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Nishikawa T, Ohtomo N, Inoue Y, Takahashi M, Ikeda H, Koike K, Yamamichi N, Fujishiro M, Tomiya T. Insulin-like Growth Factor-I Reduces Collagen Production by Hepatic Stellate Cells Through Stimulation of Collagen Degradation System via mTOR-Dependent Signaling Pathway. Biomedicines 2025; 13:566. [PMID: 40149542 PMCID: PMC11940815 DOI: 10.3390/biomedicines13030566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/13/2025] [Accepted: 02/15/2025] [Indexed: 03/29/2025] Open
Abstract
Aim: The liver is the major source of circulating insulin-like growth factor (IGF)-I. Serum IGF-I levels are decreased in cirrhotic patients depending on severity. IGF-I administration was shown to improve liver function in patients and animal models of liver cirrhosis. However, controversy exists as to whether IGF-I stimulates or reduces fibrosis in the liver. The effects of IGF-I on collagen accumulation by hepatic stellate cells (HSCs) and its mechanisms were studied. Methods: A moderately activated HSC clone was used to determine the effect of IGF-I administration on the collagen production system, including its degradation. The intracellular signaling system was also studied in the cells stimulated by IGF-I. Results: IGF-I treatment reduced total amounts of collagen deposition in a dose-related manner, while DNA synthesis was stimulated by IGF-I. IGF-I treatment did not affect transforming growth factor-beta levels and type I procollagen mRNA expression. Expression of matrix metalloproteinase (MMP)-2 and -9 was upregulated, and tissue inhibitor of metalloproteinase (TIMP)-1 expression was downregulated by IGF-I treatment. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suppressed phosphorylation of 70 kDa ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1, and abrogated IGF-I-induced increase in MMP-2 and -9 expression and decrease in TIMP-1 expression. Conclusions: IGF-I has the ability to stimulate the collagen degradation system by HSCs through an mTOR-dependent pathway independent of modulation of the activation state of HSCs.
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Affiliation(s)
- Takako Nishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo 113-0033, Japan
| | - Natsuko Ohtomo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Yukiko Inoue
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Division for Health Service Promotion, The University of Tokyo, Tokyo 113-8655, Japan
| | - Mami Takahashi
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo 113-0033, Japan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | | | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo 113-0033, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tomoaki Tomiya
- Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama 350-0451, Japan
- Health Promotion Center, Saitama Medical University, Saitama 350-0451, Japan
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Hartl L, Schwarz M, Simbrunner B, Jachs M, Wolf P, Bauer DJM, Scheiner B, Balcar L, Semmler G, Hofer BS, Dominik N, Marculescu R, Trauner M, Mandorfer M, Reiberger T. Insulin-like growth factor-1 in cirrhosis is linked to hepatic dysfunction and fibrogenesis and predicts liver-related mortality. Aliment Pharmacol Ther 2025; 61:88-98. [PMID: 39305115 PMCID: PMC11636078 DOI: 10.1111/apt.18289] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 04/23/2024] [Accepted: 09/09/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND AND AIMS We aimed to characterise insulin-like growth factor-1 (IGF-1) signalling in patients with advanced chronic liver disease (ACLD). METHODS Consecutive patients undergoing hepatic venous pressure gradient [HVPG] measurement were prospectively included. Clinical stages were defined as follows: probable ACLD (pACLD): liver stiffness ≥10 kPa and HVPG ≤5 mmHg, S0: mild PH (HVPG 6-9 mmHg), S1: clinically significant PH (CSPH), S2: CSPH with varices, S3: past variceal bleeding, S4: past/current non-bleeding hepatic decompensation and S5: further decompensation. RESULTS In total, 269 patients were included; 105 were compensated (pACLD: n = 18; S0: n = 30; S1: n = 20; S2: n = 37), and 164 were decompensated (S3: n = 11; S4: n = 89; S5: n = 64). Median levels of IGF-1 decreased with progressive cirrhosis (from pACLD: 88.5 ng/mL to S5: 51.0 ng/mL; p < 0.001). Patients with CSPH had significantly lower IGF-1 levels (63.5 ng/mL vs. 81.0 ng/mL; p = 0.001). IGF-1 showed an independent negative association with body mass index (BMI; aB: -1.56; p < 0.001), enhanced liver fibrosis (ELF) test (aB: -8.43; p < 0.001), MELD (aB: -1.13; p = 0.042) and age (per 10 years; aB: -6.87; p < 0.001). IGF-1 exhibited an excellent AUROC (0.856) for the prediction of liver-related death at 6 months of follow-up. Lower IGF-1 (per 10 ng/mL) was linked to higher risk of (further) decompensation (0.90; 95% CI: 0.83-0.98; p = 0.016), acute-on-chronic liver failure (ACLF; asHR: 0.80; 95% CI: 0.68-0.93; p = 0.004) and liver-related death (asHR: 0.76; 95% CI: 0.63-0.91; p = 0.004). CONCLUSION Decreased levels of IGF-1 reflect impaired hepatic function and fibrogenesis in patients with cirrhosis, which seems particularly relevant in obesity since low IGF-1 was independently linked to high BMI. Lower IGF-1 in cirrhosis predicts decompensation, ACLF and liver-related death.
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Affiliation(s)
- Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Peter Wolf
- Division of Endocrinology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - David Josef Maria Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Nina Dominik
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Rodrig Marculescu
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Clinical Research Group MOTION, Division of Gastroenterology and Hepatology, Department of Medicine IIIMedical University of ViennaViennaAustria
- Christian Doppler Lab for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
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Huang J, Yu J, Wang J, Liu J, Xie W, Li R, Wang C. Novel potential biomarkers for severe alcoholic liver disease. Front Immunol 2022; 13:1051353. [PMID: 36582223 PMCID: PMC9794087 DOI: 10.3389/fimmu.2022.1051353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/14/2022] [Indexed: 12/15/2022] Open
Abstract
Background Alcoholic liver disease (ALD) is a leading cause of advanced liver disease; however, minor clinical symptoms in the early stage frequently result in delayed diagnosis and therapy. Invasive liver biopsy, the gold standard for diagnosing ALD, is unsuitable for repetitive analysis. This study aims to identify potential serum biomarkers that could contribute to non-invasive disease screening and monitoring. Methods Label-free LC-MS/MS quantitative proteomics analysis was performed to identify differentially expressed proteins in the discovery cohort, followed by bioinformatics analysis based on the KEGG, GO, and String databases. Prioritized proteins were validated subsequently by quantitative assays. The area under the receiver operating characteristic curve (AUROC) was used to assess the diagnosis performance of potential biomarkers. Results A total of 161 differentially expressed proteins were identified in the discovery cohort, of which 123 were up-regulated and 38 were down-regulated. B2M, IGFALS, and IGFBP3 were evaluated, and all demonstrated excellent diagnosis performance with AUROCs of over 0.9 when distinguishing patients with severe ALD from healthy controls. The AUROC values of B2M, IGFBP3, and IGFALS were 0.7131, 0.8877, and 0.9896 for differentiating severe ALD from non-severe ALD to indicate disease severity. B2M could distinguish patients with non-severe ALD and HC participants with an AUROC value of 0.8985. The efficiency of multiple combinations of these biomarkers was superior to that of the existing liver fibrosis evaluation indices used to monitor disease progression, with AUROC values of over 0.9. IGFALS showed a positive correlation with ALT/AST (r=0.4648, P=0.0009) and may be developed as a therapeutic target. Conclusion This proteomic study identified three novel candidate proteins as promising circulating biomarkers for clinical diagnosis and disease progression and also provided the proteomic atlas for ALD pathophysiological mechanisms.
