Hepatitis: Verslype C

Colle I, Adler M, Brenard R, Henrion J, Langlet P, Michielsen P, Orlent H, Reynaert H, Sprengers D, Stärkel P, Van Damme P, Verslype C, Delwaide J, Anonymous00199. · Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, De Pintelaan 185, 9000 Gent, Belgium. · Acta Gastroenterol Belg. · Pubmed #18330099 No free full text.

This publication has no abstract.

Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, Van Geet C, Cassiman D. · Laboratory of Hepatology, Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium. · Aliment Pharmacol Ther. · Pubmed #18331464 No free full text.

Abstract: BACKGROUND: The liver plays a central role in coagulation and fibrinolysis but is also closely intertwined with the function and number of blood platelets. AIM: To describe and integrate all literature concerning blood platelets and liver disease by performing a thorough literature research. METHODS: A thorough literature research on 'blood platelets' and 'liver disease' was performed. RESULTS: Thrombocytopenia is a marked feature of chronic liver disease and cirrhosis. Traditionally, this thrombocytopenia was attributed to passive platelet sequestration in the spleen. More recent insights suggest an increased platelet breakdown and to a lesser extent decreased platelet production plays a more important role. Besides the reduction in number, other studies suggest functional platelet defects. This platelet dysfunction is probably both intrinsic to the platelets and secondary to soluble plasma factors. It reflects not only a decrease in aggregability, but also an activation of the intrinsic inhibitory pathways. The net effect, finally, is a decreased platelet function in the various types of chronic liver diseases and cirrhosis. Finally, recent data suggest that platelets are not only affected by but can also contribute to the liver disease process, as for instance, in viral hepatitis and cholestatic liver disease. CONCLUSION: Platelet research in liver disease is a growing area of investigation and could provide new pathophysiological insights.

Decock S, Verslype C, Fevery J. · Gastro-enterology/Hepatology, University Hospital Leuven, Herestraat 49, 3000 Leuven. · Acta Clin Belg. · Pubmed #17547292 No free full text.

Abstract: Worldwide approximately 200 million people are chronically infected with hepatitis C virus (HCV). Chronic HCV infection represents the leading cause of liver cirrhosis and the main indication for liver transplantation in the western world. In addition, chronic HCV infection is associated with numerous clinical manifestations, including type 2 diabetes. An obvious and frequently suggested explanation for the connection between HCV infection and type 2 diabetes is that cirrhosis by itself causes insulin resistance. However, the prevalence of type 2 diabetes in HCV cirrhosis is higher than in HBV cirrhosis (23.6% vs 9.4%). This suggests that HCV infection by itself can lead to insulin resistance and predispose to the onset of type 2 diabetes. First, HCV core protein induces hepatic steatosis by inhibition of microsomal triglyceride transfer protein and hepatic steatosis causes insulin resistance. Secondly, HCV core protein inhibits, through elevation of TNF-alfa and other factors, the insulin-signalling pathways causing insulin resistance. Moreover, recent data strongly suggest that insulin resistance is an important predictor of poor response to antiviral therapy in chronic hepatitis patients treated with peginterferon plus ribavirin.

Lin L, Verslype C, van Pelt JF, van Ranst M, Fevery J. · Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium. · Eur J Gastroenterol Hepatol. · Pubmed #17099381 No free full text.

Abstract: Coinfection with other hepatitis viruses modifies the viral profile in serum and leads to more liver damage and more rapid progression during the course of hepatitis C virus infection. The viral interference is not only carried out by virus-virus or by virus-cell interactions but also by an enhanced immune response. A superinfecting viral infection does not crossactivate protective immune responses to the pre-existing virus albeit the latter can become undetectable. The induced cytokine stimulation might enhance the hepatic inflammation. Moreover, hepatitis B virus coinfection increases the risk of development of hepatocellular carcinoma in hepatitis C virus patients through common necro-inflammatory pathways or by direct oncogenic activity of hepatitis B virus. Viral interaction also complicates the management of the coinfection because hepatitis C virus impairs the humoral response to hepatitis A virus and hepatitis B virus vaccines, and because pharmacological suppression of hepatitis C virus endangers dually infected patients with reactivation of coinfected hepatitis B virus. Optimized strategies and follow-up are thus necessary in the treatment of infection with multiple viruses. It seems thus necessary to look for markers of hepatitis B virus and/or hepatitis D virus infection in chronic hepatitis patients positive for hepatitis C virus antibodies but negative for hepatitis C virus RNA, and equally well to search for hepatitis C virus RNA in HBsAg-negative/anti-HBc-positive patients with a low level of serum hepatitis B virus DNA.

