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Biomedical subjects

A Alexopoulou

Publications and source records attributed to A Alexopoulou.

17 recordsLinked to original sources
PubMed2006

Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations.

Hepatitis B virus (HBV) strains carrying the precore stop-codon mutation (A1896) have been considered among the predisposing factors for reactivation during chemotherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV serological markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cytotoxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regimens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO-LiPA HBV PreCore kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)-(+)/hepatitis B e antigen (HBeAg)-(-) before chemotherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg-(-)/anti-HBs-(+)/anti-hepatitis B core (HBc)-(+)/HBeAg-(-) before chemotherapy. One of them reverted to HBeAg-(+) status but remained HBsAg-(-), while the other became HBsAg-(+)/HBeAg-(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild-type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop-codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild-type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg-(-) patients who had been anti-HBs-(+).

Adolescent↗
PubMed2005

Genetic heterogeneity of hepatitis viruses and its clinical significance.

The genetic heterogeneity of hepatitis B virus (HBV) (8 genotypes A-H) has been applied for tracing the route of HBV transmission and the geographical migration of HBV carriers but it also appeared to have clinical implications. The secondary structure of e encapsidation signal could explain why the precore mutant virus prevails in Mediterranean countries, where genotype D is most prevalent, while the wild type virus is frequent in Western countries, where genotype A is most prevalent. There is increasing evidence that patients infected with genotype C have more severe outcome of chronic liver disease than those infected with genotype B. Genotype B was associated with fulminant hepatitis and more severe episodes of acute exacerbation of chronic HBV infection. Patients infected with genotype B appeared to seroconvert earlier than those infected with genotype C. The hepatitis delta virus (HDV) has 3 genotypes (I, II, III) which are associated with different disease patterns. Genotype III is the most distantly related HDV genotype and is associated with the most severe outcome while genotype II with relatively mild liver disease. The most geographically widespread genotype is I and is associated with a broad spectrum of chronic liver disease. The hepatitis C virus (HCV) displays high genetic heterogeneity with six genotypes (1-6), multiple subtypes and quasispecies. This viral diversity has epidemiological and clinical implications and has been associated with the severity of liver disease, prognosis, response to treatment and failure to generate an effective protective vaccine. HCV genotype 1 is the predominant genotype in Western countries and has been associated with a low response rate to interferon-alpha (IFN-alpha) or to the combination of ribavirin and IFN-alpha. Consequently the duration of treatment has been tailored according to HCV genotype.

Animals↗
PubMed2004

Intestinal pseudo-obstruction and ureterohydronephrosis as the presenting manifestations of relapse in a lupus patient.

Intestinal pseudo-obstruction (IPO) is a rare complication of systemic lupus erythematosus (SLE). We present a 32-year old female with SLE for seven years. She was admitted with profound fatigue, frequent vomiting, colicky abdominal pain, diarrhoea and intermittent dysuria for the past 12 months. Imaging studies revealed dilated small and large bowel loops with thickened intestinal wall and multiple fluid levels. Urinary tract involvement was also demonstrated. The patient responded well to immunosuppressive treatment. IPO in the context of SLE has been described only in anecdotal case reports. Half of the cases developed this complication during the course of lupus as in the present case. Concomitant ureterohydronephrosis was present in approximately two-thirds of the cases. Early recognition of the syndrome is necessary for the institution of the appropriate medical treatment and prevention of inappropriate surgical intervention.

Adult↗
PubMed2000

Interferon treatment with or without oral ganciclovir in HBeAg-negative chronic hepatitis B: a randomized study.

