Journal of Hepatology

Editorial Board

2012-03-01

EASL Clinical School of Hepatology, Bologna

2012-03-01

ILC Barcelona 2012 by EASL

2012-03-01

EASL Monothematic Conference, Tallinn

2012-03-01

EASL-AASLD Special Conference, Prague

2012-03-01

Focus

Scott L. Friedman — 2011-11-09

Increasing attention is focused on the nature and origins of chronic inflammation in patients with morbid obesity and non-alcoholic fatty liver disease (NAFLD). Smoldering inflammation without an obvious precipitant is also recognized in a range of related disorders that includes atherosclerosis, dementia, type 2 diabetes and even cancer . Studies of this ‘autoinflammation’ have zeroed in on an intracellular multi-protein scaffold known as the inflammasome, whose primary function is to activate an inflammatory cascade as part of the innate immune response’s cytosolic surveillance . Activation of the inflammasome culminates in the auto-catalytic cleavage of caspase-1 that facilitates processing and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In other words, increased IL-1β is among the most important consequences of inflammasome activation. While originally characterized in classic immune cells, it is now clear that the inflammasome is also present in non-immune cells, including hepatocytes and hepatic stellate cells, as well as hepatic macrophages and dendritic cells. Inflammasomes are classified by the specific type of pattern recognition receptors (PRRs) within the inflammasome that have evolved to distinguish among a range of stimuli (e.g., bacterial or viral proteins, or crystals). Among these, for example, the Nod-like receptor (NLR) family of innate immune cell sensors, specifically NLRP3 (also known as NALP3 or cryopyrin), has been linked to obesity-induced inflammation .

Hepatitis C treatment – Clearing the mind

Daniel M. Forton — 2011-11-23

The issue of whether the hepatitis C virus (HCV) affects brain function continues to arouse interest, investigation, and debate. Symptoms such as fatigue, poor memory, and concentration (“brain fog”) are commonplace and an effect of this infection on mental health related quality of life, which is independent of liver fibrosis, is well established . However, despite convergent lines of evidence pointing to a biological effect of HCV within the CNS and some hypothesised mechanisms, there remains, as yet, a lack of incontrovertible evidence to definitively prove the fact. Parallels with HIV infection are commonly drawn, where AIDS related dementia is now rare with highly active anti-retroviral therapy (HAART) but milder neurocognitive impairments can persist despite immune reconstitution and viral suppression . A degenerative brain process is not seen in HCV monoinfection and there remains doubt in the hepatology community as to whether HCV is a virus that can trigger neurological dysfunction. Furthermore, there does not appear to be a clinical consensus as to whether the relatively mild neurocognitive symptoms in HCV infection represent a significant or important element of the disease.

Liver-induced inflammation hurts the brain

Rita Garcia-Martinez, Juan Cordoba — 2011-11-21

The immune system is activated following injury or infection. The local response can be accompanied by a systemic response, which includes the synthesis and release of different mediators by innate immune cells. The liver is not an exception and when exposed to an acute or chronic insult generates an inflammatory response that may affect other organs. Liver-induced inflammation is able to cause disturbances in the central nervous system (CNS) including metabolic (hyperthermia, somnolence, loss of body weight) and behavioural manifestations (lethargy, anhedonia, decreased social interaction). These manifestations are collectively termed “sickness behaviour” , and are attributed to dysfunction of the CNS.

p53-Mediated regulation of hepatic lipid metabolism: Forging links between metabolism, atherogenesis, and cancer

Sabrina A. Stratton, Michelle Craig Barton — 2011-11-02

No discussion of cancer biology is complete without mention of tumor suppressor p53 and its stress-activated protection of the genome. A plethora of regulatory signaling impinges on p53 to either limit p53 protein levels, in the absence of stress signaling, or to rapidly induce protein levels and mediate cell cycle arrest or cell death in the face of threats to genome integrity . Although reports of p53 regulation and functions in cellular surveillance add up to an astounding number, recent discoveries that illustrate functions of p53 in cellular metabolism reveal that much is left to learn . The ability of the p53-null mouse to survive to adulthood with few apparent challenges to normal development casts a shadow over likely roles for p53 in normal, cellular homeostasis . Early development of specific tumors, the profile of which is dependent on strain, is the most striking phenotype of p53−/− mice. However, closer examination of these mice reveals that all is not perfect during development, as female mice lacking p53 have diminished fecundity and a significant number exhibits exencephaly . Additionally, once other structurally similar members of the p53 family were uncovered, including p63, p73 and multiple isoforms of all p53 family members, complexity in their potential cross-talk or functional compensation was suspected. This was borne out by the altered profiles of tumors that develop in mice variously depleted in the family members; for example, p53+/−; p73+/− mice develop hepatocellular carcinoma (HCC) and other tumors never found in p53+/− or p53−/− mice . Clearly, levels of p53 are carefully regulated during embryogenesis, as deletion of the primary negative regulator of p53 protein levels, Mdm2, leads to early embryonic lethality at implantation .

Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: An international multicenter cohort study

2011-10-31

Background & Aims: Long-term viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this study was to investigate the efficacy and safety of entecavir plus tenofovir combination in 57 CHB partial responders or multidrug resistant patients.Methods: Investigator-initiated open-label cohort study. Quantitative HBV-DNA measurement and resistance testing (line-probe-assays and direct-sequencing) at baseline and every 3months.Results: Fifty seven patients (37 HBeAg+), median age 45years, previously treated with a median of three lines of antiviral therapy (range 1–6), 24/57 with advanced liver disease, were included. Median ALT at baseline was 1.0ULN (range 0.3–22) and HBV-DNA 1.5×104IU/ml (range 500–1×1011IU/ml). Median treatment duration of combination therapy was 21months. HBV-DNA level dropped 3 logs (median, range 0–8log; p<0.0001), 51/57 patients became HBV-DNA undetectable, median after 6months (95% CI, 4.6–7). The probability for HBV DNA suppression was not reduced in patients with adefovir or entecavir resistance or in patients with advanced liver disease. Viral suppression led to decline in ALT (median 0.7ULN; range 0.2–2.4; p=0.001). Five patients lost HBeAg (after 15, 18, 20, 21, and 27months, respectively), one patient showed HBs-seroconversion. Patients with advanced disease did not show clinical decompensation, two patients with cirrhosis and undetectable HBV DNA developed HCCs. No death, newly induced renal impairment or lactic acidosis were reported.Conclusions: Rescue therapy with entecavir and tenofovir in CHB patients harboring viral resistance patterns or showing only partial antiviral responses to preceding therapies was efficient, safe, and well tolerated in patients with and without advanced liver disease (249).

IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C

2011-09-27

Background & Aims: Polymorphisms in the region of the interleukin (IL)28B gene have been associated with pegylated-interferon (PEG-IFN) and ribavirin treatment response mainly in genotype 1 HCV infections. However, there are few data on HCV genotype 4 (HCV-4) infection. We evaluated, in a unique well-characterized cohort of HCV-4 patients, the association of IL28B polymorphism with response to treatment or liver disease severity.Methods: This study included 164 HCV-4 patients from different ethnic groups (Egyptian, European, and Sub-Saharan African). Among these patients, 82 were studied for response and 160 for disease severity. Free DNA extracted from all the 164 patient’s serum samples was analyzed by direct sequencing of the SNP rs12979860 of IL28B. Genetic and bio-clinical features from patients having sustained virological response (43 SVR patients) and from those who did not respond to treatment or had a relapse after the end of the treatment (39 NR patients) were compared. IL28B polymorphism was compared between the 78 patients with mild fibrosis (Metavir score F0–F1) and the 82 with advanced fibrosis (F2–F4).Results: Our data showed a better treatment response rate of the C allele of the IL28B gene SNP rs12979860 (p=0.0008). The response rates were 81.8%, 46.5%, and 29.4% for genotype CC, CT, and TT, respectively. No significant relationship was found between rs12979860 and the severity of the disease.Conclusions: The SNP rs12979860 is strongly associated with SVR in patients infected with HCV-4, but not with liver disease severity. Analysis of IL28B genotype might be used to guide treatment for these patients.

Hepatitis B virus infection and fatty liver in the general population

2011-10-24

Background & Aims: In animal studies, expression of hepatitis B virus (HBV) proteins causes hepatic steatosis. We aimed to study the prevalence of fatty liver in people with and without HBV infection in the general population.Methods: We performed a cross-sectional population study in Hong Kong Chinese. Intrahepatic triglyceride content (IHTG) was measured by proton-magnetic resonance spectroscopy.Results: One thousand and thirteen subjects (91 HBV patients and 922 controls) were recruited. The median IHTG was 1.3% (0.2–33.3) in HBV patients and 2.1% (0–44.2) in controls (p <0.001). Excluding subjects with significant alcohol consumption, the prevalence of nonalcoholic fatty liver disease was 13.5% (95% confidence interval [CI] 6.4%, 20.6%) in HBV patients and 28.3% (95% CI 25.3%, 31.2%) in controls (p=0.003). The fatty liver prevalence differed in HBV patients and controls aged 40–59years but was similar in those aged 60years or above. After adjusting for demographic and metabolic factors, HBV infection remained an independent factor associated with lower risk of fatty liver (adjusted odds ratio 0.42; 95% CI 0.20, 0.88; p=0.022). HBV patients also had a lower prevalence of metabolic syndrome (11.0% vs. 20.2%; p=0.034), but the difference was mainly attributed to lower triglyceride levels. Among HBV patients, viral genotypes, HBV DNA level and hepatitis B e antigen status were not associated with fatty liver.Conclusions: HBV infection is associated with a lower prevalence of fatty liver, hypertriglyceridemia and metabolic syndrome. Viral replication may affect lipid metabolism and this warrants further studies.

Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: A step toward the truth in the absence of a gold standard

2011-09-02

Background & Aims: Liver fibrosis stage is traditionally assessed with biopsy, an imperfect gold standard. Two widely used techniques, FibroTest®, and liver stiffness measurement (LSM) using Fibroscan® have been validated using biopsy, and therefore the true performances of these estimates are still unknown in the absence of a perfect reference.The aim was to assess the relative accuracy of FibroTest, LSM, and biopsy using methods without gold standard in patients with chronic hepatitis C (CHC) and controls.Methods: A total of 1289 patients with CHC and 604 healthy volunteers, with assessment of fibrosis stage by the three techniques, and alanine aminotransferase (ALT) taken as a control test, were analyzed by latent class method with random effects. In the volunteers, the false positive risk of biopsy was obtained from a large surgical sample of four normal livers.Results: The latent class model with random effects permitted to conciliate the observed data and estimates of test performances. For advanced fibrosis, the specificity/sensitivity was for FibroTest 0.93/0.70, LSM 0.96/0.45, ALT 0.79/0.78 and biopsy 0.67/0.63, and for cirrhosis FibroTest 0.87/0.41, LSM 0.93/0.39, ALT 0.78/0.08 and biopsy 0.95/0.51. The analysis of the discordances between pairs suggested that the variability of the model was mainly related to the discordances between biopsy and LSM (residuals>10; p<0.0001).Conclusions: A method without the use of a gold standard confirmed the accuracy of FibroTest and Fibroscan for the diagnosis of advanced fibrosis and cirrhosis in patients with chronic hepatitis C. The variability of the model was mostly due to the discordances between Fibroscan and biopsy.

Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition

2011-10-24

Background & Aims: Chronic hepatitis C virus (HCV) infection is associated with altered cerebral metabolism and cognitive dysfunction. We aimed to evaluate the effect of pegylated interferon/ribavirin (PIFN/R) and HCV clearance on cerebral metabolism, and neuropsychological performance.Methods: Fifteen non-cirrhotic HCV positive subjects underwent 1H MR spectroscopy (MRS) before, during, and after treatment with PIFN/R. The metabolites of interest namely, N-acetylaspartate (NAA), choline (Cho), myo-inositol (MI), and the control metabolite creatine (Cr), were acquired from 3 different brain regions; left basal ganglia, left frontal cortex, and left dorso-lateral pre-frontal cortex. Coinciding with this, subjects also underwent a battery of neuropsychological tests to evaluate the domains of verbal learning, memory, attention, language, executive functioning, and motor skills. Seven HCV positive controls (not receiving anti-viral therapy) underwent MRS and neuropsychological testing at two time points, 12weeks apart, to examine for variation in cerebral metabolites over time and the practice effect of repeat neuropsychological testing.Results: Significant reductions in basal ganglia Cho/Cr (p=0.03) and basal ganglia MI/Cr (p=0.03) were observed in sustained virological responders (SVRs, n=8), but not non-responders/relapsers (NR/R, n=6), indicative of reduced cerebral infection and/or immune activation in those who cleared virus. SVRs demonstrated significant improvements in verbal learning, memory, and visuo-spatial memory. A small but significant improvement in neurocognitive function secondary to the practice effect was seen in both HCV controls and HCV subjects during treatment.Conclusions: HCV eradication has a beneficial effect on cerebral metabolism and selective aspects of neurocognitive function and is an important factor when contemplating anti-viral therapy in HCV, especially in those with mild disease.

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

2011-10-24

Background & Aims: We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0–28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1.Methods: We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0–28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1.Results: Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0–2), phase 2 (day 7–28), and day 0–28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p<0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p<0.001). There were no racial differences in HCV RNA declines during phase 1, day 2–7, phase 2, and day 0–28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p=0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (⩾600,000IU/ml), and in CA with ⩾1log10IU/ml decrease in HCV RNA from day 0 to 28.Conclusions: SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1.

Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe

2011-10-24

Background & Aims: The FibroScan XL probe facilitates liver stiffness measurement (LSM) by transient elastography (TE) in obese patients, yet factors affecting its accuracy have not been described. Our objectives were to examine the prevalence, risk factors, and causes of discordance between fibrosis estimated by the FibroScan XL probe and biopsy.Methods: Two hundred and ten patients with chronic liver disease (45% viral hepatitis, 55% nonalcoholic fatty liver disease (NAFLD) and a body mass index (BMI) ⩾28kg/m2) underwent liver biopsy and TE with the FibroScan XL probe. Predictors of discordance ⩾2 fibrosis stages between measures, which occurred in 11% of patients (n=24), were identified by comparing patient, TE, and biopsy characteristics of discordant and non-discordant cases.Results: Fibrosis estimated by the FibroScan XL probe was greater than biopsy in 75% (18/24) of discordant cases. Although biopsy quality was not associated with discordance, discordant cases were less likely to have ⩾10 valid shots (75% vs. 97%; p=0.001), a success rate ⩾60% (67% vs. 95%; p <0.0005), and an interquartile range over median liver stiffness (IQR/M) <21% (37% vs. 57%; p=0.07) than non-discordant cases. However, only increased BMI (odds ratio [OR] 1.09perkg/m2; 95% confidence interval [CI] 1.01–1.18; p=0.04) was independently associated with discordance; liver stiffness was of borderline significance (OR 1.73perlog10-transformed value; 95% CI 0.95–3.18; p=0.08). Discordance was 4- to 5-fold more frequent among patients with severe obesity (BMI ⩾40kg/m2: 32% vs. 8%) and liver stiffness above the median of 7.0kPa (20% vs. 4%; both p <0.0005).Conclusions: Discordance between liver fibrosis estimated by biopsy and TE using the FibroScan XL probe was infrequent in this obese population. Patients with severe obesity and elevated liver stiffness have the greatest risk of discordance.

Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

2011-10-24

Background & Aims: Tolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated.Methods: This sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15mg oral tolvaptan (n=63; increased to 30 or 60mg if needed) or placebo (n=57) once-daily for 30days. At baseline, 44% had mild hyponatremia (serum sodium 130–134mmol/L), 56% had marked hyponatremia (serum sodium <130mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C.Results: Tolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p<0.0001) and day 30 (p<0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (⩽60ml/min and >60ml/min), or serum creatinine levels (<1.5mg/dl and ⩾1.5mg/dl). Hyponatremia recurred 7days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p=0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p=0.11). Adverse event rates, withdrawals, and deaths were similar in both groups.Conclusions: One month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.

Liver transplantation from hepatitis B surface antigen positive donors: A safe way to expand the donor pool

2011-10-24

Background & Aims: The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study.Methods: From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42months (range 12–60). All recipients were HBcAb positive and were given antiviral prophylaxis.Results: Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection.Conclusions: OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

PPARα is down-regulated following liver transplantation in mice

2011-10-26

Background & Aims: Graft dysfunction is one of the major complications after liver transplantation, but its precise mechanism remains unclear. Since steatotic liver grafts are susceptible to post-transplant dysfunction, and peroxisome proliferator-activated receptor (PPAR) α plays an important role in the maintenance of hepatic lipid homeostasis, we examined the role of PPARα in liver transplantation.Methods: Livers were harvested from Sv/129 wild-type (Ppara+/+) mice and PPARα-null (Ppara−/−) mice and transplanted orthotopically into syngeneic Ppara+/+ mice.Results: Hepatocellular damage was unexpectedly milder in transplanted Ppara−/− livers compared with Ppara+/+ ones. This was likely due to decreased lipid peroxides in the Ppara−/− livers, as revealed by the lower levels of fatty acid oxidation (FAO) enzymes, which are major sources of reactive oxygen species. Hepatic PPARα and its target genes, such as FAO enzymes and pyruvate dehydrogenase kinase 4, were strongly down-regulated after transplantation, which was associated with increases in hepatic tumor necrosis factor-α expression and nuclear factor-κB activity. Inhibiting post-transplant PPARα down-regulation by clofibrate treatment markedly augmented oxidative stress and hepatocellular injury.Conclusions: Down-regulation of PPARα seemed to be an adaptive response to metabolic alterations following liver transplantation. These results provide novel information to the understanding of the pathogenesis of early post-transplant events.

Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma

2011-10-24

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. Although sorafenib has been shown to improve survival of patients with advanced HCC, this improvement is modest and patients eventually have refractory disease. This study aims at investigating the antitumor, antiangiogenesis and antimetastatic activities of dovitinib in preclinical models of HCC.Methods: 21-0208 and SK-HEP1 cells as well as patient-derived HCC models were employed to study the antitumor effect of dovitinib. Changes of biomarkers relevant to FGFR/VEGFR/PDGFR pathways were determined by Western blotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry.Results: Treatment of SK-HEP1 cells with dovitinib resulted in G2/M cell cycle arrest, inhibition of colony formation in soft agar and blockade of bFGF-induced cell migration. Dovitinib inhibited basal expression and FGF-induced phosphorylation of FGFR-1, FRS2-α and ERK1/2. In vivo, dovitinib potently inhibited tumor growth of six HCC lines. Inhibition of angiogenesis correlated with inactivation of FGFR/PDGFR-β/VEGFR-2 signaling pathways. Dovitinib also caused dephosphorylation of retinoblastoma, upregulation of p-histone H2A-X and p27, and downregulation of p-cdk-2 and cyclin B1, which resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. In an orthotopic model, dovitinib potently inhibited primary tumor growth and lung metastasis and significantly prolonged mouse survival.Conclusions: Dovitinib demonstrated significant antitumor and antimetastatic activities in HCC xenograft models. This study provides a compelling rationale for clinical investigation in patients with advanced HCC.

Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C

2011-10-24

Background & Aims: Assessment of the risk of hepatocellular carcinoma (HCC) development is essential for formulating personalized surveillance or antiviral treatment plan for chronic hepatitis C. We aimed to build a simple model for the identification of patients at high risk of developing HCC.Methods: Chronic hepatitis C patients followed for at least 5years (n=1003) were analyzed by data mining to build a predictive model for HCC development. The model was externally validated using a cohort of 1072 patients (472 with sustained virological response (SVR) and 600 with nonSVR to PEG-interferon plus ribavirin therapy).Results: On the basis of factors such as age, platelet, albumin, and aspartate aminotransferase, the HCC risk prediction model identified subgroups with high-, intermediate-, and low-risk of HCC with a 5-year HCC development rate of 20.9%, 6.3–7.3%, and 0–1.5%, respectively. The reproducibility of the model was confirmed through external validation (r2=0.981). The 10-year HCC development rate was also significantly higher in the high-and intermediate-risk group than in the low-risk group (24.5% vs. 4.8%; p<0.0001). In the high-and intermediate-risk group, the incidence of HCC development was significantly reduced in patients with SVR compared to those with nonSVR (5-year rate, 9.5% vs. 4.5%; p=0.040).Conclusions: The HCC risk prediction model uses simple and readily available factors and identifies patients at a high risk of HCC development. The model allows physicians to identify patients requiring HCC surveillance and those who benefit from IFN therapy to prevent HCC.

Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: Lipiodol vs. drug-eluting beads

2011-10-24

Background & Aims: Transarterial chemoembolisation (TACE) is usually performed by injecting an emulsion of a drug and iodised oil. Drug-eluting beads (DEBs) have undeniable pharmacological advantages by offering simultaneous embolisation and sustained release of the drug to the tumour. No data are currently available on liver/biliary injury following DEB-TACE. This study describes and compares liver/biliary injuries encountered with TACE in tumours developed in cirrhotic (hepatocellular carcinoma (HCC)) and non-cirrhotic (endocrine tumours (NETs)) livers.Methods: In consecutive patients treated for a well-differentiated metastatic NET (n=120) or a HCC (n=88), 684 CT- and MR-scans were analysed. Liver/biliary injuries were classified as follows: dilated bile duct, portal vein narrowing, portal venous thrombosis and biloma/liver infarct. A generalised estimating equation logistic regression model was used.Results: A liver/biliary injury followed 17.2% (82/476) of sessions in 30.8% (64/208) of patients. The occurrence of liver/biliary injury was associated with DEB-TACE (OR=6.63; p<0.001) irrespectively of the tumour type. Biloma/parenchymal infarct was strongly associated with both DEB-TACE (OR=9.78; p=0.002) and NETs (OR: 8.13; p=0.04). Biloma/liver infarcts were managed conservatively but were associated with an increase in serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatases, and gamma glutamyl transpeptidase (p=0.005, p=0.005, p=0.012, and p=0.006, respectively).Conclusions: Liver/biliary injuries are independently associated with DEB-TACE. Biloma/liver infarct, the most serious injury, is independently associated with both DEB-TACE and NETs. The absence of such an association in TACE of HCC may be explained by the hypertrophied peribiliary plexus observed in cirrhosis, which protects against the ischemic/chemical insult of bile ducts. We suggest caution when using DEB-TACE in the non-cirrhotic liver.

Impact of geographic disparity on liver allocation for hepatocellular cancer in the United States

2011-10-24

Background & Aims: Liver allocation for hepatocellular cancer (HCC) is undergoing constant re-evaluation in the United States, but the impact of geographic differences in organ access has not been examined.Methods: From February 28th, 2002 until November 20th, 2009, 9730 adult patients with T2 HCC and 326 Beyond Milan HCC patients were studied using the UNOS database. Kaplan–Meier survival curves were generated and log-rank tests were used to test for differences in survival curves.Results: Length of waiting time and presence/absence of loco-regional therapy in T2 HCC patients did not significantly impact transplant recipient (p=0.65) and graft survival (p=0.74) (B). Regions with median waiting times >6months performed more loco-regional therapy (D) and had significantly higher waiting list dropout rates (Regions 1: p=0.01; 5: p<0.001, and 9: p<0.001). T2 HCC post-transplant outcomes were not significantly different between UNOS regions () or between T2 and Beyond Milan HCC patients (transplant recipient p=0.37, and graft p=0.72 survival) (C). The Beyond Milan cohort had significantly greater dropout/death (p=0.007) and a worse overall survival trend (p=0.11) (C).Conclusions: Analysis of the UNOS database shows inhomogeneous access to liver transplantation in the United States. Regions with longer waiting times had significantly higher T2 HCC dropout rates (), and used more loco-regional therapy (D). Conversely, T2 HCC patients had uniform liver transplant outcomes despite geographic differences (). Beyond Milan HCC patients showed significantly greater dropout/death (p=0.007) and a worse overall survival trend in an intent-to-treat analysis (p=0.11) (C).

Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

Kimchi Nguyen, Charlotte D’Mello, Tai Le, Stefan Urbanski, Mark G. Swain — 2011-10-24

Background & Aims: Cholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (Tregs) can suppress inflammation; however, a role for Tregs in modulating sickness behaviours has not been evaluated.Methods: A mouse model of cholestatic liver injury due to bile duct ligation (BDL) was used to study the role of Tregs in sickness behaviour development.Results: BDL mice developed reproducible sickness behaviours, as assessed in a social investigation paradigm, characterized by decreased social investigative behaviour and increased immobility. Depletion of peripheral Tregs in BDL mice worsened BDL-associated sickness behaviours, whereas infusion of Tregs improved these behaviours; however, liver injury severity was not altered by Treg manipulation. Hepatic IL-6 mRNA and circulating IL-6 levels were elevated in BDL vs. control mice, and were elevated further in Treg-depleted BDL mice, but were decreased after infusion of Tregs in BDL mice. IL-6 knock out (KO) BDL mice exhibited a marked reduction in sickness behaviours, compared to wildtype BDL mice. Furthermore, IL-6 KO BDL mice injected with rmIL-6 displayed sickness behaviours similar to wildtype BDL mice, whereas saline injection did not alter behaviour in IL-6 KO BDL mice. BDL was associated with increased hippocampal cerebral endothelial cell p-STAT3 expression, which was significantly reduced in IL-6 KO BDL mice.Conclusions: Tregs modulate sickness behaviour development in the setting of cholestatic liver injury, driven mainly through Treg inhibition of circulating monocyte and hepatic IL-6 production, and subsequent signalling via circulating IL-6 acting at the level of the cerebral endothelium.

Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis

2011-10-26

Background & Aims: Despite major public health concern, therapy for non-alcoholic fatty liver, the liver manifestation of the metabolic syndrome often associated with insulin resistance (IR), remains elusive. Strategies aiming to decrease liver lipogenesis effectively corrected hepatic steatosis and IR in obese animals. However, they also indirectly increased mitochondrial long-chain fatty acid oxidation (mFAO) by decreasing malonyl-CoA, a lipogenic intermediate, which is the allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT1A), the key enzyme of mFAO. We thus addressed whether enhancing hepatic mFAO capacity, through a direct modulation of liver CPT1A/malonyl-CoA partnership, can reverse an already established hepatic steatosis and IR in obese mice.Methods: Adenovirus-mediated liver expression of a malonyl-CoA-insensitive CPT1A (CPT1mt) in high-fat/high-sucrose (HF/HS) diet-induced or genetically (ob/ob) obese mice was followed by metabolic and physiological investigations.Results: In association with increased hepatic mFAO capacity, liver CPT1mt expression improved glucose tolerance and insulin response to a glucose load in HF/HS and ob/ob mice, showing increased insulin sensitivity, and corrected IR in ob/ob mice. Surprisingly, hepatic steatosis was not affected in CPT1mt-expressing obese mice, indicating a clear dissociation between hepatic steatosis and IR. Moreover, liver CPT1mt expression rescued HF/HS-induced impaired hepatic insulin signaling at the level of IRS-1, IRS-2, Akt, and GSK-3β, most likely through the observed decrease in the HF/HS-induced accumulation of lipotoxic lipids, oxidative stress, and JNK activation.Conclusions: Enhancing hepatic mFAO capacity is sufficient to reverse a state of IR and glucose intolerance in obese mice independently of hepatic steatosis.

