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Reply Letter.
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Reply Letter.

Hepatology. 2017 Apr 24;:

Authors: Pastore N, Attanasio S, Brunetti-Pierri N

PMID: 28437874 [PubMed - as supplied by publisher]




Low-level viremia in hepatitis B patients on antiviral treatment: Can we ignore it?
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Low-level viremia in hepatitis B patients on antiviral treatment: Can we ignore it?

Hepatology. 2017 Apr 24;:

Authors: Min AD

PMID: 28437872 [PubMed - as supplied by publisher]




Reply (to LTE 17-0412).
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Reply (to LTE 17-0412).

Hepatology. 2017 Apr 24;:

Authors: Kagawa T, Adachi Y

PMID: 28437871 [PubMed - as supplied by publisher]




Alpha1-antitrypsin deficiency and c-JUN.
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Alpha1-antitrypsin deficiency and c-JUN.

Hepatology. 2017 Apr 24;:

Authors: Ponzetto A, Perez-Perez GI, Figura N

PMID: 28437866 [PubMed - as supplied by publisher]




A Novel Role of Astrocyte Elevated Gene-1 (AEG-1) in Regulating Non-alcoholic Steatohepatitis (NASH).
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A Novel Role of Astrocyte Elevated Gene-1 (AEG-1) in Regulating Non-alcoholic Steatohepatitis (NASH).

Hepatology. 2017 Apr 24;:

Authors: Srivastava J, Robertson CL, Ebeid K, Dozmorov M, Rajasekaran D, Mendoza R, Siddiq A, Akiel MA, Jariwala N, Shen XN, Windle JJ, Subler MA, Mukhopadhyay ND, Giashuddin S, Ghosh S, Lai Z, Chen Y, Fisher PB, Salem AK, Sanyal AJ, Sarkar D

Abstract
Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1(ΔHEP) ). Alb/AEG-1 mice developed spontaneous NASH while AEG-1(ΔHEP) mice were protected from high fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and WT mice that developed steatosis upon feeding high fat diet. In-depth molecular analysis unraveled that inhibition of PPARα activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased NF-κB-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 siRNA provided marked protection from HFD-induced NASH in wild-type mice.
CONCLUSION: AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. This article is protected by copyright. All rights reserved.

PMID: 28437865 [PubMed - as supplied by publisher]




SIRT3 Acts As a Negative Regulator of Autophagy Dictating Hepatocyte Susceptibility to Lipotoxicity.
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SIRT3 Acts As a Negative Regulator of Autophagy Dictating Hepatocyte Susceptibility to Lipotoxicity.

Hepatology. 2017 Apr 24;:

Authors: Li S, Dou X, Ning H, Song Q, Wei W, Zhang X, Shen C, Li J, Sun C, Song Z

Abstract
Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be fully elucidated. SIRT3 is an NAD(+) -dependent deacetylase primarily located inside mitochondria. In this study, we demonstrated that a SFAs-rich high-fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated FAs-rich HFD. Unexpectedly, SIRT3 expression/activity were significantly elevated in the livers of mice exposed to the SFAs-rich HFD. Using cultured HepG2 and AML-12 hepatocytes, we demonstrated that unlike monounsaturated FAs, SFAs upregulates SIRT3 expression/activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate-induced cell death, which can be alleviated by SIRT3 siRNA transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, whereby enhancing the susceptibility of hepatocytes to SFAs-induced cytotoxicity. Mechanistic investigations elucidate that SIRT3 overexpression causes manganese superoxide dismutase (MnSOD) deacetylation/activation, which depleted intracellular superoxide contents, leading to AMP-activated protein kinase (AMPK) inhibition and mTORC1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhances autophagy flux. The similar result was observed in the liver tissue from SIRT3 knockout mice.
CONCLUSION: our data identified SIRT3 to be a novel negative regulator of autophagy, whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. This article is protected by copyright. All rights reserved.

