Resolution Of Liver Injury Research Articles

Fibrosis regression following hepatitis C antiviral therapy

Hepatitis C virus (HCV) infection is one of the most common causes of liver pathology. It is a major etiological factor of continuous liver injury by triggering an uncontrolled inflammatory response, causing liver fibrosis and cirrhosis. Liver fibrosis is a dynamic process that can be reversible upon timely cessation of the injurious agent, which in cases of HCV is represented by the sustained virological response (SVR) following antiviral therapies. Direct-acting antiviral therapy has recently revolutionized HCV therapy and minimized complications. Liver fibrosis can be assessed with variable invasive and non-invasive methods, with certain limitations. Despite the broad validation of the diagnostic and prognostic value of non-invasive modalities of assessment of liver fibrosis in patients with HCV, the proper interpretation of liver stiffness measurement in patients after SVR remains unclear. It is also still a debate whether this regression is caused by the resolution of liver injury following treatment of HCV, rather than true fibrosis regression. Regression of liver fibrosis can possess a positive impact on patient's quality of life reducing the incidence of complications. However, fibrosis regression does not abolish the risk of developing hepatocellular carcinoma, which mandates regular screening of patients with advanced fibrosis.

2267 Drug-Induced Autoimmune Hepatitis From Valerian Root Tea

INTRODUCTION: Differentiating drug induced liver injury from other causes of acute hepatitis, especially autoimmune hepatitis can be difficult secondary to overlapping histological features and confounding laboratory abnormalities. Stopping the offending drug should usually result in resolution of liver injury. We describe a rare case of drug induced liver injury secondary to valerian root tea with overlapping features of autoimmune hepatitis which resolved with limited duration steroid therapy. CASE DESCRIPTION/METHODS: Our patient is a 47-year-old female with hypothyroidism who presented with acute onset of generalized abdominal discomfort, jaundice and vomiting without fever or confusion. She denied prior similar episodes. She reported regular use of valerian tea for insomnia for a duration of 3 months prior to presentation. Physical examination revealed jaundice, mild diffuse abdominal tenderness and no features of chronic liver disease. Labs showed elevated alanine aminotransferase of 2741 U/L, aspartate aminotransferase of 1847 U/L, alkaline phosphatase of 199 U/L, total bilirubin of 9.2 mg/dL, albumin of 3.4 g/dL and International normalized ratio of 1.4. Autoimmune work up revealed positive smooth muscle antibody, mildly elevated Immunoglobulin G of 1980 mg/dL and negative antinuclear and mitochondrial antibodies. Viral hepatitis panel was negative. Imaging of the abdomen was unremarkable. Liver biopsy showed severe acute hepatitis with extensive necroinflammatory activity with plasma cells and bridging necrosis without significant fibrosis. With no significant improvement in liver enzymes after stopping valerian root tea and with concern for autoimmune hepatitis, she was started on prednisone 60 mg daily with improvement of transaminitis. Transaminases have remained normal for several months after stopping prednisone (Table 1, Figure 1). DISCUSSION: Diagnosing autoimmune like drug induced liver injury and differentiating it from autoimmune hepatitis can be difficult. Steroids should be considered in cases with severe or prolonged elevation of liver enzymes that do not resolve after stopping the offending drug. Valerian root can cause severe form of autoimmune like drug induced liver injury that responds to steroids. Complete recovery is possible with steroids for limited duration. Relapse following steroid cessation should prompt further evaluation for autoimmune hepatitis.

The expert consensus on clinical cure (functional cure) of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection remains a major world public health problem. Current guidelines for the prevention and treatment of chronic hepatitis B (CHB) have suggested clinical cure (also known as functional cure) as the ideal therapeutic goal, which is associated with decreased risk of cirrhosis and hepatocellular carcinoma. Clinical cure is defined as sustained, undetectable serum HBsAg, HBeAg and HBV DNA with or without seroconversion to anti-HBs, but with the persistence of residual cccDNA, accompanied by resolution of liver injury after the completion of a finite course of treatment. Accumulating data from a series of randomized controlled trials as well as clinical practice have confirmed certain clinical benefit of optimal sequential/ combination strategies of direct acting antiviral drugs (DAA) [such as nucleoside analogues (NA)] or immunomodulators (such as pegylated interferon alpha (Peg-IFN)] for appropriately selected CHB patients. This consensus provides an updated and comprehensive analysis of the data supporting the use of combination therapies and summarizes the roadmap towards clinical cure of CHB to guide decision-making in clinical practice.

