Non-alcoholic Liver Cirrhosis Research Articles

Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Associations of non-alcoholic fatty liver disease and cirrhosis with liver cancer in European and East Asian populations: A Mendelian randomization study.

The positive relationships of non-alcoholic fatty liver disease (NAFLD) and cirrhosis with liver cancer were shown in previous observational studies, while further Mendelian randomization (MR) investigations are needed to confirm the possible causal associations. This study aimed to explore whether NAFLD and cirrhosis were causally related to liver cancer using MR in European and East Asian populations. For European populations, NAFLD data were obtained from a genome-wide meta-analysis (8434 patients and 770 180 controls). The data on chronic elevation of alanine aminotransferase (cALT), a proxy of NAFLD, were derived from Million Veteran Program (68 725 patients and 95 472 controls). Cirrhosis data were collected from two sources: a genome-wide association study of five cohorts (4829 patients and 72 705 controls) and FinnGen (1931 patients and 216 861 controls). Liver cancer data were collected from FinnGen (304 patients and 174 006 controls). For East Asian populations, the data on cirrhosis (2184 patients and 210 269 controls) and hepatocellular carcinoma (1866 patients and 195 745 controls) were obtained from Biobank Japan. Three, 41, seven, six, and three single-nucleotide polymorphisms were used for NAFLD (European), cALT (European), cirrhosis (European-five cohorts), cirrhosis (European-FinnGen), and cirrhosis (East Asian), respectively. We used inverse-variance weighted as the primary method to calculate the odds ratio (OR) and 95% confidence interval (CI). Among European populations, genetically-predicted NAFLD, cALT, cirrhosis (five cohorts), and cirrhosis (FinnGen) were positively associated with liver cancer, with ORs (95% CIs) of 6.62 (3.81-11.50) (p < .001), 2.59 (1.70-3.94) (p < .001), 3.38 (2.41-4.75) (p < .001), and 2.62 (1.20-5.72) (p = .015). Among East Asian populations, there was also a positive association between genetically-predicted cirrhosis and hepatocellular carcinoma (OR = 2.12; 95% CI = 1.78-2.52; p < .001). This study utilized MR to complementarily confirm the positive connections of NAFLD and cirrhosis with liver cancer, as identified in earlier observational research. Subsequent MR investigations involving more liver cancer cases are needed.

The empirical dietary inflammatory pattern score and the risk of nonalcoholic fatty liver disease and cirrhosis.

Diet plays an important role in the pathogenesis of NAFLD. Inflammation is a potential mechanism linking diet to NAFLD development and its progression to cirrhosis.1 We analyzed data from a large, prospective cohort of US women to examine the influence of dietary inflammatory potential on the long-term risk of developing NAFLD and cirrhosis. We prospectively followed 96,016 women in the Nurses' Health Study II cohort (1995-2017) who were free of chronic liver disease, including NAFLD, at baseline. The inflammatory potential of the diet was ascertained using an established, food-based empirical dietary inflammatory pattern score. Cox proportional hazard models were used to estimate multivariable-adjusted hazard ratios and 95% CIs for incident NAFLD and cirrhosis. Over 2,085,947 person-years of follow-up, we documented 4389 cases of incident NAFLD and 102 cases of incident cirrhosis. Increasing cumulative average empirical dietary inflammatory pattern (EDIP) score was significantly and positively associated with incident NAFLD (multivariable-adjusted HR 1.31 per each 1-U increase in EDIP score, p-trend < 0.0001) and cirrhosis (p-trend of 0.034). Our findings also were consistent when examining recent diets using simple updated EDIP scores. In analyses of specific EDIP components, we observed an increased risk of incident NAFLD and cirrhosis with higher consumption of certain proinflammatory components of the EDIP score. Dietary patterns with a higher proinflammatory potential may be associated with a higher risk of developing both NAFLD and cirrhosis. Reducing the inflammatory potential of diet may potentially provide an effective strategy for preventing the development of NAFLD and progression to cirrhosis.

