Long-term clinical outcomes in steatotic liver disease and incidence of liver-related events, cardiovascular events and all-cause mortality.

BACKGROUND: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown. AIMS: To evaluate the risk of liver-related events, MACE and death among patients with SLD. METHODS: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD. RESULTS: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death. CONCLUSIONS: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications.

The effects of food insecurity on hepatic steatosis and fibrosis in people with HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥18 years on antiretroviral therapy, HIV RNA<200 copies/mL, and without other known liver diseases were screened for NAFLD (CAP≥263 decibels/meter) and advanced fibrosis (LSM≥11 kilopascals) by vibration controlled transient elastography at eight US centers. Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 (31%) of participants, including 97/348 (28%) with NAFLD and 18/41 (44%) with advanced fibrosis. In multivariable analysis, FI was associated with lower odds of NAFLD (OR=0.57,95%CI:0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR=1.38,95%CI:0.65-2.90). We identified a significant interaction between FI and diabetes (p=0.02) on fibrosis risk, with a greater odds of fibrosis among food insecure PWH and diabetes (OR=3.83,95%CI:1.15-12.73) but not among food insecure nondiabetics (OR=1.12,95%CI:0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, a greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

Natural history of clinical outcomes and hepatic decompensation in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis. METHODS: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured. RESULTS: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years. CONCLUSION: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years.

PNPLA3 rs738409, age, diabetes, sex, and advanced fibrosis jointly contribute to the risk of major adverse liver outcomes in metabolic-associated steatotic liver disease.

BACKGROUND AND AIMS: The patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 variant is associated with Steatotic Liver Disease (SLD) and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALO) and how non-modifiable and modifiable conditions modify this relationship. APPROACH AND RESULTS: 2,075 adults with biopsy-confirmed Metabolic-Associated SLD (MASLD) were enrolled in the MASLD CRN studies and followed prospectively until death, transplant, or withdrawal of consent. 104 MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. SubHazard ratio (sHR): 1.4, 95% confidence interval (CI): 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (T2DM) (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) vs. noncarriers (53%), p=0.03, and p value for interaction<0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or T2DM (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p value for interaction between PNPLA3 and each factor<0.01. CONCLUSIONS: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by advanced fibrosis, age, T2DM, and sex.

New and emerging treatments for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading etiology of chronic liver disease worldwide, with increasing incidence and prevalence in the setting of the obesity epidemic. MASH is also a leading indication for liver transplantation, given its associated risk of progression to end-stage liver disease. A key challenge in managing MASH is the lack of approved pharmacotherapy. In its absence, lifestyle interventions with a focus on healthy nutrition and regular physical activity have been the cornerstone of therapy. Real-world efficacy and sustainability of lifestyle interventions are low, however. Pharmacotherapy development for MASH is emerging with promising data from several agents with different mechanisms of action (MOAs) in phase 3 clinical trials. In this review, we highlight ongoing challenges and potential solutions in drug development for MASH and provide an overview of available data from emerging therapies across multiple MOAs.

A prospective study on the prevalence of at-risk MASH in patients with type 2 diabetes mellitus in the United States.

BACKGROUND: There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. AIM: To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. METHODS: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. RESULTS: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). CONCLUSION: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis.

High concordance between nonalcoholic fatty liver disease and metabolic dysfunction associated steatotic liver disease in the TARGET-NASH real world cohort.

INTRODUCTION: This study investigates the applicability of the new MASLD nomenclature to the real-world TARGET-NASH US adult cohort. METHODS: The new MASLD/MASH nomenclature was applied to patients enrolled with pragmatic diagnoses of NAFL, NASH and NASH cirrhosis and concordance was determined between the definitions. RESULTS: 99% of TARGET-NASH participants met the new MASLD diagnostic criteria. 1484/1541 (96.3%, kappa 0.974) NAFL patients (MASL), 2195/2201 (99.7%, kappa 0.998) NASH patients (MASH), and 1999/2003 (99.8%, kappa 0.999) NASH cirrhosis patients met the new criteria. CONCLUSION: The new MASLD nomenclature is highly concordant with the prior TARGET-NASH pragmatic definitions.

