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Bedogni G.,University of Trieste | Bedogni G.,University of Milan | Kahn H.S.,National Center for Chronic Disease Prevention and Health Promotion | Bellentani S.,Liver Center | Tiribelli C.,University of Trieste
BMC Gastroenterology | Year: 2010

Background: Liver steatosis is often found in association with common cardiometabolic disorders, conditions that may all occur in a shared context of abdominal obesity and dyslipidemia. An algorithm for identifying liver steatosis is the fatty liver index (FLI). The lipid accumulation product (LAP) is an index formulated in a representative sample of the US population to identify cardiometabolic disorders. Because FLI and LAP share two components, namely waist circumference and fasting triglycerides, we evaluated the ability of LAP to identify liver steatosis in the same study population from the Northern Italian town where FLI was initially developed.Methods: We studied 588 individuals (59% males) aged 21 to 79 years. Liver steatosis was detected by ultrasonography and coded ordinally as none, intermediate and severe. 44% of the individuals had liver steatosis. Using proportional-odds ordinal logistic regression, we evaluated the ability of log-transformed LAP (lnLAP) to identify liver steatosis. We considered the benefits to our model of including terms for sex, age, suspected liver disease and ethanol intake. We calculated the 3-level probability of liver steatosis according to lnLAP and sex, providing tables and nomograms for risk assessment.Results: An ordinal proportional-odds model consisting of lnLAP and sex offered a reasonably accurate identification of liver steatosis. The odds of more severe vs. less severe steatosis increased for increasing values of lnLAP (odds ratio [OR] = 4.28, 95%CI 3.28 to 5.58 for each log-unit increment) and was more likely among males (OR = 1.88, 95%CI 1.31 to 2.69).Conclusion: In a study sample of adults from Northern Italy, the simple calculation of LAP was a reasonably accurate approach to recognizing individuals with ultrasonographic liver steatosis. LAP may help primary care physicians to select subjects for liver ultrasonography and intensified lifestyle counseling, and researchers to select patients for epidemiologic studies. A more thorough assessment of LAP's potential for identifying liver steatosis will require its cross-evaluation in external populations. © 2010 Bedogni et al; licensee BioMed Central Ltd.

Uriarte I.,University of Navarra | Banales J.M.,University of Navarra | Saez E.,University of Navarra | Arenas F.,University of Navarra | And 3 more authors.
Hepatology | Year: 2010

Bicarbonate secretion from cholangiocytes is required for appropriate adjustment of primary canalicular bile along the biliary tract. In human and rat cholangiocytes, bicarbonate secretion is mediated by anion exchanger (AE) 2, an electroneutral Na-independent Cl/HCO3 AE also involved in intracellular pH (pHi) regulation. In Ae2a,b-deficient mice, pHi is increased in lymphocytes and fibroblasts, whereas it is surprisingly normal in cholangiocytes. Here, we analyze the mechanisms for HCO3 secretion in cultured Ae2a,b /and Ae2a,b /mouse cholangiocytes by microfluorimetric measurement of pHi changes upon established perfusion maneuvers. Cl withdrawal by isethionate-based perfusions showed that Ae2a,b /but not Ae2a,b /mouse cholangiocytes can display Cl/HCO3 exchange, which is therefore entirely mediated by Ae2. Nevertheless, simultaneous withdrawal of Cl and Na revealed that mouse cholangiocytes possess an additional transport activity for HCO3 secretion not observed in control rat cholangiocytes. Propionate-based maneuvers indicated that this supplemental Na-driven HCO3-secreting activity is Cl-independent, consistent with a Na-HCO3 cotransport (NBC). NBC activity is greater in Ae2a,b /than Ae2a,b /mouse cholangiocytes, and membrane-depolarization experiments showed that it is electrogenic. Consistent with the potential role of Slc4a4/Nbc1 as the involved transporter, Ae2a,b /mouse cholangiocytes exhibit up-regulated expression of this electrogenic NBC carrier. Whereas Ae2-mediated Cl/HCO3 exchange in Ae2a,b /mouse cholangiocytes is stimulated by cyclic adenosine monophosphate (cAMP) and acetylcholine, the NBC activity is down-regulated by cAMP and adenosine triphosphate (ATP) in Ae2a,b /mouse cholangiocytes. Polarized Ae2a,b /mouse cholangiocytes placed in Ussing chambers show decreased (but not abolished) cAMP-dependent Cl current and increased ATP-dependent/Ca2-activated Cl secretion, which run in parallel with decreased cystic fibrosis transmembrane conductance regulator messenger RNA expression and increased intracellular Ca2 levels. Conclusion: Bicarbonate secretion in mouse cholangiocytes involves two differentially regulated activities: Ae2-mediated Cl/HCO3 exchange and Na-HCO3 cotransport. Copyright © 2010 by the American Association for the Study of Liver Diseases.

Pauli-Magnus C.,University of Basel | Meier P.J.,University of Basel | Stieger B.,University of Zurich | Stieger B.,Liver Center
Seminars in Liver Disease | Year: 2010

Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 (ABCB4) and BSEP (ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis. © 2010 by Thieme Medical Publishers, Inc.

Hirschfield G.M.,University of Toronto | Hirschfield G.M.,Liver Center
Best Practice and Research: Clinical Gastroenterology | Year: 2011

Primary biliary cirrhosis is the archetypal autoimmune liver disease, with the disease label describing a chronic granulomatous lymphocytic small bile duct cholangitis, which now most commonly presents asymptomatically and at an early pre-cirrhotic stage. Disease is more common than thought, with 1 in 1000 women over the age of 40 affected. Characteristic immunologic features of the disease assist clinicians in ready non-invasive diagnosis of patients, even if asymptomatic with only anicteric/cholestatic liver biochemical profiles. Over 90% of patients are anti-mitochondrial antibody positive, and for those negative, a significant proportion have highly specific anti-nuclear antibody profiles. Liver biopsy remains useful in certain settings where clarity is needed to confirm diagnosis, exclude alternative disease, and assess the relative contribution of PBC to other co-existent liver injury, and seeks to demonstrate in particular the classic bile duct lesions, as well as the degree of interface activity. © 2011 Elsevier Ltd. All rights reserved.

Markusic D.,Liver Center
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Lentiviral vectors are a powerful tool to achieve regulated expression of transgenes in vivo and in vitro. The doxycycline-inducible system is well characterized and can be used to regulate expression mediated by lentiviral vectors. Because many different doxycycline-inducible lentiviral vectors have been described, choosing the best vector system can be difficult. This chapter can be used as a guide to select the optimal system for a particular application.

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