Endocrine-liver bidirectional regulation: From mechanistic research to multidisciplinary clinical practice

Abstract

A close bidirectional regulatory network exists between endocrine disorders and liver dysfunction, and their reciprocal imbalance is a key driver of metabolic liver diseases and chronic liver diseases. Based on the review, this letter systematically appraises its value in elucidating bidirectional crosstalk mechanisms across the thyroid, parathyroid, pancreas, adrenal, and sex hormone axes with the liver, while identifying limitations in mechanistic depth and clinical translation. Aligned with current clinical needs and research hotspots, we propose targeted research directions, including strengthening multi-omics biomarker screening, optimizing individualized management for special populations, and refining interdisciplinary collaboration, so as to provide comprehensive theoretical support and practical references for multidisciplinary team diagnosis and treatment of endocrine-related liver diseases.

Key Words: Endocrine system; Liver function; Multidisciplinary team; Metabolic liver disease; Hormonal imbalance

Core Tip: The endocrine system and liver form a dynamic bidirectional network via hormone synthesis/metabolism and signaling regulation. Hormones (e.g., thyroid hormones, insulin) maintain hepatic glucose/lipid homeostasis and bile acid metabolism; conversely, chronic liver diseases disrupt endocrine balance through impaired hormone clearance, hypothalamic-pituitary axis dysfunction, and systemic inflammation, forming a “liver disease-endocrine disorder” vicious cycle. Key research gaps include insufficient exploration of the gut microbiota-endocrine-liver axis, lack of special population data, and delayed integration of emerging therapies. Future efforts should focus on molecular mechanism refinement, special population studies, and multidisciplinary team practice to achieve precise management of endocrine-related liver diseases.

TO THE EDITOR

We have read with great interest the review published by Vargas-Beltran et al[1]. Centered on the interplay between the endocrine system and liver function, this review systematically summarizes the pathophysiological links between multiple endocrine axes (thyroid, parathyroid, pancreas, adrenal glands, and sex hormones) and liver diseases, offering substantial academic value and clinical relevance.

The review’s notable contributions are threefold. First, it delineates the mechanisms of liver injury induced by common clinical endocrine abnormalities, including lipid metabolism disorders, oxidative stress activation, and impaired hormone conversion; second, it outlines the application prospects of emerging drugs such as thyroid hormone receptor β (THRβ) agonists and glucagon-like peptide-1 (GLP-1) receptor agonists; third, it breaks from the traditional “single-organ disease” paradigm to emphasize the key viewpoint that “endocrine and liver diseases mutually exacerbate each other”. For instance, advanced chronic liver disease (ACLD) patients not only develop euthyroid sick syndrome due to impaired hormone metabolism but also suffer from adrenal insufficiency caused by insufficient cortisol synthesis substrates and inflammatory factor inhibition. This analysis of the “mutually reinforcing” mechanism directly underscores the necessity of multidisciplinary team (MDT) collaboration among endocrinology, hepatology, and gastroenterology departments, aligning with the current trend of systemic and holistic clinical practice.

