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Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.
Vilar-Gomez, E, Pirola, CJ, Sookoian, S, Wilson, LA, Belt, P, Liang, T, Liu, W, Chalasani, N
The American journal of gastroenterology. 2021;(5):994-1006
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Abstract
INTRODUCTION This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). METHODS PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. RESULTS The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. DISCUSSION This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.
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Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
Carrat, F, Fontaine, H, Dorival, C, Simony, M, Diallo, A, Hezode, C, De Ledinghen, V, Larrey, D, Haour, G, Bronowicki, JP, et al
Lancet (London, England). 2019;(10179):1453-1464
Abstract
BACKGROUND Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
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Outcomes of Bariatric Surgery in Patients with Cirrhosis.
Miñambres, I, Rubio, MA, de Hollanda, A, Breton, I, Vilarrasa, N, Pellitero, S, Bueno, M, Lecube, A, Marcuello, C, Goday, A, et al
Obesity surgery. 2019;(2):585-592
Abstract
CONTEXT Information concerning the risk-benefit profile of bariatric surgery in subjects with liver cirrhosis is scarce. Our aim was to describe the long-term outcomes of bariatric surgery in a cohort of patients with liver cirrhosis submitted to bariatric surgery. METHODS This was a multicenter, retrospective observational study performed by the Obesity Group of the Spanish Society of Endocrinology and Nutrition (GOSEEN), with a review of patients with cirrhosis who had undergone bariatric surgery during the period from April 2004 to March 2017 in ten public reference hospitals in Spain. RESULTS Data on 41 patients with cirrhosis submitted to obesity surgery were collected (mean age 53.8 ± 7.9 years, 46.3% women, presurgical BMI 45 ± 8.3 kg/m2). All but one patient belonged to Child-Pugh class A, and sleeve gastrectomy was conducted in 68.3% of cases. Percentage of total weight loss (%TWL) was 26.33 ± 8.3% and 21.16 ± 15.32% at 1 and 5 years after surgery, respectively. This was accompanied by a significant reduction of type 2 diabetes, high blood pressure, and dyslipidemia and by an improvement of liver enzymes over time. Model for End-Stage Liver Disease (MELD) index increased from 7.2 ± 1.9 to 9.8 ± 4.6 after 5 years. Seven patients (17%) developed early postsurgical complications. No postsurgical mortality was observed. During follow-up, only five patients developed liver decompensation. CONCLUSIONS Bariatric surgery in selected patients with liver cirrhosis has metabolic benefits that could have a positive impact on liver prognosis. TRIAL REGISTRATION Controlledtrials.com Identifier: 10.1186/ISRCTN15009106.
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Screening of esophageal varices in children using esophageal capsule endoscopy: a multicenter prospective study.
Cardey, J, Le Gall, C, Michaud, L, Dabadie, A, Talbotec, C, Bellaiche, M, Lamireau, T, Mas, E, Bridoux-Henno, L, Viala, J, et al
Endoscopy. 2019;(1):10-17
Abstract
BACKGROUND Esophagogastroduodenoscopy (EGD) is the standard method for diagnosis of esophageal and gastric varices in children. In this prospective study we evaluated the use of PillCam esophageal capsule endoscopy (ECE) in pediatric patients. METHODS Patients aged 7 to 18 years presenting with portal hypertension and/or cirrhosis underwent ECE (PillCam ESO 2, Given Imaging Ltd.) followed by EGD. RESULTS 102 patients were screened, 81 (52 boys; mean age 13.96 ± 0.25 years) were included and 21 were excluded (16 for "candy test" failure). Esophageal varices were identified by EGD in 62 patients (77 %) and by ECE in 57 patients (70 %) using the de Franchis classification (DFC). The sensitivity of ECE for esophageal varices was 92 % and the specificity was 100 % using DFC. Based upon 57/81 patients with small, medium, and large varices on both ECE and EGD, using DFC, the sensitivity, specificity, positive (PPV) and negative predictive value (NPV) were 55 %, 92 %, 89 %, and 63 %, respectively, giving a total overall accuracy of 72 %. To improve sensitivity and specificity in classification of esophageal varices, we propose using a modified score. This score detected esophageal varices with 100 % sensitivity, 93 % specificity, 94 % PPV, and 100 % NPV, giving a total overall accuracy of 97 %. All patients preferred ECE over EGD. No capsule retention was recorded. CONCLUSIONS ECE is a well-tolerated and safe procedure in children. Using the modified score, the sensitivity of ECE is currently sufficient to detect esophageal varices and replace EGD in infants with suspicion of esophageal varices or when EGD is refused.
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Alfapump® system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study.
Bureau, C, Adebayo, D, Chalret de Rieu, M, Elkrief, L, Valla, D, Peck-Radosavljevic, M, McCune, A, Vargas, V, Simon-Talero, M, Cordoba, J, et al
Journal of hepatology. 2017;(5):940-949
Abstract
BACKGROUND AND AIMS Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump® [AP]) compared with LVP standard of care [SoC]. METHODS A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months. RESULTS Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC. CONCLUSIONS The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival. Lay summary: The alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients. www.clinicaltrials.gov#NCT01528410.
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Contrast-enhanced US with Perfluorobutane(Sonazoid) used as a surveillance test for Hepatocellular Carcinoma (HCC) in Cirrhosis (SCAN): an exploratory cross-sectional study for a diagnostic trial.
