Data regarding the prevalence of hepatic fibrotic burden across the spectrum of hypothyroidism are scarce. Hence, we aimed to evaluate the prevalence of liver fibrotic burden across the spectrum of hypothyroidism.

30,091 individuals who attended a Health Management Centre between 2019 and 2021 were cross-sectionally analyzed. Participants were categorized as having strict-normal thyroid function, low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism. Hepatic fibrosis was assessed by vibration-controlled transient elastography (VCTE). Significant and advanced fibrosis were defined as liver stiffness measurement in VCTE of 8.1-9.6 and 9.7-13.5 kPa, respectively.

Among both men and women, low-normal thyroid function group, subclinical hypothyroidism group, and overt hypothyroidism group all have more liver fibrosis present, including mild fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis, than the strict-normal thyroid function group. The low-normal thyroid function group have the similar liver fibrotic burden to the subclinical hypothyroidism group. The highest liver fibrotic burden was noted in the overt hypothyroidism group. Both significant and advanced liver fibrosis were significantly associated with low-normal thyroid function, subclinical hypothyroidism, and overt hypothyroidism in both men and women.

Liver fibrotic burden are highly prevalent in subjects with overt hypothyroidism. Moreover, fibrotic burden increased across the spectrum of hypothyroidism even within the low normal thyroid function. These results suggested that screening for liver fibrosis in patients with hypothyroidism is necessary.

Hypothyroidism is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) but it is not clear whether subclinical hypothyroidism (SCH) increases the risk of MASLD and whether SCH patients with MASLD require treatment. In this study, we reviewed articles published in PubMed from 2013 to 2024 with SCH/hypothyroidism and MASLD as keywords. According to the studies retrieved, SCH increases the likelihood of developing MASLD. Thyroid hormones influence energy metabolism and storage in adipose tissues, as well as fatty acid and cholesterol metabolism and transport in the liver. L-T4 replacement therapy reduces the prevalence of MASLD, especially in patients with severe SCH or mild SCH with dyslipidemia. Recent studies showed that thyroid hormone analogues and thyroid hormone β receptor agonists obtained positive results in the treatment of MASLD in animal models and clinical trials, and Resmetirom has been approved by the US. Food and Drug Administration (FDA) under the name Rezdiffra for use in conjunction with dietary and exercise regimens for managing non-cirrhotic NASH in adults with moderate to advanced fibrosis.

The association between suboptimal thyroid function ((sub)clinical hypothyroidism or low-normal thyroid function) and the metabolic syndrome and MASLD (metabolic dysfunction-associated steatotic liver disease) has been clearly established. Furthermore, in MASLD, intracellular thyroid hormone concentrations are low and the activation of the thyroid hormone receptor (THR) is reduced. Administration of thyroid hormone has been shown to reduce liver triglycerides by stimulating fatty acid disposal through lipophagy and beta-oxidation, and to lower LDL-cholesterol. As thyroid hormone exerts its effects in many different organs, including the heart and bone, several drug candidates have been developed as selective thyromimetics for the THR-β nuclear receptor with potent and liver-targeted activity. Importantly, these compounds have reduced affinity for the THR-α nuclear receptor and tissue distribution profiles that differ from endogenous thyroid hormones, thereby reducing unwanted cardiovascular side effects. The most advanced compound, resmetirom, is an oral drug that demonstrated, in a large phase III trial in patients with MASH (metabolic dysfunction-associated steatohepatitis), the ability to reduce liver fat, decrease aminotransferase levels and improve atherogenic dyslipidaemia with a good tolerability profile. This translated into histological improvement that led to accelerated approval of this drug for active fibrotic steatohepatitis, a milestone achievement as a first MASH drug.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

It is known that thyroid hormone can regulate hepatic metabolic pathways including cholesterol, de novo lipogenesis, fatty acid oxidation, lipophagy, and carbohydrate metabolism. Thyroid hormone action is mediated by the thyroid hormone receptor (THR) isoforms and their coregulators, and THRβ is the main isoform expressed in the liver. Dysregulation of thyroid hormone levels, as seen in hypothyroidism, has been associated with dyslipidemia and metabolic dysfunction-associated fatty liver disease. Given the beneficial effects of thyroid hormone in liver metabolism and the advances illuminating the use of thyroid hormone analogs such as resmetirom as therapeutic agents in the treatment of metabolic dysfunction-associated fatty liver disease, this review aims to further explore the relationship between TH, the liver, and metabolic dysfunction-associated fatty liver disease. Herein, we summarize the current clinical therapies and highlight future areas of research.