Verslype C, Michielsen P, Adler M, Orlent H, Sprengers D, Delwaide J, D'heygere F, Langlet P, Brenard R, Colle I, Reynaert H, Stärkel P, Henrion J, Anonymous00136. · Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #16268417 No free full text.

Abstract: Infection with the hepatitis C virus (HCV) represents an important public health problem and is a leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Chronic hepatitis C is a heterogeneous disease. Many patients have mild disease at presentation but not all of them will develop advanced liver disease. However, the identification of these patients with mild hepatitis C who will show progressive disease is difficult and is based on histological criteria and the assessment of co-factors (age, alcohol intake, steatosis). In addition, serum transaminases that are persistently normal on several occasions during 18 months may point to a more benign course. Patients with mild hepatitis C should not be excluded "a priori" from the possibility of being treated, as treatment with pegylated interferon and ribavirin is safe and effective in this group. Overall, the decision to initiate therapy should be individualized and based on the severity of the disease by liver biopsy, the potential of serious side effects, the probability of response and the motivation of the patient.

Verslype C, Yap SH. · Department of Liver and Pancreatic Disease, UZ Gasthuisberg, Leuven Belgium. · Acta Gastroenterol Belg. · Pubmed #10925475 No free full text.

This publication has no abstract.

Cornelis T, Hiele M, Vermeire S, Libbrecht L, Verslype C. · Department of Medicine, Division of Gastroenterology, University Hospitals Leuven, Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #18720941 No free full text.

Abstract: We report on a patient who was diagnosed six years before with celiac disease, with a current combined problem of asplenism, mesenteric cysts and elevated liver function tests. The implications of splenic atrophy mimic those of post-splenectomy patients. Mesenteric lymph node cavitation is a rare complication of celiac disease that is most often associated with splenic atrophy. The pathogenesis is unknown. The clinical implications of the cavitated mesenteric lymph nodes are unclear. The association of celiac disease with liver disease was reported many years ago, but only recently these associations have been more clearly defined. Liver involvement shows a clinical spectrum varying from nonspecific reactive hepatitis, chronic active hepatitis, steatohepatitis to frank cirrhosis. Associations with autoimmune hepatitis, autoimmune cholangitis, primary biliary cirrhosis and primary sclerosing cholangitis have been described. In our patient, we found no obvious cause for the necrotizing hepatitis and the negative auto-antibodies made it impossible to firmly establish the diagnosis of autoimmune hepatitis. The causal relationship with celiac disease, if any, remains unproven.

Severi T, Vander Borght S, Libbrecht L, VanAelst L, Nevens F, Roskams T, Cassiman D, Fevery J, Verslype C, van Pelt JF. · Laboratory of Hepatology, University Hospital Gasthuisberg, O&N Building Bus 703, Herestraat 49, Leuven, Belgium. · Chem Biol Interact. · Pubmed #17482587 No free full text.

