Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients.

The aims of this study were to assess hepatitis B surface antigen (HBsAg) seroconversion and to determine its impact on the natural course of the disease in patients with HBeAg-negative chronic hepatitis B (CHB) during lamivudine (LMV) treatment. A total of 183 consecutive patients with HBeAg-negative CHB who were treated with LMV were included in the study. Data were retrospectively collected from outpatient visit charts. The primary endpoint was HBsAg seroconversion to anti-HBs. The secondary endpoint was to determine the development of cirrhosis. Loss of HBsAg was confirmed in 10 patients and seroconversion to anti-HBs in nine patients during LMV treatment or after its discontinuation. HBsAg seroconversion was achieved on-treatment in four patients after a median treatment duration of 30 months and off-treatment in the remaining five patients in a median 61 months after LMV discontinuation. The cumulative probability of HBsAg seroconversion increased from 0.6% at 1 year and 1.9% at 5 years to 21.5% at 10 years of LMV during and after LMV treatment. HBsAg clearance was preceded by undetectable serum hepatitis B virus (HBV) DNA. The majority of the patients responding to treatment had undetectable HBV DNA levels at 24 weeks of treatment. The cumulative probability of LMV resistance increased from 2.2% at 1 year to 37.3% at 5 years. No baseline parameter predicting either HBsAg seroconversion or the emergence of LMV resistance was identified. None of the patients with HBsAg seroconversion experienced virological breakthrough or disease progression during the follow-up period. These results indicate that HBsAg seroclearance can occur in patients with HBeAg-negative CHB under LMV therapy and predicts better clinical outcome.

Cutaneous, pulmonary and hepatic sarcoidosis associated with autoimmune complications during interferon-alpha treatment for hepatitis C virus infection.

A patient with hepatitis C virus (HCV) infection was diagnosed with cutaneous, pulmonary and hepatic sarcoidosis following interferon alpha therapy. There are only a few cases of sarcoidosis associated with this treatment. This is the first case who not only developed sarcoidosis, but also autoimmune hypothyroidism and thrombocytopenia during interferon alpha therapy due to the immunomodulatory effects of the drug.

Lamivudine prophylaxis for prevention of chemotherapy-induced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies.

Although hepatitis B virus (HBV) reactivation in HBV carriers undergoing immunosuppressive therapy is clearly documented, the role of antiviral prophylaxis in such individuals is still controversial. The aim of this study was to determine the efficacy of lamivudine prophylaxis in HBV carriers with haemato/oncological malignancies, who receive chemotherapy. Eighteen HBV carriers with malignancy, who were candidates for chemotherapy, were enrolled. Eight subjects (three with leukaemia, four with lymphoma and one with multiple myeloma) were enrolled for prophylactic lamivudine therapy. The remaining 10 patients (six with leukaemia, three with lymphoma and one with breast cancer) were not treated with lamivudine and were used as a control. Lamivudine was administered beginning on the same day as the chemotherapy and was maintained for a year after chemotherapy was discontinued. No HBV-related mortality was observed in either group. In the lamivudine-treated group, none of the subjects had clinical, biochemical or serological evidence of HBV reactivation during the time they were receiving chemotherapy and after their chemotherapy was discontinued. In contrast, five of the 10 HBV carriers not receiving lamivudine therapy experienced a reactivation of HBV infection. This reactivation of HBV was observed during the chemotherapy in four with one individual experiencing a HBV activation 12 months after chemotherapy was discontinued. No lamivudine-related major adverse effects were observed. Hence prophylactic lamivudine treatment in HBV carriers with haemato/oncological malignancy receiving chemotherapy prevents chemotherapy-induced HBV reactivation.

Prevalence of hepatitis-G virus and hepatitis-C virus infection in patients with non-Hodgkin's lymphoma.

