Francesco Donato

STATEMENTS FROM THE TAORMINA EXPERT MEETING ON OCCULT HEPATITIS B VIRUS INFECTION

Giovanni Raimondo*, Jean-Pierre Allain, Maurizia R. Brunetto, Marie-Annick Buendia, Ding-Shinn Chen, Massimo Colombo, Antonio Craxi, Francesco Donato, Carlo Ferrari, Giovanni B. Gaeta, Wolfram H. Gerlich, Massimo Levrero, Stephen Locarnini, Thomas Michalak, Mario U. Mondelli, Jean-Michel Pawlotsky, Teresa Pollicino, Daniele Prati, Massimo Puoti, Didier Samuel, Daniel Shouval, Antonina Smedile, Giovanni Squadrito, Christian Trepo, Erica Villa, Hans Will, Alessandro R. Zanetti, Fabien Zoulim

A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma

The aim of the study was to assess whether co‐infection by hepatitis‐B virus (HBV) and hepatitis‐C virus (HCV) is associated with a higher risk of developing hepatocellular carcinoma (HCC) than each infection alone. A meta‐analysis of data published up to June 1997 was performed. HBsAg and anti‐HCV antibodies or HCV RNA (anti‐HCV/HCV RNA) were considered as serological markers of current HBV and HCV infection respectively. A total of 32 case‐control studies were suitable for a quantitative overview. The summary odds ratios (OR) were 13.7 for HBsAg positivity and 11.5 for anti‐HCV/HCV RNA positivity. The OR for anti‐HCV was lower among studies using second‐ or third‐generation anti‐HCV or HCV RNA (OR, 8.2) with respect to studies with first‐generation anti‐HCV test (OR, 19.1). When combining data from the studies with second‐ or third‐generation anti‐HCV or HCV RNA, the OR for HBsAg positivity and anti‐HCV/HCV RNA negativity was 22.5 (95% confidence interval (CI), 19.5–26.0), the OR for anti‐HCV/HCV RNA positivity and HBsAg negativity was 17.3 (95% CI, 13.9–21.6), and the OR for both markers positivity was 165 (95% CI: 81.2–374, based on 191 cases and 8 controls exposed). A synergism was found between HBV and HCV infections, the OR for co‐infection being greater than the sum and lower than the product of those for each infection alone. The interaction was therefore negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process. Int. J. Cancer 75:347–354, 1998.

Association of change in left ventricular mass with prognosis during long-term antihypertensive treatment

Objective: The aim of the present study was to assess the prognostic value of changes in left ventricular hypertrophy in hypertensive patients with time. Design: Two hundred and fifteen uncomplicated hypertensive patients underwent a high-quality baseline echocardiogram for left ventricular anatomy evaluation and in 151 of those patients the echocardiographic examination was repeated 10± 1.4 years after the initial study. Methods: Left ventricular mass index changes were evaluated, in relation to the incidence of non-fatal cardiovascular events, adjusted for traditional cardiovascular risk factors. Results: According to the presence or absence of left ventricular hypertrophy (left ventricular mass index >134g/m2 in men and >110g/m2 in women) at baseline and at the end of follow-up study, patients were divided into four groups: with normal left ventricular mass at both examinations (n=78), with regression of left ventricular hypertrophy (n=32), with persistence of left ventricular hypertrophy (n=34) and with hypertrophy development (n=7). After adjustment for traditional cardiovascular risk factors, the cumulative incidence of non-fatal cardiovascular events was significantly higher in the group of patients without regression of left ventricular hypertrophy. Cox survival analysis showed the presence of left ventricular hypertrophy at the end of follow-up study to be the most important factor related to cardiovascular events. Conclusions: The present findings strongly indicate that the lack of decrease or the increase of left ventricular mass after antihypertensive treatment can be associated with a higher risk for cardiovascular events, which is significantly reduced and almost normalized by complete regression of left ventricular hypertrophy.