DIAGNOSTIC VALUE OF NITROGEN METABOLISM DISORDERS IN NON-ALCOHOLIC FATTY LIVER DISEASE IN COMORBID PATIENTS WITH METABOLIC SYNDROME AND STRATIFICATION OF DISEASE STAGES

The aim of the study is to determine the significance of hyperammonemia for the diagnosis of non-alcoholic fatty liver disease (NAFLD) in patients with metabolically associated comorbid pathology.&#x0D; Materials and Methods. A single-stage cohort randomized study was conducted to examine NAFLD in patients with metabolically associated pathology – type 2 diabetes, obesity, hypertension, coronary artery disease, and dyslipidemia. The study included 96 patients, who were divided into 3 groups: patients with steatotic liver disease (n=33), patients with non-alcoholic steatohepatitis (n=47) and patients with newly diagnosed liver cirrhosis (n=16). For NAFLD diagnosis, non-invasive methods were also applied (APRI, FIB4, NAFLD fibrosis score). To diagnose hepatocellular insufficiency, the authors evaluated ammonia level in capillary blood. Statistical processing was carried out by parametric and nonparametric methods, correlation and cluster analysis (Statistica 10.0). We also calculated odds ratio.&#x0D; Results. Metabolic syndrome in patients aged 64.2±0.85 (64.9 % females and 35.1 % males, Charleson comorbidity index 4.57±0.12) was represented by type 2 diabetes (100 %), insulin-treated diabetes (2/3 of patients), hypertension (1/3 of patients, stage 3 of NAFLD), obesity (87.5 %), coronary heart disease (90.6 %), steatotic liver disease (34.4 %), non-alcoholic steatohepatitis (49 %) and asymptomatic liver cirrhosis (16,6 %). According to NFS results, stage F3–F4 fibrosis was diagnosed in 52.1 % of patients, F2 fibrosis in 47.9 %; hyperammonemia was found in 91.7 % (up to 111.1±4.86 (101.3–120.7) µmol/l). Hyperammonemia developed from steatosis to non-alcoholic steatohepatitis and liver cirrhosis and correlated with the stage of liver fibrosis, hepatitis activity, and metabolic syndrome key criteria. NFS calculator and hyperammonemia diagnosis made it possible to stratify the stages of non-alcoholic fatty liver disease.

How non-alcoholic fatty liver disease and cirrhosis affect the heart.

Liver diseases affect the heart and the vascular system. Cardiovascular complications appear to be a leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD) and cirrhosis. The predominant histological changes in the liver range from steatosis to fibrosis to cirrhosis, which can each affect the cardiovascular system differently. Patients with cirrhotic cardiomyopathy (CCM) and NAFLD are at increased risk of impaired systolic and diastolic dysfunction and for suffering major cardiovascular events. However, the pathophysiological mechanisms behind these risks differ depending on the nature of the liver disease. Accurate assessment of symptoms by contemporary diagnostic modalities is essential for identifying patients at risk, for evaluating candidates for treatment, and prior to any invasive procedures. This review explores current perspectives within this field.

Hepatic T-cell senescence and exhaustion are implicated in the progression of fatty liver disease in patients with type 2 diabetes and mouse model with nonalcoholic steatohepatitis