Park, JH, Park, MS, Lee, SJ, Jeong, WK, Lee, JY, Park, MJ, Han, K, Nam, CM, Park, SH, Lee, KH
BMC cancer. 2017;(1):279
Abstract
BACKGROUND Ultrasonography (US) is widely used as a standard surveillance tool for patients who are at a high risk of having hepatocellular carcinoma (HCC); however, conventional B-mode US appears to be insufficient in order to ensure the early detection of HCC. Perfluorobutane allows very stable Kupffer phase imaging for at least 60 min, which is tolerable for examinations of the entire liver. The purpose of our study is to evaluate the added value of contrast-enhanced US using perfluorobutane to that of conventional B-mode US as an HCC surveillance tool for patients with liver cirrhosis. METHODS/DESIGN SCAN (Sonazoid-US for surveillance of hepatoCellulArcarciNoma) is a prospective, multi-institutional, diagnostic trial using an intra-individual comparison design in a single arm of patients. This study was approved by our five institutional review board and informed consent was obtained from all participating. We obtained consent for publication of these data (contrast enhanced US images, CT or MRI images, laboratory findings, age, sex) from all participating patients. All patients will undergo conventional B-mode US immediately followed by contrast-enhanced US. The standardized case report forms will be completed by operating radiologists after B-mode US and contrast-enhanced US, respectively. If any lesion(s) is detected, the likelihood of HCC will be recorded. The primary endpoints are a detection rate of early-stage HCC and a false referral rate of HCC. Intra-individual comparison using Mcnemar's test will be performed between B-mode US and contrast-enhanced US. The study will include 523 patients under HCC surveillance in five medical institutions in Korea. DISCUSSION SCAN is the first study to investigate the efficacy of contrast-enhanced US in surveillance using two reciprocal endpoints specialized for the evaluation of a surveillance test. SCAN will provide evidence regarding whether patients can truly benefit from contrast-enhanced US in terms of the detection of early stage HCC while avoiding additional unnecessary examinations. In addition to the study protocol, we elaborate on potentially debatable components of SCAN, including the design of an intra-individual comparison study, study endpoints, composite reference standards, and indefinite imaging criteria regarding the likelihood of HCC. TRIAL REGISTRATION The date of trial registration (ClincalTrials.gov: NCT02188901 ) in this study is July 3, 2014. The last patient enrolled in August 30, 2016 and follow up to see the primary end point is still ongoing. All authors have no other relationships/conditions/circumstances that present a potential conflict of interest of relationships. Our study protocol has undergone peer-review by the funding body (GE Healthcare). No other relationships/conditions/circumstances that present a potential conflict of interest. Also, we clearly stated in the 'competing interests' section of my manuscript.
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Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial.
Forns, X, Lee, SS, Valdes, J, Lens, S, Ghalib, R, Aguilar, H, Felizarta, F, Hassanein, T, Hinrichsen, H, Rincon, D, et al
The Lancet. Infectious diseases. 2017;(10):1062-1068
Abstract
BACKGROUND The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING AbbVie.
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Tolerance and outcomes of sorafenib in elderly patients treated for advanced hepatocellular carcinoma.
Williet, N, Clavel, L, Bourmaud, A, Verot, C, Bouarioua, N, Roblin, X, Merle, P, Phelip, JM
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2017;(9):1043-1049
Abstract
INTRODUCTION Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). METHODS This was a bicentric retrospective study including all patients ≥75years and treated with sorafenib for advanced HCC between January 2010 and March 2014. RESULTS Of the 51 patients included (median age: 78 years, range: 75-92; performance status (PS) 0-1: 98%; cirrhosis: 88.2%; Child-Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3-4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p=0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p=0.01), or other cardiovascular histories (OR: 30.9; p=0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p<0.0001). CONCLUSION Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival.
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Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for spontaneous bacterial peritonitis in cirrhotic ascites: a prospective randomized open-label comparative multicenter study.
Assem, M, Elsabaawy, M, Abdelrashed, M, Elemam, S, Khodeer, S, Hamed, W, Abdelaziz, A, El-Azab, G
Hepatology international. 2016;(2):377-85
Abstract
BACKGROUND AND AIM Primary prevention of spontaneous bacterial peritonitis (SBP) is an important strategy to reduce morbidity and mortality in cirrhotic patients with ascites. Efficacy and safety of alternating rifaximin and norfloxacin as primary prophylaxis is questionable. METHODS Three hundred thirty-four cirrhotic patients with high SAAG (≥1.1) ascites, protein level in ascitic fluid less than 1.5 g/dL with advanced liver disease (Child-Pugh score >9 points with serum bilirubin level >3 mg/dL) or renal impairment (serum creatinine level >1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or serum sodium level <130 mEq/L) were included in an open-label, randomized study aimed at comparing alternating use of norfloxacin and rifaximin vs. norfloxacin or rifaximin alone as primary prophylaxis for SBP. Both intention-to-treat and per-protocol efficacy analyses were done after 6 months of treatment by assessment of ascitic fluid neutrophil count. Safety analysis was done for all intention-to-treat populations. RESULTS Alternating norfloxacin and rifaximin showed superior prophylaxis by intention-to-treat (74.7 vs. 56.4% vs. 68.3%, p < 0.048). Pairwise analysis showed that alternating regimen had lower probability to develop SBP when compared to a norfloxacin-based regimen in intention-to-treat (p = 0.016) and per protocol analysis (p = 0.039). There was no difference among the studied groups regarding the incidence and severity of adverse events reported. CONCLUSIONS Alternating norfloxacin- and rifaximin-based primary prophylaxis for SBP showed higher efficacy with the same safety profile when compared with monotherapy of norfloxacin.
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Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening.
Ratziu, V, Harrison, SA, Francque, S, Bedossa, P, Lehert, P, Serfaty, L, Romero-Gomez, M, Boursier, J, Abdelmalek, M, Caldwell, S, et al
Gastroenterology. 2016;(5):1147-1159.e5
Abstract
BACKGROUND & AIMS Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). METHODS Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. RESULTS In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 μmol/L; P < .001). CONCLUSIONS A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.