Telomere shortening as genetic risk factor of liver cirrhosis

Cirrhosis is the main complication of chronic liver disease, leads to progressive liver function impairment and is the main risk factor for the development of liver cancer. Liver failure at endstage cirrhosis is associated with increased mortality with liver transplantation as the only possible treatment at this stage. The pathogenesis of liver cirrhosis is not completely elucidated. Although the common factors leading to liver injury, such as viral hepatitis, alcohol consume or fatty liver disease can be identified in the majority of patients a small percentage of patients have no apparent risk factors. Moreover given the same risk factors, some patients progress to cirrhosis whereas others have a benign course, the reason remains unclear. In order to develop new diagnostic and therapeutic tools, it is s essential to understand the pathogenesis of cirrhosis. The identification of genetic risk factors associated with cirrhosis is one of the possible approach to achieve these goal. In the past years several studies have supported the role of telomere shortening and cirrhosis. In the recent year several studies on the relation between several single nucleotide polymorphism (SNPs) and cirrhosis have been published; it has been proposed also a cirrhosis risk score based on seven SNPs. Also epidemiological studies on identical twins and in different ethnic groups have been supporting the importance of the role of genetic risk factors. Finally in the very recent years it has been suggested that telomere shortening may represent a genetic risk factor for the development of cirrhosis

Telomeres and atherosclerosis

Abstract The pathogenesis of atherosclerosis, an age-related disorder, may be due to a premature biological ageing. Cellular senescence, the finite replicative lifespan of cells, plays a critical role in the pathogenesis of atherosclerosis. The biological mechanism that triggers the onset of cellular senescence is thought to be telomere shortening. The two major mechanisms responsible for telomere shortening are the end-replication problem, oxidative DNA damage as well as inflammation induced by environmental risk factors. Repair of the endothelium depends on the presence of endothelial progenitor cells which depends on the hematopoietic stem cells (HSC) reserves. In numerous past studies, short LTL has been associated with atherosclerosis. Here we review the literature on telomere biology and coronary artery disease (CAD)

The use of stable and radioactive sterol tracers as a tool to investigate cholesterol degradation to bile acids in humans in vivo

Alterations of cholesterol homeostasis represent important risk factors for atherosclerosis and cardiovascular disease. Different clinical-experimental approaches have been devised to study the metabolism of cholesterol and particularly the synthesis of bile acids, its main catabolic products. Most evidence in humans has derived from studies utilizing the administration of labeled sterols; these have several advantages over in vitro assay of enzyme activity and expression, requiring an invasive procedure such as a liver biopsy, or the determination of fecal sterols, which is cumbersome and not commonly available. Pioneering evidence with administration of radioactive sterol derivatives has allowed to characterize the alterations of cholesterol metabolism and degradation in different situations, including spontaneous disease conditions, aging, and drug treatment. Along with the classical isotope dilution methodology, other approaches were proposed, among which isotope release following radioactive substrate administration. More recently, stable isotope studies have allowed to overcome radioactivity exposure. Isotope enrichment studies during tracer infusion has allowed to characterize changes in the degradation of cholesterol via the “classical” and the “alternative” pathways of bile acid synthesis. Evidence brought by tracer studies in vivo, summarized here, provides an exceptional tool for the investigation of sterol metabolism, and integrate the studies in vitro on human tissue

Telomere and telomerase in chronic liver disease and hepatocarcinoma

The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma

Lung fibrosis, bone marrow fibrosis and liver cirrhosis: A Short Telomere Syndrome or a casual association?

Background: Telomere-mediated disease has diverse presentations that span the age spectrum. Their type, age of onset, and severity depend on the extent of the telomere length defect. During adult life, telomerase mutations may represent risk factors rather than genetic determinants and need other factors to contribute to disease development. This is case of diseases such as aplastic anemia, pulmonary fibrosis and liver cirrhosis which may occur as single disease or together in a syndromic clustering. Here we report a case of a man most likely affected by a short telomere syndrome. Case report: A 58 years old man, presented for evaluation of pulmonary fibrosis diagnosed few years earlier in a different medical center. He also presented a mild bone marrow fibrosis and a liver cirrhosis, both diagnosed one year prior evaluation with a bone marrow analysis and liver biopsy. The patient was an active smoker, obese, with digital clubbing and inspiratory Velcro crackles at the right lower lobe. Laboratory tests showed thrombocytopenia and liver enzymes alteration. He rapidly developed ascites and progression of the pulmonary fibrosis, the patient became oxygen-dependent in few months. Methods: Sequencing and mutation analysis of hTERT and hTERC genes, Leukocyte Telomere length (LTL) and Telomerase activity (TA) were evaluated. Results: In our patient LTL was shorter and TA reduced compared to the controls. Genes sequencing did not show any hTERT and hTERC mutations. Conclusions: This is a report on a short telomere syndrome involving lung, liver and bone marrow, associated to very short telomere and absent telomerase activity not in the setting of dyskeratosis congenita. The fact that short telomeres mediate inflammation and fibrosis provides a rationale for pursuing translational strategies aimed at preventing telomere shortening or its cellular consequences as a therapeutic approac

Fatty liver, carotid disease and gallstones: A study ofage-related associations

AIM: To evaluate carotid intima-media thickening (IMT)and plaques, gallstone disease (GD) and fatty liver (FL)as a function of age.METHODS: In 449 subjects, FL and carotid diseasewere assessed ultrasonographically. In a subgroup of65/449 patients with non-alcoholic fatty liver disease(NAFLD), carotid disease, GD and associated factorswere determined.RESULTS: FL of unspecifi ed etiology was more commonin younger and GD in older individuals. FL subjectshad an increased prevalence of IMT and a decreasedprevalence of plaques and manifested carotid diseaseearlier. Plaques were more common in subjects with GD.Age was an independent predictor of carotid diseaseoutcome and FL was a protective factor for plaques. InNAFLD, there was an inverse correlation between bodyweight and age and the latter independently predictedcarotid fi ndings.CONCLUSION: Cardiovascular risk in patients with FLand NAFLD needs to be assessed as a function of ageand body weight

Nonalcoholic fatty liver disease and aging: epidemiology to management

Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients

Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population.

BACKGROUND: The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols. METHODS: We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38-79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids). RESULTS: A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=-0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age. CONCLUSION: These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined

Bile acids and nonalcoholic fatty liver disease: An intriguing relationship

Non-alcoholic fatty liver disease (NAFLD) stands nowadays as a leading cause of progressive impairment of liver function. The role of bile acids in the modulation of hepatic lipid metabolism is interesting and controversial; previous evidence showed an inhibitory effect of bile acids on lipogenesis, which was attributed to the activation of the FXR-SHP axis and consequent depression of the LXRα-SREBP-1c lipogenic pathway. Evidence from our research group has shown that both exogenous administration of bile acids and endogenous exposure to bile acid overload (as in cholestasis) may reduce hepatic fat accumulation in rat models, although by different mechanisms. The findings in the paper by Nagahashi et al are quite surprising, showing the development of fatty liver disease in SphK2 -/- mice, in association with a decreased expression of SREBP1c and lipogenic enzymes like FAS. The metabolic effects of bile acids on hepatic lipid metabolism seem to be strictly dependent on the experimental model utilized to induce fat liver accumulation, as well as on the modality of bile acid exposure (exogenous vs endogenous) and the relative activation of the LXR/FXR pathways. Experimental evidence like that brought by Nagahashi et al1 may bring an enormous contribution in this field, in the perspective of novel pharmacological targets for the treatment of NAFLD