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Background & Aims: HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection., Methods: The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up., Results: The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders., Conclusion: Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients., Lay Summary: Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment., Competing Interests: Conflict of interest Dr. Nahon received honoraria from Astra-Zeneca, Abbvie, Bayer, Bristol-Myers Squibb, Gilead and Ipsen. He consults for Abbvie and Bristol-Myers Squibb. Dr Roudot-Thoraval received honoraria from Gilead and AbbVie. Dr Roulot received honoraria from Gilead. All other authors report no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The results of various studies attempting to assess the risks of venous thromboembolism in liver cirrhosis have been conflicting. Furthermore, although the incidence of venous thromboembolism is thought to be low in Asians, the relationship between venous thromboembolism and liver cirrhosis has not been investigated in Asian countries., Objective: We investigated the risks of venous thromboembolism in cirrhotic patients in Taiwan to evaluate whether the risk is higher than in the general population., Methods: The data from 1,000,000 National Health Insurance beneficiaries were utilized. All adult beneficiaries were followed from 1 January 2007 to 31 December 2010 to identify those who developed venous thromboembolism. Each identified patient with liver cirrhosis was matched with 10 non-cirrhotic patients on the basis of high-dimensional propensity score. Cox regression models were applied to compare the hazards of venous thromboembolism in the matched cohorts., Results: A total of 757,940 patients were enrolled. After matching, 2223 cirrhotic patients and 22,230 non-cirrhotic patients were selected. The adjusted hazard ratio of venous thromboembolism was significantly increased by having cirrhosis (1.71; 95% confidence interval [CI] 1.05-2.78). A subgroup analysis revealed a much higher hazard ratio of venous thromboembolism in an advanced cirrhosis subgroup (n = 293) than in a matched non-cirrhosis subgroup (n = 2930) (4.36; 95% CI 1.36-14.01)., Conclusion: The risk of venous thromboembolism may be higher in Asian patients with cirrhosis than in the general Asian population, especially in those with advanced cirrhosis., (© 2014 International Society on Thrombosis and Haemostasis.)

Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, played an important role in immune-mediated diseases. The promoter region of MIF, which had functional polymorphisms, controlled MIF expression. MIF polymorphism was associated with many inflammatory diseases. But the association of MIF polymorphism with chronic hepatitis B (CHB) or HBV-induced liver cirrhosis (HC) had not yet been reported. In present study, polymorphism of MIF-173 was genotyped in 95 CHB patients, 73 HC patients and 90 healthy controls in southern China. The frequency of MIF-173 C/C genotype in patients with CHB or HC was statistically significantly higher than that in healthy controls, respectively. Moreover, difference in the distribution of MIF-173 C allele between CHB patients and healthy controls was statistically significant. However, there was no statistical relationship between MIF-173 genotype and clinical features in patients with CHB or HC. Our results suggest that MIF-173 C/C polymorphism might be associated with increased risk of CHB or HC in Chinese southern population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Schistosome worms inhabit mammalian mesenteric veins. Their eggs cause chronic inflammation, which progresses to periportal fibrosis in 5 to 30% of cases, increasing portal blood pressure and leading to esophageal varices. Episodes of bleeding cause hepatic necrosis and may ultimately lead to hepatic failure and the death of the patient. Schistosome infections can also cause pulmonary hypertension and heart failure. The mechanisms of fibrogenesis and fibrolysis are beginning to be unraveled, but it remains unclear why disease occurs only in certain subjects, as also observed for other types of chronic liver inflammation, as in hepatitis C or B. We summarize here the results that showed that fibrosis progression is determined by a genetic locus on chromosome 6. The CCN2 gene at this locus, encodes CTGF that is a crucial regulator of fibrosis. Two groups of CCN2 polymorphisms independently modulate the progression of hepatic fibrosis. These results were obtained in an Asian population, but were extended to humans living in Africa and South America and are presently tested in liver fibrosis of other etiological origins., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: A subset of patients with hepatocellular carcinoma (HCC) present with massive tumours. It is unknown why certain patients develop these massive tumours, and whether this presentation is specific to the underlying viral aetiology or patient demographics such as gender, race and age., Methods: All patients with HCC at Bellevue Hospital Center, New York from 1998 to 2012 were identified and relevant demographic and clinical information was collected. Computed tomography/magnetic resonance imaging (CT/MRI) images were reviewed and the maximal tumour diameter on axial sections was recorded. Cirrhosis was defined histologically or by radiographical criteria. The two cohorts of massive and non-massive HCC were compared., Results: A total of 361 patients with HCC were identified, of which 58 were categorized as having a massive HCC using a 13 cm size cut-off. Univariate and multivariate analysis demonstrated a significant association of massive HCC with age <40 years; hepatitis B or Asian ethnicity; and a lack of cirrhosis or platelet count >100., Discussion: Massive HCC represents a tumour subtype that is associated with young, chronic hepatitis B carriers with non-cirrhotic livers. The clinical implications of this finding are that patients with massive HCC are typically excellent resection candidates barring the presence of gross vascular invasion or distant metastases., (© 2012 International Hepato-Pancreato-Biliary Association.)