The treatment of HBeAg-negative chronic hepatitis B with alpha interferon alone is unsatisfactory. We evaluated the efficacy of combined administration of interferon-a2a (IFN) with oral ganciclovir, a nucleoside analogue. Forty patients with hepatitis B virus (HBV)-DNA-positive/HBeAg-negative chronic hepatitis B, were randomized to receive 4.5 MU IFN thrice weekly, subcutaneously, alone or in combination with 3 g ganciclovir per os daily for 26 weeks and followed for 12 months after treatment. Mean serum HBV-DNA levels decreased by 4.0 log10 in the combination group (from 5 x 106 to 4.8 x 102 copies/ml) and by 2.2 log10 in the interferon group (from 8 x 106 to 4.8 x 104 copies/ml) by quantitative polymerase chain reaction (PCR). HBV-DNA became undetectable in 11 of 20 (55%) and in three of 20 (15%) patients in the two groups, respectively (P=0.02). The alanine aminotransferase levels became normal in all patients receiving combination therapy, compared to 75% of those in the interferon group. After cessation of therapy, HBV-DNA increased or reappeared in all patients with 85% also relapsing biochemically. One year after treatment, three patients in each group (15%) remained in sustained biochemical remission with very low serum HBV-DNA levels (median 15 700 copies/ml). We conclude that, in HBeAg-negative chronic hepatitis B, 6-month combination therapy with oral ganciclovir and IFN is associated with complete biochemical remission in all treated patients and a 4 log10 decrease in serum HBV-DNA levels. The end of treatment efficacy of this combination scheme is far super- ior to that of IFN monotherapy but sustained responses are few. Further studies are warranted to evaluate the efficacy of prolonged combination schemes with nucleoside analogues and IFN, compared to IFN monotherapy.

Administration, Oral↗
PubMed1998

Core variability does not affect response to interferon alpha in HBeAg negative chronic hepatitis B.

BACKGROUND/AIMS: The pre-core stop codon variant (A 1896) of hepatitis B virus (HBV) has been associated with chronic active liver disease with acute exacerbations and a high relapse rate after an initial response to alpha-interferon (IFN-alpha) therapy. Poor sustained response has been correlated with a high prevalence of mutations in the core region, potentially enabling escape from the immune system. The aim of this study was to analyse the predictive factors of response to IFN-alpha in such patients. METHODS: We studied the baseline clinical, biochemical, histological, serological and virological parameters in 30 hepatitis B s antigen positive (HBsAg-positive)/hepatitis B e antigen negative (HBeAg-negative) Greek patients with chronic liver disease. The patients were selected from a cohort who received IFN-alpha for 24 weeks. These were divided into three groups of ten sequential patients: those with no response to IFN-alpha treatment, those who relapsed after an initial response, and those with a sustained response. Serum HBV DNA was measured by a liquid hybridisation method, and the anti-HBc IgM was quantitated by the IMx analyser. The amino-acid sequence of core protein residues 40-89, a region where a clustering of mutations has been detected previously in severe hepatitis, was compared with a sequence from an HBeAg positive patient with chronic liver disease. RESULTS: Multiple logistic regression analysis showed that the initial response to IFN-alpha could be predicted by pre-treatment absence of HBcAg staining in the liver and high ALT values, but no parameter could predict sustained response. The pre-treatment extent and pattern of aminoacid substitutions in the core region sequenced was similar in all groups studied and was not associated with IFN-alpha response. CONCLUSIONS: In HBsAg-positive/HBeAg-negative patients with chronic liver disease, response to IFN-alpha therapy was not correlated with genomic variability of the core region. Other parameters such as pre-treatment HBcAg positivity in the liver and alanine aminotransferase values indicative of disease activity before treatment were associated with initial IFN-alpha response.

Adult↗
PubMed1997

Emergence and selection of HBV variants in an anti-HBe positive patient persistently infected with quasi-species.

BACKGROUND/AIMS: Infection with the hepatitis B e antigen (HBeAg) negative variant of hepatitis B virus (HBV) causes chronic liver disease characterised by occasional acute exacerbations. This virus exhibits a high prevalence of mutations in the core region. Our aim was to study the changes in the pre-core/core region of the virus in relation to exacerbations of the disease. METHODS/RESULTS: We performed direct sequencing on DNA amplified from 7 sequential sera taken over a 5-year period from a hepatitis B surface antigen (HBsAg) and anti-HBe positive Greek patient infected with the HBeAg negative variant. The patient had chronic hepatitis with several acute exacerbation episodes and underwent interferon therapy twice. We found significant variability in the core region at different time points. To determine whether these variants were present in the initial serum sample and subsequently selected under immune pressure or whether they arose de novo during the course of the disease, we cloned the pre-core/core region from 4 sera before and after episodes of acute exacerbation. Fifteen clones from each time point were sequenced. Fourteen nucleotide mutations in the pre-core/core region were recorded, 7 (50%) of which led to amino-acid substitutions. All the amino-acid changes occurred at recognised B- and CD4+ epitopes. The cloning results indicate the presence of quasi-species in all the samples investigated. Some of the variants present as a minor population in the first sample appear to have been selected and become dominant in subsequent sera. However, the emergence of novel variants, not present at a detectable level in earlier samples, during the course of the disease, was also established. The quasi-species nature of HBV only became apparent after the cloning experiments and was not obvious from the direct sequencing results. CONCLUSIONS: New dominant variants occurring during the course of the disease arose either by the selection of pre-existing mutants that were not detected by direct sequencing or by mutation of existing strains. All changes were located within B- and CD4+ epitopes. The continuous production and selection of variants may enable virus to evade elimination by the immune system, resulting in persistent infection.

