Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD. APPROACH AND RESULTS: We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 , and ASXL1 , and correlated with age ( p <0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non- DNMT3A -CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 -1.28 and OR: 1.30, 1.12 -1.49, respectively, p <0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 -3.15, p =0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 -2.00, 1.30 -3.15, p =0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non- DNTM3A -CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 -4.53; OR: 4.8, 1.60 -17.0, p =0.02). CONCLUSIONS: We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.

Reappraisal of the conventional hemostasis tests as predictors of perioperative bleeding in the era of rebalanced hemostasis in cirrhosis.

New global laboratory procedures mimicking the in vivo hemostasis process led to the changing paradigm of cirrhosis from the prototype of hemorrhagic diseases to a condition in which hemostasis is normal but fragile, thus justifying the hemorrhagic/thrombotic tendencies that affect these patients. The new paradigm was instrumental to change the management of cirrhosis. For example, international guidelines warn against the entrenched practice of testing patients with conventional hemostasis tests and infusing those with abnormalities with fresh-frozen plasma, coagulation factor concentrates, or platelets, prior to surgery/invasive procedures. These recommendations are, however, largely disattended. The practice of testing patients with the prothrombin time or viscoelastometry and using arbitrary cutoffs to make decisions on perioperative prophylaxis is still common and probably driven by medicolegal issues. There is no doubt that prothrombin time and congeners tests are unable to predict bleeding in cirrhosis. However, it cannot be excluded that some tests may be useful in patients who are severely decompensated. Large prospective collaborative studies are warranted. Enrolled patients should be randomized to receive perioperative prophylaxis based on laboratory testing (eg, viscoelastometry, thrombomodulin-modified thrombin generation) or to usual care. However, for these trials to be useful, a third group of patients who do not receive prophylaxis should be included. In conclusion, until results from these studies are available, physicians attending cirrhosis should refrain from using laboratory tests with arbitrary cutoffs to make decision on perioperative prophylaxis. Decision should be made by considering the clinical history of individual patients and the risk of hemorrhage of specific procedures.

Residual burden of liver disease after HCV clearance in hemophilia: a word of caution in the era of gene therapy.

Ruling out advanced fibrosis/cirrhosis is mandatory for persons with hemophilia (PWH) who are candidates for gene therapy. However, clinical evaluation and noninvasive tests (NITs) may be inaccurate after hepatitis C virus (HCV) clearance. We conducted a prospective hepatological screening to detect advanced fibrosis/cirrhosis in PWH after HCV clearance. Any risk factor of chronic liver damage was registered by using biochemical data, liver stiffness measurement (LSM), and ultrasound (US). A pre/post-HCV clearance analysis was conducted prospectively in a subgroup of patients who underwent LSM, US, and NITs for fibrosis. We evaluated 119 patients (median age, 53 years; range, 36-87 years) with a previous HCV infection (hemophilia A, n = 108; hemophilia B, n = 11). Ninety-six (81%) presented at least 1 potential risk factor of chronic liver damage. Metabolic risk factors were the most prevalent, with 51 patients (44%) having US steatosis. In 21 patients (18%), clinical, biochemical, liver morphology, and/or LSM were suggestive of advanced fibrosis/cirrhosis. Furthermore, 10 patients (8%) had esophageal varices and 3 (3%) had hepatocellular carcinoma. In 57 patients included in the prospective analysis, LSM and NITs were reduced after HCV clearance (P < .05), but US signs specific of cirrhosis remained unchanged. Overall, 23 of 80 patients (29%) with LSM <10 KPa had at least 1 US sign suggestive of advanced fibrosis/cirrhosis. A similar proportion (18%) was observed for LSM <8 KPa. Overall, risk factors of chronic liver damage are frequent after HCV clearance, but changes in LSM and NITs after clearance may be inaccurate to rule out advanced fibrosis/cirrhosis. A specific diagnostic workup is warranted to evaluate liver health in PWH in the era of gene therapy.

Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia.

Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg/kg one i.p. dose) or saline in two experimental protocols­placebo (vehicle) and simvastatin (25 mg/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p < 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia

Decompensation in Direct-Acting Antiviral Cured Hepatitis C Virus Compensated Patients With Clinically Significant Portal Hypertension: Too Rare to Warrant Universal Β-Blocker Therapy.