Immunosenescence and exhaustion are involved in the development and progression of type 2 diabetes (T2D) and metabolic liver diseases, including fatty liver, fibrosis, and cirrhosis, in humans. However, the relationships of the senescence and exhaustion of T cells with insulin resistance-associated liver diseases remain incompletely understood. To better define the relationship of T2D with nonalcoholic fatty liver disease, 59 patients (mean age 58.7 ± 11.0 years; 47.5% male) with T2D were studied. To characterize their systemic immunophenotypes, peripheral blood mononuclear cells were analyzed using flow cytometry. Magnetic resonance imaging (MRI)-based proton density fat fraction and MRI-based elastography were performed using an open-bore, vertical-field 3.0 T scanner to quantify liver fat and fibrosis, respectively. The participants with insulin resistance had a significantly larger population of CD28 − CD57+ senescent T cells among the CD4+ and CD8 + T cells than those with lower Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values. The abundances of senescent CD4+ and CD8 + T cells and the HOMA-IR positively correlated with the severity of liver fibrosis, assessed using MRI-based elastography. Interleukin 15 from hepatic monocytes was found to be an inducer of bystander activation of T cells, which is associated with progression of liver disease in the participants with T2D. Furthermore, high expression of genes related to senescence and exhaustion was identified in CD4+ and CD8 + T cells from the participants with nonalcoholic steatohepatitis or liver cirrhosis. Finally, we have also demonstrated that hepatic T-cell senescence and exhaustion are induced in a diet or chemical-induced mouse model with nonalcoholic steatohepatitis. In conclusion, we have shown that T-cell senescence is associated with insulin resistance and metabolic liver disease in patients with T2D.

Nestin, CD44, Ki-67, GS and AQP4 expression in the brain neurogenic niches of deceased patients with liver cirrhosis of different degree

The aim of the study. Immunohistochemical study of Nestin, CD44, Ki-67, GS, AQP4 expression in the subventricular zone of the lateral ventricle and hippocampus of deceased patients with liver cirrhosis depending on the age and Child–Pugh score. Materials and methods. The brains of 90 deceased patients aged 65 ± 3 years with non-alcoholic liver cirrhosis (LC) Child–Pugh class A, B and C were studied, which comprised 3 groups: group “A” – 30 deceased patients with compensated LC; “B” – 30 deceased patients with subcompensated LC (“mild decompensation”); “C” – 30 deceased patients with decompensated LC. Control group included brains of 30 patients died from acute cardiovascular failure and did not have liver disease. Each group was divided into 2 subgroups: patients ≤59 y. o. and patients ≥60 y. o. Grade 1–4 hepatic encephalopathy was detected in 59 out of 90 (65.55 %) patients with LC. The immunohistochemical levels of Nestin, CD44, Ki-67, GS and AQP4 were evaluated in paraffin tissue sections of the subventricular zones (SVZ) of the anterior and lower horns of the brain lateral ventricles, as well as the subgranular zone (SGZ) of the dentate gyrus (DG) and other structures of hippocampus in standardized fields of view of the microscope Scope A1 Carl Zeiss (Germany) using Videotest-Morphology 5.2.0.158 software. Results. In SVZ of control subgroups, Nestin+ astrocyte-like stem cells were localized mainly in subventricular glial nodules (SGN) and to a lesser extent in astrocytic ribbon. In brains of patients with compensated and subcompensated LC, there was increased Nestin expression compared to control (by 61.36 % and 208.74 %, respectively) due to increased numbers of Nestin+ cells in astrocytic ribbons. In the hippocampus of control and cirrhotic patients, Nestin expression was determined mainly in astrocyte-like cells of the fimbria-fornix, “glial plates” around the blood vessels entering the choroid plexus and subpial zone. In the SVZ of patients with subcompensated LC, the expressions of Nestin, CD44, and Ki-67 were maximally increased (by 208.74 %, 37.83 %, and 3 times, respectively), moreover, in the areas of periventricular reparative astrogliosis, in small foci of encephalolysis in the head of caudate nucleus, among GS+ and CD44+ astrocytes clusters of astrocyte-like Nestin+ and CD44+ cells were detected. In patients with decompensated LC, a significant decrease in Nestin and CD44 expression and absence of Ki-67 were observed in the SVZ, with a simultaneous maximum increase in the expression of GS and AQP4. Conclusions. In the neurogenic niches of the lateral ventricles and hippocampus of patients with compensated and subcompensated LC, there are signs of activation of neural stem cells and niche astrocytes with increased expression of Nestin, CD44, and Ki-67, which reaches maximum in subcompensated LC. Clusters of astrocyte-like Nestin+ and CD44+ cells appear in foci of periventricular repair, which probably migrate from active adjacent subventricular niche. In the brains of the patients with decompensated LC and severe Grade 3–4 hepatic encephalopathy, deep astrocytic dysmetabolic dystrophy is associated with substantial decrease in the activity of subventricular stem niche and expected astrocytogenesis.

