Abundant studies have showed that both hypothyroidism and subclinical hypothyroidism are associated with NonAlcoholic Fatty Liver Disease (NAFLD). Besides, NAFLD and Type 2 Diabetes Mellitus (T2DM) regularly coexist, which act synergistically and lead to many adverse outcomes. However, the relationship between NAFLD and thyrotropin levels (TSH) in T2DM patients remains unknown. This mini review sought to examine the evidence about association between TSH levels and NAFLD. We found that TSH level may be an independent risk factor for NAFLD in patients with T2DM. In doing so, this review may provide novel insight and highlight that further studies are needed to explore the mechanisms and targeted treatment.

Non-alcoholic fatty liver disease; Thyrotropin; Type 2 diabetes mellitus

Non-Alcoholic Fatty Liver Disease (NAFLD) is emerging as a public health burden worldwide with a histological spectrum ranging from steatosis to Non-Alcoholic Steato Hepatitis (NASH) and cirrhosis [1,2]. It has been recognized as one of the most prominent causes of chronic liver diseases, steeply rising a worldwide prevalence to 25% in 2019 [1,3,4]. A significant body of evidence holds the view that NAFLD is a multisystem disease [5] and increases the risk of developing cardiometabolic diseases, including Type 2 Diabetes (T2DM) [6]. Pathologically, NAFLD is closely related to the characteristic of Insulin Resistance (IR) and metabolic syndrome [7]. The global prevalence of NAFLD among patients with T2DM is 55.5% [8]. These two conditions could act synergistically and lead to many adverse outcomes, including liver-related mortality and all-cause mortality [5,9]. Thus, identifying the risk factors for NAFLD in advance is essential to reduce the liver-mortality of patients with T2DM.

It is well-known that thyroid hormones regulate various metabolic processes, including carbohydrates, lipids, and proteins. Thyroid hormone is involved in hepatic lipid metabolism and hepatic IR [10]. Previous studies have revealed that both hypothyroidism and subclinical hypothyroidism are associated with NAFLD [11-13]. Our previous study has demonstrated that high-normal Serum thyrotropin (TSH) levels were significantly associated with the presence of NAFLD in patients with T2DM with euthyroid function [14]. Thyroid function and T2DM are both closely associated with increased risks of NAFLD. To date, few review exist regarding the association between NAFLD and thyroid hormone in T2DM patients. Therefore, this mini-review summarizes literatures exploring the association of thyrotropin level and NAFLD in clinical evidences, as well as comprehensively elaborate the role and related mechanisms of thyrotropin in T2DM patients with NAFLD, aiming to provide the mechanism-based therapeutic strategies for clinicians to manage NAFLD in patients with T2DM.

The association of thyrotropin level and NALFD

Thyroid hormones regulate various metabolic processes and exert important roles in hepatic lipid metabolism. There is considerable evidence to support the negative role of increased TSH level in the development of NAFLD. Chung, et al. [12] revealed that TSH levels was related to NAFLD in a dose-dependent manner among patients with subclinical hypothyroidism. Similarly, the other study [15] demonstrated that the spectrum of hypothyroidism including subclinical hypothyroidism and low-normal thyroid function is independently associated with NAFLD and advanced fibrosis in a dose-dependent manner. Notably, high TSH levels have been reported to be associated with the severity of hepatic steatosis [16]. In addition, in euthyroid subjects, several studies have demonstrated that high TSH levels are associated with the risk of NAFLD [15,17-20]. Janovsky et al. [19] found that higher TSH values were associated with higher prevalence of NAFLD (OR=1.22; p<0.01). In addition, Tahare et al. [20] detected that TSH levels was an independent risk factor of NAFLD after multivariate adjustment (OR=1.12; p=0.033). Furthermore, in euthyroid patients with overweight or obese children [21] or adolescents [22], chronic hepatitis B (CHB) [23], elevated TSH concentration is a significant risk for hepatic steatosis. However, these association was not observed in Gökmen FY, et al. study [24]. Considering some systematic review and meta-analysis were performed to explore these inconsistence [13,25,26], we preferred to support that TSH levels may increase the risk of NAFLD, regardless of thyroid function status.

