Higher ALT Levels Research Articles

Cyclophosphamide-Busulfan Instead of Busulfan-Cyclophosphamide for Conditioning in Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract 2268Poster Board II-245Busulfan-cyclophosphamide (BU-CY) is the established non total body irradiation based myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of intravenous busulfan has facilitated its application and reduced toxicity. Theoretical considerations and pharmacological data indicate that previous application of busulfan may trigger liver toxicity of subsequent cyclophosphamide. A reverse order of cyclophosphamide-busulfan (CY-BU) would be preferable. Recent animal data confirmed this hypothesis, showing less liver toxicity and better outcomes in mice treated with CY-BU. While CY-BU was not feasible in patients with oral busulfan, it has become a possibility with the introduction of i.v. busulfan. We were therefore interested in exploring this concept and changed the order of drug application to CY-BU in 2003 in those patients not on a multicentre standardized BU-CY protocol. We now retrospectively analyzed in this single centre cohort study liver toxicity and transplantation outcome in patients receiving BU and CY as conditioning regimen for allogeneic HSCT. We analyzed 93 consecutive patients between 1993 and 2008, 52 male (55.9%), median age 46 years (range 16 to 70) with hematological malignancies (AML 41 [44.1%], ALL 11 [11.8%], CML 12 [12.9%], myelodysplastic syndrome and myeloproliferative neoplasia 22 [23.7%], lymphoproliferative disorders 4 [4.3%]) or other diseases (3 [3.2%]), receiving an allogeneic HSCT from an HLA- identical sibling (52 [55.9%]), other family member (3 [3.2%]) or a matched unrelated donor (38 [40.9%]) after conditioning regimen with BU-CY (34 patients; 18 patients with oral, 16 patients since 2003 with i.v. busulfan) or CY-BU (59 patients). Outcomes were analyzed using a Cox regression model, adjusting for disease, stage, donor type, stem cell source, previous total body irradiation (TBI) and busulfan administration (oral vs. intravenous). Pretransplant patient characteristics were comparable in the two cohorts for age, gender, underlying disease, stem cell source, donor type and EBMT risk score, but differed in stage (advanced disease BU-CY 28 [84,8%] vs. CY-BU 40 [66.7%]) and previous TBI (BU-CY 16 [48.5%] vs. CY-BU 9 [15.0%]). Liver function as measured by levels of bilirubin and liver enzymes (aspartate amino transferase [AST], alanine amino transferase [ALT], gamma glutamyl transpeptidase [GGT] and alkaline phosphatase [AP]) was not different between the groups before starting conditioning regimen. In contrast liver function differed significantly at day 20, with higher levels of ALT (median 51.0 vs 27.0 IU/l; p=0.012) and a higher incidence of veno-occlusive disease (VOD) (5/34 vs. 1/59, p=0.036) in the BU-CY group (Figure 1A). The cumulative incidence of transplant-related mortality (TRM) at 2 years was significantly higher in patients receiving BU-CY (BU-CY 0.48, CY-BU 0.24, p=0.024; hazard ratio 4.594 for BU-CY, 95% CI 1.382-15.268, p=0.013) (Figure 1B). The cumulative incidence of TRM with BU i.v.-CY was lower (0.44) than with BU oral-CY (0.56) but still higher than CY-BU. This did translate into a higher overall survival in patients after conditioning regimen with CY-BU (hazard ratio for mortality 0.426 for CY-BU, 95% CI 0.184-0.987, p=0.047). Time to engraftment (BU-CY median 13 days vs. CY-BU median 14 days), cumulative incidence of acute GVHD and relapse were similar between patients receiving BU-CY or CY-BU. These data support the concepts derived from Sadeghi et al in their mouse model in favor of CY-BU compared to the traditional BU-CY. They form the basis for prospective controlled studies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Clinical and histological features of non-alcoholic fatty liver disease