Nonselective ß-blockers improve decompensation-free survival in viremic hepatitis C virus compensated cirrhotic patients with clinically significant portal hypertension, but their protective role after sustained virological response by direct-acting antiviral (DAA) is undefined. We evaluated the incidence of decompensation in DAA-cured Child-A patients without high-risk varices. During the 49-month (12-60) follow-up, only one of 148 patients decompensated (ascites), with a 4-year cumulative risk of 1%, but decompensation was associated with hepatocellular carcinoma. The risk of decompensation in DAA cured hepatitis C virus compensated Child-A cirrhotic patients with clinically significant portal hypertension but without high-risk varices is negligible; thus, questioning the need for nonselective ß-blocker treatment in this setting (see Visual abstract, Supplemental Digital Content, 1, http://links.lww.com/AJG/B861). JOURNAL/ajgast/04.03/00000434-202106000-00035/inline-graphic1/v/2021-05-28T144026Z/r/image-tiff.

Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort.

BACKGROUND & AIMS: Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. METHODS: This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. RESULTS: One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23-37%) on US and 47.7% (95% CI 39-56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38-62%) and 85.3% (95% CI 75-92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. CONCLUSION: While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. LAY SUMMARY: Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

Evaluation of three "beyond Baveno VI" criteria to safely spare endoscopies in compensated advanced chronic liver disease.

BACKGROUND: Liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm3 exclude varices needing treatment (VNT) in viral compensated advanced chronic liver disease (cACLD), saving-up to 20-25% endoscopies (Baveno VI criteria). Refinements of such criteria to further reduce endoscopies and an approach without LSM (Platelet 150/MELD 6) were later proposed. AIMS: To assess LSM 25/platelet 125, LSM 25/platelet 110 (Expanded-Baveno VI) and Platelet 150/MELD 6 accuracy versus Baveno VI criteria, and the impact of platelet count variability on criteria accuracy in all-etiologies cACLD. METHODS: cACLD patients undergoing screening endoscopy with laboratory data within 6 months and LSM within one year. RESULTS: Of 442 patients, 31% had varices (7% with VNT). Baveno VI criteria had 100% sensitivity (Se) and negative predictive value (NPV) and spared 19.5% endoscopies. "LSM 25/platelet 125" and "Expanded-Baveno VI" criteria maintained such accuracy, sparing 15% and 24% more endoscopies, respectively (p < 0.001). Platelet 150/MELD 6 was less accurate, misclassifying 10% VNT. Platelet count variability exceeded 8% and one VNT patient was misclassified with both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria considering the previous platelet count. CONCLUSIONS: Both "Expanded-Baveno VI" and "LSM 25/platelet 125" criteria are accurate in cACLD, but the former are more advantageous. Platelet 150/MELD 6 proved inadequate.

Multimodality treatment of hepatocellular carcinoma: How field practice complies with international recommendations.

BACKGROUND: Management of hepatocellular carcinoma (HCC) is framed within standardized protocols released by Scientific Societies, whose applicability and efficacy in field practice need refining. AIM: We evaluated the applicability and effectiveness of guidelines for the treatment of HCC of the American Association for the Study of the Liver (AASLD). METHODS: 370 consecutive cirrhotic patients with de novo HCC in different stages, 253 BCLC A, 66 BCLC B, 51 BCLC C received treatment through a multidisciplinary team (MDT) decision and were followed until death or end of follow-up. RESULTS: Treatment was adherent to AASLD recommendations in 205 (81%) BCLC A patients, 36 (54%) BCLC B, and 27 (53%) BCLC C. Radiological complete response was achieved in 165 (45%) patients after the first-line treatment, in 22 (19%) after a second-line and in 9 (23%) after a third-line treatment. Adherence to AASLD recommendation allowed a lower yearly mean mortality rate in BCLC A patients compared with other treatment (5.0% vs 10.4% P = .004), whereas upward treatment stage migration compared with the standard of care was associated with reduced yearly mortality in BCLC B (8.6% vs 20.7%, P = .029) and BCLC C (42.6% vs 59.0%, P = .04) patients. CONCLUSIONS: HCC multimodality treatment including other than first-line therapy is common in clinical practice and impact on the achievement of complete response. Personalized treatment was able to provide survival benefits to patients whose profile is not accounted for by international recommendations, which need to be amended.

Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis.

BACKGROUND & AIMS: Vitamin K antagonists (VKAs) promote recanalization of portal vein thrombosis (PVT) in patients with cirrhosis. However, the benefit of PVT recanalization might be offset by major and minor bleeding associated with use of anticoagulants. We evaluated harmful and beneficial effects of VKA in patients with PVT and cirrhosis. METHODS: We performed a retrospective study of 63 consecutive patients with cirrhosis given anticoagulants for the first detection of non-neoplastic PVT from 2003 to 2015 in Italy. We collected data on bleeding events in these patients and compared them with those from patients without cirrhosis with venous thromboembolism (VTE) (n = 160) for up to 4 years. Time in the therapeutic range, based on the international normalized ratio, was used to determine the quality of anticoagulation. We also collected data from 139 patients with cirrhosis who did not receive VKAs (controls), to analyze portal hypertension-related events. We performed survival analyses to determine the effects of VKA in patients with PVT vs controls. RESULTS: The group with VTE and the group with PVT were comparable in age, sex, and time in the therapeutic range, but patients with VTE received VKAs for a longer time period (31.1 ± 16.9 mo vs 23.3 ± 16.2 mo; P = .002). The incidence of major or minor bleeding was higher in patients with PVT than patients with VTE (major, 24% vs 7%; P = .012; minor, 29% vs 19%; P = .024). Patients with PVT had a higher rate of major bleeding from the upper-gastrointestinal tract than patients with VTE (P = .019), but there were no significant differences in other types of major bleeding (P = .376). Patients with PVT and controls had the same rate of upper-gastrointestinal bleeding. Complete recanalization in patients with PVT receiving VKA (n = 31) was independently associated with increased portal hypertension-related event-free and transplantation-free survival times. CONCLUSIONS: In a retrospective analysis of 63 patients with cirrhosis given anticoagulants for PVT, we found VKA use to increase risk of minor bleeding, compared with patients without cirrhosis given VKA. However, this risk is offset by the ability of VKA to increase portal hypertension-related, event-free, and transplantation-free survival of patients with PVT recanalization. Portal hypertension, rather than anticoagulants, could account for the difference in risk of major bleeding between patients with PVT vs patients with VTE.

The impact of infection by multidrug-resistant agents in patients with cirrhosis. A multicenter prospective study.

BACKGROUND & AIMS: Bacterial strains resistant to antibiotics are a serious clinical challenge. We assessed the antibiotic susceptibility of bacteria isolated from infections in patients with cirrhosis by a multicentre investigation. RESULTS: Three hundred and thirteen culture-positive infections (173 community acquired [CA] and 140 hospital acquired [HA]) were identified in 308 patients. Urinary tract infections, spontaneous bacterial peritonitis and bacteremias were the most frequent. Quinolone-resistant Gram-negative isolates were 48%, 44% were extended-spectrum beta-lactamase producers and 9% carbapenem resistant. In 83/313 culture-positive infections (27%), multidrug-resistant agents (MDRA) were isolated. This prevalence did not differ between CA and HA infections. MDRA were identified in 17 of 37 patients on quinolone prophylaxis, and in 46 of 166 not on prophylaxis (45% vs 27%; P<.03). In 287 cases an empiric antibiotic therapy was undertaken, in 37 (12.9%) this therapy failed. The in-hospital mortality rate of this subset of patients was significantly higher compared to patients who received an effective broad(er)-spectrum therapy (P=.038). During a 3-month follow-up, 56/203 culture-positive patients (27.6%) died, 24/63 who have had MDRA-related infections (38%) and 32/140 who have had antibiotic-susceptible infections (22.8%) (P=.025). Multivariate analysis disclosed MDRA infection, age, hepatocellular carcinoma, bilirubin, international normalized ratio and the occurrence of portal hypertension-related complications independent predictors of death. CONCLUSIONS: Infection by MDRA is frequent in patients with cirrhosis and the prognosis is severe, especially in patients unresponsive to empiric antibiotic therapy.

Determinants of esophageal varices bleeding in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIMS: Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), yet treatment safety may be challenged by portal hypertension. We therefore assessed the prevalence, risk factors and clinical consequences of esophageal varices (EVs) in sorafenib-treated patients with HCC. METHODS: Starting in 2008, all compensated patients with advanced or intermediate HCC not eligible for other therapies were consecutively enrolled in a prospective evaluation of sorafenib therapy, all with pretreatment by upper-gastrointestinal endoscopy (UGE). RESULTS: A total of 150 patients received sorafenib for 4.6 (95% CI, 3.3-5.6) months. At baseline, 61 (41%) patients were EV free (group A), 78 (52%) had EVs (61 small EVs (group B), 17 medium/large EVs (group C)) and 11 (7%) previously endoscopically treated EVs (group D). Propranolol was given to all patients with medium/large EVs and those with previous bleeding. Twelve patients (8%) bled from EVs after 36 (18-260) days of sorafenib. During sorafenib, bleeding occurred in six of 26 group B patients with neoplastic portal vein thrombosis (nPVT), three of nine group C patients with nPVT, two of five group D patients with nPVT and one of six without nPVT (p < 0.0001), nPVT being the strongest independent predictor of bleeding by multivariate analysis (HR = 15.4, 95% CI 1.84-129.6). CONCLUSION: UGE screening is worthwhile in HCC patients allocated to sorafenib since it identifies patients with EVs at risk of bleeding during therapy, particularly those with nPVT.