Cigarette smoking and bladder cancer in men : A pooled analysis of 11 case-control studies

The primary risk factor for bladder cancer is cigarette smoking. Using a combined analysis of 11 case‐control studies, we have accurately measured the relationship between cigarette smoking and bladder cancer in men. Available smoking information on 2,600 male bladder cancer cases and 5,524 male controls included duration of smoking habit, number of cigarettes smoked per day and time since cessation of smoking habit for ex‐smokers. There was a linear increasing risk of bladder cancer with increasing duration of smoking, ranging from an odds ratio (OR) of 1.96 after 20 years of smoking (95% confidence interval [CI] 1.48–2.61) to 5.57 after 60 years (CI 4.18–7.44). A dose relationship was observed between number of cigarettes smoked per day and bladder cancer up to a threshold limit of 15–20 cigarettes per day, OR = 4.50 (CI 3.81–5.33), after which no increased risk was observed. An immediate decrease in risk of bladder cancer was observed for those who gave up smoking. This decrease was over 30% after 1–4 years, OR = 0.65 (0.53–0.79), and was over 60% after 25 years of cessation, OR = 0.37 (0.30–0.45). However, even after 25 years, the decrease in risk did not reach the level of the never‐smokers, OR = 0.20. (0.17–0.24). The proportion of bladder cancer cases attributable to ever‐smoking was 0.66 (0.61–0.70) for all men and 0.73 (0.66–0.79) for men younger than 60. These estimates are higher than previously calculated. Int. J. Cancer 86:289–294, 2000.

Mortality for liver disease in patients with HIV infection : A cohort study

We undertook this study to assess the association between the various potential causes of liver disease in HIV-seropositive patients and mortality due to liver failure. Three hundred and eight in-hospital deaths were observed from 1987 to December 1995 in a prospectively followed cohort of 1894 HIV-seropositive patients. For each study subject, clinical data were evaluated to assess whether liver failure had substantially contributed to mortality. A case control study nested in the cohort was then performed, which compared demographic and clinical variables observed at enrollment and during follow-up between patients who died for liver disease as the main or concurrent cause of death (cases) and those who died as a result of illness related to AIDS or other causes (controls). Among 308 in-hospital deaths, liver failure was found the cause of death in 35 patients (12%); in 16 cases, it was the primary cause and in 19 cases it was concurrent. Multivariate analysis showed that in-hospital liver-disease-related mortality was independently associated with hepatitis B surface antigen reactivity (odds ratio [OR], 9; 95% confidence interval [CI], 3.8-21.7) and history of alcohol abuse (OR, 2.3; 95% CI, 1-5.2). Prevention and treatment of hepatitis B virus infection and alcohol intake are management priorities in HIV-seropositive patients.

Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.

Objective: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals. The aim of the study was to compare the main features of HCC in HIV-seropositive individuals with those in to HIV-negative patients. Patients and methods: All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study as cases. HCC cases that occurred in the province of Brescia, North Italy, in the period 1995–1998 and all cases reported at the Italian Liver Cancer Project were enrolled as controls. All data were collected using a standardized case report form. The main clinical and epidemiological characteristics of patients with HCC and their survival were compared between HIV-positive and uninfected subjects. Results: Forty-one HIV-infected subjects with HCC were identified. Multivariate analysis adjusted for age and sex identified an association between HIV infection and HCV infection [odds ratio (OR), 11; P = 0.005], and infiltrating tumours and/or extranodal metastasis at presentation (OR = 11.8; P < 0.001). HIV infection was independently associated with shorter survival (hazard ratio, 1.63; P = 0.015). Conclusions: HCC in HIV-infected patients is mainly associated with underlying chronic hepatitis C and has a more aggressive clinical course. Thus, preventative strategies (including the treatment of hepatitis C) should be implemented in the management of HIV/HCV-coinfected patients.

Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus.

A total of 204 patients with liver biopsy-proven hepatitis C virus (HCV) infection, 84 with and 120 without human immunodeficiency virus (HIV) coinfection, were studied, to evaluate variables possibly associated with the stage of liver fibrosis. All patients were injection drugs users, with a mean age of 32 years and an estimated duration of HCV infection of 12 years. Twenty-four patients (11%) had many fibrous septa with (5%) or without (6%) cirrhosis, 56 (27%) had few fibrous septa, and 124 (60%) had no fibrous septa. In all patients, an association was found between CD4 cell counts <500 cells/mm(3)and the presence of many fibrous septa (odds ratio, 3.2; P=.037), independent of HIV infection and other factors. These results suggest that HIV infection-induced CD4 depletion is independently associated with the severity of liver fibrosis in chronic HCV infection.

