Rockey, Don C.

Background and Aims: Transient elastography (TE), shear wave elastography, and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). Approach and Results: A comprehensive search for studies assessing LSM by TE, shear wave elastography, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), using histopathology as the standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV coinfection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. Conclusions: LSM from TE, shear wave elastography, and MRE shows acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Background and Aims: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. Approach and Results: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR−) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66–6.25 and 0.23–0.80, 1.89–5.24 and 0.12–0.64, and 1.32–7.15 and 0.15–0.86, respectively; LR+ and LR− for NAFLD F2-4, F3-4, and F4 were 2.65–3.37 and 0.37–0.39, 2.25–6.76 and 0.07–0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. Conclusions: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Background and Aims: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. Approach and Results: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database’s inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%–96% and specificity was 48%–50%, while at 25 kPa, its sensitivity and specificity were 57%–85% and 82%–93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. Conclusions: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Abstract Background and study aims Current guidelines conditionally recommend performing early colonoscopy (EC) (< 24 hours) in patients admitted with acute lower gastrointestinal bleeding (LGIB). It remains unclear whether this practice is implemented widely. Therefore, we used the Nationwide Inpatient Sample to investigate trends for timing of colonoscopy in patients admitted with acute LGIB. We also assessed trend of hospitalization and mortality in patients with LGIB. Patients and methods Adult patients with LGIB admitted from 2005 to 2014 were examined. ICD-9-CM codes were used to extract LGIB discharges. Trends were assessed using Cochrane-Armitage test. Factors associated with mortality, cost of hospitalization, and length of stay (LOS) were assessed by multivariable mixed-effects and exact-matched logistic, linear regression, and accelerated-failure time models, respectively. Results A total of 814,647 patients with LGIB were included. The most common etiology of LGIB was diverticular bleeding (49 %) and 45 % of patients underwent EC. Over the study period, there was no change in the trend of colonoscopy timing. Although admission with LGIB increased over the study period, the mortality rate decreased for patients undergoing colonoscopy. Independent predictors of mortality were age, surgery (colostomy/colectomy) during admission, intensive care unit admission, acute kidney injury, and blood transfusion requirement. Timing of colonoscopy was not associated with mortality benefit. However, cost of hospitalization was $ 1,946 lower and LOS was 1.6 days shorter with EC. Conclusion Trends in colonoscopy timing in management of LGIB have not changed over the years. EC is associated with lower LOS and cost of hospitalization but it does not appear to improve inpatient mortality.

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

Loss of retinyl ester (RE)-rich lipid droplets (LDs) from hepatic stellate cells (HSCs) is cited as a key event in their cellular transdifferentiation to activated, pro-fibrotic myofibroblasts; however, it remains unclear if changes in LD morphology or RE content are causal for transdifferentiation. To better understand LD dynamics in vitro within a common model of HSC activation, we used novel approaches preserving LD morphology and allowing for quantitation of RE. The size and quantity of LDs within in vitro and in vivo bile duct ligation (BDL)-activated HSCs were quantitated using adipocyte differentiation-related protein (ADRP) labeling and oil red o (ORO) staining (gold standard), and RE content was determined using fluorescence microscopy. We found during HSC activation in vitro that LD number differed significantly when measured by ADRP and ORO, respectively ( day 1: 56 vs. 5, P = 0.03; day 4: 101 vs. 39, P = 0.03; day 14: 241 vs. 12, P = 0.02). Ex vivo HSCs activated in vivo contained the same number of LDs as day 4 in vitro activated HSCs (118 vs. 101, P = 0.54). Decline in LD RE occurred beyond day 4 in vitro and day 1 ex vivo , after HSC transdifferentiation was underway. Lastly, in situ HSCs examined using electron microscopy show LDs tend to be smaller but are ultimately retained in BDL injured livers. Therefore, we conclude that during HSC transdifferentiation, LDs are not lost but are retained, decreasing in size. Additionally, RE content declines after transdifferentiation is underway. These data suggest that these LD changes are not causal for HSC transdifferentiation.NEW & NOTEWORTHY Loss of retinoid-laden lipid droplets from hepatic stellate cells has long been held as a hallmark of their transdifferentiation into activated myofibroblasts, the dominant cells that drive hepatic fibrosis. This study demonstrates that stellate cells activated in culture and after liver injury in vivo retain their lipid droplets and that these droplets become smaller and more numerous, with decreases in droplet retinoid concentration occurring only after cellular transdifferentiation is underway.