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Affiliation(s)
- Jia Huang
- Medical School of Chinese PLA, Beijing, China,Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiachi Yu
- Medical School of Chinese PLA, Beijing, China,Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jianan Wang
- Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jiayu Liu
- Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wei Xie
- Medical School of Chinese PLA, Beijing, China
| | - Ruibing Li
- Medical School of Chinese PLA, Beijing, China,Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China,*Correspondence: Chengbin Wang, ; Ruibing Li,
| | - Chengbin Wang
- Medical School of Chinese PLA, Beijing, China,Department of Laboratory Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China,*Correspondence: Chengbin Wang, ; Ruibing Li,
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Colombo BDS, Ronsoni MF, Soares E Silva PE, Fayad L, Wildner LM, Bazzo ML, Dantas-Correa EB, Narciso-Schiavon JL, Schiavon LL. Prognostic significance of insulin-like growth factor-I serum levels in acute decompensation of cirrhosis. Biomarkers 2017; 22:127-132. [PMID: 27775431 DOI: 10.1080/1354750x.2016.1252949] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 09/11/2016] [Indexed: 12/22/2022]
Abstract
CONTEXT IGF-I serum levels are suppressed in cirrhosis, but its prognostic significance is unknown. OBJECTIVES To investigate the prognostic value of IGF-I in patients admitted for acute decompensation of cirrhosis. MATERIALS AND METHODS Cohort study that included 103 patients. IGF-I was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Ninety-day mortality was 26.2% and it was independently associated with MELD, age and IGF-I. The Kaplan-Meier survival probability at 90 days was 94.3% in patients with IGF-I ≥13 ng/mL and 63.2% for patients with IGF-I <13 ng/mL (p = .001). DISCUSSION AND CONCLUSION IGF-I levels are independently associated with mortality in acute decompensation of cirrhosis.
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Affiliation(s)
| | | | | | - Leonardo Fayad
- a Division of Gastroenterology , Federal University of Santa Catarina , Florianópolis , Brazil
| | - Letícia Muraro Wildner
- b Department of Clinical Analysis , Federal University of Santa Catarina , Florianópolis , Brazil
| | - Maria Luiza Bazzo
- b Department of Clinical Analysis , Federal University of Santa Catarina , Florianópolis , Brazil
| | | | | | - Leonardo Lucca Schiavon
- a Division of Gastroenterology , Federal University of Santa Catarina , Florianópolis , Brazil
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Abdel-Razik A, Eldars W, Elhelaly R, Elzehery R. C-reactive protein and insulin-like growth factor-1 in differential diagnosis of ascites. J Gastroenterol Hepatol 2016; 31:1868-1873. [PMID: 27010362 DOI: 10.1111/jgh.13386] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/12/2016] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIM Insulin-like growth factor-1 (IGF-1) and C-reactive protein (CRP) are produced mainly by the liver; the output of these markers in response to inflammatory processes may be affected in patients with hepatic dysfunction. This may explain the differences in IGF-1 and CRP values in patients with non-portal and portal hypertension ascites. We aimed to evaluate serum and ascitic fluid IGF-1 and CRP as diagnostic markers in the differential diagnosis of benign and malignant ascites. METHODS In this prospective study, 398 consecutive patients with ascites were included. Serum and ascitic fluid levels of IGF-1 and CRP were measured using an enzyme-linked immunosorbent assay. RESULTS Patients were divided into group 1, due to benign ascites (n = 324), and group 2, due to malignant ascites (n = 74). Serum and ascitic IGF-1 were significantly increased in malignant ascites than benign ascites group [305 ± 65.7 ng/mL vs 95 ± 53.8 ng/mL; P < 0.001 and 288 ± 54.7 ng/mL vs 83.2 ± 36.7 ng/mL; P < 0.001], respectively. Serum and ascitic CRP were significantly higher in malignant ascites than benign ascites patients [12.8 ± 6.3 mg/mL vs 6.1 ± 4.9 mg/mL; P < 0.001 and 5.1 ± 2.2 mg/mL vs 1.6 ± 1.3 mg/mL; P < 0.001], respectively. At a cutoff value of 309.4 ng/mL and 7.8 mg/mL, serum IGF-1 and CRP had (95.1%, 81%) sensitivity and (88.6%, 75.5%) specificity for detecting malignant ascites [area under the curve: 0.932, 0.845], respectively. At a cutoff value of 291.6 ng/mL and 2.6 mg/mL, ascitic IGF-1 and CRP had (94.6%, 84%) sensitivity and (83.2%, 80.3%) specificity for detecting malignant ascites (area under the curve: 0.911, 0.893) correspondingly. CONCLUSION Elevated serum and ascitic fluid IGF-1 and CRP levels were associated with malignant ascites.
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Affiliation(s)
- Ahmed Abdel-Razik
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Waleed Eldars
- Medical Microbiology and Immunology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rania Elhelaly
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rasha Elzehery
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Correa CG, Colombo BDS, Ronsoni MF, Soares E Silva PE, Fayad L, Silva TE, Wildner LM, Bazzo ML, Dantas-Correa EB, Narciso-Schiavon JL, Schiavon LDL. Circulating insulin-like growth factor-binding protein 3 as prognostic biomarker in liver cirrhosis. World J Hepatol 2016; 8:739-748. [PMID: 27330683 PMCID: PMC4911508 DOI: 10.4254/wjh.v8.i17.739] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 05/03/2016] [Accepted: 05/17/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prognostic significance of insulin-like growth factor-binding protein 3 (IGFBP-3) in patients with cirrhosis. METHODS Prospective study that included two cohorts: outpatients with stable cirrhosis (n = 138) and patients hospitalized for acute decompensation (n = 189). Development of complications, mortality or liver transplantation was assessed by periodical phone calls and during outpatient visits. The cohort of stable cirrhosis also underwent clinical and laboratory evaluation yearly (2013 and 2014) in predefined study visits. In patients with stable cirrhosis, IGFBP-3 levels were measured at baseline (2012) and at second re-evaluation (2014). In hospitalized subjects, IGFBP-3 levels were measured in serum samples collected in the first and in the third day after admission and stored at -80 °C. IGFBP-3 levels were measured by immunochemiluminescence. RESULTS IGFBP-3 levels were lower in hospitalized patients as compared to outpatients (0.94 mcg/mL vs 1.69 mcg/mL, P < 0.001) and increased after liver transplantation (3.81 mcg/mL vs 1.33 mcg/mL, P = 0.008). During the follow-up of the stable cohort, 17 patients died and 11 received liver transplantation. Bivariate analysis showed that death or transplant was associated with lower IGFBP-3 levels (1.44 mcg/mL vs 1.74 mcg/mL, P = 0.027). The Kaplan-Meier transplant-free survival probability was 88.6% in patients with IGFBP-3 ≥ 1.67 mcg/mL and 72.1% for those with IGFBP3 < 1.67 mcg/mL (P = 0.015). In the hospitalized cohort, 30-d mortality was 24.3% and was independently associated with creatinine, INR, SpO2/FiO2 ratio and IGFBP-3 levels in the logistic regression. The 90-d transplant-free survival probability was 80.4% in patients with IGFBP-3 ≥ 0.86 mcg/mL and 56.1% for those with IGFBP3 < 0.86 mcg/mL (P < 0.001). CONCLUSION Lower IGFBP-3 levels were associated with worse outcomes in patients with cirrhosis, and might represent a promising prognostic tool that can be incorporated in clinical practice.
