Early and accurate prognostic assessment is crucial to prevent disease progression in liver failure. Thyroid hormones (THs), particularly triiodothyronine (T3), are key metabolic regulators and play an important role in liver regeneration. Liver failure is frequently complicated by non‑thyroidal illness syndrome (NTIS), characterized by low T3 with normal or slightly elevated TSH and T4. This review examines the pathophysiological regulation of the hypothalamic‑pituitary‑thyroid (HPT) axis in liver failure, highlights the prognostic value of TH profiles (TSH, T3, T4), and discusses the controversies surrounding TH replacement therapy (THRT) in acute‑on‑chronic liver failure (ACLF) with NTIS.
Introduction
The liver is central to TH metabolism (activation, inactivation, transport). Severe liver dysfunction disrupts these processes, leading to NTIS. NTIS is common in ACLF and is closely linked to disease severity and poor prognosis. This review systematically examines TH dysfunction mechanisms, the clinical significance of TH profiling for prognosis, and therapeutic strategies for ACLF with NTIS.
Pathophysiological Mechanisms of the HPT Axis in Liver Failure
Hypothyroidism: Decreased T3 reduces LDL receptor expression and PPARα signaling, promoting hepatic lipid accumulation and steatohepatitis. Elevated TSH increases TR expression and cAMP signaling, promoting gluconeogenesis and worsening hyperlipidemia. Hypothyroidism also aggravates oxidative stress (ROS) and liver fibrosis.
Hyperthyroidism: Can cause congestive hepatopathy, autoimmune liver damage, or ATD‑induced hepatotoxicity. Guidelines recommend monitoring liver function during ATD therapy; radioactive iodine is an alternative.
NTIS in liver failure: Characterized by significantly reduced FT3 with normal or slightly elevated TSH and FT4. Key mechanisms: impaired hepatic DIO1 activity (reduced T4‑to‑T3 conversion), decreased synthesis of transport proteins (TBG, transthyretin, albumin), and blunted HPT axis feedback due to reduced pituitary reactivity. NTIS is a key biomarker of disease severity and poor prognosis.
Prognostic Value of TH Profiles in Liver Failure
TSH: Low TSH independently predicts short‑term mortality. The HINT score (incorporating TSH, INR, neutrophils) and modified CLIF‑OFs score outperform MELD and MELD‑Na in risk stratification.
T3: T3 promotes liver regeneration by activating Wnt/β‑catenin and Ras‑Raf‑MEK‑ERK pathways, upregulating cyclins, inhibiting CDK inhibitors (p16, p27) and tumor suppressors (p53, p73), and counteracting TGF‑β/SMAD signaling. Low T3 syndrome (low FT3) is an independent risk factor for mortality in ACLF. Composite scores (FT3‑MELD, MELD‑Thyro using FT3/FT4 ratio) improve predictive accuracy. Dynamic monitoring of declining FT3 identifies patients requiring urgent intervention (e.g., liver transplantation).
Treatment Advances for ACLF with NTIS
Current stance: No major guidelines recommend THRT for ACLF with NTIS. NTIS is considered an adaptive metabolic defense; indiscriminate THRT may cause harm.
Clinical utility: TH levels (FT3, FT4) are valuable for risk stratification and transplant decision‑making, but not as a direct guide for hormone replacement. Successful liver transplantation normalizes TH levels.
Experimental approaches: Thyroid hormone receptor (TR) agonists promote liver regeneration in preclinical models, but human safety/efficacy data are lacking. Prospective RCTs are needed; THRT cannot be routinely recommended.
Discussion
TH parameters offer a unique metabolic perspective (reflecting systemic exhaustion and regenerative capacity) that complements traditional scores (MELD, CLIF‑C). However, limitations include: most evidence is retrospective/single‑center; optimal cutoff values for FT3/TSH are heterogeneous; it remains unclear whether TH suppression is maladaptive or adaptive. TH markers should be used as complementary biomarkers, not standalone criteria.
Future Research Directions
Large‑scale multicenter prospective studies to verify if THRT improves survival and organ recovery in ACLF with NTIS.
Determine optimal drug selection (T3, T4, or combination), dosage, and duration.
Safety evaluation in patients with unstable cardiovascular function.
Elucidate the role of T3 in hepatocyte proliferation and liver regeneration to identify new treatment targets.
Conclusions
In ACLF patients, NTIS is common and characterized by low T3. T3 levels are closely related to disease severity and short‑term prognosis, reflecting liver regenerative capacity. Combining TH profiles (TSH, FT3, FT4) with traditional scoring systems (MELD, CLIF‑C) may improve prognostic accuracy and help identify high‑risk patients for timely intervention.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00657
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
