Letter: The Prognostic Role of IGF-1 in Chronic Liver Disease—Authors' Reply

Abstract

We thank Osama et al. [1] for their interest in our manuscript on the role of insulin-like growth factor-1 (IGF-1) in hepatic dysfunction and fibrogenesis, as well as its prognostic role in advanced chronic liver disease (ACLD) [2]. Specifically, we want to thank the authors for pointing out that our study underscores the prognostic value of IGF-1 in regards to liver-related outcomes such as (further) decompensation, acute-on-chronic liver failure (ACLF) and liver-related death in patients with ACLD.

Osama et al. refer to a manuscript that reported IGF-1 as a potential biomarker for hepatic decompensation in patients with cACLD [3]. Interestingly, in our studied subgroup of cACLD patients, lower levels of IGF-1 were independently predictive of ACLF (per 10 ng/mL; aHR: 0.77; 95% CI: 0.60–0.99; p = 0.043) and liver-related death (per 10 ng/mL; aHR: 0.60; 95% CI: 0.44–0.82; p = 0.001), but not of first hepatic decompensation (per 10 ng/mL; aHR: 0.86; 95% CI: 0.68–1.08; p = 0.190).

Furthermore, in the study by Saeki and colleagues, there was no significant difference in clinical outcome between different strata of IGF-1 in patients with dACLD [3]. Conversely, we found that in our cohort of patients with dACLD, lower IGF-1 was an independent predictor of ACLF in competing risk regression analysis (per 10 ng/mL; aHR: 0.82; 95% CI: 0.70–0.95; p = 0.011). Moreover, there was a trend towards higher risk of liver-related death (per 10 ng/mL; aHR: 0.85; 95% CI: 0.71–1.03; p = 0.100) and further decompensation (per 10 ng/mL; aHR: 0.93; 95% CI: 0.86–1.01; p = 0.098) in patients with dACLD. Notably, while the number of patients with dACLD in our study (n = 164) was considerably larger than in the paper of Saeki and colleagues (n = 54) [3], the observed trend of IGF-1 predicting further decompensation or death did not achieve statistical significance, which may still be attributed to the somewhat limited sample size. Further research is required to fully illuminate the prognostic significance of plasma IGF-1 levels in patients with dACLD.

Concerning the risk of clinical events of patients with particularly high IGF-1 levels, we found that among patients included in our study with plasma IGF-1 levels above the 75th percentile (i.e. IGF-1 ≥ 91.5 ng/mL), merely 4.5% (3/67) died during the follow-up. Moreover, notably, all these deaths were non-liver-related. Thus, while the cited paper by Mukama et al. [4] found a U-shaped effect of IGF-1 levels on cancer formation and mortality among a population of n = 7461 patients with diverse medical conditions, a similar U-shaped effect regarding the risk of liver-related outcomes was not found in our cohort of patients with ACLD. However, Dichtel et al. [5] found that in non-ACLD patients with metabolic dysfunction-associated liver disease (MASLD), raising IGF-1 levels via growth hormone (GH) administration successfully reduced hepatic steatosis, thus underlining a potential involvement of the disrupted GH-IGF-1-axis in liver disease progression and the patients' prognosis.

While we do not have any information on the presence of sarcopenia, frailty or osteodystrophy for our studied patient cohort, we want to emphasise that ACLD is associated with a number of endocrinological alterations [6-9], that all likely contribute to alterations in the musculoskeletal system.

Lukas Hartl: conceptualization, investigation, writing – original draft, methodology, formal analysis, data curation, resources, visualization. Michael Schwarz: conceptualization, investigation, data curation, writing – original draft, formal analysis, validation. Benedikt Simbrunner: writing – review and editing, data curation. Mathias Jachs: writing – review and editing, data curation. Peter Wolf: methodology, writing – review and editing. David Josef Maria Bauer: data curation, writing – review and editing. Bernhard Scheiner: data curation, writing – review and editing. Lorenz Balcar: writing – review and editing, data curation. Georg Semmler: data curation, writing – review and editing. Benedikt Silvester Hofer: writing – review and editing, data curation. Nina Dominik: data curation, writing – review and editing. Rodrig Marculescu: methodology, validation. Michael Trauner: writing – review and editing. Mattias Mandorfer: data curation, writing – review and editing. Thomas Reiberger: conceptualization, project administration, supervision, resources, writing – original draft, methodology.

L.H., M.S., M.J., P.W., L.B., G.S., B.S.H., N.D. and R.M. have nothing to disclose. B.Sim. received travel support from AbbVie and Gilead. D.J.M.B. received speaker fees from AbbVie and Siemens, as well as grant support form Gilead and Siemens, as well as travel support from AbbVie and Gilead. B.Sch. received travel support from AbbVie, Ipsen and Gilead. M.T. served as a speaker and/or a consultant and/or an advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus and Shire and received travel support from AbbVie, Falk, Gilead and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx. He is also a co-inventor of patents on the medical use of 24-norursodeoxycholic acid. M.M. served as a speaker and/or a consultant and/or an advisory board member for AbbVie, Collective Acumen, Gilead, Takeda and W. L. Gore & Associates and received travel support from AbbVie and Gilead. T.R. served as a speaker and/or a consultant and/or an advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens and W. L. Gore & Associates as well as travel support from AbbVie, Boehringer Ingelheim, Gilead and Roche.

The article is linked to Hartl et al. paper. https://doi.org/10.1111/apt.18289 and https://doi.org/10.1111/apt.18339.