The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Searches
2.2. Inclusion and Exclusion Criteria
2.3. Study Selection and Data Extraction
3. Results
3.1. Searching Results
3.2. In Vitro and In Vivo Studies (Table 2)
Study/Year | Techniques for Analysis of Results | Main Findings | p-Value |
---|---|---|---|
Nishizawa et al., 2012 [21] | Histological and biochemical analysis RT-PCR Immunochemical analysis | ↑ Liver triglyceride content (9 mg/g vs. 1mg/g) ↑ Serum AST and ALT, steatosis, and hepatic cell injury in GH-deficient rat (SDR) (mean ALT 30 IU/L vs. 12 IU/L; mean AST 250 IU/L vs. 100 IU/L) ↓ CPT-1, ↑ expression of enzymes for triglyceride synthesis ↑ Oxidative stress markers in SDR compared with those in the control GH and/or IGF-I administration improved all these changes | Liver triglyceride content: p < 0.001 Serum AST: p < 0.05 Serum ALT: p < 0.01 |
Nishizawa et al., 2016 [26] | Histological analysis Immunoblotting pPCR | ↓ Tissue triglyceride content, ↓ cells showing ballooning necrosis, ↓ fibrosis in cells in mice NASH model treated by IGF-1(ballooning necrosis cell number/HPF reduced by circa 50%; tissue triglyceride reduced approximately by 20%) IGF-1-induced cellular senescence of HSCs IGF-1 treatment in the NASH mouse model induced a decrease in the expression of activated markers for HSCs (relative mRNA 𝛼SMA reduced by approximately 60%) p53 is necessary for the IGF-I-induced senescence in HSCs | Ballooning necrosis: cell number p < 0.03 Tissue triglyceride content p < 0.05 Expression of mRNA 𝛼SMA: p < 0.04 |
Hosui et al., 2016 [25] | RT-PCR Western blot Immunohistochemistry and immunoblotting | ↑ CD36 in STAT5KO mice compared to those in control mice (more than 16-fold) In STAT5KO mice, CD36 gene expression is increased resulting in increased lipogenesis, fatty acid uptake, and steatosis. Improvement of abnormal lipid accumulation in STAT5/CD36 double KO mice compared to those in STAT5KO mice | |
Fukunaga et al., 2018 [27] | RT-PCR Western blot Immunohistochemistry | IGF-1 increased ABCA1 mRNA expression 3 folds compared to those in the controls ABCA1 activity decreased in mice after administration of PolyEthylene Glycol (PEG), a GH receptor inhibitor. ↓ Cholesterol content in HepG2 cells treated by IGF-1 as compared to those in the control | ABCA expression p < 0.05 Cholesterol content: p < 0.05 |
Sarmento-Cabral et al., 2021 [31] | Blood and hepatic lipid analysis Histological analysis | ↑ TG levels, hepatic fatty acids, and de novo lipogenesis in GHR knock-down mice compared with controls Improvement in whole-body lipid oxidation, fat mass, and insulin levels in male mice treated with IGF-1. ↑ALT levels, ↑steatosis, and hepatocyte ballooning (markers of liver injury) in GHR knock-down mice even after IGF-1 administration |
3.3. Human Studies (Table 3)
Study/Year | Techniques for Analysis of Results | Main Findings | p-Value |
---|---|---|---|
Ichikawa et al., 2007 [17] | Clinical, laboratory and liver histology data | ↓ level of GH is associated with steatosis grade 2–3 (univariate RR = 0.196; multivariate RR = 0.199) ↓ level of IGF-1 is associated with fibrosis GH/IGF-1 ratio is significantly lower in patients with steatosis grade 2–3 compared to those with grade 1 No significant difference in GH/IGF-1 ratio among different grades of steatosis | Level of GH is associated with steatosis grade 2–3 univariate: p = 0.0269 multivariate; p = 0.0414 GH/IGF-1 ratio (p < 0.001) |