Adult↗
PubMed1996

Whole genome analysis of hepatitis B virus from four cases of fulminant hepatitis: genetic variability and its potential role in disease pathogenicity.

The precore stop-codon variant of hepatitis B virus (HBV) has been associated with fulminant hepatitis but is also found in patients with persistent infection and chronic hepatitis. We have examined the possibility that the severe outcome of infection in patients with fulminant disease may be a result of additional genomic variation. We sequenced the entire HBV genome from three patients of Greek and one patient of Chinese origin with fulminant hepatitis, and from two patients with hepatitis B e antigen (HBeAg) positive chronic infection from the same regions, using direct sequencing of amplified viral DNA. Three of the fulminant cases were infected with the precore stop-codon variant HBeAg negative) and the fourth with the wild-type (HBeAg) positive virus. We compared sequences from our four fulminant isolates, and an additional fulminant isolate reported by others, with HBeAg positive carriers from the same regions and 12 published HBV genomes. There was a higher number of nucleotide and amino-acid substitutions throughout the HBV genome in the precore variant fulminant sequences than in the wild type. A cluster of mutations previously identified in the X region (126-132) in sequences reported in Japanese patients and encompassing the Enhancer II-Core Promoter region (1751-1768), were not found in our patients. We conclude that although there are no changes common to all sequences of HBV isolates from fulminant cases, some of these changes are in recognized cis-acting regulatory elements, whilst others are in the immediate vicinity of such elements. The effect of these mutations on viral genome transcription must now be determined.

Amino Acid Sequence↗
PubMed1995

Fulminant hepatitis associated with hepatitis B virus e antigen-negative infection: importance of host factors.

The precore stop-codon variant of hepatitis B virus (HBV) has been implicated in fulminant hepatitis. The precore/core regions of such variants from two sets of patients with interpartner transmission resulting in fulminant hepatitis in the contact, were sequenced to establish whether further sequence variations in the core region are specifically associated with the fulminant disease. In both sets of patients, there was sequence diversity of the precore/core region from the wild type, leading to numerous amino acid substitutions in the core region. Between the infecting source and the contact, there was only one amino acid change in one set of patients and none in the other. In addition, in the second set of patients, serum samples from four different time points were investigated. Sequence data showed no variation in each patient at the nucleotide level in the core region, even in the case of the source, who was followed for 3 years. In this same pair of subjects, the remainder of the genome was sequenced and was identical at the nucleotide level. Therefore, it appears that, at least in some cases of fulminant hepatitis caused by infection with the precore variant, the nucleotide sequence of the patient with fulminant hepatitis is identical to that observed in the asymptomatic source of infection. These data indicate that the severity and outcome of infection in such cases are unrelated to any additional variation in the entire HBV genome, and that the changed clinical picture is dependent on host factors, possibly the HLA environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Hepatitis C virus infection in Greece and its role in chronic liver disease and hepatocellular carcinoma.

The aim of this study was to evaluate the prevalence of hepatitis C virus infection (HCV) in Greece, to estimate its frequency in chronic liver disease and to explore the role of HCV infection in the aetiology of hepatocellular carcinoma. A series of 1034 patients with chronic liver disease of various aetioloigies and 299 patients with hepatocellular carcinoma allocated to two case-control studies was tested for anti-HCV. Twelve recent reports on HCV infection in Greece were reviewed and analyzed. The results of the present study indicate the existence of a large pool of HCV infection in Greece and an impressive spread of the virus in high-risk groups. Chronic HCV infection was found to account for 83.6% of patients with chronic non-A, non-B hepatitis parenterally transmitted, 56.5% of cases of sporadic community-acquired disease and for almost 1/4 of all patients with chronic liver disease. The relative risks for development of hepatocellular carcinoma of patients with chronic HCV infection was 6.3 in the first and 13.7 in the second case-control study, increasing to 20.0 and 18.7, respectively, when hepatitis B surface antigen (HBsAg) was positive. Serum HBV-DNA was positive and/or anti-HBc IgM levels were high in 12 of 15 (80%) patients with hepatocellular carcinoma positive only for HBsAg, and in 7 of 15 (47%) positive both for HBsAg and antibodies to HCV. The present data support the view that hepatitis B and C virus have an interacting role in the origin of hepatocellular carcinoma.

