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Biomedical subjects

F Oliveri

Publications and source records attributed to F Oliveri.

At least 19 recordsLinked to original sources

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves.

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves' ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Adult↗

Horse antilymphocytic globulin in hepatitis B exacerbation after bone marrow transplantation adoptive immunity transfer.

We describe the case of a HBsAg+, HBeAg+ carrier, treated with lamivudine, who experienced exacerbation of hepatitis after BMT from an anti-HBs+, anti-HBc+, anti-HBe+ donor. The serological profile of the donor and the timing of exacerbation suggested that the adoptive immunity transfer played a major pathogenetic role. Antilymphocyte globulin administration resulted in resolution of hepatitis and seroconversion to anti-HBs+. Therapy aimed at blocking the effector arm of liver damage could represent a novel approach to avoid the risk of progression to fulminant hepatitis without hampering the chances of recovery from hepatitis B.

Adoptive Transfer↗

Increasing serum levels of IgM anti-HCV are diagnostic of recurrent hepatitis C in liver transplant patients with ALT flares.

Recurrent hepatitis and acute rejection share common features which make difficult for diagnosis in liver transplant hepatitis C virus (HCV) positive patients. We studied the usefulness of quantitative monitoring of HCV RNA and immunoglobulin (Ig)M anti-HCV in the differential diagnosis between recurrent hepatitis and acute rejection in 98 consecutive anti-HCV positive liver transplant patients. Aminotransferase levels, serum HCV RNA and IgM anti-HCV were measured at the time of transplantation and monthly thereafter. A liver biopsy (LB) was obtained when serum aminotransferase levels increased to twice or more than normal. During a mean follow-up of 16 months 86 aminotransferase flares were observed. Histology was compatible with recurrent hepatitis C in 44 cases and with acute rejection in 28, doubtful in 14. The fluctuations of HCV RNA serum levels were not significantly different in the three groups. Serum IgM anti-HCV levels increased (from negative to positive or with value variations > or = 0.18) in 36 of 44 cases with recurrent hepatitis C at the time of alanine aminotransferase (ALT) flare. IgM anti-HCV remained unchanged in all rejection cases (P < 0.001), but increased in 10 of 11 histologically doubtful cases that were diagnosed as hepatitis at the second LB. Increasing serum levels of IgM anti-HCV at the time of ALT flares are significantly associated with recurrent hepatitis C in liver transplant patients. The quantitative monitoring of IgM anti-HCV appears to be an additional diagnostic tool for distinguishing recurrent hepatitis C from acute graft rejection with a 100% specificity; 100% positive predictive value and 88.9% diagnostic accuracy.

Adult↗

Hepatitis C virus infection: early diagnosis and identification of response to antiviral therapy.

Early diagnosis of hepatitis C infection and early identification of virologic response to antiviral therapy represent major hallmarks of the quality of a case. They contribute to reducing the risk of hepatitis C infection from blood product and improve disease management in patients treated with antivirals. Some of the current issues and perspectives involved in detection and quantification of viral load during the incubation phase of infection and monitoring the early phase of antiviral therapy are discussed.

Antiviral Agents↗

Molecular cloning and characterization of murine ICOS and identification of B7h as ICOS ligand.

Human ICOS (huICOS) is a T cell-specific molecule structurally related to CD28 and CTLA-4 with potent co-stimulatory activities on T cell proliferation, cytokine induction and T cell help for B cells. We have now cloned and characterized murine ICOS (muICOS). muICOS mRNA of 1.5 kb and 3.3 kb encodes a protein with a deduced molecular mass of 20.3 kDa, which is 71.7 % identical to huICOS. On the cell surface, muICOS is expressed as a disulfide-linked, glycosylated homodimer of 47-57 kDa, with subunits of approximately 26 kDa. With a panel of monoclonal antibodies we have determined the expression of muICOS in vitro and in vivo. Following activation of splenic T cells via CD3, muICOS became detectable at 12 h and reached a maximum of expression at around 48 h, thus exhibiting expression kinetics similar to huICOS. In vivo, muICOS was found to be substantially expressed in the thymic medulla and in the germinal centers and T cell zones of lymph nodes and Peyer's patches. Non-lymphoid tissue was ICOS negative. The muICOS gene was mapped to a region of chromosome 1 also harboring the CD28 and CTLA-4 genes. Using recombinant chimeric muICOS-Ig we determined that B7h, a recently cloned B7-like molecule, is a ligand for muICOS.

Amino Acid Sequence↗

Tailoring interferon dose and monitoring viral load in hepatitis C virus genotype 1b infected patients: a pilot study.

BACKGROUND AND AIMS: Complete [biochemical and virological) primary response remains the first goal of any antiviral therapy and its early assessment could be particularly useful in the management of the high viral load, genotype 1b infected patients, who have the worst chance of response. We evaluated whether tailoring interferon dose according to pre-treatment viral load and early monitoring of quantitative HCV-RNA could either improve or predict the results of recombinant alpha-2a interferon treatment in these patients. PATIENTS: Fifty-three consecutive genotype 1b HCV-infected patients, stratified in two groups by viral load (cut off 6 MEq/ml), received randomly 6 or 9 MU of recombinant alpha-2a interferon thrice weekly for 6 months, followed by 6 MU for another 6 months. METHODS: HCV-RNA was measured [b-DNA] assay) two months apart prior to therapy, at baseline, after 2 weeks of therapy and monthly thereafter. RESULTS: In the high viraemic group, complete primary response was observed in 80% of patients treated with high dose recombinant alpha 2a interferon and only in 14.3% of low dose treated patients [p<0.03]. In low viraemic patients, complete primary response was 53. 8% in low dose patients and 80% (8 out of 10) in the high dose group. Sustained response was 60% in high viraemic patients treated with high dose and absent in those treated with low dose [p<0.05]. One log viral load decrease at 2 or 4 weeks showed 0.87 and 0.80 positive predictive values, 0.95 and 1.0 negative predictive values with 96% and 100% sensitivities and 83% and 70% specificities. CONCLUSIONS: 6 MU recombinant alpha-2a interferon thrice weekly schedules were completely ineffective in the large majority (85.7%) of patients with viral load above 6 million HCV-RNA copies/ml and the treatment failure could be predicted by lack of one log viral load decrease after 2-4 weeks of treatment.

Adult↗

High prevalence of G1 and G2 TT-virus infection in subjects with high and low blood exposure risk: identification of G4 isolates in Italy.

BACKGROUND/AIMS: A non-enveloped single-stranded DNA virus (TTV) was detected in Japanese patients with fulminant hepatitis (47%) and chronic liver disease of unknown etiology (46%) more frequently than in blood donors (12%). Subsequent studies, however, questioned the association of TTV with liver disease. We further investigated the role of this novel virus in liver diseases. METHODS: We tested 106 patients and 102 blood donors for TTV by polymerase chain reaction using conserved region primers. RESULTS: TTV DNA was found in 19 of 102 volunteer blood donors (18.6%) and in 27 of 106 patients with liver disease (25.5%): 10 of 28 chronic hepatitis B (35.7%), 9 of 28 chronic hepatitis C (32.1%) and 8 of 50 (16%) cryptogenic liver disease patients. Previous interferon treatment was not associated with a significantly lower prevalence of TTV infection. TTV prevalence was higher in patients with blood exposure (42.8%, 6/14) than in patients without risk factors (21.4%, 18/84). Four of five patients (80%) with HBV familial infection and without blood exposure were also TTV positive. Partial nucleotide sequences from 3 Italian isolates diverged more than 30% from the 2 prototype genotypes G1 and G2 and were 88% homologous to the recently described genotype G4. CONCLUSIONS: G1 and G2 TTV are common in Italy and in the USA in liver disease patients and in blood donors. The prevalence is high in patients with blood exposure but also in subjects without risk factors; other routes of transmission should therefore be considered.

Adolescent↗

Treatment of patients with chronic hepatitis C and cirrhosis.

The most cost effective strategy for antiviral therapy of chronic hepatitis C is the earliest identification and treatment of patients at risk of developing life-threatening complications such as hepatocellular carcinoma. Liver fibrosis represents the best predictor of unfavourable outcome. However, some patients with liver fibrosis already have a histological diagnosis of cirrhosis and there is a debate about whether alpha interferon is still effective in lowering the risk of disease progression in such patients. We identified some of the reasons that may explain seemingly contradictory results of studies addressing this issue. A major cause appears the beginning of follow-up at different starting points during the course of clinically compensated cirrhosis. Some investigators recruited patients because of anti-HCV positivity and elevated transaminases and found cirrhosis only at histology, whereas others recruited patients because cirrhosis had been diagnosed. Ultrasonographic signs of portal hypertension appear to be a useful tool to distinguish the two phases of the disease. Another important cause of reduced response rate to antiviral therapy is the presence of cofactors of liver disease and hepatocellular carcinoma such as present or past HBV infection. Early phase cirrhotics without cofactors appear to benefit most from therapy with a significant lower risk for hepatocellular carcinoma than untreated controls. The therapeutic decision in these patients could be the same as in patients with chronic hepatitis C without cirrhosis. In contrast, the efficacy of interferon remains questionable in HCV patients who already have ultrasonographic signs of portal hypertension and/or past or present HBV coinfection. Prospective, randomized clinical trials should be performed after stratification of these patients for stage and cofactors of liver disease.