Acute hearing and visual loss caused by thiamine deficiency

BackgroundWernicke encephalopathy (WE) is a devastating acute or subacute neurological disorder caused by thiamine deficiency. Wernicke encephalopathy is characterized by the triad of ocular signs, cerebellar dysfunction, and confusion. Visual loss and hearing loss are less common findings in WE. Here, we report a case of Wernicke encephalopathy in a nonalcoholic liver cirrhosis patient who presented with acute bilateral deafness and bilateral blindness.Case presentationA 60-year-old Chinese man presented with a history of bilateral blindness and bilateral hypoacousia for 3 days. He had a history of liver cirrhosis and chronic hepatitis C virus infection and did not have a habit of alcohol consumption. Ophthalmologic and otologic examinations showed no obvious abnormalities. MRI findings revealed symmetric fluid-attenuated inversion recovery (FLAIR) hyperintensities in the bilateral medial dorsal thalamus, periventricular region around the third ventricle and tectum, and dorsal medulla oblongata. One day after hospitalization, the patient developed a mild coma. Based on the laboratory and neuroimaging findings, we diagnosed the patient with Wernicke encephalopathy. He soon regained consciousness after administration of thiamine. Both his visual acuity and his hearing function improved gradually.ConclusionsWe suggest that Wernicke encephalopathy can present with bilateral blindness and bilateral deafness.

Biomarkers of liver diseases.

The liver is one of the pivotal organs in the human body and is fundamentally responsible for detoxification and metabolism. Various disorders such as non-alcoholic fatty liver disease, fibrosis, cirrhosis, hepatocellular carcinoma, and hepatitis are associated with improper functions of the liver. Hence, biomarkers are needed to determine the severity. Further, many liver enzymes, including the cascade of aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBIL), are conventional liver biomarkers. They are not, however, unique to the liver; hence, efforts are being made to identify the precise biomarkers for liver illness that can target liver diseases. HMGB1, cytokeratin 18 (K18), glutathione-S-transferase-α (GST-α), glutamate dehydrogenase (GLDH), malate dehydrogenase (MDH), and microRNAs (miRNA) are a few examples of developing biomarkers used to detect many liver diseases. Hence, the review has highlighted various novel biomarkers of the liver so that various pathophysiological pathways and treatments can be made easier.

Human resident liver myeloid cells protect against metabolic stress in obesity.

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD.

Utility of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in non-alcoholic liver cirrhosis

The purpose of this research is to determine whether or not there is a correlation between a high neutrophil-to-lymphocyte ratio (NLR) and a high platelet-to-lymphocyte ratio (PLR) and nonalcoholic fatty liver disease (NAFLD). Methods: This was a retrospective study in the medicine department of a tertiary care facility. The demographic and clinical data was retrieved in a methodical fashion from the case records. Along with this, the data regarding the biopsy and other laboratory parameters was recorded to. This data was compared with non-NAFLD patients. Results: The non-NAFLD participants were separated from the NAFLD subjects and placed in one of the two groups. According to the findings of our investigation, a low PLR score was connected with a higher risk of NAFLD (P 0.001), whereas a high NLR score was not significantly linked to NAFLD (P &gt; 0.05). While there was shown to be a positive correlation between NLR and NAFLD, a negative association between PLR and NAFLD was discovered to exist. Conclusion: The findings of this study indicated that a strong association exists between NLR and PLR and NAFLD. we According to the findings, a lower PLR and NLR could be a risk factor for morbidity in NAFLD patients.

