Noureddin, Mazen

Diagnosing and managing metabolic dysfunction-associated steatotic liver disease (MASLD) remains a major challenge in primary care due to lack of agreement on diagnostic tools, difficulty in identifying symptoms and determining their cause, absence of approved pharmacological treatments, and limited awareness of the disease. However, prompt diagnosis and management are critical to preventing MASLD from progressing to more severe forms of liver disease. This highlights the need to raise awareness and improve understanding of MASLD among both patients and physicians. The patient perspective is invaluable to advancing our knowledge of this disease and how to manage it, as their perspectives have led to the growing recognition that patients experience subtle symptoms and that patient-reported outcomes should be incorporated into drug development. This review and expert opinion examine MASLD and metabolic dysfunction-associated steatohepatitis from the patient and physician perspective from pre-diagnosis to diagnosis and early care, through to progression to advanced liver damage. Specifically, the paper dives into the issues patients and physicians experience, and, in turn, what is required to improve diagnosis and management, including tips and tools to empower patients and physicians dealing with MASLD.

Background and Aims: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. Approach and Results: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of “agree” responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% “agree”). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. Conclusions: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Background and Aims: Magnetic resonance elastography (MRE) is an accurate, continuous biomarker of liver fibrosis; however, the optimal combination with clinical factors to predict the risk of incident hepatic decompensation is unknown. Therefore, we aimed to develop and validate an MRE-based prediction model for hepatic decompensation for patients with NAFLD. Approach and Results: This international multicenter cohort study included participants with NAFLD undergoing MRE from 6 hospitals. A total of 1254 participants were randomly assigned as training (n = 627) and validation (n = 627) cohorts. The primary end point was hepatic decompensation, defined as the first occurrence of variceal hemorrhage, ascites, or HE. Covariates associated with hepatic decompensation on Cox-regression were combined with MRE to construct a risk prediction model in the training cohort and then tested in the validation cohort. The median (IQR) age and MRE values were 61 (18) years and 3.5 (2.5) kPa in the training cohort and 60 (20) years and 3.4 (2.5) kPa in the validation cohort, respectively. The MRE-based multivariable model that included age, MRE, albumin, aspartate aminotransferase, and platelets had excellent discrimination for the 3- and 5-year risk of hepatic decompensation (c-statistic 0.912 and 0.891, respectively) in the training cohort. The diagnostic accuracy remained consistent in the validation cohort with a c-statistic of 0.871 and 0.876 for hepatic decompensation at 3 and 5 years, respectively, and was superior to Fibrosis-4 in both cohorts (p < 0.05). Conclusions: An MRE-based prediction model allows for accurate prediction of hepatic decompensation and assists in the risk stratification of patients with NAFLD.

Background and Aims: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. Approach and Results: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR140), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR140 + CVC), or TXR 90 μg + CVC 150 mg (TXR90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: −21%, TXR140; −16%, TXR140 + CVC; −13%, TXR90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR140, −2.5 kg; TXR140 + CVC, −1.7 kg; TXR90 + CVC, −1.0 kg; and CVC, −0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR140, CVC, TXR140 + CVC, and TXR90 + CVC groups, respectively. Conclusions: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Abstract There is ongoing recognition of the burden of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH), with fibrosis being the most important histological feature that is associated with progression to cirrhosis and the occurrence of major adverse liver outcomes. Liver biopsy is the gold standard applied to detect NASH and determine the stage of fibrosis, but its use is limited. There is a need for non‐invasive testing (NIT) techniques to identify patients considered at‐risk NASH (NASH with NAFLD activity score > 4 and ≥ F2 fibrosis). For NAFLD‐associated fibrosis, several wet (serological) and dry (imaging) NITs are available and demonstrate a high negative predictive value (NPV) for excluding those with advanced hepatic fibrosis. However, identifying at‐risk NASH is more challenging; there is little guidance on how to use available NITs for these purposes, and these NITs are not specifically designed to identify at‐risk NASH patients. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods to non‐invasively identify at‐risk NASH patients. This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with suspected NAFLD and potential NASH. This algorithm can be used for staging, risk stratification and the effective transition of patients who may benefit from specialty care.

