Liver Histology (liver + histology)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy,

HEPATOLOGY, Issue 2 2009
Patrick Ingiliz
Liver damage associated with chronic unexplained high serum transaminases in human immunodeficiency virus (HIV)-infected patients under combined antiretroviral therapy is unknown. Liver histology was prospectively investigated in patients presenting serum transaminase elevation for more than 6 months, after exclusion of alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, autoimmune, and genetic liver diseases. In a subgroup of patients, liver mitochondrial activities were measured by spectrophotometry and mitochondrial DNA (mtDNA) by real-time polymerase chain reaction (PCR). Thirty patients were included with median values of alanine aminotransferase (ALT) levels: 80 U/L, age: 46 years, body mass index: 23 kg/m2, HIV RNA: 200 copies/mL, CD4 count: 365/mm3, duration of HIV infection: 13 years, and duration of treatment exposure: 118, 41, and 53 months for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Histological anomalies were found in 22 of 30 patients. Steatosis was present in 18 patients, severe in nine patients, and associated with inflammation in 16 patients with a diagnosis of non-alcoholic steatohepatitis (NASH). Fibrosis was found in 18 patients, severe in six patients and associated with steatosis in 13 patients. Significant liver respiratory complex I defect, contrasting with high complex IV activity and normal mitochondrial DNA content, was observed in the group of patients compared with controls. The presence of NASH was correlated with high fasting glycemia and insulin levels, not with liver mitochondrial function or mitochondrial DNA content. Conclusions: HIV-infected patients on combined antiretroviral therapy with chronic transaminase elevation of unknown origin have a high rate of liver lesions, mostly consistent with NASH related to insulin resistance. (HEPATOLOGY 2008.) [source]


A pilot study of therapeutic vaccination with envelope protein E1 in 35 patients with chronic hepatitis C

HEPATOLOGY, Issue 5 2003
Frederik Nevens
New treatments are needed for chronic hepatitis C patients in whom viral clearance cannot be achieved. Thirty-five chronic hepatitis C patients (genotype 1) were randomized to receive 20 ,g of recombinant HCV E1 (E1) (n = 26) or placebo (n = 9) intramuscularly at weeks 0, 4, 8, 12, and 24. Thirty-four then received open-label E1 vaccine at weeks 50, 53, 56, 59, 62, and 65. Twenty-four patients (12 men, 12 women; mean age, 52 y; 18 interferon-based treatment failures; mean baseline alanine aminotransferase [ALT] level, 118 IU/L) underwent a biopsy before and after 2 courses of E1, 17 months later. Liver histology was scored by 2 blinded pathologists according to the Ishak and Metavir systems. Postinjection reactions were similar to placebo (alum only). Nine of 24 patients (38%) had improvement of 2 points or more, 10 (41%) remained stable, and 5 (21%) showed worsening in total Ishak score. Nine patients (38%) improved both on Ishak and Metavir fibrosis scores. Plasma HCV-RNA levels remained unchanged, whereas ALT levels showed a trend toward a decrease during treatment. All but 3 patients developed a significant de novo E1-specific T-cell response. The increase in anti-E1 antibody levels correlated with the decrease in total Ishak score and with the relative decreases in both Ishak fibrosis score and ALT level (all P , .01). In conclusion, E1 therapeutic vaccination is well tolerated and the observed effects warrant further study. [source]


Inhibition of TXA2 synthesis with OKY-046 improves liver preservation by prolonged hypothermic machine perfusion in rats

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7pt2 2008
Hongzhi Xu
Abstract Background and Aim:, We previously reported that hypothermic machine perfusion (HMP) for liver preservation is feasible, but hepatic microcirculatory dysfunction and significant liver damage remain major obstacles in its application when the preservation is extended to 24 h. The underlying injury mechanism is not well understood. The present study sought to investigate the role of thromboxane A2 (TXA2) in the pathogenesis of liver injury after prolonged HMP. Methods:, Livers isolated from Sprague,Dawley rats were subjected to continuous machine perfusion with University of Wisconsin (UW) solution at a flow rate of 0.4 mL/min/g liver at 4°C for 24 h. A specific TXA2 synthase inhibitor, OKY-046 (OKY), was added to UW solution during the preservation period and to the Krebs,Henseleit buffer during reperfusion. The performance of the livers after preservation was evaluated using an isolated liver perfusion system with Krebs,Henseleit buffer at a flow rate of 15 mL/min at 37°C for 30 min. Results:, Prolonged HMP induced a significant release of TXA2 into the portal circulation as indicated by markedly increased levels of TXB2 in the perfusate during reperfusion (at 30 min, 1447.4 ± 163.6 pg/mL vs 50.91 ± 6.7 pg/mL for control). Inhibition of TXA2 synthesis with OKY significantly decreased releases of TXA2 (69.8 ± 13.4 pg/mL) concomitant with reduced lactate dehydrogenase (LDH) releases (at 30 min, HMP + OKY: 144.9 ± 27.9 U/L; HMP: 369.3 ± 68.5 U/L; simple cold storage or SCS: 884.4 ± 80.3 U/L), decreased liver wet/dry weight ratio (HMP + OKY vs SCS and HMP: 3.6 ± 0.3 vs 4.4 ± 0.1 and 3.9 ± 0.2, respectively) and increased hyaluronic acid uptake (at 30 min, HMP + OKY vs SCS, HMP: 33.1 ± 2.9% vs 13.9 ± 3.6%, 18.6 ± 2.4%, respectively). Liver histology also showed significant improvement in tissue edema and hepatocellular necrosis with OKY compared with HMP without OKY. Conclusion:, The results demonstrate that TXA2 is involved in the development of hepatocellular injury induced by HMP, and inhibition of TXA2 synthesis during preservation and reperfusion protects liver hepatocytes and sinusoidal endothelial cells from injuries caused by prolonged HMP. [source]