The Role of Hypothalamic Neuropeptides in Regulation of Liver Functions in Health and Disease

The communication between brain and peripheral tissues is mediated by neuropeptides that coordinate the functions of each organ with the activities of the entire body in specific environmental conditions. Hypothalamic neuropeptides act as neurotransmitters and hormones to regulate the physiology of food intake, digestion, and metabolism, having a direct or indirect impact on the liver. Investigations on liver pathologies found that dysfunctions of neuropeptides and their receptors are associated with liver disorders such as non-alcoholic fatty liver disease, steatohepatitis, cholestasis, cirrhosis, and liver cancer. In this article, we reviewed neuropeptides that regulate energy homeostasis and lipid and glucose metabolism in the liver and are associated with liver injuries. Firstly, peptides involved in regulatory processes in the brain and liver, such as neuropeptide Y, agouti-related protein, and the galanin family, are related to obesity and its comorbidities, including type 2 diabetes and metabolic syndrome, are presented. Secondly, a comprehensive review of neuropeptides such as secretin, vasoactive intestinal peptide, substance P, and somatostatin, which are involved in liver injuries unrelated to obesity; i.e., cholestasis-induced biliary hyperplasia, cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma, is also presented. The cellular and molecular mechanisms underlining liver injuries related to the dysfunction of these neuropeptides and receptors are also described.

Dysregulated peripheral proteome reveals NASH-specific signatures identifying patient subgroups with distinct liver biology.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking. The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis. We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients. NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology.

Effect and mechanism of Dahuang Zhechong Pills in improving liver aging in rats by regulating ROS-mediated PI3K/Akt/FoxO4 signaling pathway

Recent studies have shown that the occurrence and development of common liver diseases, including non-alcoholic fatty liver disease, cirrhosis, and liver cancer, are related to liver aging(LA). Therefore, to explore the effect and mechanism of Dahuang Zhechong Pills(DHZCP), a traditional classic prescription in improving LA with multiple targets, the present study randomly divided 24 rats into a normal group, a model group, a DHZCP group, and a vitamin E(VE) group, with six rats in each group. The LA model was induced by continuous intraperitoneal injection of D-galactose(D-gal) in rats. For the LA model rats, the general situation was evaluated by aging phenotype and body weight(BW). LA was assessed by the pathological characteristics of hepatocyte senescence, hepatic function indexes, the staining characteristics of phosphorylated histone family 2A variant(γ-H2AX), and the expression levels of cell cycle arrest proteins(P21, P53, P16) and senescence-associated secretory phenotype(SASP) in the liver. The activation of the reactive oxygen species(ROS)-mediated phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)/forkhead box protein O4(FoxO4) signaling pathway was estimated by hepatic ROS expression feature and the protein expression levels of the key signaling molecules in the PI3K/Akt/FoxO4 signaling pathway. The results showed that after the treatment with DHZCP or VE for 12 weeks, for the DHZCP and VE groups, the characterized aging phenotype, BW, pathological characteristics of hepatocyte senescence, hepatic function indexes, relative expression of ROS in the liver, protein expression levels of key signaling molecules including p-PI3K, p-Akt, and FoxO4 in the liver, staining characteristics of γ-H2AX, and the protein expression levels of P16, P21, P53, interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in the liver were improved, and the effects of DHZCP and VE were similar. Based on the D-gal-induced LA model in rats, this study demonstrates that DHZCP can ameliorate LA with multiple targets in vivo, and its effects and mechanism are related to regulating the activation of the ROS-mediated PI3K/Akt/FoxO4 signaling pathway in the liver. These findings are expected to provide new pharmacological evidence for the treatment of DHZCP in aging-related liver diseases.

Metabolic Health and Disease: A Role of Osteokines?

