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The objective of the study was to observe the levels of the inflammasome and estrogen receptors alpha (ERα) and beta (ERβ) in 17 individuals with stage III and IV endometriosis before surgical procedure. It is a clinical control study. Academic tertiary care referral center. The patients were referred to undergo surgical management. The controls were individuals without endometriosis. The Institutional Research Board (IRB) of the University of Louisville approved the study. All the participants gave their informed consent to participate in the study. Only 10 ml blood were taken from patients before surgery. We examined a panel of cytokines in the plasma of the participants undergoing surgery for endometriosis and compared it to control participants. The levels of cytokines were quantitatively measured using enzyme-linked immunosorbent-assay (ELISA). Cytokines and chemokines were as follows: interleukins :IL 1-b pg/mL (control 20-50), IL6 pg/mL (control 30-60), IL8 pg/mL (control 20-60), IL15 pg/mL (control 15-30), transforming growth factor (TGF-b ng/mL) (control 20-40), tumor necrosis factor (TNFa pg/mL) (control 25-50), vascular endothelial growth factor (VEGF pg/mL) (control 20-90), interferon (IFN control 20-40), IFN-g pg/mL (15-40), ccK18 (M-30) U/L (control 68-132), ccK(M65) U/L (control 62-120). The median values of cytokines in the endometriosis cases were higher compared to controls as follows: IL1-b x 2, IL 6 x 0.7, IL8 x 3, IL15 x 2.5, TGF–b x 2, TNF-a x 3.5, VEGF x 4, and IFN-g x 2. ERβ (median) was 2.6 x higher when compared with ERα. A change of inflammatory markers in plasma leads to endometrial tissue inflammation. The ER appears to be a key to intracellular steroid metabolism since plasma levels of ER-a are lower when compared with normal values. The next step is to observe the changes of these biomarkers after surgery and to compare the results with the initial inflammasome and estrogen receptors. [ABSTRACT FROM AUTHOR]

Strong evidence indicates that inflammatory bowel disease, including Crohn disease and ulcerative colitis, is a result of an inappropriate inflammatory response in which genetic and environmental factors play important roles. This review discusses several single-nucleotide polymorphisms with either susceptibility or protective effects on inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) encompassed several chronic inflammatory disorders leading to damage of the gastrointestinal tract (GI). The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn disease (CD). Bacteria are involved in the etiology of IBD, and the genetic susceptibility, environmental factors, and lifestyle factors can affect the individual's predisposition to IBD. The review discusses the potential role of environmental factors such as diet and microbiota as well as genetics in the etiology of IBD. It is suggested that microbial ecosystem in the human bowel colonizing the gut in many different microhabitats can be influence by diet, leading to formation of metabolic processes that are essential form the bowel metabolism. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) encompasses several chronic inflammatory disorders leading to the damage of the gastrointestinal tract. The 2 principal forms of these disorders are ulcerative colitis (UC) and Crohn's disease (CD). Bacteria are involved in the etiology of IBD. Many microorganisms have been put forward as causative factors in IBD, but the primary etiologic agents are still not known. The underlying genetic, environmental, and lifestyle issues can affect the individual's predisposition to these diseases. Immune factors identified in IBD are: dysregulation of the innate and adaptive immune system directed against luminal bacteria or their products found in the intestinal lumen and inappropriate immune responses to organisms in the intestine that normally do not elicit a response, possibly because of intrinsic alterations in mucosal barrier function. However, recent advances in basic science research revealed new insights into the role of specific immune cells and their mediators in intestinal inflammation. The inflammatory mediators known as 'inflammasome' are a consequence of the metabolic products (metabolom) of cells and commensal or pathogenic bacteria. Elucidation of inflammasome and metabolom has led to the development of biomarkers specific for each disease that are involved into management strategies targeted at altering specific pathogenic mechanisms that have the potential to modify or change the natural course of these disease entities. The review discusses the potential role of biomarkers in monitoring the inflammasome and therefore the severity of intestinal damage. The microbial ecosystem in the human gut in different microhabitats and metabolic niches contribute to the bowel metabolome.In addition, this review will focus on our expanding understanding of microbial factors associated with both the initiation and maintenance of IBD. New insights acquired from murine genetic models of inflammatory bowel disease will also be discussed. [ABSTRACT FROM AUTHOR]