Transarterial chemoembolization with drug-eluting beads is effective for the maintenance of the Milan-in status in patients with a small hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the standard of care for the treatment of patients with an intermediate (Barcelona Clinic Liver Cancer [BCLC] B) hepatocellular carcinoma and to bridge patients with an early cancer to liver transplantation (LT). We explored the efficacy of TACE with drug-eluting beads (DEB) in BCLC A patients. Included are all BCLC A patients unsuitable for resection or locoregional ablation who underwent a DEB TACE between 2006 and 2012. Treatment was carried out "a la demande" until complete tumor devascularization or progression beyond Milan criteria. In patients with a complete response (CR), a contrast computed tomography (CT) scan was repeated at 3-month intervals during the first 2 years and then every 6 months alternating with abdominal ultrasound in the subsequent 3 years. Fifty-five patients had 79 tumor nodules ranging 7 to 50 mm; 32 (58%) achieved a CR that was maintained up to 4 and 7 months in 21 (38%) and 17 (31%) patients, respectively. The 24- and 36-month tumor-free survivals were 21% and 9%, respectively. The overall cumulative progression beyond Milan criteria at 3, 6, 12, and 24 months was 2%, 5%, 30%, and 54%. LT eligibility was maintained for a median of 19 months (range, 2-63 months). CR to first TACE was the strongest independent predictor of Milan-in maintenance. In conclusion, DEB TACE may effectively bridge patients with an early cancer to LT, and a CR to the first procedure may guide patient prioritization during the waiting list.

Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma.

BACKGROUND: Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established. METHODS: In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation. RESULTS: Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb- patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine. DISCUSSION: This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation.

SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells.

BACKGROUND: The poor response to antiviral treatment of hepatitis C virus (HCV)-infected patients with genotype 1b has been associated with a higher prevalence of metabolic syndrome. However, the molecular link between these clinical entities is not clear. The goal of this study was to clarify the role of genotype 1b and 2 in the genetic expression of suppressor of cytokine signaling 3 (SOCS3) and insulin receptor substrate 1 (IRS-1). METHODS: We infected human hepatocellular carcinoma cell line (HepG2) cells with human HCV genotype 1b or 2 and measured the gene and protein expression of SOCS3 at various times. We also evaluated impairment in the insulin pathway by analysis of IRS-1 and phospho-AKT. For the control, we used HepG2 cell cultures treated with non-infectious serum. We also demonstrated the occurrence of HCV infection by the detection of both positive and negative strands in the cells and culture medium. To test infection of the HepG2 cells, we performed quantitative real-time polymerase chain reaction (qRT-PCR) of viral load at different time points. We analyzed the viral genotype in the pellet and supernatant. RESULTS: At each time point, we found positive and negative strands in the infected cells, while in the medium we found positive, but no negative strands. We also detected the presence of the correct genotype in the medium. Two weeks following infection when the viral load was higher, we tested genotype 1b and 2 infected cells. SOCS3 gene expression was significantly higher in genotype 1b-infected cells (median 2.56; mean 2.82+/-0.59) compared with genotype 2 (median 1.34; mean 1.46+/-0.31) (p=0.04) and control cells (median 1.09; mean 1.02+/-0.11, p=0.02). There was no difference between cells exposed to genotype 2 and control cells. Conversely, IRS-1 was significantly lower in genotype 1b-infected cells (median 15.97; mean 15.45+/-0.67) compared with genotype 2-infected cells (median 16.45; mean 16.44+/-0.01, p=0.04). Statistically significant differences were seen when comparing the pAKT/AKT ratio in genotype 1b-infected cells (0.19+/-0.034) and not genotype 1b-infected (genotype 2-infected and non-infected) cells (0.253+/-0.004, p=0.03). This inverse regulation is compatible with interactions between the molecular expression of SOCS3, IRS-1 and phospho-AKT mediated by the genotype 1b virus. CONCLUSIONS: Up-regulation of the SOCS3 gene might be one of the mechanisms governing non-response to therapy and expression of insulin resistance mediated via a direct mechanism at this level of genotype 1b HCV.

Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities.

AIM: To investigate the prevalence of the clinical parameters of insulin resistance and diabetes in patients affected by chronic hepatitis C (CHC) or chronic hepatitis B (CHB). METHODS: We retrospectively evaluated 852 consecutive patients (726 CHC and 126 CHB) who had undergone liver biopsy. We recorded age, sex, ALT, type 2 diabetes and/or metabolic syndrome (MS), body mass index (BMI), and apparent disease duration (ADD). RESULTS: Age, ADD, BMI, prevalence of MS and diabetes in patients with mild/moderate liver fibrosis were significantly higher in CHC. However, the degree of steatosis and liver fibrosis evaluated in liver biopsies did not differ between CHC and CHB patients. At multivariate analysis, age, sex, BMI, ALT and diabetes were independent risk factors for liver fibrosis in CHC, whereas only age was related to liver fibrosis in CHB. We also evaluated the association between significant steatosis (>30%) and age, sex, BMI, diabetes, MS and liver fibrosis. Diabetes, BMI and liver fibrosis were associated with steatosis >30% in CHC, whereas only age and BMI were related to steatosis in CHB. CONCLUSION: These data may indicate that hepatitis C virus infection is a risk factor for insulin resistance.

Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin's lymphoma.

BACKGROUND/AIMS: Prevalence of HCV infection in non-Hodgkin's lymphoma is high. The impact of antiviral therapy on the natural history of this subgroup of lymphomas after a successful chemotherapy regimen is still an argument of debate. METHODS: We retrospectively examined 343 chemotherapy-treated patients referred to our centre for five consecutive years. Clinical and histological characteristics, disease free-survival (DFS) and overall-survival (OS) were compared in HCV-positive (69/343) and HCV-negative (274/343) patients. Twenty-five HCV-positive patients received antiviral treatment following chemotherapy discontinuation. Uni- and multivariate analyses were performed. RESULTS: 20% of lymphomas were HCV-positive. Indolent histology was prevalent in the HCV-positive group (p<0.05); no significant differences in OS or DFS were found between the two groups; in HCV-positive subjects, antiviral therapy, was associated with a longer DFS (p<0.05); none of the HCV-positive subjects who achieved a virological response experienced any lymphoma relapse; 29% of non responders did; at multivariate analysis, the independent factors related to a better clinical outcome were: indolent histology at the onset of lymphoma and antiviral therapy. CONCLUSIONS: Antiviral treatment in HCV-positive non-Hodgkin's lymphoma may be an important strategy to reinforce the results of a successful chemotherapy regimen; further studies are needed to validate this combined approach.

Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy.

UNLABELLED: The response to antiviral therapy is lower in hepatitis C virus (HCV) patients with genotype 1 than in those with genotype 2. Overexpression of the suppressor of cytokine signaling 3 (SOCS3) gene in liver tissue is associated with a poorer treatment outcome in patients with chronic hepatitis C viral genotype 1. Also, insulin resistance has been implicated in nonresponse to an anti-HCV treatment. To understand why HCV genotype 1 patients respond differently, we investigated SOCS3 gene expression, metabolic syndrome (MS), and the response to therapy in a cohort of patients with HCV-related hepatitis. A total of 198 patients (108 with genotype 1 and 90 with genotype 2) treated with pegylated interferon plus ribavirin were consecutively enrolled in the study. We measured SOCS3 expression in Epstein-Barr virus-transformed lymphoblastoid cell lines derived from peripheral lymphocytes of a subset of 130 patients. MS was more frequent in genotype 1 patients than in genotype 2 patients (P < 0.01). Nonresponders (P < 0.01), MS (P < 0.001), and genotype 1 (P < 0.001) were significantly related to SOCS3 overexpression. However, SOCS3 levels were higher in nonresponders also, regardless of the genotype (P < 0.01). In a univariate analysis, the genotype (P < 0.001), age (P < 0.001), SOCS3 (P < 0.001), and MS (P < 0.001) were significantly related to the response to therapy. However, in a multivariate analysis, SOCS3 was the only independent predictor of the response (odds ratio = 6.7; P < 0.005). CONCLUSION: We speculate that SOCS3 expression per se may influence the response to antiviral therapy and that the genotype 1b virus might induce its up-regulation. This may account for the different responses to therapy between genotype 1-infected and genotype 2-infected patients.