García-Galiano et al., 2007 [18] | Clinical, biochemical, and histologic data | ↓ IGF-1 levels in patients with severe steatosis compared to those in healthy subjects and morbidly obese patients ↓ Concentration of IGF-1 in blood as compared to those in non-NASH and probable-NASH group Levels of IGF-1 <130 ng/mL as well as IGF-1 < 110 ng/mL are identified as independent predictors of hepatic steatosis and degree of NASH, respectively For IGF-1 < 130 ng/mL, the area below the ROC curve was found to be 0.75, while sensitivity and specificity were 0.68 and 0.79, respectively. For IGF-1 < 110 ng/mL, the area below the ROC curve was found to be 0.80, while sensitivity and specificity were 0.81 and 0.67, respectively. | IGF-1 levels (p = 0.024) Concentration of IGF (p = 0.006) |
Koehler et al., 2012 [19] | Biochemical and histologic data | ↓ GH levels in NASH patients compared to those in controls (NASH with FS 0–1 patients had a median GH level of 0.10 ng/mL; NASH with FS ≥ 2 patients had a median GH level of 0.14 ng/mL; the controls group had a median GH level of 0.45 ng/mL) A normal GH level essentially excluded the presence of NASH with advanced fibrosis. | GH level in patients and control: p < 0.001 p < 0.001 |
Nishizawa et al., 2012 [21] | Biochemical and histologic data | High prevalence of NAFLD among adult hypopituitary patients with GHD as compared to that in the control group (77% vs. 12%) ↓ Fibrotic marker concentrations, (p = 0.04) Improvement of histological changes in patients with NASH after GH replacement therapy) Six months after GH replacement therapy, serum liver enzyme concentrations were significantly decreased. | Prevalence of NAFLD: p < 0.001 Fibrotic marker concentrations: (p = 0.04) ALT: p < 0.001; AST: p < 0.005 and 𝛾-GTP: p < 0.05 |
Cianfarani et al., 2014 [22] | Biochemical and histologic data | IGF-1 SDS levels were inversely related to the steatosis grade (r = −0.37), ballooning (r = −0.47), and NAS (r = −0.49). IGF-I/IGFBP-3 ratio was a significant predictor of liver inflammation (β = −0.285). ↓ levels of IGF-1 SDS and IGF-1/IGFBP-3 ratio in children with NASH and higher grades of steatosis | Steatosis grade: p < 0.002 Ballooning: p < 0.001 NAS: p < 0.001 IGF-I/IGFBP-3 ratio: p = 0.005 Levels of IGF-1 SDS: (p < 0.05) IGF-1/IGFBP-3 ratio: (p < 0.02) |
Sumida et al., 2015 [24] | Clinical and histological data | Negative relationship between IGF-1 SDS and the activity of lobular inflammation (r = −0.134) and fibrosis (r = −0.362, p < 0.001); No relationship between the IGF-1:SDS and steatosis grade was detected | IGF-1 SDS: p < 0.001 Fibrosis: p < 0.001 |
Dichtel et al., 2017 [11] | Biochemical and histologic data | ↓ Serum IGF-1 levels associated with lobular inflammation and hepatocyte ballooning (112 ± 47 ng/mL vs. 136 ± 57 ng/mL; 115 ± 48 ng/mL vs. 135 ± 57 ng/mL respectively) Subset analysis of patients presenting NASH demonstrated lower mean serum IGF-1 levels compared to the respective negative controls (115 ± 8 ng vs. 137 ± 8 ng) | Serum IGF-1 levels associated with lobular inflammation (p = 0.01), hepatocyte ballooning, (p = 0.05) Serum IGF-1 levels: p = 0.02 |
Rufinatscha et al., 2018 [28] | Biochemical and histologic data | ↓ IGF-1 mRNA in patients with NASH when compared to patients with simple steatosis (approximative reduction of 66%). Among the 15 NASH patients, IGF-1 expression was characterized by an inverse relation to the grade of inflammation, but no statistical significance was found. GHR mRNA levels were comparable in patients with NASH and simple steatosis | IGF-1 mRNA: p < 0.05 IGF-1 expression: p = 0.25 |
Polyzos et al., 2020 [29] | Biochemical and clinical measurements | ↓ IGF-1/intact IGFBP-3 ratio in NASH patients with fibrosis as compared to in controls with milder or no histologic lesions in the liver After performing a binary logistic regression, the IGF-1/intact IGFBP-3 ratio did not remain robustly associated with NASH or liver fibrosis (unadjusted and after adjusting for BMI and age) | IGF-1/intact IGFBP-3 ratio: p = 0.04 IGF-1/intact IGFBP-3 after performing a binary logistic regression (p = 0.06 unadjusted and p = 0.08 after adjusting for BMI and age) |
