Identification of growth differentiation factor 15 as a pro‐fibrotic factor in mouse liver fibrosis progression

Type 3 innate lymphoid cell (ILC3) has recently emerged as a crucial effector in inflammatory and fibrotic diseases. The present study was designed to determine the roles of ILC3 in liver fibrosis. By flow cytometry, we documented increased frequencies of peripheral ILC3 (Lin−CD127+CD117+CD294− lymphocytes) in patients, especially at the advanced stage of hepatitis B virus (HBV)-related chronic liver diseases, and demonstrated their correlations with disease progression. The in vitro fibrogenic effects by ILC3 were determined by co-culture experiments with LX-2 (a human hepatic stellate cell (HSC) line). The data indicate that pathogenic ILC3 can directly promote LX-2 fibrogenesis in non-contact manners by producing interleukin (IL)-17A and IL-22. Additionally, they had indirect fibrogenic effects by producing IL-22 to suppress interferon (IFN)-γ (a well-known anti-fibrotic cytokine) production by other immune cells. In carbon tetrachloride (CCl4)-induced wild-type mouse liver fibrosis models, we also documented significantly increased frequencies of both non-natural killer (NK) ILC (Lin−CD127+ lymphocytes) and ILC3 (Lin−CD127+RORγt+ lymphocytes) in liver and spleen specimens. Furthermore, the ILC3 from fibrotic mice contained more IL-17A+ILC3 and IL-22+ILC3 subsets than those from normal and less-fibrotic mice. The in vivo effects of ILC3 in liver fibrogenesis were further determined using RAG-1−/− mice with ILC depletion and further adoptive transfer of ILC3 from wild-type mice. The immunohistochemical staining of liver specimens showed the beneficial effects by ILC depletion and the detrimental effects by ILC3 transfer in CCl4-induced mouse liver fibrosis models. Collectively, ILC3 plays a pro-fibrotic role in liver fibrosis progression.

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Growth differentiation factor 15: an emerging diagnostic biomarker of liver fibrosis in chronic hepatitis C patients

Egyptian Liver Journal ◽

10.1186/s43066-021-00075-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Heba M. Adel Abou Zaghla ◽

Aziza Ahmed El Sebai ◽

Ossama Ashraf Ahmed ◽

Ayat Fawzy Ahmed ◽

Azza Abdel Rahman Saab

Keyword(s):

Hepatitis C ◽

Liver Fibrosis ◽

Early Detection ◽

Significant Positive Correlation ◽

Serum Levels ◽

Health Concern ◽

Growth Differentiation Factor 15 ◽

Positive Correlation ◽

Differentiation Factor ◽

Chronic Hcv

Abstract Background Chronic liver disease and cirrhosis are of the major health concern worldwide. Assessment of liver fibrosis is necessary to determine disease severity and prognosis at the time of presentation to determine suitable treatment. Liver biopsy is considered as standard golden method in diagnosis of liver fibrosis. However, this procedure is invasive; thus, multiple laboratory and radiologic tests are used to help determination of the degree of fibrosis. Growth differentiation factor 15 (GDF-15) is a pleiotropic cytokine involved in regulating inflammatory and apoptotic pathways. It is suggested that GDF-15 plays an important role in pathogenesis of liver fibrosis. In this study, we aimed to evaluate efficiency of growth differentiation factor 15 in diagnosing liver fibrosis. The study was a case-control study conducted on 55 chronic HCV patients recruited from hepatitis C virus clinic at Faculty of Medicine Ain Shams Research Institute (MASRI), and 30 healthy subjects age- and sex-matched. The patients were classified into three subgroups according to the degree of liver fibrosis assessed by fibro-scan. Serum concentration of GDF-15 was determined by enzyme-linked immunosorbent assay. Results Our results revealed a highly significant statistical rise in GDF-15 levels among studied chronic HCV patients with liver fibrosis when compared to the control group (p < 0.01). Furthermore, there was a significant positive correlation between the degree of fibrosis assessed by fibro-scan and GDF-15 serum levels. Levels of GDF-15 were significantly higher in patients with mild degree of fibrosis (patients’ subgroup І) when compared with the controls’ group (p < 0.01) suggesting the role of this marker in early detection of liver fibrosis. A statistically significant increase in serum GDF-15 levels was noticed among patients with advanced fibrosis “subgroup ІІІ” compared to those with mild fibrosis “subgroup І” (p < 0.05). The diagnostic sensitivity and specificity of GDF-15 were 96.7%, 98.2%, respectively at a cut-off value of 150 ng/L for discrimination between patients’ and controls’ groups. Conclusion Growth differentiation factor 15 could be a potential marker of liver fibrosis especially in early detection as its levels were significantly higher in patients’ group with liver fibrosis than controls’ group and there was a significant positive correlation between the degree of liver fibrosis and GDF-15 serum levels.

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Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD

Nutrition and Diabetes ◽

10.1038/s41387-021-00170-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Josh Bilson ◽

Eleonora Scorletti ◽

Laure B. Bindels ◽

Paul R. Afolabi ◽

Giovanni Targher ◽

...

