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Plasma Cystatin C is a predictor of renal dysfunction, ACLF and mortality in patients with acutely decompensated liver cirrhosis.
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Plasma Cystatin C is a predictor of renal dysfunction, ACLF and mortality in patients with acutely decompensated liver cirrhosis.

Hepatology. 2017 May 25;:

Authors: Markwardt D, Holdt L, Steib C, Benesic A, Bendtsen F, Bernardi M, Moreau R, Teupser D, Wendon J, Nevens F, Trebicka J, Garcia E, Pavesi M, Arroyo V, Gerbes AL

Abstract
BACKGROUND: The development of acute-on-chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF.
AIM: To investigate whether Cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF and mortality, respectively.
METHODS: We determined the plasma levels of CysC and NGAL of 429 patients hospitalized for acute decompensation of cirrhosis in the CANONIC study. The patients were followed for 90 days.
RESULTS: Patients without RD or ACLF at inclusion, but with development of either, had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL was found to be predictive of RD (OR 9.4 [1.8; 49.7]), HRS (OR 4.2 [1.2; 14.8]) and ACLF (OR 5.9 [1.3; 25.9]). CysC at day3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90 days mortality with hazard ratios for CysC of 3.1 (2.1; 4.7), and for NGAL of 1.9 (1.5; 2.4), respectively.
CONCLUSIONS: Baseline CysC is a biomarker of renal dysfunction, HRS and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis. Determining CysC at day 3 did not provide any benefit. While NGAL is also associated with short-term mortality, it fails to predict development of RD, HRS and ACLF. Baseline CysC may add to identify patients at risk earlier and might improve clinical management. This article is protected by copyright. All rights reserved.

PMID: 28545169 [PubMed - as supplied by publisher]




Linking long non-coding RNA to control bile acid signaling and cholestatic liver fibrosis.
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Linking long non-coding RNA to control bile acid signaling and cholestatic liver fibrosis.

Hepatology. 2017 May 24;:

Authors: Chiang JYL

PMID: 28543964 [PubMed - as supplied by publisher]




Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta-analysis.
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Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta-analysis.

Hepatology. 2017 May 25;:

Authors: Albillos A, Zamora J, Martínez J, Arroyo D, Ahmad I, De-la-Peña J, Garcia-Pagán JC, Lo GH, Sarin S, Sharma B, Abraldes J, Bosch J, Garcia-Tsao G, Baveno cooperation

Abstract
Endoscopic variceal ligation plus beta-blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant and, in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all-source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A vs. B/C) by means of individual time-to-event patient data meta-analysis (IPD) from randomized controlled trials. The study was IPD of 389 patients from 3 trials comparing EVL plus BB vs. BB and 416 patients from 4 trials comparing EVL plus BB vs. EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95%CI 0.18-0.89; p=0.025), but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (p for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95%CI 0.25-0.85; p=0.013).
CONCLUSION: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity. In patients with preserved liver function (Child A), combination therapy is recommended since it is more effective in preventing rebleeding, without modifying survival. In patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death as compared with combination therapy, underlining that BB is the key element of combination therapy. This article is protected by copyright. All rights reserved.

PMID: 28543862 [PubMed - as supplied by publisher]




Death and Liver Transplantation within Two Years of Onset of Drug-Induced Liver Injury.
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Death and Liver Transplantation within Two Years of Onset of Drug-Induced Liver Injury.

Hepatology. 2017 May 23;:

Authors: Hayashi PH, Rockey D, Fontana RJ, Tillmann HL, Kaplowitz N, Barnhart H, Gu J, Chalasani NP, Reddy KR, Sherker AH, Hoofnagle JH, Drug Induced Liver Injury Network (DILIN) Investigators.

Abstract
Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug-Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute-on-chronic or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%) and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute-on-chronic and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy and severe cutaneous reactions with multi-organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy's Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's Law (HR: 6.2, CI 3.4 - 11.1 vs. 2.2, CI 1.3-3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non-acute liver failure courses. nR Hy's Law better identifies risk for death compared to the original Hy's Law. This article is protected by copyright. All rights reserved.

PMID: 28543844 [PubMed - as supplied by publisher]




Statins in cirrhosis - ready for prime time.
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Statins in cirrhosis - ready for prime time.