PMID: 28437863 [PubMed - as supplied by publisher]




Assessment of preoperative liver function based on indocyanine green clearance.
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Assessment of preoperative liver function based on indocyanine green clearance.

Hepatology. 2017 Apr 24;:

Authors: Kokudo T, Hasegawa K, Kokudo N

PMID: 28437858 [PubMed - as supplied by publisher]




A small specific-sized hyaluronic acid ameliorates alcoholic liver disease (ALD) by targeting a small RNA: New hope for ALD therapy?
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A small specific-sized hyaluronic acid ameliorates alcoholic liver disease (ALD) by targeting a small RNA: New hope for ALD therapy?

Hepatology. 2017 Apr 24;:

Authors: He Y, Gao B

PMID: 28437845 [PubMed - as supplied by publisher]




Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: a Japanese nationwide survey.
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Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: a Japanese nationwide survey.

Hepatology. 2017 Apr 24;:

Authors: Kokudo T, Hasegawa K, Matsuyama Y, Takayama T, Izumi N, Kadoya M, Kudo M, Kubo S, Sakamoto M, Nakashima O, Kumada T, Kokudo N, Liver Cancer Study Group of Japan

Abstract
Because of the rarity of hepatic vein tumor thrombus (HVTT), compared with portal vein tumor thrombus (PVTT), in patients with hepatocellular carcinoma (HCC), little is known about this disease entity. The aim of this study was to evaluate the prognosis of each treatment modality for HVTT through an analysis of data collected in a Japanese nationwide survey. We analyzed data for 1,021 Child-Pugh A HCC patients with HVTT without inferior vena cava invasion registered between 2000 and 2007. Of these patients, 540 patients who underwent liver resection (LR) and 481 patients who received other treatments were compared. The propensity scores were calculated and we successfully matched 223 patients (49.0% of the LR group). The median survival time (MST) in the LR group was 2.89 years longer than that in the non-LR group (4.47 years vs 1.58 years; P < 0.001) and 1.61 years longer than that in the non-LR group (3.42 years vs 1.81 years; P = 0.023) in a propensity score-matched cohort. After curative resection, the MSTs were similar between patients with HVTT in the peripheral hepatic vein and those with HVTT in the major hepatic vein (4.85 years vs 4.67 years; P = 0.974). In the LR group, the postoperative 90-day mortality rate was 3.4% (16patients). In patients without PVTT, the MST was significantly better than that in patients with PVTT (5.67 years vs. 1.88 years; P < 0.001).
CONCLUSION: LR is associated with a good prognosis in HCC patients with HVTT, especially in patients without PVTT. This article is protected by copyright. All rights reserved.

PMID: 28437844 [PubMed - as supplied by publisher]




Autoimmune-like chronic hepatitis induced by olmesartan.
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Autoimmune-like chronic hepatitis induced by olmesartan.

Hepatology. 2017 Apr 24;:

Authors: Barge S, Ziol M, Nault JC

Abstract
Drug liver-induced injury (DILI) due to minocyclin, alpha methyldopa or nitrofurantoin may be responsible for chronic liver damage that mimic the biological and/or histological features of chronic autoimmune hepatitis and, in rare cases, progresses to cirrhosis(1). Olmesartan medoxomil is an antihypertensive drug that acts by blocking the angiotensin II receptor and is metabolized into its pharmacologically active form, olmesartan, in the intestine and in the liver before being released into the systemic circulation. After 2012, several teams reported olmesartan-associated sprue-like enteropathy (2-4). Except for one case of non-alcoholic steatohepatitis(5), no liver injury related to olmesartan has been reported in the literature to our knowledge. This article is protected by copyright. All rights reserved.

PMID: 28437842 [PubMed - as supplied by publisher]




PTEN downregulation promotes β-oxidation to fuel hypertrophic liver growth after hepatectomy in mice.
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PTEN downregulation promotes β-oxidation to fuel hypertrophic liver growth after hepatectomy in mice.

