Hepatitis: Petta S

Lonardo A, Adinolfi LE, Petta S, Craxì A, Loria P. · Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy. · Expert Rev Anti Infect Ther. · Pubmed #19344243 No free full text.

Abstract: Type 2 diabetes (T2D) and HCV infection are common conditions involving, respectively, at least 170 and 130 million people worldwide. However, the distribution of such cases does not overlap in the same age groups in different geographic areas. Following pioneering reports of increased prevalence of T2D in HCV-positive cirrhosis, interest concerning the relationship between HCV and T2D has escalated. HCV is able to induce insulin resistance (IR) directly and the role of specific viral genotypes responsible for such effect is disputed. IR has consistently been found to be closely linked to fibrosis in HCV infection, although also typically associated with T2D in prefibrotic stages. HCV infection could be associated with a reduced prevalence of metabolic syndrome owing to virus-associated reduction in BMI (reported in population but not clinical studies) and hypobetaliproteinemia. A three- to ten-fold increased risk of HCV infection was reported among diabetic patients in comparison with different control groups and a meta-analysis showed a 1.8-fold excess risk of T2D among HCV-positive compared with HBV-positive patients. Moreover, HCV positivity is associated with an increased risk of T2D in patients receiving liver or kidney transplantations. T2D and IR are independent predictors of a more rapid progression of liver fibrosis and impaired response to antiviral treatment in chronic hepatitis C. Patients with cirrhosis and T2D have an increased susceptibility to hepatic encephalopathy and hepatocellular carcinoma (HCC). However, the beneficial effects of antiviral treatment on IR and T2D are controversial. Theoretically, glycemic control in chronic hepatitis C, and particularly in cirrhotic patients, could improve the prognosis and the response to antivirals, although the evidence for this is limited. Future studies should elucidate the relationship between insulin signaling, HCV and interferon signaling, entity of cardiovascular risk in patients with HCV infection, the potential role of 'metabolic' strategies added to antiviral treatment schedules, the impact of IR on liver failure, portal hypertension and HCC, particularly in patients managed in a transplant setting.

Tarantino G, Marco VD, Petta S, Almasio PL, Barbaria F, Licata A, Bosco GL, Tripodo C, Stefano RD, Craxì A. · Cattedra e Unità Operativa di Gastroenterologia, University of Palermo, Palermo, Italy. · J Viral Hepat. · Pubmed #19200135 No free full text.

Abstract: B-lymphocyte stimulator/B activating factor (BLyS/BAFF) is a tumour necrosis factor-family cytokine that plays a key role in generating and maintaining the mature B-cell pool. BLyS/BAFF expression by macrophages is stimulated by interferon-gamma and interleukin-10, and its serum levels are increased in chronic hepatitis C (CHC). The aim of this study was to assess serum levels of BLyS/BAFF in patients with acute hepatitis C (AHC) and correlate them with disease outcome. We studied 28 patients with AHC (14 males, mean age 59.3 +/- 15 years), followed for at least 7 months since onset, comparing them with 86 CHC patients and 25 healthy blood donors (HBD). BLyS/BAFF levels were assessed at baseline (within 4 weeks of onset) and during follow-up. BLyS/BAFF median levels were significantly higher in AHC (1485 pg/mL) than in CHC (1058 pg/mL) and in HBD (980 pg/mL) (P < 0.001). BLyS/BAFF levels were higher in AHC patients evolving to chronicity (1980 pg/mL) than in those with a self-limited course (1200 pg/mL), (P = 0.02). By logistic regression analysis, higher BLyS/BAFF levels were independently associated with persistence of HCV infection (OR 29.7; 95% CI: 1.73-508.20). High serum levels of BLyS/BAFF at onset of AHC can predict its evolution to chronic infection.

Cammà C, Petta S, Di Marco V, Bronte F, Ciminnisi S, Licata G, Peralta S, Simone F, Marchesini G, Craxì A. · Cattedra & Unità Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy. · Hepatology. · Pubmed #19065558 No free full text.

Abstract: Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium-large (>or=F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996-0.999) and a high HOMA-IR score (OR, 1.296; 95%CI, 1.018-1.649), not with LSM (OR, 1.009; 95%CI, 0.951-1.070). It is noteworthy that nine of ten patients with medium-large EVs had a platelet/spleen ratio of less than 792 or an HOMA-IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996-1.000), high HOMA-IR score (OR, 1.373; 95%CI, 1.014-1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects. Conclusions: In patients with Child A HCV cirrhosis, two simple, easy-to-get tests, namely the platelet/spleen ratio and insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, significantly predict the presence of EV, outweighing the contribution given by transient elastography.

Petta S, Cammà C, Di Marco V, Alessi N, Barbaria F, Cabibi D, Caldarella R, Ciminnisi S, Licata A, Massenti MF, Mazzola A, Tarantino G, Marchesini G, Craxì A. · Cattedra ed Unità Operativa di Gastroenterologia, University of Palermo, Palermo, Italy. · Hepatology. · Pubmed #18506842 No free full text.