The significance of thyroid hormones (THs) in beige adipocyte thermogenesis remains incompletely understood. We previously reported that THs directly regulate the expression of zinc-finger protein 423 (ZFP423), an anti-thermogenic factor, in adipose tissue. This study investigates the interaction between THs and adrenergic signaling in regulating thermogenic capacity and activation of beige adipocytes formed in response to Zfp423 deletion. We demonstrate that THs are indispensable for uncoupling protein 1 (UCP1)-dependent thermogenesis, leading to increased energy expenditure in mice with adipocyte-specific Zfp423 knockout. Targeted activation of the thyroid receptor isoform TRβ, which plays a central role in the inguinal depot, is sufficient to enhance energy expenditure in hypothyroid Zfp423iAKO mice. Mechanistically, THs and ZFP423 pathways cooperate to regulate early B cell factor 2 (EBF2)-mediated activation of the Ucp1 gene. RNA sequencing (RNA-seq) analysis of human adipose tissue samples supports the relevance of this regulatory network for human adipose tissue plasticity.

Thyroid hormone (TH) action is mediated by thyroid hormone receptor (THR) isoforms. While THRβ1 is likely the main isoform expressed in liver, its role in human hepatocytes is not fully understood.

To elucidate the role of THRβ1 action in human hepatocytes we used CRISPR/Cas9 editing to knock out THRβ1 in induced pluripotent stem cells (iPSC). Following directed differentiation to the hepatic lineage, iPSC-derived hepatocytes were then interrogated to determine the role of THRβ1 in ligand-independent and -dependent functions.

We found that the loss of THRβ1 promoted alterations in proliferation rate and metabolic pathways regulated by T3, including gluconeogenesis, lipid oxidation, fatty acid synthesis, and fatty acid uptake. We observed that key genes involved in liver metabolism are regulated through both T3 ligand-dependent and -independent THRβ1 signaling mechanisms. Finally, we demonstrate that following THRβ1 knockout, several key metabolic genes remain T3 responsive suggesting they are THRα targets.

These results highlight that iPSC-derived hepatocytes are an effective platform to study mechanisms regulating TH signaling in human hepatocytes.

The medical community acknowledges the presence of thyroid disorders and nonalcoholic fatty liver disease (NAFLD). Nevertheless, the interconnection between these two circumstances is complex. Thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), and thyroid-stimulating hormone (TSH), are essential for maintaining metabolic balance and controlling the metabolism of lipids and carbohydrates. The therapeutic potential of THs, especially those that target the TRβ receptor isoform, is generating increasing interest. The review explores the pathophysiology of these disorders, specifically examining the impact of THs on the metabolism of lipids in the liver. The purpose of this review is to offer a thorough analysis of the correlation between thyroid disorders and NAFLD, as well as suggest potential therapeutic approaches for the future.

Lipids and thyroid hormones (TH) are closely interrelated. However, previous studies have not mentioned the linkage encompassing the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) alongside TH level, as well as sensitivity indices.

This cross-sectional study leverages expansive datasets from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012. Weighted multivariate linear regression, smoothed curve fitting and sensitivity analyses were used to investigate the associations of the NHHR with the thyroid. Subgroup analyses and interaction tests were conducted to determine the robustness of the findings across diverse segments of the population, ensuring the consistency and generalizability of the observed associations.

The NHHR was significantly positively correlated with free triiodothyronine (FT3) levels, thyroid-stimulating hormone (TSH) levels, the FT3 to FT4 ratio (FT3/FT4), and the quantile-based thyroid feedback index for FT3 (TFQIFT3) and negatively correlated with free thyroxin (FT4) levels [0.17(0.07-0.27), P = 0.001; 0.60 (0.03-1.17), P = 0.040; 0.06 (0.04-0.08), P < 0.0001; 0.23 (0.16-0.30), P < 0.0001; and -0.65 (-1.05--0.24), P = 0.002]. Smoothed curve fitting revealed nonlinear correlations of the NHHR with thyroid function and thyroid hormone sensitivity indices. In subgroup analyses, interaction tests, and smoothed curve fitting analyses, different populations presented largely consistent statistical differences.

Among American adults, the NHHR was significantly positively correlated with FT3 levels, TSH levels, the FT3/FT4 and the TFQIFT3. Conversely, a negative association was noted between the NHHR and FT4 levels.

To evaluate the association between subclinical hypothyroidism and hepatic steatosis and fibrosis using the noninvasive diagnostic methods transient hepatic elastography (TE) and controlled attenuation parameter (CAP) in patients with subclinical hypothyroidism.

This was a cross-sectional study including women with confirmed spontaneous subclinical hypothyroidism and an age- and body mass index (BMI)-matched control group without thyroid disease or circulating antithyroperoxidase (anti-TPO) antibodies. Exclusion criteria were age > 65 years, thyroid-stimulating hormone (TSH) > 10.0 mIUI/L, BMI ≥ 35 kg/m2, diabetes, or other chronic liver diseases. Liver stiffness was classified according to TE values (in kPa) and ranged from absence of fibrosis (F0) to advanced fibrosis (F3). Hepatic steatosis was classified according to CAP values (in dB/m) and ranged from low-grade (S1) to advanced (S3) steatosis.

Of 68 women enrolled, 27 were included in the subclinical hypothyroidism group and 41 in the control group. Advanced steatosis (S3) was more frequent in the subclinical hypothyroidism group (25.9% versus 7.3%, respectively, p = 0.034). Circulating anti-TPO was an independent factor associated with advanced steatosis (odds ratio 9.5, 95% confidence interval 1.3-68.3). In multiple linear regression analysis, TE values (which evaluated fibrosis) correlated negatively with free thyroxine levels.

