Ersilio Del Ninno

Hepatocellular carcinoma in Italian patients with cirrhosis.

BACKGROUND AND METHODS Patients with cirrhosis of the liver are recognized as being at risk for hepatocellular carcinoma. The magnitude of the risk, the natural history of this disease, and the possibilities for detecting potentially curable tumors in patients in the Western world are unknown. To address these questions, we examined 447 Italian patients with well-compensated cirrhosis (which was of viral origin in 62 percent of them) from 1985 through 1990, performing serum alpha-fetoprotein assays and real-time ultrasonography every 3 to 12 months. RESULTS Hepatocellular carcinoma was found in 30 patients (7 percent) at base line and in another 29 patients (7 percent of 417 patients free of tumor at base line) during follow-up periods averaging 33 months (range, 1 to 48). The cumulative hazard of the development of hepatocellular carcinoma during follow-up was higher among patients with persistently elevated serum alpha-fetoprotein levels (12 with tumors among 42 with such levels) than among those with fluctuating levels (11 among 82) or those with consistently normal levels (6 among 255). Only 17 patients had potentially operable tumors. The proportion of potentially operable tumors among those detected during follow-up was significantly lower than the proportion at enrollment (4 of 29 vs. 13 of 30, P = 0.027). The survival at one year of the 12 patients who underwent surgery was 67 percent, and the tumor-recurrence rate was 60 percent. Outcome was not appreciably different for the five patients who refused surgery. CONCLUSIONS In the West, as in Asia, patients with cirrhosis of the liver are at substantial risk for hepatocellular carcinoma, with a yearly incidence rate of 3 percent. Our screening program did not appreciably increase the rate of detection of potentially curable tumors.

The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients†

Large databases of consecutive patients followed for sufficiently long periods are needed to establish the rates, chronology, and hierarchy of complications of cirrhosis as well as the importance of other potential causes of liver disease. In accordance with this goal, a cohort of patients with compensated cirrhosis due to hepatitis C virus (HCV) was followed for 17 years. Two hundred and fourteen HCV RNA–seropositive patients with Child‐Pugh class A cirrhosis who had no previous clinical decompensation were prospectively recruited and followed up with periodic clinical and abdominal ultrasound examinations. During 114 months (range 1–199), hepatocellular carcinoma (HCC) developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. Clinical status remained unchanged in 154 (72%) and progressed to Child‐Pugh class B in 45 (21%) and class C in 15 (7%). HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% per year and was higher in patients with other potential causes of liver disease than in those without them (5.7% vs. 3.6%; P = .04). In conclusion, hepatitis C–related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease. HCC was the first complication to develop and the dominant cause for increased mortality. (HEPATOLOGY 2006;43:1303–1310.)

Randomized Study of Peginterferon-α2a Plus Ribavirin vs Peginterferon-α2b Plus Ribavirin in Chronic Hepatitis C

BACKGROUND & AIMS Ribavirin (RBV) combined with either pegylated interferon (PegIFN) alpha2a or PegIFNalpha2b is the standard of care for chronic hepatitis C virus (HCV) infection. Due to the lack of head-to-head studies, the 2 PegIFNs have not been directly compared. The endpoints of our study were safety and antiviral efficacy of the 2 regimens. METHODS Treatment-naïve patients with chronic hepatitis C were randomly (1:1) assigned after stratification for HCV genotype to receive either 1.5 mcg/Kg/week PegIFNalpha2b plus RBV 800-1200 mg/day or 180 mcg/week PegIFNalpha2a plus RBV 800-1200 mg/day for 24 or 48 weeks according to HCV genotype. The study was powered to detect a difference of at least 10% in safety and efficacy of the 2 regimens. RESULTS The 212 patients on PegIFNalpha2a and the 219 patients on PegIFNalpha2b had similar baseline characteristics, including cirrhosis (20% vs 18%, respectively). By intention to treat, the 2 groups showed similar rates of treatment-related serious adverse events (1% vs 1%, respectively) and drop out rates for adverse effects (7% vs 6%, respectively). Overall, sustained virologic response (SVR) rate was higher in PegIFNalpha2a than in PegIFNalpha2b patients (66% vs 54%, respectively, P = .02), being 48% vs 32% in the 222 HCV-1 and -4 patients (P = .04), and 96% vs 82%, respectively, in the 143 HCV-2 patients (P = .01). PegIFNalpha2a independently predicted SVR in the logistic regression analysis (odds ratio, 1.88; 95% confidence interval: 1.20-2.96). CONCLUSIONS Although the 2 regimens showed a similar safety profile, the PegIFNalpha2a-based treatment yielded significantly more SVR than PegIFNalpha2b.

A 28-Year Study of the Course of Hepatitis Δ Infection: A Risk Factor for Cirrhosis and Hepatocellular Carcinoma

BACKGROUND & AIMS Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. METHODS We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. RESULTS Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. CONCLUSIONS Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.

Ultrasound-assisted percutaneous liver biopsy: Superiority of the Tru-Cut over the Menghini needle for diagnosis of cirrhosis

A total of 1192 consecutive patients with diffuse liver disease were randomized to have percutaneous liver biopsy specimens taken with the Menghini or the Tru-Cut needle, to compare tissue yield, safety, and accuracy of the two needles for diagnosing cirrhosis. The sites of puncture were determined by prebiopsy ultrasound scans. Adequate samples were obtained from 94% with the Tru-Cut needle and from 79.2% with the Menghini needle (p less than 0.001). Accuracy in diagnosing cirrhosis was 89.5% for the Tru-Cut needle and 65.5% for the Menghini needle (p less than 0.05). Complication rates were very low and similar for both needles. Under these conditions, the Tru-Cut needle is superior to the Menghini needle for diagnosing cirrhosis.

