Hepatitis: Kansu A

Kansu A. · Pediatric Gastroenterology Department, Ankara University School of Medicine, Ankara, Turkey. · Recent Pat Antiinfect Drug Discov. · Pubmed #18221187 No free full text.

Abstract: Chronic hepatitis B in children is mainly asymptomatic, but they are at life long risk for severe complications. Treatment is considered to suppress the virus and to prolong the survival by preventing the progression to cirrhosis and HCC. Therapeutic options for children are interferon-alpha (IFN-alpha) with antiviral, antiproliferative and immuno-modulatory effects and lamivudine (LAM) which inhibits HBV replication and increases cellular immune response. IFN-alpha, 5 MU/m(2), thrice weekly for 6 months is used in patients with high ALT levels which is associated with virologic response rate of 30-40%. Predictors of response are high ALT levels, low HBVDNA levels and high histological activity index. The response is sustained in 85%-90% of responders. Adverse events include flu-like syndrome, bone marrow suppression, hair loss, and psychiatric side effects, induction of autoimmunity and temporarily suppression of weight gain and growth velocity. LAM, a nucleoside anolog, leads to a virologic response rate of 20-30% when used for 12 months. High ALT levels, low HBVDNA levels and high histological activity index predict better response. Maintenance of HBeAg seroconversion is 56-80%. Longer courses of treatment with LAM increases the seroconversion rate but with high mutation rate and viral resistance. Except for causing mutations, LAM doesn't have serious adverse events. Different timing and durations of combination treatment with IFN and LAM were also evaluated without any significant superiority over monotherapy. In conclusion, the best approach for treatment of chronic HBV infection in children haven't been determined yet. Future developments concerning new drugs and different treatment strategies are needed.

Dikici B, Ozgenc F, Kalayci AG, Targan S, Ozkan T, Selimoglu A, Doganci T, Kansu A, Tosun S, Arslan N, Kasirga E, Bosnak M, Haspolat K, Buyukgebiz B, Aydogdu S, Girgin N, Yagci RV. · Department of Pediatrics, Dicle University Medical Faculty, Diyarbakir, Turkey. · J Gastroenterol Hepatol. · Pubmed #14731120 No free full text.

Abstract: BACKGROUND AND AIM: The aim of the present study was to compare the therapeutic efficacy of three different regimens in childhood chronic hepatitis B (CHB) infection. METHODS: A total of 182 children with CHB infection were prospectively allocated to three random groups. Sixty-two patients in the first group received high-dose interferon (IFN)-alpha 2b (10 MU/m2) thrice/weekly alone for 6 months. In the second (n = 60) and third groups (n = 60), IFN-alpha was used for 6 months (5 MU/m2) thrice/weekly in combination with lamivudine (LAM) (4 mg/kg, maximum 100 mg/day) for 12 months. Lamivudine was started simultaneously with IFN in the second group, while it was started 2 months prior to IFN injections in the third group. RESULTS: The initial mean alanine aminotransferase (ALT) values for the first, second and third groups were 109 +/- 93 IU/L, 101 +/- 64 IU/L and 92 +/- 42 IU/L, respectively (P > 0.05). At the end of the therapy, ALT values decreased to 82 +/- 111 IU/L, 38 +/- 41 IU/L and 29 +/- 16 IU/L in groups 1, 2 and 3, respectively. The mean ALT value of the first group was significantly different to the second and third groups (P = 0.046 and P = 0.002, respectively) at the end of the therapy and these differences were found to be sustained after 18 months. However, results in the second and third groups were similar (P > 0.05). There were no significant differences in HBeAg clearance and anti-HBe seroconversion at the initial stage, 12 months and 18 months between the three groups (P > 0.05). Hepatitis B virus (HBV) DNA clearance in the first group was different from the second and third groups, while the second and third groups had similar HBV DNA clearance ratios at 12 and 18 months. No significant difference was found in the complete response (normalization of ALT, clearance of HBV DNA and seroconversion of anti HBe) ratios of all groups (at 12 months: 28.8, 45.5, 35.8% and at 18 months 33.3, 49 and 34% in groups 1, 2 and 3, respectively, P > 0.05). CONCLUSIONS: Although the ALT normalization and HBV DNA clearance ratios of IFN plus LAM combination groups were better than the high-dose IFN-alpha monotherapy group, no significant difference was found in the complete response ratios of all three groups.

