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. 2025 Feb 21;16(7):e00829. doi: 10.14309/ctg.0000000000000829

Serum Insulin-Like Growth Factor 1 and the Prognosis of Patients With Advanced Liver Diseases: A Meta-Analysis

Yihan Liu 1,✉, Haojie Xue 1, Yang Liu 2,✉, Han Li 2,✉, Qian Liang 3, Longhui Ma 3, Ming Zhao 2,✉, Junying Liu 3,✉
PMCID: PMC12330352  PMID: 39981963

Abstract

INTRODUCTION:

Serum insulin-like growth factor 1 (IGF-1), a hepatocyte-derived cytokine, has been suggested to reflect hepatic function reserve. The aim of this systematic review and meta-analysis was to investigate the association between serum IGF-1 levels on the admission and prognosis of patients with advanced liver diseases.

METHODS:

A thorough examination of the literature was conducted across various databases, namely PubMed, Embase, Web of Science, Wanfang, and CNKI, with the aim of identifying relevant cohort studies. The data were synthesized using the random-effects model, taking into account the potential impact of heterogeneity.

RESULTS:

A total of 9 cohorts were included. Patients with a low serum level of IGF-1, as compared with those with a high IGF-1 at baseline, exhibited a significantly poorer transplant-free survival (risk ratio: 3.03, 95% confidence interval: 2.17 to 4.22, P < 0.001), with no significant heterogeneity observed (P for Cochrane Q test = 0.92, I2 = 0%). A sensitivity analysis, which was conducted by excluding 1 study at a time, yielded consistent results (risk ratio: 2.94–3.24, P all < 0.05). In addition, consistent results were observed in further subgroup analyses based on various factors, including cutoffs of IGF-1, country of the study, patient diagnosis, methods for measuring serum IGF-1, follow-up duration, analytic model, and quality scores (P for subgroup difference all > 0.05).

DISCUSSION:

A diminished serum IGF-1 level on admission could potentially serve as an indicator for an unfavorable prognosis among patients afflicted with advanced liver disease, such as severe hepatitis and cirrhosis.

KEYWORDS: insulin-like growth factor 1, hepatitis, cirrhosis, liver diseases, meta-analysis

INTRODUCTION

Patients with advanced liver diseases often exhibit conditions such as progressed fibrosis, cirrhosis (both compensated and decompensated), and acute-on-chronic liver failure as well as experience substantial impairment in liver function (1–3). Advanced liver diseases are correlated with increased susceptibility to various complications, including portal hypertension, ascites, spontaneous bacterial peritonitis, gastroesophageal varices, hepatic encephalopathy, malnutrition, and sarcopenia (4,5). These complications have a detrimental impact on both the quality of life and clinical prognosis of affected patients. Considering the importance of the liver in the regulation and participation of energy metabolism, changes in cytokines and hormones related to energy metabolism have been observed during the pathogenesis and progression of advanced liver diseases, such as cirrhosis (6,7). Insulin-like growth factor 1 (IGF-1) is synthesized primarily in hepatocytes, implicated in growth and metabolic regulation, and assumes a pivotal role in the pathological manifestation of diverse liver disorders (8). A growing body of evidence indicates that patients with advanced liver diseases exhibit diminished circulating levels of IGF-1, which may be associated with compromised hepatic function (9,10). Moreover, a reduction in IGF-1 can be observed in individuals with liver dysfunction-related sarcopenia, potentially exerting an active influence on the progression of liver diseases through various mechanisms, such as insulin resistance, proinflammation, enhanced oxidative stress response, and stimulation of liver fibrosis (11–13). In individuals diagnosed with hepatocellular carcinoma (HCC), a diminished level of serum IGF-1 has been acknowledged as an indicator of cancer advancement and unfavorable survival outcomes (14). Nonetheless, the precise association between serum IGF-1 and the prognosis of patients with advanced liver diseases remains largely unknown. Given this lack of knowledge, a meta-analysis was conducted to assess the potential prognostic significance of serum IGF-1 in individuals with advanced liver disease.

