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Liver disease is known as one of the leading co-morbidities in HIV infection, with 18% of non-AIDS-related mortality. There is constant crosstalk between liver parenchymal (hepatocytes) and non-parenchymal cells (macrophages, hepatic stellate cells, endothelial cells), and extracellular vesicles (EVs) are one of the most important ways of cell-to-cell communication. We briefly cover the role of EVs in liver disease as well as what is known about the role of small EVs, exosomes, in HIV-induced liver disease potentiated by alcohol as one of the second hits. We also touch large EVs, apoptotic bodies (ABs), in HIV-induced liver injury, the mechanisms of their formation and potentiation by second hits, and their role in the progression of liver disease. Liver cells are an important source of EVs, which may provide the connection between different organs via secretion into the circulating blood (exosomes) or serve for the communication between the cells within the organ (ABs). Understanding the role of liver EVs in HIV infection and the involvement of second hits in EV generation would provide a new angle for the analysis of HIV-related liver disease pathogenesis and progression to end-stage liver disease. People living with HIV-1 (PLWH) are at risk of developing chronic liver disease. They are often coinfected with hepatitis viruses B and C and misuse alcohol. Combining these 'second hits' factors with HIV infection greatly accelerates liver damage. The exact mechanisms are not clear. The liver contains different types of cells. Most are hepatocytes, which cannot replicate HIV but can be stressed by HIV and alcohol metabolites. During this process, hepatocytes release small extracellular vesicles called exosomes. Liver exosomes can carry toxic viral proteins and nucleic acids. When hepatocyte exosomes are captured by other liver cells, such as stellate cells, Kupffer macrophages, and sinusoidal endothelial cells, they change the functions of these cells. If hepatocytes die due to high HIV and alcohol toxicity, they form large particles called apoptotic bodies. Like exosomes, these large apoptotic bodies also change the functions of neighboring cells they capture. Macrophages and stellate cells exposed to – extracellular vesicles containing HIV proteins and nucleic acids promote liver inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion injury (IRI) is a severe complication frequently encountered in liver surgery, seriously affecting the therapeutic effects, tissue function. Various immune cells are involved in hepatic IRI, including macrophages, NKT cells, DCs, CD4 + T cells, and CD8 + T cells, among which CD4 + T cells play a critical role in this process. This article aims to summarize the functions and changes in various CD4 + T cell type counts and related cytokine levels in hepatic IRI and to review the possible mechanisms of mutual conversion between T cell types. We have covered the functions and changes that occur in Th1, Th17, and Treg cells in liver IRI, as well as the pathways and factors associated with them. We also discuss the prospects of clinical application and future directions for therapeutic advances. This section explores the current clinical trials involving CD4 + T cells, especially Tregs, explains the limitations of their application, and summarizes the future development trends of cell engineering and their combination with the CAT technology. We also provide new ideas and therapeutic targets for alleviating liver IRI or other liver inflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis. Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis. Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects. [ABSTRACT FROM AUTHOR]