Under physiological and pathological conditions, there exists a dynamic bidirectional regulatory network between endocrine organs (thyroid gland, parathyroid gland, pancreas, adrenal glands, gonads) and the liver, with the gut microbiota participating in regulating this cyclic process (Figure 1). In the physiological state, the gut microbiota regulates the body’s endocrine function through its metabolites and synergizes with endocrine hormone secretion to maintain hepatic homeostasis. In the pathological state, gut microbiota dysbiosis and endocrine disorders (e.g., insulin resistance, hypothyroidism) induce hepatic injury through pro-inflammatory and fibrogenic pathways, while liver dysfunction in turn impairs hormone clearance and gut barrier integrity, thereby exacerbating systemic imbalance and forming a pathological vicious cycle. This visualization clarifies the core regulatory framework but also highlights gaps that the original review failed to fully address. However, aligned with current research frontiers and unmet clinical needs, the review has several areas for refinement: (1) Inadequate elaboration on the “gut microbiota-endocrine-liver” axis. The gut microbiota acts as a critical intermediary in endocrine-liver crosstalk. Its metabolites (e.g., short-chain fatty acids, bile acids) modulate insulin sensitivity and cortisol synthesis to regulate hepatic function[2]. However, the review confines its analysis to direct endocrine organ-liver interactions, omitting this core regulatory link. This oversight risks neglecting multi-layered intermediary mechanisms, hindering a full explanation of clinical observations such as “microbiota-based interventions alleviating metabolic dysfunction-associated steatotic liver disease (MASLD) complicated with insulin resistance”[3]; (2) Insufficient coverage of special populations. Endocrine-liver interplay exhibits distinct clinical/pathophysiological features across elderly, pediatric, and pregnant patients. In older adults with ACLD, age-related sarcopenia and hypogonadism frequently coexist with MASLD, exacerbating frailty, insulin resistance, and fall risk[4]. In children, obesity-related MASLD often overlaps with growth hormone resistance and pubertal insulin resistance, resulting in a distinct natural history and therapeutic responsiveness compared to adults[5]. During pregnancy, intrahepatic cholestasis of pregnancy and gestational diabetes mellitus exemplify how pregnancy-induced hormonal adaptations disrupt bile acid homeostasis and promote hepatic steatosis[6]. The lack of dedicated analysis for these groups limits the generalizability of the review’s conclusions to special populations; (3) Delayed integration of emerging therapeutic evidence. Several pivotal clinical advances have not been fully incorporated. For example, the THRβ agonist resmetirom significantly improved steatohepatitis and fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH) and F1B-F3 fibrosis in a phase 3 randomized controlled trial, findings that supported its subsequent United States Food and Drug Administration approval for adults with noncirrhotic MASH and moderate-to-advanced fibrosis[7]. Similarly, a phase 3 trial demonstrated that the GLP-1 receptor agonist semaglutide induced MASH resolution and fibrosis stage improvement in a substantial proportion of patients[8]. Given the review’s focus on traditional therapeutic agents, its clinical guiding value for MASLD/MASH in the current treatment landscape is diminished; (4) Absence of multi-organ synergistic biomarkers. Serum fibroblast growth factor 21 (FGF21) reflects both hepatic insulin resistance and thyroid function, with its elevation correlating with subclinical hypothyroidism and advanced MASLD[9]. Fetuin-A, a hepatokine, links hepatic steatosis to pancreatic β-cell dysfunction by inhibiting insulin receptor signaling[10]. The review’s failure to systematically summarize such multi-organ biomarker panels impedes early disease detection and risk stratification; and (5) Mechanistic gaps in intracellular signaling pathways. The review could be strengthened by explicitly linking endocrine signals to defined intracellular pathways in hepatocytes and liver non-parenchymal cells. For example, thyroid hormones not only regulate systemic energy expenditure but also promote hepatic fatty acid β-oxidation via the THRβ-PPARα axis and downstream effectors (e.g., carnitine palmitoyltransferase 1A), thereby influencing MASLD/MASH pathogenesis[11]. Similarly, chronic insulin resistance activates stress kinases (e.g., c-Jun N-terminal kinase) and the nuclear factor-κB pathway in hepatocytes and Kupffer cells, stimulating pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6) that propagate steatohepatitis and fibrosis[12]. Outlining such concrete signaling cascades bridges basic mechanistic insights with clinical phenotypes.