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Affiliation(s)
- Carina Gabriela Correa
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Bruno da Silveira Colombo
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Marcelo Fernando Ronsoni
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Pedro Eduardo Soares E Silva
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Leonardo Fayad
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Telma Erotides Silva
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Letícia Muraro Wildner
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Maria Luiza Bazzo
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Esther Buzaglo Dantas-Correa
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Janaína Luz Narciso-Schiavon
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
| | - Leonardo de Lucca Schiavon
- Carina Gabriela Correa, Bruno da Silveira Colombo, Marcelo Fernando Ronsoni, Pedro Eduardo Soares e Silva, Leonardo Fayad, Telma Erotides Silva, Esther Buzaglo Dantas-Correa, Janaína Luz Narciso-Schiavon, Leonardo de Lucca Schiavon, Division of Gastroenterology, Federal University of Santa Catarina, Florianópolis, Santa Catarina 88.040-001, Brazil
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Ren J, Anversa P. The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome. Biochem Pharmacol 2014; 93:409-17. [PMID: 25541285 DOI: 10.1016/j.bcp.2014.12.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 12/11/2014] [Accepted: 12/11/2014] [Indexed: 12/31/2022]
Abstract
Metabolic syndrome is a cluster of risk factors including obesity, dyslipidemia, hypertension, and insulin resistance. A number of theories have been speculated for the pathogenesis of metabolic syndrome including impaired glucose and lipid metabolism, lipotoxicity, oxidative stress, interrupted neurohormonal regulation and compromised intracellular Ca(2+) handling. Recent evidence has revealed that adults with severe growth hormone (GH) and insulin-like growth factor I (IGF-1) deficiency such as Laron syndrome display increased risk of stroke and cardiovascular diseases. IGF-1 signaling may regulate contractility, metabolism, hypertrophy, apoptosis, autophagy, stem cell regeneration and senescence in the heart to maintain cardiac homeostasis. An inverse relationship between plasma IGF-1 levels and prevalence of metabolic syndrome as well as associated cardiovascular complications has been identified, suggesting the clinical promises of IGF-1 analogues or IGF-1 receptor activation in the management of metabolic and cardiovascular diseases. However, the underlying pathophysiological mechanisms between IGF-1 and metabolic syndrome are still poorly understood. This mini-review will discuss the role of IGF-1 signaling cascade in the prevalence of metabolic syndrome in particular the susceptibility to overnutrition and sedentary life style-induced obesity, dyslipidemia, insulin resistance and other features of metabolic syndrome. Special attention will be dedicated in IGF-1-associated changes in cardiac responses in various metabolic syndrome components such as insulin resistance, obesity, hypertension and dyslipidemia. The potential risk of IGF-1 and IGF-1R stimulation such as tumorigenesis is discussed. Therapeutic promises of IGF-1 and IGF-1 analogues including mecasermin, mecasermin rinfabate and PEGylated IGF-1 will be discussed.
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Affiliation(s)
- Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
| | - Piero Anversa
- Departments of Anesthesia and Medicine and Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Puche JE, Castilla-Cortázar I. Human conditions of insulin-like growth factor-I (IGF-I) deficiency. J Transl Med 2012; 10:224. [PMID: 23148873 PMCID: PMC3543345 DOI: 10.1186/1479-5876-10-224] [Citation(s) in RCA: 177] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 11/07/2012] [Indexed: 12/13/2022] Open
Abstract
Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.
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Affiliation(s)
- Juan E Puche
- Applied Molecular Medicine Institute (IMMA), School of Medicine, Department of Medical Physiology, Universidad CEU San Pablo, Madrid, Spain
| | - Inma Castilla-Cortázar
- Applied Molecular Medicine Institute (IMMA), School of Medicine, Department of Medical Physiology, Universidad CEU San Pablo, Madrid, Spain
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9
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Ilias I, Paparrigopoulos T, Tzavellas E, Karaiskos D, Kontoleon P, Liappas I. IGF-I and IGFBP-3 before and after inpatient alcohol detoxification in alcohol-dependent subjects. Med Sci Monit 2012; 17:CR547-51. [PMID: 21959607 PMCID: PMC3539473 DOI: 10.12659/msm.881979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background It is unclear whether alcohol detoxification has an effect on factors that are involved in growth, metabolic functions and cell proliferation. Alcohol abuse is associated with low IGF-I levels that tend to rise after alcohol withdrawal. There is a paucity of studies on the course of IGFBP-3 (the main binding protein for IGF-I) after alcohol detoxification. Material/Methods We prospectively assessed IGF-I and IGFBP-3 changes at the time of admission and after 4 to 6 weeks of detoxification in an inpatient alcohol detoxification facility in 118 alcohol-dependent subjects given a regular hospital diet. No participants dropped out of the study. Results Changes in IGF-I after alcohol detoxification showed a marked dimorphism in altered hepatic biochemistry upon admission, with a rise in those with normal liver enzymes upon admission (p=0.016, Kruskall-Wallis) and a drop in those with elevated liver enzymes upon admission (p=0.05); the latter was noted in subjects that had consumed alcohol close to the time of admission. Overall, however, IGF-I and IGFBP-3 were within normal limits for most subjects both upon admission and after alcohol detoxification; no significant differences were detected among the examined parameters in men vs. women, and there were no significant correlations of IGF-I, IGFBP-3 or the IGF-I/IGFBP-3 molar ratio with BMI or age. Conclusions Regardless of hepatic enzymes’ elevation, alcohol detoxification had overall slight effects on IGF-I and IGFBP-3.
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Affiliation(s)
- Ioannis Ilias
- Department of Endocrinology, Diabetes and Metabolism, Elena Venizelou Hospital, Athens, Greece.
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10
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Jeyaratnaganthan N, Grønbaek H, Holland-Fischer P, Espelund U, Chen JW, Flyvbjerg A, Vilstrup H, Frystyk J. Ascites from patients with alcoholic liver cirrhosis contains higher IGF-I bioactivity than serum. Clin Endocrinol (Oxf) 2010; 72:625-32. [PMID: 19769623 DOI: 10.1111/j.1365-2265.2009.03707.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Patients with liver cirrhosis have diminished hepatic IGF-I generation, resulting in low circulating levels, whereas data on IGF-I in ascites are sparse. Therefore, we compared the IGF-system in serum and ascites from cirrhotic patients. DESIGN AND PATIENTS The study comprised 43 patients (12 females) with ascites and liver function of 58 +/- 10% of normal. Serum and ascites were collected concomitantly in the fasting state. In 11 patients, second serum and ascitic samples were collected within the first week. Eleven matched controls were also included. All samples were assayed for IGF-related parameters by immunoassays and by cell-based IGF-I bioassay. RESULTS As compared with controls, serum total IGF-I, total IGF-II, pro-IGF-II and bioactive IGF-I were reduced in liver patients, whereas IGF-binding protein 1 (IGFBP-1), IGFBP-2 and the soluble IGF-II receptor were elevated (P < 0.005 for all). In ascites, all IGF-related peptides but pro-IGF-II were further reduced as compared with serum (P < 0.001). By contrast, bioactive IGF-I was fourfold elevated in ascites as compared with serum (2.20 +/- 0.33 vs. 0.55 +/- 0.08 microg/l, P < 0.001). In ascites, the IGF-I bioactivity signal was completely blocked by addition of IGFBP-3. Repetitive measurements (n = 11) in ascites showed that all peptides but IGFBP-1 remained unchanged within 1 week. CONCLUSIONS It is a novel observation that the in vitro bioactivity of IGF-I can be higher in fluids from an extravascular compartment than in serum, in contrast to immunoreactive levels. This supports different roles for endocrine and paracrine/autocrine IGF-I, but the pathophysiological significance of our observation remains to be clarified.