Apoptotic cell death does not parallel other indicators of liver damage in chronic hepatitis C patients

JOURNAL OF VIRAL HEPATITIS, Issue 3 2000
Rodrigues
The mechanisms of hepatocyte damage and the events that lead to high rates of chronic liver disease in hepatitis C virus (HCV) infection remain unclear. Recent in vitro studies have suggested that the HCV core protein may disrupt specific signalling pathways of apoptosis. This prompted us to study patients with chronic HCV infection to: determine the extent of apoptosis in the liver; evaluate whether clinical and biochemical data are correlated with histological findings; and to investigate if apoptosis is related to the histological activity of the disease. Twelve patients with chronic hepatitis C were included in the study. Liver histology was scored by using the histological activity index (HAI) of Knodell et al. DNA fragmentation was assessed in liver tissue by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling (TUNEL) assay. Routine methods were used to determine serum markers of liver disease. Bile acids were measured in serum and liver by gas chromatography. Patients were placed, according to their HAI score, into group A (3.8 ± 0.3) or group B (7.8 ± 0.8) (P < 0.01). Liver enzymes tended to be higher in group B patients than in patients of group A. Levels of toxic bile acids in serum were greater in patients than in controls (P < 0.01). Chenodeoxycholic acid values were slightly higher in serum and liver of patients in group A. Liver biopsies with low HAI scores showed an increased rate of apoptosis (18.0 ± 4.0 apoptotic cells per field) compared to those with higher HAI scores (6.6 ± 2.1, P < 0.05) or to controls (3.5 ± 0.4, P < 0.01). Hence, less severe liver disease, associated with lower histological grades and biochemistries, as well as increased levels of chenodeoxycholic acid, induces an expanded apoptotic response. The lower apoptotic rate in advanced liver disease may be associated with the high incidence of hepatocellular dysplasia/neoplasia. [source]


Neonatal hemochromatosis , medical treatment vs.

LIVER TRANSPLANTATION, Issue 11 2005
Transplantation: The king's experience
The aim of our study was to compare the outcome of medical treatment vs. liver transplantation in infants with neonatal hemochromatosis (NH) referred to King's College Hospital from 1990-2002. We conducted a retrospective review of 19 children from 14 families. Fifteen children presented at birth and 4 during the first week of life. One child was diagnosed by cordocentesis at 30 weeks of gestation. NH recurred in 7 of 9 families with further children. In one family, 2 children from different fathers were affected. All patients had elevated ferritin levels, hypoalbuminemia, and coagulopathy. Liver histology showed parenchymal collapse, diffuse fibrosis, and moderate to severe hepatocyte hemosiderin deposition. Extrahepatic siderosis was demonstrated by magnetic resonance in 2 patients, lip biopsy in 3, and autopsy in 10. Ten patients received a chelation-antioxidant cocktail: 1 survived, 4 died, and 5 required liver transplantation, of whom 2 died. One of the 9 infants who did not receive the cocktail survived with medical support, 3 died, and 5 required transplantation, of whom 3 died. Seven children are alive, 5 after transplantation, at a median follow-up of 5.6 years, with excellent quality of life and no recurrence of the disease. In conclusion, chelation-antioxidant treatment does not appear to modify the prognosis of NH, at least in severe cases. Liver transplantation, with 50% long-term survival, remains the treatment of choice and should be promptly offered to those infants who do not improve with supportive medical treatment. (Liver Transpl 2005;11:1417,1424.) [source]


Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings

PEDIATRIC BLOOD & CANCER, Issue 3 2003
Päivi Halonen MD
Abstract Background During modern intensified therapy for childhood acute lymphoblastic leukemia (ALL) serum liver enzymes reach fairly high levels. Since no recent data on liver histopathology after therapy are available, we conducted a study of the subject. Procedure Liver biopsy specimens were evaluated and serum liver function tests and lipid profiles measured from 27 consecutive children, aged 3.5,17.6 years, treated according to the regimens for standard (SR) and intermediate risk (IR) ALL. Results None of the patients had entirely normal liver histology. Fatty infiltration was detected in 25 out of 27 (93%) and siderosis in 19 out of 27 patients (70%). Fourteen (52%) had both. Three (11%) also had mild portal and/or periportal fibrosis in addition to fatty change and siderosis. Fatty change was mainly microvesicular. Siderosis was in most cases grade II/IV to III/IV (in 16/19 or 84%). No hepatitis or cirrhosis was found. Serum total and LDL-cholesterol levels were higher in the patients with fibrosis than in the patients with fatty change (P,=,0.036, P,=,0.042) or with siderosis,±,fatty change (P,=,0.036, P,=,0.042). In serial ALT measurements a value of 300 U/L or more was oftener reached in the fibrosis than in the fatty change or siderosis groups (in 33 vs. in 12 or in 4% of the measurements, respectively, P,=,0.014, in Kruskall,Wallis test). Conclusions Microvesicular fatty change and siderosis are the main liver findings after current therapy for childhood ALL. Fibrosis occurs rarely. High values in serial serum ALT measurements repeatedly or a disturbed serum lipid profile may facilitate decisions about the need for a liver biopsy. Med Pediatr Oncol 2003;40:148,154. © 2003 Wiley-Liss, Inc. [source]