Hepatology. 2017 May 22;:

Authors: Tsochatzis EA, Bosch J

PMID: 28543643 [PubMed - as supplied by publisher]




TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases via cAMP/Gαs signaling.
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TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases via cAMP/Gαs signaling.

Hepatology. 2017 May 23;:

Authors: Masyuk TV, Masyuk AI, Lorenzo Pisarello M, Howard BN, Huang BQ, Lee PY, Fung X, Sergienko E, Ardesky RJ, Chung TD, Pinkerton AB, LaRusso NF

Abstract
Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA-treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5(-/-) ;Pkhd1(del2/del2) mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5(-/-) ;Pkhd1(del2/del2) mice. TGR5 expression and its co-localization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide.
CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD. This article is protected by copyright. All rights reserved.

PMID: 28543567 [PubMed - as supplied by publisher]




Emphasis on Harms of Hepatocellular Carcinoma Surveillance: Just Pretending Innocent After Taking Advantages?
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Emphasis on Harms of Hepatocellular Carcinoma Surveillance: Just Pretending Innocent After Taking Advantages?

Hepatology. 2017 May 24;:

Authors: Wang Z, Han J, Zhang H, Wu MC, Yang T

PMID: 28543435 [PubMed - as supplied by publisher]




Unscheduled Screening Tests Cannot Be Termed as Surveillance.
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Unscheduled Screening Tests Cannot Be Termed as Surveillance.

Hepatology. 2017 May 24;:

Authors: Xu XJ, Wang HZ, Bie P

PMID: 28543365 [PubMed - as supplied by publisher]




HCC Surveillance: Striving for a Better Balance of Benefits and Harms.
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HCC Surveillance: Striving for a Better Balance of Benefits and Harms.

Hepatology. 2017 May 24;:

Authors: Atiq O, Tiro J, Yopp AC, Muffler A, Marrero JA, Parikh ND, Murphy C, McCallister K, Singal AG

PMID: 28543272 [PubMed - as supplied by publisher]




FIB-4 stage of liver fibrosis predicts incident heart failure among HIV infected and uninfected patients.
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FIB-4 stage of liver fibrosis predicts incident heart failure among HIV infected and uninfected patients.

Hepatology. 2017 May 24;:

Authors: So-Armah KA, Lim JK, Lo Re V, Tate JP, Chung-Chou HC, Butt AA, Gibert CL, Rimland D, Marconi VC, Goetz MB, Rodriguez-Barradas MC, DeBakey ME, Budoff MJ, Tindle HA, Samet JH, Justice AC, Freiberg MS, VACS Project Team

Abstract
Liver fibrosis is common, particularly in human immunodeficiency virus infected (HIV+) people. HIV+ people have excess congestive heart failure (CHF) risk compared to uninfected people. It remains unknown if stage of liver fibrosis influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether: 1) stage of liver fibrosis is independently associated with incident CHF; 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after 4/1/2003 in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease (CVD) were followed until their first CHF event, death, last follow-up date or 12/31/2011. Liver fibrosis was measured by FIB-4, calculated using age, aminotransferases and platelets.
OUTCOME: incident CHF (ICD-9 codes). Cox proportional hazards regression models were adjusted for CVD risk factors. Among 96,373 participants over 6.9 years, 3,844 incident CHF events occurred. FIB-4 between 1.45-3.25 (moderate fibrosis) and FIB-4>3.25 (advanced fibrosis/cirrhosis) were associated with CHF (HR (95% CI)=1.17 (1.07-1.27); 1.65(1.43-1.92)). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status.
CONCLUSIONS: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom CVD risk is elevated and liver disease is common. This article is protected by copyright. All rights reserved.

PMID: 28543215 [PubMed - as supplied by publisher]




Loss of L- Selectin Guided CD8(+) but not CD4(+) Cells, Protects Against Ischemia Reperfusion Injury in a Steatotic Liver.
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Loss of L- Selectin Guided CD8(+) but not CD4(+) Cells, Protects Against Ischemia Reperfusion Injury in a Steatotic Liver.

