Progression Of Chronic Liver Disease Research Articles

Angiogenesis and Fibrogenesis in Chronic Liver Diseases.

Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.

Human keratin 8 variants promote mouse acetaminophen hepatotoxicity coupled with c-jun amino-terminal kinase activation and protein adduct formation.

Keratins 8 and 18 (K8/K18) are the intermediate filaments proteins of simple-type digestive epithelia and provide important cytoprotective function. K8/K18 variants predispose humans to chronic liver disease progression and poor outcomes in acute acetaminophen (APAP)-related liver failure. Given that K8 G62C and R341H/R341C are common K8 variants in European and North American populations, we studied their biological significance using transgenic mice. Mice that overexpress the human K8 variants, R341H or R341C, were generated and used together with previously described mice that overexpress wild-type K8 or K8 G62C. Mice were injected with 600 mg/kg of APAP or underwent bile duct ligation (BDL). Livers were evaluated by microarray analysis, quantitative real-time polymerase chain reaction, immunoblotting, histological and immunological staining, and biochemical assays. Under basal conditions, the K8 G62C/R341H/R341C variant-expressing mice did not show an obvious liver phenotype or altered keratin filament distribution, whereas K8 G62C/R341C animals had aberrant disulphide cross-linked keratins. Animals carrying the K8 variants displayed limited gene expression changes, but had lower nicotinamide N-methyl transferase (NNMT) levels and were predisposed to APAP-induced hepatotoxicity. NNMT represents a novel K8/K18-associated protein that becomes up-regulated after K8/K18 transfection. The more pronounced liver damage was accompanied by increased and prolonged JNK activation; elevated APAP protein adducts; K8 hyperphosphorylation at S74/S432 with enhanced keratin solubility; and prominent pericentral keratin network disruption. No differences in APAP serum levels, glutathione, or adenosine triphosphate levels were noted. BDL resulted in similar liver injury and biliary fibrosis in all mouse genotypes. Expression of human K8 variants G62C, R341H, or R341C in mice predisposes to acute APAP hepatotoxicity, thereby providing direct evidence for the importance of these variants in human acute liver failure.

Anticoagulant Therapy in Patients with Cirrhosis.

Recent studies have greatly expanded our understanding of the coagulopathy of cirrhosis. It is clear that cirrhosis patients are at a risk of both bleeding and thrombosis. While prediction of these events remains challenging, cirrhosis patients are not protected from the development of venous and arterial thrombosis. In fact, studies show that hypercoagulability may promote hepatic decompensation and development of fibrosis. Anticoagulation for thrombosis is now becoming a common prospect in many clinical situations. Our understanding of the efficacy and safety of commonly used therapeutics is only beginning to emerge and the risks and benefits remain unclear in this unique population. In this review, we discuss the role of anticoagulation in the treatment and prevention peripheral and splanchnic thrombosis in patients with cirrhosis, as well as examine the potential role of anticoagulants in altering the progression of chronic liver disease.

The hop constituent xanthohumol exhibits hepatoprotective effects and inhibits the activation of hepatic stellate cells at different levels.

Xanthohumol is the principal prenylated flavonoid of the female inflorescences of the hop plant. In recent years, various beneficial xanthohumol effects including anti-inflammatory, antioxidant, hypoglycemic activities, and anticancer effects have been revealed. This review summarizes present studies indicating that xanthohumol also inhibits several critical pathophysiological steps during the development and course of chronic liver disease, including the activation and pro-fibrogenic genotype of hepatic stellate cells. Also the various mechanism of action and molecular targets of the beneficial xanthohumol effects will be described. Furthermore, the potential use of xanthohumol or a xanthohumol-enriched hop extract as therapeutic agent to combat the progression of chronic liver disease will be discussed. It is notable that in addition to its hepatoprotective effects, xanthohumol also holds promise as a therapeutic agent for treating obesity, dysregulation of glucose metabolism and other components of the metabolic syndrome including hepatic steatosis. Thus, therapeutic xanthohumol application appears as a promising strategy, particularly in obese patients, to inhibit the development as well as the progression of non-alcoholic fatty liver disease.

Hepatic myofibroblasts and fibrogenic progression of chronic liver diseases.

