Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction

Assy, Nimer; Pruzansky, Yosef; Gaitini, Diana; Orr, Zila Shen; Hochberg, Zèev; Baruch, Yaacov

doi:10.1016/j.jhep.2008.02.013

Cited by 61 publications

(57 citation statements)

References 51 publications

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“…Animal experiments show that the majority of the circulating IGF1 pool and IGFBPs originates from the liver (35,36). The reduction in metabolic liver function after TIPS, as measured by the decrease in GEC, may explain the lack of change in circulating IGF1 after TIPS (37). Another possible explanation is related to the fact that the production of key components of the growth factor system is also nutritionally regulated (38).…”

Section: Discussionmentioning

confidence: 99%

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis

Holland-Fischer¹,

Vilstrup²,

Frystyk³

et al. 2009

European Journal of Endocrinology

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Objective: Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) into patients with liver cirrhosis usually induces a gain in body cell mass. Changes in the IGF system in favor of anabolism may be involved. We, therefore measured blood concentrations of the components of the IGF system in cirrhosis patients before and after elective TIPS. Design and methods: The study comprised 17 patients and 11 healthy controls. Patients were examined before and 1, 4, 12, and 52 weeks after TIPS. Biochemical analyses of the IGF system were compared with changes in body composition (bioimpedance analysis), glucose and insulin, and metabolic liver function (galactose elimination capacity). Results: After TIPS, body cell mass rose by 3.2 kg (95% confidence interval (CI): 1.0-5.5) at 52 weeks, in correlation with baseline liver function (r 2 Z0.22; PZ0.03). Peripheral blood concentrations of total IGF1 and 2, bioactive IGF1, and the IGF-binding proteins (IGFBP-1, -2, and -3) remained unchanged throughout the study period. There was no change in fasting glucose, whereas fasting insulin rose by 40% (CI: 11-77%) and glucagon by 58% (CI: 11-132%) from baseline to 52 weeks after TIPS. Conclusion: Our data confirm that TIPS was associated with an increase in body cell mass in patients with liver cirrhosis, but without any change in the circulating IGF system. Thus, the results do not support the notion that effects on the circulating IGF system are involved in the anabolic effects of TIPS insertion.

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Section: Discussionmentioning

confidence: 99%

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis

Holland-Fischer¹,

Vilstrup²,

Frystyk³

et al. 2009

European Journal of Endocrinology

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“…However, the relevance of the IGF system, especially IGF-I, to hepatocellular carcinoma is somewhat different from other malignancies. Because the majority of circulating IGF-I is produced by the liver, the levels of IGF-I reflect hepatic function and are inversely correlated with the severity of background chronic liver disease (8,9). In addition, recent study has shown that a decrease in serum IGF-I levels is associated with the development of hepatocellular carcinoma, independent of the grade of hepatic dysfunction (10).…”

Section: Introductionmentioning

confidence: 99%

Serum Insulin-like Growth Factor-I Level Is an Independent Predictor of Recurrence and Survival in Early Hepatocellular Carcinoma: A Prospective Cohort Study

Cho

Lee

Yoo

et al. 2013

Clinical Cancer Research

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Purpose: Insulin-like growth factor-I (IGF-I) reflects hepatic synthetic function and plays an important role in the development and progression of various cancers. In this study, we investigated whether pretreatment serum IGF-I levels predict time-to-recurrence (TTR) and overall survival (OS) in patients with early-stage hepatocellular carcinoma after curative treatment.Experimental Design: Consecutive patients with hepatocellular carcinoma who had undergone surgical resection, radiofrequency ablation, or percutaneous ethanol injection as curative treatments of early hepatocellular carcinoma were included from two prospective cohorts and the training set (n ¼ 101) and the validation set (n ¼ 91) were established. Serum samples were collected before treatment and the levels of IGF-I and IGF-binding protein-3 (IGFBP-3) were analyzed with regard to their associations with recurrence and survival.Results: In the training set, patients with low IGF-I levels showed significantly shorter TTR [median, 14.6 months; 95% confidence interval (CI), 1.8-27.5] than patients with high IGF-I levels (median, 50.8 months; 95% CI, 36.9-64.7; P < 0.001) during a median follow-up period of 52.4 months. In the multivariate analysis, low levels of IGF-I were an independent predictor of recurrence (HR, 2.49; 95% CI, 1.52-4.08; P < 0.001). Furthermore, together with high-serum a-fetoprotein and multiple tumors, low levels of IGF-I remained an independent predictor of poorer survival (HR, 8.00; 95% CI, 1.94-33.01; P ¼ 0.004). Applied to the independent validation set, low-serum IGF-I levels maintained their prognostic value for shorter TTR and OS.Conclusions: Low-baseline IGF-I levels independently correlated with shorter TTR and poorer survival in patients with early-stage hepatocellular carcinoma after curative treatment. Clin Cancer Res; 19(15); 4218-27. Ó2013 AACR.

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“…Once released from IGFBPs, IGF1 can bind and activate the receptor (IGF1R), and by activation of mitogen activated protein (MAP) kinase and PI3 kinase induce genes involved in cell survival, growth, and differentiation [6]. Liver fibrosis reduces the IGF1 expression in the liver [7,8]. Administration of recombinant IGF1 or enhancing IGF1 expression using a viral vector significantly reduced liver fibrosis in rats with CCl 4 -induced liver cirrhosis [9,10].…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

Sokolović¹,

Rodríguez‐Ortigosa²,

Bloemendaal³

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4(-/-) mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4(-/-) mice, and compared to that of Abcb4(-/-) littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4(-/-) mice resulted in stimulation of fibrogenic processes - as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.

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Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction

Cited by 61 publications

References 51 publications

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis

Serum Insulin-like Growth Factor-I Level Is an Independent Predictor of Recurrence and Survival in Early Hepatocellular Carcinoma: A Prospective Cohort Study

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

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