Hypersensitivity syndrome reactions (HSR) to antiepileptic drugs (AED) are associated with severe clinical cutaneous adverse reactions (SCAR). We aimed (1) to assess HSRs to AEDs using the in vitro lymphocyte toxicity assay (LTA) in patients who manifested HSRs clinically; (2) to correlate LTA results with the clinical syndrome; (3) to correlate LTA results with the human leukocyte antigen (HLA) allele B*1502 (HLA-B*1502) positivity in a Han Chinese-Canadian population; and (4) to determine the cytokine network in this population. Patients that developed fever and cutaneous eruptions in the presence or absence of organ involvement within 8 weeks of exposure to carbamazepine (CBZ), phenytoin (PHY), or lamotrigine (LTG) were enrolled. Control patients received AEDs without presenting HSR. We investigated 10 CBZ-HSR patients (4 with Stevens-Johnson syndrome [SJS]), 24 CBZ-controls, 10 PHY-HSR patients (4 with drug-induced liver injury [DILI]), 24 PHY-controls,6 LTG-HSR patients (1 with SJS and 1 with DILI), and 24 LTG-controls. There were 30 Han Chinese individuals (14 HSR patients and 16 controls) in our cohort. LTA toxicity greater than 12.5% ± 2.5% was considered positive. Differences among groups were determined by analysis of variance. In addition, we measured cytokine secretion in the patient sera between 1 month and 3 years after the event. All Han Chinese individuals and 30% of Caucasians were genotyped for HLA-B*1502. A perfect correlation (r = 0.92) was observed between positive LTA and clinical diagnosis of DILI and SJS/toxic epidermal necrolysis (TEN). HLA-B*1502 positivity in Han Chinese is a predictor of CBZ-HSR and PHY-HSR. HLA-B*1502-negative Han Chinese receiving only CBZ or a combination of CBZ and PHY tolerated the drug(s) clinically, presenting negative CBZ-LTA and PHY-LTA. However, 3 patients presenting negative CBZ-LTA and PHY-LTA, as well as negative HLA-B*1502, showed positive LTG-LTA (38%, 28%, and 25%, respectively), implying that they should not be prescribed LTG. Three patients had LTA positive to both PHY and CBZ, and 3 others had LTA positive to both PHY and LTG. Clinically, all 6 patients presented HSR to both drugs that they tested positive to (cross-reactivity). Patients were grouped based on the clinical presentation of their symptoms as only rash and fever or as a triad of rash, fever and DILI or SJS/TEN that characterizes 'true' HSR. Levels of proinflammatory cytokines were significantly higher in patient sera compared with control sera. More specifically, the highest levels of tumor necrosis factor-[alpha] have been measured in patients presenting 'true' HSR, as were the apoptotic markers Fas, caspase 8 activity, and M30. The LTA is sensitive for DILI and SJS/TEN regardless of drug or patient ethnicity. HSR prediction will prevent AED-induced morbidity. In Han Chinese, HLA-B*1502 positivity is a predictor for CBZ-HSR and PHY-HSR. Its negativity does not predict a negative LTG-HSR. There is cross-reactivity between AEDs. Additionally, T-cell cytokines and chemokines control the pathogenesis of SJS/TEN and DILI, contributing to apoptotic processes in the liver and in the skin. [ABSTRACT FROM AUTHOR]

Cytokines and chemokines are proteins that play a critical role in the regulation of immunity and inflammation in patients with chronic Hepatitis C. The aim of our study was to correlate serum cytokines, chemokines and apoptosis in non-treated chronic hepatitis C patients with various degrees of inflammation and fibrosis. We studied 778 patients: 59 had low Knodell fibrosis score and low Knodell histological activity index; 372 had mild fibrosis and low histological activity index; 270 had moderate fibrosis and moderate histological activity index; and, 77 had high fibrosis and high histological activity index on their biopsy. Serum cytokines, chemokines and apoptosis were measured by enzyme-linked-immunosorbent-assay. Multivariate analysis was employed for statistical purposes. A positive correlation was seen between the degree of inflammation and tumor necrosis factor-alpha (TNF-alpha) levels (r = 0.92) in non-cirrhotic patients and between interleukin 2 in all patients (r = 0.85). Interleukin-8 increased significantly at higher histological activity indices and continued to increase in patients with cirrhosis. Transforming growth factor-beta (TGF-beta) levels increased significantly with the severity of fibrosis, but decreased in cirrhotics. In conclusion, cytokines, chemokines and apoptosis levels reflect the progression of inflammation and fibrosis in hepatitis C infected patients, but their signatures differ. [ABSTRACT FROM AUTHOR]

Many processes related to the consumption or breakdown of alcohol that contribute to alcohol-induced liver disease are mediated by small proteins known as cytokines, which are produced and secreted by liver cells and many other cells throughout the body. Through a variety of actions, cytokines regulate certain biochemical processes in the cells that produce them as well as in neighboring cells. For example, in case of an infection, they attract white blood cells to the tissues, triggering an inflammatory response. In the liver, persistent cytokine secretion resulting in chronic inflammation leads to conditions such as hepatitis, fibrosis, and cirrhosis. Cytokines also regulate a process known as programmed cell death, or apoptosis, which is in part responsible for alcohol-induced destruction of liver tissue. Two cytokines--tumor necrosis factor alpha and transforming growth factor beta-play prominent roles in apoptosis. Finally, a cytokine network mediates the harmful effects of a bacterial protein called endotoxin on the liver. Because of their diverse functions, cytokines might make attractive targets in the prevention or treatment of alcoholic liver disease, and researchers already have obtained encouraging results when testing such approaches. [ABSTRACT FROM AUTHOR]