The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis

2011-10-24

Background & Aims: Neoadjuvant chemotherapy prior to liver surgery for colorectal metastases can cause marked steatosis (⩾33%) and steatohepatitis defined by non-alcoholic fatty liver disease activity score (NAS) as adverse effects on liver parenchyma. The aim of this study was to evaluate the steatosis level prior to liver resection using proton magnetic resonance spectroscopy (1H MRS) and to compare it with digital quantification of steatosis (DQS) and “classical” histopathology.Methods: 1H MRS at 3T evaluated steatosis in 35 patients with colorectal liver metastasis, planned for liver resection. Non-tumorous liver parenchyma samples were obtained after surgery for classical histopathology and DQS utilising automated software for quantification of histopathological slides using image processing.Results: Classical histopathology defined marked steatosis in nine patients. Histopathology was less reliable than DQS (interclass correlation coefficient – ICC 0.771) or 1H MRS (ICC 0.722) in steatosis estimation. 1H MRS showed very similar steatosis levels and high reliability compared to DQS (ICC 0.955). Steatohepatitis was observed in seven patients (NAS ⩾4) and 1H MRS was able to predict it with 100% sensitivity and 89% specificity at threshold 10.9%, without knowing lobular inflammation or hepatocyte ballooning. BMI was significantly higher in the groups with marked steatosis and steatohepatitis. Standard blood tests or chemotherapy had no predictive value.Conclusions: 1H MRS is a reliable non-invasive tool for steatosis assessment, and interestingly, it was able to predict steatohepatitis defined by NAS ⩾4 in patients planned for liver resection of colorectal metastases after neoadjuvant chemotherapy.

Endogenous formation of Nε-(carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis

2011-09-09

Background & Aims: Increased lipid peroxidation and inflammation are major factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A lipoxidation product that could play a role in the induction of hepatic inflammation is Nε-(carboxymethyl)lysine (CML). The aim of the present study was to investigate the relationship between steatosis and CML and to study the role of CML in hepatic inflammation.Methods: We included 74 obese individuals, which were categorized into 3 groups according to the grade of hepatic steatosis. CML accumulation in liver biopsies was assessed by immunohistochemistry and plasma CML levels were measured by mass spectrometry. Plasma CML levels were also determined in the hepatic artery, portal, and hepatic vein of 22 individuals, and CML fluxes across the liver were calculated. Hepatocyte cell lines were used to study CML formation during intracellular lipid accumulation and the effect of CML on pro-inflammatory cytokine expression. Gene expression levels of the inflammatory markers were determined in liver biopsies of the obese individuals.Results: CML accumulation was significantly associated with the grade of hepatic steatosis, the grade of hepatic inflammation, and gene expression levels of inflammatory markers PAI-1, IL-8, and CRP. Analysis of CML fluxes showed no release/uptake of CML by the liver. Lipid accumulation in hepatocytes, induced by incubation with fatty acids, was associated with increased CML formation and expression of the receptor for advanced glycation endproducts (RAGE), PAI-1, IL-8, IL-6, and CRP. Pyridoxamine and aminoguanidine inhibited the endogenous CML formation and the increased RAGE, PAI-1, IL-8, IL-6, and CRP expression. Incubation of hepatocytes with CML-albumin increased the expression of RAGE, PAI-1, and IL-6, which was inhibited by an antibody against RAGE.Conclusions: Accumulation of CML and a CML-upregulated RAGE-dependent inflammatory response in steatotic livers may play an important role in hepatic steatosis and in the pathogenesis of NAFLD.

p53, a novel regulator of lipid metabolism pathways

2011-10-31

Background & Aims: In this study we aimed at characterizing the regulation of hepatic metabolic pathways by the p53 transcription factor.Methods: Analysis of gene expression following alteration of p53 status in several human- and mouse-derived cells using microarray analysis, quantitative real-time PCR, chromatin immunoprecipitation, and reporter gene assays. A functional assay was performed to determine lipid transfer activity.Results: We identified a novel role for the p53 protein in regulating lipid and lipoprotein metabolism, a process not yet conceived as related to p53, which is known mainly for its tumor suppressive functions. We revealed a group of 341 genes whose expression was induced by p53 in the liver-derived cell line HepG2. Twenty of these genes encode proteins involved in many aspects of lipid homeostasis. The mode of regulation of three representative genes (Pltp, Abca12, and Cel) was further characterized. In addition to HepG2, the genes were induced following activation of p53 in human primary hepatic cells isolated from liver donors. p53-dependent regulation of these genes was evident in other cell types namely Hep3B cells, mouse hepatocytes, and fibroblasts. Furthermore, p53 was found to bind to the genes’ promoters in designated p53 responsive elements and thereby increase transcription. Importantly, p53 augmented the activity of secreted PLTP, which plays a major role in lipoprotein biology and atherosclerosis pathology.Conclusions: These findings expose another facet of p53 functions unrelated to tumor suppression and render it a novel regulator of hepatic lipid metabolism and consequently of systemic lipid homeostasis and atherosclerosis development.

Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans

2011-10-24

Background & Aims: Mechanisms leading to non-alcoholic steatohepatitis (NASH) have remained unclear, and non-invasive diagnosis of NASH is challenging. In this study, we investigated the benefits of measuring serum interleukin 1 receptor antagonist (IL-1RA) levels.Methods: Liver biopsies from 119 morbidly obese individuals (47.5±9.0years, BMI 44.9±5.9kg/m2) were used for histological and gene expression assessment. In a cross-sectional population-based cohort of 6447 men (58±7years, BMI 27.0±3.9kg/m2) the association of serum IL1-RA with serum alanine aminotransferase (ALT) levels was investigated.Results: Serum levels of IL-1RA, and liver mRNA expression of IL1RN are associated with NASH and the degree of lobular inflammation in liver (p<0.05). The decrease in serum IL-1RA level and expression of IL1RN after obesity surgery correlated with the improvement of lobular inflammation (p<0.05). We developed a novel NAFLD Liver Inflammation Score, including serum Il-1RA concentration, which performed better to diagnose NASH than did previously published scores. Results from the population study confirmed the potential of measuring serum IL-1RA level. The strongest determinants of the ALT concentration at the population level were Matsuda insulin sensitivity index (r2=0.130, p=7×10−197) and serum IL-1RA concentration (r2=0.074, p=1×10−110). IL-1RA concentrations associated significantly with ALT levels even after adjusting for BMI, alcohol consumption and insulin sensitivity (p=2×10−21).Conclusions: IL-1RA serum levels associate with liver inflammation and serum ALT independently of obesity, alcohol consumption and insulin resistance, suggesting a potential use of IL-1RA as a non-invasive inflammatory marker for NASH.

EASL Clinical Practice Guidelines: Wilson’s disease

European Association for the Study of the Liver — 2012-03-01

Summary: This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers in the diagnosis and management of patients with Wilson’s disease. The goal is to describe a number of generally accepted approaches for diagnosis, prevention, and treatment of Wilson’s disease. Recommendations are based on a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases using entries from 1966 to 2011. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system used in other EASL CPGs was used and set against the somewhat different grading system used in the AASLD guidelines (A and B). Unfortunately, there is not a single randomized controlled trial conducted in Wilson’s disease which has an optimal design. Thus, it is impossible to assign a high or even a moderate quality of evidence to any of the questions dealt with in these guidelines. The evaluation is mostly based on large case series which have been reported within the last decades.

Are there opportunities for chemotherapy in the treatment of hepatocellular cancer?

Uzma Asghar, Tim Meyer — 2011-10-04

Summary: Hepatocellular cancer is a significant global health problem yet the prognosis for the majority of patients has not changed significantly over the past few decades. For patients with advanced disease, sorafenib is currently the standard of care providing a survival advantage of 2–3months in selected patients. Cytotoxic chemotherapy has been used for over 30years but definite evidence that it prolongs survival has been lacking. Resistance remains a significant barrier for both targeted and cytotoxic agents and an understanding of the underlying mechanisms is critical if outcomes are to be improved. Here, we summarise the past and current data that constitute the evidence base for chemotherapy in HCC, review the causes of chemoresistance and suggest strategies to overcome these barriers.