METHODS

The presented study adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (15) and the Cochrane Handbook of Systematic Reviews of Interventions (15). The protocol of this meta-analysis was prospectively registered on PROSPERO with the registration code CRD42024542479.

Inclusion and exclusion criteria of studies

The formulation of the inclusion criteria followed the design guidelines of the Population, Intervention, Comparison, Outcomes, and Study and was aligned with the objective of the meta-analysis.

P (participants): Adult patients with advanced liver diseases, such as severe hepatitis, cirrhosis, and complications of cirrhosis.

I (exposure): The baseline measurement of serum IGF-1 was conducted, and admission with a low serum level of IGF-1 was considered as an exposure. The cutoff values used to define patients with a low serum level of IGF-1 were consistent with the definitions used in the original studies.

C (control): Patients with a high serum level of IGF-1 at admission.

O (outcomes): Transplant-free survival (TFS) compared between patients with a low vs high serum level of IGF-1 at admission.

S (study design): Cohort studies, including prospective cohort and retrospective cohort studies.

Other study types, such as reviews, editorials, letters, and meta-analyses, were excluded. Furthermore, studies were excluded if they enrolled patients with HCC at baseline, included patients after liver transplant, or did not report the outcome of interest during follow-up. In cases where there was overlap in the populations being studied, the meta-analysis incorporated the study with the largest sample size.

Database searching

A thorough investigation was performed in electronic databases, namely PubMed, Embase, Web of Science, Wanfang, and CNKI, encompassing the period from their inception until December 5, 2023, with the aim of identifying studies published within this specific time span. The search strategy involved combining the terms (“insulin like growth factor 1” OR “insulin like growth factor-1” OR “somatomedin C” OR “IGF1” OR “IGF-1”) AND (“cirrhosis” OR “cirrhotic” OR “liver failure” OR “hepatic failure” OR “hepatitis” OR “liver disease” OR “hepatic disease”) AND (“survival” OR “mortality” OR “death” OR “deaths” OR “prognosis” OR “prognostic” OR “predictive” OR “prediction”). The analysis included only full-length articles published in peer-reviewed journals written in English or Chinese languages. In addition, relevant review and original articles were manually screened for potential studies of interest.

Data collecting and quality evaluating

The process of conducting literature searches, collecting data, and assessing study quality was performed independently by 2 authors. In cases where discrepancies arose, a third author was involved to facilitate discussion and achieve consensus. Concerning the studies incorporated in the analysis, we meticulously gathered comprehensive data encompassing study characteristics, general status of the encompassed patient population, diagnosis and etiologies of liver diseases, sample size, mean age, proportions of patients with Child-Pugh Class C at admission, methods for measuring serum IGF-1, cutoff values for analyses of IGF-1, follow-up durations, and variables adjusted when the association between serum IGF-1 and TFS were analyzed. To assess the caliber of each study, the Newcastle-Ottawa Scale (NOS) (16) was used, which evaluates various aspects such as participant selection, comparability among groups, and the validity of outcomes. This scale assigns a maximum of 9 stars, where a higher rating indicates a study of greater rigor.

Statistics

This study uses relative risks (RRs) and their corresponding 95% confidence intervals to summarize the relationship between serum IGF-1 and TFS in patients suffering from advanced liver diseases. Whenever possible, the RR and confidence interval derived from the regression model with the most extensive adjustment were extracted. To ensure stability and standardize variance, a logarithmic transformation was applied to the RR and its corresponding SE in each individual study (15). To assess the heterogeneity among the studies, the Cochrane Q test and I2 statistic (17) were used, whereby an I2 value surpassing 50% indicates significant heterogeneity. The outcomes were amalgamated by using a random-effects model, which has been suggested for addressing potential heterogeneity among the studies (15). A sensitivity analysis was conducted by systematically excluding 1 study at a time to verify the reliability and stability of the findings. Subgroup analyses were undertaken to evaluate the influence of predetermined study characteristics on the outcome, including the cutoff of IGF-1 in each study, country of study, patient diagnosis, methods used for measuring serum IGF-1, duration of follow-up, analytic model, and quality scores of the included studies. The assessment of publication bias was performed using a funnel plot and the Egger regression asymmetry test, which relies on subjective judgments of symmetry (18). Statistical analyses were conducted using RevMan (Version 5.1; Cochrane Collaboration, Oxford, UK) and Stata software (Version 12.0; Stata Corporation, College Station, TX).