To investigate the clinical and histological features in Chinese patients with non-alcoholic fatty liver disease (NAFLD). 108 patients with biopsy-proven NAFLD were enrolled in this study. Clinical, demographic, and biochemical data were compared between NAFLD patients with abnormal ALT and those with normal ALT. Simple fatty liver, nonalcoholic steatohepatitis(NASH) and cirrhosis were diagnosed in 49 (45.4%), 57(52.7%) and 2 (1.9%) patients, respectively. ALT and AST levels of NASH group were higher than those of simple fatty liver group (t = 2.55, 3.13; P = 0.01, 0.00). Fifty of the 77 patients (64.9%) with abnormal ALT levels were diagnosed as non-alcoholic steatohepatitis (NASH), and twenty-six were diagnosed as simple fatty liver, according to liver histology. Among the 31 patients with normal ALT levels, nine (29%) had NASH and twenty-two had simple fatty liver (P = 0.00). The patients with normal ALT had lower necroinflammatory grade than patients with abnormal ALT (x2 = 10.30, P = 0.01), but they had similar degree of steatosis and fibrosis (x2 = 5.52, 6.12; P = 0.12, 0.01). AST, g-glutamyltransferase, total cholesterol, apolipoprotein A1, apolipoprotein B and systolic blood pressure of patients with normal ALT were all lower than those of patients with abnormal ALT (t = 5.91, 2.00, 2.30, 2.10, 3.14, 2.43; P = 0.00, 0.05, 0.02, 0.04, 0.00, 0.02), while spleen thickness and AST/ALT ratio in patients with normal ALT were higher than those with abnormal ALT significantly (t = 3.70, 2.95; P = 0.00, 0.01). Multivariate analysis revealed that ALT (OR = 2.78, 95% CI 1.06-7.3, P = 0.04) was the only independent predictor of NASH, and ALT had low accuracy in predicting NASH, the area under the receiver operating characteristics curves of ALT to predict NASH was 0.69 (95% CI 0.59-0.8, P = 0.00). NAFLD patients have higher ALT level, and elevated serum level of ALT is independent predictor of the degree of inflammation, but not of steatosis and fibrosis.

Predictors of Treatment Response in Chronic Hepatitis B

The ultimate goal of treatment for chronic hepatitis B is to reduce liver-related complications and mortality. Sustained hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) clearance 6-12 months after stopping treatment are the short-term surrogate outcomes for interferon or peginterferon therapy. As most patients require long-term nucleos(t)ide analogue treatment, which also has the risk of drug resistance in the case of incomplete viral suppression, maintained hepatitis B virus (HBV) DNA suppression to an undetectable level is the appropriate surrogate outcome. Because no antiviral treatment is perfect, it is desirable for treatment response to be predicted and the treatment regimen modified accordingly. At baseline, high ALT and low HBV DNA levels can predict response to both (peg)interferon and nucleos(t)ide analogues. Genotype A HBV responds best to peginterferon but HBV genotype has no predictive value for nucleos(t)ide analogue treatment. HBV DNA is a good on-treatment predictor of response for nucleos(t)ide analogues but not for (peg)interferon. The data supporting the use of quantitative HBsAg and HBeAg to predict response to peginterferon is stronger than that for nucleos(t)ide analogues. In conclusion, predictors of response are useful to provide the most appropriate antiviral therapy to the most suitable patients, in order to achieve the best response and improve the clinical outcome of chronic hepatitis B patients.

Factors That Predict Response of Patients With Hepatitis B e Antigen–Positive Chronic Hepatitis B to Peginterferon-Alfa

Therapy with pegylated interferon (PEG-IFN)-alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN-alfa therapy. The study included 542 patients treated with PEG-IFN-alfa-2a (180 microg/wk, 48 wk) and 266 patients treated with PEG-IFN-alfa-2b (100 microg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 x 10(3) IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed. HBV genotype, high levels of alanine aminotransferase (ALT; >or=2 x upper limit of normal), low levels of HBV DNA (<2.0 x 10(8) IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels. The best candidates for a sustained response to PEG-IFN-alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response.

Longer Duration of HBV-Active Antiretroviral Therapy is Linked to Favorable Virological Outcome in HIV-HBV Co-infected Patients

Background: HBV-HIV co-infection is associated with increased liver-related morbidity and mortality. Herein we analyzed HBV-related virologic and clinical outcomes in HBV-HIV patients in the HAART era. Methods: HBsAg positive HIV-infected patients followed at a US academic center between 1990 and 2008 were assessed in a retrospective and longitudinal study. Factors associated with HBsAg and/or HBeAg clearance and with advanced liver disease were evaluated using logistic regression. Results: 72 patients were evaluated. Their median time of follow-up and of adherence to HBV-active HAART were 3 and 1 years, respectively. HBeAg and HBsAg cleared in 17.6% and 5.5% of patients, respectively. More prolonged use of HBV-active HAART predicted clearance of HBeAg (odds ratio [OR] 2.66, 95% CI 1.15–6.16, p = .02) and of HBsAg (OR 1.54, 95% CI 1.02–2.31, p = .04). Patients clearing HBsAg tended to have higher baseline CD4 (mean CD4 counts: 550 vs. 246 cells/mm3; p = .06). Rate of diagnosis of liver-related complications and death were 24.6/1,000 and 10.5/1,000 patient-years, respectively. Higher ALT levels before HAART initiation were associated with the diagnosis of cirrhosis during follow-up (OR 1.02, 95% CI 1.002–1.03, p = .02). Conclusions: Prolonged use of HBV-active HAART favors HBsAg and HBeAg clearance in HIV-HBV co-infected patients. Those with higher ALT levels at presentation have higher risk of being diagnosed with cirrhosis during the first few years of follow-up.