Non invasive evaluation of portal hypertension using transient elastography

Laurent Castera, Massimo Pinzani, Jaime Bosch — 2011-07-18

Summary:: The development of portal hypertension is a common consequence of chronic liver diseases leading to the formation of esophageal and gastric varices responsible for variceal bleeding, associated with a high mortality rate, as well as other severe complications such as portosystemic encephalopathy and sepsis. Measurement of hepatic venous pressure gradient (HVPG) and upper GI endoscopy are considered the gold standards for portal hypertension assessment in patients with cirrhosis. However, both types of investigation are invasive and HVPG measurement is routinely available and/or performed with adequate standards only in expert centres. There is thus a need for non invasive methods able to predict, with acceptable diagnostic accuracy, the progression of portal hypertension toward the levels of clinically significant (i.e. HVPG ⩾10mmHg) and severe (HVPG ⩾12mmHg) as well as the presence and the size of oesophageal varices. Transient elastography (TE) is a novel non invasive technology that allows measuring liver stiffness and that has gained popularity over the past few years. Although TE has been initially proposed to assess liver fibrosis, a good correlation has been reported between liver stiffness values and HVPG as well as the presence of oesophageal varices, suggesting that it could be an interesting tool for the non invasive evaluation of portal hypertension. This review is aimed at discussing the advantages and limits of TE and the perspectives for its rationale use in clinical practice for the management of patients with portal hypertension.

Obesity, inflammation, and liver cancer

Beicheng Sun, Michael Karin — 2011-11-24

Obesity has become a universal and major public health problem with increasing prevalence in both adults and children in the 21st century, even in developing countries. Extensive epidemiological studies reveal a strong link between obesity and development and progression of various types of cancers. The connection between obesity and liver cancer is particularly strong and obesity often results in liver diseases such as non-alcoholic fatty liver disease (NAFLD) and the more severe non-alcoholic steatohepatitis (NASH). NASH is characterized by fatty liver inflammation and is believed to cause fibrosis and cirrhosis. The latter is a known liver cancer risk factor. In fact due to its much higher prevalence obesity may be a more substantial contributor to overall hepatocellular carcinoma burden than infection with hepatitis viruses. Here we review and discuss recent advances in elucidation of cellular and molecular alterations and signaling pathways associated with obesity and liver inflammation and their contribution to hepatocarcinogenesis.

The adolescent and liver transplantation

Patrizia Burra — 2011-09-29

Summary: The outcome of liver transplantation is usually reported in terms of graft and patient survival, medical and surgical complications, and quality of life, but when it comes to transplanted adolescents such conventional parameters are unable to give a full account of their life with a new liver, and their transition from adolescence to adulthood is a time when they are particularly vulnerable.Adolescents with liver transplants have excellent survival rates, over 80% of them surviving more than 10years. Graft loss is most often associated with complications such as chronic rejection, hepatic artery thrombosis, and biliary complications. Calcineurin inhibitors may have various side effects, including hypertension and nephrotoxicity. Liver-transplanted adolescents are also exposed to viral infections, among which Epstein-Barr virus is very common and associated with the onset of post-transplant lymphoproliferative disorders. Growth retardation may also be an issue in some liver transplant recipients.Future studies will determine the best way to assess the functional immune status of adolescents with a transplanted liver with a view to ensuring the best treatment to induce tolerance without the complications of excessive immunosuppression.Schooling may be disrupted due to adolescent transplant recipients’ poor adherence. Non-adherence is associated with a poor medical outcome. Both physical and psychosocial functioning is reportedly lower among young liver transplant recipients than in the general population.

Sorafenib use while waiting for liver transplant: We still need to wait

Richard S. Finn — 2011-11-28

COMMENTARY ON Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: a cost–benefit analysis while awaiting data on sorafenib safety. Vitale A, Volk ML, Pastorelli D, Lonardi S, Farinati F, Burra P, Angeli P, Cillo U. Hepatology 2010 Jan;51(1):165–73.

A dive into the complexity of type I interferon antiviral functions

Maxime Touzot, Vassili Soumelis, Tarik Asselah — 2011-07-28

COMMENTARY ON: A diverse range of gene products are effectors of the type I interferon antiviral response. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. Nature. 2011 Apr 28;472(7344):481–485. Copyright (2011). Abstract reprinted by permission from Macmillan Publishers Ltd.http://www.ncbi.nlm.nih.gov/pubmed/21478870

Genomic risk of hepatitis C-related hepatocellular carcinoma

Yujin Hoshida, Bryan C. Fuchs, Kenneth K. Tanabe — 2011-09-29

COMMENTARY ON:: Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H, Koike K, Kamatani N, Kubo M, Nakamura Y, Matsuda K. Nat Genet. 2011 May;43(5):455–458. Copyright (2011). Abstract reprinted by permission from Macmillan Publishers Ltd.http://www.ncbi.nlm.nih.gov/pubmed/21499248Abstract: To identify the genetic susceptibility factor(s) for hepatitis C virus-induced hepatocellular carcinoma (HCV-induced HCC), we conducted a genome-wide association study using 432,703 autosomal SNPs in 721 individuals with HCV-induced HCC (cases) and 2890 HCV-negative controls of Japanese origin. Eight SNPs that showed possible association (P<1×10(−5)) in the genome-wide association study were further genotyped in 673 cases and 2596 controls. We found a previously unidentified locus in the 5′ flanking region of MICA on 6p21.33 (rs2596542, P(combined)=4.21×10(−13), odds ratio=1.39) to be strongly associated with HCV-induced HCC. Subsequent analyses using individuals with chronic hepatitis C (CHC) indicated that this SNP is not associated with CHC susceptibility (P=0.61) but is significantly associated with progression from CHC to HCC (P=3.13×10(−8)). We also found that the risk allele of rs2596542 was associated with lower soluble MICA protein levels in individuals with HCV-induced HCC (P=1.38×10(−13)).

Towards common denominators in primary biliary cirrhosis: The role of IL-12

Ana Lleo, M. Eric Gershwin, Alberto Mantovani, Pietro Invernizzi — 2011-10-17

There have been significant advances in our understanding of the immunobiology of primary biliary cirrhosis (PBC) and, in particular, a rigorous dissection of not only the serologic abnormalities, including antimitochondrial autoantibodies (AMA), but also the definition of autoreactive CD4+ and CD8+ T cells . Further, there is increasing evidence for the interplay of genetic and environmental factors in individual host susceptibility. One paradox has been the selected destruction of small bile ducts in PBC despite the presence of mitochondrial antigens in virtually all nucleated cells. This enigma is being addressed with the critical observation that during apoptosis, biliary epithelial cells (BECs) translocate immunologically intact PDC-E2 into apoptotic bodies, constituting an apotope, which is able to induce pro-inflammatory cytokine secretion from mature monocyte derived macrophages (MDM) from patients with PBC in the presence of AMA, including high levels of interleukin-12 (IL-12) . Importantly, data from genetic studies of humans with PBC, murine models, and in vitro experiments have identified the IL-12 signaling pathway as a key player in the effector mechanisms that lead to biliary destruction. In fact, genome wide association studies from three different populations have identified at least three IL-12 related genes strongly associated to PBC: IL12A, IL12RB2, and STAT4 . In addition, the deletion of IL-12p40 on the transforming growth factor β receptor II dominant negative (dnTGF-βRII) murine model of PBC has established that the IL-12p40 subunit is essential for the development of autoimmune cholangitis .