Hepatology. 2017 Apr 24;:

Authors: Kachaylo E, Tschuor C, Calo N, Borgeaud N, Limani P, Piguet AC, Dufour JF, Foti M, Graf R, Clavien PA, Humar B

Abstract
In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration-associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor PTEN is a key inhibitor of the AKT-mTOR axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, while its role in regenerating liver remains unknown. Here, we show that PTEN downregulation promotes liver growth in a TRAS-dependent way. In wild type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with upregulated β-oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver-specific Pten(-/-) mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection-induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten(-/-) mice and correlated with the disappearance of TRAS. Partial inhibition of β-oxidation led to persisting TRAS in Pten(-/-) mice and abrogated hypertrophic liver growth. PTEN downregulation may promote β-oxidation via β-catenin, while hypertrophy was dependent on mTORC1.
CONCLUSION: PTEN downregulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands, and emphasize the need of lipids for regeneration. This article is protected by copyright. All rights reserved.

PMID: 28437835 [PubMed - as supplied by publisher]




Hepatology Highlights.
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Hepatology Highlights.

Hepatology. 2017 May;65(5):1429-1431

Authors: Dufour JF

PMID: 28423194 [PubMed - in process]




Pentraxin-3 Modulates LPS-induced Inflammatory Response and Attenuates Liver Injury.
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Pentraxin-3 Modulates LPS-induced Inflammatory Response and Attenuates Liver Injury.

Hepatology. 2017 Apr 19;:

Authors: Perea L, Coll M, Sanjurjo L, Blaya D, El Taghdouini A, Rodrigo-Torres D, Altamirano J, Graupera I, Aguilar-Bravo B, Llopis M, Vallverdú J, Caballeria J, van Grunsven LA, Sarrias MR, Ginès P, Sancho-Bru P

Abstract
Acute-on-chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute phase proteins such as Pentraxin-3 (PTX3) are released, however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. Role of PTX3 was evaluated in cultured human cells, liver tissue slices and mice with acute-on-chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis (AH). PTX3 expression was up-regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells (HSC) were the main cell types expressing PTX3 in liver injury. Ex vivo, and in vivo studies showed that PTX3 treatment attenuated LPS-induced liver injury, inflammation and cell recruitment. Mechanistically, PTX3 mediated HSC wound-healing response. Moreover, PTX3 modulated LPS-induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TRIF-dependent response and favoring a macrophage IL-10-like phenotype. Additionally, hepatic and plasma PTX3 levels were up-regulated in patients with AH, a prototypic acute-on-chronic condition and its expression correlated with disease severity scores, endotoxemia, infections and short-term mortality. Thus, suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury.
CONCLUSION: Experimental and human evidences suggest that in addition to being a potential biomarker for AH, PTX3 participates in wound-healing response and attenuates LPS-induced liver injury and inflammation. Therefore, administration of PTX3 could be a promising therapeutic strategy in acute-on-chronic conditions, particularly those associated with endotoxemia. This article is protected by copyright. All rights reserved.

PMID: 28422322 [PubMed - as supplied by publisher]




Hepatic steatosis, hepatitis C and human immunodeficiency viruses: A complex interplay.
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Hepatic steatosis, hepatitis C and human immunodeficiency viruses: A complex interplay.

Hepatology. 2017 Apr 19;:

Authors: Pembroke T, Sebastiani G

PMID: 28422314 [PubMed - as supplied by publisher]




Regulome Networks and Mutational Landscape in Liver Cancer: An Informative Path to Precision Medicine.
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Regulome Networks and Mutational Landscape in Liver Cancer: An Informative Path to Precision Medicine.

Hepatology. 2017 Apr 19;:

Authors: Yi S, Sahni N

PMID: 28422313 [PubMed - as supplied by publisher]




Reply to LTE HEP 17-0330.
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Reply to LTE HEP 17-0330.