Fatal deterioration of neurological disease after orthotopic liver transplantation for valproic acid-induced liver damage

PEDIATRIC TRANSPLANTATION, Issue 3 2000
Nilüfer Kayihan
Abstract: We describe a 12-year-old girl with an early onset neurologic disease of slow progressiveness and electro-encephalography showing epileptic activity. The girl developed fulminant liver failure 5 months after the start of valproic acid treatment. Repeated mitochondrial assays failed to prove a mitochondrial disorder, but muscle biopsies were slightly pathological. Liver histology indicated acute-on-chronic liver disease. Six weeks after a successful orthotopic liver transplantation her neurological condition deteriorated rapidly, soon leading to generalized cortical disease and death. Post-mortem brain examination showed advanced central nervous destruction. We suggest that this is a late-onset Huttenlocher variant of Alpers' syndrome, where fulminant liver failure can be triggered by valproic acid, and orthotopic liver transplantation can subsequently trigger a fatal neurologic deterioration. Our case illustrates that when a referral center receives a previously unknown patient with hepatocellular insufficiency, it might be impossible to differentiate between fulminant vs. acute-on-chronic liver failure, and the decision whether to perform a liver transplantation or not would become difficult. [source]


Fulminant Liver Failure After Vancomycin in a Sulfasalazine-Induced DRESS Syndrome: Fatal Recurrence After Liver Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
M. Mennicke
DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a rare drug hypersensitivity reaction with a significant mortality. We describe a 60-year-old man with polyarthritis treated with sulfasalazine who developed DRESS and fulminant liver failure after additional vancomycin treatment. Liver histology revealed infiltration of granzymeB+ CD3+ lymphocytes in close proximity to apoptotic hepatocytes. After a superurgent liver transplantation and initial recovery, the patient developed recurrent generalized exanthema and eosinophilia, but only moderate hepatitis. Histology showed infiltration of FasL+ lymphocytes and eosinophils in the transplanted liver. Treatment with high-dose methylprednisolone was unsuccessful. Postmortem examination revealed extensive necrosis of the liver transplant. This case report illustrates that patients with DRESS may develop fulminant liver failure and that DRESS recurrence can recur in the transplanted liver. Histological and immunological investigations suggest an important role of granzymeB and FasL mediated cell death in DRESS associated hepatitis. [source]


The impact of diabetes and obesity on liver histology in patients with hepatitis C

DIABETES OBESITY & METABOLISM, Issue 3 2003
F. Friedenberg
Aim:, An association between diabetes mellitus and HCV has been recognized previously. No study has examined whether there is an independent association between the degree of hepatic fibrosis and the incidence of diabetes in HCV patients when controlling for other risk factors. Methods:, We reviewed the charts of 264 consecutive patients with chronic HCV infection at a referral liver centre from January 1991 to December 1999. Demographic background, medical history, laboratory and liver biopsy results were retrieved. Results:, The prevalence of diabetes was 16.3%. Gender, intravenous drug use, steatosis scores, aminotransferase levels and iron studies were similarly distributed in patients with and without diabetes (all p > 0.05). In contrast, mean age was greater in the diabetic group (49.8 vs. 44.3, p = 0.003). The prevalence of diabetes was substantially higher in African-Americans (p = 0.001) and those with BMI > 30 (p = 0.015). Although the fibrosis score was higher in diabetics (, = 0.14, p = 0.03), that association did not remain significant when controlling for diabetes risk factors (p > 0.3). The degree of steatosis and fibrosis both tended to increase with increasing BMI (, = 0.47, p < 0.001 and , = 0.13, p = 0.03, respectively). Even after controlling for diabetes, age, gender, race, and current alcohol use, those associations remained (both p < 0.001). Conclusions:, The prevalence of diabetes in our group of HCV patients was high, consistent with other studies. Diabetes is not an independent predictor of degree of fibrosis. Body mass index is an independent predictor of both fibrosis and steatosis in HCV patients. [source]


Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B,,

HEPATOLOGY, Issue 3 2010
Ting-Tsung Chang
One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ,2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (,2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ,1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010) [source]


Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression,

HEPATOLOGY, Issue 6 2009
Kimberley D. Bruce
Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring. Conclusion: Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis. (HEPATOLOGY 2009.) [source]


Transcription factor 7,like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH,

HEPATOLOGY, Issue 2 2009
Giovanni Musso
Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7,like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of ,-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index,, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test,derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of ,-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups. Conclusion: TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients. (HEPATOLOGY 2008.) [source]


Inflammation and drug hepatotoxicity: Aggravation of injury or clean-up mission?,

HEPATOLOGY, Issue 5 2005
Hartmut Jaeschke
BACKGROUND & AIMS Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. METHODS C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1 alpha (macrophage inflammatory protein-1 alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (lpr) and FasL-deficient (gld) mice compared with that in wild-type mice. CONCLUSIONS NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes. [source]