Several studies have reported that hepatitis-C virus may have a role in the development of non- Hodgkin's lymphoma. Hepatitis-G virus has hepatitis-C virus like characteristics. The possible association between hepatitis-G virus infection and non-Hodgkin's lymphoma is not clear. The aim of this study was to determine the prevalence of hepatitis-G virus and hepatitis-C virus infection in patients with non-Hodgkin's lymphoma without blood transfusion. Forty-four patients with non-Hodgkin's lymphoma were enrolled in the study. Serum samples derived from the patients were tested for antibodies against hepatitis-C virus by ELISA. Hepatitis-G virus and hepatitis-C virus RNA were detected by reverse transcription-polymerase chain reaction. Only two of 44 patients (5%) with non-Hodgkin's lymphoma were positive for Anti- HCV and hepatitis C virus RNA. One patient had low grade non-Hodgkin's lymphoma with follicular mixed histopathology while the other had intermediate grade with diffuse large cell histopathology. Hepatitis-G virus infection was detected in none of the patients. We concluded that hepatitis-G virus does not seem to be in association with non-Hodgkin's lymphoma.

Circulating IL-2, IL-10 and TNF-alpha in chronic hepatitis B: their relations to HBeAg status and the activity of liver disease.

BACKGROUND/AIMS: Preferential production of immunoregulatory cytokines may play an important role in the pathogenesis of chronic hepatitis B. We aimed to determine the serum levels of IL-2, IL-10 and TNF-alpha in patients with chronic hepatitis B and to correlate these findings with the activity of liver disease, HBeAg/anti-HBe status and replication level of the virus. METHODOLOGY: Seventy-two chronic hepatitis B patients were categorized into 4 groups according to activity of liver disease and HBeAg status. Group 1 (n = 13): HBeAg and HBV DNA-positive with persistently normal ALT. Group 2 (n = 20): HBeAg and HBV DNA-positive patients with persistently elevated ALT. Group 3 (n = 19): HBeAg and HBV DNA-negative patients with persistently normal ALT. Group 4 (n = 20): HBeAg-negative patients with persistently elevated ALT and variable serum HBV DNA. IL-2, IL-10 and TNFa levels were determined in stored patient sera. RESULTS: Apart from group 1 patients, all patients groups had higher IL-2 levels compared to controls suggesting that IL-2 production is increased when liver disease becomes active in HBeAg-positive phase of HBV infection. Only group 2 patients had elevated IL-10 levels compared to controls. None of the HBeAg-negative patients had detectable TNF-alpha levels while 64% HBeAg-positive patients had elevated levels of TNF-alpha irrespective of the activity of liver disease. Except TNF-alpha, no association was found between HBV DNA status and the presence or absence of detectable cytokines in circulation. CONCLUSIONS: Our results suggest that circulating cytokine profile in chronic hepatitis B is related with the HBeAg status, replication level of the virus and the activity of liver disease.

The Incidence of Hepatitis G Virus in Patients with Hematological Malignancies: The Relationship to the Number of Blood and Blood Products Transfusions.

The hepatitis G virus has been detected in patients with post-transfusion hepatitis. The precise transmission rate of the hepatitis G virus is not clear. This study aims to investigate the transmission rate of HGV and the relationship between the number of blood transfusions and the blood products used in multitransfused patients with hematological malignancies. Serum samples were obtained from 80 patients with hematologic malignancies hospitalized between January 1997 and December 1998 at Ibn'i Sina Hospital, University of Ankara. The patients were divided into three groups according to transfusion numbers. Group A received between 0 and 10 units of blood and blood products, Group B received 10-20 units, and Group C received more than 20 units. All patients received blood and blood products for a median of 6.8 Units/whole life. The hepatitis G virus was detected using the reverse transcription polymerase chain reaction. Of the eighty patients, four (5.0 %) were HBs-Ag positive, one (1.25%) was Anti-HCV positive, and one (1.25%) was HGV-RNA positive. Multiple blood transfusions may be an important risk factor for transmission-transmitted viral infections, but based upon the present experience, there is no significant relationship between the number of blood transfusions and blood products and the transmission rate of HGV infection in patients with hematological malignancies.