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Affiliation(s)
- Nilani Jeyaratnaganthan
- The Medical Research Laboratories, Clinical Institute, and Medical Department M (Diabetes & Endocrinology), Aarhus University Hospital, DK-8000 Aarhus C, Denmark
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11
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Assy N, Pruzansky Y, Gaitini D, Shen Orr Z, Hochberg Z, Baruch Y. Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction. J Hepatol 2008; 49:34-42. [PMID: 18456366 DOI: 10.1016/j.jhep.2008.02.013] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2007] [Revised: 01/11/2008] [Accepted: 02/11/2008] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIMS Previous studies reported decreased serum IGF-1 levels in cirrhosis. We aimed to correlate GH-stimulated IGF-1 responses with both MELD and Child-Pugh scores and determine the impact of portal hypertension and nutrition on IGF-1 responses. METHODS Fifty-three patients (56+/-2 yrs) with cirrhosis were enrolled. Serum IGF-1 levels were measured by RIA before and 24h after a single injection of GH (0.06 mg/kg). RESULTS Compared to controls, basal IGF-1 levels were significantly decreased in patients with cirrhosis (17.3+/-6.3 vs 13.6+/-5.1, P<0.001). Increments in IGF-1 levels were significantly lower in cirrhotic patients (controls: 133% vs 49% in MELD score <10, 38% in MELD score 11-18, and 13% in MELD score 19-24, p<0.001). 37% of patients had blunted IGF-1 responses. Increments in IGF-1 levels correlated with albumin (r=0.6), portal congestive index (r=0.4), and MAMC (r=0.25). By multivariate analysis, only CP (OR 5.7) and MELD scores (OR 4.5) accurately differentiated between blunted or non-blunted IGF-1 responses and not portal hypertension (OR 0.9) or malnutrition (OR 1.35). CONCLUSIONS Cirrhosis is associated with low IGF-1 levels and an attenuated response to exogenous GH. These findings correlate better with the extent of hepatic dysfunction rather than the presence of portal hypertension or malnutrition.
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Affiliation(s)
- Nimer Assy
- Liver Unit, Ziv Medical Center, Safed 13100, Israel.
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12
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Lorenzo-Zúñiga V, Bartolí R, Masnou H, Montoliu S, Morillas RM, Planas R. Serum concentrations of insulin-like growth factor-I (igf-I) as a marker of liver fibrosis in patients with chronic hepatitis C. Dig Dis Sci 2007; 52:3245-50. [PMID: 17410466 DOI: 10.1007/s10620-006-9437-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2006] [Accepted: 05/12/2006] [Indexed: 01/06/2023]
Abstract
Liver biopsy was until recently the only way of evaluating liver fibrosis. Noninvasive tests for hepatic fibrosis, without potential risks, are desired by clinicians as well as patients. Insulin-like growth factor-I (IGF-I) synthesis is disturbed in liver fibrosis and reflects the severity of the clinical stage. We assessed serum IGF-I levels in patients with chronic hepatitis C (CHC) to correlate with liver fibrosis and antiviral therapy. Forty patients with CHC and persistently abnormal alanine aminotransferase values were enrolled and treated with peginterferon alpha-2a 180 microg per week plus ribavirin for 24 (n=20) or 48 (n=20) weeks. All patients underwent liver biopsy before treatment (METAVIR fibrosis stage F0, n=13; F1-F2, n=14; F3, n=7; F4, n=6). Serum IGF-I was measured at baseline, at the end of treatment period, and 24 weeks after finishing treatment. Mean IGF-I values were significantly lower in patients with advanced fibrosis (F4, 65.9+/-17.9 ng/mL) than in the others (F0, 145.2+/-47.1; F1-F2, 150.3+/-89.6; and F3, 121.4+/-35.2 ng/mL; P < .05). Serum IGF-I levels increased during combined therapy, being this increment markedly higher in patients with sustained virologic response. In conclusion, IGF-I synthesis is disturbed in CHC and reflects the severity of the liver fibrosis. Combined therapy improves serum IGF-I levels. IGF-I could represent a good, noninvasive marker of liver fibrosis.
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Affiliation(s)
- Vicente Lorenzo-Zúñiga
- Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Barcelona, Spain.
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13
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Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrhosis. BMC Gastroenterol 2005; 5:7. [PMID: 15745444 PMCID: PMC555751 DOI: 10.1186/1471-230x-5-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2004] [Accepted: 03/03/2005] [Indexed: 01/04/2023] Open
Abstract
Background The exogenous administration of Insulin-like Growth Factor-I (IGF-I) induces hepatoprotective and antifibrogenic actions in experimental liver cirrhosis. To better understand the possible pathways behind the beneficial effect of IGF-I, the aim of this work was to investigate severe parameters involved in oxidative damage in hepatic tissue from cirrhotic animals treated with IGF-I (2 μg. 100 g-1. day-1). Iron and copper play an important role in oxidative mechanisms, producing the deleterious hydroxyl radical (*OH) that peroxides lipid membranes and damages DNA. Myeloperoxidase (MPO) and nitric oxide (NO) are known sources of free radicals and induce reduction of ferritin-Fe3+ into free Fe2+, contributing to oxidative damage. Methods Liver cirrhosis was induced by CCl4 inhalation in Wistar male rats for 30 weeks. Healthy controls were studied in parallel (n = 10). Fe and Cu were assessed by atomic absoption spectrometry and iron content was also evaluated by Perls' staining. MPO was measured by ELISA and transferrin and ferritin by immunoturbidimetry. iNOS expression was studied by immuno-histochemistry. Results Liver cirrhosis was histologically proven and ascites was observed in all cirrhotic rats. Compared to controls untreated cirrhotic rats showed increased hepatic levels of iron, ferritin, transferrin (p < 0.01), copper, MPO and iNOS expression (p < 0.01). However, IGF-treatment induced a significant reduction of all these parameters (p < 0.05). Conclusion the hepatoprotective and antifibrogenic effects of IGF-I in cirrhosis are associated with a diminution of the hepatic contents of several factors all of them involved in oxidative damage.
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Castilla-Cortazar I, Diez N, Garcia-Fernandez M, Puche JE, Diez-Caballero F, Quiroga J, Diaz-Sanchez M, Castilla A, Casares AD, Varela-Nieto I, Prieto J, Gonzalez-Baron S. Hematotesticular barrier is altered from early stages of liver cirrhosis: Effect of insulin-like growth factor 1. World J Gastroenterol 2004; 10:2529-34. [PMID: 15300898 PMCID: PMC4572155 DOI: 10.3748/wjg.v10.i17.2529] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: The pathogenesis of hypogonadism in liver cirrhosis is not well understood. Previous results from our laboratory showed that IGF-1 deficiency might play a pathogenetic role in hypogonadism of cirrhosis. The administration of IGF-1 for a short period of time reverted the testicular atrophy associated with advanced experimental cirrhosis. The aim of this study was to establish the historical progression of the described alterations in the testes, explore testicular morphology, histopathology, cellular proliferation, integrity of testicular barrier and hypophyso-gonadal axis in rats with no ascitic cirrhosis.
METHODS: Male Wistar rats with histologically-proven cirrhosis induced with carbon tetrachloride (CCl4) for 11 wk, were allocated into two groups (n = 12, each) to receive recombinant IGF-1 (2 μg/100 g.d, sc) for two weeks or vehicle. Healthy rats receiving vehicle were used as control group (n = 12).
RESULTS: Compared to controls, rats with compensated cirrhosis showed a normal testicular size and weight and very few histopathological testicular abnormalities. However, these animals showed a significant diminution of cellular proliferation and a reduction of testicular transferrin expression. In addition, pituitary-gonadal axis was altered, with significant higher levels of FSH (P < 0.001 vs controls) and increased levels of LH in untreated cirrhotic animals. Interestingly, IGF-1 treatment normalized testicular transferrin expression and cellular proliferation and reduced serum levels of LH (P = ns vs controls, and P < 0.01 vs untreated cirrhotic group).