Abstract: Retinol-binding protein 4 (RBP4) is an adipocytokine associated with insulin resistance (IR). We tested serum levels of RBP4 to assess its link with steatosis in patients with genotype 1 chronic hepatitis C (CHC) or nonalcoholic fatty liver disease (NAFLD). Nondiabetic patients with CHC (n = 143) or NAFLD (n = 37) were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR by the homeostasis model assessment. Biopsies were scored by Scheuer classification for CHC, and Kleiner for NAFLD. Steatosis was tested as a continuous variable and graded as absent-mild <30%, or moderate-severe > or =30%. Thirty nondiabetic, nonobese blood donors served as controls. RBP4 levels were measured by a human competitive enzyme-linked immunosorbent assay kit (AdipoGen). Mean values of RBP4 were similar in NAFLD and CHC (35.3 +/- 9.3 microg/L versus 36.8 +/- 17.6; P = 0.47, respectively), and both were significantly higher than in controls (28.9 +/- 12.1; P = 0.02 and P = 0.01, respectively). RBP4 was higher in CHC patients with steatosis than in NAFLD (42.1 +/- 19.7 versus 35.2 +/- 9.3; P = 0.04). By linear regression, RBP4 was independently linked to steatosis only (P = 0.008) in CHC, and to elevated body mass index (P = 0.01) and low grading (P = 0.04) in NAFLD. By linear regression, steatosis was independently linked to homeostasis model assessment score (P = 0.03) and high RBP4 (P = 0.003) in CHC. By logistic regression, RBP4 was the only variable independently associated with moderate-severe steatosis in CHC (odds ratio, 1.045; 95% confidence interval, 1.020 to 1.070; P = 0.0004), whereas waist circumference was associated with moderate-severe steatosis in NAFLD (odds ratio, 1.095; 95% confidence interval, 1.007 to 1.192; P = 0.03). CONCLUSION: In nondiabetic, nonobese patients with genotype 1 CHC, serum RBP4 levels might be the expression of a virus-linked pathway to steatosis, largely unrelated to IR.

Petta S, Cammà C, Di Marco V, Alessi N, Cabibi D, Caldarella R, Licata A, Massenti F, Tarantino G, Marchesini G, Craxì A. · Cattedra ed Unità Operativa di Gastroenterologia, University of Palermo, Palermo, Italy. · Am J Gastroenterol. · Pubmed #18477344 No free full text.

Abstract: OBJECTIVES: Metabolic factors may affect the course of chronic hepatitis C (CHC). Insulin resistance (IR) determines steatosis, but its direct role in affecting progression of hepatic fibrosis is less clear. We aimed to assess whether increasing degrees of IR, up to overt diabetes, are linked to steatosis and higher stages of fibrosis in patients with CHC resulting from genotype 1 HCV (G1-HCV). METHODS: Two hundred one consecutive patients with G1-HCV infection were evaluated by liver biopsy and anthropometric and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Nondiabetic patients were defined as insulin resistant if HOMA-IR was >2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer), and graded for steatosis. RESULTS: Ninety-six patients were noninsulin resistant (group 1), 76 were insulin resistant without diabetes (group 2), and 29 were diabetic (group 3). At multivariate analysis, fibrosis of >/=3 was independently associated with high necroinflammatory activity (odds ratio [OR] 2.994, 95% confidence interval [CI] 1.422-6.098), low platelets (OR 0.994, 95% CI 0.981-0.999), low cholesterol (OR 0.987, 95% CI 0.976-0.998), high ferritin (OR 1.002, 95% CI 1.001-1.004), and a high prevalence of IR (OR 2.692, 95% CI 1.463-4.954). Diabetic patients were twice as likely to have severe fibrosis (60%) than those with IR but no diabetes (30%) (P= 0.006). The degree of steatosis and that of fibrosis were weakly associated with each other (P= 0.42). CONCLUSIONS: In subjects with CHC resulting from G1-HCV, IR and overt diabetes are major determinants of advanced fibrosis, regardless of the degree of steatosis, mainly in the presence of severe necroinflammation.

Tarantino G, Cabibi D, Cammà C, Alessi N, Donatelli M, Petta S, Craxì A, Di Marco V. · Cattedra ed Unità Operativa di Gastroenterologia ed Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy. · J Viral Hepat. · Pubmed #18266647 No free full text.