The results of this study strengthen the hypothesis that hepatic steatosis is associated with autoimmune (positive anti-TPO) subclinical hypothyroidism, independently from BMI. However, subclinical hypothyroidism alone does not appear to be associated with a significantly increased risk of hepatic fibrosis.

Epidemiological studies have reported an association between primary hypothyroidism and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the magnitude of the risk and whether this risk changes with the severity of MASLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between primary hypothyroidism and the risk of MASLD.

We systematically searched PubMed, Scopus and Web of Science from database inception to 31 January 2024, using predefined keywords to identify observational studies in which MASLD was diagnosed by liver biopsy, imaging or International Classification of Diseases codes. A meta-analysis was performed using random-effects modelling.

We identified 24 cross-sectional and 4 longitudinal studies with aggregate data on ~76.5 million individuals. Primary hypothyroidism (defined as levothyroxine replacement treatment, subclinical hypothyroidism or overt hypothyroidism) was associated with an increased risk of prevalent MASLD (n=24 studies; random-effects OR 1.43, 95% CI 1.23 to 1.66; I2=89%). Hypothyroidism was also associated with a substantially higher risk of metabolic dysfunction-associated steatohepatitis or advanced fibrosis (n=5 studies; random-effects OR 2.84, 95% CI 2.07 to 3.90; I2=0%). Meta-analysis of data from four longitudinal studies showed that there was a marginally non-significant association between hypothyroidism and risk of developing MASLD over a median 4.5-year follow-up (random-effects HR 1.39, 95% CI 0.98 to 1.97; I2=85%). Sensitivity analyses did not modify these findings. The funnel plot did not reveal any significant publication bias.

This large and updated meta-analysis provides evidence that primary hypothyroidism is significantly associated with both an increased presence of and histological severity of MASLD.

Exploring the connection between Hashimoto's thyroiditis (HT) and non-alcoholic fatty liver disease (NAFLD) through integrated genetic approaches.

We utilized integrated genetic approaches, such as single-cell RNA sequencing (scRNA-seq) data analysis, Mendelian Randomization (MR), colocalization analysis, cell communication, and metabolic analyses, to investigate potential correlations between HT and NAFLD.

Through the integrated analysis of scRNA-seq data from individuals with HT, NAFLD, and healthy controls, we observed an upregulation in the proportion of CD4+central memory (CD4+CM) T cells among T cells in both diseases. A total of 63 differentially expressed genes (DEGs) were identified in the CD4+CM cells after the differential analysis. By using MR, 8 DEGs (MAGI3, CSGALNACT1, CAMK4, GRIP1, TRAT1, IL7R, ERN1, and MB21D2) were identified to have a causal relationship with HT, and 4 DEGs (MAGI3, RCAN3, DOCK10, and SAMD12) had a causal relationship with NAFLD. MAGI3 was found to be causally linked to both HT and NAFLD. Therefore, MAGI3 was designated as the marker gene. Reverse MR and Steiger filtering showed no evidence of reverse causality. Colocalization analyses further indicated close links between MAGI3 and HT as well as NAFLD. Finally, based on the expression levels of MAGI3, we stratified CD4+CM cells into two subsets: MAGI3+CD4+CM cells and MAGI3-CD4+CM cells. Functional analyses revealed significant differences between the two subsets, potentially related to the progression of the two diseases.

This study delves into the potential connections between HT and NAFLD through integrated genetic methods. Our research reveals an elevated proportion of CD4+CM cells within T cells in both HT and NAFLD. Through MR and colocalization analysis, we identify specific genes causally linked to HT and NAFLD, such as MAGI3. Ultimately, based on MAGI3 expression levels, we categorize CD4+CM cells into MAGI3+CD4+CM cells and MAGI3-CD4+CM cells, uncovering significant differences between them through functional analyses.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.

Thyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research.

The searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD.

Overall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p<0.001) in the overall meta-analysis. The continuous variable meta-analysis indicated that individuals with high levels of TSH (SMD=1.32, 95% CI 0.660 to 1.970, p<0.001) had significantly higher levels of liver fibrosis than those with low levels.

Our findings only validate that there is a correlation between the occurrence of NAFLD and abnormal levels of THs, and it is expected that more observational studies will still be conducted in the future to further demonstrate the relationship between thyroid hormones and NAFLD.

Registered number in PROSPERO: CRD42023405052.

Thyroxine receptor beta (TRβ) is a ligand-dependent nuclear receptor that participates in regulating multiple biological processes, particularly playing an important role in lipid metabolism regulation. TRβ is currently a popular therapeutic target for nonalcoholic steatohepatitis (NASH), while no drugs have been approved to treat this disease. MGL-3196 (Resmetirom) is the first TRβ agonist that has succeeded in phase III clinical trials for the treatment of NASH; therefore, studying its molecular mechanism of action is of great significance. In this study, we employed molecular dynamic simulation to investigate the interaction mode between MGL-3196 and TRβ at the all-atom level. More importantly, by comparing the binding patterns of MGL-3196 in several prevalent TRβ mutants, it was identified that the mutations R243Q and H435R located, respectively, around and within the ligand-binding pocket of TRβ cause TRβ to be insensitive to MGL-3196. This indicates that patients with NASH carrying these two mutations may exhibit resistance to the medication of MGL-3196, thereby highlighting the potential impact of TRβ mutations on TRβ-targeted treatment of NASH and beyond.