Abstract: Hepatitis virus replication in the liver is often accompanied by inflammation resulting in the formation of reactive oxygen species (ROS) and nitric oxide (NO) and these may induce cell death. We investigated whether the expression of HBx or HCV core protein in HepG2 cells has an influence on the sensitivity of these cells for oxidative radicals. Our previous study, using the inducible HBV model of HepAD38, revealed that oxidative-stress-related genes are upregulated by virus replication. In the present study, we examined the intracellular pro-oxidant status with dichlorofluorescein (DCF) in HepG2 cell lines transfected with HBx, HbsAg and HCV core. Baseline intracellular oxidative levels were not different in the cell lines expressing viral proteins as compared to control. However, when these cells were exposed to H(2)O(2), the viral protein expressing cells, especially those expressing HBx, showed a reduced level of ROS. This suggests that HBx and HCV core transfected cells can convert H(2)O(2) to less reactive compounds at a higher rate than the control cells. When HBx or HCV core expressing cells were exposed to peroxynitrite (a highly reactive product formed under physiological conditions through interaction of superoxide (O(2)(-)) with NO) these cells were less sensitive to induction of cell death. In addition, these cell lines were less prone to cell death when exposed to H(2)O(2) directly. In conclusion, HBx and HCV core expression in HepG2 cells leads to a survival benefit under oxidative stress which in vivo can be induced during inflammation.

Katoonizadeh A, Decaestecker J, Wilmer A, Aerts R, Verslype C, Vansteenbergen W, Yap P, Fevery J, Roskams T, Pirenne J, Nevens F. · Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium. · Liver Int. · Pubmed #17355453 No free full text.

Abstract: AIMS/BACKGROUND: A model for end stage liver disease (MELD) score >30 was proposed as an excellent predictor of mortality in patients with non-acetaminophen-induced acute liver failure (ALF). We analyzed the prognostic value of MELD score in our patients with ALF who were prospectively registered in our database since 1990. METHODS: Overall, 106 patients met the criteria of ALF. Excluding seven patients with acetaminophen etiology, 99 patients (42+/-15 years, 40M/59F) were studied. RESULTS: Causes were cryptogenic (n=38), viral (n=29), drugs (n=20) and miscellaneous (n=12). Of these, 37% (n=37) survived with medical management alone (group I), 16% (n=16) died (group II) and 46% (n=46) underwent liver transplantation (group III). The strongest predictors of poor outcome were advanced encephalopathy, cryptogenic/drug-induced/hepatitis B etiology and a high MELD score. At the time of diagnosis, King's College Hospital criteria and MELD score >30 had similar high negative predictive value (92% and 91%, respectively) and low positive predictive value (52% and 56%, respectively). The predictive values improved only slightly during follow-up. The best cut-off point for MELD score to discriminate between survivors and nonsurvivors was >35, with a sensitivity and specificity of 86% and 75%, respectively. CONCLUSIONS: MELD score, which mostly takes into consideration the degree of liver impairment, has a similar prognostic value as King's College Hospital criteria to predict outcome in adult patients with nonacetaminophen-induced ALF. Overall, all current scores miss accuracy and therefore there is a clear need for factors that can better predict the regeneration of the liver in this setting.

Severi T, Ying C, Vermeesch JR, Cassiman D, Cnops L, Verslype C, Fevery J, Arckens L, Neyts J, van Pelt JF. · Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium. · Mol Cell Biochem. · Pubmed #16960659 No free full text.

Abstract: We used human hepatoma HepAD38 cells, in which HBV production is under the control of a tetracycline-regulated promotor, to investigate changes induced in the host cell by HBV replication that could contribute to malignant transformation. Parameters of oxidative stress (malondialdehyde, glutathione) and cell proliferation were determined at different times after induction (0-96 h). In HBV-producing cells, the redox status peaked at 72 h. cDNA micro array analysis at 72 h post induction revealed 3 groups of genes that were up-regulated by HBV: (i) heat shock proteins, (ii) oxidative and metabolic stress and (iii) growth and apoptosis related genes. Continuous HBV production did not accelerate karyotypic changes in cells cultured for 4 months (18 passages). In conclusion: HBV replication modulates host gene expression and induces oxidative stress. In this HepAD38 model early events (0-4 days) in the host cell after induction of HBV replication can be studied under strictly defined conditions.