Ethics statement

Institutional Review Board approval was not required because this is a meta-analysis.

RESULTS

Literature search and study retrieval

Figure 1 depicts the step-by-step procedures involved in the literature search and study retrieval process. Initially, a thorough search of databases resulted in the identification of 1,192 records. Subsequently, 241 duplicate entries were identified and eliminated. Through meticulous assessment of titles and abstracts, 926 studies were excluded because of their lack of alignment with the objectives of the meta-analysis. Further examination of the remaining 25 studies led to the exclusion of an additional 16 studies, with the specific reasons for their exclusion outlined in Figure 1. Ultimately, a total of 9 studies were deemed suitable for inclusion (19–27).

Figure 1.

Figure 1.

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Flowchart of database search and study inclusion. IGF-1, insulin-like growth factor-1.

Study characteristics

In the meta-analysis, 4 prospective cohorts (19–21,25) and 5 retrospective cohorts (22–24,26,27) were incorporated. These studies were conducted in various countries, including Denmark, Italy, Israel, China, Brazil, and Japan, and published between 1993 and 2023. The characteristics of these studies are concisely presented in Table 1. Regarding the diagnostic criteria, 6 studies (19–21,25–27) encompassed patients diagnosed with liver cirrhosis, while the remaining 3 studies focused on patients with more severe hepatitis (22–24). The mean ages of the included patients ranged from 38 to 69 years, with male proportions varying from 64% to 92%. Serum IGF-1 was measured for each patient at admission using the radioimmunoassay in 3 studies (19,21,24), the immunoradiometric assay in 2 studies (20,27), and with the enzyme-linked immunosorbent assay in 4 studies (22,23,25,26). Most of the included studies used the median of IGF-1 as the cutoff for defining low vs high serum IGF-1 at admission (19–24,26), whereas the other 2 used the receiver operating characteristic curve-derived value (25) and quartiles of IGF-1 (27) as the cutoffs. The follow-up durations varied among the included studies from within hospitalization to 57.1 months. Univariate analysis was performed on 5 of the included studies when the association between serum IGF-1 and TFS of these patients was analyzed (19,21–24), whereas a multivariate analysis was conducted on the other 4 studies (20,25–27) with adjustment of age, sex, and other potential confounding factors. The NOS of the included studies ranged 5 to 9 stars, indicating moderate-to-good study quality (Table 2).

Table 1.

Characteristics of the included cohort studies

Study Location Study design Patient diagnosis Sample size Mean age (yr) Men (%) CP class C (%) IGF-1 assay Cutoff of IGF-1 Median follow-up duration Variables matched or adjusted
Moller 1993 Denmark PC Alcoholic cirrhosis 36 52.2 83.3 58 RIA Median (3.1 nmol/L) 13.2 mo None
Caregaro 1997 Italy PC Cirrhosis (alcoholic 65.7%, viral 34.3%) 64 57 71.9 40.6 IRMA Median (5.5 nmol/L) 24 mo Age and sex
Assy 1998 Israel PC Viral cirrhosis 15 54.7 73.3 46.7 RIA Median (10 nmol/L) 24 mo None
Lou 2001 China RC Severe viral hepatitis 12 44 91.3 100 ELISA Median (3.9 nmol/L) During hospitalization None
Min 2001 China RC Severe viral hepatitis 18 38.5 66.7 100 ELISA Median (13.2 nmol/L) During hospitalization None
Zhang 2008 China RC Severe viral hepatitis with hypoglycemia 20 45 70 100 RIA Median (2.0 nmol/L) During hospitalization None
Colombo 2017 Brazil PC Acute decompensation cirrhosis (viral 44.1%, alcoholic 17.5%) 103 54.2 69.9 36.9 ELISA ROC curve analysis derived (1.7 nmol/L) 3 mo Age, sex, ascites, hepatic encephalopathy, bacterial infection, Child-Pugh C, higher MELD scores and ACLF at admission
Yao 2020 China RC Acute decompensation cirrhosis (viral 81.4%, alcoholic 12.4%) 386 55.8 71.8 33.4 ELISA Median (5.6 nmol/L) 12 mo Age, sex, jaundice, upper gastrointestinal bleeding, Child-Pugh, and MELD score
Saeki 2023 Japan RC Cirrhosis (alcoholic 39.2%, viral 35.1%) 148 69 64.9 36.5 IRMA Q1:Q2-4 (5.4 nmol/L) 57.1 mo Age, sex, TB, albumin, sodium, prothrombin time, Child-Pugh, and MELD score
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ACLF, acute-on-chronic liver failure; CP, Child-Pugh; ELISA, enzyme-linked immunosorbent assay; IGF-1, insulin-like growth factor-1; IRMA, immunoradiometric assay; MELD, Model for End-Stage Liver Disease; PC, prospective cohort; Q1:Q2-4, the first vs the second to the fourth quartiles; RC, retrospective cohort; RIA, radioimmunoassay; ROC, receiver operating characteristic; TB, total bilirubin.