M1773 Clinical and Histologic Features Associated with Steatosis in a Cohort of Patients with Chronic Hepatitis C

Steatosis occurs in some patients with chronic hepatitis C and has been associated with fibrosis. Steatosis may result from viral mediated factors such as genotype 3 or coexistant metabolic syndrome. The aim of this study was to evaluate the association of demographic and clinical factors with the presence of steatosis and to evaluate the association between steatosis and histologic features on biopsy and disease progression. Methods: 598 patients underwent biopsy for HCV staging over a 10 year period and were well characterized clinically and histologically. Demographic and clinical data were collected retrospectively. Liver biopsies were read by two clinicians masked to clinical data. Biopsies were systematically evaluated by histology activity index (HAI) [Knodell 1981] and steatosis was graded 0-3. Disease progression was characterized by the fibrosis index (fibrosis stage 0-4/years since first risk factor). Results: The mean age was 49 ± 9 years and the mean BMI was 30 ± 7 kg/m2. The mean duration of infection was 26 ± 9 years. The population was 61% male and was 41% African American, 39% Non-Hispanic White and 20% Hispanic. Diabetes mellitus (DM) was present in 22%, hypertension in 36%, hyperlipidemia in 10% and past alcohol use in 26%. Steatosis (fat >5%) was present in 48% of patients. Those with steatosis had higher mean ALT level (91 ± 81 vs 70 ± 57, p<0.001) and higher mean BMI (30.9 ± 6.9 vs 28.7 ± 6.8, p=0.001). Patients with genotype 3 infection were more likely to have steatosis compared to other genotypes (72% vs 47%, p=0.009). Sixty five percent of Hispanics had steatosis compared to 44% of Non-Hispanic Whites and 43% of African Americans (p<0.001). Steatosis was more common in patients with DM (64% vs 43%, p<0.001). There was no association between steatosis and AST level, duration of infection, gender, hypertension, hyperlipidemia or past alcohol abuse. In multivariate analysis, Hispanic race, BMI and DM remained associated with steatosis. Patients with steatosis on liver biopsy had higher mean levels of portal inflammation (2.3 ± 0.9 vs 2.0 ± 0.8, p<0.001), interface hepatitis (2.9 ± 1.9 vs 2.2 ± 1.8, p<0.001), lobular inflammation (1.3 ± 0.7 vs 0.9 ± 0.9, p<0.001), fibrosis (2.7 ± 1.1 vs 2.4 ± 1.2, p=0.002) and total HAI (9.1 ± 3.8 vs 7.5 ± 3.9, p<0.001). Fibrosis index was higher in those with steatosis (0.12 ± 0.07 vs 0.10 ± 0.07, p=0.021). Conclusion: The presence of steatosis on biopsywas associatedwithmore histologic activity and faster rates of disease progression by fibrosis index. BMI, DM and Hispanic race can help clinicians identify patients at risk for steatosis.

Sustained Response of Hepatitis B e Antigen-Negative Patients 3 Years After Treatment with Peginterferon Alfa-2a

Patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B treated with peginterferon alpha-2a with or without lamivudine achieve significantly higher 6-month posttreatment rates of response compared with those treated with lamivudine alone. The durability of <or=3-year posttreatment response was investigated in this study. Patients received peginterferon alpha-2a only (180 microg once weekly; n = 177), in combination with lamivudine (100 mg daily; n = 179) or lamivudine alone (n = 181) for 48 weeks. A total of 315 patients (116, 114, and 85, respectively) participated in this posttreatment observational study. Three years after treatment, the percentage of patients with normal alanine aminotransferase (ATL) was higher for patients treated with peginterferon alpha-2a (31%) than with lamivudine (18%; P = 0.032). Similarly, 28% of patients treated with peginterferon had hepatitis B virus (HBV) DNA levels <or= 10,000 copies/mL versus 15% of patients treated with lamivudine (P = .039). Peginterferon alpha-2a treatment and high baseline ALT level were independent baseline predictors of long-term virologic response (P = .040 and P = .01, respectively). Of the patients who had been treated with a peginterferon alpha-2a-containing regimen, 8.7% cleared hepatitis B surface antigen (HBsAg; 44% of those with undetectable HBV at 3-year posttreatment follow-up) compared with none treated with lamivudine alone. Biochemical and virologic responses were sustained for <or=3 years in approximately 25% of patients given a 48-week course of peginterferon alpha-2a, with or without lamivudine. The increased rate of HBsAg clearance in patients with HBeAg-negative chronic hepatitis B supports the use of peginterferon alpha-2a as a first-line treatment.