Low-dose TNF-, protects against hepatic ischemia-reperfusion injury in mice: Implications for preconditioning

HEPATOLOGY, Issue 1 2003
Narci Teoh
Tumor necrosis factor , (TNF-,) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor ,B (NF-,B) and cell cycle entry. We examined the pattern of TNF-, release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF-, rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-, levels, but, during a second prolonged ischemic interval peak, TNF-, values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 ,g or 5 ,g/kg body weight TNF-, 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-, pretreatment activated NF-,B DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of "preconditioning" can be simulated by TNF-, injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-, levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury. [source]


Relapse of hepatitis C in a pegylated-interferon-,-2b plus ribavirin-treated sustained virological responder

HEPATOLOGY RESEARCH, Issue 6 2010
Hideki Fujii
A 41-year-old woman with chronic hepatitis C was treated with pegylated-interferon (PEG-IFN)-,-2b plus ribavirin for 24 weeks. She had hepatitis C virus (HCV) genotype 2a (1600 KIU/mL), and her liver histology showed mild inflammation and fibrosis. Four weeks after the start of the therapy, she achieved a rapid virological response (RVR) and then a sustained virological response (SVR). Serum alanine aminotransferase (ALT) levels remained within normal ranges and HCV RNA continued to be negative. However, ALT levels flared with the re-emergence of HCV RNA in the serum 1.5 years after discontinuation of therapy. HCV RNA obtained from sera before therapy and after relapse shared a 98.6% homology with the E2 region, and phylogenetic analyses indicated that they were the same HCV strain. These results eliminated the possibility of a re-infection and strongly indicated a late relapse of the disease. Therefore, follow-up is necessary for chronic hepatitis C patients after SVR, even if they respond well to therapy, including RVR. [source]


Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice

HEPATOLOGY RESEARCH, Issue 12 2008
Yuko Nakanishi
Aim:, Nonalcoholic fatty liver disease (NAFLD) represents a growing health concern due to its rapidly increasing prevalence worldwide. Nonalcoholic steatohepatitis (NASH) is a progressing form of NAFLD, and recently many studies have reported that it could eventually develop into hepatocellular carcinoma (HCC). We previously reported that 6-month-old male galectin-3 knockout (gal3,/,) mice developed clinicopathological features similar to those of NAFLD in humans. Our aim was to investigate the changes in liver histology in gal3,/, mice by long-term observation. Methods:, We initially investigated three 15-month-old gal3,/, mice, of which two developed multiple liver nodules with dysplastic changes. Then, we histopathologically examined the liver specimens of the 15-, 20- and 25-month-old gal3,/, mice and attempted to evaluate the liver morphology by contrast enhanced computed tomography (CT) before sacrifice. Results:, At the age of 15 months or later, gal3,/, mice developed liver nodules with varying degrees of architectural and nuclear atypia based on mild to moderate delicate zone 3 fibrosis. In addition, we successfully confirmed the presence of some of the liver nodules by CT. We report herein that gal3,/, mice develop dysplastic liver nodules and HCC. Conclusions:, We believe that it would be interesting to use this murine model to investigate liver carcinogenesis based on a natural history of NAFLD. Furthermore, CT scanning might be a useful tool for longitudinal evaluation of morphological changes in vivo. [source]


Validity of FibroScan values for predicting hepatic fibrosis stage in patients with chronic HCV infection

JOURNAL OF DIGESTIVE DISEASES, Issue 2 2009
Ryosuke TAKEMOTO
OBJECTIVE: The aim of this study was to validate the FibroScan system compared with liver histology and serum markers for the diagnosis of hepatic fibrosis. We also tried to determine the cut-off levels and assess the feasibility of using FibroScan values to predict the fibrosis stage. METHODS: In 44 patients with HCV infection, liver stiffness was evaluated by FibroScan, serum fibrosis markers and a liver biopsy. Associations between these indices were also analyzed. RESULTS: FibroScan values showed a good correlation with serum levels of type IV collagen, hyaluronic acid and procollagen-III-peptide, and with the platelet count. Compared with liver histology, the FibroScan values increased proportionally with the progression of the histological fibrosis stage. Advanced fibrosis (F3 or F4) could be efficiently predicted by a FibroScan cut-off value of 15 kPa. The FibroScan sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 100%, 73.9%, 77.8%, 100%, and 86.4%, respectively. CONCLUSION: FibroScan values gave a good correlation with various markers of fibrosis and increased proportionally with the progression of the hepatic fibrosis stage. A FibroScan value of 15 kPa was found to be a significant separation limit for differentiating advanced fibrosis stages (F3 and F4) from the milder stages (F0,F2). FibroScan values are clinically useful for predicting the fibrosis stages and helpful in managing interferon therapy in patients with chronic hepatitis C. [source]


Experimental acute alcohol pancreatitis-related liver damage and endotoxemia: synbiotics but not metronidazole have a protective effect