The clinical and pathogenetic significance of estrogen receptor-β expression in chronic liver diseases and liver carcinoma

Estrogen receptor‐α (ERα) is variably expressed in hepatocellular carcinoma (HCC) and is believed to be correlated with prognosis and survival. Recently, another estrogen receptor (ERβ) has been identified, but its relevance in liver diseases is unknown.

Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas

PURPOSE To establish whether segmental transcatheter arterial chemoembolization (TACE) treatment may improve the rates of survival in patients with compensated cirrhosis and inoperable hepatocellular carcinoma (HCC). MATERIALS AND METHODS Fifty-six patients with compensated cirrhosis and inoperable HCC were treated with segmental TACE. One hundred forty treatments (mean, 2.5 per patient; 30-60 mg Epirubicin, 4-10 mL Lipiodol, and Gelfoam particles) were administered. RESULTS During the 69-month study, 25 patients (45%) died of tumor progression, 12 (21%) of liver failure, nine (16%) of gastrointestinal hemorrhage, and three (5%) of other causes; seven patients (13%) are still alive. The 3-year rate of survival was 32%. Intention-to-treat analysis determined that patients with Child-Pugh class A disease (n = 44; 79%) or a single <5-cm HCC (n = 21; 37%) had a higher rate of survival than those with Child-Pugh class B disease (n = 12; 21%; P <.002) or a larger HCC (n = 35; 63%; P <.02) and patients (n = 41) who were treated with more than one course of TACE had a higher rate of survival than those who were treated with a single TACE procedure (n = 15; P <.0003). Multivariate analysis was used to predict rates of survival by number of treatments (hazard ratio, 0.6; CI, 0.48-0.86; P <.004), Child-Pugh class (hazard ratio, 2.8; CI, 1.41-5.74; P <.003), and tumor size (hazard ratio, 3.8; CI, 1.81-8.01; P <.001). The 3-year rate of survival in patients with Child-Pugh class A disease and a < or =5-cm-HCC (n = 16) was 56%. This result was similar to the 50% 3-year rate of survival in untreated historic controls with similar characteristics. CONCLUSION The rate of survival in patients with compensated cirrhosis and inoperable HCC did not appear to improve with use of TACE therapy.

Serum levels of hepatitis C virus core antigen as a marker of infection and response to therapy

OBJECTIVES:Hepatitis C virus (HCV) core antigen is a recently developed marker of hepatitis C infection. We compared the predictive power of HCV core antigen with reverse transcription polymerase chain reaction (RT-PCR) and branched DNA assay for HCV-RNA as markers of infection and response to interferon therapy.METHODS:Four hundred and forty-four sera from 111 patients (65 men, 52 yr) with chronic hepatitis C, receiving ribavirin together with standard interferon (n = 61) or pegylated interferon (n = 50) were retrospectively investigated.RESULTS:Pretreatment, RT-PCR, branched DNA (median 621,887 IU/ml), and HCV core antigen (median 57 pg/ml) gave positive results in 100%, 99%, and 94% of the sera; the correlation between HCV core antigen and branched DNA was 0.75. The median HCV RNA level among the 7 of 111 (6%) patients that had a negative core Ag result was 15,016 IU/ml. Pretreatment levels of HCV core antigen were significantly lower in the 41 patients with a sustained virological response than in the 39 relapsers and 31 nonresponders (17 pg/ml, 114 pg/ml, 58 pg/ml; p-value 0.005). Independently of treatment schedule, wk 12 more than 2 log10 reduction of viremia or a negative result for HCV core antigen had 100% negative predictive value (NPV) for a response to therapy compared to 94% for negative RT-PCR. The positive predictive value (PPV) of HCV core antigen and branched DNA was only 47% and 48%.CONCLUSIONS:In conclusion, the HCV core antigen is a less sensitive test of HCV viremia than HCV-RNA assays and is competitive with the bDNA assay as an early predictor of a nonresponse.

Onset of inflammatory bowel diseases during combined alpha-interferon and ribavirin therapy for chronic hepatitis C: report of two cases.

We report two patients who developed an inflammatory bowel disease (IBD) shortly after beginning combined alpha-interferon and ribavirin treatment for HCV-related chronic hepatitis. The previous clinical history was negative for IBD in both patients, who developed diarrhoea and rectal bleeding 10 days and 6 months, respectively, after the initiation of therapy. The history, therapeutic management and the possible causal relationships of these cases are discussed.

Long-term titrated recombinant interferon-α2a in chronic hepatitis C: a randomized controlled trial

Summary. The efficacy and tolerability of 12‐month treatment with titrated doses of recombinant interferon‐α2a (IFN‐α2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN‐α2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n= 35), or to no therapy (n= 32; controls). End‐of‐treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P= 0.031). Follow‐up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 2 7 non‐responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti‐IFN neutralizing anti‐bodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long‐term clearance of HCV RNA and normal ALT levels in 23% of patients.