Infección crónica por el virus de la hepatitis C y enfermedad hepática asociada en una prisión española

The objective of this study was to determine the prevalence and genotype distribution of chronic hepatitis C virus (HCV) infection in a penitentiary population. The secondary objective was to describe histological findings in liver of the biopsied population, and identify risk factors associated with liver fibrosis and inflammatory activity. Among 800 inmates, 730 accepted HCV antibody screening and PCR confirmation. Sociodemographic, behavioral, and incarceration-related variables were analyzed. Liver biopsy was offered to individuals with chronic HCV infection. Advanced liver disease was defined as fibrosis 3 and/or an inflammatory activity index score 8). HCV antibodies were found in 279 inmates. PCR confirmed HCV infection in 250 inmates, yielding a prevalence of 34.2% (95% confidence interval [CI]: 30.8-37.8). Intravenous drug use was independently associated with HCV infection, odds ratio (OR) 51.7 (95% CI: 31-86). Genotypes were 1a 32.9%, 3 29.7%, 1b 18.4% and 4 17.1%. Fifty-one liver biopsies were performed; advanced liver disease was found in 7 patients (13.7%) based on fibrosis and in 31 patients (60.7%) based on the inflammatory activity index. High AST and ALT levels were associated with advanced liver disease established on both fibrosis and inflammatory activity (P<.05). Lengthy intravenous drug use was associated with inflammatory activity (P=.02; OR 1.2; 95% CI: 1.03-1.7). Persistent HCV infection is highly prevalent among prison inmates and is associated with intravenous drug abuse. HCV genotype diversity is higher in prison inmates than in the general population. Higher transaminase levels are associated with advanced liver disease.

Hepatitis B e antigen‐negative mutations in the precore and core promoter regions in Korean patients

Most patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B have variants of the hepatitis B virus (HBV) that include mutations in the precore or core promoter regions of the HBV genome. The aim of this study was to investigate the patterns of precore and core promoter mutations and their relationship to HBeAg expression in Korean patients. Four hundred seventy-five Korean patients with chronic HBV infection between February 1995 and December 2003 were enrolled in this study. There were 236 HBeAg-positive and 239 HBeAg-negative patients. Blood samples were tested for HBsAg, anti-HBs, HBeAg, hepatitis B e antibody (anti-HBe), liver function tests, and serum HBV DNA. Mutations in the precore and core promoter regions were determined by direct sequencing. In the core promoter region, the C1740, C1753, T1762/A1764, and T1766 mutations were associated with HBeAg escape (all; P < 0.05). In the precore region, a higher frequency of the C1802, A1828, T1846, A1850, C1858, T1862, and A1896 mutations was found in HBeAg-negative patients (all; P < 0.05). In particular, the A1896 mutation was associated with high serum levels of ALT and HBV DNA in HBeAg-negative patients (P = 0.014 and 0.026, respectively). Mutations around the Kozak sequence (nucleotides 1809-1812) were found in 6.7% of patients and were not associated with undetectable HBeAg (P = 0.13). In Korean patients, various mutations in the precore and core promoter regions were associated with HBeAg escape and amelioration of hepatic inflammation in HBeAg- negative patients. Only the A1896 mutation contributed to HBeAg-negative chronic hepatitis B.