Durnez A, Verslype C, Nevens F, Fevery J, Aerts R, Pirenne J, Lesaffre E, Libbrecht L, Desmet V, Roskams T. · Department of Morphology and Molecular Pathology, KULeuven University Hospital Gasthuisberg, Belgium. · Histopathology. · Pubmed #16879391 No free full text.

Abstract: AIMS: Cytokeratin (CK) 7 and CK19 expression, present in hepatic progenitor cells (HPCs) and in cholangiocytes but not in normal hepatocytes, has been reported in some hepatocellular carcinomas (HCCs); however, the incidence and relevance of this expression in HCC in Caucasians is not known. Therefore, our aim was to study the occurrence and clinicopathological characteristics of HCC expressing CK7 and/or CK19 in 109 Caucasian patients. METHODS AND RESULTS: The expression of hepatocellular differentiation markers (Hepar, canalicular polyclonal carcinoembryonic antigen), biliary/progenitor cell markers (CK7, CK19), alpha-fetoprotein (AFP), p53 and beta-catenin in HCC was semiquantitatively assessed by immunohistochemistry. Of 109 HCCs, 78 were CK7-/CK19- (72%), 13 CK7+/CK19- (12%), seven CK7-/CK19+ (6%), 11 CK7+/CK19+ (10%). CK19 expression was significantly associated with elevated serum AFP (400 ng/ml) (P = 0.023), tumour AFP expression (P < 0.0001), presence in serum of anti-hepatitis B core (P = 0.016), less fibrosis in non-neoplastic parenchyma (P = 0.009) and less nuclear beta-catenin expression (P = 0.021). CK7 expression was significantly associated with elevated serum bilirubin (> 2 mg/dl) (P = 0.0005) and less nuclear beta-catenin expression (P = 0.003). HCC expressing CK19 had a higher rate of recurrence (P = 0.009, hazard ratio 12.5, n = 31) after liver transplantation compared with CK19- tumours. CONCLUSIONS: In our series, 28% of HCCs contained cells expressing CK7 and/or CK19. They potentially derive from HPCs. The higher recurrence rate of CK19+ HCC after transplantation suggests a worse prognosis for these HCCs compared with CK19- HCC.

Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, Verslype C, Fevery J, Nevens F. · Department of Hepatology, University Hospital Gasthuisberg, KU Leuven, Belgium. · Crit Care. · Pubmed #16859530 links to  free full text

Abstract: INTRODUCTION: Patients with acute-on-chronic liver failure show an aggravated hyperdynamic circulation. We evaluated, in a controlled manner, potential changes in systemic haemodynamics induced by the molecular adsorbent recirculating system (MARS) and the Prometheus system liver detoxification devices in a group of patients with acute-on-chronic liver failure. METHODS: Eighteen patients (51.2 +/- 2.3 years old; Child-Pugh score, 12.5 +/- 0.2; Maddrey score, 63.1 +/- 5.0; hepatic venous pressure gradient, 17.6 +/- 0.9 mmHg) with biopsy-proven alcoholic cirrhosis and superimposed alcoholic hepatitis were either treated with standard medical therapy (SMT) combined with MARS (n = 6) or Prometheus (n = 6) or were treated with SMT alone (n = 6) on three consecutive days (6 hours/session). Liver tests, systemic haemodynamics and vasoactive substances were determined before and after each session. RESULTS: Groups were comparable for baseline haemodynamics and levels of vasoactive substances. Both MARS and Prometheus decreased serum bilirubin levels (P < 0.005 versus SMT), the Prometheus device being more effective than MARS (P = 0.002). Only MARS showed significant improvement in the mean arterial pressure (Deltachange, +9 +/- 2.4 mmHg versus -0.3 +/- 2.4 mmHg with Prometheus and -5.2 +/- 2.1 mmHg with SMT, P < 0.05) and in the systemic vascular resistance index (Deltachange, +131.5 +/- 46.2 dyne x s/cm5/m2 versus -92.8 +/- 85.2 dyne x s/cm5/m2 with Prometheus and -30.7 +/- 32.5 dyne x s/cm5/m2 with SMT; P < 0.05), while the cardiac index and central filling remained constant. This circulatory improvement in the MARS group was paralleled by a decrease in plasma renin activity (P < 0.05), aldosterone (P < 0.03), norepinephrine (P < 0.05), vasopressin (P = 0.005) and nitrate/nitrite levels (P < 0.02). CONCLUSION: The MARS device, and not the Prometheus device, significantly attenuates the hyperdynamic circulation in acute-on-chronic liver failure, presumably by a difference in removal rate of certain vasoactive substances. These findings suggest conspicuous conceptual differences among the albumin dialysis devices.

