Invernizzi Pietro, Bernuzzi Francesca, Lleo Ana, Pozzoli Vanila, Bignotto Monica, Zermiani Paola, Crosignani Andrea, Battezzati Pier Maria, Zuin Massimo, Podda Mauro, Raggi Chiara
Liver Unit and Center for Autoimmune Liver Diseases Humanitas Clinical and Research Center, Rozzano, Italy.
Gastroenterology and Liver Unit, San Paolo Hospital Medical School, University of Milan, Milan, Italy.
Dig Liver Dis. 2014 Apr;46(4):363-8. doi: 10.1016/j.dld.2013.11.008. Epub 2013 Dec 27.
Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence.
To evaluate the clinical significance of telomerase activity and telomere length in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.
In this population-based case control study, 48 women with primary biliary cirrhosis (25 with cirrhosis), 12 with chronic hepatitis C matched by age and severity of disease, and 55 age-matched healthy women were identified. Mononuclear cells from the peripheral blood of patients and controls were isolated. Telomere length and telomerase activity were measured.
Telomere length and telomerase activity did not differ between cases (5.9 ± 1.5 kb) and controls (6.2 ± 1.4 kb, pc=0.164). Telomere shortening and advanced-stage disease strongly correlated with telomerase activity. Patients with advanced disease retained significantly less telomerase activity than those with early-stage disease (0.6 ± 0.9 OD vs. 1.5 ± 3.7 OD, p=0.03). Telomere loss correlated with age, suggesting premature cellular ageing in patients with primary biliary cirrhosis.
Our data strongly support the telomere hypothesis of human cirrhosis, indicating that telomere shortening and telomerase activity represent a molecular mechanism in the evolution of human cirrhosis in a selected population of patients.
外周血单个核细胞中的染色体不稳定性在原发性胆汁性肝硬化的发病中起作用。我们推测原发性胆汁性肝硬化患者可能存在端粒功能障碍，进而导致染色体不稳定和细胞衰老。
评估原发性胆汁性肝硬化患者外周血单个核细胞中端粒酶活性和端粒长度的临床意义。
在这项基于人群的病例对照研究中，确定了48例原发性胆汁性肝硬化女性患者（25例伴有肝硬化）、12例年龄和疾病严重程度相匹配的慢性丙型肝炎患者以及55例年龄匹配的健康女性。分离患者和对照者外周血中的单个核细胞，测量端粒长度和端粒酶活性。
病例组（5.9±1.5 kb）和对照组（6.2±1.4 kb，p=0.164）的端粒长度和端粒酶活性无差异。端粒缩短和晚期疾病与端粒酶活性密切相关。晚期疾病患者的端粒酶活性显著低于早期疾病患者（0.6±0.9 OD对1.5±3.7 OD，p=0.03）。端粒丢失与年龄相关，提示原发性胆汁性肝硬化患者存在细胞过早衰老。
我们的数据有力支持了人类肝硬化的端粒假说，表明端粒缩短和端粒酶活性是特定患者人群中人类肝硬化演变的一种分子机制。
