Hepatology : official journal of the American Association for the Study of Liver Diseases
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Magnetic resonance elastography (MRE), an advanced magnetic resonance-based imaging technique, and acoustic radiation force impulse (ARFI), an ultrasound-based imaging technique, are accurate for diagnosing nonalcoholic fatty liver disease (NAFLD) fibrosis. However, no head-to-head comparisons between MRE and ARFI for diagnosing NAFLD fibrosis have been performed. We compared MRE versus ARFI head-to-head for diagnosing fibrosis in well-characterized patients with biopsy-proven NAFLD. This cross-sectional analysis of a prospective cohort involved 125 patients (54.4% female) who underwent MRE, ARFI, and contemporaneous liver biopsies scored using the Nonalcoholic Steatohepatitis Clinical Research Network histological scoring system. The performances of MRE versus ARFI for diagnosing fibrosis were evaluated using area under the receiver operating characteristic curves (AUROCs). The mean (± standard deviation) age and body mass index were 48.9 (±15.4) years and 31.8 (±7.0) kg/m(2) , respectively. For diagnosing any fibrosis (≥ stage 1), the MRE AUROC was 0.799 (95% confidence interval [CI] 0.723-0.875), significantly (P = 0.012) higher than the ARFI AUROC of 0.664 (95% CI 0.568-0.760). In stratified analysis by presence or absence of obesity, MRE was superior to ARFI for diagnosing any fibrosis in obese patients (P < 0.001) but not in nonobese patients (P = 0.722). The MRE AUROCs for diagnosing ≥stages 2, 3, and 4 fibrosis were 0.885 (95% CI 0.816-0.953), 0.934 (95% CI 0.863-1.000), and 0.882 (95% CI 0.729-1.000); and the ARFI AUROCs were 0.848 (95% CI 0.776-0.921), 0.896 (95% CI 0.824-0.968), and 0.862 (95% CI 0.721-1.000). MRE had higher AUROCs than ARFI for discriminating dichotomized fibrosis stages at all dichotomization cutoff points, but the AUROC differences decreased as the cutoff points (fibrosis stages) increased. ⋯ MRE is more accurate than ARFI for diagnosing any fibrosis in NAFLD patients, especially those who are obese.
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Randomized Controlled Trial Multicenter Study Comparative Study
Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + β-blocker for prevention of variceal rebleeding.
Gastroesophageal variceal bleeding in patients with cirrhosis is associated with significant morbidity and mortality, as well as a high rebleeding risk. Limited data are available on the role of transjugular intrahepatic portosystemic shunt (TIPS) with covered stents in patients receiving standard endoscopic, vasoactive, and antibiotic treatment. In this multicenter randomized trial, long-term endoscopic variceal ligation (EVL) or glue injection + β-blocker treatment was compared with TIPS placement in 72 patients with a first or second episode of gastric and/or esophageal variceal bleeding, after hemodynamic stabilization upon endoscopic, vasoactive, and antibiotic treatment. Randomization was stratified according to Child-Pugh score. Kaplan-Meier (event-free) survival estimates were used for the endpoints rebleeding, death, treatment failure, and hepatic encephalopathy. During a median follow-up of 23 months, 10 (29%) of 35 patients in the endoscopy + β-blocker group, as compared to 0 of 37 (0%) patients in the TIPS group, developed variceal rebleeding (P = 0.001). Mortality (TIPS 32% vs. endoscopy 26%; P = 0.418) and treatment failure (TIPS 38% vs. endoscopy 34%; P = 0.685) did not differ between groups. Early hepatic encephalopathy (within 1 year) was significantly more frequent in the TIPS group (35% vs. 14%; P = 0.035), but during long-term follow-up this difference diminished (38% vs. 23%; P = 0.121). ⋯ In unselected patients with cirrhosis, who underwent successful endoscopic hemostasis for variceal bleeding, covered TIPS was superior to EVL + β-blocker for reduction of variceal rebleeding, but did not improve survival. TIPS was associated with higher rates of early hepatic encephalopathy.
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Randomized Controlled Trial
Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: A randomized, controlled trial.
Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests) and is used to justify preprocedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet count), and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR >1.8 and/or platelet count <50 × 10(9) /L) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG-guided transfusion strategy or standard of care (SOC; 1:1 TEG:SOC). The TEG group would receive FFP if the reaction time (r) was >40 min and/or PLT if maximum amplitude (MA) was <30 mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions versus 5 in the TEG group (100% vs. 16.7%; P < 0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone (P < 0.0001 vs. SOC), 2 received PLT (6.7%; P = 0.009 vs. SOC), and 3 both FFP and PLT (not significant). Postprocedure bleeding occurred in only 1 patient (SOC group) after large-volume paracentesis. ⋯ In patients with cirrhosis and significant coagulopathy before invasive procedures, TEG-guided transfusion strategy leads to a significantly lower use of blood products compared to SOC (transfusion guided by INR and platelet count), without an increase in bleeding complications. Remarkably, even in patients with significant coagulopathy, postprocedure bleeding was rare, indicating that TEG thresholds should be reevaluated.
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Ferroptosis is a recently recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. ⋯ These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in HCC cells.