Maintenance of skeletal health is tightly regulated by osteocytes, osteoblasts, and osteoclasts via coordinated secretion of bone-derived factors, termed osteokines. Disruption of this coordinated process due to aging and metabolic disease promotes loss of bone mass and increased risk of fracture. Indeed, growing evidence demonstrates that metabolic diseases, including type 2 diabetes, liver disease and cancer are accompanied by bone loss and altered osteokine levels. With the persistent prevalence of cancer and the growing epidemic of metabolic disorders, investigations into the role of inter-tissue communication during disease progression are on the rise. While osteokines are imperative for bone homeostasis, work from us and others have identified that osteokines possess endocrine functions, exerting effects on distant tissues including skeletal muscle and liver. In this review we first discuss the prevalence of bone loss and osteokine alterations in patients with type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cirrhosis, and cancer. We then discuss the effects of osteokines in mediating skeletal muscle and liver homeostasis, including RANKL, sclerostin, osteocalcin, FGF23, PGE2, TGF-β, BMPs, IGF-1 and PTHrP. To better understand how inter-tissue communication contributes to disease progression, it is essential that we include the bone secretome and the systemic roles of osteokines.

Ammonia level and Alzheimer type 2 astrocytes in the brain of deceased patients with liver cirrhosis of the varying degree

The aim of the study – comparative analysis of the ammonia level and Alzheimer type 2 astrocytes in the brain cortex and white matter of cerebral hemispheres, hippocampus, thalamus, striatum and cerebellum in the deceased patients with liver cirrhosis of classes A, B and C according to Child–Pugh. Materials and methods. The study was performed on the brain of deceased 90 patients (65 ± 3 years) suffered from non-alcoholic liver cirrhosis (LC) of classes A (n = 30, group “A”), B (n = 30, group “B”) and C (n = 30, group “C”) according to Child–Pugh score, among which 59 (65.55 %) patients had clinical symptoms of hepatic encephalopathy of I–IV grades. The control group included postmortem brains of 30 patients (59.0 ± 2.5 years) who died from acute cardiovascular insufficiency and did not suffer from liver diseases or intoxication. A retrospective analysis of clinical and laboratory data from case histories was carried out. For histochemical (HC) determination of the ammonia in paraffin sections of the cerebral cortex and white matter, hippocampus, thalamus, striatum and cerebellum we used the protocol with Nessler’s reagent proposed by Gutierrez-de-Juan et al. (2017). In the noted brain regions, the analysis of HC ammonia optical density was performed in five standardized fields of view (×200) of the microscope scope A1 “Carl Zeiss” (Germany) with Jenoptik camera progress Gryphax 60 N-C1ꞌꞌ1.0x426114 (Germany) using ImageJ software; in each noted brain region the number of Alzheimer’s type 2 astrocytes (AA2) was counted per twenty standardized fields of view at magnification ×400. Results. HC method for ammonia detection with Nessler’s reagent according to V. Gutiérrez-de-Juan et al. (2017) reveals region-dependent fine-grained expression of ammonia in the brain neuropil of deceased patients in control and cirrhotic groups. In control patients, a very low HC ammonia expression is observed with higher values in cerebellum, thalamus, and striatum, while still ranked as negative. Increased HC ammonia expression (compared to control) is observed in deceased patients with compensated LC of “A” group in the cortex, thalamus, striatum and cerebellum; in subcompensated LC of “B” group – as well in the white matter and hippocampus. In deceased patients with decompensated LC of “C” group, in cerebellum, thalamus and striatum HC ammonia expression is maximally increased (by 6.18, 5.72, and 5.50 folds, respectively). Significant correlations are present between patients’ postmortem brain HC ammonia expression and the last intravital indicators of the blood total bilirubin, AST, ALT, albumin, leukocytic intoxication index. In compensated cirrhosis, increase in AA2 numbers compared to control is found in thalamus, striatum and cerebellum, which corresponds to AA2-astrocytosis of I degree. In subcompensated cirrhosis, AA2-astrocytosis of moderate II degree is found in the cortex, thalamus and cerebellum; AA2-astrocytosis of I degree – in striatum. In decompensated cirrhosis, pronounced AA2-astrocytosis of III degree is determined in the cortex, thalamus, striatum and cerebellum; moderate AA2-astrocytosis of II degree – in cerebral white matter, and mild AA2-astrocytosis of I degree – in the hippocampus. There is a moderate, strong, and very strong positive relationship between the levels of AA2-astrocytosis and HC ammonia expression in the thalamus, striatum, and cerebellum. Conclusions. In deceased patients with LC, the neuropil HC ammonia expression in cerebellum, thalamus, striatum, and cerebral cortex directly correlates with the severity of LC according to Child–Pugh, reaching a maximum in LC of class C, and has significant correlations with intravital blood levels of total bilirubin, AST, ALT, albumin, leukocytic intoxication index. With LC progression, AA2-astrocytosis increases significantly in thalamus, cerebellum, striatum and cerebral cortex, which positively correlates with HC ammonia expression in these brain regions.

