Recent advances in alcohol-related liver disease (ALD): summary of a Gut roundtable meeting

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area. In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver (EASL) International Liver Congress (ILC) in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

An experimental DUAL model of advanced liver damage

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol-associated and metabolic-associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol-associated liver disease plus metabolic-associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA-sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets

Influence of the area and distance between electrodes on resistivity measurements of concrete

Differences between the cell cross section and the electrodes area produce a heterogeneous distribution of the electric field that causes a non-linear relationship between electric resistance and distance for low values of electrode separation. Therefore, in actual structures, it is usually not correct to measure the resistivity of concrete by using the direct method because the electrodes area is smaller than the cross section of the concrete piece. In this experimental research the influence of the area and the distance between electrodes on the resistivity measurement is analyzed and a semi-empirical model is explained, in which the values of the electrical resistance with respect to distance are adjusted. Based on this model, two new non-destructive methods are proposed in order to measure the electrical resistivity of concrete when using electrodes with a smaller area than the cross section of the piece: one includes varying the distance between electrodes and the other uses electrodes with a different area, but maintains a fixed distance between them.Financial support from the Spanish Government (projects MAT2012-38429-C04-04 and IPT-2012-0069-310000) and from the Universitat Politecnica de Valencia (PAID-05-12) is gratefully acknowledged. The pre-doctoral scholarship granted to Roman Bataller Prats within the program "Formacion de Personal Investigador (FPI) 2012'' from the Universitat Politecnica de Valencia and to Jose Enrique Ramon within the program "Formacion de Profesorado Universitario'' from the Ministry of Education, Culture and Sport (FPU 13/00911) are also gratefully acknowledged.Gandía-Romero, JM.; Ramón Zamora, JE.; Bataller Prats, R.; Palací-López, DG.; Valcuende Payá, MO.; Soto Camino, J. (2017). Influence of the area and distance between electrodes on resistivity measurements of concrete. Materials and Structures. 50(71):1-12. https://doi.org/10.1617/s11527-016-0925-2S1125071Andrade C, Alonso C, Goñi S (1993) Possibilities for electrical resistivity to universally characterise mass transport processes in concrete. In: Dhir RK, Jones MR (eds) Proceedings of concrete 2000: economic and durable construction through excellence. E&FN Spon, London, pp 1639–1652Alonso C, Andrade C, González JA (1988) Relation between concrete resistivity and corrosion rate of the reinforcements in carbonated mortar made with several cement types. Cem Concr Res 18:687–698Hornbostel K, Larsen CK, Geiker MR (2013) Relationship between concrete resistivity and corrosion rate: a literature review. Cement Concr Compos 39:60–72Morris W, Vico A, Vazquez M, Sanchez SR (2002) Corrosion of reinforcing steel evaluated by means of concrete resistivity measurements. Corros Sci 44(1):81–99Andrade C, D’Andrea R, Rebolledo N (2014) Chloride ion penetration in concrete: the reaction factor in the electrical resistivity model. Cement Concr Compos 47:41–46Hussain SE, Maslehuddin M (1996) Effect of moisture, chloride and sulphate contamination on the electrical resistivity of Portland cement concrete. Constr Build Mater 10(3):209–214Andrade C (2004) Calculation of initiation and propagation periods of service-life of reinforcements by using the electrical resistivity. In: Kovler K, Marchand J, Mindness S and Weiss J (eds) Internat, symposium on advances in concrete through science and engineering, RILEM Symp, RILEM Pubs. SARL, Evanston, pp 23–30D´Andréa R (2010) Predicción de la durabilidad del hormigón armado a partir de indicadores de corrosión: aplicación de la resistividad eléctrica. Doctoral Thesis. Universidad Politécnica de MadridXiao LZ, Li ZJ, Wei XS (2007) Selection of superplasticizer in concrete mix design by measuring the early electrical resistivities of pastes. Cement Concr Compos 29(5):350–356Navarro H, Gandia JM, Valcuende M, Soto J (2013) Estimación de la durabilidad del hormigón, mediante técnicas de espectroscopía de impedancia y métodos basados en la resistividad eléctrica. VII International Workshop on Sensors and Molecular Recognition, Valencia, pp 356–370AASHTO TP95-15 (2015) Standard method of test for surface resistivity indication of concrete’s ability to resist chloride ion penetration. American Association of State Highway and Transportation Officials. Washington, DCAASHTO TP115-15 (2015). Provisional standard method of test for electrical resistivity of a concrete cylinder tested in a uniaxial resistance test. American Association of State Highway and Transportation Officials. Washington, DCASTM Standard WK37880 (2012) New test method for measuring the surface resistivity of hardened concrete using the Wenner four-electrode method. ASTM InternationalPolder RB (2001) Test methods for on-site measurement of resistivity of concrete-A RILEM TC-154 technical recommendation. Constr Build Mat 15(2):125–135UNE 83988-1 (2008) Concrete durability. Test methods. Determination of the electrical resistivity. Part 1: Direct test (reference method)UNE 83988-2 (2014) Concrete durability. Test methods. Determination of the electrical resistivity. Part 2: Four points or Wenner methodGjörv OE, Vennesland Ø, El-Busaidy (1977) AHS electrical resistivity of concrete in the oceans. In: Proceedings of the 9th annual offshore technology conference, HoustonHötte C (2003) Bestimmung des feuchtezustandes von mauerwerk mit hilfe von multiring-elektroden”—Untersuchungen zum ankoppelungsmörtel und an probewänden. Diplomarbeit, Institut für Bauforschung, Technische Hochschule AachenHope BB, Ip AK, Manning DG (1985) Corrosion and electrical impedance in concrete. Cem Concr Res 15(3):525–534Bataller R, Gandía JM, García-Breijo E, Alcañiz M, Soto J (2015) A study of the importance of the cell geometry in non-Faradaic systems. A new definition of the cell constant for conductivity measurement. Electrochim Acta 153:263–27

Bariatric surgery is associated with alcohol-related liver disease and psychiatric disorders associated with AUD

Background/Aims Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated.Methods A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching.Results The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD.Conclusions Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency

Bariatric surgery is associated with alcohol-related liver disease and psychiatric disorders associated with AUD

Background/Aims Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated.Methods A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching.Results The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85-1.95], ALD [OR: 1.29; 95% CI: 1.22-1.37], cirrhosis [OR, 1.39; 95% CI: 1.37-1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37-3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD.Conclusions Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency

Recent advances in alcohol-related liver disease (ALD): summary of a Gut roundtable meeting

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area. In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver (EASL) International Liver Congress (ILC) in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions

Impact of liver inflammation on bile acid side chain shortening and amidation

Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4 alpha (HNF4 alpha) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7 alpha-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4 alpha levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH