Psychopathological chronic sequelae of the 2009 earthquake in L'Aquila, Italy.

BACKGROUND: To date, there are no data available among the general adult population on the long-term psychological sequelae of the earthquake that occurred in the town of L'Aquila, Italy in 2009. We investigated the prevalence of post-traumatic stress disorder (PTSD) and major depression (MD) and identified risk factors for these disorders among adult survivors more than one year after the earthquake. METHODS: Telephone interviews were conducted among a random sample of 957 resident adults. The interviews were performed using a questionnaire on exposure to the earthquake, the Mini-International Neuropsychiatric Interview for PTSD, and the Patient Health Questionnaire 8 for MD. Univariate and multivariate logistic regression analyses were conducted to assess potential risk factors. RESULTS: The prevalence rates of PTSD and MD were 4.1% (95% CI=3.0-5.5) and 5.8% (95% CI=4.5-7.5), respectively. The risk factors for PTSD were economic difficulties not necessarily related to the earthquake, chronic disease, death of a relative or friend, and serious economic difficulties as consequence of the earthquake, whereas those for MD were female gender, economic difficulties not necessarily related to the earthquake, not having a permanent job and living in L'Aquila. LIMITATIONS: The major limitations were the cross sectional design and the uncertain accuracy of the diagnoses compared with clinical diagnoses. CONCLUSIONS: Psychological symptoms are frequent even 14-19 months after the L'Aquila earthquake. The mental health care providers in the area of L'Aquila should be aware of the possibility of PTSD or MD among their users.

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan-Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event-free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47-2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2-7.4) and decreased event-free survival by a factor of 1.7 (0.9-3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).

BACKGROUND/AIMS: The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS: A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS: The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS: This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.

Prevalence of anti-HCV among spouses and offspring of anti-HCV positive subjects: an Italian multicentre study.

The role of familial environment in the spreading of hepatitis C virus (HCV) infection is not well established. We studied 1670 family members for 578 anti-HCV+ subjects enrolled in 8 centres distributed throughout Italy. The prevalence of anti-HCV positivity was significantly higher in spouses than in offspring (15.6% and 2.1% respectively; p < 0.01), with no difference between northern and central-southern regions of Italy. Anti-HCV positivity was found almost exclusively in adults; among offspring, during the first two decades of life, the prevalence of anti-HCV positivity was significantly lower than in subjects over 20 years old (0.6% vs 3.1%, respectively).

Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C. Evaluation of HCV genotypes during and after long-term follow-up.

Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon.

Interferon antibodies in patients with chronic hepatitic C virus infection treated with recombinant interferon alpha-2 alpha.

Patients treated with alpha-2a interferon for chronic hepatitis C may produce anti-interferon antibodies whose effect, if any, on the individual response to therapy has not been fully clarified. The prevalence and kinetics of anti-interferon, including those of neutralizing type, have been studied in 60 patients with chronic hepatitis C enrolled in a randomized controlled trial of recombinant alpha-2a interferon. Thirty patients received interferon while 30 were untreated controls. Two different methods, an enzyme immunoassay and an antiviral neutralization bioassay, were used and serial serum samples from each patient were analyzed. Enzyme immunoassay-positive anti-interferon appeared in 60.7% of treated patients within 6 months of therapy; antiviral neutralization bioassay-positive anti-interferon appeared in 52.9% of these enzyme immunoassay-positive patients, and was associated with high enzyme immunoassay reactivity and long-term persistence. Anti-interferon was detected in 75% of patients showing no response to interferon. Antibodies were also detected in three out of six patients who showed alanine aminotransferase normalization persisting up to the end of treatment and in 8 out of 14 patients who showed an initial marked reduction or even normalization of alanine aminotransferase, followed by reactivation of liver damage during treatment. Interestingly, patients who became anti-interferon positive before complete alanine aminotransferase normalization later showed reactivation of liver damage independently of interferon dose reduction, while patients who became positive for anti-interferon after complete alanine aminotransferase normalization either did not reactivate or did so only after interferon dose reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of chronic hepatitis C with recombinant human interferon-alpha 2a: results of a randomized controlled clinical trial.

Sixty consecutive patients with chronic hepatitis C were included in a randomized controlled trial of recombinant human interferon-alpha 2a vs. no treatment. Treated patients received tapering doses of interferon thrice weekly for 1 yr. Twenty treated cases (66.7%) normalized serum aminotransferase levels within the first 4 mo of treatment, but reactivation or breakthrough frequently occurred afterward (20% in both cases). Only one of the untreated patients showed spontaneous normalization of serum aminotransferase levels. Liver histology did not improve in patients without a biochemical response or with breakthrough during therapy, whereas it did not worsen in long-term responders and reactivating patients. Lack of response does not appear to be related to serum interferon antibodies, although their early appearance is more frequent in patients who showed reactivation later on. No biochemical parameter was found to be predictive for positive response to treatment. Antibody to c100 became negative in 62.5% of long-term responders, whereas no change was recorded in other treated patients or controls. Reactivation and breakthrough often occur during treatment, and further studies are needed to determine the most effective schedule (dose and time) of interferon treatment. Loss of c100 antibody during therapy may be a marker of long-term maintenance of response to interferon therapy.

Treatment with interferon(s) of community-acquired chronic hepatitis and cirrhosis type C. The TVVH Study Group.

Two hundred and thirty-four patients with chronic non-A, non-B hepatitis, 86% positive for anti-HCV by ELISA, were treated with recombinant interferon-alpha 2a or with natural (human-leukocytes-derived) interferon-alpha using different dosage and periods of administration. Interim analysis of follow-up data indicate that 65-70% of patients treated initially with 6 MU, thrice weekly, of recombinant interferon-alpha 2a achieved a complete biochemical response (normalization of alanine aminotransferase: ALT) during therapy compared to 56-58% of those treated with 3 MU, thrice weekly, of recombinant or natural interferon-alpha. A 12-month schedule of interferon administration appeared superior to a 6-month schedule in reducing the probability of reactivation of liver disease after therapy withdrawal, although further data are needed to confirm such a conclusion. The probability of response to interferon in terms of maintaining normal ALT after withdrawal did not appear to be influenced by sex, while it was significantly higher in patients aged below 45 years and in those without cirrhosis.

Serum alanine aminotransferase levels among volunteer blood donors: effect of sex, alcohol intake and obesity.

Serum alanine aminotransferase (ALT) activity and antibody to hepatitis B core antigen (anti-HBc) were proposed as surrogate markers of non-A, non-B (NANB) infection. In this study we analyzed 649 consecutive repeat blood donors to define the possible exclusion rate if both surrogate markers were implemented in our Blood Service, and to assess risk factors associated with elevated ALT levels. One hundred and seven blood donors (16.5%) had slightly elevated ALT levels (higher than the upper reference value, but less than twice this level), but only 15 (2.3%) had a level higher than mean log + 2.25 SD. Seventy-seven (11.8%) resulted anti-HBc positive. Blood donors with elevated ALT levels and those who were anti-HBc positive belonged to different populations, being only 6 (0.9%) positive for both surrogate markers. Only two known donors (0.3%) resulted anti-HCV positive, and each of them was implicated in one of the four post-transfusion hepatitis (PTH) cases observed in 200 recipients of blood from these 649 donors. Both were negative for anti-HBc but one had elevated ALT levels. Male sex, age, alcohol use and obesity resulted all independently and significantly associated with elevated ALT levels. For both alcohol use and body weight we observed a significant linear relationship with serum ALT levels. These findings suggest that in our Region the exclusion of blood donors with ALT levels above the reference value, or those anti-HBc positive, would exclude an unacceptably high rate of blood donors without proven evidence of post-transfusion hepatitis prevention.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon therapy of cryptogenic chronic active liver disease and its relationship to anti-HCV.

In a randomized controlled trial of Interferon (IFN) in 60 patients (30 treated and 30 controls) with cryptogenic chronic active liver disease, 70% of treated patients showed complete response, but a high rate of biochemical relapse (62%) was noted. In these cases, a second response to higher doses of IFN has been more difficult and less frequent. A response to IFN was found in 88.5% of anti-HCV positive treated patients and only in 25% of anti-HCV negative. We suggest that serum anti-HCV is a suitable test to predict the response to IFN.

Antibody to hepatitis C virus in cryptogenic chronic liver disease.

The prevalence of antibody to hepatitis C virus (HCV) was studied in 207 patients with chronic liver disease of unknown etiology, in relation to clinical, epidemiological and histological features. Serum antibody to C-100 epitope of HCV was detected by ELISA in 82.6% of patients, with a significant difference compared with a group of patients with primary biliary cirrhosis (10%). The presence of anti-HCV antibody in serum did not correlate with age, sex, histological diagnosis, and activity and duration of the disease, nor with serum anti-HBc, used as a marker of exposure to hepatitis B virus infection. These results strongly support the view that most cases that were previously defined as cryptogenic forms of chronic liver disease are in fact related to HCV infection. There was a correlation between serum anti-HCV antibody and history of risk for parenteral exposure or of acute hepatitis. This correlation was particularly evident for transmission by parenteral route, suggesting that HCV infection may be transmitted often by this route (36.8% among anti-HCV antibody-positive patients and 11.1% among anti-HCV-negative patients). Liver disease in patients without risk factors for parenteral transmission and with lower prevalence of anti-HCV antibody may be caused by other as yet unidentified non-A, non-B (non-C) agents or may be of nonviral origin.

Antibodies to hepatitis C virus in patients with hepatocellular carcinoma.

To study the potential relationship between the hepatitis C virus (HCV), the major etiologic agent of parenterally transmitted non-A, non-B hepatitis, and the development of hepatocellular carcinoma (HCC), we tested the presence of anti-HCV antibodies in sera from a large panel of HCC patients of different racial and geographical origins. Anti-HCV antibodies were detected in 82 out of 114 (71.9%) HBsAg-negative HCC patients and in 15 out of 53 (28.3%) HBsAg-positive patients. No significant difference in the prevalence of anti-HCV antibodies was found in the HBsAg-negative HCC patients when they were divided according to presence of anti-HBs and/or anti-HBc antibodies, or absence of all hepatitis B virus (HBV) serological markers. The prevalence of anti-HCV antibodies was similar in HCC patients of Caucasian and African origin. No differences were noted when the patients were grouped according to sex. The mechanisms by which HCV might contribute to the development of HCC need to be further investigated. As for HBV infection, the necro-inflammation associated with HCV infection may induce cirrhosis, regeneration and eventually malignant transformation. The finding that few anti-HCV patients had HCC which is not superimposed on cirrhosis suggests that HCV could, however, exert some direct effect on the development of HCC.

Cryptogenic chronic active liver disease. Evaluation of serum aminoterminal peptide of type III procollagen as a marker of histological activity.

Sera from 64 patients with HBsAg-negative chronic liver disease with or without cirrhosis were investigated for aminoterminal peptide of type III procollagen (sP-III-P) as a suitable marker of hepatic fibrosis; 244 healthy control subjects were included in the study. A close correlation (p less than 0.01) between sP-III-P levels and histological activity was observed; on the contrary, no correlation was found between the same serum marker of liver fibroplasia and biochemical activity or clinical severity of the disease. We conclude that sP-III-P as a suitable marker of liver overload of collagen fibers is strongly correlated with the histological activity of the disease. Local immune reactions produce soluble substances that might stimulate fibroblastic activity. The test has a significant sensitivity and a very high specificity as a marker of chronic liver disease with histological activity.

[Treatment of cryptogenic chronic liver diseases with recombinant alpha-2a interferon. Preliminary results of a randomized controlled clinical trial]. / Trattamento delle epatopatie croniche criptogenetiche con interferone alfa-2a ricombinante. Risultati preliminari di uno studio clinico randomizzato controllato.

Fifty-six consecutive patients with cryptogenic chronic active liver disease were enrolled in a randomized controlled clinical trial of alpha-2a interferon and randomly assigned to a control group (28 patients) and to a treated one (28 patients). All had a histologic diagnosis of chronic active hepatitis (with superimposed cirrhosis in 50% of them) and presented a persistent elevation in aminotransferases, during the last year. Ad-interim analysis shows that 19 out of 28 treated patient (68%) have normalized the aminotransferases during the eight months of therapy, with a statistically significant difference (p less than 0.01) between treated and control group; nevertheless, in 58% of them, we noted rising aminotransferases at low doses of interferon with subsequent normalization when the dose was increased to previous effective levels. Retrospectively, the antibody directed to virus C (anti-HCV) was found positive in 84% of our patients, and its presence was strongly associated with response to interferon treatment. Our preliminary results seem to demonstrate that interferon is truly effective, mainly at high doses, in cryptogenic chronic active liver disease; these data with the high prevalence of anti-HCV and the association between anti-HCV and response to therapy, may confirm a possible etiologic role of virus C in causing this subgroup of liver disease.

Recombinant human interferon alfa-2a in community-acquired non-A, non-B chronic active hepatitis. Preliminary results of a randomized, controlled trial.