Verslype C, George C, Buchel E, Nevens F, van Steenbergen W, Fevery J. · Department of Medicine, Division of Liver and Pancreas Diseases, University Hospital Gasthuisberg, B 3000 Leuven, Belgium. · Aliment Pharmacol Ther. · Pubmed #15771755 links to  free full text

Abstract: AIM: To study features in older patients with autoimmune hepatitis, as this was considered mainly a disease of young females. METHODS: Analysis of 28 patients diagnosed at age > or =65 years compared with 84 younger patients. RESULTS: The incidence was similar at all age decades. The ratio M:F was 1:3 (> or =65 years) vs. 1:2 (<65 years). Presenting symptoms were not different when compared with younger patients and consisted of general malaise and fatigue (36%), jaundice +/- other symptoms (50%), or ascites (11%). Antinuclear antibodies (ANA) > or = 1/80 were positive in 93%, smooth muscle antibodies (SMA) > 1/40 in 50%, anti-liver kidney microsomes (anti-LKM) proved always negative. Histology showed acute necrotizing hepatitis in 19%, severe interphase hepatitis in 15%, chronic hepatitis with plasmo-lymphocytic infiltrate in 30%, cirrhosis in 29% (with active inflammation in one-third); biopsy was refused in 11%. The elderly responded very well to low doses of methylprednisolone (< or =8 mg) and azathioprine (1 mg/kg). This schedule obviates side-effects such as infections seen with higher dosages. CONCLUSION: Autoimmune hepatitis has to be also looked for in the elderly with acute and chronic hepatitis. The steroid therapy should be individualized but kept at a low dose.

Ali S, van Pelt JF, Verslype C, Nevens F, Fevery J, Yap SH. · Department of Hepatobiliary and Pancreas Diseases, University Hospital Gasthuisberg, B-3000, Leuven, Belgium. · Acta Gastroenterol Belg. · Pubmed #15285571 No free full text.

Abstract: BACKGROUND: TT viruses are single-stranded DNA viruses, suggested to be involved in non A-E hepatitis. We studied the prevalence of TTV infection in acute or chronic hepatitis in Belgium in comparison with that in blood donors and in patients regularly receiving blood products. METHODS: TTV-DNA was detected by PCR using the primer set of Takahashi et al (1998) or a nested-PCR specific for genotype-2, because it had been reported that this subtype might be more pathogenic (Tagger et al. 1999). RESULTS: TTV-DNA was present in 49% of 128 patients with chronic hepatitis C, in 54% of 54 with chronic hepatitis B and in 54% of 24 with acute liver failure. This prevalence is similar to the 47% in 127 patients with clotting disorders, or the 64% in 103 undergoing chronic haemodialysis, but lower than the 29.7% found in 340 healthy blood donors. Significant differences in clinical or biochemical characteristics between TTV- positive or TTV-negative patients could not be substantiated. The genotype-2 subgroup comprised 3.9%, but they also did not differ from non genotype-2 patients. CONCLUSIONS: The prevalence of TTV infection was higher in patients than in healthy blood donors. Its clinical significance remains questionable since clinical and biochemical characteristics were not different between TTV positive and TTV negative patients. The higher prevalence of TTV in patients might be related to parenteral transmission, but the relatively high prevalence in healthy blood donors points to an additional presumably faeco-oral infection. The presence of TTV in animals suggests that infection might also originate from food. Long term follow-up will have to define whether co-infection with TTV eventually alters the natural history of chronic hepatitis.

van Pelt JF, Severi T, Crabbé T, Eetveldt AV, Verslype C, Roskams T, Fevery J. · Department of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, Herestraat 49, Leuven B 3000, Belgium. · Cancer Lett. · Pubmed #15159022 No free full text.

