Browsing by Author "Abdelmalek, Manal F."
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Item A multisociety Delphi consensus statement on new fatty liver disease nomenclature(Wolters Kluwer, 2023) Rinella, Mary E.; Lazarus, Jeffrey V.; Ratziu, Vlad; Francque, Sven M.; Sanyal, Arun J.; Kanwal, Fasiha; Romero, Diana; Abdelmalek, Manal F.; Anstee, Quentin M.; Arab, Juan Pablo; Arrese, Marco; Bataller, Ramon; Beuers, Ulrich; Boursier, Jerome; Bugianesi, Elisabetta; Byrne, Christopher D.; Castro Narro, Graciela E.; Chowdhury, Abhijit; Cortez-Pinto, Helena; Cryer, Donna R.; Cusi, Kenneth; El-Kassas, Mohamed; Klein, Samuel; Eskridge, Wayne; Fan, Jiangao; Gawrieh, Samer; Guy, Cynthia D.; Harrison, Stephen A.; Kim, Seung Up; Koot, Bart G.; Korenjak, Marko; Kowdley, Kris V.; Lacaille, Florence; Loomba, Rohit; Mitchell-Thain, Robert; Morgan, Timothy R.; Powell, Elisabeth E.; Roden, Michael; Romero-Gómez, Manuel; Silva, Marcelo; Singh, Shivaram Prasad; Sookoian, Silvia C.; Spearman, C. Wendy; Tiniakos, Dina; Valenti, Luca; Vos, Miriam B.; Wong, Vincent Wai-Sun; Xanthakos, Stavra; Yilmaz, Yusuf; Younossi, Zobair; Hobbs, Ansley; Villota-Rivas, Marcela; Newsome, Philip N.; NAFLD Nomenclature consensus group; Medicine, School of MedicineThe principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.Item Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis(Wiley, 2022) Sanyal, Arun J.; Anstee, Quentin M.; Trauner, Michael; Lawitz, Eric J.; Abdelmalek, Manal F.; Ding, Dora; Han, Ling; Jia, Catherine; Huss, Ryan S.; Chung, Chuhan; Wong, Vincent Wai-Sun; Okanoue, Takeshi; Romero-Gomez, Manuel; Muir, Andrew J.; Afdhal, Nezam H.; Bosch, Jaime; Goodman, Zachary; Harrison, Stephen A.; Younossi, Zobair M.; Myers, Robert P.; Medicine, School of MedicineBackground and aims: Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver-related complications in patients with NASH cirrhosis. Approach and results: Patients with compensated cirrhosis due to NASH were enrolled in two placebo-controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha-smooth muscle actin (α-SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis-4 index [FIB-4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver-related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow-up of 16.6 months, 71 (6.3%) had a liver-related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α-SMA expression, ML-based fibrosis parameters, LS, ELF, NFS, and FIB-4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α-SMA, ML-based fibrosis parameters, NFS, and LS were associated with an increased risk of events. Conclusions: In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver-related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis.Item Comparison of clinical prediction rules for ruling out cirrhosis in nonalcoholic fatty liver disease (NAFLD)(Wiley, 2022) Brandman, Danielle; Boyle, Marie; McPherson, Stuart; Van Natta, Mark L.; Sanyal, Arun J.; Kowdley, Kris; Neuschwander-Tetri, Brent; Chalasani, Naga; Abdelmalek, Manal F.; Terrault, Norah A.; McCullough, Art; Bettencourt, Ricki; Caussy, Cyrielle; Kleiner, David E.; Behling, Cynthia; Tonascia, James; Anstee, Quentin M.; Loomba, Rohit; Members of the Nonalcoholic Steatohepatitis Clinical Research Network; Medicine, School of MedicineBackground and aims: Patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis benefit from referral to subspecialty care. While several clinical prediction rules exist to identify advanced fibrosis, the cutoff for excluding cirrhosis due to NAFLD is unclear. This analysis compared clinical prediction rules for excluding biopsy-proven cirrhosis in NAFLD. Methods: Adult patients were enrolled in the NASH Clinical Research Network (US) and the Newcastle Cohort (UK). Clinical and laboratory data were collected at enrolment, and a liver biopsy was taken within 1 year of enrolment. Optimal cutoffs for each score (eg, FIB-4) to exclude cirrhosis were derived from the US cohort, and sensitivity, specificity, positive predictive value, negative predictive value and AUROC were calculated. The cutoffs were evaluated in the UK cohort. Results: 147/1483 (10%) patients in the US cohort had cirrhosis. All prediction rules had similarly high NPV (0.95-0.97). FIB-4 and NAFLD fibrosis scores were the most accurate in characterising patients as having cirrhosis (AUROC 0.84-0.86). 