11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis.

A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta‐hydroxysteroid dehydrogenase‐1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet‐induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride‐induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1 –/–, and hepatic myofibroblast‐specific, Hsd11b1 fl/fl/Pdgfrb‐cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte‐specific Hsd11b1 fl/fl/albumin‐cre mice did not differ from that of controls, ruling out 11βHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1α1, an effect attenuated by the 11βHSD1 inhibitor [4‐(2‐chlorophenyl‐4‐fluoro‐1‐piperidinyl][5‐(1H‐pyrazol‐4‐yl)‐3‐thienyl]‐methanone. HSCs from Hsd11b1 –/– and Hsd11b1 fl/fl/Pdgfrb‐cre mice expressed higher levels of Acta2 and Col1α1 and were correspondingly more potently activated. In vivo [4‐(2‐chlorophenyl‐4‐fluoro‐1‐piperidinyl][5‐(1H‐pyrazol‐4‐yl)‐3‐thienyl]‐methanone administration prior to chemical injury recapitulated findings in Hsd11b1 –/– mice, including greater fibrosis. Conclusion: 11βHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11βHSD1 inhibitors on liver injury and repair are likely to be context‐dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167‐2181).

PWE-114 Modulation of non-canonical nfkb pathways may underlie the anti-inflammatory, resolution-like activation of circulating cd14hi monocytes in hyper-acute liver failure

<h3>Introduction</h3> 3 monocyte (Mφ) subsets exist: CD14^hi/CD16^-, CD14^hi/CD16⁺and CD14^lo/CD16⁺. Reduced CD14^hiMφ surface expression of HLA-DR and failure to secrete pro-inflammatory cytokines in response to lipopolysaccharide (LPS) are thought to contribute to high infection rates and increased morbidity and mortality in Acute Liver Failure (ALF). We wanted to define CD14^hi. We investigated CD14^hiMφ phenotype and function and related gene expression profiles in hyperacute ALF (hALF). <h3>Method</h3> Admission blood samples were obtained from 45 patients with hALF and from 19 healthy controls (HC). Mφ were phenotyped by flow cytometry (FCM) using fluorochrome-labelled antibodies to CD14, CD16, HLA-DR, HLA-DQ, CD86, CD80, CD40, CD163 and TLR4. Peripheral blood mononuclear cells (PBMCs) (10 HC, 11 hALF) were stimulated with LPS. Mφ intracellular TNFα, IL6 and IL10 were measured by FCM. CD14^hi/CD16^-and CD14^hi/CD16⁺Mφ from 4 patients with paracetamol-hALF and 3 HC were sorted by FCM and the extracted RNA used for transcriptome analysis (Affymetrix ST1 GeneChip®). We used Qlucore omics explorer package for initial gene identification and MetaCore^TMfor molecular pathway analysis. <h3>Results</h3> A higher% of CD14^hi/CD16⁺and lower% of CD14^lo/CD16⁺Mφ were seen in hALF compared to HC (6.7% vs 4% and 1.2% vs 6.1%, p &lt; 0.01). Both CD14^hiMφ subsets expressed lower surface levels of HLA-DR, HLA-DQ and CD86 (p &lt; 0.001) but CD40 was unchanged and CD80 higher in hALF compared to HC (p &lt; 0.001). Mφ TLR4 expression was similar in hALF and HC. Although CD14^hi/CD16^-Mφ CD163 was similar, CD14^hi/CD16⁺CD163 was higher in hALF than in HC (p &lt; 0.001). CD14^hi/CD16⁺Mφ in patients who died or required transplantation had lower CD86 and higher CD163 than those who survived with medical management alone (p &lt; 0.05). In response to LPS the 2 CD14^hisubsets were the predominant producers of cytokines. Compared to HC, only intracellular TNFα was lower in hALF CD14^hiMφ (p &lt; 0.01) whilst IL6 tended to be so (p &lt; 0.1) with no differences in IL10. TNFα production in CD14^hiMφ correlated with HLA-DR, HLA-DQ, CD86 and TLR4 expression (p &lt; 0.01). Enrichment networks statistics identified reduced gene expression for MHC II processing (CIITA, HLA-DM, HLA-DP, HLA-DQ) and non-canonical NFκB signalling (NIK, NFκB2). <h3>Conclusion</h3> Circulating CD14^hiMφ in hALF display phenotypic and functional similarities with anti-inflammatory, resolution-like macrophages that may be due to down-regulated non-canonical NFκB pathways. These 9pre-primed9 Mφ may be beneficial in the resolution of liver injury in hALF but leave the patient dangerously susceptible to further infections. <h3>Disclosure of interest</h3> None Declared.

Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis

Triggers and exacerbants of cirrhotic cardiomyopathy (CC) are poorly understood, limiting treatment options in patients with chronic liver diseases. Liver transplantation alone reverses some features of CC, but the physiology behind this effect has never been studied. We aimed to determine whether reversal of liver injury and fibrosis in mouse affects cardiac parameters. The second aim was to determine whether cardiomyopathy can be induced by specifically increasing systemic bile acid (BA) levels. 6-8 week old male C57BL6J mice were fed either chow (n = 5) or 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) (n = 10) for 3 weeks. At the end of 3 weeks, half the mice in the DDC fed group were randomized to chow (the reversed [REV] group). Serial ECHOs and electrocardiographic analysis was conducted weekly for 6 weeks followed by liver tissue and serum studies. Hearts were analysed for key components of function and cell signalling. Cardiac physiological and molecular parameters were similarly analysed in Abcb11(-/-) mice (n = 5/grp) fed 0.5% cholic acid supplemented diet for 1 week. Mice in the REV group showed normalization of biochemical markers of liver injury with resolution of electrocardiographic and ECHO aberrations. Catecholamine resistance seen in DDC group resolved in the REV group. Cardiac recovery was accompanied by normalization of cardiac troponin-T2 as well as resolution of cardiac stress response at RNA level. Cardiovascular physiological and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11(-/-) mice. Cardiomyopathy resolves with resolution of liver injury, is associated with cholanaemia, and can be induced by BA feeding.

Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans

Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-β1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls. In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.

Hepatic stellate cell behavior during resolution of liver injury.

Acute self-limiting and chronic liver injury are both associated with activation and proliferation of hepatic stellate cells (HSCs). In chronic injury, activated stellate cells are the major source of the collagens that comprise fibrosis and cirrhosis, as well as of the tissue inhibitors of metalloproteinases (TIMPs) which inhibit collagen degradation. Recovery from acute and chronic injury is characterized by apoptosis of activated HSCs, which removes extracellular matrix-producing cells that are also expressing TIMPs, thereby relieving the inhibition of matrix degradation. HSC apoptosis is regulated in progressive injury and counterbalances cell proliferation. Apoptosis probably also represents a default pathway for the HSCs. The survival of activated HSCs in liver injury is dependent on soluble growth factors and cytokines, and on components of the fibrotic matrix. Additionally, stimulation of death receptors expressed on HSCs can precipitate their apoptosis. Our increasing understanding of the process of stellate cell behavior in recovery from injury is likely to be important to the design of antifibrotic therapies.

Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.

Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent leads to cirrhosis and liver failure. Exciting progress has been made in understanding the mechanisms of hepatic fibrosis. Major advances include: (i) characterization of the components of extracellular matrix (ECM) in normal and fibrotic liver; (ii) identification of hepatic stellate cells as the primary source of ECM in liver fibrosis; (iii) elucidation of key cytokines, their cellular sources, modes of regulation, and signalling pathways involved in liver fibrogenesis; (iv) characterization of key matrix proteases and their inhibitors; (v) identification of apoptotic mediators in stellate cells and exploration of their roles during the resolution of liver injury. These advances have helped delineate a more comprehensive picture of liver fibrosis in which the central event is the activation of stellate cells, a transformation from quiescent vitamin A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The progress in understanding fibrogenic mechanisms brings the development of effective therapies closer to reality. In the future, targeting of stellate cells and fibrogenic mediators will be a mainstay of antifibrotic therapy. Points of therapeutic intervention may include: (i) removing the injurious stimuli; (ii) suppressing hepatic inflammation; (iii) down-regulating stellate cell activation; and (iv) promoting matrix degradation. The future prospects for effective antifibrotic treatment are more promising than ever for the millions of patients with chronic liver disease worldwide.