Rinella, Mary E.

Pediatric metabolic dysfunction–associated steatotic liver disease (MASLD) has become more prevalent on a global scale over the last decades and is associated with significant comorbidities in childhood and a 40-fold higher risk of early mortality in young adulthood. MASLD has now become the leading indication for liver transplantation in young adults in the United States. However, pediatric MASLD is still perceived as an indolent condition by many patients, families, and clinicians. In this Call to Action, we aim to raise awareness of pediatric MASLD as a public health crisis. Herein, we describe insufficient screening and disease staging practices, and a lack of accurate non-invasive tests and effective pharmacotherapy, both stemming from a paucity of multicenter clinical trials in pediatric MASLD. We provide clear steps to address this public health emergency by promoting awareness campaigns, educating and empowering patients and families, addressing barriers including access to care, nutritional and exercise support programs, establishing multidisciplinary care, launching community initiatives, and conducting clinical trials in pediatric MASLD for an age-based evaluation of novel diagnostic and therapeutic options. We conclude by highlighting the urgent need for comprehensive public health policies to control the tide of pediatric MASLD and call upon stakeholders to act now.

Background. Chronic kidney disease (CKD) is a well-recognized complication in patients undergoing liver transplantation (LT), particularly those with metabolic dysfunction-associated steatohepatitis (MASH), a leading cause of cirrhosis in the modern era. This study sought to refine risk stratification for CKD events post-LT in cirrhosis patients with MASH by leveraging baseline renal function at transplant. Methods. A total of 717 MASH cirrhosis patients who had LT (1997–2017) at 7 US centers (NailMASH Consortium) were analyzed. Patients were categorized by estimated glomerular filtration rate (eGFR) at transplant: low (LGFR, eGFR ≤30 mL/min/1.73 m²), medium (MGFR, eGFR >30–≤60 mL/min/1.73 m²), and high (HGFR, eGFR >60 mL/min/1.73 m²). Time-related eGFR intercepts, slopes, and assessments of advanced-stage CKD (aCKD) events, defined as 2 eGFR levels <30 mL/min/1.73 m² separated by ≥90 d, were examined. Results. Post-LT, LGFR group showed increased eGFR, whereas the HGFR group experienced a decline. The 3-mo mark was identified as a “reset point,” signifying a new reference level, beyond which a different rate of decline was observed. After 3 mo, mean eGFRs of the LGFR group approached MGFRs, whereas the mean eGFR of the HGFR group continued to decrease but remained higher than other groups during a 60-mo follow-up. LGFR patients had significantly higher aCKD probability than MGFR and HGFR groups. Subanalysis at 3 mo post-LT revealed more aCKD events in the LGFR group compared with MGFR and HGFR groups ( P < 0.0001). Conclusions. The study underscores renal impact of LT in MASH cirrhosis, indicating unique eGFR trajectories post-LT tied to baseline eGFR, with a reset point at 3 mo. Monitoring post-LT renal function, especially in those at aCKD risk, is crucial. Renal-sparing immunosuppression may help, regardless of baseline eGFR. Further studies are needed for interventions addressing renal dysfunction of patients with MASH post-LT.

Abstract Background and Aims Non‐invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction‐associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice. Methods We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis. Results Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system‐level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost‐effectiveness to payers. Conclusions This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system‐level barriers. Multi‐level interventions are likely required to address these barriers.

Background: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. Methods: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. Results: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). Conclusions: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Occurrence of metabolic dysfunction–associated steatotic liver disease (MASLD) is common following liver transplantation (LT). MASLD can be classified as a recurrent disease when it occurs in patients receiving LT for metabolic dysfunction–associated steatohepatitis (MASH) or as de novo when it occurs in patients undergoing transplantation for non-metabolic dysfunction–associated steatohepatitis etiologies of liver disease. Fibrosis progression in patients with MASLD is accelerated, with progression to cirrhosis occurring more rapidly compared with the general (ie, non-LT) population. Moreover, the metabolic burden in LT recipients with MASLD is high and synergizes with liver disease to negatively affect the clinical course. Despite the oversized clinical burden of MASLD among LT recipients, there is currently a lack of regulatory approach and pathway for therapeutics development in this patient population. The present document, thus, provides guidance for therapeutics development that incorporates nuances of transplant care in patients with post-LT MASLD to facilitate drug development.

Background and Aims: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. Approach and Results: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was −0.5 (95% CI, −0.7 to −0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events. Conclusions: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

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.

The 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.