Liver fibrogenesis is a dynamic and highly integrated molecular, tissue and cellular process that during the course of a chronic liver disease (CLD) leads progressively to an excess deposition of extracellular matrix (ECM) components in an attempt to limit the consequences of chronic parenchymal injury. Irrespective of etiology, liver fibrogenesis is sustained and modulated by an intense cross talk occurring between different hepatic cell populations that involves the synthesis and release of several mediators, including growth factors, cytokines, chemokines, reactive oxygen species, adipokines, vasoactive agents and plasma proteins. In this scenario a major pro-fibrogenic role is played by a heterogeneous population of α-smooth muscle actin (α-SMA) positive cells defined as hepatic myofibroblasts (MFs). Hepatic MFs are highly proliferative and contractile cells, primarily responsible for excess deposition of ECM components and involved in ECM altered remodeling observed in CLDs. MFs also represent a unique and critical cellular crossroad able to integrate incoming paracrine or autocrine signals, released from all hepatic cell populations involved or available in the microenvironment, as well as to synthetize and release mediators which sustain and perpetuate fibrogenesis, chronic inflammatory response and neo-angiogenesis. This review has been designed to offer critical knowledge on hepatic MFs, including terminology, essential definitions and characterization of MFs, with a focus on the origin of these cells (mainly from hepatic stellate cells and portal fibroblasts or, to a lesser extent, bone marrow-derived cells), the process of activation and the functional responses that these cells can operate in the fibrogenic progression of CLDs.

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis. HSCs were obtained from WT and Axl(-/-) mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl(-/-) mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl(-/-) mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management.

Study of FibroTest and hyaluronic acid biological variation in healthy volunteers and comparison of serum hyaluronic acid biological variation between chronic liver diseases of different etiology and fibrotic stage using confidence intervals

ObjectivesPersonalized ranges of liver fibrosis serum biomarkers such as FibroTest or hyaluronic acid could be used for early detection of fibrotic changes in patients with progressive chronic liver disease. Our aim was to generate reliable biological variation estimates for these two biomarkers with confidence intervals for within-subject biological variation and reference change value. Design and methodsNine fasting healthy volunteers and 66 chronic liver disease patients were included. Biological variation estimates were calculated for FibroTest in healthy volunteers, and for hyaluronic acid in healthy volunteers and chronic liver disease patients stratified by etiology and liver fibrosis stage. ResultsIn healthy volunteers, within-subject biological coefficient of variation (with 95% confidence intervals) and index of individuality were 20% (16%–28%) and 0.6 for FibroTest and 34% (27%–47%) and 0.79 for hyaluronic acid, respectively. Overall hyaluronic acid within-subject biological coefficient of variation was similar among non-alcoholic fatty liver disease and chronic hepatitis C with 41% (34%–52%) and 45% (39%–55%), respectively, in contrast to chronic hepatitis B with 170% (140%–215%). Hyaluronic acid within-subject biological coefficients of variation were similar between F0–F1, F2 and F3 liver fibrosis stages in non-alcoholic fatty liver disease with 34% (25%–49%), 41% (31%–59%) and 34% (23%–62%), respectively, and in chronic hepatitis C with 34% (27%–47%), 33% (26%–45%) and 38% (27%–65%), respectively. However, corresponding hyaluronic acid indexes of individuality were lower in the higher fibrosis stages. ConclusionNon-overlapping confidence intervals of biological variation estimates allowed us to detect significant differences regarding hyaluronic acid biological variation between chronic liver disease subgroups.

Primary biliary cirrhosis is a generalized autoimmune epithelitis.

Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice.

Roles of Nrf2 and autophagy in liver fibrosis

Liver fibrosis is an essential stage in the progression of chronic liver disease to liver cirrhosis,and its incidence is high in the world. The mechanism of liver fibrosis that involves many cytokines and signaling pathways is complicated and is understood by people more and more clearly. This review presents that nuclear factor- erythroid 2- related factor- 2( Nrf2)- mediated antioxidant response plays a critical role in suppressing the progression of liver fibrosis. In addition,autophagy is also an important and complex regulator of liver fibrosis in different pathways. The possible mechanism of interaction between Nrf2 and autophagy in liver fibrosis is also described in this review.Currently,the research combining Nrf2 and autophagy is considered the future direction for the study of liver fibrosis,providing a new idea for the treatment of liver fibrosis.