BackgroundCurative surgical treatments afford the best prognosis for patients with intrahepatic cholangiocarcinoma (iCCA); however, the comparative effectiveness of treatment options and factors associated with curative treatment receipt for early stage iCCA remain unknown.MethodsThe authors identified patients who were diagnosed with early stage iCCA, defined as a unifocal tumor <3 cm, during 2004–2018 from the National Cancer Database. Multivariable logistic and Cox regression analyses were used to identify the factors associated with curative treatment and overall survival (OS), respectively.ResultsThe proportion of patients with early stage iCCA increased from 4.5% in 2004 to 7.3% in 2018, with the odds of early stage detection increasing by 3.1% per year (odds ratio [OR], 1.031; 95% CI, 1.015–1.049). Of 1093 patients who had early stage iCCA, 464 (42.5%) underwent resection, 113 (10.3%) underwent ablation, 62 (5.7%) underwent liver transplantation, and 454 (41.5%) received noncurative treatments. Hispanic patients (adjusted OR [aOR], 0.57; 95% CI, 0.33–0.97) and Black patients (aOR, 0.47; 95% CI, 0.28–0.77) were less likely to receive curative treatments than White patients. Compared with patients who underwent surgical resection, those who underwent liver transplantation had a trend toward improved OS (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.37–1.08), whereas those who underwent local ablation (aHR, 1.39; 95% CI, 1.01–1.92) and noncurative treatments (aHR, 3.97; 95% CI, 3.24–4.88) experienced worse OS.ConclusionsMore than one third of patients with early stage iCCA did not receive curative treatment, with Hispanic and Black patients being less likely to receive curative treatments than White patients. Surgical resection and liver transplantation were associated with improved survival compared with local ablation. Future studies should investigate disparities in curative treatment receipt and outcomes for early stage iCCA.

Abstract Background and Aims Immunotherapy has emerged as an effective treatment for patients with advanced‐stage HCC. We aimed to investigate the efficacy of immunotherapy for advanced HCC in a nationwide cohort and racial and ethnic disparities in access to immunotherapy. Approach and Results We used the US National Cancer Database to identify patients with tumor‐node‐metastasis stage 3 or 4 HCC between 2017 and 2018. We performed multivariable Cox regression to identify factors associated with overall survival (OS) and logistic regression to identify factors associated with receipt of immunotherapy. Of the 3,990 patients treated for advanced HCC, 3,248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first‐line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR: 0.76, 95% CI: 0.65–0.88) after adjusting for covariates. There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted OR [aOR]: 0.63, 95% CI: 0.46–0.83) and Black patients (aOR: 0.71, 95% CI: 0.54–0.89) less likely to receive immunotherapy compared with White patients. There was a significant interaction between race‐ethnicity and facility type, with higher disparity observed in nonacademic centers (interaction p = 0.004). Conclusions Immunotherapy was associated with improved OS compared with chemotherapy in advanced HCC. There are significant disparities in early access to immunotherapy, likely due to differential access to clinical trials and experimental therapies. A comprehensive approach to monitoring and eliminating racial‐ethnic disparities in the management of advanced HCC is urgently needed.

Abstract Background and Aims The NASH Clinical Research Network histologic scoring system, the gold‐standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). Approach and Results Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80–0.85) and interrater (0.60–0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68–0.79), including those extending scores from 0–2 to 0–4. Steatosis measures (interrater ICCs, 0.72–0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory‐Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70–0.87. Conclusions After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

Background and Aims Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers (PLCs). Differences in their clinical features and outcomes are open for investigation in a large‐scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC. Approach and Results The Surveillance, Epidemiology, and End Results Program 18 Database (2000‐2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis versus HCC. Cox regression analysis was used to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non‐Hispanic White race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis versus HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months; P < 0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR] = 1.02; 95% CI = 0.99‐1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥5 cm (aHR = 0.83; 95% CI = 0.80‐0.86), lymph node involvement (aHR = 0.76; 95% CI = 0.72‐0.81), distant metastasis (aHR = 0.76; 95% CI = 0.73‐0.79), poorly/undifferentiated tumors (aHR = 0.88; 95% CI = 0.83‐0.94), and those receiving noncurative treatment (aHR = 0.96; 95% CI = 0.93‐0.98). Conclusions We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with PLC. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.