Hepatic steatosis in patients with chronic hepatitis C virus genotype 2 or 3 does not affect viral response in patients treated with peginterferon α‐2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®) for 16 or 24 weeks

Hepatic steatosis is common in patients infected with hepatitis C virus (HCV). The effect of steatosis on anti-HCV therapy efficacy is unclear. We studied host and viral factors associated with steatosis and the effect of steatosis on treatment efficacy using the database of a large prospective trial in patients with HCV genotypes 2 and 3. Out of 885 patients assessed for steatosis, a total of 614 patients or 69% had steatosis. Patients with genotype 3 were more likely to have steatosis than those with genotype 2 (79 vs. 59%, P<0.001). Using the logistic regression model, steatosis was associated with genotype 3 (P<0.0001), older age (P=0.0025), heavier weight (P<0.0001), higher HCV RNA (P<0.0001), and higher ALT levels (P=0.015). By univariate analysis, steatosis was associated with lower sustained virological response (SVR) in patients with genotype 3, but not in patients with genotype 2. When all factors associated with steatosis and SVR were evaluated by logistic regression analysis; genotype, age, bodyweight, histological diagnosis, ALT quotient, baseline HCV RNA and treatment duration were associated with the probability of SVR, but gender, race and steatosis were not. Further analysis showed that steatosis remained a non-significant factor while baseline viral load was significantly associated with the probability of an SVR. Steatosis did not influence the efficacy of treatment in our study population. Baseline viral load is a confounding factor, particularly in patients infected with genotype 3 and once baseline viral load was accounted for, the association between steatosis and SVR was not relevant.

Nonalcoholic fatty liver disease in asymptomatic Brazilian adolescents

To evaluate the prevalence and clinical characteristics of Nonalcoholic fatty liver disease (NAFLD) among asymptomatic Brazilian adolescents. Transversal observational study included asymptomatic adolescents with central obesity from private and public schools in Salvador-Bahia, northeastern Brazil. The children answered a questionnaire that included age, gender, race, and medical history, and were submitted to a complete physical exam and abdominal ultrasound. Biochemical exams included: ALT, AST, GGT, C reactive protein (CRP), fasting glucose, insulin, cholesterol and triglycerides. Criteria for NAFLD included: the presence of steatosis in ultrasound and/or high level of ALT, negative or occasional historic of intake of alcohol (<or= 140 g/wk), negative investigation for hepatitis A, B, C, auto-immune hepatitis, Wilson disease and hemochromatosis. From October, 2005 to October, 2006, the study included 1801 subjects between 11 and 18 years of age and a mean age of 13.7+/-2.0 years. One hundred ninety-nine had central obesity. The prevalence of NAFLD was 2.3%, most of whom were male and white. Insulin resistance (IR) was observed in 22.9% of them and had positive correlations with ALT and GGT (P<0.05). Elevated CRP was observed in 6.9% of the cases; however, it was not associated with WC, IR or liver enzymes. The prevalence of NAFLD in Brazilian adolescents was low. The ethnicity may have influence this frequency in the population studied, which had a large proportion of African descendents.

781: HELLP syndrome II. Concurrent eclampsia in 70 cases

To determine disease presentation, course and outcome in patients with HELLP syndrome alone or in conjunction with eclampsia. Two HELLP syndrome databases from a single institution, one spanning 1981-1996 (old database or ODB, n=520) and the expanded version spanning 2000-2006 (new database or NBD, n=173) were queried to identify all patients with concurrent eclampsia (E-HELLP) or without (HELLP). Only patients with complete Class 1 HELLP (platelets <50,000/uL) or Class 2 HELLP (>50,000 - <100,000/uL) syndrome with LDH>600 IU/L and AST or ALT >70 IU/L were included in the study. No eclamptic patients without complete HELLP syndrome were included in the analysis. Outcomes and laboratory data were evaluated and comparisons made between E-HELLP or HELLP in the ODB and NDB. Data were collected and analyzed by appropriate tests. Differences were considered significant if p<0.05. In the combined groups of 693 patients there were 70 patients (62 in ODB and 8 in NDB) with eclampsia (E-HELLP) and 623 without eclampsia (HELLP). Except for significantly more nulliparity in E-HELLP patients (p=0.024 in ODB), there were no demographic differences between groups. E-HELLP patients in ODB had higher admission urine protein (p=0.0474) and serum uric acid (p=0.0016, possibly due to prior seizure), lower hematocrit nadir (p=0.0287), and more red cell transfusions (p=0.0052) and plasma exchange procedures (p=0.0474) than HELLP. Other than lower systolic blood pressures at admission (p=0.0170) and at delivery (p=0.0509) than HELLP, E-HELLP patients had higher ALT levels (p=0.0384) in the NDB. Despite the relatively large size of the study groups, we were unable to detect in either data set a significant worsening of maternal or perinatal outcome in E-HELLP patients compared to HELLP alone. Eclampsia does not appear to contribute a significant adverse impact upon the course or outcome of complete HELLP syndrome pregnancies.