Overexpression of Squamous Cell Carcinoma Antigen 1 Is Associated with the Onset and Progression of Human Hepatocellular Carcinoma

Previous studies indicated Squamous Cell Carcinoma Antigen 1 (SCCA1) may be involved in tumorigenesis and progress of various human malignancies by inhibiting cell apoptosis and promoting cell proliferative activity. The aim of the study was to further investigate SCCA1 expression in different extent of liver diseases and evaluate the clinical significance and prognostic value in HCC. Eighty nine patient-matched tumors and peritumoral surgical specimens and 56 liver biopsies specimens from 23 patients with chronic hepatitis B (CHB), 19 with dysplastic nodule (DN), and 14 with HCC were enrolled. An additional four normal liver (NL) samples were used as controls. SCCA1 expression in liver tissue was measured by immunochemistry. Another 28 HCC specimens and paired non-tumor tissues were used for SCCA1 detection by Western blot. The prognostic value of SCCA1 expression in HCC was evaluated by the Cox proportional hazards regression model analysis. Western blot analysis showed SCCA1 positive rate in HCC was higher than the matched adjacent noncancerous tissues (p <0.001). Immunohistochemistry revealed that SCCA1-positive rate increased gradually from NL, CHB, PNT to DN and HCC (p <0.05). Clinicopathological analysis showed that SCCA1 expression was positively associated with tumor differentiation (p = 0.043) and patients' Child-Pugh score (p = 0.021). The SCCA1-poistive group showed better overall survival than the negative group (p = 0.029). Importantly, SCCA1 expression was an independent prognostic factor for the overall survival of HCC patients (hazard ratio = 3.757, p <0.001). SCCA1 expression pattern may relate to the progression of chronic liver diseases. Furthermore, our study supports a potential association of negative SCCA1 expression with poor outcome in HCC.

Increased expression of the Glucose-transporter GLUT1 during hepatic stellate cell activation promotes hepatic fibrosis

Normal liver reveals only low expression of the facilitative glucose transporter (GLUT) 1. Recently, we have shown that GLUT1 expression is increased in hepatocellular carcinoma (HCC), where GLUT1 acts as a tumor promotor. Hyperglycemia is one of the factors known to induce and promote hepatic fibrogenesis, and the activation of hepatic stellate cells (HSCs) is the key event of hepatic fibrosis. Furthermore, these cells form and transduce the HCC stroma. The aim of this study was to assess the expression and functional role of GLUT1 in hepatic fibrosis. Methods and Results: Hepatic GLUT1 expression was significantly increased in different murine models of hepatic fibrosis, namely chronic TAA or CCl4-application, bile-duct-ligation and dietary models of non-alcoholic steatohepatitis (NASH). Also in cirrhotic human livers and human NASH GLUT1 expression was increased. Interestingly, hepatic GLUT1 expression revealed a significant correlation with collagen I and alpha-sma levels indicating activated HSCs as cellular source of GLUT1, which was confirmed by immunohistochemical analysis. In line with this, we found that GLUT1 expression increased during in vitro activation of primary murine and human HSCs. To gain insight in the functional role of GLUT1 in activated HSCs we inhibited GLUT1 expression with siRNA or the specific GLUT1 inhibitor WZB117 and found that GLUT1 suppression impaired glucose uptake and lactate secretion of HSCs indicative for reduced anaerobic glycolysis. Functional analysis demonstrated that reduced GLUT1 expression led to lower apoptosis resistance of HSCs. Transgenic GLUT1 knockdown mice subjected to TAA induced liver fibrosis model revealed less pronounced liver damage than WT animals confirmed by hepatic sirius red staining and alpha-sma protein expression. In line with this, treatment with GLUT1 inhibitor WZB117 in combination with the NASH inducing MCD diet resulted in less hepatic alpha-sma and collagen I expression than animals treated with vehicle. Conclusions: Increased GLUT1 expression during HSC activation functionally affects HSCs, and herewith, likely promotes the development and progression of hepatic fibrosis. Therefore and based on its known role as tumor-promotor, GLUT1 appears as attractive novel target to inhibit the progression of chronic liver disease. Corresponding author: Czech, Barbara E-Mail:barbara.czech@ukr.de

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.

Assessment of T-Cell Immunoregulatory Cytokine Patterns for Liver Fibrosis in Chronic Hepatitis B Patients Before and After Interferon Therapy

Many of the chronic hepatitis B patients have a higher risk of developing liver disease, such as cirrhosis and/or hepatocellular carcinoma. Cytokines play an important role in the host response to hepatitis B virus (HBV) infection. Present study was planned to assess the T-cell immunoregulatory cytokine patterns in chronic hepatitis B patients & correlate them in response to interferon therapy. Study comprised of two groups. Group A included 25 treatment naïve chronic hepatitis B patients. Group B included 25 chronic hepatitis B patients who had received 4 to 6 months of peg interferon treatment. Control group included 25 apparently healthy individuals. Assessment of cytokines was done by quantitative type of sandwich ELISA. Pre and post treatment viral load was determined by real time PCR. HBeAg was done by ELISA. HBV DNA levels in group A patients was 1.4 x 107 copies/ml, and HBeAg positivity was 18/25. HBV DNA levels in group B patients were 5.2 x 105 copies/ml, and HBeAg positivity was 08/25. When compared to cytokine patterns, TH2 associated cytokines were significantly higher in group A patients (P<0.01), and TH1 associated cytokines were significantly higher in group B patients. Interferon therapy might be effective in decreasing the viral burden, and in turn may delay the progression of chronic liver disease. Out of the four cytokines assessed, IL-18, and IL-4 can be used as a marker of response to Interferon therapy.

