Early and accurate prognostic assessment is important to prevent disease progression in liver failure. Thyroid hormones (TH), especially triiodothyronine (T3), are important metabolic regulators and play an important role in liver regeneration. Liver failure is often associated with non-thyroid disease syndrome (NTIS), which is characterized by normal or slightly elevated TSH and T4 but low T3.
This review examines the pathophysiological regulation of the hypothalamic-pituitary-thyroid (HPT) axis in liver failure, focuses on the prognostic value of the TH profile (TSH, T3, T4), and discusses the controversy surrounding TH replacement therapy (THRT) in acute chronic liver failure (ACLF) with NTIS.
introduction
The liver is the center of TH metabolism (activation, inactivation, and transport). Severe liver dysfunction disrupts these processes, leading to NTIS. NTIS is common in ACLF and is closely associated with disease severity and poor prognosis. This review systematically examines the mechanisms of TH dysfunction, the clinical significance of TH profiling for prognosis, and treatment strategies for ACLF with NTIS.
Pathophysiological mechanisms of 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, promotes gluconeogenesis, and worsens hyperlipidemia. Hypothyroidism also exacerbates oxidative stress (ROS) and liver fibrosis
- Hyperthyroidism: Can lead to congestive liver damage, autoimmune liver damage, or ATD-induced hepatotoxicity. Guidelines recommend monitoring liver function during ATD treatment. Radioactive iodine is an alternative
- NTIS in liver failure: Characterized by a significant decrease in FT3 with normal or slightly elevated TSH and FT4. Main mechanisms: decreased hepatic DIO1 activity (decreased T4 to T3 conversion), decreased synthesis of transport proteins (TBG, transthyretin, albumin), blunted HPT axis feedback due to decreased pituitary reactivity. NTIS is an important biomarker of disease severity and poor prognosis
Prognostic value of TH profile in liver failure
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TSH: Low TSH independently predicts short-term mortality. The HINT score (incorporating TSH, INR, and neutrophils) and modified CLIF‑OF score outperform MELD and MELD‑Na in risk stratification.
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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 blocking TGF-β/SMAD signaling. Low T3 syndrome (low FT3) is an independent risk factor for death in ACLF. Composite scores (FT3‑MELD, MELD‑Thyro using FT3/FT4 ratio) improve prediction accuracy. Dynamic monitoring of FT3 decline identifies patients requiring emergency intervention (e.g. liver transplantation)
Advances in the treatment of ACLF with NTIS
- Current stance: There are no major guidelines recommending THRT for ACLF with NTIS. NTIS is considered an adaptive metabolic defense. Indiscriminate THRT can cause harm
- Clinical utility: TH levels (FT3, FT4) are useful for risk stratification and transplantation decision-making, but are not useful as a direct guide to hormone replacement. Successful liver transplantation normalizes TH levels
- Experimental approach: Thyroid hormone receptor (TR) agonists promote liver regeneration in preclinical models, but safety/efficacy data in humans are lacking. Prospective RCTs are needed. THRT is not routinely recommended
discussion
TH parameters provide a unique metabolic perspective (reflecting whole body fatigue and regenerative capacity) that complements traditional scores (MELD, CLIF‑C). However, there are some limitations: 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 rather than independent standards.
Future research directions
- Large multicenter prospective study testing whether THRT improves survival and organ recovery in ACLF with NTIS
- Determine optimal drug selection (T3, T4, or combination), dosage, and duration
- Safety assessment in patients with unstable cardiovascular function
- Elucidating the role of T3 in hepatocyte proliferation and liver regeneration and identifying new therapeutic targets
conclusion
NTIS is common in ACLF patients and is characterized by low T3. T3 levels reflect the regenerative capacity of the liver and are closely related to disease severity and short-term prognosis. Combining TH profiles (TSH, FT3, FT4) with traditional scoring systems (MELD, CLIF‑C) may improve prognostic accuracy and help identify high-risk patients who require timely intervention.
sauce:
Reference magazines:
Zhou, H. others (2026) Mechanism and prognostic value of thyroid hormone in liver failure. Journal of Clinical and Translational Hepatology. DOI:10.14218/JCTH.2025.00657. https://www.xiahepublishing.com/2310-8819/JCTH-2025-00657.