Antiviral Agents↗

Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon.

OBJECTIVE: The response rate to alpha interferon (IFN) of chronic anti-HBe-positive hepatitis B is variable. We studied whether type, dose, and schedule of IFN, and type and frequency of posttreatment monitoring, influence the response rate. METHODS: Seventy-two consecutive anti-HBe-positive chronic hepatitis B patients (59 male and 13 female, median age 41 yr) stratified by sex and histology were randomly allocated to three treatment arms. Twenty-seven patients (A) received 10 million units alpha-N1 IFN i.m. t.w. for 24 wk (total dose: 720 million units); 21 (B) received 9 million units alpha-2a IFN i.m. t.w. for 4 wk, followed by 18 million units for 12 wk and 9 million units for 8 wk (972 million units); 24 (C) received 2 alpha-2a IFN courses (9 million units i.m. t.w. for 16 and 12 wk separated by a 6-month interval [756 million units]). Primary response was defined by normal ALT and serum HBV-DNA levels below 10 pg/ml at the end of therapy and sustained response by normal ALT (tested monthly), undetectable HBV-DNA and IgM anti-HBc (<7 I.U. Paul Ehrlich Institute) (tested every 3 months) during the posttreatment follow-up. RESULTS: At the end of treatment, 12, 8, and 13 patients from groups A, B, and C, respectively, were responders. At the 18-month follow-up, two patients in group A and only one in groups B and C maintained the response. Overall, after 34 months (median posttreatment follow-up), three patients were long term responders, whereas three showed a sustained remission after relapse. CONCLUSIONS: The rate of long term response to interferon of anti-HBe-positive chronic hepatitis B is poor, independent of IFN type, dose, or schedule; the more stringent the monitoring, the higher the relapse rate.

Adult↗

Hepatocyte proliferation rate is a powerful parameter for predicting hepatocellular carcinoma development in liver cirrhosis.

AIMS: A sound predictive test is lacking for the identification of cirrhotic patients at high risk of developing hepatocellular carcinoma. The present study evaluates the measurement of hepatocyte expression of silver stained nucleolar organiser region (AgNOR) proteins as a risk factor for the development of hepatocellular carcinoma in cirrhosis. METHODS: Liver biopsies from 176 cirrhotic patients included in a follow up surveillance programme for hepatocellular carcinoma development were evaluated prospectively for hepatocyte AgNOR protein quantity. The follow up programme consisted of clinical and biochemical assessment every three months, and ultrasound scanning and serum alpha-fetoprotein (alpha FP) assessment every six months. Histological sections from the needle biopsies performed at enrollment were stained selectively for AgNOR proteins and the percentage of hepatocytes with an AgNOR protein area > or = 7 micron 2, indicative of a proliferative state (AgNOR proliferation index (AgNOR-PI)), was measured. RESULTS: During the mean (SD) follow up time of 65.5 (36.29) months (range, 12-143; median, 67), hepatocellular carcinoma was diagnosed in 48 of 176 patients (27.3%). The AgNOR-PI of the whole series ranged from 0% to 5% (median, 0.9%), and was significantly higher in patients with liver cell dysplasia and hepatitis B surface antigen (HBsAg) positivity (p < 0.0001 and p = 0.0002, respectively). The 176 patients were divided into two groups according to their AgNOR-PI scores; a cut off value of 2.5% defined by the receiver operating characteristic curve and the Youden index was used. Forty two patients were included in the high AgNOR-PI (< 2.5%) group, and 134 patients the low AgNOR-PI (< 2.5%) group. In the high AgNOR-PI group, 25 of 42 patients developed hepatocellular carcinoma, in contrast to only 23 of 134 patients (17.2%) in the group with a low AgNOR-PI (p < 0.0001). Hepatocellular carcinoma development was also significantly more frequent in patients with liver cell dysplasia and HBsAg positivity. Multivariate analysis using AgNOR-PI, liver cell dysplasia, HBsAg positivity, and hepatitis C virus (HCV) infection as covariates demonstrated that the AgNOR-PI parameter was the only significant predictor of hepatocellular carcinoma development. CONCLUSIONS: These results demonstrate that a high hepatocyte proliferation rate is a major risk factor for hepatocellular carcinoma development in the cirrhotic liver. Therefore, the evaluation of the hepatocyte proliferation rate is very important to identify patients requiring a more strict follow up programme for early diagnosis of hepatocellular carcinoma.