Table 2.

Study quality evaluation using the Newcastle-Ottawa Scale

Study Representativeness of the exposed cohort Selection of the nonexposed cohort Ascertainment of exposure Outcome not present at baseline Control for age and sex Control for other confounding factors Assessment of outcome Enough long follow-up duration Adequacy of follow-up of cohorts Total points
Moller 1993 1 1 1 1 0 0 1 1 1 7
Caregaro 1997 1 1 1 1 1 0 1 1 1 8
Assy 1998 1 1 1 1 0 0 1 1 1 7
Lou 2001 0 1 1 1 0 0 1 1 0 5
Min 2001 0 1 1 1 0 0 1 1 0 5
Zhang 2008 1 1 1 1 0 0 1 1 0 6
Colombo 2017 1 1 1 1 1 1 1 1 0 8
Yao 2020 1 1 1 1 1 1 1 1 1 9
Saeki 2023 1 1 1 1 1 1 1 1 1 9
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Meta-analysis results

The pooled results from 9 studies (19–27) demonstrated that patients with a low serum level of IGF-1, compared with those with a high IGF-1 at baseline, exhibited a significantly poorer TFS (RR: 3.03, 95% CI: 2.17 to 4.22, P < 0.001; Figure 2a). There was no significant heterogeneity observed (P for Cochrane Q test = 0.92, I2 = 0%). The sensitivity analysis, which was conducted by excluding 1 study at a time, yielded consistent results (RR: 2.94 to 3.24, P all < 0.05). Further subgroup analyses suggest that the association between serum IGF-1 and TFS was found to be consistent in the following studies: in studies with the cutoffs of IGF-1 < and ≥5 nmol/L (P for subgroup difference = 0.35, Figure 2b); in Asian and non-Asian studies (P for subgroup difference = 0.41, Figure 3a); in studies of patients with liver cirrhosis and severe hepatitis (P for subgroup difference = 0.60, Figure 3b); in studies with serum IGF-1 measured with radioimmunoassay, immunoradiometric assay, and enzyme-linked immunosorbent assay (P for subgroup difference = 0.78, Figure 4a); in studies with follow-up duration within or longer than 12 months (P for subgroup difference = 0.27, Figure 4b); in studies with univariate and multivariate analysis (P for subgroup difference = 0.40, Figure 5a); and in studies with different NOS (P for subgroup difference = 0.60, Figure 5b).

Figure 2.

Figure 2.

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Forest plots for the meta-analysis of the association between serum level of IGF-1 at admission and TFS of patients with advanced liver diseases: (a) Forest plots for the overall meta-analysis and (b) Forest plots for the subgroup analysis according to the cutoffs of IGF-1 among the included studies. IGF-1, insulin-like growth factor-1; TFS, transplant-free survival.

Figure 3.

Figure 3.

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Forest plots for the subgroup analyses of the association between serum level of IGF-1 at admission and TFS of patients with advanced liver diseases: (a) Forest plots for the subgroup analysis according to the study country and (b) Forest plots for the subgroup analysis according to the diagnosis of the patients. IGF-1, insulin-like growth factor-1; TFS, transplant-free survival.

