Konstantinos D. Pantazis

Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance.

Objective Tamoxifen induced hepatotoxicity has not been investigated in breast cancer patients with pre-existing liver steatosis. The aim of our study was to investigate the most common predisposing factors for non-alcoholic fatty liver disease in breast cancer patients with liver steatosis, treated with adjuvant tamoxifen therapy, in order to evaluate their role in the appearance of tamoxifen induced hepatotoxicity. Methods Clinical and laboratory evaluation, including an oral glucose tolerance test, was done in 60 women with breast cancer and liver steatosis before the beginning of adjuvant tamoxifen treatment and every 6 months during treatment. Tamoxifen induced hepatotoxicity was defined as abnormal liver function tests during tamoxifen treatment whereas these test results were below the normal range at baseline control. Statistical evaluation of data was performed using parametric methodology (the chi-squared test, and Students t-test, P < 0.05). Results Twenty-six patients (43.3%) exhibited tamoxifen induced hepatotoxicity (group A) whereas 34 (56.7%) did not (group B). The mean overall follow-up period for the whole group was 37.5 months (SD 27.8, range 6–120 months) and did not differ between the two groups (P = 0.055). There was significant statistical difference in body mass index (BMI) and baseline fasting glucose, cholesterol and triglyceride levels between the two groups. Eighteen of 26 patients (69.2%) from group A had impaired glucose tolerance compared with only 8/34 patients (23.5%) from group B (P < 0.001), a finding observed even in BMI matched patients from the two groups (62.5% vs 12.5%, P = 0.002). Conclusions Tamoxifen induced hepatotoxicity is observed in a great proportion of breast cancer patients with pre-existing liver steatosis, especially those with higher BMI and higher glucose and lipid levels at baseline control. Glucose intolerance before the beginning of tamoxifen treatment seems to be a predictor of the hepatotoxicity, unrelated to baseline BMI.

Clinical significance of serum procalcitonin levels in patients with acute or chronic liver disease

Objective To evaluate the diagnostic value of serum procalcitonin levels in patients with acute or chronic liver disease, with or without bacterial infections and to correlate the results with the clinical outcome and the laboratory findings for these patients. Methods One hundred and six consecutive hospitalized patients with liver disease were evaluated for procalcitonin levels on admission. Fifteen of them (14.2%) had acute alcoholic hepatitis on cirrhotic background (group A), 20 (18.9%) had alcoholic cirrhosis without hepatitis and/or bacterial infection (group B), 16 (15.1%) had decompensated cirrhosis with proved bacterial infection (group C), 42 (39.6%) had uncomplicated viral hepatitis-related cirrhosis (group D) and 13 (12.3%) had acute icteric viral hepatitis (group E). Serum procalcitonin levels were measured using an immunoluminometric assay. Statistical analysis was based on Students t-test and the non-parametric Kruskall–Wallis test (P<0.05). Results Serum procalcitonin levels were significantly higher in cirrhotic patients with bacterial infection (9.80±16.80 ng/ml) than in those without bacterial infection (0.21±0.13 ng/ml, P=0.001), whereas they were within normal range (<0.5 ng/ml) in all patients with uncomplicated cirrhosis, irrespective of the cause of cirrhosis. Seven of 15 group A patients (46.2%) and 4/13 group E patients (30.8%), all of them cirrhotics, had procalcitonin levels higher than 0.5 ng/ml on admission, without established bacterial infection. Conclusion Serum procalcitonin levels remain below the threshold of 0.5 ng/ml in all patients with uncomplicated cirrhosis, irrespective of the cause of the disease, while they are significantly elevated when bacterial infection complicates the course of the disease. A significant proportion of patients with acute alcoholic hepatitis on a cirrhotic background as well as of patients with acute on chronic viral hepatitis, without bacterial infection, exhibit serum procalcitonin levels above 0.5 ng/ml, suggesting that this cut-off value is probably not enough to discriminate between patients with or without bacterial infection within these subgroups of patients with liver disease.

Anticardiolipin antibodies in chronic hepatitis B and chronic hepatitis D infection, and hepatitis B-related hepatocellular carcinoma. Relationship with portal vein thrombosis.

Objective To assess the presence of anticardiolipin antibodies (ACAs) in patients with chronic hepatitis B virus (HBV) infection, chronic hepatitis D virus (HDV) infection and HBV‐related hepatocellular carcinoma (HCC) and to associate this with the incidence of portal vein thrombosis (PVT) in HCC patients. Patients and methods Sixty‐five cirrhotic patients with HBV‐related HCC, 28 naive patients with chronic HBV infection and 14 naive patients with chronic HDV infection were enrolled prospectively in the study. Thirty‐two healthy blood donors were used as controls. The ACAs (immunoglobulin G and immunoglobulin M) were measured using an enzyme‐linked immunosorbent assay system. Statistical analysis used non‐parametric methodology (chi‐squared test, Student t‐test and Fisher exact test, P value < 0.05). Results Eleven of the 65 patients with HCC (16.9%) showed a positive ACA titre and 22 of the patients (34%) had PVT. Of these patients, eight (36%) had a positive ACA titre. In contrast, from the 43 patients without PVT, only three (11%) showed a positive titre. From the 28 HBV patients, six (21.5%) had a positive ACA titre, and six out of 14 (42.8%) HDV patients also showed a positive ACA titre. Three of the six ACA positive HBV patients presented an extrahepatic manifestation of the disease. One out of 32 control patients (3%) had positive ACAs. Conclusion Both chronic HBV and chronic HDV infections are potent stimulants for the production of ACAs. The presence of ACAs in a great proportion of HBV‐cirrhosisrelated HCC patients with PVT suggests their possible participation in thrombotic mechanisms and in the hypercoagulable state that occurs in advanced liver disease and HCC.