CONCLUSION: The testicular barrier is altered from an early stage of cirrhosis, shown by a reduction of transferrin expression in Sertoli cells, a diminished cellular proliferation and an altered gonadal axis. The treatment with IGF-1 could be also useful in this initial stage of testicular disorder associated with compensated cirrhosis.
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Affiliation(s)
- Inma Castilla-Cortazar
- Department of Human Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
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15
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Bassanello M, De Palo EF, Lancerin F, Vitale A, Gatti R, Montin U, Ciarleglio FA, Senzolo M, Burra P, Brolese A, Zanus G, D'Amico DF, Cillo U. Growth hormone/insulin-like growth factor 1 axis recovery after liver transplantation: a preliminary prospective study. Liver Transpl 2004; 10:692-8. [PMID: 15108263 DOI: 10.1002/lt.20111] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Many studies on cirrhotic patients have shown that insulin-like growth factor 1 (IGF-1) plasma levels are related to the severity of liver dysfunction. This result suggests that IGF-1 is probably useful for monitoring liver function in the perioperative course of orthotopic liver transplantation (OLT). Growth hormone (GH), IGF-1 plasma levels, and routine liver function tests were measured in 15 adult cirrhotic patients undergoing OLT. Measurements were made at the beginning of the operation; during OLT; 24 hours after reperfusion; and in the morning on days 7, 30, and 90. Twenty age-matched healthy volunteers with normal liver function served as controls. The study group had significantly higher GH levels and lower IGF-1 levels in the preoperative period compared with the controls. All patients achieved a complete functional hepatic recovery 1 month after OLT, although in 6 of them, the graft had an initial poor function (Group-IPF). GH and IGF-1 levels achieved near normal range within 1 week after OLT, and they had no significant correlations with other routine biochemistry tests in this period. IGF-1 levels in Group-IPF rose more slowly than in the group with a normal recovery of graft function. Surprisingly, 24 hours after reperfusion, IGF-1 levels were higher in Group-IPF than in the group with normal graft function. In conclusion, the severe GH/IGF-1 axis impairment found in patients with end-stage cirrhosis reverted very rapidly in the first days after successful OLT. Such a quick, postoperative modulation of IGF-1 plasma level by the graft suggests that this hormone has the potential to become one of the early indicators of post-OLT liver function recovery.
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Affiliation(s)
- Marco Bassanello
- Clinica Chirurgica I, Dipartimento di Scienze Chirurgiche e Gastroenterologiche, University of Padua, School of Medicine, Padua, Italy
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Gnainsky Y, Spira G, Paizi M, Bruck R, Nagler A, Abu-Amara SN, Geiger B, Genina O, Monsonego-Ornan E, Pines M. Halofuginone, an inhibitor of collagen synthesis by rat stellate cells, stimulates insulin-like growth factor binding protein-1 synthesis by hepatocytes. J Hepatol 2004; 40:269-77. [PMID: 14739098 DOI: 10.1016/j.jhep.2003.10.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Halofuginone, an inhibitor of collagen synthesis, prevented and caused resolution of established hepatic fibrosis. A genomic approach in vivo was used to search for additional genes responsible for halofuginone mode of action. METHODS Fibrosis was induced in rats by thioacetamide (TAA) and evaluated by collagen type I gene expression and the levels of collagen, tissue inhibitors of metalloproteinases-2 and smooth-muscle actin. Halofuginone was given in the diet. cDNA from liver biopsies was hybridized on Atlas arrays comprising of 588 genes. The results were confirmed by Northern blots and in situ hybridization. RESULTS Insulin-like growth factor binding protein-1 (IGFBP-1) was one of the 13 genes differentially expressed in the fibrotic liver after halofuginone treatment. After 2 and 4 weeks, halofuginone prevented the TAA-induced down-regulation of IGFBP-1 gene expression. Halofuginone also prevented the TAA-dependent changes in IGFBP-3 gene expression. Halofuginone affected IGFBP-1 synthesis in rat hepatocytes and cells of hepatocyte origin and caused time- and dose-dependent increases in the IGFBP-1 gene expression and synthesis by HepG2 cells. The IGFBP-1 secreted by HepG2-inhibited stellate cell motility. CONCLUSIONS Halofuginone is an anti-fibrotic drug that inhibits collagen synthesis by stellate cells and preventing alteration in the synthesis of IGFBPs by hepatic cells.
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Affiliation(s)
- Yulia Gnainsky
- Institute of Animal Sciences, Agricultural Research Organization, the Volcani Center, PO Box 6, Bet Dagan 50250, Israel
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17
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García-Fernández M, Castilla-Cortázar I, Díaz-Sánchez M, Díez Caballero F, Castilla A, Díaz Casares A, Varela-Nieto I, González-Barón S. Effect of IGF-I on total serum antioxidant status in cirrhotic rats. J Physiol Biochem 2004; 59:145-6. [PMID: 14649879 DOI: 10.1007/bf03179879] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Affiliation(s)
- M García-Fernández
- Department of Human Physiology, School of Medicine, University of Málaga, Madrid, Spain
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Nøjgaard C, Johansen JS, Christensen E, Skovgaard LT, Price PA, Becker U. Serum levels of YKL-40 and PIIINP as prognostic markers in patients with alcoholic liver disease. J Hepatol 2003; 39:179-86. [PMID: 12873813 DOI: 10.1016/s0168-8278(03)00184-3] [Citation(s) in RCA: 117] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS YKL-40 (growth factor) and PIIINP (N-terminal propeptide of Type III procollagen) are potential markers of liver fibrosis. The aim was to evaluate the prognostic value of serum YKL-40 and PIIINP levels in patients with alcoholic liver disease. METHODS Three hundred and seventy patients with alcoholic liver disease were studied in a trial of malotilate with a median follow-up period of 470 days; 75 patients died; 336 patients had a liver biopsy on entry. Serum levels of YKL-40 and PIIINP were determined by radioimmunoassay (RIA). RESULTS Serum YKL-40 and PIIINP were elevated in the patients compared to controls. Patients with steatosis or no fibrosis had the lowest serum levels of YKL-40 and PIIINP, whereas patients with alcoholic hepatitis and/or cirrhosis had the highest levels. Serum YKL-40 was associated with the presence of fibrosis, and serum PIIINP was also associated with the different grades of fibrosis. Patients with elevated serum YKL-40 or PIIINP had shorter survival than patients with normal serum levels of YKL-40 (P<0.0001) or PIIINP (P=0.044). High degree of fibrosis predicted shorter survival (P=0.004). CONCLUSIONS Serum levels of YKL-40 and PIIINP are elevated in alcoholic patients, related to the presence of liver fibrosis and may provide prognostic information.
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Affiliation(s)
- Camilla Nøjgaard
- Department of Gastroenterology and Alcohol Unit, Hvidovre Hospital, Hvidovre, Denmark.
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Affiliation(s)
- Anders Juul
- Department of Growth and Reproduction, University of Copenhagen, Blegdamsvej 9 Rigshopitalet, Section 5064, Copenhagen 2100, Denmark.