Figure 4.

Figure 4.

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Forest plots for the subgroup analyses of the association between serum level of IGF-1 at admission and TFS of patients with advanced liver diseases: (a) Forest plots for the subgroup analysis according to the assays for serum IGF-1 and (b) Forest plots for the subgroup analysis according to the follow-up duration. ELISA, enzyme-linked immunosorbent assay; IGF-1, insulin-like growth factor-1; IRMA, immunoradiometric assay; RIA, radioimmunoassay; TFS, transplant-free survival.

Figure 5.

Figure 5.

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Forest plots for the subgroup analyses of the association between serum level of IGF-1 at admission and TFS of patients with advanced liver diseases: (a) Forest plots for the subgroup analysis according to the analytic models and (b) Forest plots for the subgroup analysis according to the study quality scores. IGF-1, insulin-like growth factor-1; NOS, Newcastle-Ottawa Scale; TFS, transplant-free survival.

Publication bias

Figure 6 presents the funnel plots that depict the correlation between serum IGF-1 levels on admission and TFS in patients diagnosed with advanced liver diseases. A visual examination of the plots reveals a symmetrical distribution, suggesting the absence of significant publication bias. In addition, the implementation of Egger regression tests resulted in a low probability value (P = 0.81), further confirming the conclusion of minimal publication bias.

Figure 6.

Figure 6.

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Funnel plots for the publication bias underlying the meta-analysis of the association between serum level of IGF-1 at admission and TFS of patients with advanced liver diseases. IGF-1, insulin-like growth factor-1; RR, relative risk; TFS, transplant-free survival.

DISCUSSION

This systematic review and meta-analysis synthesized the results from the existing body of evidence derived from 9 cohort studies, indicating that individuals with advanced liver diseases and a low baseline serum IGF-1 level exhibit an increased susceptibility to TFS compared with those with a high serum IGF-1 level. In addition, consistent results were obtained through subsequent sensitivity analyses, which involved the exclusion of 1 study at a time. Furthermore, subgroup analyses revealed that various study characteristics, including the cutoffs of IGF-1 in each study, study country, patient diagnosis, methods for measuring serum IGF-1, follow-up duration, analytic model for assessing the association, and study quality scores, did not significantly alter the findings. Collectively, the results from the meta-analysis suggest that a diminished serum IGF-1 level on admission could potentially serve as an indicator for an unfavorable prognosis among individuals afflicted with advanced liver ailments, including severe hepatitis and cirrhosis.

Based on our current understanding, this study represents the inaugural meta-analysis that consolidates the correlation between serum IGF-1 and the prognosis of individuals afflicted with advanced liver diseases. Our findings indicate that a diminished serum IGF-1 on admission could potentially be linked to an unfavorable TFS in these patients. However, the precise mechanisms responsible for this association are not well understood. From a physiological standpoint, as hepatocytes are the primary source of IGF-1 synthesis, a lower level of serum IGF-1 may serve as an indicator of compromised hepatic functional reserve, consequently heightening the likelihood of mortality. A preliminary cross-sectional study conducted in Turkey involved a sample of 42 patients diagnosed with liver cirrhosis. The findings indicate a positive correlation between serum levels of albumin and IGF-1, whereas a negative correlation was observed between the serum levels of IGF-1, serum creatinine, sodium levels, and spleen size. These correlations were found to be independent of the etiology of cirrhosis (10). Similarly, a separate study conducted in Iran included a sample of 100 patients with varying degrees of cirrhosis severity. The results demonstrate a negative association between the serum level of IGF-1 and severity of liver cirrhosis, as determined by the Child-Pugh and Model for End-Stage Liver Disease scores (28). It is noteworthy to acknowledge that the association between serum IGF-1 and the extent of liver fibrosis was observed in both individuals with established liver disease and in those with early-stage liver fibrosis. In a group of patients diagnosed with type 2 diabetes and no apparent alcohol consumption, a negative correlation was identified between serum IGF-1 levels and markers of liver fibrosis (29). Furthermore, a recent investigation has established a connection between IGF-1 and the progression of hepatic diseases in patients with chronic hepatitis B virus infection (30). The study revealed a gradual decrease in serum levels of IGF-1 as liver disease progressed from chronic hepatitis B to liver cirrhosis and HCC (30).

