Hepatic Inflammation In Patients Research Articles

Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury

Background and aimsCurrently, research on biopsy-proven acute drug-induced liver injury (DILI) remains limited. This study aimed to identify clinical characteristics and risk factors for significant hepatic inflammation in patients with acute DILI. MethodsAn ambispective cohort study was conducted on biopsy-proven acute DILI patients admitted to our hospital from 2012 to 2018. Using the Scheuer scoring system, patients were categorized into G0-2 or G3-4 groups and followed up for 12 months after first admission. Clinical characteristics and outcomes were retrieved from medical records. ResultsThe median age of the 157 enrolled patients (65.6% female) was 40.4 (interquartile range (IQR), 31.9–49.1) years. The median latency and length of hospitalization were 30.0 (IQR, 5.0–60.0) and 18.0 (IQR, 12.0–26.0) days. The proportions of patients in the G0-2 and G3-4 groups were 54.8% and 45.2%, respectively. Logistic regression analysis revealed that females (odds ratio (OR): 2.623, 95% confidence interval (CI): 1.169–5.887, p = 0.019), higher body mass index (OR: 1.168, 95% CI: 1.029–1.325, p = 0.016), higher total bilirubin (OR: 1.004, 95% CI: 1.000–1.007, p = 0.047), and lower prothrombin activity (OR: 0.976, 95% CI: 0,957–0.995, p = 0.013) were associated with significant hepatic inflammation. The predominance of the hepatocellular injury pattern (60.5%) at admission transformed into a predominance of the cholestatic pattern (60.5%) at discharge. During follow-up, 23 patients (14.6%) developed chronic DILI, with nine patients (5.7%) progressing to cirrhosis. Moreover, 15 female patients (9.6%) developed autoimmunity (3cases in the G0-2 group vs 12 cases in the G3-4 group, p < 0.05). ConclusionAcute DILI patients with high-risk factors were more likely to develop significant hepatic inflammation, and females with significant inflammation were at a higher risk of developing autoimmunity during follow-up.

A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease

This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10mg or semaglutide 1mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. Among 145 randomized participants (efinopegdutide n= 72, semaglutide n= 73), 33.1% had T2DM. At baseline, mean BMI was 34.3kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p= 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. In patients with NAFLD, treatment with efinopegdutide 10mg weekly led to a significantly greater reduction in LFC than semaglutide 1mg weekly. EudraCT: 2020-005136-30; NCT:04944992. Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH.

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus.

Fibroblast growth factor 21 (FGF21) is a liver‐derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype‐ and context‐dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases.

Metabolic and Genetic Risk Factors Are the Strongest Predictors of Severity of Alcohol-Related Liver Fibrosis

Individual risk for developing alcohol-related liver disease (ALD) varies greatly. We hypothesized that metabolic risk factors and genetic polymorphisms predict severity of ALD. Biopsy-controlled, cross-sectional study in patients with a history of excessive drinking. We measured the homeostatic model assessment of insulin resistance (HOMA-IR), plasma triglycerides, high- and low-density lipoproteins (HDL, LDL), and total cholesterol. Moreover, we genotyped four single nucleotide polymorphisms in PNPLA3 (rs738409C>G), TM6SF2 (rs58542926C>T), MBOAT7 (rs641738C>T), and HSD17B13 (rs72613567T>TA). We assessed predictors of higher fibrosis stage using multivariable ordered logistic regression. Of 325 included patients, 25% had severe fibrosis or cirrhosis and 59% had HOMA-IR ≥2.5. HOMA-IR increased for each fibrosis stage, while there was a similar decrease in LDL and total cholesterol. Individuals with risk variant PNPLA3 rs738409-G or TM6SF2 rs58542926-T had higher fibrosis stage. In multivariable regression, HOMA-IR ≥2.5 (OR = 3.04, 95% CI 1.90-4.87), LDL <2.60 mmol/L (OR = 2.05, 95% CI 1.33-3.16), TM6SF2 rs58542926-T (OR = 1.99, 95% CI1.17-3.37), age above 50 years (OR = 1.66, 95% CI 1.03-2.70), and PNPLA3 rs738409-G (OR=1.54, 95% CI 1.11-2.12) independently predicted higher fibrosis stage. Independent predictors of hepatic inflammatory activity were HOMA-IR, active drinking, age, and PNPLA3 risk variant. Active drinking, elevated triglycerides, and PNPLA3 risk variant predicted steatosis. Insulin resistance is the strongest predictor of liver fibrosis stage and hepatic inflammation in patients with alcohol-related liver disease. Genetic susceptibility further aggravates this risk. These data highlight the clinical value of detailed metabolic and genetic profiling of patients with excessive alcohol use.