Adult↗

Quantitative detection of hepatitis C virus RNA in the serum of patients with chronic hepatitis C treated with interferon: a pilot study.

BACKGROUND: It is not known whether the measurement of serum hepatitis C virus (HCV) RNA by reverse transcription polymerase chain reaction (RT-PCR) could improve the management of patients with chronic hepatitis C being treated with interferon. OBJECTIVES: We analysed, in a pilot study, the relations between the variations of HCV-RNA and alanine aminotransferase (ALT) serum levels in 18 anti-HCV positive patients treated with interferon. STUDY DESIGN: Serum HCV-RNA was measured, using a non competitive coamplification assay (Amplicor HCV Monitor), before (at 3, 2 and 1 months and baseline), during (first, third and sixth month) and after treatment for at least 8 months (range 8-17 months). HCV-RNA levels fluctuations were correlated with those of ALT and treatment outcome. According to the ALT pattern, four patients were non responders, seven partial responders, four relapsers and two long term responders. RESULTS: The median and mean baseline HCV-RNA levels were significantly different in patients infected by HCV type 1, 2 and 3, being 248,449, 235,506; 4170, 17,866 and 22,315, 79,273 molecules per ml, respectively (P < 0.0001). We did not find any significant difference between median and mean baseline viremia of responders and non responders. After 1 month of treatment viremia was below the sensitivity levels of the assay in 77.7% (14/18) of the patients who normalized ALT, at least temporarily. On the contrary, HCV-RNA remained detectable in non responders. CONCLUSIONS: Our data suggest that HCV-RNA detection using Amplicor Monitor at the first month of treatment can be useful to identify non responders, avoiding three additional months of treatment as would be required by ALT monitoring alone. During the post-treatment follow-up, persistence of undetectable HCV-RNA and normal ALT levels helps to identify long term responders from patients with the risk of relapse in spite of biochemical remission.

Adolescent↗

The prevalence of hepatitis C virus types in patients of the same geographic area, according to the source of infection and liver disease.

BACKGROUND: The duration and stage of hepatitis C might be associated with the source of infection and hepatitis C virus (HCV) types. OBJECTIVE: We studied the relationship among the different HCV types, source, duration, and stage of infection in 100 patients from the Apulia, southern Italy, selected from consecutive clinical records. They were 20 parenterally infected haemophiliacs with 10-20 years of disease history, but without cirrhosis; 20 patients (matched for sex, age and disease) and without known risk factor for parenteral infections; 60 patients with community acquired infection (ten with CAH and ten with cirrhosis with less than 20 years disease history; 20 with cirrhosis and hepatocellular carcinoma (HCC) and more than 20 years of liver disease and 20 matched cases with cirrhosis without HCC). RESULTS: Type 1 and 2 HCVs had comparable prevalence in patients with long lasting and recent HCV infection, 56 and 64%, 26 and 30% respectively. HCV type 3 was found in 6.5-12% of the patients with recent HCV infection, but it was not detected in those with infection longer than 20 years. Type 1 b HCV was more frequently found in HCC patients (68% of cases) than in the other forms of liver disease. The opposite was observed for HCV types (2 and 3). CONCLUSIONS: The prevalence of the different HCV types appears associated with the source and duration of the infection. The interesting association between HCV type 1 b and HCC prompts further studies in larger series of patients.

Adolescent↗

A new hepatitis C virus-like flavivirus in patients with cryptogenic liver disease associated with elevated GGT and alkaline phosphatase serum levels.

