of SCH patients compared to 44.2% of euthyroid patients (P < 0.001) [Figure 2]. This significant difference persisted even after stratifying by age, sex, and diabetes duration.
- Comparison of diabetic peripheral neuropathy prevalence between euthyroid and subclinical hypothyroidism (SCH) patients, demonstrating significantly higher prevalence in the SCH group.
Beyond prevalence differences, SCH patients with DPN exhibited more severe neuropathic manifestations than their euthyroid counterparts with DPN. This was evident in significantly higher DNS scores (2.94 ± 0.88 vs. 2.14 ± 0.82, P < 0.001) and NPSI scores (39.2 ± 14.8 vs. 29.5 ± 13.6, P < 0.001), indicating more pronounced symptom burden [Figures 3 and 4].
- Diabetic neuropathy symptom scores in euthyroid and subclinical hypothyroidism (SCH) patients with diabetic peripheral neuropathy, showing greater symptom severity in SCH patients.
- Neuropathic pain symptom inventory (NPSI) scores comparing pain severity between euthyroid and subclinical hypothyroidism (SCH) patients with diabetic peripheral neuropathy, revealing significantly higher pain scores in SCH patients.
Further analysis revealed a clinically significant gradient in neuropathy severity corresponding to thyroid status. Among patients with DPN, the mean composite neuropathy severity score was significantly higher in the SCH group compared to euthyroid patients (11.8 ± 3.6 vs. 7.9 ± 3.2, P < 0.001). When stratified by severity categories, 58.8% of SCH patients with DPN had severe neuropathy compared to only 26.5% of euthyroid patients with DPN (P < 0.001). SCH patients demonstrated greater impairment in timed functional tests, including a 24% slower time to complete the 10 m walk test (15.2 ± 4.8 vs. 12.3 ± 3.6 s, P = 0.003). Importantly, this gradient persisted after adjustment for glycemic control.
Nerve conduction parameters
Our electrophysiological assessment revealed significant differences between SCH and euthyroid patients. The SCH group showed reduced nerve conduction velocities and amplitudes across multiple nerves, with particularly striking differences in lower extremity nerves [Table 2].
| Parameter | Euthyroid (n=308) | SCH (n=48) | P-value |
|---|---|---|---|
| Sural nerve | |||
| SNAP amplitude (μV) | 9.57±5.84 | 6.38±4.86 | <0.001 |
| Conduction velocity (m/s) |
42.35±6.92 | 38.43±7.62 | <0.001 |
| Peroneal nerve | |||
| CMAP amplitude (mV) | 4.86±2.37 | 3.64±2.18 | <0.001 |
| Conduction velocity (m/s) |
44.27±5.64 | 40.75±6.31 | <0.001 |
| Distal latency (ms) | 4.53±0.89 | 5.11±1.08 | <0.001 |
| Tibial nerve | |||
| CMAP amplitude (mV) | 9.75±4.31 | 7.94±4.12 | 0.005 |
| Conduction velocity (m/s) |
42.93±5.27 | 39.86±5.91 | <0.001 |
| Distal latency (ms) | 4.68±0.97 | 5.19±1.12 | 0.001 |
| Median nerve (sensory) | |||
| SNAP amplitude (μV) | 23.64±11.58 | 20.15±11.05 | 0.045 |
| Conduction velocity (m/s) |
51.42±6.83 | 48.64±7.22 | 0.009 |
| Median nerve (motor) | |||
| CMAP amplitude (mV) | 8.94±2.87 | 8.25±2.97 | 0.117 |
| Conduction velocity (m/s) |
52.76±5.38 | 50.38±6.31 | 0.007 |
| Distal latency (ms) | 3.59±0.58 | 3.82±0.68 | 0.012 |
| Ulnar nerve (sensory) | |||
| SNAP amplitude (μV) | 18.53±9.87 | 16.42±9.64 | 0.177 |
| Conduction velocity (m/s) |
53.17±6.25 | 51.05±6.84 | 0.028 |
| Ulnar nerve (motor) | |||
| CMAP amplitude (mV) | 9.12±2.72 | 8.66±2.89 | 0.284 |
| Conduction velocity (m/s) |
55.34±5.56 | 53.42±6.24 | 0.034 |
| Distal latency (ms) | 2.87±0.46 | 3.04±0.50 | 0.021 |
Data are presented as mean±SD. SCH: Subclinical hypothyroidism, SNAP: Sensory nerve action potential, CMAP: Compound muscle action potential
The most pronounced differences appeared in sural [Figure 5a and b] and peroneal nerve [Figure 6a and b] parameters, which typically show early involvement in diabetic neuropathy.
- (a) Sural nerve sensory action potential amplitude comparison between euthyroid and subclinical hypothyroidism (SCH) groups, showing reduced amplitudes in SCH patients. (b) Sural nerve conduction velocity in euthyroid versus SCH patients, demonstrating significantly slower conduction in the SCH group.
