Relationships among neurotransmitters, cytokines and cognitive performance for individuals with hepatitis C achieving sustained virologic response: A pilot study.

An important extrahepatic consequence of Hepatitis C is its adverse impact on the central nervous system and cognitive performance. We aimed to determine whether there is a significant relationship between selected neurotransmitters and cytokines and cognitive performance in patients with Chronic Hepatitis C before and after achieving sustained virologic response (SVR). Pre-SVR, elevated kynurenine was associated with increased immediate and delayed visual memory, whereas post-SVR the positive associations are between kynurenine and immediate and delayed verbal memory. TGF-B was consistently negatively associated with both immediate and delayed visual memory pre- and post-SVR. These concomitant changes may have important clinical relevance.

Cytokine balance is restored as patient-reported outcomes improve in patients recovering from chronic hepatitis C.

BACKGROUND & AIMS: Chronic hepatitis C (CHC) has a negative impact on patient-reported outcomes (PROs). Although most CHC patients who achieve sustained virologic response (SVR) show an improvement in PRO scores, some continue to experience impairment in PROs. The aim was to investigate if serum biomarkers (selected neurotransmitters and cytokines) are associated with changes in PROs in CHC patients who achieve SVR. METHODS: Data were utilized from a prospective clinical trial of ledipasvir/sofosbuvir fixed-dose combination. Chronic genotype 1 HCV subjects without cirrhosis (N = 40, age: 45.3 ± 11.5, 48% male, 90% white) were treated for 12 weeks open label with 97% achieving SVR24. PRO questionnaires included Short Form-36 (SF-36), Fatigue Severity Scale (FSS), Beck Depression Inventory-II (BDI-II), Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Sera were used for measurement of selected neurotransmitters and cytokines. Data were collected at baseline and follow-up week 24. RESULTS: Changes in physical health correlated with changes in several biomarkers. BDNF negatively correlated with SF-36 physical health summary score (rho = -0.34, P < 0.05), SF-36 physical functioning (rho = -0.34, P < 0.05), SF-36 bodily pain (rho = -0.39, P < 0.05) and FACIT-F physical well-being (rho = -0.54, P < 0.001). Changes in emotional well-being (FACIT-F) were positively associated with changes in serotonin (rho = 0.34, P < 0.05), but negatively associated with changes in GABA and BDNF (rho = -0.4, P = 0.01, and rho = -0.35, P < 0.05 respectively). CONCLUSIONS: These data indicate relationships between PROs and serum biomarkers pre- and post-SVR in CHC. These concomitant changes may have important clinical relevance.

Adipocytokine expression associated with miRNA regulation and diagnosis of NASH in obese patients with NAFLD.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with visceral adiposity. The secretion of adipocytokines from white adipose tissue (WAT) promoting necroinflammation, and/or fibrosis may play important roles in the pathogenesis of non-alcoholic steatohepatits (NASH). In a previous study, reduced expression of a number of miRNA species in WAT concomitant with histological diagnosis of NASH was successfully demonstrated. In this study, we measure the expression of several predicted miRNA regulatory targets relevant to NAFLD and NASH including mTOR, FAS, IL20, SEMA4C, ADAMTS6 and IL13RA. We then examine hepatic receptor expression by immunohistochemical staining and qPCR. METHODS: White adipose tissue was collected from 24 obese patients undergoing bariatric surgery with biopsy-proven NAFLD. Extracted total RNAs from the adipose tissue were reverse transcribed and profiled for gene expression by qPCR for specific individual mRNA targets defined after identification by any two of three of the major prediction services: miRanda, TarBase or PicTar. All liver biopsies were read by a singly hepatopathologist. The same liver tissue was used to stain for hepatic receptor expression for FASLG and IL20. Additionally, the same tissue was used for qPCR for FASLG and IL20. RESULTS: Increases in the expression of IL13RA, mTOR, IL20, SEMA4C and FAS were detected and negatively correlated with putative regulatory miRNA. Hepatic receptor expression for FAS and IL20 was noted to correlate with markers of inflammation and severity of NAFLD. CONCLUSION: These data are consistent with the hypothesis that specific adipocytokines secreted by WAT will impact hepatic tissue and participate in the pathogenesis of NASH.

Hepatitis C and metabolic syndrome.

Hepatitis C virus (HCV) and the hepatic manifestation of metabolic syndrome, nonalcoholic fatty liver disease, are the two major causes of chronic liver disease worldwide. Liver histology of both diseases can be associated with steatosis, oxidative stress and fibrogenesis. Although better defined for HCV, approximately 20% of patients with these diseases can also develop cirrhosis or hepatocellular carcinoma. In recent years, it has become clear that the presence of metabolic syndrome and nonalcoholic fatty liver disease negatively impacts HCV-related outcomes, while simultaneously, the progression of HCV may have metabolic consequences in that it encourages or exacerbates insulin resistance. A growing body of evidence suggests that successful treatment of HCV may rely on understanding and addressing the complex and often mutually confounding relationship between HCV and the individual elements that comprise metabolic syndrome.

Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

BACKGROUND: Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. AIMS: To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. METHODS: Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. RESULTS: Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. CONCLUSIONS: These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

Expression of cytokine signaling genes in morbidly obese patients with non-alcoholic steatohepatitis and hepatic fibrosis.

BACKGROUND: White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients. METHODS: We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes. RESULTS: Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM. CONCLUSIONS: Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.