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Alcohol-Induced Increases in Insulin-Like Growth Factor Binding Protein-1 Are Partially Mediated by TNF. Alcohol Clin Exp Res 2002. [DOI: 10.1097/00000374-200210000-00016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kumar V, Silvis C, Nystrom G, Deshpande N, Vary TC, Frost RA, Lang CH. Alcohol-Induced Increases in Insulin-Like Growth Factor Binding Protein-1 Are Partially Mediated by TNF. Alcohol Clin Exp Res 2002. [DOI: 10.1111/j.1530-0277.2002.tb02458.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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22
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Donaghy AJ, Delhanty PJD, Ho KK, Williams R, Baxter RC. Regulation of the growth hormone receptor/binding protein, insulin-like growth factor ternary complex system in human cirrhosis. J Hepatol 2002; 36:751-8. [PMID: 12044524 DOI: 10.1016/s0168-8278(02)00049-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS The liver is the central organ of the endocrine growth hormone/insulin-like growth factor I (GH/IGF-I) axis and cirrhosis effects a state of acquired GH resistance. Low IGF-I levels are associated with adverse clinical outcomes in cirrhotic patients and may be pathogenic to the complications of cirrhosis. We examined the impact of cirrhosis on hepatic mRNA and serum protein levels for the GH receptor (GHR)/binding protein (GHBP), IGF-I, IGF binding protein (IGFBP)-3 and the acid-labile subunit (ALS). METHODS Fifty patients with cirrhosis were studied and liver tissue was obtained from 18. Gene expression was assessed by Northern analysis and serum protein levels by immunoassay. RESULTS In cirrhotic liver GHR mRNA and GH binding to microsomal membranes were decreased by 61 and 56%, respectively. Serum GHBP levels were decreased only in severe disease, not correlating with GHR mRNA or GH binding. Hepatic IGF-I and ALS mRNA were significantly decreased by 84 and 68%, respectively, in parallel with serum protein, suggesting transcriptional regulation. Hepatic IGFBP-3 mRNA was unchanged but low serum IGFBP-3 suggested post-transcriptional regulation. CONCLUSIONS The decreased mRNA and serum levels for the GH-dependent, hepatocyte produced proteins IGF-I and ALS confirm the importance of GH receptor loss to the GH resistance of cirrhosis.
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Affiliation(s)
- Anthony J Donaghy
- Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia
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De Palo EF, Bassanello M, Lancerin F, Spinella P, Gatti R, D'Amico D, Cillo U. GH/IGF system, cirrhosis and liver transplantation. Clin Chim Acta 2001; 310:31-7. [PMID: 11485752 DOI: 10.1016/s0009-8981(01)00511-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The GH-related effects are primarily mediated by insulin-like growth factor I (IGF-I), a peptide hormone almost completely produced by the liver. Liver cirrhosis is usually accompanied by a fall in protein turnover. Furthermore, an important consequence of chronic liver disease (CLD) is growth hormone/insulin-like growth factor (GH/IGF) axis modification and growth failure. Nutritional status also suffers in this condition, and IGF-I has been proposed as a marker of hepatocellular dysfunction, malnutrition and survival. CLD is characterised by alterations of various clinical biochemistry laboratory parameters. Aminotransferases, bilirubin, plasma proteins, together with prothrombin time and gamma globulins, are usually examined for laboratory diagnostic and/or monitoring purposes. These traditional parameters are also used in the perioperative liver transplantation, but an early signal of graft functioning has still not been established. The aim of the present work is a review of the possibility offered by the clinical biochemistry laboratory GH/IGF investigation in the outcome of liver transplantation.
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Affiliation(s)
- E F De Palo
- Clinical Biochemistry, Department of Medical Diagnostic Sciences, University of Padova, Padua, Italy
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Anker SD, Volterrani M, Pflaum CD, Strasburger CJ, Osterziel KJ, Doehner W, Ranke MB, Poole-Wilson PA, Giustina A, Dietz R, Coats AJ. Acquired growth hormone resistance in patients with chronic heart failure: implications for therapy with growth hormone. J Am Coll Cardiol 2001; 38:443-52. [PMID: 11499736 DOI: 10.1016/s0735-1097(01)01385-7] [Citation(s) in RCA: 157] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVES We aimed to determine whether growth hormone (GH) resistance is present in patients with chronic heart failure (CHF) and whether it may be linked to the biochemical response to GH treatment. BACKGROUND Acquired GH resistance is a feature of severe illness, in particular, cachexia. In patients with CHF, the response to GH therapy appears to be variable. METHODS Biochemical markers of the GH-insulin-like growth factor-I (IGF-I) axis were compared in 21 cachectic patients with CHF, 51 noncachectic patients and 26 healthy control subjects. In separate studies, the predictive value of baseline biochemical variables for the IGF-I response to GH treatment was analyzed. RESULTS Cachectic patients showed an increase of total GH and immunologically intact GH (p < or = 0.0002) and a decrease of GH-binding protein (BP) (p = 0.005), IGF-BP3 (p = 0.01) and IGF-I (p = 0.06), compared with noncachectic patients. Similar changes were found when the cachectic group was compared with the control group. No differences were found between noncachectic patients and control subjects. Levels of GH-BP correlated with the IGF-I/GH ratio in all subgroups (all p < or = 0.002). Baseline GH-BP levels were related to the increase of IGF-I levels in response to GH treatment in patients with CHF after 24 h (r = 0.83, p = 0.005; n = 9; study 2), 44 days (r = 0.52, p = 0.007; n = 25; study 3) and 96 days (r = 0.54, p = 0.006; n = 24; study 3). CONCLUSIONS Most cachectic and some noncachectic patients with CHF show features of acquired GH resistance. The principal predictors of the biochemical features of GH resistance and of the poor biochemical response to short-term and longer-term GH treatment are GH-BP plasma levels. The presence of GH resistance is potentially a major factor determining the response to GH therapy in patients with CHF.
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Affiliation(s)
- S D Anker
- Franz-Volhard-Klinik, Max Delbrück Centrum for Molecular Medicine, Charité, Berlin, Germany.
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Muguerza B, Castilla-Cortázar I, García M, Quiroga J, Santidrián S, Prieto J. Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic rats. BIOCHIMICA ET BIOPHYSICA ACTA 2001; 1536:185-95. [PMID: 11406353 DOI: 10.1016/s0925-4439(01)00045-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Insulin-like growth factor-I (IGF-I) is produced mainly in the liver and it induces beneficial effects on the nutritional status, the liver function and oxidative hepatic damage in cirrhotic rats. The aim of this work was to analyze the effect of IGF-I on mechanisms of fibrogenesis in cirrhotic rats. Liver cirrhosis was induced by CCl(4) inhalation and phenobarbital in Wistar rats. Ten days after stopping CCl(4) administration (day 0), rats received either IGF-I (2 microg/100 g bw/day) (CI+IGF) or saline (CI) subcutaneously during 14 days. Animals were sacrificed on day 15. As control groups were used: healthy rats (CO) and healthy rats treated with IGF-I (CO+IGF). Liver histopathology, hydroxyproline content, prolyl hydroxylase activity, collagen I and III mRNA expression and the evolution of transformed Ito cells into myofibroblasts were assessed. Among the two control groups (CO+IGF), no differences were found in hydroxyproline content and these levels were lower than those found in the two cirrhotic groups. Compared with untreated cirrhotic rats, the CI+IGF-I animals showed a significant reduction in hydroxyproline content, prolyl hydroxylase activity and collagen alpha 1(I) and alpha1(III) mRNA expression. A higher number of transformed Ito cells (alpha-actin +) was observed in untreated cirrhotic animals as compared to CO and CI+IGF groups. In summary, treatment with IGF-I reduced all of the studied parameters of fibrogenesis. In conclusion, low doses of IGF-I induce in vivo an antifibrogenic effect in cirrhotic rats.
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Affiliation(s)
- B Muguerza
- Department of Physiology, School of Medicine and Liver Unit, University of Navarra, Pamplona, Spain
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Ormarsdóttir S, Mallmin H, Olofsson H, Blum WF, Lööf L. Circulating levels of insulin-like growth factors and their binding proteins in patients with chronic liver disease: lack of correlation with bone mineral density. LIVER 2001; 21:123-8. [PMID: 11318981 DOI: 10.1034/j.1600-0676.2001.021002123.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Insulin-like growth factor-I (IGF-I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF-I levels and BMD in patients with CLD of other causes. METHODS Fifty-eight patients with CLD were included. Age- and sex-matched normal individuals served as controls. Serum levels of IGF-I and IGF-II and their binding proteins (IGFBP-1-3) were measured by radioimmunoassay. BMD was measured by dual energy X-ray absorptiometry. RESULTS IGF-I levels were 57+/-33 and 136+/-48 ng/ml; p<0.0001 in patients and controls, respectively. IGF-II and IGFBP-3 levels were lower (p<0.0001) and IGFBP-1 and IGFBP-2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP-2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF-I, IGF-II, IGFBP-1-3 and BMD in either patients or controls. CONCLUSION Patients with CLD have low levels of IGF-I, IGF-II and IGFBP-3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.
