Long-term effects of the new direct antiviral agents (DAAs) therapy for HCV-related mixed cryoglobulinaemia without renal involvement: a multicentre open-label study.

OBJECTIVES: To investigate the long-term effects and safety of new direct anti-viral agents (DAAs) in patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC) without renal involvement. METHODS: The study enrolled 22 consecutive patients, 19 received sofosbuvir-based regimen and three patients received other DAAs, individually tailored according to latest guidelines. As of December 2016, the median length of follow-up was 17 months (range 13-21). RESULTS: Extra-hepatic manifestations at enrollment were: purpura and arthralgia (12 cases), peripheral neuropathy (10 cases) and marginal zone B- lymphomas (2 cases). After a four-week DAA therapy, all patients became HCV- negative. Moreover, after 48 weeks since the beginning of DAA treatment, sustained regression of purpura and arthralgias was observed respectively in eight and in nine cases; peripheral neuropathy improved in seven cases, and cryocrit median values decreased from three (1-20) at baseline to two (1-12) after 48 weeks. Two cases with indolent marginal zone lymphomas did not show any haematological response: size and number of the involved nodes remained unchanged. In addition, the monoclonal B-cell population found in the peripheral blood in four cases did not disappear after recovery from HCV- RNA. Mild side effects occurred in nine patients, but six patients developed ribavirin-related anaemia requiring reduction of ribavirin dose. CONCLUSIONS: DAA therapy is safe and effective to eradicate HCV in MC, but seems associated with satisfactory clinical response in mild or moderate cryoglobulinaemic vasculitis and no response in B-NHL.

HCV-related liver and lymphoproliferative diseases: association with polymorphisms of IL28B and TLR2.

To explore the relationship between innate immunity and hepatitis C Virus (HCV) in determining the risk of cirrhosis (CIR), hepatocellular carcinoma (HCC), mixed cryoglobulinemia syndrome (MCS) and non-Hodgkin lymphoma (NHL), we investigated the impact of the toll-like receptor-2 (TLR2) and interleukin-28B (IL28B) genetic variants. TLR2 -174 del variant was associated with TLR2 expression and with specific downstream molecules that drive the expression of different interleukins; rs12979860 Il28B was important in response to interferon-treatment and in spontaneous clearance of HCV. The risk for liver and lymphoproliferative diseases in HCV progression was clarified by stratifying 862 HCV-positive patients into groups based on liver (CIR, HCC) and lymphoproliferative HCV-related diseases (MCS, NHL) and compared with chronic HCV (CHC) infection. Analysis of TLR2-IL28B haplotypes showed an association of wild type haplotype with the lymphoproliferative diseases (OR 1.77, p = 0.029) and a slight increase in HCV viral load (HR 1.38, p = 0.054). Wild type haplotype (TLR2 ins/ins- IL28B C/C) was also found associated with older age in patients with an hepatic diseases (in CIR and in HCC p = 0.038 and p = 0.020, respectively) supporting an effect of innate immunity in the liver disease progression. TLR2 and IL28B polymorphisms in combination showed a role in the control of HCV viral load and different HCV disease progression.

Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC.

BACKGROUND: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined. AIMS: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored. METHODS: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled. RESULTS: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis. CONCLUSION: NUC therapy appeared to be safe and effective in CV-related HBV.

Impact of immunogenetic IL28B polymorphism on natural outcome of HCV infection.

With the aim of investigating whether interleukin 28B gene (IL28B) rs1297860 polymorphism is associated with different hepatitis C (HCV) infection statuses, we compared IL28B allelic distribution in an Italian case series of 1050 patients with chronic infection and different outcomes, 47 individuals who spontaneously cleared HCV, and 178 blood donors. Furthermore, we compared IL28B variants among 3882 Caucasian patients with chronic infection, 397 with spontaneous clearance, and 1366 blood donors reported in PubMed. Overall data confirmed a relation between IL28B C allele and HCV spontaneous clearance. Furthermore, we found that IL28B T allele had a weak relation with chronic HCV progression to hepatocellular carcinoma. Study findings are in accordance with the hepatocellular carcinogenic model where IL28B TT genotype, by promoting a persistent chronic hepatitis which leads to both hepatocyte injury and chronic inflammation, could facilitate HCC development. Conversely, patients with lymphoproliferative disorders had not any significantly different IL28B rs1297860 allelic distribution than those with chronic HCV, but, like all chronic HCV-related diseases, they showed a lower CC frequency than patients who spontaneously cleared HCV. Study results confirmed the model of persistent HCV infection as a risk factor for the pathogenesis of both liver and lymphoproliferative disorders.

Alcohol and HCV chronic infection are risk cofactors of type 2 diabetes mellitus for hepatocellular carcinoma in Italy.

Type 2 diabetes mellitus (DM2) has been associated with hepatocellular carcinoma (HCC) development. To study this relationship, we enrolled 465 HCC patients compared with 618 Cirrhotic cases and 490 Controls. The prevalence of DM2 is significantly higher in HCC patients with an Odds Ratio of 3.12 versus Controls. In HCC cases with alcohol abuse, the frequency of DM2 is the highest. In our HCC patients, when HCV infection is associated with alcohol abuse, the liver cancer develops earlier. In addition, multivariate analysis shows that alcohol consumption is an independent risk factor for HCC more relevant than HCV infection.

Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease.

BACKGROUND: Previous studies have reported the association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). AIMS: To explore the relationships among DM2, antidiabetic therapy and HCC risk. METHODS: We recruited 610 HCC patients compared with 618 matched cirrhotic patients and 1696 Controls. The odds ratio (OR) for HCC in diabetic subjects treated with insulin, sulphonylureas and metformin was calculated. RESULTS: DM2 prevalence was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in Controls (P<0.0001). The OR for HCC in diabetic HCC patients vs Controls was 3.12 [confidence interval (CI) 2.40-3.90; P<0.001] in univariate analysis and 2.50 (CI 1.70-3.69; P<0.0001) in multivariate analysis. Comparing diabetic HCC patients vs liver cirrhosis (LC) cases, univariate analysis showed an OR for HCC of 2.09 (CI 1.50-2.90; P<0.001), whereas on multivariate analysis we found an OR of 1.46 (CI 1.07-1.98; P=0.02). In 84% of the cases, type 2 diabetes mellitus has been present before the HCC diagnosis. Multivariate analysis showed that metformin treatment was associated with a strong and statistically significant reduction of the risk of HCC, as compared with the use of sulphonylureas or insulin, in diabetic HCC patients vs Controls and vs LC cases (OR of 0.15; CI 0.04-0.50; P=0.005 and OR=0.16; CI 0.06-0.46; P=0.0006 respectively). CONCLUSIONS: Our study shows that DM2 is an independent risk factor for HCC and pre-exists to HCC occurrence. In DM2 patients with HCC, metformin therapy is associated with a reduced HCC risk and seems to have a protective effect on HCC development.

Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease.

AIM: To explore the association between hepatocellular carcinoma (HCC) and type 2 diabetes mellitus, describe the temporal relations between the onset of diabetes and the development of HCC and evaluate the possible effects of antidiabetic therapy on HCC risk. METHODS: We recruited 465 HCC patients, 618 with cirrhosis and 490 control subjects. We evaluated the odds ratio (OR) for HCC by univariate and multivariate analysis. Moreover, OR for HCC in diabetic subjects treated with insulin or sulphanylureas and with metformin were calculated. RESULTS: The prevalence of diabetes mellitus was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in the Control group. By univariate and multivariate analysis, the OR for HCC in diabetic patients were respectively 3.12 (CI 2.2-4.4, P < 0.001) and 2.2 (CI 1.2-4.4, P = 0.01). In 84.9% of cases, type 2 diabetes mellitus was present before the diagnosis of HCC. Moreover, we report an OR for HCC of 2.99 (CI 1.34-6.65, P = 0.007) in diabetic patients treated with insulin or sulphanylureas, and an OR of 0.33 (CI 0.1-0.7, P = 0.006) in diabetic patients treated with metformin. CONCLUSION: Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.

Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin.

AIM: To investigate the relationships between Type 2 diabetes mellitus (DM2) and the risk of hepatocellular carcinoma (HCC). METHODS: We studied the association between DM2 and HCC in a large case-control study that enrolled 465 consecutive Caucasian patients with HCC (78.3% males, mean age 68.5 +/- 8.9 years) compared with an age and sex matched control group of 490 subjects. RESULTS: Prevalence of DM2 was significantly higher in HCC patients (31.2% vs 12.7%; OR = 3.12, 95% CI: 2.22-4.43) and in HCC cases with alcohol abuse. DM2 has been diagnosed before the appearance of HCC in 84.1% of diabetic HCC subjects with mean duration of 141.5 mo, higher in cases treated with insulin than in those with oral antidiabetic agents (171.5 vs 118.7 mo). Compared to controls, males DM2 with HCC were more frequently treated with insulin (38.1% vs 17.6%, P = 0.009) and with sulfonylurea with or without metformin than with diet with or without metformin (84% vs 68.3%, P = 0.049). CONCLUSION: DM2 in our patients is associated with a 3-fold increase risk of HCC. In most of our cases DM2 pre-existed to HCC. Patients with DM2 and chronic liver disease, particularly insulin treated males, should be considered for HCC close surveillance programs.

Coffee and tea consumption and risk of hepatocellular carcinoma in Italy.

The role of coffee in the aetiology of hepatocellular carcinoma has raised great interest. In Italy, coffee consumption is high, thus allowing the investigation of the topic over a broad range of consumption. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 incidents, histologically confirmed cases of hepatocellular carcinoma aged 43-84 years. Controls were 412 subjects admitted to the same hospitals' networks for acute, non-neoplastic diseases unrelated to diet. Coffee and tea consumption were assessed using a validated food-frequency questionnaire. Odds ratios (ORs) and corresponding the 95% confidence intervals (CI) were computed using unconditional multiple logistic regression, adjusting for hepatitis viruses seropositivity, alcohol intake, smoking habits and other potential confounding factors. Compared to people who drunk <14 cups/week of coffee, the risk of hepatocellular carcinoma decreased for increasing levels of consumption (OR=0.4, 95% CI: 0.2-1.1 for >or=28 cups/week, p for trend = 0.02). In the present study, inverse relations were observed across strata of hepatitis C and, B virus infections and alcohol drinking. No significant association emerged with consumption of decaffeinated coffee (OR=0.7, 95% CI=0.2-2.5) or tea (OR=1.4, 95% CI=0.8-2.7). The present study supports the hypothesis of a favourable effect of coffee, though not decaffeinated coffee and tea, on the risk on hepatocellular carcinoma.

Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy.

Mortality rates of hepatocellular carcinoma (HCC) are high in Italy compared with other Western countries. To elucidate further the role of hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol drinking, and tobacco smoking in the etiology of HCC, we carried out a hospital-based case-control study in two areas of Italy: the province of Pordenone in the Northeast and the town of Naples in the South. A total of 229 HCC cases (median age, 66 years) and 431 controls (median age, 65 years) answered a questionnaire and provided blood samples between 1999 and 2002. Odds ratios (OR), percent attributable risks, and corresponding 95% confidence intervals were computed using unconditional multiple logistic regression. ORs for hepatitis B surface antigen (HBsAg) positive versus HBsAg negative and for anti-HCV antibody positive versus anti-HCV antibody negative were 20.2 and 15.6, respectively. Positivity for both markers was associated with an OR of 51.6. Sensitive molecular techniques applied to sera in a subset of HCC cases disclosed a very small number of occult hepatites. Maximal lifetime alcohol intake of > or =35 versus <7 drinks/wk was associated with an HBV/HCV adjusted OR of 5.9. Tobacco smoking was unrelated to HCC risk overall but seemed to enhance HCC risk among virus carriers. Overall, 61% of HCC were attributable to HCV, 13% to HBV, and 18% to heavy alcohol drinking. In conclusion, our study confirms the importance of HCV in HCC etiology in Italy where the widespread dissemination of the virus dates back four or five decades.