Abdelmalek, Manal F.

ABSTRACT Hepatic angiosarcoma is a rare and aggressive liver tumor. We report a case study of an 82-year-old elderly gentleman who presented with failure to thrive and ascites. Initially suspected to be cirrhosis, biopsy results eventually concluded angiosarcoma of the liver. Our patient presented with an infiltrative form, rather than distinct masses, which led to portal hypertension and ascites. The variance in symptomatology and radiology presentations make a diagnosis of hepatic angiosarcoma challenging and require a high index of suspicion.

Abstract Despite its considerable and growing burden, there are currently no Food and Drug Administration‐approved treatments for metabolic dysfunction‐associated steatotic liver disease or its progressive form, metabolic dysfunction‐associated steatohepatitis (MASH). Several glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and other agents are in various phases of clinical development for use in MASH; an ideal therapy should reduce liver fat content, improve chronic liver disease, help mitigate metabolic comorbidities and decrease all‐cause mortality. Because of interconnected disease mechanisms, metabolic dysfunction‐associated steatotic liver disease/MASH often coexists with type 2 diabetes (T2D), obesity and cardiovascular disease. Various GLP‐1RAs are Food and Drug Administration‐approved for use in T2D, and two, liraglutide and semaglutide, are approved for overweight and obesity. GLP‐1RAs decrease glucose levels and body weight and improve cardiovascular outcomes in people with T2D who are at high risk of cardiovascular disease. In addition, GLP‐1RAs have been reported to reduce liver fat content and liver enzymes, reduce oxidative stress and improve hepatic de novo lipogenesis and the histopathology of MASH. Weight loss may contribute to these effects; however, the exact mechanisms are unknown. Adverse events that are commonly associated with GLP‐1RAs include vomiting, nausea and diarrhoea. There is a lack of evidence from meta‐analyses regarding the increased risk of acute pancreatitis and various forms of cancer with GLP‐1RAs. Large‐scale, phase 3 trials, which will provide definitive data on GLP‐1RAs and other potential therapies in MASH, are ongoing. Given the spectrum of modalities under investigation, it is hoped that these trials will support the identification of pharmacotherapies that provide clinical benefit for patients with MASH.

Background: NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies. Methods: A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptide [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity. Results: NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEP MZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEP MZA (−0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3 MZA was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3 MZA . Conclusions: These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEP MZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEP MZA assessment could inform future development and optimization of NASH-related pharmacotherapies.

Background: Cenicriviroc (CVC) is a novel, orally administered antagonist of chemokine receptor types 2/5 that has demonstrated antifibrotic activity in a phase 2b study of patients with NASH. This phase 2, open-label, rollover study investigated the long-term safety and tolerability of CVC in patients with NASH and stage 0–4 liver fibrosis. Methods: Eligible patients who completed the phase 2 CENTAUR study or reached a predefined endpoint in the phase 3 AURORA study were rolled over and received open-label CVC 150 mg once daily. Safety assessments were conducted at the start of the study, and patients were seen in the clinic every 3 months until the study sponsor terminated CVC development. Safety endpoints included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, adverse event severity, and clinical laboratory assessments. Results: A total of 167 patients were enrolled, with a median treatment duration of 33.6 months. Before study termination, 36 patients (21.6%) prematurely discontinued the study. Treatment-related TEAEs were reported in 28 patients (16.8%). The most common treatment-related TEAEs were 4 cases of diarrhea (2.4%) and 2 cases each (1.2%) of abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, hypertriglyceridemia, myalgia, pruritus, and rash. The majority of these treatment-related events were mild in intensity, and none were life-threatening. There were no clinically meaningful changes in hepatic function, chemistry, or liver parameters from baseline to the end of the study. Conclusions: In this rollover study, CVC 150 mg once daily was well tolerated in patients with NASH and stage 0–4 liver fibrosis. No new safety signals were reported, and these data further support the safety and tolerability of CVC.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to determine the prevalence, clinical, and echocardiographic (TTE) features of HFpEF in patients with biopsy-proven NAFLD. Methods: We performed a retrospective single-center cohort study of patients with biopsy-proven NAFLD in the Duke NAFLD Biorepository and Clinical Database. Study entry was at the time of liver biopsy and patients were followed until death or 5/1/2023. Clinical and echocardiographic data were abstracted via manual chart review. HFpEF was defined as: at least one TTE characteristic (left atrial volume index ≥ 29 ml/m 2 , septal wall thickness ≥ 1 cm, or evidence of diastolic dysfunction) and signs or symptoms of heart failure (diagnosis of heart failure on problem list, hospitalization for heart failure, elevated NT pro-BNP level, jugular venous distention, use of loop diuretics, pulmonary or peripheral edema, fatigue, or exertional symptoms). Descriptive statistics were evaluated. Results: A total of 742 patients were included in the study. The mean age of the cohort was 50 +/- 12 years, and 83% were White. 95 (13%) had TTE both prior to study entry and during follow up, while 279 patients (38%) had TTE only during follow up. A total of 185 patients met criteria for HFpEF during follow up. After removing patients with TTE evidence of HFpEF prior to study entry, there were 132 cases of incident HFpEF over a mean follow up of 9.1 years, representing 47% of those with TTE after liver biopsy, and 18% of the overall cohort. Considering only TTE criteria, 142 patients had incident HFpEF. During follow up, 12 patients were hospitalized for heart failure. Conclusions: HFpEF is common in patients with NAFLD and a small percentage of patients do not have a chart diagnosis despite meeting echocardiographic criteria, suggesting that HFpEF may be under-recognized. Screening for HFpEF and/or formal care pathways to address early heart failure will be important to prevent morbidity and mortality in this population.