The association of thyrotropin level and T2DM

It is well known for decades that thyroid hormones are important mediators of glucose homeostasis [27,28]. Thyroid hormones could regulate circulating insulin and control intestinal absorption of glucose as well as hepatic gluconeogenesis [29]. Several studies have shown that a low-normal thyroid hormone level is associated with high Fasting Plasma Glucose (FPG) levels and a high glycosylated hemoglobin (HbA1c) level [30]. Furthermore, higher-normal serum TSH levels were associated with the incidence of T2DM [31]. A longitudinal study has demonstrated that TSH levels was associated with the values of glycosylated hemoglobin (HbA1c) and Fasting Plasma Glucose (FPG) and that there was an increased risk of NAFLD with increasing levels of HbA1c independent of obesity [32]. In addition, in euthyroid subjects, a high-normal TSH level was significantly related to insulin resistance and increased glycemic variability and may contribute to glycemic disorders [30,33,34], revealing an increased risk of prevalence of diabetes. Concordantly, a 7-year prospectively study [35] elucidated that baseline concentration of TSH was associated with T2DM in a large cohort of euthyroid subjects and gradually increased TSH was an independent risk of developing diabetes regardless of sex and thyroid autoimmunity. A higher but in normal range serum TSH level was closely related to central obesity and hyperlipidemia in patients with T2DM, which plays a crucial role in the pathogenesis of NAFLD [36]. Combine, a high-normal TSH level may be supposed as a significant additional risk factor for the NAFLD in T2DM patients.

The association of thyrotropin level and patients with T2DM and NALFD

Considering the clinical evidence indicating TSH level be associated the risk of NALFD and exacerbated metabolic disorders in patients with T2DM, it is likely that TSH plays an important role in the incidence of NAFLD in patients with T2DM. However, limited data exist exploring the association between TSH levels and NAFLD in patients with T2DM. In a cross-sectional study included 2289 adults with T2DM [14], our team revealed that a high-normal TSH level was an independent risk factor for NAFLD in patients with T2DM (p<0.05), which was consistent with another study with small sample [37], showing that NAFLD in euthyroid T2DM patients may be associated with thyroid hormone resistance-like manifestation. From a diverse aspect, a case-control study [38] suggested that elevated Thyroid Per Oxidase Anti-Body (TPOAb) titer is closely related to NAFLD. Eveline et al. [39] demonstrated that low-dose levothyroxine reduces intrahepatic lipid content in T2DM patients. Consequently, TSH levels may be considered as a significant risk factor of NAFLD in T2DM and more studies are needed to confirm these association.

Considering NAFLD is common amongst individuals with T2DM, there is emerging evidence revealing a detrimental outcome for people with co-existent diabetes and NAFLD. The relationship between these two conditions could be explained by insulin resistance and compensatory hyperinsulinemia, which leads to abnormal lipid metabolism and hepatic triglyceride accumulation in NAFLD [40]. One of the sources of the accumulation of triacylglycerol (TAG) within the liver comes from De Novo Lipogenesis (DNL) [41], which is increased in a state of hyperinsulinemia, such as insulin resistance [42]. Although the mechanism for the association between TSH levels and an increase risk of NAFLD in patients with T2DM remains elusive, 

some possible mechanisms are available to explain the relationship. Increased TSH levels were associated with increased triglyceride concentrations, visceral obesity, and reduced insulin sensitivity, which may promote the occurrence of NAFLD [31]. In addition, alteration in serum levels of cytokines and adipokines will influence liver inflammation and increase lipogenesis [43]. The level of TSH could affect the value of adipokines, contributing to the development of NAFLD [44,45].