Hepatology. 2017 May 20;:

Authors: Kolachala VL, Palle S, Shen M, Feng A, Shayakhmetov D, Gupta NA

Abstract
BACKGROUND & AIMS: Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically non-existent. The objective of the current study was to delineate contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury.
METHODS: RNA sequencing was performed on isolated steatotic primary hepatocytes and T cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high fat diet (HFD) fed mice. CD8(-/-) and CD4(-/-) mice along with CD8 and L-selectin antibody treated mice were fed on a HFD and hepatocellular injury was assessed by histology, propidium iodide injection and ALT after IRI.
RESULTS: RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes vs. lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8(+) cells, ALT and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8(+) /CD62L(+) (L-selectin) cells in HFD fed mice after IRI. CD8(-/-) mice and CD8 depleted C57BL/6 mice, demonstrated significant protection from injury, which was not seen in CD4(-/-) mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L selectin ligand MECA-79 was increased in HFD fed mice undergoing IRI.
CONCLUSION: Blockade of CD8 and L-selectin but not CD4, ameliorated hepatocellular injury, confirming that CD8(+) cells are critical drivers of injury in a steatotic liver. This represents a novel therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. This article is protected by copyright. All rights reserved.

PMID: 28543181 [PubMed - as supplied by publisher]




Correction.
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Correction.

Hepatology. 2017 Jun;65(6):2135

Authors:

PMID: 28543164 [PubMed - in process]




Correction.
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Correction.

Hepatology. 2017 Jun;65(6):2135-2136

Authors:

PMID: 28543163 [PubMed - in process]




Hepatology Highlights.
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Hepatology Highlights.

Hepatology. 2017 Jun;65(6):1783-1784

Authors: Dufour JF

PMID: 28543162 [PubMed - in process]




Correction.
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Correction.

Hepatology. 2017 Jun;65(6):2136

Authors:

PMID: 28543161 [PubMed - in process]




Syndecan-1 Limits the Progression of Liver Injury and Promotes Liver Repair in Acetaminophen-Induced Liver Injury.
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Syndecan-1 Limits the Progression of Liver Injury and Promotes Liver Repair in Acetaminophen-Induced Liver Injury.

Hepatology. 2017 May 22;:

Authors: Nam EJ, Hayashida K, Aquino RS, Couchman JR, Kozar RA, Liu J, Park PW

Abstract
Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. While mechanisms that trigger APAP-induced liver injury are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan-1, the major cell surface HSPG of hepatocytes, in APAP-induced liver injury. Ablation of syndecan-1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times after APAP overdose were unaffected by syndecan-1, suggesting that syndecan-1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan-1 null (Sdc1-/-) mice were traced to a deficiency in Akt activation in hepatocytes, which led to a delayed increase in GSK-3β-mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK-3β and caspases protected mice from APAP-induced liver injury. Moreover, administration of purified syndecan-1, HS, or engineered heparan compounds containing 2-O-sulfate groups rescued Sdc1-/- mice from APAP-induced liver injury by potentiating Akt signaling and inhibiting GSK-3β-mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine (NAC).
CONCLUSION: These results demonstrate that 2-O-sulfated domains in syndecan-1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in APAP-induced liver injury. We propose that syndecan-1 is a critical endogenous factor that controls the balance between pro-survival signaling and apoptosis in hepatocytes in APAP liver disease. This article is protected by copyright. All rights reserved.

PMID: 28543100 [PubMed - as supplied by publisher]




Sofosbuvir and Ribavirin in Adolescents 12 to 17 Years Old With Hepatitis C Virus Genotype 2 or 3 Infection.
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Sofosbuvir and Ribavirin in Adolescents 12 to 17 Years Old With Hepatitis C Virus Genotype 2 or 3 Infection.

Hepatology. 2017 May 22;:

Authors: Wirth S, Rosenthal P, Gonzalez-Peralta RP, Jonas MM, Balistreri WF, Chuan-Hao L, Hardikar W, Kersey K, Massetto B, Kanwar B, Brainard DM, Shao J, Svarovskaia E, Kirby B, Arnon R, Murray KF, Schwarz KB

Abstract
BACKGROUND & AIMS: Children with chronic hepatitis C virus (HCV) infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with HCV genotype 2 or 3.
METHODS: Fifty-two patients received sofosbuvir 400mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled, and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12).
RESULTS: The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naïve, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% CI, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in Phase 2 and 3 sofosbuvir studies, the AUCtau and Cmax for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%.
CONCLUSION: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic HCV genotype 2 or 3 infection. http://ClinicalTrials.gov NCT02175758. This article is protected by copyright. All rights reserved.

PMID: 28543053 [PubMed - as supplied by publisher]