Inhibition of Carnitine Palmitoyltransferase 1A in HSC Protects Against Fibrosis

CPT1A is overexpressed in HSCs from patients with fibrosis and positively correlates with fibrosis and NAFLD activity score.

source: J Hepatology

Summary

[Posted 03/Aug/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: The results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment.

BACKGROUND: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored.

DETAILS: CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, induced fibrosis in mice lacking CPT1A specifically in HSCs. Herein, study shows that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor ß1 (TGFß1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFß1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride.

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Source: Fondevila, M. F., Fernandes, U., Heras, V., et al. (2022). Inhibition of Carnitine Palmitoyltransferase 1A in Hepatic Stellate Cells Protects Against Fibrosis. J Hepatology. 2022; 77(1): 15-28. Published: July, 2022. DOI: 10.1016/j.jhep.2022.02.003.



AKD is Common and Associated with Poor Outcomes In Patients with Cirrhosis and AKI

AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse 90- and 180-day survival and de novo CKD.

source: J Hepatology

Summary

Acute Kidney DiseaseiIs Common and Associated with Poor Outcomes In Patients with Cirrhosis and Acute Kidney Injury

[Posted 11/Jul/2022]

AUDIENCE: Gastroenterology, Nephrology, Internal Medicine

KEY FINDINGS: AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse survival and de novo CKD. Interventions that target AKD may improve outcomes of patients with cirrhosis and AKI.

BACKGROUND: Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months, which is proposed to be the time-window where critical interventions can be initiated to alter downstream outcomes of AKI. In cirrhosis, AKD and its impact on outcomes have been scantly investigated. Study aim was to define the incidence and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI.

DETAILS: Hospitalized patients with cirrhosis and AKI in the Cerner-Health-Facts database from 1/2009-09/2017 (n = 6,250) were assessed for AKD and were followed-up for 180 days. AKI and AKD were defined based on KDIGO and ADQI AKD and renal recovery consensus criteria, respectively. The primary outcome measure was mortality, and the secondary outcome measure was de novo chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes. AKD developed in 32% of our cohort. On multivariable competing-risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 (subdistribution hazard ratio [sHR] 1.37; 95% CI 1.14-1.66; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14-1.64; p = 0.001) days. The incidence of de novo CKD was 37.5%: patients with AKD had higher rates of de novo CKD (64.0%) compared to patients without AKD (30.7%; p 0.001). After adjusting for confounders, AKD was independently associated with de novo CKD (sHR 2.52; 95% CI 2.01-3.15; p 0.001) on multivariable competing-risk analysis.

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Source: Patidar, K. R., Naved, M. A., Grama, A., et al. (2022). Acute Kidney Disease Is Common and Associated with Poor Outcomes In Patients With Cirrhosis And Acute Kidney Injury. J Hepatology. 2022; 77(1): 108-115. Published: July, 2022. DOI: 10.1016/j.jhep.2022.02.009.



Hepatitis B Surface Antigen Levels

Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

source: J Infect Disease

Summary

Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study

[Posted 14/Jun/2022]

AUDIENCE: Infectious Disease, Internal Medicine

KEY FINDINGS: Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

BACKGROUND: Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis.

DETAILS: Analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3-4) or cirrhosis (Ishak 5-6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (<=7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4).

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Copyright © Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Sonneveld, M. J., Hansen, B. H., Brouwer, W. P., et al. (2022). Hepatitis B Surface Antigen Levels Can Be Used to Rule Out Cirrhosis in Hepatitis B e Antigen-Positive Chronic Hepatitis B: Results From the SONIC-B Study. J Infect Disease. 2022; 225(11): 1967-1973. Published: June 6, 2022. DOI: 10.1093/infdis/jiaa192.



Pickle Juice Intervention for Cirrhotic Cramps Reduction

Study shows sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.

source: Am J Gastro.

Summary

The PICCLES Randomized Controlled Trial

[Posted 13/Jun/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: In a randomized trial, sips of pickle brine consumed at cramp onset improve cramp severity without adverse events.

BACKGROUND: Muscle cramps are common among persons with cirrhosis and associated with poor health-related quality of life. Treatment options are limited. We sought to determine whether pickle juice can improve muscle cramp severity.