Abstract: Several studies have documented the important association between hepatitis C virus (HCV) infection and hepatocellular carcinoma. The mechanisms involved are still unknown and could involve viral proteins. We investigated the effect of HCV-core protein on DNA repair after UV-induced DNA damage. Therefore, we developed and characterized stably transfected HepG2 cell lines that express HCV-core protein as demonstrated by immunohistochemistry. These cells were significantly less capable to repair the DNA damage than control cells. This suppression of DNA repair by HCV-core protein renders the cells more sensitive to acquire mutations that in combination with enhanced in vivo cell turnover in the infected liver might increase the likelihood of malignant transformation of HCV-infected cells by other viral factors or upon exposure to environmental factors (food, drugs, smoking, alcohol, etc.). Interestingly, expression of the full-length HCV core did increase the cell doubling time in one of the cell lines we had developed that could not be attributed to an increase in apoptosis or change in telomerase activity in these cells.

Verslype C, Nevens F, Sinelli N, Clarysse C, Pirenne J, Depla E, Maertens G, van Pelt J, Desmet V, Fevery J, Roskams T. · Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium. · J Hepatol. · Pubmed #12547410 No free full text.

Abstract: BACKGROUND/AIMS: A simple and reproducible hepatic immunohistochemical staining (IHS) for hepatitis C virus (HCV) is not available. We aimed to validate hepatic IHS with monoclonal antibody (Mab) IG222, directed against the HCV-envelope 2 (E2) protein. METHODS: A three-step indirect immunoperoxidase method was used for frozen sections and a two-step indirect EnVision technique was used for paraffin-embedded sections. RESULTS: Naturally or in vitro HCV infected primary human hepatocytes were immunoreactive to HCV-E2. In the patient study (n=253), IHS had a sensitivity of 96% and a specificity of 91%. Six patients who showed positivity in the liver with Mab IG222, but remained anti-HCV and HCV-RNA negative, had hepatitis C-like changes in their liver biopsy. In one patient HCV-RNA could be detected in the liver biopsy. We confirmed early graft reinfection in patients transplanted for HCV-related disease (34 patients with serial biopsies). Treatment for acute cellular rejection with steroids was associated with an increase in staining intensity. In nine patients with clearance of HCV-RNA during antiviral therapy, seven achieved negativation of immunoreactivity and two a marked reduction. CONCLUSIONS: The IHS with Mab IG222 is an accurate tool for diagnosis and clinical management of chronic hepatitis C.

De Vos R, Verslype C, Depla E, Fevery J, Van Damme B, Desmet V, Roskams T. · Department of Morphology and Molecular Pathology, U.Z.-K.U. Leuven, Minderbroedersstraat 12, Leuven, Belgium. · J Hepatol. · Pubmed #12175633 No free full text.

Abstract: BACKGROUND/AIMS: Molecular and structural studies of hepatitis C virus (HCV) replication and infection have been performed on cultured cells and on serum of infected patients. No conclusive studies were conducted yet on human liver biopsies. This paper describes the ultrastructural findings of hepatitis C virus components in liver biopsies. METHODS: Liver specimens from acutely and chronically HCV-infected chimpanzees (five each) and 29 chronic hepatitis C patients were studied. Diagnosis of HCV infection was based on clinical, serological, light microscopic and immunohistochemical data and on HCV RNA polymerase chain reaction. RESULTS: In HCV-infected chimpanzees, tubular aggregates were observed in the cytoplasm of a significant number of hepatocytes and proven by immuno-electron microscopy to contain HCV-E2 viral envelope material. Identical tubular aggregates were seen in hepatocytes of chronic HCV-infected patients, although in smaller quantity and less frequently. A few single enveloped virus-like particles of 50-60 nm in diameter were seen for the first time in the hyaloplasm of hepatocytes of HCV-infected chimpanzees and patients. CONCLUSIONS: For the first time, HCV envelope material was ultrastructurally identified in hepatocytes of HCV-infected chimpanzees and patients. Virus-like particles, although strongly suggestive for HCV, failed final confirmation at least by routinely used methods.