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Affiliation(s)
- S Ormarsdóttir
- Department of Internal Medicine, University Hospital, Uppsala, Sweden.
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Santolaria F, Pérez-Manzano JL, Milena A, González-Reimers E, Gómez-Rodríguez MA, Martínez-Riera A, Alemán-Valls MR, de la Vega-Prieto MJ. Nutritional assessment in alcoholic patients. Its relationship with alcoholic intake, feeding habits, organic complications and social problems. Drug Alcohol Depend 2000; 59:295-304. [PMID: 10812289 DOI: 10.1016/s0376-8716(99)00129-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
To establish their ability to predict malnutrition, irregular feeding, alcoholic intake, derangement of social and familial links and organic complications (liver cirrhosis) were assessed in 181 hospitalized male alcoholic. BMI was under 18.5 kg/m(2) in 8.9%, between 18.5-20 kg/m(2) in 8.9%, 20-25 kg/m(2) in 42%, 25-30 kg/m(2) in 32.2% and over 30 kg/m(2) in 8.2% of patients. Malnutrition was related to the intensity of ethanol intake, development of social or familial problems, irregularity of feeding habits and cirrhosis with ascites. Irregularity of feeding habits was also related to heavy drinking and to social or familial derangement. By logistic regression analysis, the only variables which independently predict malnutrition were irregular feeding habits and liver cirrhosis with ascites. In a second step, irregular feeding was dependent on social or familial troubles and daily intake of ethanol. So, malnutrition related to alcoholism seems multifactorial in its pathogenesis.
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Affiliation(s)
- F Santolaria
- Servicio de Medicina Interna, Hospital Universitario de Canarias, Universidad de La Laguna, Tenerife, Spain
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Castilla-Cortazar I, Garcia M, Quiroga J, Diez N, Diez-Caballero F, Calvo A, Diaz M, Prieto J. Insulin-like growth factor-I reverts testicular atrophy in rats with advanced cirrhosis. Hepatology 2000; 31:592-600. [PMID: 10706548 DOI: 10.1002/hep.510310308] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The pathogenesis of hypogonadism in cirrhosis is not completely understood. The levels of insulin-like growth factor-I (IGF-I), an anabolic factor with trophic actions on testes, are reduced in cirrhosis. This study was undertaken to evaluate whether rats with advanced cirrhosis develop hypogonadism and whether the administration of IGF-I exerts beneficial effects on testicular structure and function. Wistar rats with ascitic cirrhosis induced with CCl(4) were allocated into 2 groups (n = 10, each) to receive recombinant IGF-I (20 microg x kg(-1) x d(-1), subcutaneously) or vehicle for 3 weeks. Healthy rats receiving vehicle were used as the control group (n = 10). At baseline, both cirrhotic groups showed similar deterioration of liver function tests. Compared with controls, nontreated cirrhotic rats showed decreased serum levels of IGF-I (P <.05), reduced testicular size and weight (P <.001), and intense histopathological testicular abnormalities, including reduced tubular diameters (P <.001), loss of the germinal line (P <. 001), and diminutions in cellular proliferation, spermatogenesis (P <.001), and testicular transferrin expression (P <.001). In addition, low serum testosterone (P <.01) and high serum LH (P <.01) were present in untreated cirrhotic animals. Cirrhotic rats that received IGF-I showed full recovery of testicular size and weight and of all histopathological abnormalities (P <.001 to <.01 vs. nontreated cirrhotic rats; P = ns vs. controls). Serum levels of sex hormones tended to normalize. In conclusion, IGF-I deficiency may play a pathogenetic role in hypogonadism of cirrhosis. Low doses of IGF-I for a short period of time revert testicular atrophy and appear to improve hypogonadism in advanced experimental cirrhosis.
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Affiliation(s)
- I Castilla-Cortazar
- Department of Physiology, Liver Unit, University of Navarra, Pamplona, Spain.
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29
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Møller S, Juul A, Becker U, Henriksen JH. The acid-labile subunit of the ternary insulin-like growth factor complex in cirrhosis: relation to liver dysfunction. J Hepatol 2000; 32:441-6. [PMID: 10735614 DOI: 10.1016/s0168-8278(00)80395-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS In the circulation, insulin-like growth factor-I (IGF-I) is bound in a trimeric complex of 150 kDa with IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). Whereas circulating IGF-I and IGFBP-3 are reported to be low in patients with chronic liver failure, the level of ALS has not been described in relation to hepatic dysfunction. The aim of the present study was therefore to measure circulating and hepatic venous concentrations of ALS in relation to hepatic function and the IGF axis. METHODS Twenty-five patients with cirrhosis (Child class A/B/C:5/10/10) and 30 controls with normal liver function were studied. During a haemodynamic investigation, blood samples were collected from the hepatic vein and femoral artery, and the plasma concentrations of ALS, IGF-I and IGFBP-3 were determined. RESULTS Hepatic venous and arterial concentrations of ALS were significantly decreased in the cirrhotic patients compared with the controls (-69% and -68%, respectively, both p<0.001). IGF-I and IGFBP-3 were similarly decreased in the cirrhotic patients (-51%,p<0.001). A significant hepatic extraction of ALS was found in the controls (6%, p<0.01) and in the cirrhotic patients (8%, p=0.08). ALS correlated significantly with indicators of liver dysfunction, including the Child-Turcotte score (r=-0.69, p<0.0001), IGF-I (r=0.82, p<0.0001) and IGFBP-3 (r=0.74, p<0.0001). CONCLUSIONS Circulating and hepatic venous ALS are decreased in patients with cirrhosis with significant relations to liver dysfunction and other components of the IGF complex. A small hepatic extraction was found in controls, which suggests extrahepatic production of ALS. Future studies should focus on organ-specific removal of ALS.
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Affiliation(s)
- S Møller
- Department of Clinical Physiology, Herlev Hospital, Denmark,
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30
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Caregaro L, Alberino F, Gatta A. État nutritionnel des patients avec maladies du foie : épidémiologie et pronostic. NUTR CLIN METAB 1999. [DOI: 10.1016/s0985-0562(99)80051-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Abstract
Breast cancer risk in women rises with increasing alcohol intake and is widely assumed to be mediated by increased oestrogen concentrations. However, observations that mechanisms and risk are likely to differ between pre- and postmenopausal women suggest that the postmenopausal disease in particular, may involve a promoting role for concomitants of hyperinsulinaemia which is commonly associated with alcoholic cirrhosis of the liver. The MEDLINE database and ongoing studies were examined for clinical, epidemiological and laboratory data on; (a) alcohol-related increase in the incidence of breast cancer in relation to menopausal status, oestrogen concentrations and the oestrogen receptor (ER) status of the tumour; (b) activation of insulin-like growth factor 1 receptor (IGF1R) in mammary tissue by alcohol-related hyperinsulinaemia; (c) interaction between ER and IGF1R in breast cancer cell systems. Epidemiological association between alcohol intake and increased breast cancer risk is more clearly seen in postmenopausal than premenopausal women, and a significant risk is associated with intake of more than two drinks (over 30 g) daily over a period of years. Alcohol-related hyperinsulinaemia is reported to increase with increasing degrees of cirrhosis and damage to liver function. Laboratory evidence suggests that hyperinsulinaemia can stimulate expression of IGF1R in mammary tissue, and this protein is likely to have a crucial role in mitogenesis and transformation to an oestrogen-independent malignant phenotype. It is postulated that in women with a history of long-term intake of moderate quantities of alcohol, the concomitants of hyperinsulinaemia may help to stimulate progression in precancerous breast lesions in the years leading up to the menopause and may increase the risk of breast cancer manifesting after the menopause.