TSH combined with Thyroid Stimulating Hormone Receptor (TSHR) is an important form to regulate thyroid function. TSHR also expresses in extra-thyroid tissues and cells, such as liver, kidney and brain [46]. Therefore, the study showed that TSH combined with TSHR on hepatocytes could increase the concentration of triglycerides in hepatocytes and promote hepatic steatosis [47]. Furthermore, it has been long known that Sterol Regulatory Element Binding Proteins (SREBPs) are the general name of three major nuclear transcription factors of regulating lipid metabolism. Among them, SREBP-1c, mainly expressed in liver and adipocytes, is directly involved in the regulation of expression of enzymes related to fatty acid and triglyceride synthesis [48]. In addition, Peroxisome Proliferator Activated Receptors (PPARs) are ligand activated nuclear transcription factors with three subtypes. PPARa plays an important role in liver fat synthesis, energy stability as well as glucose and lipid metabolism [49]. TSH regulates triglyceride anabolism mainly through cAMP/PKA/PPARa signal pathway and affects the phosphorylation state of SREBP-1c to involve in the regulation of triglyceride anabolism [50].

The above mechanisms could contribute to the development of hepatic steatosis. Of note, NAFLD accounts for one of the worldwide clinical and financial burden and its incidence is increasing steeply, it is essential to make every potential attempt to understand its various possible etiologies better.

TSH-based therapeutic strategies

There are several possible TSH-based pharmacological strategies for NALFD in patients with T2DM in clinical practice. Based on above evidence indicating the elevated TSH level may promote or aggravate NAFLD, TSH-targeted strategies may be emerged for the treatment of NAFLD.

Thyroid hormone accelerates energy metabolism by upregulation of AMP-Activated Protein Kinase (AMPK) [51], which is an energy sensor, enhancing insulin sensitivity [52]. Given its crucial role, the AMPK pathway has been extensively studied as a potential therapeutic target. Metformin is the first line therapeutic agent in the management of T2DM patients, exerting significant roles in lowering body fat and improve hepatic insulin sensitivity by acting on the AMPK pathway [53]. Metformin may be served as one of TSH-targeted strategies. A prospective study found that metformin was associated with low TSH levels among patients with treated hypothyroidism [54]. In consistent, Al-Alusi, et al. [55] found that metformin suppressed TSH levels and Cappelli, et al. [56] showed a vital decrease in TSH levels in euthyroid patients after metformin therapy.

Thyroid Hormone (TH) has favorable metabolic effects [10], including the ability of reducing low-density lipoprotein cholesterol dramatically [57,58]. Apart from dyslipidemia, there is mounting evidence showing that the supply of thyroid hormone is beneficial for various rodent models of NAFLD [59-61]. Through TH-derived therapies, TH and TH analogs decreased hepato-steatosis. Additionally, Low-dose levothyroxine (LT4) could decrease Intrahepatic Lipid Content (IHLC) in euthyroid male patients with T2DM. This indicated that TH or TH analogs may be another possible treatment of NAFLD in patients with T2DM [39].

This review revealed that a high-normal TSH level may be an independent risk factor for NAFLD in T2DM patients. NAFLD and T2DM regularly coexist, increasing the risks for liver-related mortality and all-cause mortality. Some studies have showed that thyroid hormone disorder contributes the development of NAFLD and T2DM [39,62,63]. In addition, in euthyroid subjects, high TSH levels are associated with the risk of NAFLD [16,18]. Our previous study [14] provided a strong rationale in evaluating the risk of NAFLD in T2DM. However, it was a cross-sectional study having limited power to reflect the causal effect of TSH levels on NAFLD in T2DM patients. In addition, few data exist exploring the relationship between serum thyroid hormone levels in the normal range and NAFLD in patients with T2DM. In doing so, this review highlighted that no randomized controlled trial has yet prospectively measured the association between high-normal TSH levels and the risk of NAFLD. Owing to NAFLD is common among individuals with T2DM, there is also an urgent need for prospective trials to identify this kind of relationship and relevant mechanisms. Given limited treatment strategy, other studies are needed to investigate the role of TSH in the development of NAFLD in patients with T2DM and the potential targeted therapy. All in all, this review identified critical science gaps that need to be filled if TSH level is an independent risk in the development of NAFLD, so that thyroid hormone levels should be considered in evaluating the risk of NAFLD in T2DM patients and providing targeted treatment to maximize therapeutic benefit.