- (a) Peroneal nerve compound muscle action potential amplitude comparison between euthyroid and subclinical hypothyroidism (SCH) groups, showing significantly reduced amplitudes in SCH patients and (b) peroneal nerve conduction velocity in euthyroid versus SCH patients, demonstrating significantly slower conduction in the SCH group.
Association between SCH and DPN
Univariate analysis showed a strong association between SCH and DPN (crude odds ratio [OR] 3.06, 95% CI 1.60– 5.86, P = 0.001). To determine whether this relationship was independent of other established risk factors, we performed multivariate logistic regression analysis with stepwise adjustment for potential confounders [Table 3]. After initial adjustment for age and sex (Model 1), the association remained significant (adjusted OR 2.93, 95% CI 1.51–5.68, P = 0.002). Further, adjustment for BMI, diabetes duration, and HbA1c (Model 2) yielded similar results (adjusted OR 2.76, 95% CI 1.40–5.42, P = 0.003). In our fully adjusted model incorporating lipid parameters, hypertension, and albuminuria (Model 3), SCH maintained an independent association with DPN (adjusted OR 2.58, 95% CI 1.31–5.08, P = 0.006). These findings demonstrate that the relationship between SCH and DPN exists independently of demographic characteristics, metabolic parameters, and established risk factors for neuropathy.
| Model | OR | 95% CI | P-value |
|---|---|---|---|
| Unadjusted | 3.06 | 1.60–5.86 | 0.001 |
| Model 1 | 2.93 | 1.51–5.68 | 0.002 |
| Model 2 | 2.76 | 1.40–5.42 | 0.003 |
| Model 3 | 2.58 | 1.31–5.08 | 0.006 |
Model 1: Adjusted for age and sex Model 2: Model 1+BMI, diabetes duration, and HbA1c Model 3: Model 2+lipid profile, hypertension, and albuminuria. OR: Odds ratio, CI: Confidence interval
Correlation between TSH levels and neuropathy parameters
To further explore the thyroid-nerve relationship, we analyzed correlations between TSH levels and various neuropathy parameters across our entire cohort, regardless of thyroid classification. Serum TSH showed significant positive correlations with neuropathic symptom scores (DNS: r = 0.365, P < 0.001; NPSI: r = 0.342, P < 0.001) and significant negative correlations with nerve conduction parameters, particularly sural nerve amplitude (r = −0.298, P < 0.001) and peroneal nerve conduction velocity (r = −0.276, P < 0.001). Linear regression analysis confirmed serum TSH as an independent predictor of DNS score (β = 0.232, P < 0.001) and NPSI score (β = 0.205, P < 0.001) after adjustment for age, sex, diabetes duration, and HbA1c. This suggests a dose-response relationship between thyroid dysfunction and neuropathy severity.
Influence of thyroid autoimmunity
Among patients with SCH, those positive for anti-TPO antibodies showed a higher DPN prevalence (76.7%) compared to antibody-negative patients (61.1%), though this difference did not reach statistical significance (P = 0.221). However, antibody-positive patients demonstrated significantly more severe neuropathic symptoms (DNS score: 3.17 ± 0.83 vs. 2.59 ± 0.88, P = 0.034) and greater reductions in nerve conduction velocities, suggesting thyroid autoimmunity might influence neuropathy presentation.
DISCUSSION
Our investigation into the relationship between SCH and DPN has yielded several clinically relevant findings. In our cohort of 384 T2DM patients, we found a considerable SCH prevalence of 12.5% and demonstrated a significant independent association between SCH and DPN. Patients with both conditions exhibited more severe neuropathic manifestations and greater nerve conduction impairments than those with DPN but normal thyroid function. Moreover, TSH levels correlated with neuropathy severity independent of glycemic control and other established risk factors.
The 12.5% SCH prevalence in our diabetic population aligns with the range reported in previous studies (4.7–23%).[11-14] This variability across studies likely reflects differences in population characteristics, diagnostic thresholds, and laboratory methodologies. Our findings are consistent with a meta-analysis by Han et al., who reported a pooled SCH prevalence of 10.2% in T2DM.[12] The moderate prevalence in our study reflects our demographic profile, which included substantial proportions of older individuals and women – both recognized risk factors for thyroid dysfunction.[7,8]
The robust association between SCH and DPN we observed builds on emerging evidence linking thyroid dysfunction with diabetic complications. Our results parallel findings from smaller studies, including work by Zhao et al., who found associations between elevated TSH and DPN in T2DM patients,[17] and Allam et al. who reported higher SCH prevalence in diabetic patients with peripheral neuropathy.[27] Our study advances this knowledge through comprehensive assessment of both thyroid function and peripheral neuropathy, utilizing standardized clinical, electrophysiological, and symptomatic evaluations in a larger cohort.