Hunan interleukin-1 receptor antagonist: A potential prognostic marker of liver cirrhosis in chronic hepatitis B patients

Background: Chronic hepatitis B infection is a consequence of the interplay between the HBV and the host immune response. T-cell immune response correlates with fibrosis and hepatic inflammation in patients with chronic HBV infection. Therefore, the progression of infection is determined by the host inflammatory response. This study aimed at determining a novel inflammatory prognostic marker of liver cirrhosis in chronic hepatitis B patient. Methods & Materials: Three categories of chronic hepatitis B patients with non-cirrhotic, cirrhotic and acute flare infections were recruited. Control group were recruited from healthy undergraduate students of Faculty of Medicine and health sciences Universiti Putra Malaysia that were HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc negative. A total of 40 human cytokines and chemokines were screened using magnetic beads multiplexed Luminex assay. The plate was then read immediately using the Luminex analyser (Luminex corp. Texas, USA). Results: Human Interleukin-1 receptor antagonist (IL-1ra) was found to be positively correlated with liver cirrhosis (r = 0.2066; p < 0.05) and acute flare (r = 0.2258; p < 0.05) while in non-cirrhotic patients was found to be negatively correlated (r = 0.3938; p < 0.05). Similarly, IL-1ar was also found to be significantly associated with Elevated ALT (r = 0.268; p < 0.05), and AST level with IL-1ar (r = 0.257; p < 0.05). IL-1ra is secreted by immune system cells secreted by the liver, it is considered as an acute phase reactant that functions as proinflammatory cytokine by stimulating natural killer cells. It has been shown that knocking down of IL-1ra in mice decreased liver inflammation. Conclusion: This study found significant correlations of IL-1ra liver cirrhosis in chronic hepatitis B infected patients and with elevated ALT. Therefore, IL-1ra might serves as a novel prognostic factor of liver cirrhosis and acute flare.

Influence of increased physical activity without body weight loss on hepatic inflammation in patients with nonalcoholic fatty liver disease

BackgroundPhysical activity (PA) that includes an accumulated exercise regimen that meets or exceeds a certain intensity reduces intrahepatic fat, leading to the improvement of nonalcoholic fatty liver disease (NAFLD) in afflicted patients. However, whether an increase in comprehensive PA, including activities of daily living, contributes to ameliorating the pathophysiology of NAFLD remains unclear. This study aimed to examine whether PA improves liver function in patients with NAFLD.MethodsThe study included 45 patients with NAFLD who underwent follow-up examinations at least 6 months—but no later than 1 year—after their baseline examinations. The patients were interviewed about their daily activities and exercise habits to determine whether they had engaged in at least 3 metabolic equivalents (METs) per day during the previous 6 months; the quantity of PA, expressed in Ekusasaizu (Ex) units, was calculated as METs multiplied by hours. Patients who had achieved at least a 1-Ex increase in PA per week compared to baseline at the time of their follow-up interview (the PA increase group) were compared to those whose PA was the same or lower at the time of follow-up (the PA non-increase group).ResultsThere were no significant changes in all blood and biochemical parameters in the PA non-increase group at the time of follow-up when compared with baseline levels. In the PA increase group, aspartate aminotransferase, alanine aminotransferase, and γ-guanosine triphosphate levels were all significantly lower at follow-up than they were at baseline. Body weight did not change significantly from baseline to follow-up in both groups.ConclusionsIn the present study, hepatic inflammation improvement was accompanied by increased PA but not decreased body weight. Increasing PA may be effective for the improvement of hepatic inflammation even without body weight loss. Our results indicate the effectiveness of PA monitoring for the management of NAFLD.Trial registrationUMIN-CTR, UMIN000038530

Pemafibrate decreases markers of hepatic inflammation in patients with non-alcoholic fatty liver disease.