JOURNAL OF DIGESTIVE DISEASES, Issue 4 2005
F MAROTTA
OBJECTIVE: The aim of this study was to test the effect of gut manipulation by either novel synbiotics or by metronidazole on either endotoxemia or the severity of liver damage in the course of acute pancreatitis from alcohol ingestion. METHODS: Sprague,Dawley rats were fed for 1 week through an intragastric tube a liquid diet with either: (i) 1 mL t.i.d. of a mixture of synbiotics (Lactobacillus acidophilus, Lactobacillus helveticus and Bifidobacterium in an enriched medium); (ii) 20 mg/kg t.i.d. metronidazole; or (iii) standard diet. Then, acute pancreatitis was induced by caerulein and when the disease was full-blown, rats were fed an alcohol-rich diet. Synbiotic and metronidazole treatment was given for a further 2 weeks. Transaminase and endotoxemia levels were measured before treatment, after 6 h, after 24 h and 2 weeks later, at the time the rats were killed. Liver samples were obtained for histological analysis. RESULTS: Synbiotics but not metronidazole improved the acute pancreatitis-induced increase in endotoxemia and transaminase levels. The addition of alcohol worsened these variables to a limited extent in the synbiotic-treated group, while metronidazole had a negative effect on liver damage. CONCLUSIONS: Gut flora pretreatment with synbiotics was able to effectively protect against endotoxin/bacterial translocation, as well as liver damage in the course of acute pancreatitis and concomitant heavy alcohol consumption. The beneficial effect of synbiotics on liver histology seems to be correlated with endotoxemia. Metronidazole did not produce such a beneficial effect; in fact, it further worsened liver damage when alcohol was added to the background of ongoing acute pancreatic inflammation. [source]


Evidence that channel catfish, Ictalurus punctatus (Rafinesque), mortality is not linked to ingestion of the hepatotoxin microcystin-LR

JOURNAL OF FISH DISEASES, Issue 5 2002
G S Snyder
Catfish farms located in the south-eastern USA using brackish (3,5 g NaCl L,1) well water experience sporadic fish kills sometimes with high mortality. An investigation of three catastrophic losses occurring in this region identified no involvement of infectious diseases or traditional water quality problems, including oxygen, ammonia or nitrite. The high mortality and time course of the problem was indicative of exposure to a toxin. Attempts by other workers to explain the cause of this unique syndrome (high chloride associated toxicosis of catfish, HCTC), suggested that the losses might be because of microcystin-producing blooms of Microcystis aeruginosa, but our investigations failed to support this conclusion. We found that (1) the liver histology of catfish experimentally exposed to pure microcystin-LR is very different from that of catfish sampled during outbreaks of HCTC; (2) measurements of microcystin-LR concentrations in the three cases were far lower than the concentration required to kill catfish by experimental immersion; (3) the HCTC toxin appears to have a short half-life, whereas microcystin-LR does not; (4) experimental gavage of catfish with massive amounts of microcystin-LR does not cause the acute mortality typical of HCTC; (5) outbreaks of HCTC appear to be associated with heavy blooms of Anacystis marina, a halophytic cyanobacteria, not with blooms of M. aeruginosa. [source]


Efficacy of interferon-, treatment in Japanese children with chronic hepatitis C

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 4 2003
EISUKE NAKASHIMA
Abstract Background: We investigated the efficacy of natural interferon (IFN)-, treatment in 34 Japanese children with chronic hepatitis C. Methods: Thirty-four children completed 6 months of therapy with natural IFN-, and were followed for 12 months or longer. We examined the serum hepatitis C virus (HCV) RNA titer and liver histology before, during, and after IFN treatment. Results: At 6 months after the cessation of IFN-, treatment, 16 patients (47%) had normal serum alanine aminotransferase concentration and no detectable serum HCV RNA. There were no major side-effects, excluding some influenza-like symptoms during the IFN-, treatment. Most genotype 2a patients had a complete response (80%). Moreover, patients who had a low HCV RNA titer (<102 copies/mL) after 1 month of IFN-, treatment became complete responders at 6 months after the cessation of treatment. Histological improvement was observed in almost all patients after IFN-, treatment. Conclusion: Interferon-, treatment is safe and effective for children with chronic hepatitis C and has no serious side-effects. A HCV RNA concentration of <102 copies/mL after 1 month of IFN-, treatment and genotype 2a may be useful predictors of long-term IFN efficacy. © 2003 Blackwell Publishing Asia Pty Ltd [source]


Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2002
Jason M Hui
Abstract Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non-alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection. Methods: In 124 chronic hepatitis C patients, the association between liver histology and the following was investigated: demographic and anthropometric data, alcohol intake, alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein,cholesterol, high-density lipoprotein,cholesterol, triglyceride, transferrin saturation, ferritin, insulin, c-peptide, glucose and insulin resistance (homeostasis model). Results: By multivariate analysis, genotype 3 was associated with increased steatosis grade (P = 0.02). There were significant pairwise interactions between genotype 3 status and total cholesterol (P = 0.01), current alcohol intake (P = 0.04) and serum ALT (P = 0.01). This showed that the etiology of steatosis was different in patients with genotype 3 and those with non-genotype 3 chronic hepatitis C infection. In genotype 3 patients, the degree of steatosis was inversely associated with serum cholesterol (P = 0.005) and positively associated with serum triglyceride (P = 0.02). There was no association between body mass index (BMI) and the extent of steatosis. Among patients with other genotypes, the steatosis grade was strongly influenced by BMI (P < 0.0001) and serum ALT (P < 0.01). Independent predictors of fibrosis were age (P = 0.001), past alcohol intake (P = 0.04), ALT (P = 0.002), serum insulin (P = 0.001) and portal inflammation (P < 0.001). Conclusions: Hepatitis C genotype 3 may interfere with pathways of hepatic lipid metabolism, whereas increased BMI appears to be a more important pathogenic factor in other genotypes. Although steatosis and BMI were not associated with hepatic fibrosis, their relationship with serum insulin suggests that metabolic factors related to insulin action could influence fibrogenesis in hepatitis C. [source]