Cryptosporidiosis in patients with diarrhea and chronic liver diseases.

The aim of this study was to evaluate the epidemiology and clinical significance of Cryptosporidium in patients with diarrhea and chronic liver diseases. The study included 150 patients with chronic liver diseases and diarrhea, and 50 subjects with diarrhea as a control group. Stool samples were screened for the presence of Cryptosporidium by microscopic examination after modified Ziehl-Neelsen staining and detection of Cryptosporidium coproantigen by enzyme-linked immunosorbent assay (ELISA). The prevalence of Cryptosporidium infection in patients with chronic liver diseases was 30% (45/150) versus 14% (7/50) in controls. Cryptosporidium infection increased with the progression of chronic liver diseases from Child-Pugh class A to Child-Pugh class C (p< 0.001) and from model for end-stage liver disease (MELD) score ≤ 9 to MELD score > 9 (p< 0.031). Nine patients in Child-Pugh class C with diarrhea associated with Cryptosporidium infection developed hepatic encephalopathy, and only diarrhea was identified as a precipitating factor for hepatic encephalopathy. Cryptosporidium is one of the important causes of diarrhea in patients with chronic liver diseases. The infection significantly increased with the progression of chronic liver diseases. In patients with advanced chronic liver diseases, Cryptosporidium infection may be a precipitating factor of hepatic encephalopathy.

Vitamin A and retinol-binding protein deficiency among chronic liver disease patients

ObjectiveVitamin A deficiency (VAD) is associated with the progression of chronic liver disease (CLD). The aim in this study was to assess levels of serum retinol and retinol-binding protein (RBP) as well as liver vitamin A stores in the presence of liver cirrhosis and hepatocellular carcinoma. MethodsWe ascertained the serum retinol and RBP levels of randomly selected CLD patients divided into two groups, one given 1500 UI (n = 89) and the other receiving 2500 UI (n = 89) doses of retinyl palmitate for the relative dose response test. Blood samples were collected in a fasting state and 5 and 7 h after supplementation. ResultsThe prevalence of VAD was 62.4%. There was a progressive drop in serum retinol (P < 0.001) and RBP (P = 0.002) according to the severity of the liver disease, and a greater prevalence of severe VAD was noted in cirrhosis Child & Pugh C (52.8%). Fifty percent of the patients presented a low availability of RBP relative to retinol concentration, and there was no peak in RBP levels regardless of the dose of retinyl palmitate administered. ConclusionsOur findings suggest serum retinol and RBP are relevant as indicators of vitamin A nutritional status in the presence of CLD. Liver vitamin A store cannot be evaluated using the RDR test because CLD causes a reduction in RBP synthesis and interferes with the mobilization of endogenous vitamin A. Considering how the patients already showed a drop in RBP relative to retinol concentrations, it is reasonable to assume vitamin A supplementation may trigger harmful effects in CLD patients.

Paediatric lver transplantation for children treated at public health facilities in South Africa: Time for change.

Paediatric liver transplantation (PLT) is the only therapeutic option for many children with end-stage chronic liver disease or irreversible fulminant hepatic failure and is routinely considered as a therapy by paediatric gastroenterologists and surgeons working in developed countries. In South Africa (SA), a PLT programme is available at Red Cross War Memorial Children's Hospital in Cape Town since November 1991, and another has rapidly developed at the Wits Donald Gordon Medical Centre in Johannesburg over the past decade. However, for most children with progressive chronic liver disease who are reliant on the services provided at public health facilities in SA, PLT is not an option because of a lack of resources in a mismanaged public health system. Thisarticlebriefly outlines theservices offered at Chris Hani Baragwanath Academic Hospital - whichis typical of public health facilities inSA -and proposes that resources be allocated to establish an innovative, nationally funded centre that would enable greater numbers of children access to a PLT programme.

Update on implications and mechanisms of angiogenesis in liver fibrosis.