Thyroid hormones are important regulators of hepatic lipid homeostasis and whole-body energy expenditure. Recent evidence suggests that euthyroid individuals with metabolic dysfunction-associated steatohepatitis (MASH) develop intrahepatic hypothyroidism that promotes progression of MASH.

A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases from inception till March 2024, using the following keywords: hypothyroidism and nonalcoholic fatty liver disease; MASLD and thyroid function; intrahepatic hypothyroidism; TRβ agonists; and resmetirom. Relevant studies were extracted that described pathogenesis of MASH in the context of thyroid functions.

In euthyroid individuals with MASH, there is decreased conversion of prohormone thyroxine (T4) to bioactive tri-iodothyronine (T3) and increased conversion of T4 to inactive metabolite reverse T3 (rT3). Consequently, reduced levels of T3 results in impaired intrahepatic TRβ signaling, a state of intrahepatic hypothyroidism, which promotes progression of MASH. Hepatic TRβ activation leads to metabolically beneficial effects in the liver including mitochondrial fatty acid uptake and β-oxidation, mitochondrial biogenesis, increasing surface low-density lipoprotein (LDL) receptor density and lowering of circulatory LDL-cholesterol. In recent years, selective thyroid hormone mimetics that exhibit TRβ-selective binding and liver-selective uptake have been designed. Resmetirom, a liver-specific thyromimetic, improves intrahepatic TRβ signaling and in clinical trials significantly improved liver inflammation, fibrosis and lipid profile in patients with MASH.

In euthyroid individuals with MASH, development of intrahepatic hypothyroidism results in further progression of the disease. In clinical trials, resmetirom treatment results in a significant improvement in steatosis, inflammation and fibrosis and is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of noncirrhotic MASH with moderate to advanced fibrosis.

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is recently introduced to better highlight the pathogenic significance of cardiometabolic dysfunction, as compared with non-alcoholic fatty liver disease. This study aimed to investigate the association between low thyroid function and MASLD in the new context.

We recruited 2901 participants for our retrospective cohort study from 2016 to 2021. Participants were divided into strict-normal thyroid function and low thyroid function groups (low-normal thyroid function, subclinical hypothyroidism) based on initial thyroid stimulating hormone (TSH) levels, respectively. Cox regression models were used to estimate the hazard ratios (HRs) and 95% CI.

During a median follow-up of 15.6 months, 165 (8.9%) strict-normal thyroid function subjects and 141 (13.4%) low thyroid function subjects developed MASLD; this result was statistically relevant (P < 0.05). Univariate regression analysis showed that low thyroid function and subclinical hypothyroidism were statistically significantly associated with MASLD (low thyroid function: HR1.53; 95% CI 1.22-1.92; subclinical hypothyroidism: HR1.95; 95% CI 1.47-2.60).

MASLD is associated with low thyroid function and the relationship between MASLD and low thyroid function is independent.

Increasing visceral fat deposition with raised prevalence of obesity and metabolic syndrome is associated with many adverse conditions, especially cardiovascular diseases and diabetes. Although there are many studies that investigate hepatic steatosis in hypothyroidism and subclinical hypothyroidism, to the best of our knowledge, there is no study investigating its relationship with pancreatic steatosis. In the present study, the purpose was to investigate this relationship.

Physical and biochemical characteristics of 30 hypothyroid, 30 subclinical hypothyroid, and 30 euthyroid volunteers were recorded in this cross-sectional study. Liver and pancreatic steatosis were evaluated with ultrasonography.

It was found that pancreatic steatosis was increased in hypothyroid and subclinical groups when compared to the control group, and hepatic steatosis was increased in the subclinical group when compared to the control group (steatosis; p = 0.002, p = 0.004, p = 0.001, p = 0.002, p = 0.002, p = 0.004). Pancreatic steatosis was positively correlated with age, hepatic steatosis, height, weight, BMI, waist circumference, hip circumference, hemoglobin, Insulin, alanine aminotransferase, Triglyceride, Creatinine, and gamma-glutamyltransferase and was negatively correlated with total cholesterol, high-density lipoproteins.

The prevalence of pancreatic steatosis was found to be increased in hypothyroidism and subclinical hypothyroidism when compared with the euthyroid control group.

Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis.

Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR.

TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis.

These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.