Long-term outcome of chronic hepatitis B in caucasian patients: mortality after 25 years

Objective: To assess risk factors for liver-related death, we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic hepatitis (CH) at presentation. Methods: Follow-up studies included clinical and ultrasound examinations, biochemical and virological tests, and cause of death. Results: Sixty-one (87%) patients underwent spontaneous HBeAg seroconversion. During a median period of 22.8 years after HBeAg seroclearance, 40 (66%) patients became inactive carriers, whereas the remaining 21 (34%) showed alanine aminotransferase elevation: one (1%) had HBeAg reversion, nine (15%) detectable serum HBV DNA but were negative for HBeAg, eight (13%) concurrent virus(es) infection and three (5%) concurrent non-alcoholic fatty liver disease. Liver-related death occurred in 11 (15.7%) patients, caused by hepatocellular carcinoma in five and liver failure in six. The 25-year survival probability was 40% in patients persistently HBeAg positive, 50% in patients with HBeAg negative CH or HBeAg reversion and 95% in inactive carriers. Older age, male sex, cirrhosis at entry and absence of sustained remission predicted liver-related death independently. The adjusted hazard ratios (95% CI) for liver related death were 33 (3.01–363) for persistently HBeAg positive patients and 38.73 (4.65–322) for those with HBeAg negative CH or HBeAg reversion relative to inactive carriers. Conclusion: Most patients with HBeAg seroconversion became inactive carriers with very good prognosis. The risk of liver-related mortality in Caucasian adults with CH is strongly related with sustained disease activity and ongoing high level of HBV replication independently of HBeAg status.

Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy.

Objective: Intrahepatic cholangiocarcinoma (ICC) is a rare type of primary liver cancer (PLC) arising from intrahepatic bile ducts. We carried out a case–control study to assess the association between ICC and hepatitis B and C virus (HBV and HCV) infections, alcohol intake, and hepatolithiasis in Brescia, North Italy. Methods: Among 370 subjects with histology-based diagnosis of PLC who were resident in the area and hospitalized in 1995–2000, 26 (7%) ICC cases were identified. A total of 824 subjects unaffected by hepatic diseases and frequency-matched with PLC cases by age, sex, date, and hospital of admission were recruited as controls. Results: Among ICC cases the mean age was 65 years, 80.8% were males, and 38.5% had cirrhosis. Seropositivity for anti-HCV, HBsAg, alcohol intake > 80 g/day and history of hepatolithiasis were found in 25%, 13%, 23.1%, and 26.9% of ICC cases and in 5.8%, 6.7%, 32.9%, and 10.6% of controls, respectively. The odds ratios adjusted for demographic factors by logistic regression (95% confidence interval; 95% CI) were 9.7 (1.6–58.9) for anti-HCV, 2.7 (0.4–18.4) for HBsAg, and 6.7 (1.3–33.4) for hepatolithiasis, whereas no association was found with alcohol drinking. Conclusions: HCV and hepatolithiasis may be risk factors for ICC in Western countries.

Hepatocellular Adenoma and Focal Nodular Hyperplasia: Value of Gadoxetic Acid–enhanced MR Imaging in Differential Diagnosis

PURPOSE To retrospectively evaluate the utility of gadoxetic acid-enhanced magnetic resonance (MR) imaging in the differential diagnosis of hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). MATERIALS AND METHODS This study had institutional review board approval; the requirement for informed consent was waived. Eighty-two patients (58 patients with FNH and 24 patients with HCAs) with 111 lesions were included in the study. There were 74 female patients and eight male patients (mean age, 41.9 years±13.2 [standard deviation]; age range, 11-78 years). Two readers reviewed all images in terms of signal intensity (SI) features on unenhanced, dynamic, and hepatobiliary phase images. For quantitative analysis, contrast enhancement ratio (CER), lesion-to-liver contrast (LLC), and SI ratio on dynamic and hepatobiliary phase images were calculated. RESULTS The CER of FNH in the arterial phase (mean, 94.3%±33.2) was significantly higher than that of HCAs (mean, 59.3%±28.1) (P<.0001). During the hepatobiliary phase, the LLC of FNH showed minimally positive values (mean, 0.05±0.01) and that of HCAs demonstrated strong negative values (mean, -0.67±0.24) (P<.0001). The area under the receiver operating characteristic curve of the hepatobiliary phase SI ratio for differentiation of the two tumors was 0.97, and a sensitivity of 92% and specificity of 91% were found with a cutoff value of 0.87. Among six FNH lesions that showed atypical hypointensity during the hepatobiliary phase, four had a large central scar, one contained a substantial fat component, and one had abundant radiating fibrous septa. Three HCAs were isointense during the hepatobiliary phase owing to severe hepatic steatosis. CONCLUSION Gadoxetic acid-enhanced MR imaging facilitates the differentiation of FNH from HCA.