Serum cytotoxin and oxidant stress markers in N-acetylcysteine treated thioacetamide hepatotoxicity of rats.

N-acetylcysteine (NAC) is a glutathione precursor used to treat several clinical conditions where intracellular oxidant-antioxidant balance is disturbed, among which, acetaminophen induced hepatotoxicity may be counted. In this study, administering thioacetamide (TAA) as a hepatotoxic agent, a rat model of hepatotoxicity has been established, to investigate some of the immune mediated basic oxidant-antioxidant homeostatic mechanisms involved, and potential serum markers for follow-up of disease and treatment. To do this, four experimental groups receiving saline/saline, saline/NAC, saline/TAA and NAC/TAA as intraperitoneal injections, have been formed. Rat serum tumor necrosis factor-alpha (TNF-alpha), Interleukin1-beta (IL1-beta), malondialdehyde (MDA) as a measure of final oxidant damage and the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) have been assayed. Hepatocellular damage has been measured via the biochemical estimates ALT, AST and LDH as well as histopathological grading. It was found that both TNF-alpha and IL1-beta were significantly elevated in saline/TAA receivers (P<0.01) when compared to NAC/TAA receivers. Serum MDA was also increased in TAA receivers in addition to SOD (P<0.05) and GSH-Px (P<0.05). Serum nitrite levels have also been assayed to give an estimate of nitric oxide that is suggested as a counter-balancer of oxidant stress. NAC/saline receivers had the highest levels of nitrites in the serum (P<0.05). Our results indicate that part of the hepatocellular injury to rat liver, induced by TAA is mediated by oxidative stress caused by the action of cytokines imparted by the enzymatic SOD and GSH-Px and non-enzymatic gaseous nitric oxide mechanisms causing an alleviation on administration of NAC. In addition, TNF-alpha, IL1-beta, MDA, SOD, GSH-Px and nitrites are potential candidates of serum indicators for monitorization of pathophysiological stage of liver disease.

Influence of two blood conservation techniques (cardiotomy reservoir versus cell-saver) on biocompatibility of the heparin coated cardiopulmonary bypass circuit during coronary revascularization surgery.

Blood conservation during cardiac surgery is critically important because of the inherent risks in homologous blood transfusions. Two techniques for the intraoperative conservation of blood--retransfusion of the red cells using a cell-saver (CS), or retransfusion of the blood using a cardiotomy suction (CTR) system--were compared using biocompatibility markers, granulocyte activation, and production of oxygen-free radicals (OFR). In the CTR group, heparin coated circuits with an uncoated cardiotomy reservoir were used. For the CS group, identical heparin coated cardiopulmonary bypass (CPB) sets, without a cardiotomy reservoir but with a CS, were used. In each group, eight patients had coronary artery bypass grafting performed. The capacity of the whole blood and the granulocytes to produce OFR was estimated by a chemiluminescence, and granulocyte activation was measured as release of the granulocyte granule proteins myeloperoxidase (MPO) and lactoferrin. A significantly reduced capacity to produce OFR by the whole blood was noted at 45 minutes of CPB in the CTR group (68% +/- 17% vs 94% +/- 16% in the CS group). MPO release was higher after 3 hours (p = 0.05) and 20 hours (p < 0.05), postoperatively, in the CTR group (417 +/- 77 micrograms/L and 257 +/- 31 micrograms/L vs 246 +/- 25 micrograms/L and 164 +/- 12 micrograms/L, respectively, in the CS group). We conclude that the heparin coated CPB circuit with the uncoated cardiotomy reservoir may be less biocompatible than the identical CPB set used together with the CS.

Effects of heparin coating of cardiopulmonary bypass circuits on in vitro oxygen free radical production during coronary bypass surgery.