Ustundag G, Kuloglu Z, Kirsaçlioğlu CT, Kansu A, Erden E, Girgin N. · Department of Pediatrics, Gastroenterology Unit, Ankara University School of Medicine, Ankara, Turkey. · Pediatr Int. · Pubmed #19261129 No free full text.

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Kuloglu Z, Krsaçloglu CT, Kansu A, Erden E, Girgin N. · Department of Pediatric Gastroenterology, Ankara University School of Medicine, Ankara, Turkey. · J Pediatr Gastroenterol Nutr. · Pubmed #18030234 No free full text.

Abstract: AIM: To evaluate histological changes with interferon monotherapy or interferon plus lamivudine combination therapy in children with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. PATIENTS AND METHODS: 31 children aged 2-13 years were randomly treated with interferon (IFN) (group 1, n = 16) or IFN plus simultaneously started lamivudine (group 2, n = 15). IFN-alpha 2a was given 9 MU/m2 3 times per week for 6 months in each group; lamivudine was given 4 mg x kg(-1) x day(-1) for 24 months. Liver biopsy specimens were evaluated according to the Knodell score before therapy and after 24 months of therapy. Histological response was defined as a decrease in the histological activity index (HAI) score by at least 2 points. Efficacy of therapy was evaluated at 24 months of therapy in all children. RESULTS: Alanine aminotransferase normalization, HbeAg, and hepatitis B virus DNA clearance were not different. Complete response and histological response were 37.5%/62.5% and 40%/46.7% in groups 1 and 2, respectively (P = NS). At baseline and at 24 months of therapy, total HAI and components of HAI were not different in the 2 groups. In comparison with baseline, a significant decrease in scores of periportal +/- bridging necrosis was observed in group 1 (P = 0.01); periportal +/- bridging necrosis, intralobular degeneration, focal necrosis, and necroinflammation scores significantly decreased in group 2 (P = 0.04 and P = 0.02) at 24 months of therapy. CONCLUSIONS: The addition of lamivudine to IFN-alpha did not increase the effectiveness of the treatment in terms of complete and histological responses. Both therapies seemed to be effective in the regression of periportal +/- bridging necrosis. In addition, combination therapy was also effective in the regression of intralobular degeneration, focal necrosis, and necroinflammatory activity index.

Kuloğlu Z, Kansu A, Demirçeken F, Arici ZS, Berberoğlu M, Ocal G, Girgin N. · Division of Gastroenterology, Department of Pediatrics, Ankara University, School of Medicine, Ankara, Turkey. · J Pediatr Endocrinol Metab. · Pubmed #17642422 No free full text.

Abstract: AIM: To evaluate the height and weight patterns of children with chronic hepatitis B (CHB) with and without treatment. METHODS: Thirty-four patients with immunoactive CHB randomly assigned to receive interferon-alpha2a (IFN) (5 mIU/m2, 6 months, group I) or IFN (same dose and duration) plus lamivudine (4 mg/kg/day, 24 months) (group II). Fifteen immunotolerant patients (group III) were followed without any treatment. Height (Ht-SDS), weight (Wt-SDS) and growth velocity (GV-SDS) standard deviation scores were monitored for a total of 36 months. RESULTS: Ht-SDS was significantly lower in group II than in group I one year after completion of IFN treatment (p < 0.05). Wt-SDS was significantly higher in group I than the other groups two years after completion of IFN treatment (p < 0.05). In groups I and II, the percentage of children showing abnormal GV-SDS decreased once treatment was completed (p < 0.05). CONCLUSION: CHB does not have deleterious effects on height and weight. Although IFN treatment temporarily compromises weight gain and growth velocity, lamivudine does not have any additional adverse effect.

