Ibrahim, Samar H

Abstract Context Variants in melanocortin 4 receptor (MC4R) pathway-related genes have been associated with obesity. The association of these variants with cardiometabolic parameters are not fully known. Objective We compared the severity of obesity and cardiometabolic risk markers in children with MC4R pathway-related clinically reported genetic variants relative to children without these variants. Methods A retrospective chart review was performed in children with obesity who underwent multigene panel testing for monogenic obesity. Results Data on a total of 104 children were examined, with 93 (89%) identified as White. Thirty-nine (37.5%) patients had clinically reported variants in the MC4R pathway, and the remaining 65 patients did not have reported MC4R pathway-related variants. Among the MC4R-related variants, PCSK1 risk alleles were most common, reported in 15 children (14%). The maximum body mass index percent of the 95th percentile was not different between groups (P = .116). Low-density lipoprotein cholesterol (LDL-C) was not different between groups (P = .132). However, subgroup analysis demonstrated higher LDL cholesterol in children with the PCSK1 c.661A>G risk allele relative to those with MC4R-related variant of uncertain significance (P = .047), negative genetic testing (P = .012), and those with non-MC4R related variants (P = .048). The blood pressure, fasting glucose, hemoglobin A1C, total cholesterol, alanine transaminase, and high-density lipoprotein cholesterol were not different between groups. Conclusion Variants in the MC4R pathway-related genes were not associated with severity of obesity and cardiometabolic risk markers except for the c.661A>G PCSK1 risk allele, which was associated with higher LDL-C levels.

AbstractObjectivesTo compare long‐term transplant outcomes (organ rejection and retransplant) of simultaneous liver/kidney transplant (SLK) versus isolated kidney transplant (IK) for patients with primary hyperoxaluria (PH).MethodsThe Rare Kidney Stone Consortium PH registry was queried to identify patients with PH who underwent SLK or IK from 1999 to 2021. Patient characteristics and long‐term transplant outcomes were abstracted and analyzed. Statistical comparisons were performed with Kaplan–Meier plots and Cox proportional hazards models.ResultsWe identified 250 patients with PH, of whom 35 received care at Mayo Clinic and underwent SLK or IK. Patients who underwent SLK as their index transplant had lower odds of kidney rejection than did those who underwent IK (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.08–0.99; p = .048). The immunoprotective effect of concomitant liver and kidney transplant appeared to enhance outcomes for patients with PH. Additionally, the odds of retransplant were significantly lower for patients who underwent SLK as their index transplant than for those who underwent IK (HR, 0.08; 95% CI, 0.02–0.42; p = .003). Of five patients who underwent IK and had maintained graft function for at least 5 years after transplant, three (60%) had documented vitamin B6 responsiveness.ConclusionsPatients with PH who underwent SLK had a lower risk of kidney rejection and retransplant than those who underwent IK. Accurate genetic assessment for vitamin B6 responsiveness may optimize IK allocation. Novel therapeutics, such as lumasiran, have been introduced as promising agents for the management of PH.

AbstractMetabolic dysfunction‐associated steatotic liver disease (MASLD) is increasing globally in pediatric populations. Currently, MASLD management primarily relies on lifestyle interventions, which pose challenges in sustaining long‐term weight loss. This study investigated the use of weight loss medications in MASLD care through an international survey of 166 pediatric gastroenterologists and hepatologists. The results indicated a notable interest in weight loss medications, with 38% of practitioners considering or using them, particularly glucagon‐like peptide‐1 receptor agonists. However, the survey also revealed a tendency among clinicians to refer patients to specialists, emphasizing the potential gap between acknowledgment and prescription practices. Challenges include the lack of guidelines and uncertainty regarding side effects. The study highlights a pressing need for education, with over 90% of the respondents expressing an interest. Our study highlights the current management of MASLD, the potential role of pharmacotherapy, and highlights avenues for improved care and education in this dynamic field.

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction–associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

Background: NASH is the progressive form of NAFLD characterized by lipotoxicity, hepatocyte injury, tissue inflammation, and fibrosis. Previously, Rho-associated protein kinase (ROCK) 1 has been implicated in lipotoxic signaling in hepatocytes in vitro and high-fat diet-induced lipogenesis in vivo. However, whether ROCK1 plays a role in liver inflammation and fibrosis during NASH is unclear. Here, we hypothesized that pathogenic activation of ROCK1 promotes murine NASH pathogenesis. Methods and Results: Patients with NASH had increased hepatic ROCK1 expression compared with patients with fatty liver. Similarly, hepatic ROCK1 levels and activity were increased in mice with NASH induced by a western-like diet that is high in fat, fructose, and cholesterol (FFC). Hepatocyte-specific ROCK1 knockout mice on the FFC diet displayed a decrease in liver steatosis, hepatic cell death, liver inflammation, and fibrosis compared with littermate FFC-fed controls. Mechanistically, these effects were associated with a significant attenuation of myeloid cell recruitment. Interestingly, myeloid cell-specific ROCK1 deletion did not affect NASH development in FFC-fed mice. To explore the therapeutic opportunities, mice with established NASH received ROCKi, a novel small molecule kinase inhibitor of ROCK1/2, which preferentially accumulates in liver tissue. ROCK inhibitor treatment ameliorated insulin resistance and decreased liver injury, inflammation, and fibrosis. Conclusions: Genetic or pharmacologic inhibition of ROCK1 activity attenuates murine NASH, suggesting that ROCK1 may be a therapeutic target for treating human NASH.

LSECs are a unique population of endothelial cells within the liver and are recognized as key regulators of liver homeostasis. LSECs also play a key role in liver disease, as dysregulation of their quiescent phenotype promotes pathological processes within the liver including inflammation, microvascular thrombosis, fibrosis, and portal hypertension. Recent technical advances in single-cell analysis have characterized distinct subpopulations of the LSECs themselves with a high resolution and defined their gene expression profile and phenotype, broadening our understanding of their mechanistic role in liver biology. This article will review 4 broad advances in our understanding of LSEC biology in general: (1) LSEC heterogeneity, (2) LSEC aging and senescence, (3) LSEC role in liver regeneration, and (4) LSEC role in liver inflammation and will then review the role of LSECs in various liver pathologies including fibrosis, DILI, alcohol-associated liver disease, NASH, viral hepatitis, liver transplant rejection, and ischemia reperfusion injury. The review will conclude with a discussion of gaps in knowledge and areas for future research.

Abstract With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.