Background & Aims: It was recently shown that semi-annual surveillance for hepatocellular carcinoma (HCC) in cirrhotic patients provides a prognostic advantage over the annual program; however, its cost-effectiveness (CE) in the general cirrhotic population still needs to be defined., Methods: A Markov model was built to compare CE of these two strategies, considering literature results and treatment modalities of 918 cirrhotic patients from the Italian Liver Cancer (ITA.LI.CA) database., Results: Results from the Markov model suggest that, compared to annual surveillance, semi-annual surveillance leads to a gain in quality-adjusted life expectancy, in an unselected cirrhotic population, of 1.35 quality-adjusted life-months (QALMs) over 10 years since surveillance start in compensated patients, and of 0.73 QALMs in decompensated patients. Semi-annual surveillance was more cost-effective in compensated than in decompensated cirrhosis, with an incremental CE ratio (ICER) of 1997 and 3814€/QALM, respectively. In compensated cirrhosis, semi-annual surveillance was more cost-effective than the annual program when the annual HCC incidence was ≥3.2% and the relative survival gain after cancer diagnosis was ≥20% with respect to the annual program. In decompensated cirrhosis, semi-annual surveillance was cost-effective in patients amenable to liver transplantation. In both groups, CE of semi-annual surveillance improved with the increase of annual incidence and the survival benefit obtainable with HCC treatment., Conclusions: Both surveillance strategies for HCC in cirrhotic patients can be recommended, according to the individual risk profile for HCC occurrence and the expected survival gain obtainable after tumor diagnosis and therapy., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis., Methods: The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA., Results: Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis., Conclusions: Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: A recent genome-wide association study identified genetic polymorphism (rs738409 C>G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD., Methods: Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patient's phenotype., Results: The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.12-2.11 p = 0.008) and was, among ALD patients, significantly associated with steatosis (p = 0.048), fibrosis (p = 0.001), and greater risk of cirrhosis (p = 0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR = 2.08; 95% CI = 1.15-3.77; p = 0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p = 0.03) and negatively correlated with the hepatic venous pressure gradient (r = -0.41, p = 0.006)., Conclusions: In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: In the United States, among patients with hepatocellular carcinoma (HCC) and portal hypertension from chronic hepatitis-B virus infection, 44% were Hispanic and 28% were African American. Because our institution (Bronx Lebanon Hospital Center, Bronx, NY) predominantly serves these populations, we studied retrospectively the characteristics of patients with chronic hepatitis-B virus infection., Methods: We reviewed the medical records of all patients aged > 18 years with chronic hepatitis-B virus infection who had been evaluated at our institution between January 1, 2002 and May 31, 2005., Results: We identified 167 patients with chronic hepatitis-B virus infection. Only 12 (7%) patients underwent chronic hepatitis-B virus treatment. One-hundred-forty-six (87%) patients without decompensated liver cirrhosis were not treated owing to the following reasons: normal alanine aminotransferase level (86%), active injection drug or heavy alcohol use (9%), lack of health insurance coverage (3%) and noncompliance with visits during the evaluation period (2%). HCC screening was performed in 78 patients (47%). Lack of insurance coverage and compliance issues were predictors for HCC screening (p = 0.04 and p < 0.001, respectively)., Conclusions: In the South Bronx, 87% patients were not considered candidates for hepatitis-B virus treatment because of normal alanine aminotransferase levels and the interference of potentially modifiable social factors. Only 47% of our patients with chronic hepatitis-B virus infection underwent HCC screening because of lack of insurance coverage and compliance issues.

Background/aims: The interval at which liver biopsy should be repeated in untreated patients with chronic hepatitis C is not defined. We examined fibrosis change by METAVIR scoring in these patients in whom two or more liver biopsies were available., Methods: One hundred and eighty patients with histologically proven chronic hepatitis C were studied. Mean delay between biopsies was 3.67+/-2.69 years and 3.08+/-1.43 in the 16 patients having three biopsies. Univariate and multivariate analyses were performed to determine factors associated with liver fibrosis progression., Results: Median rate of fibrosis progression per year was 0.04 (0.00-0.55) to first biopsy, 0.00 (-0.84-1.02) between first and second biopsy (NS), and 0.17 (0.00-1.50) between second and third biopsy (P<0.05). In multivariate analysis, only age at first biopsy >40 years (OR=5) (2-12) and alcohol consumption of 1-50 g per day (OR=4) (2-12) and more than 50 g per day (OR=8) (3-23) were associated with severe fibrosis. The number of patients who increased in fibrosis stage was significantly higher after 4 years (P<0.02)., Conclusions: An interval of at least 4-5 years is needed between liver biopsies to measure change in patients with mild liver disease.

Screening is widely used to detect early hepatocellular carcinoma in Asian patients with cirrhosis. Its effectiveness in Caucasian patients has been suggested, but remains to be proven. Therefore we prospectively studied 118 French patients (68 males, 50 females, age 55 +/- 12) with Child-Pugh A or B cirrhosis (alcoholic in 82) and without detectable hepatocellular carcinoma. The screening program consisted of ultrasound examination of the liver and determination of blood alpha-fetoprotein and des-gamma-carboxyprothrombin levels every 6 months. The median follow up was 36 months (range 4-48). Only four patients were lost to follow up. Fourteen hepatocellular carcinomas were detected, in six cases by ultrasonography alone, in four by alpha-fetoprotein alone, in three by ultrasonography and alpha-fetoprotein and in one case by ultrasonography and des-gamma-carboxyprothrombin, but never by des-gamma-carboxyprothrombin alone. The tumor presented as a unique nodule in nine patients. The tumor was less than 3 cm in diameter without portal thrombosis or metastasis in three cases. Surgery was performed in only one case. In this study, the annual incidence of hepatocellular carcinoma was high (5.8%), but the screening methods used did not effectively identify potentially resectable tumors in Caucasian patients with cirrhosis.