Efficacy of granulocyte-macrophage colony-stimulating factor or lamivudine combination with recombinant interferon in non-responders to interferon in hepatitis B virus-related chronic liver disease patients

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2002
RAJKUMAR C GUPTAN
AbstractBackground and Aims : Non-response to interferon (IFN) monotherapy is a major therapeutic problem in the management of chronic hepatitis B infection. The efficacy of combination therapy to enhance the immunomodulatory effect of IFN by combining granulocyte-macrophage colony-stimulating factor (GMCSF) or decreasing viral load by adding an antiviral agent such as lamivudine was evaluated prospectively. Methods : Twenty-four patients with chronic hepatitis B who were non-responders to previous IFN therapy were randomized to receive an IFN and GMCSF (group A, n = 10) or IFN and lamivudine (group B, n = 14) combination for 6 months. The end-of-treatment response was assessed by hepatitis B virus (HBV)-DNA and hepatitis B e antigen (HBeAg) determination. Results : All patients successfully completed both the treatment schedules. The mean age, alanine aminotransferase (ALT) levels, liver histology, HBV-DNA levels and distribution of HBV genotypes were comparable between the two groups. At the end of treatment there was a significant decrease in mean ALT levels. The HBV-DNA and HBeAg loss was seen in six of 10 (60%) patients in group A and in seven of 14 (50%) patients in group B. During a mean follow-up of 15 ± 3 months, two of six (33%) patients in group A and three of seven (43%) patients in group B relapsed with HBV-DNA and HBeAg positivity, which meant an overall sustained response of 40% and 28%, respectively. None of the factors such as HBV viral load, ALT levels or liver histology could predict the non-response to combination therapy or occurrence of relapse. There was a trend in patients with genotype A compared with genotype D towards non-response to therapy, although the difference was not significant. Conclusions : The combination of IFN plus GMCSF or lamivudine was effective in non-responders to IFN monotherapy. Larger studies using such combination therapies would be helpful in improving treatment strategies for chronic hepatitis B. © 2002 Blackwell Publishing Asia Pty Ltd [source]


Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 8 2000
John G McHutchison
Abstract Background and Aims: Chronic hepatitis C is a slowly progressing inflammatory disease of the liver that can lead to cirrhosis and its complications. Assessment of liver damage in hepatitis C has been primarily via histological evaluation. Liver biopsy, while useful in determining the extent of liver damage, has associated costs and places patients at a small but finite risk of bleeding. Studies in small patient populations have identified serum markers shown to correlate with liver histology, including pro-collogen III peptide and hyaluronic acid (HA). To determine whether serum HA was a reliable predictor of cirrhosis and fibrosis, we examined serum HA concentrations from 486 chronic Hepatitis C virus (HCV) patients. Methods and Results: Patients were anti-HCV and HCV RNA positive, with elevated alanine aminotransferase values and underwent a liver biopsy. Sera were obtained at the baseline for HA using radioimmunoassay methodology. Patients with cirrhosis had significantly higher serum HA concentrations compared with non-cirrhotic patients (382 ± 31 vs 110 ± 9 ,g/L respectively, P < 0.001). Patients with fibrosis had significantly higher mean serum HA concentrations (179 ± 11 ,g/L) compared with patients without fibrosis (62 ± 20 ,g/L; P < 0.001). The correlation between HA concentration and the components of the Knodell histological activity index score revealed no strong associations with the exception of fibrosis, which showed moderate correlation (R = 0.5421, P < 0.001). The clinical value of HA measurement appears to be its ability to exclude cirrhosis. A HA value of < 60 ,g/L excluded the presence of cirrhosis or significant fibrosis with a predictive value of 99 and 93%, respectively. Conclusions: Serum HA measurement may be clinically useful to non-invasively assess the degree of fibrosis and cirrhosis. Further prospective studies are warranted to determine the clinical utility of HA as a non-invasive marker of liver fibrosis. [source]


Synergistic antiviral effect of a combination of mouse interferon-, and interferon-, on mouse hepatitis virus

JOURNAL OF MEDICAL VIROLOGY, Issue 2 2003
Uichiro Fuchizaki
Abstract Although interferon (IFN)-, and IFN-, have been reported to exhibit a synergistic antiviral effect through the different signaling pathways in vitro, their therapeutic efficacy is not well defined in vivo. The current study was carried out to investigate the combined antiviral effect in a model of mouse hepatitis virus Type 2 (MHV-2) infection, in which fulminant hepatitis is developed. MHV-2 was injected intraperitoneally into 4-week-old ICR mice, IFN or the vehicle was administered intramuscularly for 5 days, and the antiviral effect was evaluated based on survival periods, liver histology, serum alanine transaminase (ALT) levels, and MHV-2 virus titers in the liver tissues. The animals in the group treated with a combination of IFN-, and IFN-, survived for longer periods than the groups treated with IFN-, alone and IFN-, alone (IFN-, 103 (IU/mouse)/-, 103 vs. IFN-, 103, P,<,0.005; IFN-, 103/-, 103 vs. IFN-, 103, P,<,0.001). This is consistent with the lower levels of hepatocellular necrosis and serum ALT and the decreased titers of MHV-2 virus in the liver tissues (48 hr, P,<,0.001; 72 hr, P,<,0.001). These findings indicate that a combination of IFN-, and IFN-, exhibits a synergistic antiviral effect on MHV-2 infection. The biology of MHV-2 is quite different from that of human hepatitis viruses; however, these results suggest the beneficial combined therapy of IFN-, and IFN-, for the treatment of human viral hepatitis. J. Med. Virol. 69:188,194, 2003. © 2003 Wiley-Liss, Inc. [source]