The outbreak of COVID-19 is a serious health threat worldwide. Different degrees of liver injury or liver dysfunctions have been reported in patients with COVID-19 infection. However, currently, it remains unclear to what extent liver diseases should be considered as significant risk factors for the severity and mortality of COVID-19. Moreover, the mechanisms involved in liver injury in severe COVID-19 infection are not yet well understood. This review summarizes the current evidence on liver function abnormalities in COVID-19 patients and the effects of preexisting liver disease on the disease severity. This review also illustrates the possible underlying mechanisms linking COVID-19 to liver injury, as well as provides recommendations to prevent liver damage in COVID-19 infection. The elevated levels of ALT, AST, GGT and bilirubin are common in more severe patients than non-severe or mild COVID-19 patients. Patients with preexisting medical conditions including chronic hepatic diseases are at higher risk for severe illness from COVID-19 infection. The drug's effects, possible viral inclusion in liver cells, systemic inflammation and hypoxia are potential causes of liver injury in severe COVID-19. Nevertheless, further studies are needed focusing on the preexisting hepatic diseases on prevention, treatment and outcome of COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: Liver disease is an increasing cause of worldwide mortality, and currently the only curative treatment for end-stage liver disease is whole organ allograft transplantation. Whilst this is an effective treatment, there is a shortage of suitable grafts and consequently some patients die whilst on the waiting list. Cell therapy provides an alternative treatment to increase liver function and potentially ameliorate fibrosis. Areas covered: In this review, we discuss the different cellular sources for therapy investigated to date in humans including mature hepatocytes, hematopoietic stem cells, mesenchymal stromal cells and hepatic progenitor cells. Cells investigated in animals include embryonic stem cells, induced pluripotent stem cells and directly reprogrammed cells. We then appraise the experience and evidence base underlying each cell type. Expert opinion: We discuss how this field may evolve in the years to come focusing on opportunities to enhance the intrinsic regenerative response with therapeutic targets and cell therapies. Growing expertise in tissue engineering will likely lead to increasingly complex bio-reactors and bio-artificial livers, which open a further avenue to restore liver function and delay or prevent the need for transplantation. [ABSTRACT FROM AUTHOR]

Introduction: Mounting evidence highlights platelet involvement in liver regeneration via interaction with liver cells, growth factors release, and signaling contributions. Existing research suggests a compelling biological rationale for utilizing platelet biology, with the goal of improving liver function and accelerating its regenerative potential. Despite its expanding application in several clinical areas, the contribution of the platelet and its therapeutic implementation in liver regeneration so far has not yet fulfilled the initial high expectations. Areas covered: This review scrutinizes the progress, current updates, and discusses how recent understanding - particularly in the clinical implications of platelet-based therapy - may enable strategies to introduce and harness the therapeutic potential of the platelet during liver regeneration. Expert commentary: Several clinical and translational studies have facilitated a platform for the development of platelet-based therapy to enhance liver regeneration. While some of these therapies are effective to augment liver regeneration, the others have had some detrimental outcomes. The existing evidence represents a challenge for future projects that are focused on directly incorporating platelet-based therapies to induce liver regeneration. [ABSTRACT FROM AUTHOR]

Introduction: There is significant unmet need in Primary Biliary Cholangitis (PBC) in patients under-responsive to the only approved therapy Ursodeoxycholic Acid (UDCA) who are at increased risk of progressing to end-stage liver disease. Obeticholic Acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second line therapy in PBC and has recently been licenced by the FDA. Areascovered: The pharmacology and biology of OCA as an FXR agonist and its clinical benefits. A systematic review was undertaken of published literature, meeting abstracts and trial registries using the search terms FXR, FGF-19 (& FGF-15), Obeticholic Acid and INT-747. Expertcommentary: OCA reduces exposure to toxic hydrophobic bile acids through reduction in bile acid synthesis (by direct and indirect (via enterocyte-released FGF19) actions on Cyp7A1-mediated bile acid synthesis) and bile acid excretion by hepatocytes. It significantly improves liver biochemical parameters strongly associated with risk of disease progression in UDCA under-responsive patients and the key side-effect of pruritus can be reduced by optimised dosing. OCA will be the first stratified therapy introduced in PBC, however confirmatory trial and real life data are needed to confirm that suggestive biochemical improvements are matched by improvement in key clinical outcomes. [ABSTRACT FROM PUBLISHER]

Liver disease is a leading cause of morbidity and mortality. Liver transplantation remains the only proven treatment for end-stage liver failure but is limited by the availability of donor organs. Hepatocyte cell therapy, either with bioartificial liver devices or hepatocyte transplantation, may help address this by delaying or preventing liver transplantation. Early clinical studies have shown promising results, however in most cases, the benefit has been short lived and so further research into these therapies is required. Alternative sources of hepatocytes, including stem cell-derived hepatocytes, are being investigated as the isolation of primary human hepatocytes is limited by the same shortage of donor organs. This review summarises the current clinical experience of hepatocyte cell therapy together with an overview of possible alternative sources of hepatocytes. Current and future areas for research that might lead towards the realisation of the full potential of hepatocyte cell therapy are discussed. [ABSTRACT FROM PUBLISHER]

