Lower free triiodothyronine (fT3) levels in cirrhosis are linked to systemic inflammation, higher risk of acute-on-chronic liver failure, and mortality

Abstract

BackgroundAdvanced chronic liver disease (ACLD) may affect thyroid hormone homeostasis. We aimed to analyze the pituitary-thyroid axis in ACLD and the prognostic value of triiodothyronine (fT3).MethodsPatients with ACLD (liver stiffness measurement ≥10kPa) undergoing hepatic venous pressure gradient [HVPG] measurement between 06/2009-09/2022 and available fT3 levels were included. Clinical stages of ACLD were defined as: probable ACLD (pACLD): LSM ≥10kPa and HVPG ≤5mmHg, S0: mild portal hypertension (PH; HVPG 6-9mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non-bleeding hepatic decompensation and S5: further decompensation.ResultsAmong 297 patients with ACLD, 129 were compensated (pACLD: n=10; S0: n=33; S1: n=42; S2: n=44), while 168 were decompensated (S3: n=12; S4: n=97; S5: n=59). Median levels of TSH numerically increased with progressive ACLD stage (from pACLD: 1.2μIU/mL to S5: 1.5μIU/mL; p=0.152), while fT3 decreased (from pACLD: 3.2pg/mL to S5: 2.5pg/mL; p<0.001. Free thyroxin (fT4) levels remained unchanged (p=0.338). TSH (aB: 0.45; p=0.046) and fT3 (aB: -0.17; p=0.048) were independently associated with systemic C-reactive protein levels. Lower fT3 was linked to higher risk of (further) decompensation (adjusted subdistribution hazard ratio, asHR: 0.60; 95%CI: 0.37-0.97; p=0.037), acute-on-chronic liver failure (ACLF; asHR: 0.19; 95%CI: 0.08-0.49; p<0.001) and liver-related death (asHR: 0.14; 95%CI: 0.04-0.51; p=0.003).ConclusionIncreasing TSH and declining fT3 levels are observed with progressive ACLD stages. The association of TSH and fT3 with systemic inflammation suggests a liver disease-associated non-thyroidal illness syndrome. Lower fT3 levels in patients with ACLD indicate increased risk for decompensation, ACLF and liver-related death.Lay SummaryIn a large well-characterized cohort of patients with advanced chronic liver disease (ACLD), we found a decline of free triiodothyronine (fT3) throughout the clinical stages of ACLD, paralleled by a numerical increase of thyroid stimulating hormone (TSH). This suggests a progressive development of a non-thyroidal illness syndrome in association with ACLD severity. Importantly, C-reactive protein independently correlated with TSH and fT3, linking thyroid dysbalance in ACLD to systemic inflammation. Lower fT3 indicated an increased risk for subsequent development of hepatic decompensation, acute-on-chronic liver failure and liver-related death.Clinical trial numberVienna Cirrhosis Study (VICIS; NCT: NCT03267615)

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