The current document has been developed by the Liver Forum who mandated the NAFLD-Associated Comorbidities Working Group - a multistakeholder group comprised of experts from academic medicine, industry and patient associations - to identify aspects of diverse comorbidities frequently associated with non-alcoholic steatohepatitis (NASH) that can interfere with the conduct of therapeutic trials and, in particular, impact efficacy and safety results. The objective of this paper is to propose guidance for the management of relevant comorbidities in both candidates and actual participants in NASH therapeutic trials. We relied on specific guidelines from scientific societies, when available, but adapted them to the particulars of NASH trials with the aim of addressing multiple interacting requirements such as maintaining patient safety, reaching holistic therapeutic objectives, minimising confounding effects on efficacy and safety of investigational agents and allowing for trial completion. We divided the field of action into: first, analysis and stabilisation of the patient's condition before inclusion in the trial and, second, management of comorbidities during trial conduct. For the former, we discussed the concept of acceptable vs. optimal control of comorbidities, defined metabolic and ponderal stability prior to randomisation and weighed the pros and cons of a run-in period. For the latter, we analysed non-hepatological comorbid conditions for changes or acute events possibly occurring during the trial, including changes in alcohol consumption, in order to detail when specific interventions are necessary and how best to manage concomitant drug intake in line with methodological constraints. These recommendations are intended to act as a guide for clinical trialists and are open to further refinement when additional data become available.

Thyroid hormones (THs) exert instrumental effects in regulating lipids metabolism. Whereas, research investigating the relationship between sensitivity indices to THs and metabolic dysfunction-associated fatty liver disease (MAFLD) have contradicted this. This study was designed to approach the correlation between sensitivity indices to THs and MAFLD in euthyroid subjects.

An overall sample of 6356 euthyroid participants were enrolled in a Chinese hospital. Free triiodothyronine to free thyroxine ratio (FT3/FT4), thyrotropin triiodothyronine resistance index (TT3RI), thyrotropin thyroxine resistance index (TT4RI), thyroid stimulating hormone index (TSHI) and thyroid feedback quantile-based indices (TFQIFT3 and TFQIFT4) were collected as sensitivity indicators to THs. Participants were split into two groups based on whether they suffered with MAFLD or not. And participants were categorized into quartiles based on sensitivity indicators to THs. The effects of sensitivity indices to THs on MAFLD were analyzed using regression analysis. Bootstrap was performed to assess the mediation effect of triglyceride glucose (TyG) index on the relationship between sensitivity parameters to THs and MAFLD.

The incidence of MAFLD in euthyroid subjects was 34.47%. As FT3/FT4, TT3RI and TFQIFT3 levels rose, so did the MAFLD prevalence. After adjustment for confounders, logistic regression analyses indicated that the high-level FT3/FT4 and TFQIFT3 still remained risk factors for MAFLD. The relevance of FT3/FT4 and MAFLD was stronger among those whose age ≤ 40 years and had non-visceral obesity. And the interrelation between TFQIFT3 and MAFLD was stronger in subjects whose age ≤ 40 years. Mediation analyses suggested that TyG index had a noteworthy indirect impact on the relationship between FT3/FT4, TFQIFT3 and MAFLD.

Increased FT3/FT4 and TFQIFT3 were significantly related to MAFLD prevalence in populations with normal thyroid function. TyG index partly mediated the relevance between FT3/FT4, TFQIFT3 and MAFLD.

The incidence of non-obese non-alcoholic fatty liver disease (NAFLD), characterized by the presence of a fatty liver in individuals with a normal body mass index, is on the rise globally. Effective management strategies, including lifestyle interventions such as diet and exercise therapy, are urgently needed to address this growing public health concern. The aim of this study was to investigate the association between non-obese NAFLD, dietary habits, and physical activity levels. By elucidating these relationships, this research may contribute to the development of evidence-based recommendations for the management of non-obese NAFLD. The study had a single-center retrospective cross-sectional design and compared clinical data and dietary and physical activity habits between patients with and without non-obese NAFLD. Logistic regression analysis was utilized to investigate the relationship between food intake frequency and the development of NAFLD. Among the 455 patients who visited the clinic during the study period, 169 were selected for analysis, including 74 with non-obese NAFLD and 95 without NAFLD. The non-obese NAFLD group showed a less-frequent consumption of fish and fish products as well as olive oil and canola/rapeseed oil, while they showed more frequent consumption of pastries and cake, snack foods and fried sweets, candy and caramels, salty foods, and pickles compared to the non-NAFLD group. Logistic regression analysis revealed that NAFLD was significantly associated with the consumption of fish, fish products, and pickles at least four times a week. The physical activity level was lower and the exercise frequency was lower in patients with non-obese NAFLD compared to those without NAFLD. The results of this study suggest that a low consumption of fish and fish products and high consumption of pickles may be associated with a higher risk of non-obese NAFLD. Moreover, dietary habits and physical activity status should be taken into consideration for the management of patients with non-obese NAFLD. It is important to develop effective management strategies, such as dietary and exercise interventions, to prevent and treat NAFLD in this patient population.

Thyroid function variation within the thyroxine reference range has negative metabolic effects. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a recently proposed definition.

We aim to explore the effects of thyroid function status on prevalence and mortality of MAFLD.