Ethanol metabolism in hepatocytes causes the generation of reactive oxygen species, endoplasmic reticulum stress and alterations in mitochondrial energy and REDOX metabolism. In ethanol-exposed liver disease, autophagy not only acts as a cleanser to remove damaged organelles and cytosolic components, but also selectively clears specific targets such as lipid droplets and damaged mitochondria. Moreover, ethanol appears to play a role in protecting hepatocytes from apoptosis at certain concentrations. This article describes the evidence, function and potential mechanism of autophagy in ethanol-exposed liver disease and the controversy surrounding the effects of ethanol on autophagy. [ABSTRACT FROM AUTHOR]

Acute liver failure is a rare and often devastating condition consequent on massive liver cell necrosis that frequently affects young, previously healthy individuals resulting in altered cognitive function, coagulopathy and peripheral vasodilation. These patients frequently develop concurrent acute kidney injury (AKI). This abrupt and sustained decline in renal function, through a number of pathogenic mechanisms such as renal hypoperfusion, direct drug-induced nephrotoxicity or sepsis/systemic inflammatory response contributes to increased morbidity and is strongly associated with a worse prognosis. Improved understanding of the pathophysiology AKI in the context of acute liver failure may be beneficial in a number of areas; the development of new and sensitive biomarkers of renal dysfunction, refining prognosis and organ allocation, and ultimately leading to the development of novel treatment strategies, these issues are discussed in more detail in this expert review. [ABSTRACT FROM AUTHOR]

The advantages of MRI in the investigation of liver disease are well documented. Recent developments, including fast scanning technique and new MRI contrast agents, enable improved detection and characterization of focal liver lesions. Therefore, a definitive diagnosis can be made avoiding invasive procedures, such as liver biopsy. In this article, a special emphasis is placed on the clinical use of combined perfusional and hepatocyte-selective MRI contrast agents, which allow us to obtain morphologic and vascular information, owing to the dynamic study, as well as functional information, owing to the hepatocyte-selective phase of enhancement. Different clinical scenarios are considered in order to highlight the proper use of the hepatocyte phase to noninvasively characterize and detect different focal liver lesions. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome. The increasing prevalence of the metabolic syndrome is paralleled by an increasing prevalence of NAFLD, which has become one of the most common chronic liver diseases. NAFLD comprises a morphological spectrum ranging from nonalcoholic fatty liver (NAFL), characterized by accumulation of fat in hepatocytes, to nonalcoholic steatohepatitis (NASH). The key histological features of NASH accepted by most pathologists include steatosis, hepatocellular ballooning and lobular inflammation, whereas, like in other chronic liver diseases, the presence of fibrosis is not considered a requirement for the diagnosis. The diagnosis of NASH and the distinction from NAFL carries important prognostic and therapeutic implications because NASH, in contrast to NAFL, is associated with an increased risk of progression to cirrhosis and hepatocellular carcinoma. Hepatocellular ballooning is a key feature required for the diagnosis of NASH and a component of currently used histological grading and staging systems of NAFLD. However, it represents an ill-deined form of liver cell injury associated with cell swelling and rounding of the cytoplasm, the detection of which is prone to intra- as well as inter-observer variation. Some of the factors that may contribute to ballooning are the rearrangement of the intermediate filament cytoskeleton, accumulation of small-droplet fat in the cytoplasm and dilation of the endoplasmic reticulum. The rearrangement of the intermediate filament cytoskeleton can be demonstrated by the loss of keratin 8/18 immunostaining of the cytoplasm, and may thus be evaluated in the future as a marker for the more objective detection of hepatocellular ballooning in NASH. [ABSTRACT FROM AUTHOR]