59/494 (12%) patients in the UK cohort had cirrhosis. Prediction rules had high NPV (0.92-0.96), and FIB-4 and NAFLD fibrosis score the most accurate in the prediction of cirrhosis in the UK cohort (AUROC 0.87-0.89). Conclusions: This cross-sectional analysis of large, multicentre international datasets shows that current clinical prediction rules perform well in excluding cirrhosis with appropriately chosen cutoffs. These clinical prediction rules can be used in primary care to identify patients, particularly those who are white, female, and <65, unlikely to have cirrhosis so higher-risk patients maintain access to specialty care.Item Current and Future Therapeutic Regimens for Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Chalasani, Naga P.; Anstee, Quentin M.; Kowdley, Kris V.; George, Jacob; Goodman, Zachary D.; Lindor, Keith; Medicine, School of MedicineNASH/NAFLD is rapidly becoming one of top causes of cirrhosis, hepatocellular carcinoma and indication for liver transplantation. Except for life style modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is hard to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD and has been shown to improve liver histology. In order to have approved regimens for treatment of NASH/NAFLD, a number of issues that must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced stage of fibrosis, it is not an independent predictor of long term mortality. In contrast, there is significant data to suggest that stage of fibrosis is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, a number of important secondary endpoints, including non-invasive biomarkers, long term outcomes, and patient reported outcomes, must be considered. In 2017, a few phase 3 clinical trials for treatment of NASH are in progress. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH enriches the pipeline of emerging therapies. Conclusion: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD.Item Diagnostic Modalities for Non-alcoholic Fatty Liver Disease (NAFLD), Non-alcoholic Steatohepatitis (NASH) and Associated Fibrosis(Wiley, 2018) Younossi, Zobair M.; Loomba, Rohit; Anstee, Quentin M.; Rinella, Mary E.; Bugianesi, Elisabetta; Marchesini, Giulio; Neuschwander-Tetri, Brent A.; Serfaty, Lawrence; Negro, Francesco; Caldwell, Stephen H.; Ratziu, Vlad; Corey, Kathleen E.; Friedman, Scott L.; Abdelmalek, Manal F.; Harrison, Stephen A.; Sanyal, Arun J.; Lavine, Joel E.; Mathurin, Philippe; Charlton, Michael R.; Goodman, Zachary D.; Chalasani, Naga P.; Kowdley, Kris V.; George, Jacob; Lindor, Keith; Medicine, School of MedicineNAFLD is a spectrum comprised of isolated steatosis, NASH, advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and don't carry a significant risk for adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high prevalence rates to low rates are noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition as an important liver disease, the diagnosis of NASH still requires a liver biopsy which is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, it suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathologic features. A number of non-invasive modalities to diagnose NASH and stage liver fibrosis are being developed. These include predictive models (NAFLD fibrosis score) and serum biomarkers such as Enhanced Liver Fibrosis, (ELF). Other tests are based on radiologic techniques such as transient or MR elastography (MRE) which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have AUROC between 0.76 to 0.90% with MRE having the best predictive performance. In summary, developing accurate, safe and easily accessible non-invasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease but to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH.Item Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension(Elsevier, 2020-04) Chalasani, Naga; Abdelmalek, Manal F.; Garcia-Tsao, Guadalupe; Vuppalanchi, Raj; Alkhouri, Naim; Rinella, Mary; Noureddin, Mazen; Pyko, Maxmillan; Shiffman, Mitchell; Sanyal, Arun; Allgood, Adam; Shlevin, Harold; Horton, Rex; Zomer, Eliezer; Irish, William; Goodman, Zachary; Harrison, Stephen A.; Traber, Peter G.; Medicine, School of MedicineBackground & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (–0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (–0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices.Item Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels(Wolters Kluwer, 2019-10-01) Gawrieh, Samer; Wilson, Laura A.; Cummings, Oscar W.; Clark, Jeanne M.; Loomba, Rohit; Hameed, Bilal; Abdelmalek, Manal F.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Kowdley, Kris; Kleiner, David; Doo, Edward; Tonascia, James; Sanyal, Arun; Chalasani, Naga; Network and the NASH Clinical Research; Medicine, School of MedicineBackground and aims: Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels. Methods: We evaluated 534 adults with biopsy-proven NAFLD and ALT and AST < 40 U/L within 3 months of their liver biopsy. Histological phenotypes of primary interest were NASH with stage 2-3 fibrosis (NASH F2-3) and cirrhosis. Using multiple logistic regression models with Akaike’s Information Criteria (AIC), we identified variables associated with these histological phenotypes. We developed and internally validated their clinical prediction models. Results: The prevalence of NASH F2-F3 and cirrhosis were 19% and 7%, respectively. The best multiple regression AIC model for NASH F2-3 consisted of type 2 diabetes, White race, lower LDL, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The best AIC model for cirrhosis consisted of lower platelet count, lower AST/ALT ratio, higher BMI, and female sex. The area under the receiver operator curves of the prediction models were 0.70 (95% CI: 0.65-0.76) for detecting NASH-F2-3 and 0.85 (95% CI: 0.77-0.92) for detecting cirrhosis. When models were fixed at maximum Youden’s index, their positive and negative predictive values were 35% and 88% for NASH F2-F3 and 30% and 98% for cirrhosis, respectively. Conclusion: Clinically significant histological phenotypes are observed in patients with NAFLD and normal aminotransferase levels. Our models can assist the clinicians in excluding advanced liver histology in NAFLD patients with normal aminotransferase levels.Item Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH(Wiley, 2019-02-21) Chalasani, Naga; Abdelmalek, Manal F.; Loomba, Rohit; Kowdley, Kris V.; McCullough, Arthur J.