Radiofrequency‐Assisted Liver Resection Does Not Induce Severe Liver Damage

We read with interest the article by Mitsuo et al. [1] and were surprised by the conclusion that RF-assisted hepatectomy may induce severe postoperative liver damage and that the RF-assisted technique is not a safe procedure for liver transection in partial hepatectomy. We believe that to avoid misinterpretation and not to discredit an emerging and efficient procedure, certain issues need to be discussed. The authors used the original RF ‘‘CoolTip’’ precoagulation technique as it was described by Weber and Habib [2]. This technique implies that the noninsulated tip of the electrode is inserted through the entire liver mass until it reaches the undersurface, and when coagulation is completed, it is retracted upward to the liver surface in consecutive coagulation cycles. Precoagulation performed in this manner is maximal and complete for each cycle (cycle end is determined by change in current and impedance by generator) and requires more time and more RF energy than is really necessary. The liver surface is cut after the entire transection line has been precoagulated. Also, needlessly large coagulated and desiccated margins are achieved and, after transection, subsequently left on the remnant liver. The RF-assisted technique described by Mitsuo et al. used Pringle’s maneuver. It is unclear why Pringle’s maneuver was used, when this is a minimal blood-loss liver transection technique where only precoagulated, devitalized, liver tissue is cut. On the other hand, it is well established that hepatic blood flow occlusion is associated with a significant increase in the coagulation area which will lead to more extensive tissue necrosis and subsequently cause high levels of ALT [3–5]. The possibility of not using Pringle’s maneuver is one of the significant advantages of RF hepatectomy since ischemia– reperfusion hepatocellular injury is avoided. Furthermore, vascular occlusion abolishes the protective ‘‘heat sink’’ effect on vessels we do not intend to occlude. It is unclear why there was a 15% bile leak rate in the RF group compared with a 0% leak in the conventional group. RF energy induces desiccation and coagulation resulting in ‘‘welding’’ of the liver tissue, and it is equally effective for blood vessels and bile ducts. If there was no bleeding from the cut vessels, why should there be more bile leaks? In our series we have had no significant postoperative bleeding and no bile leaks. The authors did not specify the anatomic location of the resected segments. This is an important issue because the extent of liver mobilization and manipulation is an important cause of hepatocyte injury during liver surgery [6]. The degree of postcoagulation elevation of AST and ALT is noticeably higher in patients who have had preoperative chemotherapy and the incidence of these patients has not been described [7]. RF resection techniques in which Pringle’s maneuver is not used are not associated with high ALT levels. We base our observations on more than 250 RF ‘‘CoolTip’’-assisted hepatectomies using our own modification of the original Habib technique called the ‘‘sequential coagulate cut technique’’ [8, 9]. The electrode is advanced through liver tissue in the same way as the CUSA tip under optical guidance, the width of the coagulation rim is minimal, and Pringle’s maneuver is never used. In only five patients we had ALT levels close to 1000, while the majority had levels within the 100–200 range and all returned to normal within 7 days. There was no increase in the bilirubin level and postoperative bile fistulas were not observed. M. Milicevic (&) P. Bulajic The First Surgical Clinic, University of Belgrade School of Medicine, Koste Todorovica No. 6, Belgrade 11000, Serbia e-mail: machak@sbb.co.yu

Significant Prevalence of Histologic Disease in Patients With Chronic Hepatitis B and Mildly Elevated Serum Alanine Aminotransferase Levels

Serum ALT remains the most accessible test available to clinicians for monitoring chronic hepatitis B virus infection, but appropriate action when ALT levels are only mildly elevated is ambiguous in standard guidelines. A retrospective study was conducted to investigate the prevalence of significant histology in a patient population with mildly elevated serum ALT levels. A total of 193 consecutive patients were selected and divided into 2 groups according to HBeAg status. Patients were further divided into cohorts on the basis of their highest ALT elevation during follow-up and whether it was 1-1.5 times the upper limit of normal (ULN), 1.5-2 times the ULN, or greater than twice the ULN. The ULN that was used is 30 U/L for men and 19 U/L for women. In all cohorts there was a substantial fraction of patients with histologic disease as evaluated by liver biopsy. HBeAg-negative patients were older, had lower viral load, and had a higher prevalence of disease. After adjustments for age, HBeAg status and HBV DNA viral load were not predictors of significant histology. Age >35 years, male gender, and increasing ALT levels were predictors for significant histology on multivariate analysis. A substantial proportion of patients with mildly elevated ALT levels have significant histologic disease. The prevalence increased with the higher ALT levels and age.

Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails

Recent studies have suggested that an occult hepatitis B virus (HBV) infection negative for HBsAg but positive for HBV-DNA contributes to hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Some follow-up studies have suggested the clinical importance of occult HBV infections in HCC development even after interferon (IFN) therapy, but a recent study denies the significance of the impact of occult HBV infection. Focusing on HCC development in patients in whom hepatitis C virus (HCV) eradication by interferon (IFN) therapy had failed, we conducted this study in order to assess the impact of occult HBV infections on HCC development in these patients. We enrolled 141 patients with chronic hepatitis C (histological stage F2 or F3) who were seropositive for HCV-RNA even after IFN therapy. Serum HBV-DNA was assayed using the real-time polymerase chain reaction. During follow-up, ultrasonography and/or computed tomography (CT) were performed at least every 6 months to monitor HCC development. The cumulative incidence rates of HCC were 8.9%, 25.7% and 53.7% at 5 years, 10 years and 15 years, respectively, after IFN therapy. Multivariate analysis indicated that low platelet counts (<12 x 10(4)/mm(3)), occult HBV infection, high ALT levels (>/=80 IU/L) after IFN therapy and the staging of liver fibrosis were important independent factors affecting the appearance of HCC. Occult HBV was a risk factor for HCC development in patients with chronic hepatitis C in whom HCV eradication had failed. Therefore, patients with chronic hepatitis C with occult HBV should be monitored carefully for HCC after IFN therapy.

Prevalence of Fibrosis and Cirrhosis in Chronic Hepatitis B: Implications for Treatment and Management

To document the prevalence and factors associated with severe fibrosis and cirrhosis in a large population of Asian chronic hepatitis B (CHB) patients. Transient elastography was performed in unselected CHB patients. Liver stiffness score of <8.1 kPa was used as a cut-off for the presence of severe fibrosis or liver cirrhosis. 1315 patients were recruited, of which 951 (72%) were treatment-naive. Of these, 319 (34%) had severe fibrosis, with higher prevalence seen in males compared with females (39% vs 24% respectively, p < 0.01. Severe fibrosis was seen with increasing age from 20% in patients <25 years to 81% in those >65 years. Higher prevalence of severe fibrosis was seen in HBeAg(+) patients compared to HBeAg(-) patients age >45 years (58% vs 43% respectively, p = 0.03), in patients with HBV DNA levels >or=4 log compared with <4 log copies/ml (41% vs 27% respectively, p < 0.01), and in patients with stepwise increase of ALT levels (<0.5 x ULN vs 0.5-1 x ULN vs 1-2 x ULN; 11% vs 30% vs 48% respectively, p < 0.01). After multivariate analysis, gender, age and ALT levels were significant factors associated with severe fibrosis. Patients who received antiviral treatment had lower ALT, stiffness score and prevalence of cirrhosis compared to treatment-naive patients [25 vs 35 U/L (p < 0.01), 6.2 vs 6.7 kPa (p = 0.031) and 14% vs 22% (p = 0.008) respectively]. The overall prevalence of severe fibrosis in CHB patients was 34% with higher rates seen in older age groups, males, and in patients with higher ALT levels.

Adefovir and lamivudine in combination compared with adefovir monotherapy in HBeAg-negative adults with chronic hepatitis B virus infection and clinical or virologic resistance to lamivudine: A retrospective, multicenter, nonrandomized, open-label study