During cardiopulmonary bypass (CPB) oxygen free radicals (OFR) are formed, which can mediate reactions damaging tissue components. Blood contact with artificial surfaces during CPB leads to an activation of leukocytes, which are one of the sources of the OFR. Heparin coating of the CPB circuit reduces granulocyte activation. In the present study, the heparin-coated circuits with noncoated cardiotomy reservoirs (Group HC) were compared with noncoated, otherwise similar CPB sets (Group C). In each group, 8 patients were operated on for coronary revascularization. The release of granulocyte granule proteins myeloperoxidase (MPO) and lactoferrin (LF) was evaluated. Production of OFR in the whole blood and in the granulocyte suspension were measured by chemiluminescence (CL). In both groups the whole blood CL declined during CPB. The whole blood CL induced by serum-opsonized zymosan, when enhanced by luminol, was significantly lower in Group HC at 45 min after CPB start (68 +/- 6% of initial values in Group HC vs. 87 +/- 6% in Group C, mean +/- SEM) and 30 min after protaminization (54 +/- 6% of initial values in Group HC vs. 72 +/- 6% in Group C, mean +/- SEM), and CL was significantly higher in Group HC at CPB end (83 +/- 5% of initial values in Group HC vs. 67 +/- 5% in Group C, mean +/- SEM) when enhanced by lucigenin. CL of isolated granulocytes showed no significant differences between the groups. Release of MPO at CPB end and of LF 45 min after start of CPB and at CPB end were significantly lower in the heparin-coated CPB circuits.

Beneficial effects of prostacyclin treatment on reperfusion of the myocardium.

A total of 20 patients with coronary artery disease were studied in order to assess the benefits of prostacyclin administration on reperfusion of the ischaemic myocardium after cardiopulmonary bypass. Ten received prostacyclin (25 ng/kg per min) while ten were untreated controls. There was no difference between groups with regard to age, preoperative ejection fraction and aortic cross-clamping times. There were no in-hospital deaths in either group. The administration of prostacyclin significantly altered the metabolic side effects of reperfusion followed by hypothermic cardioplegic arrest. Myocardial oxygen consumption after cardiopulmonary bypass was significantly higher in the prostacyclin-treated group than in controls (18.5 ml versus 13 ml; P < 0.01). Prostacyclin treatment significantly reduced the leucocyte activity: leukotriene B4 concentrations were 58 pmol/l in prostacyclin-treated patients compared with 93 pmol/l in controls (P < 0.01). Such recovery of metabolic status during reperfusion resulted in better haemodynamic function in patients receiving prostacyclin.

The beneficial effects of aminophylline administration on heparin reversal with protamine.

The aim of this study was to demonstrate the beneficial effects of aminophylline on protamine cardiotoxicity. Thirty-four patients were examined, 17 of whom received aminophylline 3 mg/kg before protamine administration, being the study group, while the other 17, being the control group, did not. All cardiac output and biochemical measurements were evaluated 5 min following protamine administration. The cAMP level was 43.4 +/- 3.51 pmol/ml in the study group and 18.7 +/- 2.98 in the control group (P < 0.0001) before protamine administration, while the oxygen extraction rate decreased from 49% to 44 +/- 2% in the control group, and from 51.2% to 47 +/- 3% in the study group (P < 0.03). The N-acetyl glucosaminidase value was 16.9 +/- 13.9 pmol/ml in the study group and 27.8 +/- 1.47 pmol/ml in the control group (P < 0.01), and myocardial lactate extraction was -0.20 +/- 0.03 in the control group and -0.07 +/- 0.07 in the study group (P < 0.001). The left ventricular stroke work index was 28.6 +/- 3.14 gm/m2 in the control group and 37 +/- 6.77 gm/m2 in the study group (P < 0.002). The findings of this study led us to conclude that the adverse effects of heparin neutralization using protamine can be relieved by aminophylline.