The intriguing co-infection of two flaviviruses (GBV-A and GBV-B) in tamarins and the recent discovery of another flavivirus (GBV-C/HGV) in humans raises the question of the relations between hepatitis C virus (HCV) and GBV-C/HGV. To address this issue the sera of 285 patients with liver disease (102 patients with cryptogenic and 183 with known forms of chronic liver disease) and 19 patients without liver disease were tested for HGV-RNA. GBV-C/HGV-RNA was detected by RT-PCR using primers encompassing 5'NC and NS5 regions and hybridization with specific biotinilated and radiolabelled probes. GBV-C/HGV RNA was found in 11 of 20 (55%) acute hepatitis C patients, in 13 of 117 (11.1%) patients with chronic hepatitis C, in 11 of 27 patients with a liver transplant (40.7%), one of 19 (5.3%) patients with chronic HBV infection, 15 out of 102 (14.7%) patients with cryptogenic liver disease and two out of 19 patients with inflammatory bowel disease. In cryptogenic patients, elevated serum gammaglutamyl transpeptidase (GGT, higher than twice the normal values) and alkaline phosphatase (ALP, above normal values) levels were significantly associated with GBV-C/HGV-RNA infection (P < 0.001). In conclusion GBV-C/HGV appears to be transmitted in humans by blood exposure and to be associated with liver disease in HCV co-infected patients and in a minority of patients with cryptogenic disease. The virus is only occasionally pathogenic for the liver and when liver damage is present; the association with the combined elevation of GGT and APH serum levels might represent a specific feature of the liver tropism of the agent.

Adolescent↗

Impact of interferon-alpha therapy on the development of hepatocellular carcinoma in patients with liver cirrhosis: results of an international survey.

Clinico-epidemiological data show that the most severe forms of hepatitis C virus (HCV) associated liver disease occur in patients with multifactorial liver damage. We found that the prevalence of hepatitis B virus (HBV) markers in anti-HCV positive patients with cirrhosis complicated by hepatocellular carcinoma (HCC) is higher than in cirrhotics with comparable age and disease history, but without HCC. HBV can persist in integrated forms in HBsAg negative, anti-HBc positive individuals and we may speculate that in such patients concurrent liver pathogens, as HCV, could cause HCC more easily than in patients without previous exposure to HBV. Analysing the relations between age at HCC diagnosis and the different risk factors in consecutive HCC patients we found that patients with single hepatitis virus infections (HBsAg and/or anti-HCV positive) were of an older median age than patients with multiple hepatitis virus infections. We also studied patients with compensated cirrhosis and hepatitis virus infections. untreated or treated with interferon-alpha. The independent effect of treatment was analysed by matching groups with regard to all the other significant HCC risk factors. The overall relative HCC risk was three times higher (risk ratio 3.1) in untreated vs treated anti-HCV positive patients and more than six times higher (risk ratio 6.2) in untreated vs treated anti-HCV positive/anti-HBc negative patients. The difference between treated and untreated patients was not statistically significant in hepatitis B surface antigen carriers and in anti-HCV positive/anti-HBc positive patients. The evidence that HBV coinfection may worsen the course of liver cirrhosis in patients with chronic hepatitis C is intriguing, but it has important practical consequences. It warrants the identification of high risk patients with chronic hepatitis C who need to be treated as early as possible and patients who can still benefit from interferon-alpha therapy once cirrhosis has already been diagnosed.

Carcinoma, Hepatocellular↗

Clinical relevance of anti-interferon antibodies in the serum of chronic hepatitis C patients treated with interferon-alpha.

The development of anti-interferon (anti-IFN) antibodies in the serum of patients undergoing antiviral therapy has been postulated as one possible cause of interpatient variability in response to therapy. We analyzed the relationship between the appearance of anti-IFN antibodies and the loss of response to interferon-alpha (IFN-alpha), as characterized by a breakthrough of serum aminotransferase after a period of complete biochemical remission. The analysis involved clinical trials where neutralizing anti-IFN antibodies were detected by standardized and comparable methods. The results show that a time relationship between breakthrough and anti-IFN antibodies is observed in only a few cases and is independent of the type of IFN-alpha preparation used. Thus, causes of IFN resistance other than anti-IFN antibodies must also be implicated in most breakthrough cases. Another potential is the selection of drug-resistant viral strains. Current ration behavior following the appearance of breakthrough (from whatever cause) in clinical practice advocates changing treatment to a different type of IFN-alpha. The detection of anti-IFN enzyme-linked immunosorbent assay (ELISA) antibodies or IFN neutralizing antibodies does not appear to provide any additional information for decision making.

Alanine Transaminase↗