Kuloglu Z, Kansu A, Berberoglu M, Adiyaman P, Ocal G, Girgin N. · Division of Gastroenterology, Department of Pediatrics, Ankara University, School of Medicine, Ankara, Turkey. · J Pediatr Endocrinol Metab. · Pubmed #17396441 No free full text.

Abstract: AIM: To assess the effect of interferon-alpha (IFN-alpha) therapy on thyroid functions in children with chronic hepatitis B infection (CHB). METHODS: Sixty-eight children (7.8 +/- 3.6 years) were treated with 5 (n = 37, group I) or 10 MU/m2 (n = 31, group II) IFN for 6 months. Thyroid hormones, thyrotropin, thyrotropin-releasing hormone stimulation test, thyroid peroxidase and thyroglobulin autoantibodies were evaluated. RESULTS: Baseline features were not different in the two groups. After therapy, thyroid dysfunction was 27% and 41.9% in groups I and II (n.s.). Subclinical hypothyroidism was 17.9%/ 29%, subclinical hyperthyroidism 5.4%/12.9%, hypothyroidism 2.7%/-, and thyroid antibody positivity 2.7%/- in groups I and II (n.s.). Thyroid dysfunction was 33.8% in the whole group (p = 0.001). Predictors of IFN induced-thyroid dysfunction were female sex and age < 6 years. Thyroid dysfunction resolved within median 6 months in all but three children. CONCLUSION: Although IFN-induced thyroid dysfunction is mostly subclinical and reversible, this side effect should be kept in mind.

Okçu-Heper A, Erden E, Doganci T, Kuloglu Z, Kansu A, Genc Y. · Department of Pathology, Ankara University, School of Medicine, Patoloji Anabilim Dali, Morfoloji Binasi, 06100, Sihhiye, Ankara, Turkey. · Pediatr Dev Pathol. · Pubmed #16808634 No free full text.

Abstract: The clinical outcome of nonobstructive neonatal cholestasis (NC) cases varies greatly and the prognosis is generally unpredictable. In this study, we aimed to evaluate the prognostic benefits of qualitative analysis of histopathological changes in nonobstructive NC cases. A total of 28 nonobstructive NC cases (18 neonatal hepatitis; 10 intrahepatic bile duct paucity) were studied. We analyzed the relationship between histopathological and clinical parameters. Hepatic inflammation, bridging necrosis, pericellular fibrosis, giant cell transformation, and extramedullary hematopoiesis were evaluated and scored according to their absence or presence in each case. The sum of the histopathological scores was accepted as "total pathological injury score." The height percentiles, the presence and the degree of hepatomegaly and ascites, and serum alanine aminotransferase (ALT), albumin, and bilirubin levels and prothrombin time were also evaluated and scored. The patients were divided into 2 clinical course groups considered "good" or "bad" according to the total clinical scores. For statistical analysis, Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristic curve were used. We found a statistically significant negative relation between the clinical course and total pathological injury score (P = 0.042) and pericellular fibrosis (P = 0.016). In conclusion, during the interpretation of liver biopsies of nonobstructive NC, scoring of histopathological changes should be done for assessing the clinical prognostic outcome.

Kansu A, Doğanci T, Akman SA, Artan R, Kuyucu N, Kalayci AG, Dikici B, Dalgiç B, Selimoğlu A, Kasirga E, Ozkan TB, Kuloğlu Z, Aydoğdu S, Boşnak M, Ertekin V, Tanir G, Haspolat K, Girgin N, Yağci RV. · Department of Pediatric Gastroenterology, Hepatology and Nutrition, Akdeniz University School of Medicine, Antalya, Turkey. · Antivir Ther. · Pubmed #16640106 No free full text.