Factors that mediate change in creatinine and acute kidney injury after the Norwood operation: insights from high-fidelity haemodynamic monitoring data.

BACKGROUND: Acute kidney injury is a common postoperative complication of paediatric cardiac surgery associated with increased morbidity and mortality. The purpose of this study is to characterise associations between haemodynamic parameters, clinical parameters, and medical interventions, on acute kidney injury. METHODS: Nine patients with univentricular physiology undergoing the Norwood procedure from a single-centre tertiary care paediatric cardiac ICU were included (September 2022 to March 2023). Patients were monitored with the T3 software. Data were analysed using a Fisher exact test, Mann-Whitney-U test, LASSO-based machine learning techniques, and receiver operator curve analyses. RESULTS: Over 27,000 datapoints were included. Acute kidney injury occurred in 2 patients (22%) during this period. Net fluid balance and renal oxygen extraction were independently associated with acute kidney injury, while commonly used metrics of pressure (systolic, diastolic, or mean arterial blood pressure) were not. The resulting acute kidney injury risk score was (4.1 × fluid balance) + (1.9 × renal oxygen extraction). The risk score was significantly higher in acute kidney injury with a score of 32.9 compared to 7.9 (p < 0.01). Optimal cut-offs for fluid balance (7 mL/hr) and renal oxygen extraction (29%) were identified. Higher serum creatinine:baseline creatinine ratio was associated with a higher mean airway pressure, higher renal oxygen extraction, higher mean arterial blood pressure, higher vasoactive inotropic score, and fluid balance. CONCLUSION: Among patients with univentricular physiology undergoing the Norwood procedure, renal oxygen extraction and a higher net fluid balance are independently associated with increased risk of acute kidney injury. Renal perfusion pressure is not significantly associated with acute kidney injury.

Impact of age on NIS2+™ and other non-invasive blood tests for the evaluation of liver disease and detection of at-risk MASH.

Background & Aims: Robust performance of non-invasive tests (NITs) across ages is critical to assess liver disease among patients with metabolic dysfunction-associated liver disease (MASLD). We evaluated the impact of age on the performance of NIS2+™ vs. other NITs. Methods: An analysis cohort (N = 1,926) with biopsy-proven MASLD was selected among individuals screened for the phase III RESOLVE-IT clinical trial and divided into ≤45, 46-55, 56-64, and ≥65 years groups. To avoid potential confounding effects, a well-balanced cohort (n = 708; n = 177/age group) was obtained by applying a propensity score-matching algorithm to the analysis cohort. Baseline values of biomarkers and NITs were compared across age groups using one-way ANOVA, and the impact of age and histology were compared through three-way ANOVA. The impact of age on NIT performance for the detection of at-risk metabolic dysfunction-associated steatohepatitis (MASH; MASLD activity score [MAS] ≥4 and fibrosis stage [F] ≥2) was also evaluated. Results: Age did not affect the distributions of NIS2+™ and APRI (aspartate aminotransferase-to-platelet ratio index), but significantly (p <0.0001) impacted those of NFS (NAFLD fibrosis score), FIB-4 (Fibrosis-4 index), and Enhanced Liver Fibrosis (ELF™) score. NIS2+™ was the only NIT on which fibrosis and MAS exerted a moderate to large effect. While the impact of fibrosis on APRI was moderate, that of MAS was low. The impact of age on FIB-4 and NFS was larger than that of fibrosis. NIS2+™ exhibited the highest AUROC values for detecting at-risk MASH across age groups, with stable performances irrespective of cut-offs. Conclusions: NIS2+™ was not significantly impacted by age and was sensitive to both fibrosis and MAS grade, demonstrating a robust performance to rule in/out at-risk MASH with fixed cut-offs. Impact and Implications: While metabolic dysfunction-associated steatotic liver disease (MASLD) can affect individuals of all ages, patient age could represent an important confounding factor when interpreting non-invasive test (NIT) results, highlighting the need for reliable and efficient NITs that are not impacted by age and that could be interpreted with fixed cut-offs, irrespective of patient age. We report the impact of age on different well-established NITs - among those tested, only two panels, NIS2+™ and APRI, were not impacted by age and can be used and interpreted independently of patient age. NIS2+™ was also sensitive to both fibrosis and MAS, further confirming its efficiency for the detection of the composite endpoint of at-risk MASH and its potential as a valuable candidate for large-scale implementation in clinical practice and clinical trials.