Data of 10 666 participants from the Third National Health and Nutrition Examination Survey (NHANES III) were used. MAFLD was diagnosed based on the new definition. Thyroid function variation within the thyroxine reference range was defined based on thyroid-stimulating hormone (TSH) levels: subclinical hyperthyroidism, <0.39 mIU/L; strict-normal thyroid function, 0.39-2.5 mIU/L; and low thyroid function, >2.5 mIU/L, which comprised low-normal thyroid function (2.5-4.5 mIU/L) and subclinical hypothyroidism (> 4.5 mIU/L). Logistic and Cox regression were used in multivariate analysis.

Low thyroid function is independently associated with MAFLD (odds ratio: 1.27). Compared with strict-normal thyroid function, subclinical hypothyroidism was significantly associated with increased risk for all-cause and cardiovascular mortality in the total population (hazard ratio [HR] for all-cause: 1.23; cardiovascular: 1.65) and MAFLD population (HR for all-cause: 1.32; cardiovascular: 1.99); meanwhile, in the low-normal thyroid function group, an increasing trend in mortality risk was observed. Furthermore, low thyroid function also showed significant negative impact on mortality in the total and MAFLD population. Among thyroid function spectrum, mild subclinical hypothyroidism showed the highest HRs on mortality.

Low thyroid function is independent risk factor of MAFLD and is associated with increased risk for all-cause and cardiovascular mortality in the MAFLD population. Reevaluation of TSH reference range should be considered.

 The term non-alcoholic fatty liver disease (NAFLD) describes a condition in which excess fat accumulates in the liver, similar to alcohol-induced liver injury but affecting those who don't consume alcohol. Liver steatosis may vary from simple hepatic steatosis to more serious conditions, including non-alcoholic steatohepatitis and cirrhosis, and is linked to an increased risk of hepatocellular carcinoma (HCC). There is an estimated 20-30% prevalence of non-alcoholic fatty liver disease over the globe. The incidence rate among Indians is 26.9%. Metabolic diseases like insulin resistance, obesity, type-2 diabetes mellitus, and dyslipidemia are risk factors for NAFLD. A correlation between overt hypothyroidism and NAFLD has been discussed.

 To determine the magnitude of non-alcoholic fatty liver disease in overt hypothyroidism and to estimate the clinical and biochemical profile of patients with overt hypothyroidism and its relationship.

Throughout the course of a year, researchers from the medical department of a large hospital in southern India collected data in a cross-sectional observational study. Thyroid profile, fasting lipid profile, liver function tests, and ultrasound of the abdomen and pelvis were administered to a total of 100 male and female patients (18-60 years old) with newly diagnosed overt hypothyroidism who were visiting the outpatient department (OPD) and hospitalized in wards of general medicine.

About 75% of subjects were females, with a mean age of 37.63±7.6 years and a mean body mass index (BMI) of 25.07±1.5 kg/m². A significant correlation was found between dyslipidemia and thyroid-stimulating hormone (TSH) levels (p-value <0.001), and between dyslipidemia and ultrasonogram (USG) finding of NAFLD (p-value <0.001). A significant correlation was seen between TSH values and NAFLD findings (p-value <0.001).

NAFLD is a risk factor for developing hepatocellular carcinoma and is a known contributor to cryptogenic cirrhosis. Hypothyroidism is being studied as one of the causes of NAFLD. When hypothyroidism is diagnosed and treated early, it may reduce the likelihood of NAFLD and associated consequences.

Early identification of modifiable risk factors is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). We aimed to systematically explore the relationships between genetically predicted modifiable risk factors and NAFLD.

We applied univariable and multivariable Mendelian randomization analyses to explore the relationships between 35 modifiable risk factors and NAFLD. We also evaluated the combined results in three independent large genome-wide association studies. Genetically predicted alcohol frequency, elevated serum levels of liver enzymes, triglycerides, C-reactive protein, and obesity traits, including body mass index, waist circumference, and body fat mass, were associated with increased risks of NAFLD (all with p  < 0.05). Poor physical condition had a suggestive increased risk for NAFLD (odds ratio [OR] = 2.63, p  = 0.042). Genetically instrumented type 2 diabetes (T2DM), hypothyroidism, and hypertension all increased the risk for NAFLD, and the ORs (95% confidence interval) were 1.508 (1.20-1.90), 13.08 (1.53-111.65), and 3.11 (1.33-7.31) for a 1-U increase in log-transformed odds, respectively. The positive associations of T2DM and hypertension with NAFLD remained significant in multivariable analyses. The combined results from the discovery and two replication datasets further confirmed that alcohol frequency, elevated serum liver enzymes, poor physical condition, obesity traits, T2DM, and hypertension significantly increase the risk of NAFLD, whereas higher education and high-density lipoprotein cholesterol (HDL-cholesterol) could lower NAFLD risk.

Genetically predicted alcohol frequency, elevated serum liver enzymes, poor physical condition, obesity traits, T2DM, and hypertension were associated with an increased risk of NAFLD, whereas higher education and HDL-cholesterol were associated with a decreased risk of NAFLD.