A randomized, controlled trial was undertaken to evaluate the response to recombinant interferon alfa-2a in patients with hepatitis B surface antigen negative chronic active hepatitis of unknown aetiology (community-acquired non-A, non-B hepatitis). Thirty patients were treated with thrice weekly interferon in a dose of 6 million units for 1 month, followed by 3 million units for 3 months and 1 million units maintenance therapy for 8 months. Patients who relapsed were returned to the previously effective dose. A control group of 30 patients received no treatment and were followed up for 12 months. Overall, 21/30 (70%) of treated patients had a complete response, with normalization of serum aminotransferase levels, and a further three (10%) had a partial response (a decrease to less than 50% of baseline levels). No significant changes were observed in the control patients. Five (24%) of the 21 complete responders relapsed during months 2-4 and 8/21 (38%) relapsed during maintenance therapy. Three (23%) of these 13 patients had a return to normal serum aminotransferase levels when the dose was increased and 7/13 (54%) demonstrated a significant decrease. In a retrospective analysis of patients' sera for antibody to hepatitis C virus, 23/26 patients testing positive were treatment responders compared to 1/4 antibody negative patients. Our results suggest that interferon alfa-2a is an effective treatment for community-acquired non-A, non-B hepatitis, but reactivation during treatment occurred in 62% of patients. We recommend use of a higher dose of interferon for at least 1 year with long-term follow up in order to exclude early or late reactivation after treatment withdrawal.

Cryptogenic chronic liver disease and serum or liver hepatitis B virus markers. Their possible correlations and etiologic significance.

In an attempt to evaluate a possible correlation between cryptogenic chronic liver disease and a present or past hepatitis B virus (HBV) infection, we studied 17 patients with hepatitis B surface antigen (HBsAg)-negative, nonalcoholic chronic liver disease; 9 of them were positive for serum HBsAg detected by a solid-phase enzyme immunoassay with monoclonal antibody (M-EIA) and 8 were negative for the same marker. Liver hepatitis B core antigen (HBcAg), studied by an indirect immunofluorescence technique, was present in 55.5% of the patients positive for serum HBsAg by M-EIA. In the same group of patients, liver HBV-DNA was found in 66.6% of the patients. On the other hand, only 1 patient without serum positivity for HBsAg by M-EIA was positive for liver HBcAg and HBV-DNA. None of our patients showed serum positivity for HBV-DNA sequences. We conclude that HBV infection may be a possible cause of cryptogenic chronic liver disease; this HBV-related, HBsAg-negative chronic liver disease seems to have no viral replication or undetectable levels of HBV-DNA in serum. HBsAg, detected by a monoclonal assay, seems to be a suitable marker to identify this subgroup of patients with HBsAg-negative chronic liver disease.

HBV-DNA sequences are rarely detected in the liver of patients with HBsAg-negative chronic active liver disease and with hepatocellular carcinoma in Italy.

Hepatitis B virus sequences were studied by molecular hybridization in liver biopsies from patients with HBsAg-negative chronic liver disease or hepatocellular carcinoma, collected in Italy. Among the 42 patients with chronic liver disease who had no history of drug addiction, alcohol abuse nor evidence of metabolic and autoimmune disorders, only two (5%) had HBV-DNA sequences in the liver, although 23 of them (57%) were positive for antibodies to HBV in serum. HBV-DNA was also demonstrated in integrated form in the tumorous tissue of one out of eight cases with HBsAg-negative hepatocellular carcinoma. These incidences of HBV-DNA positivity in the liver are lower than those reported from other Mediterranean areas and similar to those of North Europe, United States and Japan, suggesting that etiologic factors other than HBV are responsible for the majority of HBsAg-negative chronic liver diseases in our region.

Antibody dependent cellular cytotoxicity (ADCC) in acute hepatitis B and in chronic active hepatitis.

Antibody-dependent cellular cytotoxicity (ADCC) of peripheral blood lymphocytes against chicken red blood cells (ChRBC) in the presence of specific antiserum has been studied in normal subjects and in patients with acute hepatitis B and with chronic active hepatitis (CAH). ADCC was significantly reduced in patients with acute hepatitis B studied three weeks after the onset of jaundice and in patients with CAH showing clinical, biochemical and histological features of activity. On the other hand, lymphocytes from patients with CAH in histological remission or in clinical and biochemical resolution, showed a significantly increased cytotoxicity. The effect of serum factors on ADCC of normal lymphocytes was investigated using serial serum samples from five patients with acute hepatitis B and five with CAH. Our data suggest that serum factors may be responsible for the impairment of ADCC in our patients, although other mechanisms may also be implied. Sera obtained at the time when ADCC of patients' lymphocytes was reduced, significantly inhibited ADCC of normal lymphocytes when compared with sera obtained at the time when ADCC of patients' lymphocytes was normal or increased. In all cases with CAH, the disappearance or reduction of inhibiting activity correlated with histological remission. In patients with CAH the study of serum factors inhibiting ADCC of normal lymphocytes may be a useful parameter in assessing disease activity.