Reverse vertical transmission of hepatitis B virus (HBV) infection from a transfusion-infected newborn to her mother

2011-10-24

Background & Aims: Clinical cases of viral infections possibly involving the transfusion of blood components are systematically investigated.Methods: Serological and molecular markers of hepatitis B virus were used including HBsAg, anti-HBc, anti-HBs, HBV DNA, and viral load. Full genome sequencing and phylogenetic analyses were performed.Results: An acute HBV infection was diagnosed in the mother of a 16-month-old daughter who had been transfused at age three weeks with one quarter of a regular red cell concentrate (RCC). The repeat donor of the index donation was free of HBV markers in two previous donations but seroconverted to anti-HBc and anti-HBs 3months post-donation of a unit containing only low level of HBV DNA. One other newborn recipient of the same RCC was asymptomatically HBV infected. A third newborn recipient whose mother had been HBV vaccinated and carried moderate level of anti-HBs was not infected. Full length nucleotide sequence identity between HBV strains from the mother and the two infected transfusion recipients provided evidence of the transfusion origin of all three infections in the absence of donor sequence.Conclusions: Reverse vertical HBV transmission was likely the result of casual mother contact with a baby carrying extremely high viral load. The blood products intended to immunodeficient newborn should be submitted to more thorough viral testing considering their increased susceptibility to infections.

Favorable association between genetic polymorphisms near the IL28B gene and hepatic steatosis: Direct or indirect?

Hidenori Toyoda, Takashi Kumada — 2012-03-01

We read with great interest the article by Tillmann et al. that investigated the association between IL28B polymorphisms and hepatic steatosis, both of which are associated with a response to combination therapy with peginterferon (PEG-IFN) and ribavirin. It will provide new insight into the role of IL28B polymorphisms on the resistance to combination therapy against hepatitis C virus (HCV) infection.

Reply to: “Favorable association between genetic polymorphisms near the IL28B gene and hepatic steatosis: Direct or indirect?”

Hans Ludger Tillmann, Jeanette J. McCarthy — 2012-03-01

We thank Drs. Toyoda and Kumada for raising the additional point that HCV amino acid substitutions have also been demonstrated to influence steatosis in the setting of HCV infection. In their study of 122 patients, 85 of whom had a beneficial IL28B genotype, Toyoda and Kumada found a trend for steatosis to be associated with IL28B polymorphism, as only 22% of the patients with beneficial genotype have steatosis compared to 40% of patients with the less beneficial genotype. Thus, their r, though not significant, is in line with our study, where we likewise found a 25% and 27% higher rate of steatosis in patients with the less beneficial IL28B (“non-C/C” for rs12979860 or “non-T/T” for rs8999017) genotype in two different cohorts of 145 and 180 patients, respectively. Similar to our and Toyoda and Kumada’s results, Cai et al. found an association between the beneficial IL28B genotype and lower steatosis frequency . However, a three center study by Trépo et al. failed to find a relevant association between IL28B genotype and steatosis, according to their statement . This latter paper, however, did not show the data, and therefore it cannot be assessed whether the association was absent or only not significant. Toyoda and Kumada’s study showed a similar trend for steatosis with IL28B, whereby IL28B is associated with different mutations in the core region, the HCV core mutation clearly shows a higher association with steatosis.

Acoustic radiation force-based shear stiffness and non-invasive panels of tests in Japanese patients with nonalcoholic fatty liver disease

Masato Yoneda, Kento Imajo, Hiroyuki Kirikoshi, Atsushi Nakajima — 2011-08-30

We read the article by Palmeri et al. with great interest. The authors concluded that Acoustic Radiation Force Impulse (ARFI) shear stiffness, in which shear wave speed is converted using the formula: shear stiffness (kPa)=(shear wave speed)2×density (1.0g/cm2) , is clinically useful for assessing advanced fibrosis (stage 3–4) in patients with nonalcoholic fatty liver disease (NAFLD). We also previously reported that ARFI shear wave speed can be used to measure advanced fibrosis in patients with NAFLD . By using the cutoff of ⩾4.24kPa for detecting advanced fibrosis as proposed by Palmeri et al. in their paper, we obtained a sensitivity of 80.0% and a specificity of 97.7% even in our population (n=54). Their study is clinically useful and valuable, because the degree of liver fibrosis must be estimated for detecting the prognosis, conducting close surveillance, and providing optimal treatment of patients with NAFLD. Because liver biopsy is invasive and is associated with a relatively high risk of complications , a rapid and non-invasive method of detecting fibrosis in patients with NAFLD is of major clinical interest.

IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?

Hans Orlent, Robert J. de Knegt, Harry L.A. Janssen — 2012-03-01

Single nucleotide polymorphism (SNP) in the region of the interleukin-28B (IL28B) gene has recently been associated with spontaneous and treatment-induced clearance of hepatitis C virus infection . The SNPs are located near the IL28B gene of chromosome 19, implicating a role for its gene product, interferon-λ3, in the immune response to hepatitis C virus. The mechanisms by which IL28B polymorphism effects the sensitivity to exogenous peginterferon-α therapy is unclear at present.

Reply to “IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?”

A.J. Thompson, P.J. Clark, A.J. Muir, M.S. Sulkowski — 2012-03-01

We appreciate the interest of Orlent et al. in our recent study and would like to comment on the issues raised in their letter. (i) The primary endpoint we selected for all genome-wide analyses of peginterferon (pegIFN)-induced cytopenia was quantitative reduction in cell counts, as a continuous variable, at week 4. We chose the continuous variable as the primary endpoint for two reasons. Firstly, this method maximizes the statistical power of the dataset. Secondly, it avoids the pitfalls of defining pre-specified thresholds for cytopenia, where timing and the chosen level of the threshold are arbitrary. We chose the week 4 timepoint to minimize confounding by dose adjustment/adherence. It is true that week 4 preceded the nadir for pegIFN-related thrombocytopenia and neutropenia in this study, which occurred between week 8 and 12. However, the rate of decline was most profound in the first 4weeks, with significant reductions in both platelet counts and neutrophil counts by week 4 . We have subsequently tested for association between the IL28B polymorphism rs12979860 and quantitative reduction of platelet/neutrophil counts at week 12. No significant association was observed.

Transient elevation of serum bile salts after partial hepatectomy is due to metabolic overload and not to cholestasis

Peter L.M. Jansen — 2011-08-30

In a recent publication Miura et al. reported on the mechanism of cholestasis after partial hepatectomy (PH) in rats . The first day after PH, they find a transient doubling of serum bile salts, a down-regulation of the bile acid uptake protein Ntcp and an up-regulation of Mrp4 and Cyp7A1. With these findings they confirm a number of earlier studies . Miura et al. consider this as evidence of cholestasis. We like to take issue with this view.