Hepatology. 2017 Apr 19;:

Authors: Price J

PMID: 28422311 [PubMed - as supplied by publisher]




Adult Onset Cystic Fibrosis Liver Disease: Diagnosis and characterization of an underappreciated entity.
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Adult Onset Cystic Fibrosis Liver Disease: Diagnosis and characterization of an underappreciated entity.

Hepatology. 2017 Apr 19;:

Authors: Koh C, Sakiani S, Surana P, Zhao X, Eccleston J, Kleiner DE, Herion D, Liang TJ, Hoofnagle JH, Chernick M, Heller T

Abstract
BACKGROUND & AIMS: Cystic fibrosis liver disease (CFLD), a leading cause of death in cystic fibrosis (CF), is mostly described in pediatric populations. Adult-onset CFLD lacks sufficient characterization and diagnostic tools.
METHODS: A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with a newly proposed CFLD criteria.
RESULTS: 36 CF patients were followed for a median of 24.5 years(IQR=15.6, 32.9). By the last follow-up, 11(31%) had died. With conventional criteria, 8(22%) patients had CFLD, and by new criterion, 17 (47%) had CFLD at a median age of 36.6 years(IQR=26.5, 43.2). By new criterion, those with CFLD had higher median ALT(42 vs 27, p=0.005), AST(26 vs 21, p=0.01), direct bilirubin(0.13 vs 0.1, p=0.01), PT(14.4 vs 12.4, p=0.002), and APRI(0.31 vs 0.23, p=0.003) over the last two years of follow-up. Subjects with a Fibroscan® >6.8kPa had higher ALT(42 vs 28U/L, p=0.02), AST(35 vs 25U/L, p=0.02), APRI(0.77 vs 0.25, p=0.0004), FIB-4(2.14 vs 0.74, p=0.0003) and lower platelet counts(205 vs 293, p=0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group(310 to 230U/L, p=0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD(143 vs 258 U/L, p=0.004) or those deceased with no CFLD(143 vs 327U/L, p=0.006).
CONCLUSION: Adult-onset CFLD may be more prevalent than previously described which suggests a later wave of CFLD that impacts morbidity. Routine liver tests, radiologic imaging, noninvasive fibrosis markers and fibroscan® can be utilized algorithmically to identify adult CFLD. Further evaluation in other CF cohorts should be performed for validation. This article is protected by copyright. All rights reserved.

PMID: 28422310 [PubMed - as supplied by publisher]




Development of a Novel Frailty Index to Predict Mortality in Patients with End-Stage Liver Disease.
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Development of a Novel Frailty Index to Predict Mortality in Patients with End-Stage Liver Disease.

Hepatology. 2017 Apr 19;:

Authors: Lai JC, Covinsky KE, Dodge JL, Boscardin WJ, Segev DL, Roberts JP, Feng S

Abstract
BACKGROUND: Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the MELDNa score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in cirrhotics.
METHODS: Consecutive outpatients listed for LT at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting due to sickness). We selected the Frailty Index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the Frailty Index to MELDNa.
RESULTS: Included were 536 cirrhotics with median MELDNa of 18. 107(20%) died/were delisted. The final Frailty Index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the Frailty Index to correctly rank patients according to their 3-mo waitlist mortality risk (i.e., C-statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa + Frailty Index together. Compared with MELDNa alone, MELDNa + Frailty Index correctly re-classified 16% of deaths/delistings (p=0.005) and 3% of non-deaths/delistings (p=0.17) with a total NRI of 19% (p<0.001). Compared to those with robust Frailty Index scores (<20%ile), cirrhotics with poor Frailty Index Scores (>80%ile) were more impaired by gait speed, IADL difficulty, exhaustion, and low physical activity [p<0.001 for each].
CONCLUSIONS: Our Frailty Index for cirrhotics, comprised of 3 performance-based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. This article is protected by copyright. All rights reserved.

PMID: 28422306 [PubMed - as supplied by publisher]