Herbal and complementary medicine are frequently integrated with conventional medicine. We aim to report a case of severe herbal-induced liver injury (HILI) due to chronic use of green tea and protein shake. We present both clinical and laboratory evidence implicating mitochondrial toxicity and an immune response leading to a hypersensitivity reaction to the products. We have recently treated a 39-year-old man with hepatotoxicity resulting from a combination of a green tea-containing powder and a branched-chain amino acid supplement that was commenced 2 months previously. The hepatotoxicity resolved by stopping the consumption of these products and no other cause was detected. We decided to perform a lymphocyte toxicity assay (LTA) to determine if there was laboratory support for this diagnosis. LTA (% toxicity) represents the response of the mitochondria to toxic injury. To determine the role of the proinflammatory and anti-inflammatory cytokines and chemokines in the patient's reaction, we measured the level of cytokines and chemokine in the media of growing cells, exposed to each product or to a combination of products. The increased cytokines and chemokines are presented as the x-fold elevations from the upper limit of normal (ULN) for matrix metalloproteinase (MMP) (pg/mL × 1.5 ULN) and interleukin (IL)-1β (pg/mL × 1.8 ULN). Higher elevations were found for interferon (IFN)-β, IFN-γ, IL-8, IL 13, IL-15 (pg/mL × 2 ULN), regulated upon activation, normal T cell expressed and presumably secreted (RANTES) (pg/mL × 2 ULN), and nuclear factor (NFκB) (pg/mL × 3 ULN). The highest increases were for vascular endothelial factor (VEGF) (pg/mL × 10 ULN), tumor necrosis factor (TNF)-α, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (pg/mL × 13 ULN). An examination of cellular markers showed the difference between programmed cell death (apoptosis) and cell death due to necrosis. In our case, cytokeratin-ccK18 (M-30) U/L was within the normal limits, suggesting that apoptosis was normal, while ccK8(M65) U/L was elevated at 1.5 × ULN. This result implies that upon the treatment of the patient's lymphocytes with the products, the mechanism of toxicity is necrosis. In susceptible individuals, the combination of protein and herbal tea produces mitochondrial toxicity and a strong T-lymphocyte-1 response, leading to HILI. There is a need of international reporting of adverse drug reactions by clinicians, laboratories, and pharmaceutical manufacturers to drug regulatory authorities. This requires internationally accepted standard definitions of reactions, as well as criteria for assessment.

Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferator activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα, results in an inhibition of FA oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1)-driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very-low-density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor α (TNF α), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis contributes to the severity of ALD by increasing the metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen-associated molecular patterns (PAMPS) via specific Toll-like receptor (TLR) bacterial overgrowth leads to the translocation of bacteria. Endotoxins and toxic ethanol metabolites enter the enterohepatic circulation, reaching the liver and inducing the activation of the nuclear factor kappa-B (NFκB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in favour of necrosis.

In alcohol-induced liver disease (ALD) and in non-alcoholic fatty liver disease (NAFLD), there are abnormal accumulations of fat in the liver. This phenomenon may be related to excessive alcohol consumption, as well as the combination of alcohol consumption and medications. There is an evolution from simple steatosis to steatohepatitis, fibrosis and cirrhosis leading to hepatocellular carcinoma (HCC). Hepatic pathology is very similar regarding non-alcoholic fatty liver disease (NAFLD) and ALD. Initially, there is lipid accumulation in parenchyma and progression to lobular inflammation. The morphological changes in the liver mitochondria, perivenular and perisinusoidal fibrosis, and hepatocellular ballooning, apoptosis and necrosis and accumulation of fibrosis may lead to the development of cirrhosis and HCC. Medical history of ethanol consumption, laboratory markers of chronic ethanol intake, AST/ALT ratio on the one hand and features of the metabolic syndrome on the other hand, may help in estimating the contribution of alcohol intake and the metabolic syndrome, respectively, to liver steatosis.

The present review is based on the research presented at the symposium dedicated to the legacy of the two scientists that made important discoveries in the field of alcohol-induced liver damage: Professors C.S. Lieber and S.W. French. The invited speakers described pharmacological, toxicological and patho-physiological effects of alcohol misuse. Moreover, genetic biomarkers determining adverse drug reactions due to interactions between therapeutics used for chronic or infectious diseases and alcohol exposure were discussed. The researchers presented their work in areas of alcohol-induced impairment in lipid protein trafficking and endocytosis, as well as the role of lipids in the development of fatty liver. The researchers showed that alcohol leads to covalent modifications that promote hepatic dysfunction and injury. We concluded that using new advanced techniques and research ideas leads to important discoveries in science., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hepatic cells are sensitive to internal and external signals. Ethanol is one of the oldest and most widely used drugs in the world. The focus on the mechanistic engine of the alcohol-induced injury has been in the liver, which is responsible for the pathways of alcohol metabolism. Ethanol undergoes a phase I type of reaction, mainly catalyzed by the cytoplasmic enzyme, alcohol dehydrogenase (ADH), and by the microsomal ethanol-oxidizing system (MEOS). Reactive oxygen species (ROS) generated by cytochrome (CYP) 2E1 activity and MEOS contribute to ethanol-induced toxicity. We aimed to: (1) Describe the cellular, pathophysiological and clinical effects of alcohol misuse on the liver; (2) Select the biomarkers and analytical methods utilized by the clinical laboratory to assess alcohol exposure; (3) Provide therapeutic ideas to prevent/reduce alcohol-induced liver injury; (4) Provide up-to-date knowledge regarding the Corona virus and its affect on the liver; (5) Link rare diseases with alcohol consumption. The current review contributes to risk identification of patients with alcoholic, as well as non-alcoholic, liver disease and metabolic syndrome. Additional prevalence of ethnic, genetic, and viral vulnerabilities are presented.

Hepatitis C virus (HCV)-induced liver disease contributes to chronic hepatitis. The immune factors identified in HCV include changes in the innate and adaptive immune system. The inflammatory mediators, known as "inflammasome", are a consequence of the metabolic products of cells and commensal or pathogenic bacteria and viruses. The only effective strategy to prevent disease progression is eradication of the viral infection. Immune cells play a pivotal role during liver inflammation, triggering fibrogenesis. The present paper discusses the potential role of markers in cell death and the inflammatory cascade leading to the severity of liver damage. We aim to present the clinical parameters and laboratory data in a cohort of 88 HCV-infected non-cirrhotic and 25 HCV cirrhotic patients, to determine the characteristic light microscopic (LM) and transmission electron microscopic (TEM) changes in their liver biopsies and to present the link between the severity of liver damage and the serum levels of cytokines and caspases. A matched HCV non-infected cohort was used for the comparison of serum inflammatory markers. We compared the inflammation in HCV individuals with a control group of 280 healthy individuals. We correlated the changes in inflammatory markers in different stages of the disease and the histology. We concluded that the serum levels of cytokine, chemokine, and cleaved caspase markers reveal the inflammatory status in HCV. Based upon the information provided by the changes in biomarkers the clinician can monitor the severity of HCV-induced liver damage. New oral well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Therefore, using the noninvasive biomarkers to monitor the evolution of the liver damage is an effective personalized medicine procedure to establish the severity of liver injury and its repair.