Liver fibrosis occurs as a compensatory response to the process of tissue repair in a wide range of chronic liver injures. It is characterized by excessive deposition of extracellular matrix in liver tissues. As the pathogenesis progresses without effective management, it will lead to formation of liver fiber nodules and disruption of normal liver structure and function, finally culminating in cirrhosis and hepatocellular carcinoma. A new discovery shows that liver angiogenesis is strictly associated with, and may even favor fibrogenic progression of chronic liver diseases. Recent basic and clinical investigations also demonstrate that liver fibrogenesis is accompanied by pathological angiogenesis and sinusoidal remodeling, which critically determine the pathogenesis and prognosis of liver fibrosis. Inhibition of pathological angiogenesis is considered to be a new strategy for the treatment of liver fibrosis. This review summarizes current knowledge on the process of angiogenesis, the relationships between angiogenesis and liver fibrosis, and on the molecular mechanisms of liver angiogenesis. On the other hand, it also presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and the role of angiogenesis in the prevention and treatment of liver fibrosis.

Inhibition of tyrosine kinase receptor Tie2 reverts HCV-induced hepatic stellate cell activation.

BackgroundHepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD.MethodsTie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined.ResultsMedia from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC.ConclusionsThese findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.

Hepatitis delta virus (HDV) coinfection among patients with HBsAg positive cirrhosis. An analysis the MASTER-B cohort

The presence of coinfection with HDV may accelerate the progression of HBV-induced chronic liver disease towards cirrhosis or may run an indolent course which leads to cirrhosis within decades. We analyzed the impact of HDV coinfection in patients with HBsAg positive cirrhosis.

Abstract 2144: Retinoid and carotenoid depletion in patients at high-risk for liver cancer

Abstract Approximately 3.2 million Americans are chronically infected with hepatitis C (HCV), forming the largest group at high-risk for hepatocellular carcinoma (HCC). Oxidative stress due to chronic inflammation impels the progression of chronic liver disease (CLD) &amp; subsequent HCC. Deficiencies in dietary antioxidants such as retinoids and carotenoids may represent a modifiable risk factor for HCC progression. This study aims to identify key predictors of serum antioxidant levels in patients with CLD, to quantify the association between systemic measures of oxidative stress and antioxidant status, and to examine the relationship between retinoid/carotenoid concentrations in serum and hepatic tissue. Patients with HCV undergoing liver biopsy (n=69) provided fasting blood, fresh tissue, urine, and responses to a diet history questionnaire (DHQ). We also collected serum and questionnaire data from healthy volunteers (n=11), and normal liver tissue from public repositories and patients without liver disease (n=11). Serum and tissue retinoid concentrations were obtained by mass spectroscopy. Serum retinol binding protein 4 (RBP4) was quantified by ELISA. Urine 8OHdG and F2α-isoprostanes were determined by mass spectroscopy. Dietary retinoid intake was estimated by DHQ. Associations between diet, serum and tissue retinoids, and urinary oxidative stress markers were assessed by Spearman correlation coefficients. Dietary β-carotene and lutein were associated with their respective serum concentrations (r = 0.24, p = 0.05; r = 0.33, p &amp;lt; 0.01). There was a significant downward trend for serum retinol, lycopene and RBP4 concentrations with progressive fibrosis; mean serum concentrations were lower in subjects with chronic HCV but no fibrosis compared to controls. Urinary isoprostanes levels were inversely correlated with serum retinol (r= -0.22, p = 0.05), β-carotene (r= -0.22 p = 0.05), and RBP4 (r= -0.25 p = 0.03). Urinary 8OHDG did not correlate with any serum retinoids or carotenoids. Serum β-carotene and lycopene were strongly associated with the respective tissue concentrations (r = 0.56, p&amp;lt;.01; r= 0.76 p&amp;lt; 0.01); however, serum retinol and tissue retinyl palmitate did not correlate in this population (r = -0.08 p = 0.55). There was a suggestive downward trend of tissue retinyl palmitate with increasing levels of fibrosis. Depletion of serum retinol, β-carotene, and RBP4 worsens with liver fibrosis severity. RBP4 might be a better marker for vitamin A status due to its stronger association with disease severity. Retinoid and carotenoid levels decline as disease progresses, and our data suggest that this decline occurs early in the disease process, even before fibrosis is apparent. In HCV patients, decreases in retinoid/carotenoid levels are accompanied by an increase in urinary F2α-isoprostanes, an indicator of lipid peroxidation due to oxidative stress. Dietary or chemopreventive strategies for replenishing antioxidant levels should be studied further. Citation Format: Yachana Kataria, Erika Enk Rueter, Ryan Deaton, Donald Jensen, Scott Cotler, Peter Gann. Retinoid and carotenoid depletion in patients at high-risk for liver cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2144. doi:10.1158/1538-7445.AM2014-2144