Stanley et al., 2021 [30] | Analysis of data from a randomized clinical trial of GHRH. | ↓ Hepatic IGF-1 expression in individuals with higher grades of steatosis and higher NAS scores. ↓IGFBP2 and IGFBP4 (r = −0.49; r = −0.12) and ↑ IGFBP6 and IGFBP7 (r = 0.25; r = 0.35) with increasing steatosis Reduction of IGFBP2 after tesamorelin was associated with lower NAS score (r = 0.35) and hepatocellular ballooning grade (r = 0.37), but not with changes in lobular inflammation grade (r = 0.17) GHRH increased circulating IGFBP-1 and IGFBP-3 but decreased IGFBP-2 and IGFBP-6 | IGFBP2 and IGFBP4: p < 0.02, p < 0.02 IGFBP6 and IGFBP7: p < 0.005, p < 0.0001 IGFBP2 was associated with lower NAS score: (p = 0.02), hepatocellular ballooning grade (p = 0.02), but not with changes in lobular inflammation grade (p = 0.28) |
Osganian et al., 2022 [33] | Gene expression analysis Immunohistochemistry | No difference in IGF-1 receptor or GH receptor gene expression across worsening stages of NAFLD/NASH compared to that in control ↓ IGF-1 gene expression across disease stages No difference in GH receptor staining intensity by the severity of NAFLD compared to that in the control group |
4. Discussion
Limitations and Strengths
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study/Year | Study Design | Country | N° of Patients with NAFLD/NASH | N° of Controls | M/F Ratio | Mean Population Age (±SD) | Research Question | Method of Diagnosis | Comment |
---|---|---|---|---|---|---|---|---|---|
Ichikawa et al., 2007 [17] | CS | Japan | 55 patients with NAFLD | - | 20 males 35 females | Fibrosis stage 0–1: 47.5 ± 16.7 Fibrosis stage 2–3: 55.4 ± 17.5 | Role of GH, IGF-1, IGFBP-3 in NAFLD development | Percutaneous liver biopsy | |
García-Galiano et al., 2007 [18] | CS | Spain | 36 morbidly obese patients (13 with probable NASH and 9 with NASH) | 12 healthy subjects | - | - | Association between the serological levels of TNF-α, IL-6, and IGF-1 with steatosis and NASH | Liver biopsy during surgery | |
Koehler et al., 2012 [19] | CS | USA | 160 patients scheduled for bariatric surgery (72 with NASH and 72 with simple steatosis) | - | 24 males 136 females | Normal histology: 50 ± 13.2 S.S.: 47.8 ± 11.1 NASH and FS 0-1: 46.4 ± 10 NASH and FS >2: 50.7 ± 10.7 | Potential endocrine basis of steatohepatitis with advanced fibrosis in NAFLD | Liver biopsy | |
Nishizawa et al., 2012 [4] | VIVO | Japan | - | - | - | - | Effect of GH and IGF-1 administration on the liver of GH-deficient rats | 5 GH-deficient rats (S.D.R.) and 5 age-matched rats as control. | |
Takahashi, 2012 [20] | R | Japan | - | - | - | - | Role of GH and IGF-1 in the liver | - | |
Nishizawa et al., 2012 [21] | CS | Japan | 66 patients with GHD. | 1994 healthy subjects | 32 males 34 females | Normal histology: 44.8 ± 16.0 NAFLD: 48.1 ± 18.0 NASH: 44.6 ± 6.4 | Prevalence of NAFLD/NASH in adult hypopituitary patients with GHD | Ultrasonography and liver biopsy | |
Cianfarani et al., 2014 [22] | CS | Italy | 99 obese children (14 with NASH) | - | 57 males 42 females | 8.73 ± 1.98 | Correlate circulating levels of IGF-1, IGF2, and IGFBP3 with NASH | Liver biopsy | |
Xanthakos et al., 2014 [23] | R | USA | - | - | - | - | Correlation between abnormalities in GH axis and NASH | - | |
Sumida et al., 2015 [24] | CS | Japan | 199 Japanese patients with NAFLD | 2911 healthy people | 92 males 107 females | NAFLD: 59 ± 10 | Correlation between levels of IGF-1 SDS and histological severity of NAFLD | Liver biopsy | |
