Liver tissue lipids in metabolic dysfunction-associated steatotic liver disease with diabetes and obesity.

Background: Diabetes and obesity are associated with altered lipid metabolism and hepatic steatosis. Studies suggest that increases in lipid accumulation in these patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are not uniform for all lipid components. This study evaluates this variation.

Accuracy of ultrasonographic fatty liver index using point-of-care ultrasound in stratifying non-alcoholic fatty liver disease patients.

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in the USA. Some of these patients develop non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis. Ultrasound imaging is one of the most used modalities for diagnosing hepatic steatosis.

Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation.

Background Aims: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood.

Approach Results: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH.

Accuracy of steatosis and fibrosis NAFLD scores in relation to vibration controlled transient elastography: An NHANES analysis.

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and increasing in the United States. Based on patient characteristics and biochemical profiles, predictive indices have been formulated to evaluate the presence and severity of NAFLD. This study evaluates the accuracy of these indices versus vibration-controlled transient elastography (VCTE™) to screen at-risk populations for NAFLD.

Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis.

Background And Aims: Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)-/- mice are completely protected from ethanol-induced liver injury, Mlkl-/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.

IL-1 receptor antagonist plus pentoxifylline and zinc for severe alcohol-associated hepatitis.

Background And Aims: Patients with severe alcohol-associated hepatitis (AH) have high mortality. Corticosteroids improve survival only for 30 days. We targeted inflammation, cellular injury, and gut leakiness in a randomized clinical trial comparing combination therapy to corticosteroids on 180-day survival.

Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice.

There is mounting evidence that microbes residing in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcohol-associated hepatitis (AH). However, mechanisms by which gut microbes synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested.

Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis.

Importance: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH).

Objective: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis.

Design, Setting, And Participants: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3).

Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans.

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH.

Design and rationale of a multicenter defeat alcoholic steatohepatitis trial: (DASH) randomized clinical trial to treat alcohol-associated hepatitis.

Background/aims: Despite high mortality of alcohol-associated hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different perturbations in AH.

Methods: Severe AH was diagnosed by liver biopsy or clinical and biochemical criteria and model for end stage liver disease (MELD) score ≥ 20 stratified by MELD scores (20-25 and ≥ 26) and randomized to a combination of an interleukin receptor 1 antagonist, Anakinra(100 mg daily for 14 days) to suppress acute inflammation, pentoxifylline (400 mg three times a day for 28 days) to prevent hepatorenal syndrome, and zinc sulfate (220 mg orally once daily for 6 months) or the standard of care therapy including methylprednisolone 32 mg orally once daily for 28 days.

Diagnostic and Prognostic Significance of Complement in Patients With Alcohol-Associated Hepatitis.

Background And Aims: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here, we investigated whether a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90-day mortality.

β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and impaired insulin sensitivity. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and reduced insulin sensitivity remains obscure. We investigated individuals with obesity-related NAFLD and hypothesized that β-hydroxybutyrate (βOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and insulin sensitivity.

The association of nonalcoholic steatohepatitis and hepatocellular carcinoma.

Background: Current guidelines recommend surveillance for hepatocellular carcinoma (HCC) in high-risk patients. This high risk is defined by the presence of cirrhosis. However, HCC due to underlying nonalcoholic steatohepatitis (NASH), even without progressing to cirrhosis, is a rising concern.

Exercise Training Rapidly Increases Hepatic Insulin Extraction in NAFLD.

Purpose: We aimed to determine the immediacy of exercise intervention on liver-specific metabolic processes in nonalcoholic fatty liver disease.

Methods: We undertook a short-term (7-d) exercise training study (60 min·d treadmill walking at 80%-85% of maximal heart rate) in obese adults (N = 13, 58 ± 3 yr, 34.3 ± 1.

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease.

Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics.

Continued muscle loss increases mortality in cirrhosis: Impact of aetiology of liver disease.

Background And Aims: Sarcopenia or skeletal muscle loss adversely affects outcomes in cirrhosis. The impact of aetiology of liver disease on the severity or the rate of muscle loss is not known.

Methods: Consecutive, well-characterized adult patients with cirrhosis due to viral hepatitis (VH), alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD) and non-diseased controls with at least two temporally distinct abdominal CT (computed tomography) scans were evaluated.

Non-invasive assessment of hepatic lipid subspecies matched with non-alcoholic fatty liver disease phenotype.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic fat accumulation. Increased hepatic saturated fats and decreased hepatic polyunsaturated fats may be particularly lipotoxic, contributing to metabolic dysfunction. We compared hepatic lipid subspecies in adults with and without NAFLD, and examined links with hallmark metabolic and clinical characteristics of NAFLD.

Impact of sleeve gastrectomy and Roux-en-Y gastric bypass on biopsy-proven non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Our aim was to study the long-term effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on NAFLD/NASH.

Methods: Between 2008 and 2015, 3813 patients had an intraoperative liver biopsy performed at the time of primary RYGB and SG at a single academic center.

Assessing liver fibrosis without biopsy in patients with HCV or NAFLD.

Staging of liver fibrosis is increasingly done using noninvasive methods, in some cases obviating the need for liver biopsy. Scores based on laboratory values and demographic variables have been developed and validated for assessing fibrosis in patients with hepatitis C virus (HCV) infection and nonalcoholic fatty liver disease (NAFLD), as have several imaging methods that measure shear-wave velocity, a reflection of fibrosis severity.

Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis.

Background: Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown.

Goals: Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH.