M. Russello

Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease

Background Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and associated with obesity and insulin resistance. We aimed to evaluate the prevalence of GD in a cross sectional study of NAFLD patients and to define whether the presence of GD is associated with diabetes and predicts more severe liver disease. Methodology/Principal Findings We merged databases of four Liver Units, comprising 524 consecutive biopsy-proven NAFLD (373 males) observed between January 2003 and June 2010. GD was diagnosed in 108 (20%), and 313 cases (60%) were classified by liver biopsy as nonalcoholic steatohepatitis (NASH). The GD subgroup was characterized by a significantly higher prevalence of females, prediabetes/diabetes, abdominal obesity and metabolic syndrome, older age, higher BMI, fasting glucose, HOMA-IR and lower ALT. The prevalence of GD progressively increased with advancing fibrosis and with the severity of necroinflammatory activity (p for trend  = 0.0001 and  = 0.01, respectively), without differences in the severity of steatosis. At multivariate analysis GD was associated with female gender (OR 1.37, 95% CI 1.04–1.8), age (OR 1.027, 95% CI1.003–1.05), fasting glucose (OR 1.21, 95% CI 1.10–1.33) and NASH (OR 1.40,95% CI 1.06–1.89), whereas ALT levels were associated with a lower GD risk (OR 0.98, 95% CI 0.97–0.99). When subjects with cirrhosis were excluded from analysis, the association between GD and fasting glucose, female gender, and NASH was maintained. Conclusion Patients with NAFLD have a high prevalence of GD, which characterizes subjects with altered glucose regulation and more advanced liver disease.

Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study

Data on HCV‐related hepatocellular carcinoma (HCC) early recurrence in patients whose HCC was previously cured, and subsequently treated by direct‐acting antivirals (DAAs), are equivocal.

Current practice of chronic hepatitis B treatment in Southern Italy.

BACKGROUND Treatment choice for chronic HBV infection is a continuously evolving issue, with a wide range of options. We aimed to evaluate the current practice of HBV therapies in the real world in Southern Italy. METHODS A prospective study enrolling over a six month period (February-July 2010) all consecutive HBsAg positive subjects, never previously treated, referred to 16 liver units in two Southern Italy regions (Calabria and Sicily). RESULTS Out of 247 subjects evaluated, 116 (46.9%) had HBV-DNA undetectable or lower than 2000 UI/ml. There were 108 (43.7%) inactive carriers, 103 (41.7%) chronic hepatitis, and 36 (14.6%) liver cirrhosis. Antiviral treatment was planned in 94 (38.0%) patients (26 cases with Interferon or Pegylated Interferon and 68 with nucleos(t)ides analogues). As many as 49.5% of subjects with chronic hepatitis did not receive antiviral treatment. DISCUSSION The majority of chronic HBsAg carrier referring centres for evaluation were not considered suitable for antiviral treatment. Nucleos(t)ides analogues are the preferred first choice for therapy. A long-lasting period of observation may be needed to make appropriate therapeutic decisions in several cases.

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity

BACKGROUND & AIMS: Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS: We performed a retrospective cohort study of 669 consecutive patients with biopsy‐proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima‐media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94–102 cm, women 80–88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single‐nucleotide polymorphisms. Variables in men and women were analyzed using chi‐squared analysis and the Mann–Whitney or Kruskal–Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. RESULTS: Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima‐media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2–106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4–4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. CONCLUSIONS: In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.

Current practice of hepatitis C treatment in Southern Italy

BACKGROUND Only a small proportion of subjects referring to hospitals for hepatitis C virus (HCV) positivity receives antiviral therapy. AIM To evaluate the rate of antiviral treatment and the causes for no treatment in HCV-RNA positive subjects seen in hospital settings. PATIENTS AND METHODS A prospective study enrolling over a 6-month period (February-July 2009) all consecutive anti-HCV positive subjects initially referred (naïve patients) to 12 liver units in Southern Italy for HCV treatment. RESULTS Out of 608 subjects evaluated, 74 (12.2%) had no detectable HCV-RNA in the serum and thus were excluded. Of the remaining 534 HCV-RNA positive subjects, 357 (66.9%) were not treated for the following reasons: 49.9% were older than 65 years of age (75% of them >70 years), 14.3% had normal liver enzymes, 13.2% had compensated/decompensated cirrhosis, 10.4% refused treatment, 9.8% had ongoing substance or alcohol abuse. Multivariate analysis showed that females (O.R. 2.27; C.I. 95% 1.05-4.90) and subjects with low educational level (O.R. 4.38; C.I. 95% 1.27-15.11) were more likely to decline therapy. CONCLUSIONS The majority of patients with HCV infection does not receive antiviral treatment. The effectiveness of the current standard therapy for HCV infection is low despite its good efficacy.

Dual therapy with peg-interferon and ribavirin in thalassemia major patients with chronic HCV infection: Is there still an indication?

BACKGROUND Iron overload and hepatitis C virus (HCV) infection together can lead to chronic liver damage in thalassemia major (TM) patients. AIMS We investigated viral, genetic, and disease factors influencing sustained virological response (SVR) after peg-interferon and ribavirin therapy in TM patients with HCV infection. METHODS We analyzed 230 TM patients with HCV infection (mean age 36.0±6.3 years; 59.1% genotype 1; 32.2% genotype 2; 3.4% genotype 3; and 5.3% genotype 4; 28.7% carried CC allele of rs12979860 in IL28B locus; 79.6% had chronic hepatitis and 20.4% cirrhosis; 63.5% naive and 36.5% previously treated with interferon alone) treated in 14 Italian centers. RESULTS By multivariate regression analysis SVR was independently associated with CC allele of IL28B SNP (OR 2.98; CI 95% 1.29-6.86; p=0.010) and rapid virologic response (OR 11.82; CI 95% 3.83-36.54; p<0.001) in 136 genotype 1 patients. Combining favorable variables the probability of SVR ranged from 31% to 93%. In genotype 2 patients, only RVR (OR 8.61; CI 95% 2.85-26.01; p<0.001) was associated with SVR higher than 80%. In 3 patients with cirrhosis a decompensation of liver or heart disease were observed. Over 50% of patients increased blood transfusions. CONCLUSION Dual therapy in TM patients with chronic HCV infection is efficacious in patients with the best virological, genetic and clinical predictors. Patients with cirrhosis have an increased risk of worsening liver or heart disease.

Characteristics and Changes over Time of Alcohol-Related Chronic Liver Diseases in Italy

Introduction To evaluate the characteristics of alcohol-related chronic liver disease (CLD) in Italy and their potential changes over time. Patients and Methods Subjects with CLD were enrolled in two national surveys performed in 2001 and in 2014 in Italy. The two surveys prospectively recruited patients aged ≥ 18 years referring to more than 80 Italian liver units scattered all over the country using similar clinical approach, analytical methods, and threshold of risky alcohol intake definition (≥ 3 units/day in men and ≥ 2 units/day in women). Results Out of 12,256 enrolled subjects, 2,717 (22.2%) reported a risky alcohol intake. Of them, anti-HCV positive was observed in 48.3% of subjects. The overall sex ratio (M/F) was 3.1, decreasing from 3.8 in 2001 to 1.3 in 2014. Women were significantly older than men (58.9 versus 53.1 years; p < 0.01) and an increasing ageing over time was observed in both sexes. The proportion of subjects with liver cirrhosis increased over time in both sexes, and decompensated stage (Child B or C) was detected in 55.9% of cases in 2001 and 46.0% in 2014. Conclusions Risky alcohol intake plays a role in more than one-fifth of CLD in Italy, with a shift over time towards an older age and a more severe liver disease stage. These data put alcohol back in the spotlight with an important role in CLD in the years to come in Italy.

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM S. Bruno, S. Bollani, J.M. Pascasio, A.L. Zignego, V. Di Marco, C. Magni, M. Rizzetto, A. Ciancio, A. Alberti, S. Piovesan, A. Mangia, J. De la Revilla, J.R. Larrubia, F. Gea, S. Babudieri, R. Perez-Alvarez, C. Colletta, R. Barcena, X. Forns, M. Romero-Gomez, M. Koch, M. Massari, M. Caremani, J. Crespo, J.M. Navarro, J. Arenas, M.B. Delgado, M. Pirisi, M. Zuin, A. Licata, F. Mazzotta, A. Colombo, M. Russello, I. Fermandez, T. Santantonio, C.M. Fernandez-Rodriguez, F. Farina, B. Ruiz Antoran, P. Maisonneuve, A. Craxì, J.L. Calleja, Italian and Spanish (IAS)-BOC Study Group. AO Fatebenefratelli e Oftalmico, Milano, Italy; Hospital Universitario Virgen del Rocio, Sevilla, Spain; Università degli Studi di Firenze, Firenze, Università degli Studi di Palermo, Palermo, AO L Sacco, Milano, Università di Torino, Torino, Università di Padova, Padova, IRCCS Casa del Sollievo e della Sofferenza, San Giovanni Rotondo, Italy; Hospital Universitario Puerta de Hierro, Madrid, Hospital Universitario de Guadalajara, Guadalajara, Hospital U. La Paz, Madrid, Spain; Università degli Studi di Sassari, Sassari, Italy; Hospital Universitario Central de Asturias, Oviedo, Spain; COQ Ospedale Madonna del Popolo, Omegna, Italy; Hospital Universitario Ramon y Cajal, Madrid, Hospital Clinic, Barcelona, Hospital Universitario de Valme, Sevilla, Spain; AO S Filippo Neri, Roma, IRCCS – ASMN Reggio Emilia, Reggio Emilia, AO di Arezzo, Arezzo, Italy; Hospital Universitario Marques de Valdecilla., Santander, Hospital Costa del Sol, Marbella, Hospital Donostia, Donostia, Hospital Universitario A Coruña, La Coruna, Spain; Università degli Studi di Novara, Novara, Università degli Studi di Milano, Milano, Azienda Ospedaliera di Siena, Siena, AO S Anna, Como, ARNAS Garibaldi, Catania, Italy; Hospital Universitario 12 de Octubre, Madrid, Spain; Università di Foggia, Foggia, Italy; Hospital U. Fundacion Alcorcon, Alcorcon, Spain; Ospedale Cà Foncello, Treviso, Epidemiology and Biostatistics, Istituto Europeo di Oncologia, Milano, Italy E-mail: savino.bruno@fbf.milano.it