Alongside the liver, white adipose tissue (WAT) is critical in regulating systemic energy homeostasis. Although each organ has its specialised functions, they must work coordinately to regulate whole-body metabolism. Adipose tissues and the liver are relatively resilient and can adapt to an energy surplus by facilitating triglyceride (TG) storage up to a certain threshold level without significant metabolic disturbances. However, lipid storage in WAT beyond a "personalised" adiposity threshold becomes dysfunctional, leading to metabolic inflexibility, progressive inflammation, and aberrant adipokine secretion. Moreover, the failure of adipose tissue to store and mobilise lipids results in systemic knock-on lipid overload, particularly in the liver. Factors contributing to hepatic lipid overload include lipids released from WAT, dietary fat intake, and enhanced de novo lipogenesis. In contrast, extrahepatic mechanisms counteracting toxic hepatic lipid overload entail coordinated compensation through oxidation of surplus fatty acids in brown adipose tissue and storage of fatty acids as TGs in WAT. Failure of these integrated homeostatic mechanisms leads to quantitative increases and qualitative alterations to the lipidome of the liver. Initially, hepatocytes preferentially accumulate TG species leading to a relatively "benign" non-alcoholic fatty liver. However, with time, inflammatory responses ensue, progressing into more severe conditions such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, in some individuals (often without an early prognostic clue). Herein, we highlight the pathogenic importance of obesity-induced "adipose tissue failure", resulting in decreased adipose tissue functionality (i.e. fat storage capacity and metabolic flexibility), in the development and progression of NAFL/NASH.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and worldwide. Though nonalcoholic fatty liver per se may not be independently associated with an increased risk for all-cause mortality, it is associated with a number of harmful metabolic risk factors, such as type 2 diabetes mellitus, hyperlipidemia, obesity, a sedentary lifestyle, and an unhealthy diet. The fibrosis stage is a predictor of all-cause mortality in NAFLD. Mortality in individuals with NAFLD has been steadily increasing, and the most common cause-specific mortality for NAFLD is cardiovascular disease, followed by extra-hepatic cancer, liver-related mortality, and diabetes. High-risk profiles for mortality in NAFLD include PNPLA3 I148M polymorphism, low thyroid function and hypothyroidism, and sarcopenia. Achieving weight loss through adherence to a high-quality diet and sufficient physical activity is the most important predictor of improvement in NAFLD severity and the benefit of survival. Given the increasing health burden of NAFLD, future studies with more long-term mortality data may demonstrate an independent association between NAFLD and mortality.

Observational studies showed that low thyroid function may perturb liver function. We aimed to evaluate the association of low thyroid function with both metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced hepatic fibrosis.

Participants who underwent abdominal ultrasonography and thyroid function test in a Chinese hospital from 2015 to 2021were enrolled. Fibrosis-4 index (FIB-4) > 2.67 and/or non-alcoholic fatty liver disease fibrosis score (NFS) > 0.676 were used to define advanced fibrosis. Descriptive analyses were performed to characterize the epidemiology of MAFLD according to levels of thyroid-stimulating hormone (TSH). The logistic regression model was applied to estimate the association of low thyroid function with MAFLD and advanced fibrosis.

A total of 19,946 participants (52.78% males, mean age: 47.31 years, 27.55% MAFLD) were included, among which 14,789 were strict-normal thyroid function, 4,328 were low-normal thyroid function, 829 were subclinical hypothyroidism. TSH levels were significantly higher in MAFLD patients with a FIB-4 > 2.67 and /or NFS > 0.676 than their counterparts. The logistic regression model adjusted for age and sex showed that low-normal thyroid function increased the risk of MAFLD (odds ratio [OR] = 1.09; 95% confidence interval [CI] 1.01-1.18). Multivariable regression model adjusted for age, sex, body mass index, type 2 diabetes, and hypertension showed low-normal thyroid function increased the risk of advanced fibrosis in patients with MAFLD (FIB-4 > 2.67: OR = 1.41, 95% CI 1.02-1.93; NFS > 0.676: OR = 1.72, 95% CI 1.08-2.72).

Elevated TSH concentrations are associated with advanced hepatic fibrosis, even in the euthyroid state.

Several lines of evidence suggest that the thyroid hormone signaling pathway is altered in patients with NAFLD and that pharmacological strategies to target the thyroid hormone/thyroid hormone nuclear receptor axis (TH/THR) in the liver may exert beneficial effects. In this study, we investigated the effect of TG68, a novel THRβ agonist, on rat hepatic fat accumulation and NAFLD-associated hepatocarcinogenesis.

Male rats given a single dose of diethylnitrosamine (DEN) and fed a high fat diet (HFD) were co-treated with different doses of TG68. Systemic and hepatic metabolic parameters, immunohistochemistry and hepatic gene expression were determined to assess the effect of TG68 on THRβ activation.

Irrespectively of the dose, treatment with TG68 led to a significant reduction in liver weight, hepatic steatosis, circulating triglycerides, cholesterol and blood glucose. Importantly, a short exposure to TG68 caused regression of DEN-induced preneoplastic lesions associated with a differentiation program, as evidenced by a loss of neoplastic markers and reacquisition of markers of differentiated hepatocytes. Finally, while an equimolar dose of the THRβ agonist Resmetirom reduced hepatic fat accumulation, it did not exert any antitumorigenic effect.