Aim of the studyNon-alcoholic fatty liver disease (NAFLD) is frequently complicated by dyslipidemia and is considered to be a hepatic manifestation of metabolic syndrome. Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator. There are no reports of the clinical effects of pemafibrate in patients with NAFLD. The aim of this study is to determine the effect of pemafibrate on patients with NAFLD.Material and methodsThis is an observational study of patients with NAFLD complicated by dyslipidemia treated with pemafibrate for three months. Patient medical records were retrospectively reviewed.ResultsThirty-eight patients were included, and all patients had dyslipidemia without diabetes. Changes in parameters after three months of pemafibrate therapy were evaluated. Weight was not significantly changed. Alanine aminotransferase, a marker of hepatic inflammation, significantly improved. Remarkably, alkaline phosphatase and γ-glutamyl transpeptidase decreased in all patients. The albumin-bilirubin score, a marker of hepatic function, improved due to significant elevation of serum albumin and decrease in total bilirubin. Lipid profiles including high-density lipoprotein cholesterol and triglycerides significantly decreased. Low-density lipoprotein cholesterol did not significantly change. The NAFLD fibrosis score significantly improved, but the FIB-4 index did not significantly change.ConclusionsThree months of pemafibrate treatment of patients with NAFLD improves markers of hepatic inflammation, function and fibrosis. This is the first clinical study evaluating the effect of pemafibrate in patients with NAFLD.

Web-based Individualized Exercise Intervention Improves Physical Performance and Hepatic Inflammation in Patients with NAFLD

Web-based Individualized Exercise Intervention Improves Physical Performance and Hepatic Inflammation in Patients with NAFLD

Serum hepatitis B core antibody as a biomarker of hepatic inflammation in chronic hepatitis B patients with normal alanine aminotransferase

Our previous studies unexpectedly indicated that the level of serum hepatitis B core antibody (anti-HBc) was positively correlated with the serum alanine aminotransferase (ALT) level. The aim of this study was to determine whether anti-HBc could serve as a potential biomarker for the detection of liver inflammation in chronic hepatitis B (CHB) patients, especially in patients with normal ALT levels. Serum anti-HBc levels were quantified in 655 treatment-naïve CHB patients, including 45 patients who underwent two liver biopsies (baseline phase and the 78th weeks of antiviral-treatment). Serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score. After antiviral-treatment, patients with HAI score reduction had significant decline in serum anti-HBc level. Multivariate analysis showed that anti-HBc was independently associated with moderate-to-severe hepatic inflammation in patients with normal ALT level. Furthermore, serum anti-HBc showed a high diagnostic accuracy for predicting moderate-to-severe inflammation in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients with normal ALT levels (area under the curve, AUC = 0.87 and 0.75; respectively). Thus, anti-HBc may be a strong indicator for assessing the hepatic inflammatory degree and used for antiviral treatment decisions in CHB patients with normal ALT levels.

N-3 fatty acid-based parenteral nutrition improves postoperative recovery for cirrhotic patients with liver cancer: A randomized controlled clinical trial

A new lipid emulsion enriched in n-3 fatty acid has been reported to prevent hepatic inflammation in patients following major surgery. However, the role of n-3 fatty acid-based parenteral nutrition for postoperative patients with cirrhosis-related liver cancer is unclear. We investigated the safety and efficacy of n-3 fatty acid-based parenteral nutrition for cirrhotic patients with liver cancer followed hepatectomy. A prospective randomized controlled clinical trial (Registered under ClinicalTrials.gov Identifier no. NCT02321202) was conducted for cirrhotic patients with liver cancer that underwent hepatectomy between March 2010 and September 2013 in our institution. We compared isonitrogenous total parenteral nutrition with 20% Structolipid and 10% n-3 fatty acid (Omegaven, Fresenius-Kabi, Germany) (treatment group) to Structolipid alone (control group) for five days postoperatively, in the absence of enteral nutrition. We enrolled 320 patients, and 312 (97.5%) were included in analysis (155 in the control group and 157 in the treatment group). There was a significant reduction of morbidity and mortality in the treatment group, when compared with the control group (total complications 78 [50.32%] vs. 46 [29.30%]; P<0.001, total infective complications, 30 [19.35%] vs. 15 [9.55%]; P=0.014), overall mortality (5 [3.23%] vs. 1 [0.64%]; P=0.210), and hospital stay (12.56±3.21d vs. 10.17±3.15d; P=0.018). We found that addition of n-3 fatty acid-based parenteral nutrition significantly improved postoperative recovery for cirrhotic patients with liver cancer following hepatectomy, with a significant reduction in overall mortality and length of hospital stay.