Keyword(s):

Type 2 Diabetes ◽

Liver Fibrosis ◽

Transient Elastography ◽

Characteristic Curve ◽

Test Statistic ◽

Alcoholic Fatty Liver ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

The Relationship

Abstract Background Type 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis. We aimed to investigate (a) whether GDF-15 concentrations were associated with liver fibrosis and involved in the relationship between T2DM and liver fibrosis and (b) what factors linked with T2DM are associated with increased GDF-15 concentrations. Methods Ninety-nine patients with NAFLD (61% men, 42.4% T2DM) were studied. Serum GDF-15 concentrations were measured by electro-chemiluminescence immunoassay. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. Regression modelling, receiver operator characteristic curve analysis and Sobel test statistics were used to test associations, risk predictors and the involvement of GDF-15 in the relationship between T2DM and liver fibrosis, respectively. Results Patients with NAFLD and T2DM (n = 42) had higher serum GDF-15 concentrations [mean (SD): 1271.0 (902.1) vs. 640.3 (332.5) pg/ml, p < 0.0001], and a higher proportion had VCTE assessed ≥F2 fibrosis (48.8 vs. 23.2%, p = 0.01) than those without T2DM. GDF-15 was independently associated with liver fibrosis (p = 0.001), and GDF-15 was the most important single factor predicting ≥F2 or ≥F3 fibrosis (≥F2 fibrosis AUROC 0.75, (95% CI 0.63–0.86), p < 0.001, with sensitivity, specificity, positive predictive (PPV) and negative predictive (NPV) values of 56.3%, 86.9%, 69.2% and 79.1%, respectively). GDF-15 was involved in the association between T2DM and ≥F2 fibrosis (Sobel test statistic 2.90, p = 0.004). Other factors associated with T2DM explained 60% of the variance in GDF-15 concentrations (p < 0.0001). HbA1c concentrations alone explained 30% of the variance (p < 0.0001). Conclusions GDF-15 concentrations are a predictor of liver fibrosis and potentially involved in the association between T2DM and liver fibrosis in NAFLD. HbA1c concentrations explain a large proportion of the variance in GDF-15 concentrations.

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Growth Differentiation Factor 15: An Emerging Diagnostic Biomarker of Liver Fibrosis in Chronic Hepatitis C Patients

QJM ◽

10.1093/qjmed/hcab091.001 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Aziza Ahmed El Sebai ◽

Ossama Ashraf Ahmed ◽

Azza Abdel Rahman Saab ◽

Heba M Adel Abou Zaghla ◽

Gina Gamal Naguib ◽

...

Keyword(s):

Hepatitis C ◽

Liver Fibrosis ◽

Early Detection ◽

Significant Positive Correlation ◽

Serum Levels ◽

Health Concern ◽

Growth Differentiation Factor 15 ◽

Positive Correlation ◽

Differentiation Factor ◽

Chronic Hcv

Abstract Background Chronic liver disease and cirrhosis are a major health concern worldwide being the sixth leading cause of all-cause mortality in people aged 25–64 years. Assessment of liver fibrosis is necessary to determine disease severity and prognosis at the time of presentation to determine suitable treatment. The gold standard method of diagnosis is liver biopsy; however, this procedure is invasive; thus, multiple laboratory and radiologic tests are used to help determine the degree of fibrosis. Growth differentiation factor 15 (GDF-15) is a pleiotropic cytokine involved in regulating inflammatory and apoptotic pathways. It plays a role in cardiovascular disease, inflammation, body weight regulation and cancer. It is suggested that GDF-15 plays an important role in pathogenesis of liver fibrosis. Aim of the Work In this study we aimed to evaluate efficiency of growth differentiation factor 15 in diagnosing liver fibrosis. Patients and Methods The study was a case- control study conducted on 55 chronic HCV patients recruited from Hepatitis C virus Clinic at Faculty of Medicine Ain Shams Research Institute (MARSI), and 30 healthy subjects age and sex matched. The patients were classified into three subgroups according to the degree of liver fibrosis assessed by fibro-scan. Serum concentration of GDF-15 was determined by enzyme-linked immunosorbent assay (ELISA). Results Results of our study revealed a highly significant statistical rise in GDF-15 levels among studied chronic HCV patients with liver fibrosis when compared to the control group (p < 0.01). Furthermore, there was a significant positive correlation between the degree of fibrosis assessed by fibro-scan and GDF-15 serum levels. Levels of GDF-15 were significantly higher in patients with mild degree of fibrosis (patients’ subgroup І when compared with the controls’ group (p < 0.01) suggesting the role of this marker in early detection of liver fibrosis. A statistically significant increase in serum GDF-15 levels was noticed among patients with advanced fibrosis “subgroup ІІІ” compared to those with mild fibrosis “subgroup І” (p < 0.05). The diagnostic sensitivity and specificity of GDF-15 were 96.7%, 98.2%, respectively at a cutoff value of 150 ng/L for discrimination between patients’ and controls’ groups. Conclusion Growth differentiation factor 15 could be a potential marker of liver fibrosis especially in early detection as its levels were significantly higher in patients’ group with liver fibrosis than controls’ group and there was a significant positive correlation between the degree of liver fibrosis and GDF-15 serum levels.

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