Aspirin for Metabolic Dysfunction-Associated Steatotic Liver Disease Without Cirrhosis: A Randomized Clinical Trial.

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown. Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD. Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023. Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months. Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified. Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn. Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Non-Hispanic Black persons with nonalcoholic fatty liver disease have lower rates of advanced fibrosis, cirrhosis, and liver-related events even after controlling for clinical risk factors and PNPLA3 genotype.

BACKGROUND AIMS: Nonalcoholic fatty liver disease (NAFLD) is less frequent in non-Hispanic persons (NHB) but there are knowledge gaps in our understanding of disease severity and outcomes of NAFLD in NHB. We compared liver histology and clinical outcomes of NAFLD in NHB and non-Hispanic White adults (NHW). METHODS: We compared liver histology and outcomes of 109 NHB and 1910 NHW adults with biopsy proven NAFLD participating in the Nonalcoholic Steatohepatitis Clinical Research Network observational studies. The relationship between self-reported NHB race/ethnicity and advanced fibrosis was assessed via multivariable logistic regression after controlling for clinical co-variates and PNPLA3 genotype. RESULTS: NHB and NHW with NAFLD had similar NAFLD activity scores (NAS, 4.4 vs 4.3, p=0.87) and proportions with definite NASH (59% vs 58%, p=1.0), but NHB had significantly lower rates of advanced fibrosis (22% vs 34%, p=0.01) or cirrhosis (4.6% vs 12.1%, p=0.010). Compared to NHW, NHB had significantly lower frequency of advanced fibrosis (OR: 0.48, 95% CI:.27-0.86, p=0.01). In a comparison between 24 NHB and 655 NHW with advanced fibrosis, the NAS (5.6 vs 4.9, p=0.01) and lobular inflammation grade (2.2 vs 1.7, p<0.002) were significantly higher among NHB with advanced fibrosis. One NHB and 23 NHW died during follow-up (0.30 vs 0.28 per 100 person-year follow-up). Seven and zero liver-related deaths occurred in NHW and NHB with NAFLD respectively. CONCLUSION: The risk of advanced fibrosis in NHB with NAFLD is significantly lower, after controlling for clinical risk factors and PNPLA3 genotype. Although their risk for advanced fibrosis was low, NHB with NAFLD and advanced fibrosis had higher NAS and lobular inflammation, indicating a difference in their relationship between necroinflammation and fibrosis.

Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease.

This commentary discusses how clinicians and various stakeholders can utilize the recently published American Association for the Study of Liver Diseases nonalcoholic fatty liver disease (AASLD NAFLD) Practice Guidance in light of the change in the nomenclature to steatotic liver disease and its subcategories. The new terminologies explained in this commentary make it easier for the readers to interchangeably use metabolic dysfunction-associated steatotic liver disease (MASLD) in place of NAFLD and metabolic-dysfunction associated steatohepatitis (MASH) instead of nonalcoholic steatohepatitis (NASH), respectively, as they read the NAFLD Practice Guidance. The guidance document is relevant and can be utilized for the diagnosis, risk stratification, and management of patients with MASLD. This commentary serves as an accompanying article to the NAFLD Practice Guidance and helps it clinical application in the light of the new nomenclature.

New Nomenclature for Nonalcoholic Fatty Liver Disease: Understanding Metabolic Dysfunction-Associated Steatotic Liver Disease, Metabolic Dysfunction- and Alcohol-Associated Liver Disease, and Their Implications in Clinical Practice.