Biomarkers↗
PubMed1993

Clinical significance of quantitative anti-HBc IgM assay in acute and chronic HBV infection.

The applicability and clinical usefulness of anti-HBc IgM quantification in acute and chronic hepatitis type B by a single run of undiluted sera is largely unknown. Serum anti-HBc IgM concentrations were measured in 153 patients with various forms of acute and chronic HBV infection by a new commercially available qualitative ELISA/2-step capture assay applying streptavidin technology. The absorbance values were expressed in anti-HBc IgM U/ml using a calibration curve produced by a series of anti-HBc IgM standards. The results were compared with those obtained with another second generation qualitative anti-HBc IgM method also in undiluted sera applying the Microparticle Enzyme Immune Assay (MEIA). In acute hepatitis B, anti-HBc IgM was always > 600 U/ml (median: > 800 U/ml) declining to median values of 135 and 85 U/ml at months 3 and 6, respectively. Values above 600 U/ml were seen in 4 out of 20 (20%) HBsAg carriers with episodes of severe HBV-induced liver damage resembling acute hepatitis B (group 2) and in 2 out of 35 (5.6%) patients with HBV induced chronic active hepatitis (group 3). Values above 100 U/ml, representing the cutoff levels for the diagnosis of acute hepatitis B in the qualitative assays, were detected in 55% (11/20) and 45.7% (16/35) of the above patients of groups 2 and 3, respectively. Anti-HBc IgM was negative or under 20 U/ml in 96.7% (29/30) of HBsAg carriers with acute or chronic liver damage unrelated to HBV (HDV, HCV or drug-induced) and in 91% (41/45) of HBsAg carriers with persistently normal ALT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1991

The role of the hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece.

HDV infection has been documented in Greece for more than 3 decades. Its epidemiology appears to be changing over the years with a decrease in the general Greek population and an invasion of the delta virus in the community of drug addicts. For the time being HDV infection has a low endemicity in the general greek population, it has been detected with high endemicity in a rural community and it is spreading epidemically in the new, increasing population of Greek drug addicts. Chronic HDV infection has been detected constantly over 20 years with a higher frequency in HBsAg positive chronic liver disease (19.5-33.5%) than in asymptomatic HBsAg carriers with normal liver enzymes (5.9-9.2%). However, in the community of Archangelos, where HDV infection is highly endemic, and probably also all over Greece, the total number of chronic HDV carriers with minimal or no liver disease appears to be higher than those with severe liver damage. HDV infection plays a significant role in terms of morbidity and mortality from acute and chronic liver disease in Greece but the situation would have been much worse if chronic HDV infection was invariably associated with severe liver damage.

Acute Disease↗
PubMedDate not supplied

Prolonged cholestatic jaundice after endoscopic retrograde cholangiography.

The main complications of endoscopic retrograde cholangiography and sphincterotomy are bleeding, pancreatitis, perforation and sepsis. Two cases of unexplained prolonged cholestatic jaundice in patients who underwent endoscopic retrograde cholangiography (ERC) for biliary obstruction due to choledocholithiasis are reported. The patients were admitted because of right upper quadrant pain, vomiting and jaundice. Laboratory tests showed increased levels of total and conjugated serum bilirubin and increased alkaline phosphatase. Ultrasound examination showed cholelithiasis and choledocholithiasis with bile duct dilatation. ERC with sphincterotomy was performed and gallstones obstructing the common bile duct were removed endoscopically. Following ERC and despite complete patency of the biliary tree, a progressive increase of total and conjugated bilirubin and of alkaline phosphatase was noted, associated with itching and total stool discoloration. The insertion of nasobiliary drain did not improve the jaundice. Prednisolone treatment for 12 days was associated with progressive restoration of serum bilirubin alkaline phosphatase to normal levels. It was postulated that the radiocontrast material used may have acted toxically on the liver with disruption of the canalicular plasma membrane. It is proposed that intrahepatic cholestasis should be added in the list of complications of endoscopic retrograde cholangiography.

Adult↗