Lack of susceptibility of Chacma baboons (Papio ursinus orientalis) to hepatitis C virus infection

JOURNAL OF MEDICAL VIROLOGY, Issue 4 2002
N.P. Sithebe
Abstract The main reason to ascertain whether baboons are susceptible to infection with hepatitis C virus (HCV) is the need to replace chimpanzees, which are endangered, as an animal model for undertaking research into the biology and host,virus interactions of HCV, and for developing a vaccine against this virus. A second reason is that baboons are a possible source of xenografts for human liver transplantation. We inoculated serum containing HCV into four Chacma baboons and monitored them for 52 weeks for evidence of infection. Serum was tested for antibody to HCV, HCV RNA, and aminotransferase concentrations at 2-week intervals for 26 weeks and thereafter at 4-week intervals. Liver tissue was examined at 28 and 52 weeks for histopathological changes and viral RNA, and at 52 weeks for viral particles using electron microscopy. Reverse transcription-polymerase chain reaction assay was used to detect HCV RNA, and the results were confirmed by Southern hybridization. Serum aminotransferase concentrations remained within the normal range and liver histology was normal during the follow-up period. Passive transmission of anti-HCV to the baboons was observed during the first 4 weeks. HCV RNA was not detectable in any serum or liver sample and electron microscopy failed to reveal viral particles in liver tissue. In conclusion, we did not find Chacma baboons to be susceptible to infection with HCV, although we cannot deny that in an immunosuppressed liver transplant recipient, infection of a baboon xenograft might occur. Another animal model for HCV infection must be sought. J. Med. Virol. 66:468,471, 2002. © 2002 Wiley-Liss, Inc. [source]


Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2003
Tzung-Yan Lee
ABSTRACT Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4 -induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg,1 twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-,1, tissue inhibitor of metallproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4 -induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis. [source]


Predictive Factors for Pure Steatosis in Alcoholic Patients

ALCOHOLISM, Issue 6 2009
Sylvie Naveau
Background:, Bearing in mind the mechanisms involved in nonalcoholic fatty liver disease, this study aims to verify whether metabolic syndrome or its various individual components are independent predictive factors for steatosis ,10% in alcoholic patients. Methods:, This study included 281 consecutive alcoholic patients with abnormal liver tests and either normal liver histology or steatosis <10% (n = 119) or steatosis ,10% (n = 162). Logistic regression analysis was used to study the relationship between metabolic syndrome components and various risk factors and the presence of steatosis ,10%. We assessed apolipoprotein A1 (ApoA-1) levels, a major protein component of plasma high-density lipoprotein (HDL), rather than HDL-cholesterol levels. Results:, Plasma ApoA-1 levels (p < 0.01), body mass index (BMI) (p < 0.01), and waist circumference (p < 0.05) were significantly higher in patients with steatosis ,10% than in patients with normal liver histology or steatosis <10%. A higher percentage of patients with steatosis ,10% had high blood pressure (p = 0.003) than patients with normal liver histology or steatosis <10%. In the logistic regression, ApoA-1 [odds ratio (OR) = 1.57 (1.10,2.22)], BMI [OR = 1.10 (1.01,1.23)], and high blood pressure [OR = 1.84 (1.10,3.06)] were positively and independently correlated with the presence of steatosis ,10%. In the multivariate regression high blood pressure was independently and positively correlated with steatosis score (r = 0.55 ± 0.26; p < 0.05). On the other hand, when the presence of high blood pressure was the dependent variable, the presence of steatosis ,10% positively and independently correlated with it [OR = 1.82 (1.05,3.15)]. Conclusion:, In alcoholic patients without fibrosis, ApoA-1, BMI, and high blood pressure on the next morning after the admission were predictive of steatosis ,10%. High blood pressure was the only metabolic syndrome component associated with the presence of alcoholic steatosis ,10% and was not correlated with other metabolic syndrome components. These findings suggest that steatosis mechanisms are different in alcoholic and nonalcoholic fatty liver. [source]


Inhibition of Caspases In Vivo Protects the Rat Liver Against Alcohol-Induced Sensitization to Bacterial Lipopolysaccharide