Reply to: “Transient elevation of serum bile salts after partial hepatectomy is due to metabolic overload and not to cholestasis”

2011-08-30

We appreciate Dr. Jansen‘s comments on our recent paper. We consider cholestasis as retention of bile not only within hepatocytes but also in the systemic circulation, because clinical cholestatic status after hepatectomy or liver transplantation is defined as high serum levels of bile acids and bilirubin . Meanwhile, as Dr. Jansen pointed out, bile acids have been considered as a trigger of liver regeneration and elevated serum levels would be a sign of hepatic overload . However, in our paper we have provided evidence indicating that intracellular bile acids are maintained at a low level when the remnant liver volume is excessively small and hepatocytes are vigorously proliferating. We would like to address the relation between transporters/pumps in the regulation of intracellular bile salt concentration and regeneration after 90% hepatectomy. On day 1, DNA replication and cell proliferation are active as shown by microarray analysis. At that time, Ntcp mRNA and protein levels are decreased, and Cyp7a1 mRNA is also down-regulated. Since Ntcp is a major transporter for bile acid uptake from the sinusoid and Cyp7a1 is the rate-limiting enzyme of bile acid synthesis, intracellular bile acid concentration seems to be low at this proliferative phase. Zhang et al. reported that overexpression of an exogenous Cyp7a1 gene impaired liver regeneration after 70% hepatectomy, which is accompanied by increased hepatocyte apoptosis and liver injury . To the contrary, on day 3, Cyp7a1 mRNA is up-regulated. Since cholesterol synthesis is enhanced at this time, possibly to build proliferating cell membranes, Cyp7a1 is transiently induced in response to cholesterol synthesis, consistent with the results of a previous study . Ntcp mRNA and protein levels are still decreased, and its cytoplasmic localization reveals loss of transport activity. In addition, Mrp4 mRNA and protein levels are increased and its localization maintained at the basolateral membrane. These findings indicate that massive hepatectomy results not only in a decrease in liver mass but also in alterations of the bile acid transport system. Thus, proliferating hepatocytes seem to be free from the influx of bile salts but able to excrete them de novo produced intracellularly in response to cholesterol synthesis. Another interesting finding is possible degradation of Ntcp protein during liver regeneration, contributing to the protection of proliferating hepatocytes at the expense of the transporter. Our paper does not provide information on which factors trigger liver regeneration but we can say that decreased intracellular bile acids may allow hepatocytes to proliferate rapidly in response to massive hepatectomy, as cells escape toxic effects induced by the substances.

Coffee consumption and reduced self-reported side effects in HIV-HCV co-infected patients during PEG-IFN and ribavirin treatment: Results from ANRS CO13 HEPAVIH

M. Patrizia Carrieri, Julien Cohen, Dominique Salmon-Ceron, Maria Winnock — 2011-09-02

Constentin and colleagues reported key results about the protective effect of elevated coffee consumption (three or more cups/day) on histological activity in patients with chronic hepatitis C. These findings bring additional evidence to the potential hepatoprotective properties of coffee in chronic liver diseases, as already suggested in studies showing its beneficial effects on liver cancer .

Corrigendum to “IL-1 cytokine family members and NAFLD: Neglected in metabolic liver inflammation” [J Hepatol 2011;55:960–962]

Herbert Tilg, Alexander R. Moschen — 2011-11-10

On the last page of the article, the name of Dr. Kamari is incorrectly spelled twice as Kumari. This should be changed to Kamari.

Erratum to “Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility” [J Hepatol 2011; 54: 1205–1213]

2011-10-26

The publisher regrets that the corresponding author was incorrectly marked. The details are now presented correctly above. The publisher would like to apologise for any inconvenience caused.

Journal of Hepatology

Editorial Board

EASL Clinical School of Hepatology, Bologna

ILC Barcelona 2012 by EASL

EASL Monothematic Conference, Tallinn

EASL-AASLD Special Conference, Prague

Contents

Focus

Hepatitis C treatment – Clearing the mind

Liver-induced inflammation hurts the brain

p53-Mediated regulation of hepatic lipid metabolism: Forging links between metabolism, atherogenesis, and cancer

Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: An international multicenter cohort study

IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C

Hepatitis B virus infection and fatty liver in the general population

Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fibrosis in patients with chronic hepatitis C: A step toward the truth in the absence of a gold standard

Effects of anti-viral therapy and HCV clearance on cerebral metabolism and cognition

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1

Discordance in fibrosis staging between liver biopsy and transient elastography using the FibroScan XL probe

Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

Liver transplantation from hepatitis B surface antigen positive donors: A safe way to expand the donor pool

PPARα is down-regulated following liver transplantation in mice

Dovitinib demonstrates antitumor and antimetastatic activities in xenograft models of hepatocellular carcinoma

Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C

Liver/biliary injuries following chemoembolisation of endocrine tumours and hepatocellular carcinoma: Lipiodol vs. drug-eluting beads

Impact of geographic disparity on liver allocation for hepatocellular cancer in the United States

Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic mice

Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis

The value of pre-operative magnetic resonance spectroscopy in the assessment of steatohepatitis in patients with colorectal liver metastasis

Endogenous formation of Nε-(carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis

p53, a novel regulator of lipid metabolism pathways

Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans

EASL Clinical Practice Guidelines: Wilson’s disease

Are there opportunities for chemotherapy in the treatment of hepatocellular cancer?

Non invasive evaluation of portal hypertension using transient elastography

Obesity, inflammation, and liver cancer

The adolescent and liver transplantation

Sorafenib use while waiting for liver transplant: We still need to wait

A dive into the complexity of type I interferon antiviral functions

Genomic risk of hepatitis C-related hepatocellular carcinoma

Towards common denominators in primary biliary cirrhosis: The role of IL-12

Reverse vertical transmission of hepatitis B virus (HBV) infection from a transfusion-infected newborn to her mother

Favorable association between genetic polymorphisms near the IL28B gene and hepatic steatosis: Direct or indirect?

Reply to: “Favorable association between genetic polymorphisms near the IL28B gene and hepatic steatosis: Direct or indirect?”

Acoustic radiation force-based shear stiffness and non-invasive panels of tests in Japanese patients with nonalcoholic fatty liver disease

IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?

Reply to “IL28B polymorphism and hepatitis C: A genetic marker of peginterferon-α sensitivity devoid from classical interferon-α side effects?”

Transient elevation of serum bile salts after partial hepatectomy is due to metabolic overload and not to cholestasis

Reply to: “Transient elevation of serum bile salts after partial hepatectomy is due to metabolic overload and not to cholestasis”

Coffee consumption and reduced self-reported side effects in HIV-HCV co-infected patients during PEG-IFN and ribavirin treatment: Results from ANRS CO13 HEPAVIH

Corrigendum to “IL-1 cytokine family members and NAFLD: Neglected in metabolic liver inflammation” [J Hepatol 2011;55:960–962]

Erratum to “Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility” [J Hepatol 2011; 54: 1205–1213]