PTH-102 Stat2 is a key inflammatory molecule in human non-alcoholic fatty liver disease and murine liver injury

<h3>Introduction</h3> In patients with non-alcoholic fatty liver disease (NAFLD), liver inflammation is a key histological feature that distinguishes benign simple steatosis from progressive non-alcoholic steatohepatitis (NASH). The mechanisms that underlie this process are poorly understood. We recently showed that <i>Stat2</i>plays a pivotal role in acute inflammation, independent of its role as an interferon mediator. The aim of the current study is to test the hypothesis that STAT2 is associated with hepatic inflammation in patients with NASH and in a murine model of liver injury. <h3>Method</h3> Expression of (phosphorylated, p) STAT2 and STAT1 was assessed by immunohistochemistry in anonymised sections of archived liver tissue taken from consenting patients with NASH at The Royal London and St Mary’s Hospitals (London, UK). STAT2^-/-and WT mice were injected with incremental doses of carbon tetrachloride (CCl4) for 4 or 6 weeks. Serum and liver tissue were harvested 24 or 72hrs after the last injection. Immunohistochemistry for activated stellate cells (anti-alpha smooth muscle actin, aSMA) and macrophage/Kupfer cells (anti-F4/80) was performed. <h3>Results</h3> Tissue from 62 patients was examined. Hepatocyte nuclear expression in NASH liver tissue was significantly greater for STAT1 (74% vs 10%, p &lt; 0.0001) and STAT2 (98% vs 35%, p &lt; 0.0001) compared to normal liver. There was a significant correlation between STAT1 expression (r = 0.6, p = 0.02), but not STAT2 and the NAFLD activity score (NAS). Animal models confirm that Stat 2 plays a role in liver inflammation – <i>Stat2^-/-</i>mice were protected from CCl₄-mediated liver injury with reduced serum alanine aminotransferase (ALT, 2165 vs 1090 iU/ml, p = 0.03), inflammation and necrosis histologically and fibrosis (Picrosirius red staining). There were no significant differences in the number of aSMA or F4/80-positive cells between WT and <i>Stat2^-/-</i>mice. <h3>Conclusion</h3> These data identify a novel role for STAT2 in the development of liver disease, with expression of STAT1 and STAT2 relating to disease grade. The protection afforded by Stat2 loss in murine models is unrelated to macrophage and stellate cell activation, and we hypothesise that the mechanism of protection is therefore reduced production of Stat2-mediated cytokine production. <h3>Disclosure of interest</h3> None Declared.

Granulocytapheresis for the Treatment of Severe Alcoholic Hepatitis: A Case Series and Literature Review

Severe alcoholic hepatitis has a high mortality rate due to limited therapeutic methods. Although corticosteroids have been used to control the inflammatory response, the outcomes vary and no standardized therapy has been established. Novel therapeutic approaches, such as anti-TNF-α, pentoxifilline, and others have been tested clinically on the basis of their cytokinemic pathophysiology with limited success. However, treatment of leukocytosis that causes cytokinemia and hepatic inflammation in patients via granulocytapheresis and leukocytapheresis showed promising results in a number of reports. Here, we report two cases of severe alcoholic hepatitis treated with granulocytapheresis. The liver function and inflammation recovered after the therapy. A review of 35 cases treated with granulocytapheresis and leukocytapheresis demonstrated their efficacy in treating alcoholic hepatitis by controlling leukocytosis as well as cytokines such as IL-8. Multidisciplinary treatment for severe alcoholic hepatitis should be considered case by case on the basis of the complexity and severity of the condition.