Figure 1 Gut microbiota-endocrine-liver axis: Bidirectional regulation in physiological homeostasis and pathological vicious cycle. There exists dynamic bidirectional crosstalk among the gut microbiota, endocrine organs (thyroid, pancreas, adrenal gland, parathyroid, gonad, pituitary), and the liver, and this figure depicts their regulatory networks in physiological homeostasis (upper light blue section) and pathological vicious cycle (lower red section). In physiological homeostasis, the gut microbiota fosters beneficial bacteria and stable short-chain fatty acids/bile acids, collaborating with endocrine organs. The thyroid regulates hepatic lipid metabolism via T3-thyroid hormone receptor β-peroxisome proliferator-activated receptor α/sterol regulatory element-binding protein 1c; pancreas maintains glucose homeostasis through insulin/phosphoinositide 3-kinase/Akt pathway; adrenal gland modulates gluconeogenesis and anti-inflammation via cortisol, parathyroid balances calcium/phosphorus, gonad regulates insulin sensitivity and inflammation via sex hormones, and pituitary orchestrates downstream axes. While the liver sustains this balance by inactivating excess hormones, synthesizing binding globulins, and supporting metabolic processes. In the pathological vicious cycle, microbial imbalance and endocrine disorders trigger a cascading loop. The thyroid dysfunction (triiodothyronine↓) worsens lipid accumulation in metabolic dysfunction-associated steatotic liver disease (MASLD), pancreatic insulin resistance activates nuclear factor-κB and hepatic stellate cells to drive hepatic fibrosis, excessive adrenal cortisol promotes MASLD, parathyroid hyperfunction (parathyroid hormone↑) causes calcium/phosphorus imbalance and hepatic calcification, gonadal hormone imbalance (testosterone↓/estrogen↑) induces insulin resistance, bile stasis, and hepatic adenoma, and pituitary dysfunction (growth hormone↓) impairs liver regeneration. While the liver amplifies this cycle through impaired hormone clearance, disrupted gut barrier (bacterial translocation), and metabolic disturbance, ultimately progressing to advanced chronic liver disease or severe MASLD. The figures in the manuscript were created with BioRender.com. ACLD: Advanced chronic liver disease; D1: Type 1 deiodinase; ERα: Estrogen receptor α; GH: Growth hormone; GLUT-4: Glucose transporter type 4; HSCs: Hepatic stellate cells; IGF-1: Insulin-like growth factor 1; MASLD: Metabolic dysfunction-associated steatotic liver disease; NF-κB: Nuclear factor-κB; PI3K/Akt: Phosphoinositide 3-kinase/Akt pathway; PPARα: Peroxisome proliferator-activated receptor α; PTH: Parathyroid hormone; SCFAs: Short-chain fatty acids; SREBP-1c: Sterol regulatory element-binding protein 1c; T3: Triiodothyronine; T4: Thyroxine; THRβ: Thyroid hormone receptor β; TSH: Thyroid-stimulating hormone.

FUTURE RESEARCH TRENDS AND PROSPECTS

To address the aforementioned limitations and align with current research priorities, we propose targeted exploration in the following directions.

Decipher precise “microenvironment-cell signaling” mechanisms

Future studies should dissect how endocrine hormones regulate hepatic stellate cells (HSCs) activation and hepatocyte death programs at the molecular level. For instance, aldosterone binds to mineralocorticoid receptors in HSCs, activating nicotinamide adenine dinucleotide phosphate oxidase-dependent reactive oxygen species production and Rho-associated kinase signaling, driving HSCs activation and extracellular matrix synthesis. In contrast, insulin resistance and glucocorticoid excess can augment hepatocyte pyroptosis through the NOD-like receptor pyrin domain-containing protein 3-caspase-1-gasdermin D pathway. Clarifying these context-dependent circuits will identify liver-specific targets for precision interventions.

Accelerate multi-omics and big data translation

Leverage metabolomics and proteomics to screen for specific biomarker panels (e.g., FGF21 + fetuin-A + bile acid derivatives), construct machine learning-based disease risk prediction models, and analyze prognostic differences across endocrine subtypes of liver disease via big data, enabling precise staging and dynamic monitoring.

Advance dedicated special population research

Design prospective studies for pregnant women, older adults, and children to delineate age- and pregnancy-related differences in endocrine-liver crosstalk, drug pharmacokinetics, and safety profiles. Based on these data, develop individualized diagnostic algorithms and treatment pathways to enhance the generalizability of findings to these vulnerable groups.

Promote interdisciplinary “gut microbiota-endocrine-liver” axis research

Explore the regulatory effects of gut microbiota on endocrine hormone metabolism via fecal microbiota transplantation, probiotic intervention, and metabolite supplementation, laying the groundwork for combined regimens of “microbial agents + endocrine-targeted therapy”.

Validate real-world MDT efficacy

Evaluate the clinical value of endocrine-liver MDT based on multi-center real-world data, focusing on endpoints such as liver fibrosis reversal, endocrine disorder remission, and mortality, to provide evidence for updating clinical practice guidelines.

CONCLUSION

In conclusion, this review establishes a solid foundation for interdisciplinary research in endocrinology and hepatology. Its emphasis on bidirectional regulation and MDT collaboration holds clear clinical implications. Future research should address the identified gaps by refining molecular mechanisms, expanding special population data, and integrating emerging evidence. These efforts will advance the theoretical system of endocrine-liver crosstalk and shift the management of endocrine-related liver diseases from “empirical treatment” to “precision and individualization”, ultimately providing innovative strategies to improve patient prognosis.

ACKNOWLEDGEMENTS

We thank all reviewers for their constructive comments, which significantly improved the manuscript.