G. Saracco

The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study†‡§

Information on the long‐term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long‐term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non‐responders to treatment. Both cohorts were Child‐Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6‐297), there were 48 (19.4%) liver‐related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6‐238), there were 47 (16.7%) liver‐related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver‐related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotrasferase (ALT) levels were associated with liver‐related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver‐related mortality. Conclusions: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver‐related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver‐related complications and other outcomes in patients with NAFLD. (HEPATOLOGY 2011;54:1208–1216)

Rapidly progressive HBsAg-positive hepatitis in Italy The role of hepatitis delta virus infection

Serum or liver markers of hepatitis delta virus (HDV) infection were found in 20 of 22 (90%) Italian patients presenting with an ostensible type B hepatitis that ran an accelerated course to cirrhosis. The features of the illness conformed to a syndrome of HDV infection in young males carrying the hepatitis B surface antigen (HBsAg); a latent HBsAg state was documented in many patients by a history of prior exposure to the hepatitis B virus (HBV) or by the absence of IgM antibodies to the HB core antigen. Characteristic of the disease were the clinical overture as a severe hepatitis, the lobular involvement by an extensive necroinflammatory reaction, the exuberant expression of intrahepatic hepatitis delta antigen and an atypical HBV profile of inactive infection or accelerated seroconversion from HBeAg to anti-HBe. Superimposed upon HBV infection, HDV may create a rapidly progressive course which resembles very aggressive hepatitis B but is infrequently observed in hepatitis B alone.

HCV genotypes in patients with liver disease of different stages and severity

UNLABELLED AIMS/MATERIAL: Hepatitis C virus (HCV) genotyping was performed in 213 anti-HCV-positive patients with chronic liver disease ranging from minimal histological changes to hepatocellular carcinoma. One hundred and twenty-two patients had non-cirrhotic chronic active or persistent hepatitis (including 29 who were asymptomatic with persistently normal ALT levels) (chronic liver disease group). The other 91 had hepatocellular carcinoma and, in all but three cases, cirrhosis (hepatocellular carcinoma group). RESULTS The overall prevalence of HCV variants was: 54.9% type 1b, 37.8% type 2, 2.5% type 1a, 2.0% type 3a, 2.0% type 4a. The genotype distribution showed no relation to the stage (chronic liver disease vs. hepatocellular carcinoma) or severity (chronic active vs. chronic persistent hepatitis) of the liver disease, or to the duration of the disease (<10 years vs. >10 years). Within the hepatocellular carcinoma group, the duration of type-1b disease was similar to that of type-2 infections. Ages at the time of infection and genotype were both independently associated with progression to cirrhosis and hepatocellular carcinoma, but multivariate analysis revealed that the effect of age was much stronger than that of genotype 1b. CONCLUSIONS The predominance of HCV type 1b in this study reflects the higher frequency of this variant in our area. Our findings indicate that infections caused by each HCV genotype are capable of progressing to hepatocellular carcinoma.

Preliminary experience with a new cytology brush in EUS-guided FNA

BACKGROUND Despite the high diagnostic yield of EUS-guided FNA, room for technical improvements remains. Recently, the EchoBrush (Cook Endoscopy, Winston-Salem, NC), a disposable cytologic brush, was introduced to the market. To date, only 1 study, limited to 10 pancreatic cyst cases, using this device has been published. OBJECTIVE To assess the diagnostic yield of the EchoBrush in a cohort of consecutive patients, irrespective of the target lesion. DESIGN Case series. SETTING Tertiary care university hospital (Molinette Hospital, Turin, Italy). PATIENTS Thirty-nine consecutive patients (12 with solid pancreatic masses, 12 with pancreatic cysts, 7 with enlarged lymph nodes, and 8 with submucosal masses) were enrolled. INTERVENTIONS The material collected with the EchoBrush and with a standard FNA needle was double-blind evaluated by 2 cytopathologists. MAIN OUTCOME MEASUREMENTS Adequacy of the sample and sensitivity and specificity of the EchoBrush method. RESULTS Adequate material for cytologic analysis was collected in 17 of 39 patients (43.6%) with a single pass of the EchoBrush. Results were better for pancreatic lesions (for solid and cystic lesions, the adequacy was 58.3% and 50%, respectively); adequacy was low (28.6% and 25%, respectively) for lymph nodes and submucosal masses. The overall sensitivity and specificity were 57.9% and 31.2%, respectively. There were no adverse events with the procedure. LIMITATION Preliminary study. CONCLUSIONS This report suggests that the EchoBrush may provide adequate cellularity to diagnose solid and cystic pancreatic lesions. More extensive studies are needed to compare the EchoBrush and standard needles.

‘e’ Antigen defective hepatitis B virus and course of chronic infection

We studied the relations between HBV heterogeneity and different phases of HBV infection and disease in 145 HBsAg-positive carriers followed-up for 28 months (range 24-60 months). Viraemia was characterized for the relative prevalence of wild-type and HBeAg minus HBVs after HBV-DNA amplification by PCR using an oligonucleotide hybridization assay. HBeAg minus HBV was detected in 27% of immunotolerant HBV carriers, in 67% of patients with chronic hepatitis B (immunoelimination phase) and in 17% of HBsAg carriers with latent infection. Serum HBV-DNA and IgM anti-HBc became undetectable and ALT levels normalized, either spontaneously or after interferon therapy in 12 (36.3%) of 33 patients with an exclusive wild-type viraemia, but only in two (5.7%) of 35 patients with homogeneous HBeAg minus HBV (p = 0.005). An HBeAg minus viraemia higher than 20% was associated, in both HBeAg- and anti-HBe-positive patients, with HBV-induced liver disease and an unfavourable outcome of hepatitis. These findings suggest that surgence of HBeAg defective HBV is a virus strategy to survive under peculiar conditions dictated by the interplay between HBV and the hosts immune system. The HBeAg/anti-HBe serological status is determined not only by the extent of virus replication and integration of HBV-DNA into cellular DNA but also by heterogeneity of HBV. The study of HBV heterogeneity in baseline sera of patients undergoing antiviral therapy appears to have a predictive value of the outcome of HBV infection in the single patient.

Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data

Background and aims: Retreatment with a combination of α interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. Methods: To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000–1200 mg/daily depending on body weight) was given for 24–60 (mean 39.5) weeks. Results: Biochemical end of treatment and sustained responses were observed in 271/581 (46.6%; 95% confidence interval (CI) 42.6–50.7%) and in 109/581 (18.7%; 95% CI 15.6–22.0%) cases, respectively. Two hundred and six of 532 patients (38.7%; 95% CI 34.6–42.9%) had an end of treatment complete response to retreatment while a complete sustained response occurred in 88 of 559 (15.7%; 95% CI 12.8–18.8%). Fifty four of 581 patients (9.2%; 95% CI 7.0–11.7%) stopped retreatment due to adverse effects. By logistic regression, complete sustained response was predicted independently by age <45 years (p=0.04), by normal pretreatment γ-glutamyltransferase levels (p=0.01), and by a second course total IFN dose of at least 432 mega units (p=0.008). Conclusions: The overall low probability of effectiveness argues against indiscriminate retreatment of all IFN monotherapy non-responders with IFN/ribavirin. Patients less than 45 years old with normal γ-glutamyltransferase levels who were retreated with high dose long course combination therapy had a complete sustained response rate of 30%.

Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality?

Chronic hepatitis C is a systemic disease inducing metabolic alterations leading to extrahepatic consequences. In particular, hepatitis C virus (HCV) infection seems to increase the risk of incident type 2 diabetes mellitus in predisposed individuals, independently of liver disease stage. The mechanisms through which hepatitis C induces T2DM involve direct viral effects, insulin resistance, pro-inflammatory cytokines and other immune-mediated processes. Many studies have reported the clinical consequences of type 2 diabetes mellitus on hepatitis C outcome, but very few studies have addressed the issue of microangiopathic complications among patients with hepatitis C only, who develop type 2 diabetes mellitus. Moreover, clinical trials in HCV-positive patients have reported improvement in glucose metabolism after antiviral treatment; recent studies have suggested that this metabolic amelioration might have a clinical impact on type 2 diabetes mellitus-related complications. These observations raise the question as to whether the HCV eradication may also have an impact on the future morbidity and mortality due to type 2 diabetes mellitus. The scope of this review is to summarise the current evidence linking successful antiviral treatment and the prevention of type 2 diabetes mellitus and its complications in hepatitis C-infected patients.

Treatment of chronic delta hepatitis with α-2 recombinant interferon

The Hepatitis Delta Virus (HDV), a defective ribonucleic acid virus dependent on the Hepatitis B Virus (HBV) is a cause of severe liver disease that often leads to cirrhosis and death. Since the HDV finds in the HBV infection a biological niche in which to thrive indefinitely, the major victims of its infection are the carriers of HBsAg. Spontaneous resolution of chronic HDV hepatitis has been observed rarely and therapeutic attempts with steroids or azathioprine and levamisole have been discouraging. With the advent of recombinant DNA technologies several human alpha-interferons (IFNs) have been synthesized by genetic engineering and the availability of large amounts of the drug has dramatically altered the therapeutic prospects of viral hepatitis. In view of the wide range of biological activities of IFN, including inhibition of viral nucleic acid replication, we have tested the tolerance and the efficacy of this drug in chronic HDV hepatitis. The preliminary results of this study are reported.

Therapy of Chronic Hepatitis C: A Critical Review

Combination therapy (Interferon plus ribavirin) is the current therapeutic gold standard for naive Hepatitis C Virus (HCV)-positive patients and with the recent advent of pegylated (PEG) IFN the rate of the sustained virological response (HCV-RNA clearance 6 months after the end of treatment) is about 54%-56% with a therapeutical gain mainly among patients with unfavourable HCV genotype (1a, 1b); in this subset of patients, a 42%-46% sustained response rate is achieved compared with 33%-36% found among genotype 1 patients treated with the standard therapy. Patients who respond to IFN monotherapy but relapse during the follow-up should be re-treated with combination therapy given for at least 6 months at the minimum dose of 3 MU thrice weekly plus ribavirin 1000 mg/daily. Recent data suggest that prolonging the time of treatment (12 months) may induce a significantly higher rate of sustained response among patients with genotype 1. The efficacy of the combination of IFN and ribavirin in retreating patients with chronic hepatitis C not responding to IFN monotherapy is controversial as it ranges between 0% and 40%. Recent data show an overall rate of sustained response of 23% when an aggressive approach is adopted but increasing the dosage and the time of treatment induces a significant therapeutic benefit only in patients with genotype 1. In conclusion, a therapeutic progress for chronic hepatitis C has been achieved during the last 10 years (56% vs 20% of sustained response rate obtained with IFN monotherapy) but several unresolved issues are yet to be addressed.

Impact of viral eradication with sofosbuvir-based therapy on the outcome of post-transplant hepatitis C with severe fibrosis

Several studies have shown that new direct‐acting antivirals maintain their efficacy in liver transplant (LT) recipients with severe hepatitis C virus (HCV) recurrence. We determined the clinical impact of sofosbuvir/ribavirin in LT through the changes in liver function and fibrosis state at 24 and 48 weeks after treatment.