Abstract: AIM: To evaluate the efficacy of two regimens of combined interferon-alpha2a (IFN-alpha2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. METHODS: A total of 177 patients received IFN-alpha2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7 +/- 3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-alpha2a, in group II (65 patients, 9.6 +/- 3.8 years) 3TC was started 2 months prior to IFN-alpha2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in nonresponders. RESULTS: Baseline alanine aminotransferase (ALT) was 134.2 +/- 34.1 and 147.0 +/- 45.3; histological activity index (HAI) was 7.4 +/- 2.7 and 7.1 +/- 2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively (P > 0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively (P < 0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I (P < 0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively (P > 0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 +/- 4.6 and 14.1 +/- 5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively (P > 0.05, P > 0.05, P > 0.05). Responders had higher HAI (HAI > 6) and higher pre-treatment ALT than non-responders. CONCLUSION: Simultaneous 3TC+IFN-alpha2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.

Kansu A, Kuloğlu Z, Demirçeken F, Girgin N. · School of Medicine, Department of Pediatrics, Division of Gastroenterology, Ankara University, Ankara, Turkey. · Turk J Gastroenterol. · Pubmed #16249973 links to  free full text

Abstract: BACKGROUND/AIMS: One of the serious side effects of interferon-a (IFN) is the possible induction of autoimmunity. However, data concerning children with chronic hepatitis B (HBV) infection is limited with conflicting results. The aim of this study was to evaluate the frequency of autoantibody positivity in children with chronic HBV infection and to assess whether IFN treatment has any influence on exacerbation of serological or clinical parameters of autoimmunity. METHODS: 61 children (32 female, mean age 7.5+/-3.8 years) were evaluated in two groups. Group I (29 patients) received 5 x 106 U/m2 IFN-a and group II (32 patients) 10 x 106 U/m2 IFN-a three times per week for six months. Autoantibody levels (anti-TPO, anti-Tg, AMA, ASMA, LKM-1, ANA, ds-DNA) and Ig G, A and M were analyzed before and after IFN treatment and 12 months after completion of therapy. RESULTS: No significant difference in autoimmune antibody positivity rate was observed between the two groups when compared at the beginning of the study and at the end of IFN treatment separately. SMA positivity rate was shown to significantly increase in group I after treatment was completed (p<0.05). None of the patients positive for autoantibodies showed further laboratory or clinical signs of autoimmunity. Thyroid hormones were within normal range in patients positive for anti-thyroid antibodies; however, thyrotropin-releasing hormone (TRH) stimulation test revealed subclinical hypothyroidism. All antibodies disappeared 12 months after completion of therapy. Overall, autoantibody positivity, pre- and posttreatment, were 16.3% and 54%, respectively (p<0.05). Age, sex, hepatitis activity index (HAI) score, HBV load and the dose of IFN had no influence on autoantibody formation. Complete and sustained response rates were similar in children with and without autoantibody. CONCLUSIONS: Autoantibody formation may occur in children with chronic HBV infection. IFN treatment leads to significant autoantibody formation, but this causes no organ dysfunction except for antithyroid antibodies associated with subclinical hypothyroidism. These results suggest that neither the presence of autoantibodies in choronic hepatitis B nor their development during IFN therapy is associated with severe autoimmune disorders in children with chronic HBV infection.

Deda G, Caksen H, Kansu A, Girgin N, Suskan E, Uysal S, Tükün A. · Department of Pediatrics, Ankara University, Faculty of Medicine, Ankara, Turkey. · Genet Couns. · Pubmed #15517829 No free full text.

Abstract: We report a 26-month-old boy with Angelman syndrome associated with Lennox-Gastaut syndrome, who developed a rash and a persistent toxic hepatitis after lamotrigine was added to valproate therapy. The patient had typical findings of both Angelman and Lennox-Gastaut syndromes. Chromosome analysis performing by FISH analysis showed a deletion in chromosome 15 (q11.2 q11.2). Although some cases of Angelman syndrome associated with Lennox-Gastaut syndrome were reported in the literature, valproate and/or lamotrigine induced toxic hepatitis in Angelman syndrome has hitherto never been described. We conclude that VPA and LTG combination should be given with great caution or avoided in patients with Angelman syndrome.