Introduction: Alcohol-related liver disease (ALD) represents the most common liver disease worldwide, however, the underlying molecular mechanisms are still poorly understood. Namely centrilobular inflammation and programmed cell death are characteristic to ALD and it remains to be elucidated why they persist despite the absence of alcohol., Aims: To study the effects of alcohol withdrawal in a cohort of heavy drinkers and the role of cirrhosis by using non-invasive biomarkers such as cytokines, apoptotic and angiogenic markers., Methods: Caspase 3-cleaved M30, M65, cytokines (IL-6, IL-8), tumor necrosis factor alpha (TNF-α), transforming growth factor (TGF-β) and vascular endothelial growth factor (VEGF) were measured in 114 heavy drinkers. The role of alcohol detoxification was investigated in 45 patients. The liver histology was available in 23 patients. Fibrosis stage and steatosis were assessed by measuring liver stiffness (LS) and controlled attenuation parameter (CAP) in all patients using transient elastography (FibroScan, Echosens, Paris). Mean observation interval between the measurements was 5.7 ± 1.4 days (mean + -SD)., Results: Patients consumed a mean of 204 ± 148 g/day alcohol with a heavy drinking duration of 15.3 ± 11.0 years. Mean LS was 20.7 ± 24.4 kPa and mean CAP was 303 ± 51 dB/m. Fibrosis distribution was F0-38.1%, F1-2-31%, F3-7.1 and F4-23.9%. Apoptotic markers M30 and M65 were almost five times above normal. In contrast, TNF- α a, IL-8 and VEGF were only slightly elevated. Patients with manifest liver cirrhosis (F4) had significantly higher levels of M30, M65, IL-6 and IL-8. Histology features such as hepatocyte ballooning, Mallory-Denk bodies, inflammation and fibrosis were all significantly associated with elevated LS, and serum levels of TNF-alpha, M30 and M65 but not with CAP and other cytokines. During alcohol detoxification, LS, transaminases, TGF- β, IL-6, IL-8 and VEGF decreased significantly. In contrast, no significant changes were observed for M30, M65 and TNF- α and M30 even increased during detoxification in non-cirrhotic patients. Profibrogenic cytokine TGF-beta and pro-angiogenic cytokine VEGF showed a delayed decrease in patients with manifest cirrhosis., Conclusion: Patients with alcohol-related cirrhosis have a pronounced apoptotic activity and a distinct inflammatory response that only partly improves after 1 week of alcohol detoxification. Alcohol withdrawal may represent an important approach to better dissect the underlying mechanisms in the setting of alcohol metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neuman, Mueller and Mueller.)

The intestinal microbiome (IM) is important for normal gastrointestinal (GI) and other organ systems' functioning. An alteration in the normal IM, dysbiosis, and changes in intestinal motility result in microorganisms' overgrowth and an alteration in intestinal permeability. The gut-brain axis is also of importance in the irritable bowel syndrome (IBS) and associated bowel overgrowth. Secondary to the epidemic of obesity, the metabolic syndrome has become a major health problem. Disturbances in the fecal microbiome are associated with the metabolic syndrome. Metabolic-associated fatty liver disease (MAFLD) is now the current terminology for non-alcoholic fatty liver disease. IM alteration by fecal transplantation is an approved treatment method for recurrent Clostridioides difficile infection. Initially performed by either duodenal infusion or colonoscopy, it is now easily performed by the administration of capsules containing stools. We discuss the intestinal microbiome-its composition, as well as the qualitative changes of microbiome composition leading to inflammation. In addition, we discuss the evidence of the effect of fecal transplantation on the metabolic syndrome and MAFLD, as well as its clinical indications.

This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.

A 52-year-old woman with a BMI of 31.2 kg/m 2 was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug's mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients.

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. Tumor cells escape the immune surveillance mechanism, avoiding immune detection and elimination by activating these checkpoints and suppressing the anti-tumor response, thus allowing formation of tumors. Antigenic modulation facilitates masking and contributes to the escape of tumor cells. In addition, there are growing cell promoters, like transforming growth factor β (TGF-β), contributing to escape mechanisms. Targeting the immunological escape of malignant cells is the basis of immune oncology. Checkpoint inhibitors, cytokines and their antibodies may enhance the immune system's response to tumors. Currently, immunomodulatory agents have been designed, evaluated in clinical trials and have been approved by both European and United States Drug Agencies. The present review is a reflection of the increasingly important role of the checkpoint inhibitors. Our aim is to review the side effects with the emphasis on hepatic adverse reactions of these novel biological drug interventions.