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Terrault, Norah; Ferguson, Beatrice; Shringarpure, Reshma; Shapiro, David; Sanyal, Arun J.; Medicine, School of MedicineNon-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. Methods In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72, and 96. Liver biopsies were obtained at baseline and 72 weeks. Results In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4, and 4% for NFS. Reductions in APRI (p=0.015) and FIB-4 (p=0.036), but not NFS (p=0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (p=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (p<0.0001); NFS (p<0.05)]. Conclusions Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate end points in NASH clinical trials.Item Validation of the accuracy of the FAST™ score for detecting patients with at-risk nonalcoholic steatohepatitis (NASH) in a North American cohort and comparison to other non-invasive algorithms(PLOS, 2022) Woreta, Tinsay A.; Van Natta, Mark L.; Lazo, Mariana; Krishnan, Arunkumar; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Diehl, Anna Mae; Abdelmalek, Manal F.; Chalasani, Naga; Gawrieh, Samer; Dasarathy, Srinivasan; Vuppalanchi, Raj; Siddiqui, Mohammad S.; Kowdley, Kris V.; McCullough, Arthur; Terrault, Norah A.; Behling, Cynthia; Kleiner, David E.; Fishbein, Mark; Hertel, Paula; Wilson, Laura A.; Mitchell, Emily P.; Miriel, Laura A.; Clark, Jeanne M.; Tonascia, James; Sanyal, Arun J.; NASH Clinical Research Network; Medicine, School of MedicineBackground and aims: Management of patients with NASH who are at elevated risk of progressing to complications of cirrhosis (at-risk NASH) would be enhanced by an accurate, noninvasive diagnostic test. The new FAST™ score, a combination of FibroScan® parameters liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and aspartate aminotransferase (AST), has shown good diagnostic accuracy for at-risk NASH (area-under-the-Receiver-Operating-Characteristic [AUROC] = 0.80) in European cohorts. We aimed to validate the FAST™ score in a North American cohort and show how its diagnostic accuracy might vary by patient mix. We also compared the diagnostic performance of FAST™ to other non-invasive algorithms for the diagnosis of at-risk NASH. Methods: We studied adults with biopsy-proven non-alcoholic fatty liver disease (NAFLD) from the multicenter NASH Clinical Research Network (CRN) Adult Database 2 (DB2) cohort study. At-risk-NASH was histologically defined as definite NASH with a NAFLD Activity Score (NAS) ≥ 4 with at least 1 point in each category and a fibrosis stage ≥ 2. We used the Echosens® formula for FAST™ from LSM (kPa), CAP (dB/m), and AST (U/L), and the FAST™-based Rule-Out (FAST™ ≤ 0.35, sensitivity = 90%) and Rule-In (FAST™ ≥ 0.67, specificity = 90%) zones. We determined the following diagnostic performance measures: AUROC, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV); these were calculated for the total sample and by subgroups of patients and by FibroScan® exam features. We also compared the at-risk NASH diagnostic performance of FAST™ to other non-invasive algorithms: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) index, and AST to platelet ratio index (APRI). Results: The NASH CRN population of 585 patients was 62% female, 79% white, 14% Hispanic, and 73% obese; the mean age was 51 years. The mean (SD) AST and ALT were 50 (37) U/L and 66 (45) U/L, respectively. 214 (37%) had at-risk NASH. The AUROC of FAST™ for at-risk NASH in the NASH CRN study population was 0.81 (95% CI: 0.77, 0.84. Using FAST™-based cut-offs, 35% of patients were ruled-out with corresponding NPV = 0.90 and 27% of patients were ruled-in with corresponding PPV = 0.69. The diagnostic accuracy of FAST™ was higher in non-whites vs. whites (AUROC: 0.91 vs 0.78; p = 0.001), and in patients with a normal BMI vs. BMI > 35 kg/m2 (AUROC: 0.94 vs 0.78, p = 0.008). No differences were observed by other patient characteristics or FibroScan® exam features. The FAST™ score had higher diagnostic accuracy than other non-invasive algorithms for the diagnosis of at-risk NASH (AUROC for NFS, FIB-4, and APRI 0.67, 0.73, 0.74, respectively). Conclusion: We validated the FAST™ score for the diagnosis of at-risk NASH in a large, multi-racial population in North America, with a prevalence of at-risk NASH of 37%. Diagnostic performance varies by subgroups of NASH patients defined by race and obesity. FAST™ performed better than other non-invasive algorithms for the diagnosis of at-risk NASH.