DETAILS: There were 82 patients were enrolled with cirrhosis and a history of >4 muscle cramps in the previous month from December 2020 to December 2021. Patients were randomized 1:1 to sips of pickle juice vs tap water at cramp onset. Our primary outcome assessed at 28 days was the change in cramp severity measured by the visual analog scale for cramps (VAS-cramps, scaled 0-10). Cramps were assessed 10 times over 28 days using interactive text messages. Secondary outcomes included the proportion of days with VAS-cramps <5, change in sleep quality, and global health-related quality of life measured using the EQ-5D. Overall, 74 patients completed the trial, aged 56.6 ± 11.5 years, 54% male, 41% with ascites, 38% with encephalopathy, and model for end-stage liver disease—sodium score 11.2 ± 4.9. Many patients were receiving other cramp therapies at baseline. The baseline VAS for cramps was 4.2 ± 3.4, the EQ-5D was 0.80 ± 0.10, and 43% rated sleep as poor. At trial completion, the respective values for the pickle juice and control arms were -2.25 ± 3.61 points on the VAS for cramps, compared with control tap water (-0.36 ± 2.87), P = 0.03; a proportion of cramp-days with VAS-cramps <5 were 46% vs 35% (P = 0.2); and the change in sleep quality was not different (P = 0.1). The end-of-trial EQ-5D was 0.78 ± 0.10 vs 0.80 ± 0.10 (P = 0.3). No differences in weight change were observed for those with and without ascites.

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Source: Tapper, E. B., Salim J., Baki, J., et al. (2022). Pickle Juice Intervention for Cirrhotic Cramps Reduction: The PICCLES Randomized Controlled Trial. Am J Gastro.. 2022; 117(6): 895-901. Published: June, 2022. DOI: 10.14309/ajg.0000000000001781.



EPLBD Reduces Further Recurrence in Patients With Recurrent CBDS

During the long-term follow-up, nearly half of the patients with recurrent CBDS experienced stone recurrence after traditional ERCP.

source: Am J Gastro.

Summary

Endoscopic Papillary Large Balloon Dilation Reduces Further Recurrence in Patients With Recurrent Common Bile Duct Stones

A Randomized Controlled Trial

[Posted 23/May/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: During the long-term follow-up, nearly half of the patients with recurrent CBDS experienced stone recurrence after traditional ERCP. The study was the first to show that EPLBD effectively reduced the recurrence of CBDS.

BACKGROUND: Up to 60% of patients with common bile duct stone (CBDS) recurrence suffer from further recurrence after endoscopic retrograde cholangiopancreatography (ERCP). There are no effective methods to prevent recurrence in most patients. In this study, aim was to assess the short-term and long-term efficacies of endoscopic papillary large balloon dilation (EPLBD) for the management of recurrent CBDS in a randomized controlled trial.

DETAILS: Consecutive patients with recurrent CBDS were eligible and randomly assigned in a 1:1 ratio to the EPLBD group or the control group. The primary outcome was the CBDS recurrence rate within 2 years after ERCP. The analysis followed the intention-to-treat principle. From 2014 to 2021, 180 patients with recurrent CBDS were included, with 90 in each group. All patients underwent complete CBDS clearance by 1 or several sessions of ERCP. The rate of complete clearance in 1 session was significantly higher with EPLBD treatment (95.6% vs 85.6%, P = 0.017). During the follow-up, the CBDS recurrence rate within 2 years was significantly lower in the EPLBD group than in the control group (21.1% [19/90] vs 36.7% [33/90], relative risk 0.58, 95% confidence interval 0.36-0.93, P = 0.021). At a median follow-up of approximately 56 months, CBDS recurrence was found in 34.4% of the patients (31/90) in the EPLBD group and 51.1% (46/90) in the control group (hazard ratio 0.57, 95% confidence interval 0.36-0.89, P = 0.012). Multiple recurrences (>=2) were also decreased in the EPLBD group (4.4% vs 18.9%, P = 0.020).

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Source: Wang, Xu., Wang, Xiangping., Sun, H., et al. (2022). Endoscopic Papillary Large Balloon Dilation Reduces Further Recurrence in Patients With Recurrent Common Bile Duct Stones: A Randomized Controlled Trial. Am J Gastro.. 2022; 117(5): 740-747. Published: May, 2022. DOI: 10.14309/ajg.0000000000001690.



Macrophage Scavenger Receptor 1 Mediates Lipid-Induced Inflammation In NAFLD

MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD.

source: J Hepatology

Summary

[Posted 3/May/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD.

BACKGROUND: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood.

DETAILS: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-a. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients.

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Source: Govaere, O., Petersen, K. P., Martinez-Lopez, N., et al. (2022). Macrophage Scavenger Receptor 1 Mediates Lipid-Induced Inflammation In Non-Alcoholic Fatty Liver Disease. J Hepatology. 2022; 76(5): 1001-1012. Published: May 1, 2022. DOI: 10.1016/j.jhep.2021.12.012.



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