Background and Aims: Non-alcoholic steatohepatitis (NASH) has been associated with fibrosis that may progress to cirrhosis. The purpose of this study was to examine hepatocytes and perisinusoidal cells in liver biopsies of 3 families (3 males and 4 females) with non-cirrhotic and cirrhotic NASH to determine unique histological changes during a period of 2-7 years from diagnosis., Methods: In this study, hepatocytes, stellate cells and Kupffer cells were analyzed using light and electron microscopy, and immunohistochemistry with specific anti-macrophage antibody staining of liver biopsies., Results: Body mass index of all patients was over 28, and all viral, metabolic markers were negative. Alcohol consumption was insignificant. In all liver biopsies, diffuse, non-zonal macrovesicular steatosis involved 40-70% of liver samples. The lobular hepatocytes showed prominent ballooning hepatocyte degeneration. No Mallory Denk hyaline bodies (MDBs) were observed in three of the patients. MDBs developed in ballooned hepatocytes of four individuals that also presented foci of lobular inflammation. The apoptotic bodies were stained by cytokeratin 18. The trichrome stain revealed portal to portal bridging fibrosis. In one family, there was a three-fold increase in relative numbers of perisinusoidal macrophages in the older sister with NASH compared to livers of the younger siblings. The special finding in livers of patients with NASH was accumulation of groups of perisinusoidal macrophages, which was not associated with focal necrosis., Conclusion: Perisinusoidal macrophages appear to accumulate in NASH. It is possible that collections of macrophages are a response to chronic portal endotoxemia or lipotoxic activation of immuno-mediators. The persistent activation of these macrophages could lead to the chronic release of pro-inflammatory cytokines and contribute to chronic inflammation, fibrosis and cirrhosis leading to HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The work performed by Dr. Neuman was founded by In Vitro Drug Safety and Botechnology. Dr. Cohen acknowledge the contribution received from Mahaffy Gastroenterology grant., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Cannabis has been used for its medicinal purposes since ancient times. Its consumption leads to the activation of Cannabis receptors CB1 and CB2 that, through specific mechanisms can lead to modulation and progression of inflammation or repair. The novel findings are linked to the medical use of Cannabis in gastrointestinal (GI) system., Purpose: The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD)., Methods and Results: This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis' active ingredients and the "entourage" plays a role in the efficacy of various strains. Some elements of Cannabis may alter disease severity as over-activation of Cannabis receptors CB1 and CB2 can lead to changes of the commensal gut flora. The endocannabinoid system (ECS) contributes to gut homeostasis. The ability of ECS to modulate inflammatory responses demonstrates the capacity of ECS to preserve gastrointestinal (GI) function. Alterations of the ECS may predispose patients to pathologic disorders, including IBD. Clinical studies in IBD demonstrate that subjects benefit from Cannabis consumption as seen through a reduction of the IBD-inflammation, as well as through a decreased need for other medication. NAFLD is characterized by fat accumulation in the liver. The occurrence of inflammation in NAFLD leads to non-alcoholic-steatohepatitis (NASH). The use of Cannabis might reduce liver inflammation., Conclusions: With limited evidence of efficacy and safety of Cannabis in IBD, IBS, and NAFLD, randomized controlled studies are required to examine its therapeutic efficacy. Moreover, since long term use of the plant leads to drug use disorders the patients should be followed continuously.

Gamma glutamyl transferase (GGT) is an enzyme in glutathione and cysteine metabolism. GGT is a standard liver enzyme test reflecting biliary tract involvement. It also has a prooxoidant activity and a modulating influence on endothelia dysfunction. GGT is associated with the metabolic syndrome and is often elevated in patients with NAFLD. There is also a role for GGT activity in several aspects cardiovascular disease. There is an association between elevated GGT and cardiovascular mortality, atrial fibrillation, exacerbation of congestive heart failure . In addition there is an association with obstructive sleep apnea. We review the evidence available and suggest that there is a need for further assessing the use of GGT, together with the presence of the metabolic syndrome as a prognostic marker.

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.

Objectives: To systematically summarize the risk relationship between different levels of alcohol consumption and incidence of liver cirrhosis., Methods: MEDLINE and Embase were searched up to March 6, 2019, to identify case-control and cohort studies with sex-specific results and more than 2 categories of drinking in relation to the incidence of liver cirrhosis. Study characteristics were extracted and random-effects meta-analyses and meta-regressions were conducted., Results: A total of 7 cohort studies and 2 case-control studies met the inclusion criteria, providing data from 2,629,272 participants with 5,505 cases of liver cirrhosis. There was no increased risk for occasional drinkers. Consumption of one drink per day in comparison to long-term abstainers showed an increased risk for liver cirrhosis in women, but not in men. The risk for women was consistently higher compared to men. Drinking ≥5 drinks per day was associated with a substantially increased risk in both women (relative risk [RR] = 12.44, 95% confidence interval [CI]: 6.65-23.27 for 5-6 drinks, and RR = 24.58, 95% CI: 14.77-40.90 for ≥7 drinks) and men (RR = 3.80, 95% CI: 0.85-17.02, and RR = 6.93, 95% CI: 1.07-44.99, respectively). Heterogeneity across studies indicated an additional impact of other risk factors., Discussion: Alcohol is a major risk factor for liver cirrhosis with risk increasing exponentially. Women may be at higher risk compared to men even with little alcohol consumption. More high-quality research is necessary to elucidate the role of other risk factors, such as genetic vulnerability, body weight, metabolic risk factors, and drinking patterns over the life course. High alcohol consumption should be avoided, and people drinking at high levels should receive interventions to reduce their intake.