Ali S, Fevery J, Peerlinck K, Verslype C, Schelstraete R, Gyselinck F, Emonds MP, Vermylen J, Yap SH. · Division of Liver and Pancreatic Diseases, Department of Medicine, University Hospital Gasthuisberg, Leuven, Belgium. · J Med Virol. · Pubmed #11857537 No free full text.

Abstract: A novel DNA virus, TT virus (TTV), has been proposed as a possible etiologic agent for non A-E hepatitis. The aim of the present study was to determine the prevalence of TTV infection using PCR in healthy blood donors and in patients with clotting disorders who have been investigated previously for GBV-C/HGV and HCV infection in Belgium. In this study, PCR using primers proposed by Takahashi et al. [(1998) Hepatology Research 12:233-239] proved far more sensitive than those used by Okamoto et al. [(1998) Journal of Medical Virology 56:128-132]. The sequence of the PCR products showed 87% identity to the published sequence. TTV was present in 29.7% of healthy blood donors, a figure intermediate between the low rate of infection observed in Scotland and the high rates in the Far East. TTV was detected in 46.5% of 127 patients studied with clotting disorders as compared to 79.5% for HCV and 11.8% for GBV-C/HGV infection. However, there was no impact on the level of serum transaminases. Treatment with interferon for HCV infection co-infected with TTV suppressed temporarily serum TTV DNA. Therefore, it was concluded that TTV DNA is detected frequently in serum of healthy blood donors in Belgium and more often in patients with clotting disorders. TTV does not cause liver disease or contribute to the severity of liver disease.

Gong ZJ, De Meyer S, Clarysse C, Verslype C, Neyts J, De Clercq E, Yap SH. · Department of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, Leuven, Belgium. · J Viral Hepat. · Pubmed #10607235 No free full text.

Abstract: Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is currently used as an immunosuppressive agent in kidney transplant recipients. After oral administration, MMF is hydrolysed to MPA, the active compound, which is a potent inhibitor of inosine monophosphate dehydrogenase (IMP-DH). Inhibition of this enzyme results in a depletion of the intracellular GTP and dGTP pools. MPA has been shown to inhibit the replication of a number of viruses, including arena viruses (Junin and Tacaribe), yellow fever virus, reovirus-1, parainfluenza-3 virus, Coxsackie B4 virus, Epstein-Barr virus and human immunodeficiency virus. To examine whether MPA also has an inhibitory effect on HBV replication, experiments were performed using cultures of primary human hepatocytes and HBV-transfected, HepG2 2.2.15 cells. After in vitro infection with HBV in human hepatocytes, HBV covalently-closed-circular (ccc) DNA and HBV mRNAs were detectable in the cells during the 10 days following infection. HBV DNA and hepatitis B surface antigen (HBsAg) were also secreted into the culture medium. In the presence of 10 microg ml-1 MPA (the therapeutic serum level of MPA as an immunosuppressive agent) in culture medium, HBV ccc DNA and HBV mRNAs became undetectable 5 days after treatment was started. The secretion of HBV DNA and HBsAg into the medium was also markedly reduced. No cytotoxic effect of the drug was noted during the experiments. The effect of MPA on HBV replication was abolished by the presence of guanosine (50 microg ml-1). In HepG2 2.2.15 cells (which contain an integrated tandem dimer of the HBV genome), MPA treatment had no significant inhibitory effect on the secretion of HBV DNA and HBsAg into the culture medium. HBV ccc DNA and HBV mRNAs in HepG2 2.2.15 cells were also not affected. The observed effect of MPA on HBV replication in primary human hepatocyte cultures may involve only episomal replication and may have clinical implications, especially before integration of HBV DNA into the host genome.