Mechanism of Metabolic Response to Hepatectomy by Integrated Analysis of Gut Microbiota, Metabolomics, and Proteomics.

Hepatectomy is a common clinical procedure for the treatment of many liver diseases, and the successful recovery of a patient's liver metabolism and function after surgery is crucial for a good prognosis. The objective of this study was to elucidate the metabolic response to hepatectomy using high-throughput sequencing analysis of 16S rRNA gene, metabolomics, and proteomics data. Fecal and serum samples from beagle dogs were collected on day 0 (LH0), day 7 (LH7), and day 28 (LH28) after laparoscopic partial hepatectomy. Liver tissue samples were taken on LH0 and LH7. Dysbiosis in the fecal microbiota was explored, and host-microbiome interactions based on global metabolic and protein profiles and inflammatory processes were determined. Results showed that the relative abundance of Allobaculum and Turicibacter was decreased and that of Escherichia-Shigella was increased after hepatectomy (P < 0.05); the phenylalanine, tyrosine, and tryptophan biosynthetic pathway, along with the phenylalanine and aminoacyl-tRNA biosynthetic pathway, was significantly associated with liver injury. The serum metabolites l-phenylalanine and l-arginine were useful as biomarkers, and the fecal metabolite l-threonine was a signature target monitor for liver recovery. The proteomics profile revealed 412 significantly different proteins and further highlighted two key signaling pathways (mitogen-activated protein kinase [MAPK] and peroxisome proliferator-activated receptor [PPAR]) involved in the response to liver injury. We systematically explored the metabolic mechanism of liver injury and recovery, providing new insights into effective ways to promote recovery after hepatectomy and improve liver function and long-term survival. These fundamental studies on hepatectomy will provide the basis for future advances in treatment and recovery from common liver diseases. IMPORTANCE As the largest parenchymal organ, the liver is a target for bacterial and viral infections, nonalcoholic fatty liver disease (NAFLD), cirrhosis, cancer, and many other diseases, constituting a serious worldwide problem. The treatment for many of these diseases involves hepatectomy. Here, we show that aberrant inflammatory processes after hepatectomy of the liver as reflected in the association between liver metabolism and gut microbiota create a grave risk. This study investigated the mechanisms of gut microbiota and host metabolism involved in liver injury and recovery after hepatectomy, using proteomics to reveal the mechanisms of postoperative liver injury and a comprehensive multi-omics approach to identify changes in metabolism after hepatectomy.