Drug-induced liver injury (DILI) is a comprehensive phenomenon. The injury to the liver may occur as an unexpected and undesired reaction to a therapeutic dose of a drug (idiosyncratic reaction) or as an expected therapeutic effect of the direct (intrinsic) toxicity of a drug taken in a large enough dose to cause liver injury. The direct toxicity (type A) reactions represent an extension of the drug's therapeutic effect; they occur relatively frequently and are typically dose-related and frequency-of-exposure-related. By contrast, idiosyncratic reactions, or type B reactions, are unpredictable, occurring only in susceptible individuals, and are unrelated to the dose or frequency of exposure. DILI encompasses both acute and/or chronic hepatic lesions. The liver injury may be the only clinical manifestation of the adverse drug effect. Otherwise, it may be accompanied by injury to other organs, or by systemic manifestations. The liver injury may be observed in 1-8 days from taking the drug. DILI cases may result in the disapproval of a new drug or in the removal of a useful drug from the market by regulatory agencies. The purpose of this review is to provide guidance to facilitate the detection and assessment of hepatotoxicity induced by therapeutics that received market authorization. This review supports the safe and effective use of drugs by patients and guides laboratory medicine professional in determining the possible drug-induced liver damage.

Background and Aim: The non-alcoholic fatty liver disease (NAFLD) and its sub-entity, the non-alcoholic steatohepatitis (NASH) represent a field of a tremendous progress in recent years. Clinicians need to remain updated with new data on pathogenesis and therapy. The present mini review aims to present some new scientific reports on the diagnosis of NAFLD and NASH for clinical practitioners., Methods: A systematic literature search of the main international databases was performed. We looked for seminal and innovative papers published in main international languages. A narrative review of the topic was consequently written., Results: This review describes new data on the diagnosis of NAFLD including NASH. Liver punction biopsy remains the gold standard. However many patients and clinicians prefer to use noninvasive methods. We present the serological tests and the imaging methods used to diagnose inflammation and fibrosis occurring in NAFLD and NASH., Conclusions: NAFLD-NASH are multifaceted entities that have to be diagnosed and treated by skilled and informed practitioners.

Previously called Crow-Fukase syndrome, POEMS syndrome is characterized by poly-neuropathy, osteo-sclerotic myeloma, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. Extremely elevated levels of serum vascular endothelial growth factor (VEGF) are characteristic of the syndrome. Chronic hepatitis B (HBV) and C (HCV) infections can also be present in POEMS. The pathogenesis of the syndrome is not well understood. The link between chronic alcohol consumption and this malignant condition has not been reported until now. In addition, no previous study has evaluated the influence of cytokine and chemokines or viruses in the severity and evolution of POEMS., Objectives: (1) to describe a heavy-alcohol user, who was diagnosed with POEMS; (2) to demonstrate the utility of quantitative measurement of serum levels of VEGF in the diagnosis of POEMS and the monitoring of therapeutic interventions; (3) to demonstrate that overproduction of pro-inflammatory cytokines is a characteristic of POEMS., Methods: We describe a case of a POEMS patient presenting HCV and who is a heavy drinker; we compare the serum levels of cytokines and chemokines between the POEMS patient with 80 patients with HCV, 12 healthy controls, and 80 individuals with alcoholic liver disease (ALD). We quantified (ELISA pg/mL) the levels of VEGF, Interferon gamma (IFN-γ), Tumor Necrosis Factor alpha (TNF-α), Regulated-upon-Activation Normal-T-cell-Expressed and presumably-Secreted (RANTES), and Nuclear Factor kappa-B (NFκB)., Results: In POEMS patients, VEGF levels were elevated versus control or other diseases, TNFα levels were higher versus control, but lower when compared with HCV or ALD patients. VEGF levels in POEMS patients decreased with therapeutic intervention., Conclusions: Chronic alcohol misuse can be a strong risk factor to rare malignancies such as POEMS syndrome. Extreme elevation of VEGF levels is diagnostic for POEMS syndrome, and should be followed to assess response to therapy. In addition, other comorbidities should be considered individually to ensure personalized therapeutic intervention., Competing Interests: The authors declare no conflict of interest. J. Neary and S.E. Goodwin are the treating physicians of the patient, L.B. Cohen clinically diagnosed and treated the patients from the control groups and M.G. Neuman designed the study and performed all the laboratory analyses of the entire study. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Objective: Herbal remedies containing pyrrilidozine alkaloids (PA)s can induce liver damage, including hepato-sinusoidal obstruction syndrome (HSOS) or veno-occlusive liver disease (VOD). Some individuals misusing alcohol consume also teas and/or herbal remedies containing PA. The interaction or additive toxicity of alcohol to PA toxicity needs to be addressed. The objectives of this study are 1) to review the scientific literature on the PA-induced liver toxicity; 2) identify possible mechanism(s) involved in PA-induced hepatocytotoxicity in the presence or absence of ethanol (EtOH) in vitro in normal human hepatocytes (NHH) in primary culture. To respond to the first objective, we systematically search all the literature engines (PubMed, Google Scholar) for liver induced damage due to PAs and summarize the results in an introductory systematic review., Original Article Experimental Design and Methods: Cells were exposed to one dose of 100 mmol/L EtOH for 24 hrs and to 2 doses of 100 mmol/L EtOH for consecutive 24 hrs periods, in the presence or absence of PAs (10 mg/mL), or the caspase-3 inhibitor IDN-1965 (50 µmol/L). Cells were analyzed for apoptosis by light microscopy, immuno-histochemistry, measuring cytokeratin-18 fragmentation, and transmission electron microscopy (TEM) (6000 cells/treatment). Cytotoxicity was determined using succinate dehydrogenase (SDH) activity, an enzyme specific to the mitochondria., Results: In NHH cells, a 100 mmol/L dose of Et-OH resulted in 22±2.5 apoptosis (p<0.001 vs. control). Two consecutive doses of 100 mmol/L Et-OH for 24 hrs each caused 36±3.0% apoptosis (p<0.001 vs. control and p<0.05 vs. one dose Et-OH). Pre-treatment with 50 µmol/L caspase inhibitor significantly reduced Et-OH-induced apoptosis [12±1.5% in 100 mmol/L (p<0.05) and 20±4.0% in 2×100 mmol/L (p<0.001)]. In addition, pre-treatment with 50 μmol caspase inhibitor in cells treated with PA + EtOH reduced apoptosis significantly (vs. non-exposed to caspase-inhibitor): Δ -22±3.0 % (p<0.05). HPC significantly decreased apoptosis compared to conditions lacking this supplementation in cells treated with EtOH-exposed cells present ballooning, Mallory bodies, changes in mitochondrial cristae and apoptosis by TEM. Pre-treatment with 50 μmol caspase inhibitor significantly reduced 100 mmol/L EtOH-induced (one dose) in NHH by 14±0.5% (p<0.05) compared to cells not exposed to the caspase-inhibitor. In cells treated concomitantly with PA and EtOH 100 mM Mallory-bodies and apo-necrotic cells have been observed. Pre-treatment with 50 μmol caspase inhibitor reduced the mitochondrial damage. A significant depletion in glutathione (GSH) was observed in Et-OH treated cells after 1 and 2 treatments (p<0.001 vs. control). Treatment with Et-OH enhanced PA-induced GSH-depletion and resulted in a significant increase in PA-induced cytotoxicity (p<0.001 vs. Et-untreated cells). Exposure to EtOH increased the cell culture media levels of the pro-inflammatory cytokine TNF. PA + EtOH-treated cells increased TNF-α levels in media compared to EtOH alone [86±8 vs. 53±5 pg/mL in cells exposed to 100 mmol/L EtOH (p<0.05) and 218±14 vs. 179±8 pg/mL in cells exposed to 2×100 mmol/L EtOH (p<0.05)]., Conclusions: PA up-regulates EtOH-induced hepatocytotoxicity by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol. There is a need for monitoring herbal medicine in order to optimize traditional medicine use and maximize the clinical benefits. Additionally, there is necessary to communicate to physicians the possible negative results of herbal remedies use. Also, the interactions between herbal remedies and drugs of misuse should be communicated to consumers.