Notably, several experimental studies have proposed potential mechanisms that explain the beneficial effects of IGF-1 in preventing liver fibrosis progression, emphasizing the significance of IGF-1 deficiency in the progression of liver diseases. In a mouse model of nonalcoholic steatohepatitis, IGF-1 was demonstrated to induce senescence of hepatic stellate cells and limit liver fibrosis in a P53-dependent manner (31). Furthermore, it has been suggested that prolonged exposure to IGF-1 may have the ability to alleviate premature senescence of hepatocytes induced by oxidative stress. This is achieved through the inhibition of the interaction between nuclear P53 and progerin, resulting in the mitigation of hepatic steatosis and fibrogenesis (32). In addition, a recent investigation has indicated that the administration of IGF-1 could potentially mitigate liver cirrhosis induced by carbon tetrachloride by downregulating high mobility group protein box-1 (33). These findings imply that a decrease in IGF-1 levels in advanced liver disease may serve as an indicator of disease severity and also present an active target for potential therapeutic interventions. A previous clinical trial in patients with liver cirrhosis showed that subcutaneous administration of IGF-1 (50–100 mg/kg/d) for 4 months was associated with increased albumin and improved energy metabolism (34). Future studies are warranted to determine if restoration of IGF-1 confers any survival benefit in patients with advanced liver disease.

In addition to the previously mentioned mechanisms, several other biological pathways may contribute to the link between low serum IGF-1 levels and poor prognosis in patients with advanced liver diseases. One such pathway involves the role of IGF-1 in modulating the immune response (35). IGF-1 has shown to exert anti-inflammatory effects by downregulating proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 (36). In advanced liver diseases, a low level of IGF-1 may fail to adequately suppress these proinflammatory cytokines, resulting in a heightened inflammatory state that exacerbates liver damage and contributes to adverse clinical outcomes. Furthermore, IGF-1 has been implicated in the regulation of hepatic progenitor cell proliferation and differentiation (37). Reduced levels of IGF-1 might impair the liver's regenerative capacity, limiting its ability to repair and regenerate damaged tissues, thereby worsening the prognosis of patients with advanced liver diseases. Finally, IGF-1 plays a significant role in metabolic regulation, and its deficiency has been implicated in hepatic insulin resistance, a critical contributor to liver damage (13). Low IGF-1 levels may exacerbate insulin resistance by disrupting glucose metabolism, increasing hepatic gluconeogenesis, and impairing lipid metabolism (38). These metabolic disturbances can lead to oxidative stress, inflammation, and steatosis, promoting fibrosis and further liver damage (12,39). In addition, IGF-1 has anti-inflammatory properties that may mitigate the detrimental effects of insulin resistance on hepatic tissues (40). Understanding these mechanisms underscores the potential dual role of IGF-1 as both a biomarker and therapeutic target in advanced liver diseases. Finally, diabetes is a prevalent comorbidity in advanced liver disease and is associated with poor TFS, particularly in cirrhotic patients (41). Hyperglycemia and insulin resistance may exacerbate liver damage through oxidative stress, inflammation, and fibrosis progression (42). IGF-1 deficiency, which closely linked to insulin resistance, may amplify these effects and further worsen prognosis (40). Notably, metformin use, which attenuates insulin resistance, has been associated with reduced mortality in patients with compensated cirrhosis (43), highlighting the potential interplay between IGF-1, diabetes management, and liver disease outcomes. The exact mechanisms and molecular pathways underlying the association between low IGF-1 and poor prognosis of patients with advanced liver diseases remain to be determined.