Kuloğlu Z, Kansu A, Berberoğlu M, Demirçeken F, Ocal G, Girgin N. · Division of Gastroenterology, Department of Pediatrics, School of Medicine, Ankara University, Ankara, Turkey. · Turk J Gastroenterol. · Pubmed #15264114 links to  free full text

Abstract: BACKGROUND/AIMS: Interferon is known to have some effects on glucose metabolism, but this issue has not been investigated in children with chronic hepatitis B infection. The aim of this study was to investigate the impact of interferon on glucose metabolism and to investigate whether autoimmunity has a role in the pathogenesis. METHODS: Fourteen patients (9 male, 6.3+/-2.7 years) with children with chronic hepatitis B infection were prospectively evaluated. They received interferon 10 MU/m2 for six months. Vral glucose tolerance test, fasting insulin and C-peptide, postprandial insulin and C-peptide, anti-GAD antibody, HOMA-IR and glucose/insulin ratio were measured before and after treatment. RESULTS: Before interferon, oral glucose tolerance test showed glucose intolerance in two patients (14.5%) and hypoglycemia in one patient (7.1%). One patient had hyperinsulinemia and insulin resistance (7.1%), and four patients had hypoinsulinemia and insulin hypersensitivity (28.5%). After interferon, oral glucose tolerance test was normal in 13 patients (92.8%). Abnormal oral glucose tolerance test persisted in the same patient, but no difference was found in insulin resistance. Hypoinsulinemia and insulin hypersensitivity were present in five patients (35.7%). DM related autoantibodies were negative in all patients before interferon; however, one patient, whose glucose metabolism was within normal limits, developed anti-GAD antibody after interferon. CONCLUSIONS: Children with children with chronic hepatitis B infection were shown to have hypoinsulinemia and insulin hypersensitivity. These children may have risk of progresssing to insuline dependent drabetes mellitus. We demonstrated that interferon did not seem to worsen glucose metabolism, but it had minimal positive impact on it. These results should be supported with other studies and interferon should be used carefully, especially in children with decreased beta cell reserve.

Serinoz E, Varli M, Erden E, Cinar K, Kansu A, Uzunalimoglu O, Yurdaydin C, Bozkaya H. · Departments of Pathology, Ankara University, Ankara, Turkey. · J Clin Gastroenterol. · Pubmed #12590241 No free full text.

Abstract: GOALS: The aim of this study was to determine the factor(s) independently affecting the HBcAg expression pattern in HBV-infected livers. BACKGROUND: Subcellular localization of HBcAg have been found to be related to the activity of liver disease, hepatocyte proliferation rate and the level of HBV replication.STUDY A total of 98 patients with biopsy proven chronic hepatitis B were included. HBcAg and proliferative cell nuclear antigen (PCNA) were immunohistochemically detected. HBcAg expression and its relationship with histologic activity index, ALT levels, PCNA score and HBV DNA levels were investigated. RESULTS: Forty-three (44%) patients were positive for HBcAg staining, with most of them (37 patients) having nuclear localization. Forty-seven percent of patients with detectable HBV DNA had nuclear staining while none of the HBV DNA negative patients had nuclear staining ( < 0.0005). Patients with positive nuclear staining had lower HAI (<8) and a lower PCNA score (<353/1,000 cell) than those with negative staining (62% vs. 39% and 90% vs. 66%, respectively, P< 0.05). In multivariate analysis, both high HBV DNA level and low HAI ( P< 0.0005 and P< 0.05, respectively) but not PCNA score, were independently associated with nuclear staining of HBcAg. CONCLUSIONS: Our results suggest that viral load and the severity of liver damage but not the rate of hepatocyte proliferation independently affects the HBcAg expression pattern.