ALCOHOLISM, Issue 6 2001
Ion V. Deaciuc
Background: The mechanisms of liver sensitization by alcohol to Gram-negative bacterial lipopolysaccharide (LPS) remain elusive. The purpose of this study was two-fold: (1) to test the hypothesis that alcohol-enhanced liver apoptosis may be a sensitizing mechanism for LPS and (2) to further characterize the liver apoptotic response to alcohol. Methods: Rats were fed a high-fat, alcohol-containing liquid diet for 14 weeks, treated with LPS (1.0 mg/kg of body weight, intravenously) or saline, followed by injection of a pan-caspase inhibitor {IDN1965;N -[(1,3-dimethylindole-2-carbonyl)-valinyl]-3-amino-4-oxo-5-fluoropentanoic acid; 10 mg/kg of body weight, intraperitoneally} or vehicle, and killed. The following parameters were assessed: plasma aspartate: 2-oxoglutarate aminotransferase activity (AST); liver histology and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) response; caspase-3, ,8, and ,9 activity; and mRNA and protein expression for two apoptosis-signaling molecules: Fas receptor and Fas ligand; and three apoptosis adaptors: Bax, Bcl-XL, and Bcl-2. Results: Alcohol-feeding-induced liver steatosis, slightly increased caspases' activity, the number of TUNEL-positive nuclei, and facilitated the LPS necrotic effect without affecting mRNA expression of apoptosis signals and adaptors. LPS induced a significant increase in AST and the number of TUNEL-positive nuclei, both effects being more pronounced in alcohol-treated rats. LPS produced hepatic necrosis only in alcohol-treated rats. LPS effects were associated with up-regulation of mRNA expression for both apoptosis adaptors and signaling molecules. IDN1965 administration 3 hr after LPS injection strongly inhibited caspases' activity, particularly that of caspase-3. IDN1965 also abolished the increase in TUNEL-positive nuclei, reversed the effect of LPS on plasma AST in alcohol-treated rats, and prevented LPS-induced necrosis. Conclusions: (1) Alcohol-enhanced liver apoptosis may not involve regulatory steps at the transcriptional level. LPS-induced liver apoptosis seems to involve transcriptional regulation of several apoptosis adaptors. Therefore, alcohol and LPS may enhance liver apoptosis through different mechanisms. (2) Alcohol-enhanced liver apoptosis precedes and may facilitate the hepatic effects of LPS. LPS superimposed on alcohol further elevates the rate of apoptosis in the liver. This may exceed the phagocytosing capacity of the liver so that all the apoptotic cells are not phagocytosed, but rather die of necrosis. [source]


Pioglitazone in the treatment of NASH: the role of adiponectin

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2010
A. Gastaldelli
Summary Background, Plasma adiponectin is decreased in NASH patients and the mechanism(s) for histological improvement during thiazolidinedione treatment remain(s) poorly understood. Aim, To evaluate the relationship between changes in plasma adiponectin following pioglitazone treatment and metabolic/histological improvement. Methods, We measured in 47 NASH patients and 20 controls: (i) fasting glucose, insulin, FFA and adiponectin concentrations; (ii) hepatic fat content by magnetic resonance spectroscopy; and (iii) peripheral/hepatic insulin sensitivity (by double-tracer oral glucose tolerance test). Patients were then treated with pioglitazone (45 mg/day) or placebo and all measurements were repeated after 6 months. Results, Patients with NASH had decreased plasma adiponectin levels independent of the presence of obesity. Pioglitazone increased 2.3-fold plasma adiponectin and improved insulin resistance, glucose tolerance and glucose clearance, steatosis and necroinflammation (all P < 0.01,0.001 vs. placebo). In the pioglitazone group, plasma adiponectin was significantly associated (r = 0.52, P = 0.0001) with hepatic insulin sensitivity and with the change in both variables (r = 0.44, P = 0.03). Increase in adiponectin concentration was related also to histological improvement, in particular, to hepatic steatosis (r = ,0.46, P = 0006) and necroinflammation (r = ,0.56, P < 0.0001) but importantly also to fibrosis (r = ,0.29, P = 0.03). Conclusions, Adiponectin exerts an important metabolic role at the level of the liver, and its increase during pioglitazone treatment is critical to reverse insulin resistance and improve liver histology in NASH patients. [source]


Development of a non-invasive algorithm with transient elastography (Fibroscan) and serum test formula for advanced liver fibrosis in chronic hepatitis B

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2010
G. L. H. WONG
Aliment Pharmacol Ther,31, 1095,1103 Summary Background, Non-invasive assessments of liver fibrosis in chronic hepatitis B were well established. Aim, To develop a combined algorithm of liver stiffness measurement (LSM) and serum test formula to predict advanced liver fibrosis in chronic hepatitis B. Methods, We reported an alanine aminotransferase (AST)-based LSM algorithm for liver fibrosis in 156 chronic hepatitis B patients, which formed the training cohort to evaluate the performance of APRI (AST-to-platelet-ratio-index), Forns index, FIB-4 and Fibroindex against liver histology. The best combined LSM-serum formula algorithm would be validated in another cohort of 82 chronic hepatitis B patients. Results, In the training cohort, LSM has the best performance of diagnosing advanced (,F3) fibrosis [area under the receiver operating characteristics curve (AUROC) 0.88, 95% confidence interval (CI) 0.85,0.91], while Forns index has the best performance among the various serum test formulae (AUROC 0.70, 95% CI 0.62,0.78). In the combined algorithm, low LSM or low Forns index could be used to exclude advanced fibrosis as both of them had high sensitivity (>90%). To confirm advanced fibrosis, agreement between high LSM and high Forns index could improve the specificity (from 99% to 100% and from 87% to 98% in the training and validation cohorts respectively). Conclusion, A combined LSM,Forns algorithm can improve the accuracy to predict advanced liver fibrosis in chronic hepatitis B. [source]