Our meta-analysis possesses several methodological strengths. First, we conducted a comprehensive literature search across 5 widely used English and Chinese electronic databases, resulting in the identification of 9 recent studies that align with the objective of our meta-analysis. Second, all the studies included in our analysis were cohort studies, enabling the establishment of a longitudinal association between low IGF-1 levels and impaired TFS in these individuals. Furthermore, the reliability of our findings was reinforced by the implementation of multiple sensitivity and subgroup analyses. The subgroup analysis, which was conducted exclusively on studies using multivariate analysis, yielded comparable findings. The results indicate that the potential link between low IGF-1 levels and unfavorable TFS outcomes in patients with advanced liver diseases is unlikely to be influenced by variables such as age, sex, and liver function. However, it is important to acknowledge that this work, being a meta-analysis of observational studies, is not without its own limitations. Specifically, there was a limited number of included studies, and the findings were derived from data at the study level, necessitating validation in larger prospective cohorts. Furthermore, there is the potential presence of unadjusted factors that may confound the relationship between low IGF-1 levels and poor TFS. For instance, factors such as body mass index, diabetic status, and concurrent medications in patients can potentially modify the serum level of IGF-1, thereby influencing the association between IGF-1 and TFS in this population. Ultimately, our study, which involved a meta-analysis of observational studies, did not establish a definitive causal link between low IGF-1 levels and impaired TFS. To ascertain the potential advantages of restoring IGF-1 levels on clinical outcomes in these individuals, further investigation through clinical trials is warranted.

From a clinical perspective, the findings of this meta-analysis highlight the potential utility of serum IGF-1 as a biomarker for risk stratification in patients with advanced liver diseases. Measuring serum IGF-1 levels on admission could help identify patients who have a higher risk of poor outcomes, facilitating early intervention and more personalized management strategies. Future studies should explore the feasibility and efficacy of integrating serum IGF-1 measurement into routine clinical practice. In addition, there is a need for clinical trials to investigate whether therapeutic interventions aimed at restoring IGF-1 levels could improve clinical outcomes in these patients. Potential interventions could include IGF-1 replacement therapy or lifestyle modifications that enhance endogenous IGF-1 production, such as exercise and dietary adjustments. Research should focus on elucidating the optimal cutoff values for IGF-1 levels in different populations and disease stages to refine its prognostic utility further. Moreover, although the current meta-analysis demonstrated a strong association between low IGF-1 levels and poor prognosis in patients with advanced liver diseases, the relationship between IGF-1 levels and hepatic insulin resistance could not be evaluated due to a lack of reported data in the included studies. Future studies should investigate this correlation, as hepatic insulin resistance may play a critical role in the progression of liver disease and may further elucidate the prognostic value of IGF-1 (44). Overall, these directions could pave the way for improved prognostic tools and therapeutic strategies, ultimately enhancing the care and survival of patients with advanced liver diseases.

In summary, the findings from this systematic review and meta-analysis suggest that a low serum IGF-1 level on admission could potentially serve as an indicator of unfavorable prognosis in patients with advanced liver disease, including severe hepatitis and cirrhosis. However, it is imperative to validate these results through extensive prospective studies on a larger scale. These findings provide support for the inclusion of serum IGF-1 measurement in the clinical risk stratification of patients with advanced liver disease.

CONFLICTS OF INTEREST

Guarantor of the article: Junying Liu, MD.

Specific author contributions: Yi.L., M.Z., J.L., and H.X. conceived and designed the study; Yi.L., H.X., and L.M. performed database search, data collection, and study quality evaluation; Yi.L., H.X., and H.L. performed statistical analysis; Yi.L., Ya.L., and M.Z. interpreted the results; Yi.L. and H.X. wrote the initial draft; M.Z. and Q.L. revised the manuscript. All authors read and approved the final version of the manuscript.

Financial support: None to report.

Potential competing interests: None to report.

Data availability statement: The authors confirm that the data supporting the findings of this study are available within the article.

ACKNOWLEDGEMENT

We thank Medjaden Inc. for the scientific editing of this manuscript.

Contributor Information

Yihan Liu, Email: 1403942587@qq.com.

Haojie Xue, Email: 1587845020@qq.com.

Yang Liu, Email: Zzly0202@163.com.

Han Li, Email: Lihan0327@126.com.

Qian Liang, Email: lqw141230@163.com.

Longhui Ma, Email: Kjk1796@163.com.

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