Circulating Microparticles as Disease-Specific Biomarkers of Severity of Inflammation in Patients With Hepatitis C or Nonalcoholic Steatohepatitis

Microparticles released into the bloodstream upon activation or apoptosis of CD4(+) and CD8(+) T cells correlate with inflammation as determined by histologic analysis in patients with chronic hepatitis C (CHC). Patients with nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) can be differentiated from those with CHC based on activation of distinct sets of immune cells in the liver. We compared profiles of circulating microparticles from patients with NAFL and NASH (n = 67) to those of CHC (n = 42), with healthy individuals (controls) using flow cytometry; the profiles were correlated with inflammation grade and fibrosis stage based on histologic analyses. We assessed the ability of the profiles to determine the severity of inflammation and fibrosis based on serologic and histologic analyses. Patients with CHC had increased levels of microparticles from CD4(+) and CD8(+) T cells; the levels correlated with disease severity based on histologic analysis and levels of alanine aminotransferase. Patients with NAFL or NASH had significant increases in numbers of microparticles from invariant natural killer T cells and macrophages/monocytes (CD14(+)), which mediate pathogenesis of NASH. Microparticles from CD14(+) and invariant natural killer T cells correlated with levels of alanine aminotransferase and severity of NASH (based on histology). Levels of microparticles could differentiate between patients with NAFL or NASH and those with CHC, or either group of patients and controls (area under the receiver operating characteristic curves ranging from 0.56 to 0.99). Quantification of immune cell microparticles from serum samples can be used to assess the extent and characteristics of hepatic inflammation in patients with chronic liver disease.

The role of circulating monocyte chemoattractant protein-1 as a marker of hepatic inflammation in patients with chronic liver disease

We investigated the relationships between plasma monocyte chemoattractant protein-1, serum C-reactive protein, and the degree of hepatic inflammation in patients with chronic liver disease. Monocyte chemoattractant protein-1 concentration was correlated with the histological hepatic inflammation (estimated by the Knodell index) and with standard liver function tests ( P < 0.01). C-reactive protein was not correlated with any of the variables studied. These results underline the role of monocyte chemoattractant protein-1 in the pathogenesis of liver impairment and suggest that this chemokine may be a reliable marker of inflammation in hepatic derangements.

Cysteinyl leukotrienes in the bile of patients with obstructive jaundice.

Cysteinyl leukotrienes (LTs) are potent proinflammatory mediators. They are predominantly excreted from blood by hepatobiliary elimination. To explore the clinical significance of biliary cysteinyl LTs, we determined their concentration changes in bile during treatment in patients with obstructive jaundice. Bile samples were obtained during endoscopic or transhepatic biliary drainage. Leukotrienes C(4), D(4), and E(4) were quantified by two-step reversed-phase high-performance liquid chromatography and subsequent radioimmunoassay. The increased excretion of cysteinyl LTs (LTC(4) + LTD(4) + LTE(4)) decreased between day 1 and 14 after drainage (means, 171 pmol/h to 79 pmol/h; P < 0.02). During drainage, the excretion was higher when there was additional cholangitis (mean, 225 and 86 pmol/h, with and without cholangitis, respectively; P < 0.001). The concentrations of LTD(4) and LTE(4) were also higher with additional cholangitis than without (LTD(4), mean 6.0 vs 2.0 nM; P < 0.05; LTE(4), 6.8 vs 2.4 nM; P < 0.02, respectively). Biliary LTC(4) was detected only in patients with cholangitis. The biliary excretion of cysteinyl LTs was positively correlated with leukocyte concentration ( r = 0.68; P < 0.005) and C-reactive protein ( r = 0.73; P < 0.005) in blood. Furthermore, only in the absence of cholangitis, the excretion was positively correlated with serum gamma-glutamyl transferase ( r = 0.76; P < 0.02) and alanine aminotransferase ( r = 0.72; P < 0.02). The excretion of biliary cysteinyl LTs increases with the severity of cholestasis and hepatic inflammation in patients with obstructive jaundice. An additional increase of cysteinyl LTs was observed during bacterial cholangitis. The increased biliary excretion of biologically active cysteinyl LTs may contribute to the aggravation of cholestasis and inflammatory reaction in obstructive jaundice.