The use of this novel thyromimetic represents a promising therapeutic strategy for the treatment of NAFLD-associated hepatocarcinogenesis.

The relationship between thyroid function parameters and metabolic dysfunction-associated fatty liver disease (MAFLD) remains controversial. Additionally, little is known about the relationship between thyroid function parameters and MAFLD in the Chinese population.

We conducted a retrospective cross-sectional study involving 177,540 individuals with thyroid function tests and MAFLD diagnosis from 2010-2018. The association between thyroid function parameters and MAFLD was evaluated on a continuous scale with restricted cubic spline (RCS) models and by the prior-defined centile categories with multivariable-adjusted logistic regression models. Thyroid function parameters included free triiodothyronine (FT3), free tetra-iodothyronine (FT4), and thyroid stimulating hormone (TSH). Additionally, fully adjusted RCS models stratified by sex, age, and location were studied.

In the RCS models, the risk of MAFLD increased with higher levels of FT3 when FT3 <5.58pmol/L, while the risk of MAFLD decreased with higher levels of FT3 when FT3 ≥5.58pmol/L (P nonlinearity <0.05). While RCS analysis suggested that the FT4 levels had a negative association with MAFLD (P nonlinearity <0.05), indicating an increase in FT4 levels was associated with a decreased risk of MAFLD. RCS analysis suggested an overall positive association between the concentration of TSH and MAFLD risk (P nonlinearity <0.05). The rising slope was sharper when the TSH concentration was less than 1.79uIU/mL, which indicated the association between TSH and MAFLD risk was tightly interrelated within this range. The multivariable logistic regression showed that populations in the 81st-95th centile had the highest risk of MAFLD among all centiles of FT3/TSH, with the 1st-5th centile as the reference category.

Our study suggested nonlinear relationships between thyroid function parameters and MAFLD. Thyroid function parameters could be additional modifiable risk factors apart from the proven risk factors to steer new avenues regarding MAFLD prevention and treatment.

Over the past decades, adapted lifestyle and dietary habits in industrialized countries have led to a progress of obesity and associated metabolic disorders. Concomitant insulin resistance and derangements in lipid metabolism foster the deposition of excess lipids in organs and tissues with limited capacity of physiologic lipid storage. In organs pivotal for systemic metabolic homeostasis, this ectopic lipid content disturbs metabolic action, thereby promotes the progression of metabolic disease, and inherits a risk for cardiometabolic complications. Pituitary hormone syndromes are commonly associated with metabolic diseases. However, the impact on subcutaneous, visceral, and ectopic fat stores between disorders and their underlying hormonal axes is rather different, and the underlying pathophysiological pathways remain largely unknown. Pituitary disorders might influence ectopic lipid deposition indirectly by modulating lipid metabolism and insulin sensitivity, but also directly by organ specific hormonal effects on energy metabolism. In this review, we aim to I) provide information about the impact of pituitary disorders on ectopic fat stores, II) and to present up-to-date knowledge on potential pathophysiological mechanisms of hormone action in ectopic lipid metabolism.

Nonalcoholic fatty liver disease (NAFLD) is a worldwide rising challenge because of hepatic, but also extrahepatic, complications. Thyroid hormones are master regulators of energy and lipid homeostasis, and the presence of abnormal thyroid function in NAFLD suggests pathogenic relationships. Specifically, persons with hypothyroidism feature dyslipidemia and lower hepatic β-oxidation, which favors accumulation of triglycerides and lipotoxins, insulin resistance, and subsequently de novo lipogenesis. Recent studies indicate that liver-specific thyroid hormone receptor β agonists are effective for the treatment of NAFLD, likely due to improved lipid homeostasis and mitochondrial respiration, which, in turn, may contribute to a reduced risk of NAFLD progression. Taken together, the possible coexistence of thyroid disease and NAFLD calls for increased awareness and optimized strategies for mutual screening and management.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and closely interconnected to the metabolic syndrome. Liver-specific and systemic signaling pathways orchestrating glucose and fatty acid metabolism contribute to intrahepatic accumulation of lipids and inflammatory processes eventually causing disease progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Since a high number of key regulatory genes regarding liver homeostasis are directly mediated via thyroid hormone (TH) signaling, targeting TH receptors (TRs) represent a promising therapeutic potential for the treatment of NAFLD.

In this review, we elucidate the effects of TH on metabolic regulations in the liver via local availability and actions. We discuss recent advances and the potential impact of thyromimetics in basic research and clinical trials including liver-targeted and TRβ-specific agents for the treatment of NAFLD.

Unselective TR targeting can be accompanied by negative side effects due to high TRβ expression in other organs and TRα-mediated effects. Recent advances in drug development and the introduction of liver-targeted thyromimetics selectively activating TRβ such as Resmetirom (MGL-3196) and VK2809 bring new hope of translating the knowledge on local TH effects into effective hepatic lipid-clearing therapies against NASH.