In June 2023, under the patronage of the American Association for Study of Liver Disease, the European Association for Study of the Liver, and the Asociación Latinoamericana para el Estudio del Hígado with the involvement of 236 participants from around the world, a new nomenclature and definition for nonalcoholic fatty liver disease (NAFLD) has been proposed. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined as presence of hepatic steatosis and at least one of the cardiometabolic risk factors with alcohol intake less than 140 g/wk for women and 210 g/wk for men and no other causes of steatosis. A new entity called combined metabolic dysfunction- and alcohol-associated liver disease (MetALD) was created outside of pure MASLD for patients with metabolic dysfunction and alcohol intake greater than that allowed for MASLD (i.e., 140-350 g/wk for women and 210-420 g/wk for men). Recent studies have confirmed a 95% overlap between NAFLD and the new MASLD diagnostic criteria. Natural history, biomarkers, and thresholds of alcohol intake in MetALD group remains to be studied and validated.

Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS: Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.

Prevalence of at-risk MASH, MetALD and alcohol-associated steatotic liver disease in the general population.

BACKGROUND: The prevalence of at-risk metabolic dysfunction-associated steatohepatitis (at-risk MASH) has not been systematically assessed. AIM: To delineate the prevalence of at-risk MASH in a large population-based cohort. METHODS: We conducted a cross-sectional analysis of 40,189 patients in the UK Biobank who underwent liver MRI. Hepatic steatosis was determined by proton density fat fraction (PDFF) ≥5%. Based on AASLD criteria, participants were classified as alcohol-associated steatotic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), combined metabolic alcoholic liver disease (MetALD) and at-risk MASH. RESULTS: Among 40,189 patients, 10,886 (27.0%) had a PDFF ≥5%, indicating SLD. Among patients with SLD, 1% had ALD, 89.0% had MASLD, 7.9% had MetALD and 2.2% had at-risk MASH. The at-risk MASH group, which included 0.6% of the general population, had the highest mean liver fat on MRI and the highest BMI. Serum biomarkers highlighted increased inflammation and metabolic changes in at-risk MASH. The prevalence of MASLD was significantly higher among men with a BMI ≥30 kg/m2. Non-obese women showed only a 12% risk of MASLD. Conversely, MetALD had similar prevalence in obese men and women and was absent in non-obese women. CONCLUSIONS: MASLD is prevalent among patients with elevated PDFF on MRI. There are different sex- and BMI-specific prevalence of different steatotic liver disorders. At-risk MASH demonstrates the most severe metabolic and inflammatory profiles. This study provides novel estimates for the at-risk MASH population that will be eligible for treatment with pharmacologic therapy when approved by regulatory authorities.

Review article: New developments in biomarkers and clinical drug development in alpha-1 antitrypsin deficiency-related liver disease.

BACKGROUND: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD. AIMS: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments. METHODS: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic. RESULTS: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies. CONCLUSIONS: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.

Postoperative Atrioventricular Block in Pediatric Patients: Impact of Congenital Cardiac Malformations and Medications.

Postoperative atrioventricular block may occur after pediatric cardiac surgery. A small proportion of those who develop atrioventricular block will require pacemaker placement. The primary aim of this study was to determine factors associated with postoperative atrioventricular block. Secondary aims included determining factors associated with pacemaker placement in those with atrioventricular block. Data from the PHIS data were utilized to identify patients under 18 years of age who underwent cardiac surgery. Those who did and did not develop atrioventricular block. Univariable analyses and regression analyses were conducted to determine factors associated with postoperative atrioventricular block. Similar analyses were conducted to determine factors associated with pacemaker placement in those with atrioventricular block. A total of 43,716 admissions were identified. Of these, 2093 (5%) developed atrioventricular block and 480 (1% of total admissions) underwent pacemaker placement. Approximately 70% of those with atrioventricular block received steroids but this was not associated with a decrease in pacemaker placement. Risk factors (congenital malformations of the heart, comorbidities, medications) associated with increased risk of atrioventricular block and pacemaker placement were identified. Postoperative atrioventricular block occurred in 5% of pediatric admissions for cardiac surgery. Of these admissions with postoperative atrioventricular block, 23% required pacemaker placement. Isoproterenol and steroids were not associated with a reduction in the likelihood of pacemaker placement.