Objective: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab., Case Report: A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis., Conclusions: We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.

This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: Chronic liver diseases may cause inflammation and progressive scarring, over time leading to irreversible hepatic damage (cirrhosis). As a result, the need to assess and closely monitor individuals for risk factors of components of matrix deposition and degradation, as well as the severity of the fibrosis using biomarkers, has been increasingly recognized., Aim: Our aim is to review the use of biomarker for diagnosing and defining the severity of liver fibrosis., Methods: A systematic literature review was done using the terms "hyaluronic acid" and "liver fibrosis" as well as the name of each biomarker or algorithm known to be employed. PubMed and Google Scholar were searched, and English language articles indexed between January 2010 and October 2014 in which HA was used as a marker of liver fibrosis were retrieved, regardless of the underlying liver disease. Each author read the publications separately and the results were analyzed and discussed., Results: Biomarkers offer a potential prognostic or diagnostic indicator for disease manifestation, progression, or both. Serum biomarkers, including HA, have been used for many years. Emerging biomarkers such as metalloproteinases have been proposed as tools that provide valuable complementary information to that obtained from traditional biomarkers. Moreover, markers of extracellular matrix degradation provide powerful predictions of risk. In order for biomarkers to be clinically useful in accurately diagnosing and treating disorders, age-specific reference intervals that account for differences in gender and ethnic origin are a necessity., Conclusions: This review attempts to provide a comprehensive analysis of the emerging risk biomarkers of liver fibrosis and to describe the clinical significance and analytical considerations of each biomarker pointing out sentinel features of disease progression., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The present review includes translational and clinical research that characterize non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Clinical and experimental evidence led to the recognition of the key toxic role played by lipotoxicity in the pathogenesis of NAFLD. The current understanding of lipotoxicity suggests that organ injury is initiated by the generation of oxidative metabolites and the translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. The injury progresses through impairment of tissue regeneration and extracellular matrix turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, predominantly stellate cells, macrophages and parenchymal cells. In response to inflammation, cytokines activate many signaling cascades that regulate fibrogenesis. This examination brings together research focusing on the underlying mechanisms of injury. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, and fibrogenesis in the liver. We searched electronic databases (Medline, Embase) for this review. This integrative work investigates different aspects of liver damage and possible repair. We aim to (1) determine the immuno-pathology of liver damage due to steatosis, (2) suggest diagnostic markers of NASH, (3) examine the role of behaviour in the development of NASH, and (4) develop common tools to study steatosis-induced effects in clinical studies. Special accent is put on co-morbidities with renal and neuropsychological disorders. Moreover, we review the evidence in literature on the role of moderate alcohol consumption in individuals that present NAFLD/NASH., Key Words: behavior, diet, imaging, non-alcoholic fatty liver, nonalcoholic steatohepatitis, laboratory markers.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical research, translational research, pathogenesis and therapies. A special accent is placed on alcohol misuse, as alcohol is a legally commercialized and taxable product. Drinking alcohol, particularly from a young age, is a major health problem. Alcoholism is known to contribute to morbidity and mortality. A systematic literature search was performed in order to obtain updated data (2008-2015). The review is focused on genetic polymorphisms of alcohol metabolizing enzymes and the role of cytochrome p450 2E1 and iron in ALD. Alcohol-mediated hepatocarcinogenesis is also discussed in the presence or absence of co-morbidities such as viral hepatitis C as well as therapeutic the role of innate immunity in ALD-HCV. Moreover, emphasis was placed on alcohol and drug interactions, as well as liver transplantation for end-stage ALD. Finally, the time came to eradicate alcohol-induced liver and intestinal damage by using betaine., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The present review spans a broad spectrum of topics dealing with alcoholic liver disease (ALD), including clinical and translational research. It focuses on the role of the immune system and the signaling pathways of cytokines in the pathogenesis of ALD. An additional factor that contributes to the pathogenesis of ALD is lipopolysaccharide (LPS), which plays a central role in the induction of steatosis, inflammation, and fibrosis in the liver. LPS derived from the intestinal microbiota enters the portal circulation, and is recognized by macrophages (Kupffer cells) and hepatocytes. In individuals with ALD, excessive levels of LPS in the liver affect immune, parenchymal, and non-immune cells, which in turn release various inflammatory cytokines and recruit neutrophils and other inflammatory cells. In this review, we elucidate the mechanisms by which alcohol contributes to the activation of Kupffer cells and the inflammatory cascade. The role of the stellate cells in fibrogenesis is also discussed.