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Affiliation(s)
- B A Stoll
- Oncology Department, St Thomas' Hospital, London, U.K
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Passilta M, Kervinen K, Kesäniemi YA. Glucose metabolism, insulin-like growth factor-I, and insulin-like growth factor-binding protein-1 after alcohol withdrawal. Alcohol Clin Exp Res 1999; 23:471-5. [PMID: 10195820 DOI: 10.1111/j.1530-0277.1999.tb04139.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Alcohol abusers often present with deteriorated glucose metabolism and insulin resistance. Changes in other glucoregulators, such as insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) may also be related to alcohol abuse. We studied the effects of alcohol withdrawal on blood glucose, serum insulin and C-peptide, and plasma IGF-I and IGFBP-1 levels in 27 noncirrhotic male alcoholics aged 43 +/- 9.0 (mean +/- SD) years on four consecutive days immediately after withdrawal. A 4-day monitoring period was conducted in four healthy nonalcoholic control men. The groups were similar in age and body mass index. Glucose, insulin, IGF-I, and IGFBP-1 did not differ significantly between the groups at the baseline, but C-peptide was higher in alcoholics (p < 0.01). After alcohol withdrawal, serum insulin and C-peptide levels increased in close correlation with each other (r = 0.82, p < 0.001). During the 4-day observation period in alcoholics, IGFBP-1 levels declined by 59%, whereas IGF-I increased by 41% (p < 0.001 for both comparisons). The change in insulin correlated inversely with the change in IGFBP-1 levels (r = -0.39, p < 0.05). In the control group, glucose, insulin, IGF-I, and IGFBP-1 remained unchanged during the 4-day monitoring period, whereas some reduction was observed in C-peptide. In conclusion, alcohol withdrawal enhances insulin production, as seen in increased C-peptide levels. An inverse correlation between the changes in insulin and that in IGFBP-1 might suggest that inhibition of IGFBP-1 by insulin remains largely unchanged during the acute phase of alcohol withdrawal.
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Affiliation(s)
- M Passilta
- Department of Internal Medicine and Biocenter Oulu, University of Oulu, Finland
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Caregaro L, Alberino F, Angeli P, Gatta A. Insulin-like growth factor 1 (IGF-1) in liver cirrhosis: a marker of hepatocellular dysfunction? J Hepatol 1998; 29:342. [PMID: 9722219 DOI: 10.1016/s0168-8278(98)80023-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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Assy N, Hochberg Z, Enat R, Baruch Y. Prognostic value of generation of growth hormone-stimulated insulin-like growth factor-I (IGF-I) and its binding protein-3 in patients with compensated and decompensated liver cirrhosis. Dig Dis Sci 1998; 43:1317-21. [PMID: 9635625 DOI: 10.1023/a:1018828412631] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Our aim was to study the prognostic value of growth hormone (GH) -stimulated insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) generation in patients with compensated [group 1 (N = 8) with a Child-Pugh (CP) score of 5-8] and decompensated postnecrotic liver cirrhosis [group 2 (N = 7) with a CP score of 9-12]. Serum levels of IGF-I, GH-binding protein (GHBP), and IGFBP-3 were measured before and 24 hr after a single subcutaneous injection of recombinant human GH (rhGH, 0.14 units/kg). Patients (mean age 56 years) were followed prospectively for three years. Six patients (40%) died during the follow-up period, of whom half had a CP score <9. Mean serum IGF-I levels 24 hr after rhGH injection (group 1 vs group 2, 17.4 +/- 6.8 vs 7.4 +/- 0.7 nmol/liter) predicted survival with 93% accuracy. Levels <10 nmol/liter portended a poor prognosis, with 15% survival at one year, whereas levels >10 nmol/liter had a 100% survival rate at one and two years, respectively. Baseline IGF-I (9.98 +/- 2.0 vs 6.38 +/- 0.8 nmol/liter), GHBP (9.2 +/- 3 vs 5.7 +/- 0.8%/50 microl), and IGFBP-3 serum levels at baseline (1.7 +/- 0.3 vs 0.86 +/- 0.2 mg/liter) and at 24 hr (2.04 +/- 0.38 vs 0.99 +/- 0.3 mg/liter) did not add to the predictive value of stimulated IGF-I levels at 24 hr and were less accurate in predicting the outcome in comparison to CP score (80%). We conclude that stimulated IGF-1 <10 nmol/liter may be a true predictor of a negative prognosis in patients with liver cirrhosis.
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Affiliation(s)
- N Assy
- Department of Medicine B, The Liver Unit, Rambam Medical Center, Haifa, Israel
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Juul A, Holm K, Kastrup KW, Pedersen SA, Michaelsen KF, Scheike T, Rasmussen S, Müller J, Skakkebaek NE. Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency. J Clin Endocrinol Metab 1997; 82:2497-502. [PMID: 9253324 DOI: 10.1210/jcem.82.8.4137] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-I circulates in its free form, which is believed to be the biologically active form. However, our knowledge of the clinical or physiological value of determination of free IGF-I in serum is limited at present. In adults, the diagnostic value of total IGF-I and IGFBP-3 determinations in patients suspected of GHD has only been reported in a few studies, whereas no previous reports on the diagnostic value of free IGF-I levels in adults suspected of GHD exist. Serum levels of free IGF-I were determined in 1430 healthy children, adolescents, and adults by a newly developed, commercially available immunoradiometric assay (Diagnostic Systems Laboratories) to establish valid normative data for this analysis. We studied the diagnostic value of free IGF-I in relation to total IGF-I and IGFBP-3 determinations in adults who were suspected of GHD. A GH provocative test, using oral clonidine, was performed in 108 adult patients who had previously been treated with GH in childhood. In healthy subjects, free IGF-I levels increased during childhood, with the highest mean values during puberty. After puberty, a subsequent decline in serum levels of free IGF-I was apparent. We found, unmeasurable free IGF-I values in 34 of the prepubertal children (3.3%). All individuals over 8 yr of age had measurable free IGF-I levels that amounted to approximately 1% of the total IGF-I concentrations. Free IGF-I levels were below--2 SD in 56 of 79 GHD patients (sensitivity, 71%) and above--2 SD in 24 of 29 patients with a normal GH response (specificity, 83%). Multiple linear regression analysis demonstrated that free IGF-I was significantly dependent on peak GH levels, duration of the disease, and number of other pituitary axes affected. We conclude that free IGF-I serum levels increase during childhood with a peak in puberty, whereafter free IGF-I levels return to prepubertal levels. Three percent of healthy prepubertal children had unmeasurable free IGF-I levels using this assay. We found that determination of the free IGF-I serum concentration may predict the outcome of a GH provocative test in adults suspected of GHD, but that a single determination of free IGF-I offered no significant advantage compared to determination of total IGF-I or IGFBP-3 serum levels.
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Affiliation(s)
- A Juul
- Department of Growth and Reproduction, National University Hospital, Copenhagen, Denmark
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Juul A, Møller S. IGF-I in chronic liver disease: a marker of hepatocellular dysfunction, malnutrition, and survival? Nutrition 1997; 13:231-2. [PMID: 9131686 DOI: 10.1016/s0899-9007(96)00407-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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