Background: Tobacco smoking during pregnancy is associated with metabolic dysfunction in children, but mechanistic insights remain limited. Hypomethylation of cg05575921 in the aryl hydrocarbon receptor repressor (AHRR) gene is associated with in utero tobacco smoke exposure. In this study, we evaluated whether AHRR hypomethylation mediates the association between maternal smoking and metabolic dysfunction in children. Methods: We assessed metabolic dysfunction using liver fat content (LFC), serum, and clinical data in children aged 7–12 years (n=78) followed since birth. Maternal smoking was self-reported at 12 weeks gestation. Methylation was measured by means of pyrosequencing at 3 sequential CpG sites, including cg05575921, at birth and at ages 7–12. Regression models were used to evaluate whether AHRR methylation mediated the association between maternal smoking and child metabolic dysfunction. Results: Average AHRR methylation at birth was significantly higher among children of nonsmoking mothers compared with children of mothers who smoked (69.8% ± 4.4% vs. 63.5% ± 5.5, p=0.0006). AHRR hypomethylation at birth was associated with higher liver fat content (p=0.01), triglycerides (p=0.01), and alanine aminotransferase levels (p=0.03), and lower HDL cholesterol (p=0.01) in childhood. AHRR hypomethylation significantly mediated associations between maternal smoking and liver fat content (indirect effect=0.213, p=0.018), triglycerides (indirect effect=0.297, p=0.044), and HDL cholesterol (indirect effect = -0.413, p=0.007). AHRR methylation in childhood (n=78) was no longer significantly associated with prenatal smoke exposure or child metabolic parameters (p>0.05). Conclusions: AHRR hypomethylation significantly mediates the association between prenatal tobacco smoke exposure and features of childhood metabolic dysfunction, despite the lack of persistent hypomethylation of AHRR into childhood. Further studies are needed to replicate these findings and to explore their causal and long-term significance.

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 Nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) share common risk factors, including obesity and diabetes. They are also thought to be mechanistically linked. The aim of this study was to define serum metabolites associated with HFpEF in a cohort of patients with biopsy‐proven NAFLD to identify common mechanisms. Methods and Results We performed a retrospective, single‐center study of 89 adult patients with biopsy‐proven NAFLD who had transthoracic echocardiography performed for any indication. Metabolomic analysis was performed on serum using ultrahigh performance liquid and gas chromatography/tandem mass spectrometry. HFpEF was defined as ejection fraction >50% plus at least 1 echocardiographic feature of HFpEF (diastolic dysfunction, abnormal left atrial size) and at least 1 heart failure sign or symptom. We performed generalized linear models to evaluate associations between individual metabolites, NAFLD, and HFpEF. Thirty‐seven out of 89 (41.6%) patients met criteria for HFpEF. A total of 1151 metabolites were detected; 656 were analyzed after exclusion of unnamed metabolites and those with >30% missing values. Fifty‐three metabolites were associated with the presence of HFpEF with unadjusted P value <0.05; none met statistical significance after adjustment for multiple comparisons. The majority (39/53, 73.6%) were lipid metabolites, and levels were generally increased. Two cysteine metabolites (cysteine s‐sulfate and s‐methylcysteine) were present at significantly lower levels in patients with HFpEF. Conclusions We identified serum metabolites associated with HFpEF in patients with biopsy‐proven NAFLD, with increased levels of multiple lipid metabolites. Lipid metabolism could be an important pathway linking HFpEF to NAFLD.