Beyond demonstrating increased DPN prevalence in SCH patients, our work reveals more severe neurological impairment in this group, as evidenced by worse neuropathic symptom scores and nerve conduction parameters. Importantly, the association between SCH and DPN remained significant after adjustment for multiple confounding factors, suggesting a relationship independent of traditional risk factors. The clinically significant gradient in neuropathy severity we observed – with 58.8% of SCH patients exhibiting severe neuropathy compared to only 26.5% of euthyroid patients – has important implications for patient care and outcomes. This severity difference translated to meaningful functional impairments, as evidenced by poorer performance on timed functional tests. The comprehensive multidimensional severity assessment approach we employed revealed that thyroid dysfunction impacts not just symptom burden but also objective neurophysiological parameters and functional capabilities. This suggests that thyroid status may influence both the structural integrity of peripheral nerves and their functional capacity, potentially through distinct but complementary pathways. Importantly, the persistence of this severity gradient after adjustment for glycemic parameters indicates that thyroid-mediated mechanisms of nerve damage may operate independently from the classical hyperglycemia-driven pathways, representing a novel therapeutic target.
Several biological mechanisms might explain the observed association between SCH and DPN. Thyroid hormones play essential roles in neuronal development and function by regulating myelination, axonal transport, and regenerative processes.[28] In hypothyroid states, even subclinical ones, reduced thyroid hormone action may impair these processes, leading to structural and functional alterations in peripheral nerves.[21,22] Histopathological studies in hypothyroid neuropathy have demonstrated demyelination, axonal degeneration, and decreased nerve fiber density – changes that could potentially compound diabetic nerve damage.[23,26]
In addition, SCH has been linked to various metabolic disruptions that might exacerbate diabetic neuropathy, including dyslipidemia, insulin resistance, and endothelial dysfunction.[27] In our study, SCH patients exhibited a more atherogenic lipid profile, potentially contributing to microvascular dysfunction and subsequent nerve injury. Furthermore, thyroid hormones regulate mitochondrial function and biogenesis – processes increasingly recognized as important in diabetic neuropathy pathogenesis.[29] Recent research by Zhu et al. demonstrated associations between thyroid hormone levels and peripheral nerve conduction in T2DM patients, suggesting thyroid hormones might influence nerve function through metabolic pathway regulation.[15]
The potential role of autoimmunity in both thyroid dysfunction and diabetic neuropathy represents another intriguing connection.[7] In our study, 62.5% of SCH patients had positive anti-TPO antibodies, indicating autoimmune thyroid disease. We observed a trend toward more severe neuropathy in antibody-positive patients, though this relationship deserves further exploration.
Recent genetic evidence supports our findings. A Mendelian randomization study by Duan et al. provided evidence for a potential causal relationship between hypothyroidism and peripheral neuropathy, suggesting genetic predisposition to thyroid dysfunction might increase neuropathy risk.[30]
Our findings have several important clinical implications. First, the high SCH prevalence in DPN patients suggests thyroid function screening should be considered in evaluating diabetic patients with neuropathic symptoms, particularly those with severe or rapidly progressive neuropathy. The substantial proportion of SCH patients with severe neuropathy in our cohort underscores the potential value of thyroid function screening specifically in patients presenting with disproportionately severe neuropathic manifestations relative to their glycemic control and diabetes duration. Our severity quantification framework provides clinicians with a practical approach to identify such patients who might benefit most from thyroid evaluation. Second, the correlation between TSH levels and neuropathy severity raises questions about whether treating SCH might improve or stabilize neurological function in these patients. While our study design cannot address this question directly, it provides rationale for future interventional research.
Limitations of the study
Several limitations of our work warrant acknowledgment. First, the cross-sectional design precludes determination of causality; longitudinal studies will be needed to establish whether SCH precedes and contributes to DPN development or whether they share common underlying mechanisms. Second, we assessed only anti-TPO antibodies, not other thyroid autoantibodies such as anti-thyroglobulin, which might have provided additional insights into autoimmune aspects of thyroid dysfunction. Third, despite adjusting for multiple confounding factors, residual confounding cannot be completely eliminated. Finally, we did not evaluate the effects of SCH treatment on neuropathy outcomes – an important area for future research.
CONCLUSION
Our study reveals a high prevalence of SCH in patients with T2DM and establishes an independent association between SCH and DPN. Patients with both conditions demonstrate more severe neuropathic manifestations and greater impairment in nerve conduction parameters. Serum TSH levels correlate with neuropathy severity independent of glycemic control and other established risk factors. These findings suggest thyroid dysfunction may contribute to diabetic neuropathy pathogenesis through mechanisms beyond glycemic control alone. The gradient of neuropathy severity observed across thyroid function categories suggests that even mild thyroid dysfunction may substantially impact the progression and functional consequences of diabetic nerve damage. Our results highlight the need to consider thyroid function in the comprehensive evaluation and management of diabetic neuropathy. Future prospective and interventional studies should explore the causal relationship between thyroid status and diabetic neuropathy, and determine whether addressing SCH might improve neurological outcomes in these patients.
Ethical approval:
The research/study approved by the Institutional Review Board at FH Medical College, number FHMC/IEC/R Cell/2023/27, dated May 19, 2023.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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