Comparative analysis of postmortem cerebral ammonia level and Alzheimer type 2 astrocytes with intravital blood laboratory parameters of deceased patients with liver cirrhosis of varying degree

Purpose - correlation analysis of the postmortem ammonia level and numbers of Alzheimer type 2 astrocytes in different parts of the brain with intravital laboratory blood parameters of deceased patients with liver cirrhosis of varying severity.&#x0D; Material and methods. Autopsied brains of 90 patients with non-alcoholic liver cirrhosis (LC) of class A, B and C according to Child-Pugh formed 3 groups: «A» (n = 30), «B» (n = 30) and «C» (n = 30). Control group - 30 patients deceased from cardiovascular failure. Cortex, white matter, hippocampus, thalamus, striatum and cerebellum were histochemically (HC) studied with Nessler's reagent for ammonia level. Correlation analysis of ammonia expression, Alzheimer type 2 astrocytes (AA2) numbers and 14 intravital laboratory blood parameters was performed.&#x0D; Results. HC method reveals region-dependent ammonia expression in the brain neuropil. The most significant correlations are observed in thalamus, striatum, cerebellum, and cortex between ammonia expression (ACUOD), AA2-astrocytosis, and lifetime values of total bilirubin (for Bil/ACUOD &amp; /AA2 r = 0.31-0.97), AST (for AST/ACUOD &amp; /AA2 r = 0.30-0.81), ALT (for ALT/ACUOD &amp; /AA2 r = 0.30-0.78), leukocyte index of intoxication (for LII/ACUOD &amp; /AA2 r = 0.34-0.76), albumin (for Alb/ACUOD &amp; /AA2 r = -0.34 to -0.78), leukocytes (for Wbc/ACUOD &amp; /AA2 r = 0.31-0.68), prothrombin index (for PI/ACUOD &amp; /AA2 r = -0.31 to -0.45) and potassium (for K+/ACUOD &amp; /AA2 r = -0.32 to -0.45), p &lt;0.05.&#x0D; Conclusion. During LC ammonia expression and AA2-astrocytosis in cerebellum, thalamus, striatum and cortex significantly correlate with each other, as well as with indicators of total bilirubin, AST, ALT, albumin, leukocytes, leukocyte index of intoxication, prothrombin index and blood potassium.

The Role of the Soluble Interleukin-6 Receptor in the Progression of Nonalcoholic Fatty Liver Disease.

The blood level of soluble IL-6 receptor was measured in patients with different clinical and morphological forms of nonalcoholic fatty liver disease and healthy donors. The relationship of the soluble IL-6 receptor with the content of IL-6, the level of the IL6 gene mRNA, and a number of markers of hepatocyte and peripheral blood leukocyte apoptosis was assessed. It has been established for the first time that progression of nonalcoholic fatty liver disease is associated with changes in the level of soluble IL-6 receptor in the blood. In patients with high activity of nonalcoholic steatohepatitis and liver cirrhosis, the blood concentration of soluble IL-6 receptor sharply decreased in comparison with the earlier stages of progression of nonalcoholic fatty liver disease (liver steatosis, nonalcoholic steatohepatitis of weak and moderate activity). This allows considering the decrease in this indicator as a new diagnostic marker for distinguishing nonalcoholic steatohepatitis of high activity from weak and moderate activity. A close correlation between changes in the level of soluble IL-6 receptor and apoptosis of peripheral blood leukocytes and hepatocytes was revealed.

Cholecystalgia: An Atypical Presentation of Congestive Heart Failure in a New Diagnosis of Alcohol-Induced Cardiomyopathy

Right upper quadrant (RUQ) pain is a frequent presenting symptom in the emergency department, and gallstone-induced acute cholecystitis is one of the main causes; in addition, RUQ pain can be a consequence of several other conditions. Although rare, it may also indicate cholecystalgia from gallbladder edema, which is usually related to other conditions, such as congestive heart failure (CHF), alcoholic and nonalcoholic liver cirrhosis, acute viral or drug-induced hepatitis, renal failure, and hypoproteinemia. We present a case of cholecystalgia resulting from gallbladder edema in a patient with a newly diagnosed alcohol-induced cardiomyopathy without the common CHF signs and symptoms.