Abstract: Eosinophilic infiltrate of liver tissue is described in primary cholestatic diseases, hepatic allograft rejection and drug-induced liver injury, but its significance and its implications in chronic hepatitis C are unknown. The aim of this study was to investigate the clinical significance of eosinophilic liver infiltrate in patients with chronic hepatitis C. We retrospectively evaluated 147 patients with chronic hepatitis C. The presence of eosinophilic infiltrate was investigated in liver biopsies, and a numeric count of eosinophilic leucocytes in every portal tract was assessed. An eosinophilic infiltrate of liver tissue (> or =3 cells evaluated in the portal / periportal spaces) was observed in 46 patients (31%), and patients who consumed drugs had an odds ratio (OR) of 4.02 (95% CI: 1.62-9.96) to have an eosinophilic infiltrate in liver biopsy. By logistic regression analysis, the presence of steatosis was independently associated with eosinophilic infiltrate (OR 5.86; 95% CI: 2.46-13.96) and homeostasis model assessment-score (OR 1.18; 95% CI: 1.00-1.39). Logistic regression analysis also showed that fibrosis staging > or = 2 by Scheuer score was associated with grading >1 by Scheuer score (OR 6.82; 95% CI 2.46-18.80) and eosinophilic infiltrate (OR 4.00; 95% CI 1.23-12.91). In conclusion, we observed that the eosinophilic infiltrate of liver tissue was significantly more frequent in patients who assumed drugs, and found a significant association between eosinophilic infiltrate, liver steatosis and liver fibrosis. These preliminary data could lead to a constant assumption of drugs as a co-factor of eosinophils-mediated liver injury in chronic hepatitis C.

Lo Iacono O, Venezia G, Petta S, Mineo C, De Lisi S, Di Marco V, Rodolico V, Amato M, Ferraro D, Giordano C, Almasio PL, Craxí A. · Department of Gastroenterology, University of Palermo, Palermo, Italy. · Aliment Pharmacol Ther. · Pubmed #17451564 No free full text.

Abstract: AIMS: To assess whether host metabolic factors influence the degree of hepatic steatosis and fibrosis in patients infected with hepatitis C virus, and to evaluate the impact of anti-viral therapy on insulin resistance and serum levels of adipocytokines. METHODS: Clinical and biochemical features, anthropometrical characteristics, and levels of fasting insulin, leptin, adiponectin and resistin were measured in 'naïve' patients with chronic hepatitis C, before, during and after therapy with Peg-Interferon-alpha 2a plus Ribavirin. RESULTS: Forty-eight patients were included (M/F 28/20; mean age 50.0 +/- 12.6 years; 62.5% genotype-1). Body mass index was 26.4 +/- 4.0 kg/m(2), and visceral obesity was present in 24 patients. At multivariate analysis (RR; 95% CI), steatosis was associated to older age (1.08; 1-1.18), necroinflammatory activity (17.67; 1.6-194.46), and raised insulin levels (1.39; 1.1-1.77). Fibrosis was related to necroinflammatory activity (25.73; 2.54-261.11), and steatosis (6.47; 1.09-38.29). Sustained viral response was achieved by 62.5% of patients and was associated with younger age (0.92; 0.85-0.99), genotype non-1 (10.61; 1.52-73.76) and absence of visceral obesity (13.78; 2.36-80.29). At the end of follow-up, insulin and the homeostasis model assessment for insulin resistance were reduced and adiponectin increased when compared with baseline, all unrelated to the outcome of treatment. CONCLUSIONS: Visceral obesity correlates with the degree of steatosis and fibrosis, and it negatively affects treatment response. Significant changes of insulin resistance and adipocytokines occur under treatment, irrespective of virological outcome.

Lo Iacono O, Petta S, Venezia G, Di Marco V, Tarantino G, Barbaria F, Mineo C, De Lisi S, Almasio PL, Craxì A. · University of Palermo, Gastroenterology and Hepatology Unit, Palermo, Italy. · Am J Gastroenterol. · Pubmed #16279902 No free full text.

Abstract: BACKGROUND: Coeliac disease (CD) is found in 5-10% of patients with chronically abnormal liver tests and no obvious cause of liver disease. In this population the efficacy of screening for CD by anti-tissue transglutaminase (anti-tTG) may be impaired by the high rate of positive anti-tTG found in chronic liver disease. AIMS: To evaluate the prevalence of coeliac disease and the role of anti-tTG in patients with non-viral, non-autoimmune chronic and no obvious cause of liver damage. METHODS: Out of 2,512 consecutive patients with abnormal liver tests, 168 (118 men, 50 women; mean age 40.7 +/- 12.6 years) were defined, on the basis of clinical data and liver biopsy, as NAFLD or cryptogenic chronic hepatitis. All were tested by recombinant IgA and IgG anti-tissue transglutaminase. Patients with a positive serology underwent endoscopy with duodenal biopsies. RESULTS: NAFLD was diagnosed in 121 patients, in 6 associated with cirrhosis, while 47 patients were considered as cryptogenic hepatitis in the absence of steatosis. Anti-tTG were positive in 20/168 patients (3 IgA alone; 11 IgG alone; 6 both IgA and IgG). Coeliac disease was found at endoscopy and confirmed by histopathology only in the 6 patients (3.6%) with both IgA and IgG anti-tTG positivity. Four of the patients with CD had NAFLD (3.3%), in 2 of them associated with cirrhosis; while 2 of those with cryptogenic hepatitis (4.2%) had CD. CONCLUSIONS: The prevalence of CD in patients with chronically abnormal liver tests of unexplained etiology is 4%, with no relation with the degree of liver steatosis. Screening should be done by testing for IgA and IgG antibodies and then evaluating by endoscopy and biopsy only patients positive for both.