Hosui et al., 2016 [25] | IVIV | Japan | - | - | - | - | Role of STAT5 in hepatic lipid metabolism | - | STAT5KO mice and their littermates as controls. |
Nishizawa et al., 2016 [26] | IVIV | Japan | - | - | - | - | Effect of IGF-1 on NASH and cirrhotic models and the underlying mechanisms | - | NASH model, methionine-choline-deficient diet-fed db/db mice, and cirrhotic model, dimethylnitrosamine-treated mice |
Takahashi, 2017 [2] | R | Japan | - | - | - | - | Role of GH and IGF-1 in the liver | - | |
Dichtel et al., 2017 [11] | CS | USA | 121 patients (80 with NASH and 41 with simple steatosis) | 21 subjects | 66 males 76 postmenopausal females | Normal histology: 50 ± 10 S.S.: 55 ± 8 NASH: 50 ± 11 | Clarify the relationship between the histological severity of NAFLD and serum IGF-1 levels | Liver biopsy | |
Fukunaga et al., 2018 [27] | IVIV | Japan | - | - | - | - | Determine the effects of IGF-1 on ABCA1 expression in GH-deficient mice | - | 3 groups (n = 5 each) of 8-week-old mice: (1) control with high-fat diet (H.F.D.) (2) H.F.D. + P.E.G. (3) H.F.D. + P.E.G. + IGF-1 |
Rufinatscha et al., 2018 [28] | CS | Austria | 29 obese patients (15 with NASH and 14 with simple steatosis) | - | Female population exclusively | S.S.: 37.8 ± 11.8 NASH: 45.1 ± 8.9 | Role of hepatic GH signaling and its metabolic consequences in patients with NAFLD | Liver biopsy | |
Polyzos et al., 2020 [29] | CS | Greece | 31 patients (16 with NASH and 15 with simple steatosis) | 50 subjects (24 lean controls and 26 obese controls) | 19 males 62 females | Normal histology: 56.6 ± 12.5 NASH: 56.6 ± 7.1 | Evaluate hormones levels in histologically confirmed NASH patients versus S.S. patients versus controls | Liver biopsy | |
Stanley TL et al., 2021 [30] | RCT | USA | 61 subjects with HIV and hepatic steatosis | - | Predominantly male | 53 ± 7 | Clarify the relationships between hepatic expression of IGF-1 and IGFBPs and evaluate the effect of GHRH therapy in adults with NAFLD | Liver biopsy | |
Sarmento-Cabral et al., 2021 [31] | VIVO | USA | - | - | - | - | Test the IGF-1-independent role of hepatocyte GHR signaling | - | Mice with adult-onset, hepatocyte-specific GHR knock-down (aHepGHRkd) treated with a vector expressing rat IGF-1 targeted specifically to hepatocytes |
Dichtel et al., 2022 [32] | R | USA | - | - | - | - | Roles of GH and IGF-1 in the liver and their potential application for the treatment of NASH | - | |
Osganian et al., 2022 [33] | * | USA | 318 patients for the gene expression cohort and 30 for the immunohistochemistry cohort | - | - | Normal histology: 41.6 ± 11.5 S.S.: 45.2 ± 11.7 NASH F0: 43.9 ± 12.2 NASH F1-F4: 45.1 ± 12.9 | IGF-1 receptor and GH receptor physiology in patients with NAFLD and NASH | Liver biopsy | |
Doycheva et al., 2022 [34] | R | USA | - | - | - | - | Pathophysiologic mechanisms of GH in NAFLD, NAFLD association with AGHD, and effect of GH treatment in patients with NAFLD | - |
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Cristin, L.; Montini, A.; Martinino, A.; Scarano Pereira, J.P.; Giovinazzo, F.; Agnes, S. The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review. Cells 2023, 12, 517. https://doi.org/10.3390/cells12040517
Cristin L, Montini A, Martinino A, Scarano Pereira JP, Giovinazzo F, Agnes S. The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review. Cells. 2023; 12(4):517. https://doi.org/10.3390/cells12040517
Chicago/Turabian StyleCristin, Luca, Amalia Montini, Alessandro Martinino, Juan Pablo Scarano Pereira, Francesco Giovinazzo, and Salvatore Agnes. 2023. "The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review" Cells 12, no. 4: 517. https://doi.org/10.3390/cells12040517