Unlabelled: Quinolones are broad spectrum antibiotics that are intensively used and can induce immediate- and delayed-type hypersensitivity reactions, either IgE or T-cell mediated, in about 2-3% of treated patients., Objective: To better understand how T cells interact with quinolones to produce the hypersensitivity and to describe the possible prevention of the reactions., Methods: We search in PubMed for quinolones and adverse reactions naming each one of the therapeutics in use and the possible hypersensitivity reactions e.g., anaphylaxis, drug-induced delayed reactions, and hypersensitivity syndrome reactions. We also performed a search on organ-specific hypersensitivity reactions including cutaneous reactions, hepatic reactions, and renal reactions., Results: Our data show that T cells are involved in delayed immune reactions to quinolones and that cross-reactivity among the different quinolones is frequent. The predictive tests for quinolone-induced hypersensitivity should be used in patients before they are given the medication., Conclusions: Early identification of the mechanism of toxicity, quantitative assessment using laboratory tests, analysis of risk factors for patient susceptibility to the quinolones, and possible drug-drug interactions may lead to appropriate patient selection for therapy, monitoring the injury early and discontinuation of the therapeutic agent., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: The quantitative, measurable detection of drinking is important for the successful treatment of alcohol misuse in transplantation of patients with alcohol disorders, people living with human immunodeficiency virus that need to adhere to medication, and special occupational hazard offenders, many of whom continually deny drinking. Their initial misconduct usually leads to medical problems associated with drinking, impulsive social behavior, and drunk driving. The accurate identification of alcohol consumption via biochemical tests contributes significantly to the monitoring of drinking behavior., Methods: A systematic review of the current methods used to measure biomarkers of alcohol consumption was conducted using PubMed and Google Scholar databases (2010-2015). The names of the tests have been identified. The methods and publications that correlate between the social instruments and the biochemical tests were further investigated. There is a clear need for assays standardization to ensure the use of these biochemical tests as routine biomarkers., Findings: Alcohol ingestion can be measured using a breath test. Because alcohol is rapidly eliminated from the circulation, the time for detection by this analysis is in the range of hours. Alcohol consumption can alternatively be detected by direct measurement of ethanol concentration in blood or urine. Several markers have been proposed to extend the interval and sensitivities of detection, including ethyl glucuronide and ethyl sulfate in urine, phosphatidylethanol in blood, and ethyl glucuronide and fatty acid ethyl esters in hair, among others. Moreover, there is a need to correlate the indirect biomarker carbohydrate deficient transferrin, which reflects longer lasting consumption of higher amounts of alcohol, with serum γ-glutamyl transpeptidase, another long term indirect biomarker that is routinely used and standardized in laboratory medicine.

Unhealthy diet and lack of physical exercise are responsible for fat accumulation in the liver, which may lead to liver disease. Histologically, the severity of the disease has two stages: nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). NAFLD is defined by the presence of steatosis with no evidence of cellular injury such as hepatocyte ballooning. NASH is a distinct entity from NAFLD, and is characterized by the presence of inflammation with hepatocytes damage, with or without fibrosis. While several therapeutic strategies have been proposed to improve this condition, the present review aims to discuss nonmedicinal interventions used to reduce liver involvement or to prevent the disease altogether. The authors investigated dietary patterns and vitamin deficiencies associated with NAFLD, and their role in enhancing disease severity. Additionally, they reviewed the role of exercise and the use of interventions, such as as intragastric balloon and bariatric surgery, for improving disease progression. The authors propose monitoring disease progression or repair by following changes in cytoadipokine levels.

Purpose: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs., Design and Methods: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data., Conclusions: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Background: We developed an experimental model of ethanol-induced dermatotoxicity and hepatocytoxicity using normal human keratinocytes and normal human hepatocytes that preserve inducible cytochrome p450 activities. The original work was described in several articles. The objective of this study was to determine whether hyaluronic acid attenuates skin necrosis, and to further clarify its uses in wound repair in humans, animal models and in vitro studies., Methods: We performed a systematic review of the literature using the terms "hyaluronic acid" and "wound healing". PubMed was searched for studies published during the period 2010-2014., Results: Hyaluronic acid is used in tissue regeneration alone or in combination with herbal or Western medicine. Scaffolds made up of hyaluronic acid were used to embed basic fibroblast growth factor., Conclusion: Hyaluronic acid extracts are safe and efficacious products to be used in skin repair.