Telomere dysfunction in peripheral blood mononuclear cells from patients with primary biliary cirrhosis

Invernizzi, Pietro; Bernuzzi, Francesca; Lleo, Ana; Pozzoli, V.; Bignotto, Monica; Zermiani, P.; Crosignani, Andrea; Battezzati, Pier Maria; Zuin, Massimo; Podda, Mauro; Raggi, Chiara

doi:10.1016/j.dld.2013.11.008

Cited by 14 publications

(12 citation statements)

References 42 publications

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“…Apart from determination on RTL in COPD, a recent study by Udomsinprasert et al 11 investigated RTL in blood leukocyte of biliary atresia (BA) being chronic liver disease and reported that RTL was significantly reduced in BA patients, especially those with advanced-stage. This previous finding is consistent with a prior study, which noted telomere shortening in primary biliary cirrhosis patients with advanced-stage compared with healthy controls 21 . All above-mentioned findings led us to speculate that alterations in telomere length in blood leukocyte would reflect the impartment of hepatic function caused by stress and inflammation, and blood leukocyte RTL may have a diagnostic value as a novel biomarker indicating ATDILI progression in tuberculosis patients.…”

Section: Discussionsupporting

confidence: 93%

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

Udomsinprasert

Chanhom

Suvichapanich

et al. 2020

Sci Rep

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Despite being relatively rare, anti-tuberculosis drug-induced liver injury (AtDiLi) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for AtDiLi. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with AtDiLi outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age-and gendermatched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RtL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after antituberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RtL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RtL as a novel indicator for AtDiLi progression (AUc = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by antituberculosis agents and might have a potential biomarker for early AtDiLi progression.Tuberculosis is a chronic respiratory infectious disease and a leading cause of morbidity and mortality worldwide. The disease is characterized by Mycobacterium tuberculosis (MTB) infection usually affecting the lungs, leading to severe coughing, fever, and chest pains 1 that mimic features of other pathologies, thereby becoming a major public health problem. Currently, standard treatment regimens for tuberculosis patients consist of isoniazid, rifampicin, pyrazinamide, and ethambutol that shorten the treatment period and enhance the therapeutic efficacy 2 . However, these anti-tuberculosis agents have been reported to be the most important causative drug-induced liver injury (DILI) in much of developing world 3 , ultimately leading to irreversible liver failure. Despite refined usage of traditional liver biomarkers including serum enzyme activities of aminotransferases and bilirubin levels 4 , these biomarkers are inadequate for early identification of DILI, and alterations in those conventional tools are not mechanistically informative. For these reasons, it would seem more appropriate to identify and develop new more sensitive and specific DILI biomarkers, which may be he...

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Section: Discussionsupporting

confidence: 93%

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

Udomsinprasert

Chanhom

Suvichapanich

et al. 2020

Sci Rep

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“…In summary, our study suggests the potential role of TA in non-neoplastic liver. This finding gained support from the work of Invernizzi et al , who also found that since numerous lymphocytes were activated and differentiated continuously in patients with early-stage of primary biliary cirrhosis, TA in peripheral blood mononuclear cells (PBMCs) was higher than that in healthy subjects 51 . Besides, Gizard et al demonstrated that telomerase was significantly activated in the development of atherosclerosis 29 .…”

Section: Discussionmentioning

confidence: 66%

Telomerase reverse transcriptase acts in a feedback loop with NF-κB pathway to regulate macrophage polarization in alcoholic liver disease

Yang

et al. 2016

Sci Rep

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Activation of Kupffer cells (KCs) plays a central role in the pathogenesis of alcoholic liver disease (ALD). C57BL/6 mice fed EtOH-containing diet showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Since telomerase activation occurs at critical stages of myeloid and lymphoid cell activation, we herein investigated the role of telomerase reverse transcriptase (TERT), the determining factor of telomerase, in macrophage activation during ALD. In our study, TERT expression and telomerase activity (TA) were remarkably increased in liver tissue of EtOH-fed mice. Moreover, EtOH significantly up-regulated TERT in isolated KCs and RAW 264.7 cells and LPS induced TERT production in vitro. These data indicate that up-regulation of TERT may play a critical role in macrophages during ALD. Furthermore, loss- and gain-of-function studies suggested that TERT switched macrophages towards M1 phenotype by regulating NF-κB signaling, but had limited effect on M2 macrophages polarization in vitro. Additionally, PDTC, a chemical inhibitor of NF-κB, could dramatically down-regulate TERT expression and the hallmarks of M1 macrophages. Therefore, our study unveils the role of TERT in macrophage polarization and the cross-talk between TERT and p65, which may provide a possible explanation for the ethanol-mediated hepatic proinflammatory response and M1 macrophage polarization.

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“…The findings from our study, however, are partially in accordance with the previous research of Invernizzi and colleagues. They found that telomere length in peripheral blood mononuclear cells was not significantly different between patients with primary biliary cirrhosis (PBC) and unaffected volunteers; whereas, an excessive telomere shortening was observed in the advanced stage PBC patients, as compared to healthy controls [ 19 ]. The reason for this discrepancy remains unexplained.…”

Section: Discussionmentioning

confidence: 99%

Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia

et al. 2015

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ObjectiveThe purpose of this study was to investigate the association of telomere length in peripheral blood leukocytes with the severity of biliary atresia (BA).MethodsOne hundred and fourteen BA patients and 114 age-matched healthy controls were enrolled. Relative telomere length (RTL) was assessed using a quantitative real-time polymerase chain reaction. Multivariate regression analysis was used to estimate RTL as an independent risk factor of BA. Receiver operating characteristic curve analysis was used to calculate the accuracy of biomarkers in the prediction of liver cirrhosis.ResultsBA patients had significantly shorter telomeres than healthy controls (p < 0.0001). The RTL in BA patients with jaundice was considerably lower than that of patients without jaundice (p = 0.005). Moreover, RTL was markedly shorter in patients with cirrhosis (F4), as compared to patients with mild fibrosis (F2) and non-fibrosis (F0-F1, p < 0.0001). Logistic regression analysis indicated that short RTL was associated with a higher risk of liver cirrhosis in BA. Tertile analysis showed a dose-response effect for this association (p trend < 0.0001). Additionally, RTL in BA children revealed a negative correlation with age (r = -0.50, p < 0.001). We noted an association between reduction of RTL and liver stiffness scores, adjusted for age and gender (b = -0.01, p < 0.0001). Short RTL can be employed to distinguish cirrhosis patients from non-cirrhosis patients (AUC = 0.78). Further analysis showed a linear correlation between leukocyte RTL and liver RTL in BA patients (r = 0.83, p < 0.001).ConclusionThe findings of this study provide evidence that telomere shortening is associated with an elevated risk of liver cirrhosis in BA.

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Telomere dysfunction in peripheral blood mononuclear cells from patients with primary biliary cirrhosis

Cited by 14 publications

References 42 publications

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

Telomerase reverse transcriptase acts in a feedback loop with NF-κB pathway to regulate macrophage polarization in alcoholic liver disease

Telomere Length in Peripheral Blood Leukocytes Is Associated with Severity of Biliary Atresia

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