The aim of this study was to assess the therapeutic effectiveness of adefovir dipivoxil (ADV), administered in combination with lamivudine (LAM) or as monotherapy, and the rate of resistance to ADV, in hepatitis B e antigen (HBeAg)-negative adult patients with chronic hepatitis B virus (HBV) infection and clinical or virologic resistance to LAM. Furthermore, we evaluated in these selected patients the clinical co-variates associated with a sustained virologic response. Data from adult outpatients aged >18 years with chronic HBV infection and clinical or virologic resistance to LAM were used in this retrospective, multicenter, nonrandomized, open-label study. Patients were selected if they received ADV 10 mg PO QD + LAM 100 mg QD PO or ADV 10 mg PO QD as monotherapy for 24 to 32 months between June 2003 and July 2006. End points were the proportions of patients who achieved virologic response (undetectable HBV-DNA [<3.3 log(10) copies/mL]) and biochemical response (normalization [<40 IU/L] of alanine aminotransferase [ALT]), and the proportions in whom resistance to ADV (rebound serum HBV-DNA >1 log(10) copies/mL compared with on-treatment nadir, as confirmed on molecular analysis) was found. HBV-DNA and ALT levels were checked every month during the first 3 months of treatment and every 3 months thereafter until 28 months. Data from each center were stored in a centralized database and analyzed by a blinded independent investigator. Data from 70 patients were included (48 men, 22 women; median age, 51 years; ADV + LAM, 36 patients; ADV monotherapy, 34). The median duration of the pharmacologic treatment in the 2 groups of patients was 28 months (range, 24-32 months). By month 3, virologic response was achieved in 30 patients (83%) in the ADV + LAM group and in 26 patients (76%) in the ADV monotherapy group. At 12 months, virologic response was achieved in 5 additional patients in the ADV + LAM group and 2 additional patients in the ADV monotherapy group. Biochemical response was found to be time dependent: in the 2 groups, the rates of biochemical response were, respectively, 56% and 54% at month 3, 80% and 71% at month 6, and 96% and 79% at month 12, persisting up to the end of the study period. The rates of clinical resistance to ADV were 3% with ADV + LAM and 18% with ADV monotherapy (with a 6% rate of resistance due to rtA181 mutation in the monotherapy group). Logistic regression analysis found that pre-treatment levels of HBV-DNA <5 log(10) copies/mL, ALT levels >150 IU/L, an inflammation score >7, and a fibrosis score <2 were the strongest covariates independently associated with a sustained virologic response in both groups of patients. No adverse events were reported in any of the patients. ADV, administered in combination with LAM or as monotherapy, appeared to be effective in this small, selected group of HBeAg-negative patients with clinical or virologic resistance to LAM, especially in those with low pretreatment HBV-DNA levels, high ALT levels, and low fibrosis scores.

Treatment of Chronic Hepatitis B in Children

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.

Clinical, virologic and phylogenetic features of hepatitis B infection in Iranian patients

To characterize the clinical, serologic and virologic features of hepatitis B virus (HBV) infection in Iranian patients with different stages of liver disease. Sixty two patients comprising of 12 inactive carriers, 30 chronic hepatitis patients, 13 patients with liver cirrhosis and 7 patients with hepatocellular carcinoma (HCC) were enrolled in the study. The HBV S, C and basal core promoter (BCP) regions were amplified and sequenced, and the clinical, serologic, phylogenetic and virologic characteristics were investigated. The study group consisted of 16 HBeAg-positive and 46 HBeAg-negative patients. Anti-HBe-positive patients were older and had higher levels of ALT, ASL and bilirubin compared to HBeAg-positive patients. Phylogenetic analysis revealed that all patients were infected with genotype D (mostly ayw2). The G1896A precore (PC) mutant was detected in 58.1% patients. HBeAg-negative patients showed a higher rate of PC mutant compared to HBeAg-positive patients (c2 = 9.682, P = 0.003). The majority of patients with HCC were HBeAg-negative and were infected with PC mutant variants. There was no significant difference in the occurrence of BCP mutation between the two groups, while the rate of BCP plus PC mutants was higher in HBeAg-negative patients (c2 = 4.308, P = 0.04). In the HBV S region, the genetic variability was low, and the marked substitution was P120T/S, with a rate of 9.7% (n = 6). In conclusion, HBV/D is the predominant genotype in Iran, and the nucleotide variability in the BCP and PC regions may play a role in HBV disease outcome in HBeAg-negative patients.

307 THE COURSE OF CHRONIC INFECTION WITH HEPATITIS DELTA VIRUS: A 20-YEARS COHORT STUDY OF 299 ITALIAN PATIENTS

common. There was no relationship with causes of BCS or with the number of thrombosed hepatic veins. ALT decreased in all patients before any treatment was performed. In patients with high, but rapidly decreasing ALT (50% decrease within 3 days), factor V level rapidly increased. No death occurred in this group (median follow-up of 78 months), whereas 2 out of 8 patients with high ALT that decreased slowly died within 3 months. Survival without liver transplantation was significantly worst in patients with high ALT than in others (5-year survival: 45 vs 68%; p = 0.003). However, ALT level did not add information to that of available prognostic scores. Conclusion: ALT level at diagnosis allows for distinguishing 2 variants of BCS. High ALT levels reflect severe, but potentially reversible, ischemic hepatic cell necrosis. High ALT level associated with acute hepatic dysfunction, should not be the sole basis for making a decision for urgent recanalization or liver transplantation. The initial course of these anomalies should also be taken into consideration.