Thyroid Diseases After Total Knee Replacement: A Multi-center, Propensity-score-matched Cohort Study

Discussion

Thyroid diseases are prevalent endocrine disorders that have significant implications for overall health and well-being (1). The purpose of this propensity score-matched study was to evaluate the risk of developing thyroid diseases post-TKR. The results revealed a mild yet consistent association between TKR and an increased risk of developing thyroid diseases.

In the crude analysis, TKR patients had a greater HR for all thyroid disorders that remained significant but attenuated after adjusting for demographics and comorbidities. The risk of thyroid diseases in TKR patients remains higher than that in non-TKR controls across all wash-out periods, which indicates the long-term association, rather than the short-term post-surgical effect. However, hyperthyroidism showed no significant difference between TKR and non-TKR patients across all wash-out periods, indicating that new-onset hyperthyroidism is mostly associated with the shortest-term postoperative phase, typically within the first 12 months following surgery. The Kaplan–Meier analysis revealed a higher cumulative probability of all thyroid diseases, hypothyroidism, and hyperthyroidism in the TKR group during the follow-up period. This finding further supports the significance of TKR as a potential risk factor for thyroid diseases.

The exact mechanism behind the link between TKR and the augmented risk of thyroid diseases is not fully understood, yet several possible mechanisms have been proposed. The surgical intervention of TKR is known to induce an inflammatory response and alter the immune system function (9); this may disrupt the regulation of thyroid hormones, leading to thyroid dysfunction. Such disruption could occur via multiple pathways, such as the hypothalamus-pituitary-thyroid (HPT) axis, modification of thyroid hormone metabolism, autoimmune reactions, and hormone activity changes at the cellular level. Surgery can damage tissues, triggering patients’ natural defense system and innate immune cells (i.e., macrophages and neutrophils). These cells release pro-inflammatory cytokines that can disrupt the production of thyroid hormones, potentially leading to an underactive thyroid function (18, 19). Moreover, these pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α may cause the up-regulation of deiodinase enzymes that are responsible for converting thyroxine (T4) into its active form, triiodothyronine (T3), or its inactive counterpart, reverse T3 (rT3) (20, 21). Overactivation of deiodinase can result in non-thyroidal illness syndrome (NTIS) or euthyroid sick syndrome, a disorder presenting low T3 and high rT3 levels (21). Additionally, the inflammatory cascade can lead to the activation of autoreactive T cells by disrupting the mechanisms that maintain self-tolerance, allowing autoreactive T cells to proliferate, and further differentiate into effector cells capable of the production of autoantibodies against thyroid antigens, such as thyroglobulin and thyroid peroxidase (anti-TPO), thereby initiating or aggravating autoimmune thyroid diseases (22).

TKR also triggers a systemic stress response that involves metabolic and hormonal changes in the body. This stress response is characterized by the release of hormones, such as cortisol and catecholamine, which could disturb normal thyroid hormone metabolism (23). The rise in cortisol and catecholamines decreases the production of TRH, which then results in a reduction in TSH secretion, and the overall production of thyroid hormones (24). Moreover, cortisol interferes with the metabolic pathway of thyroid hormones, especially the conversion of T4 to its metabolically active form, T3. High levels of cortisol can decrease the conversion rate, which leads to a decrease in the amount of active thyroid hormone for the body’s metabolic processes (24). In addition, the release of stress hormones can intensify autoimmune reactions, thus triggering or aggravating autoimmune thyroid disease (25).

Perioperative medications, for instance, NSAIDs and corticosteroids, have a significant impact on thyroid function, and in turn, increase the risk of thyroid diseases. NSAIDs can displace thyroid hormones (T4 and T3) from their binding sites on plasma proteins including thyroxine-binding globulin (TBG), increasing free (unbound) thyroid hormones in the blood (26). Some of the NSAIDs, such as aspirin, salicylate, and meclofenamate have been found to decrease the levels of total T4, free T4, total T3, and free T3 after a single dose or repeated administration (27). Moreover, long-term use of NSAIDs, especially among those with detectable anti-TPO, is associated with an increased risk of irreversible hypothyroidism due to its detrimental effects on thyroid gland functionality (28). Corticosteroids’ effects mirror stress-induced cortisol, as previously discussed.

Our findings also showed that the effect of TKR on thyroid dysfunction risk was modified by age and sex. Patients aged 65 or older who underwent TKR have an increased risk of all thyroid diseases, hyperthyroidism, and hypothyroidism. In addition, female patients who underwent TKR had a greater risk of thyroid diseases than their non-TKR counterparts, which was not seen in male patients. Such age and sex-related differences may be attributed to several factors. First, elderly people and women are inherently more susceptible to thyroid diseases as evidenced by the higher prevalence of thyroid disorders in these populations (29, 30). With advancing age, the thyroid gland changes both structure and function and hence becomes more vulnerable to external influences, including surgery and medications (31). Furthermore, age-related changes in drug metabolism and clearance can lead to higher circulating levels of medications used during and after TKR, some of which may interfere with thyroid function (32). Women are predisposed to autoimmune conditions that affect the thyroid gland. The increased risk of thyroid dysfunction in women following TKR could stem from a pre-existing higher likelihood of autoimmune thyroid diseases, such as Hashimoto’s thyroiditis or Graves’ disease (33, 34). Surgical stress and the consequent inflammatory response may activate or intensify these conditions. Furthermore, female sex hormones, especially estrogen, are known to affect thyroid function (35). Stress induced by TKR may cause changes in estrogen levels, potentially impacting thyroid hormone dynamics and metabolism (35). Finally, the response to TKR-associated factors like surgical stress, anesthesia, pain management, and recuperation may differ between females and older adults (36, 37). For instance, these groups often necessitate increased dosages of analgesics for effective pain relief, which could predispose them to thyroid dysfunction (36, 37).

To our knowledge, our study is the first study investigating the risk for thyroid disease post-TKR. Our study had many strengths. First, we used a large sample size that increased the statistical power and precision of our estimates. Second, we applied propensity score matching to balance the baseline characteristics of the TKR and control groups and to reduce the confounding bias.

Study limitations. First, we could not eliminate the possibility of misclassification bias and residual confounding, as the aforementioned biases were commonly observed in real-world studies and could potentially influence the incidence of outcome events (38, 39). In the current dataset, administrative codes were widely utilized to serve as the definition of diseases, medication prescriptions, and procedures. Misclassification bias could exist due to the inherent weaknesses of an electronic health records study, such as incomplete or inaccurate data. Second, the high proportion of white participants in our study (71.8%) indicates the necessity of further research involving different ethnic groups.

Despite these limitations, our study provides important clinical implications for the management of patients undergoing TKR. Several studies have reported that thyroid dysfunction is associated with postoperative complications (11-13). Failure to recognize or address these issues may lead to a significant reduction in the quality of life of patients undergoing TKR. Thus, the thyroid function should be monitored both before and after the surgical intervention to prevent and treat thyroid diseases in time. The identification of risk factors, such as age and sex, can aid in the development of personalized care plans and targeted interventions for high-risk patient populations. Further research should be conducted to elucidate the potential pathophysiology between TKR and thyroid dysfunction and the effect of different surgical techniques, implant materials, and rehabilitation programs on thyroid function. Furthermore, further long-term follow-up studies are needed to monitor the recurrence and progression of thyroid conditions in TKR patients over time and to determine the treatment efficacy of preventive and therapeutic measures.