New Data concerning the Epidemiology of Hepatitis B Virus Infection in Greece

There is an obvious, significant, and diachronic reduction of the prevalence of HBV infection in Greece, concerning the general population as well as some traditionally high-risk groups, mainly as a result of constant informing and the widespread initiation of preventive and prophylactic measures, as well as the improvement of health care services. Nevertheless, there are special groups and populations (economical refugees, religious minorities, HIV-positive patients, abroad pregnant women, prostitutes, etc.) who represent sacs of high HBV endemicity and need epidemiological supervision and intervention, in order to limit the spread of the infection and to further improve the existing epidemiological data.

Patient's age modifies the impact of the proposed predictors of sustained virological response in chronic hepatitis C patients treated with PEG-interferon plus ribavirin

BACKGROUND The aim of this study was to investigate the effect of patients age on the impact of typically proposed predictors of sustained virological response (SVR) in treatment-naïve, high-pretreatment viral load (>700.000 IU/ml), chronic hepatitis C (CHC) patients treated under real-life conditions in Greece. METHODS We retrospectively analyzed 185 CHC patients (14.4% cirrhotics) who had been treated with weight-adjusted dosing (1.5 microg/kg per week) of pegylated interferon-a2b (PEG) plus genotype-based ribavirin (RIB) for 24 or 48 weeks of treatment, based on viral genotype. SVR was confirmed by undetectable serum HCV-RNA 6 months after the end of treatment. RESULTS Overall, 68.5% of patients exhibited SVR and 31.5% were non-responders (non-SVRs). Among the non-SVRs, 71.4% were infected with HCV genotype-1. Importantly, 71.4% of genotype 4-infected treated patients exhibited SVR. In the multivariate analyses, only the early histological stage of liver disease (p=0.015) and the presence of genotype non-1 infection (p=0.003) were independent predictors of SVR. For patients younger than 35 years, none of the baseline parameters and neither viral genotype (p=0.284) nor the stage of liver disease (p=0.351) was an independent predictor of non-SVR, whereas for patients between 35 and 55, only the presence of genotype-1 infection independently predicted non-SVR (p=0.008). For older patients (>55 years), only the histological stage of liver disease (p=0.047) and not the viral genotype (p=0.275) independently predicted non-SVR. CONCLUSIONS The impact of the typical predictors of SVR, such as viral genotype and liver histopathology, is modified according to patients age in currently approved combination treatment.

Serum beta2-microglobulin levels in hepatitis B e antigen-negative chronic hepatitis B patients under long term lamivudine monotherapy: relationship with virological breakthrough.

OBJECTIVES To evaluate the predictive value of serum beta2-microglobulin (beta2m) levels for virological breakthrough in hepatitis B e antigen-negative chronic hepatitis B patients under long term lamivudine monotherapy. METHODS Serum beta2m levels were calculated at baseline and every three months during lamivudine monotherapy in 25 patients with chronic hepatitis B, using microparticle enzyme immunoassay technology to investigate their association with biochemical, virological and histological outcome data. Cox proportional hazard models were used to investigate the association between serum beta2m levels and virological breakthrough. RESULTS Seven of 25 (28%), nine of 25 (36%) and 14 of 25 (56%) chronic hepatitis B patients exhibited virological breakthrough at months 12, 24 and 36 of treatment, respectively. All chronic hepatitis B patients who did not show virological breakthrough in the follow-up period exhibited beta2m elevation in month 3 of treatment. The duration (in months) of serum beta2m elevation was significantly higher in the responders group than the nonresponders group (7.3 +/- 2.6 versus 3.8 +/- 3.4, P=0.02). In contrast to patients whose serum beta2m levels were increased at three months, patients whose beta2m levels were decreased had a 4.6 times higher risk of experiencing virological breakthrough (hazards ratio 4.6, 95% CI 1.22 to 17.36). When age, pretreatment serum alanine aminotransferase and hepatitis B virus DNA levels, and grade of liver disease were simultaneously included in the same Cox model, decreased beta2m status was still associated with increased risk of virological breakthrough (hazards ratio 12.2, 95% CI 1.28 to 116.8). CONCLUSIONS In hepatitis B e antigen-negative chronic hepatitis B patients under long term lamivudine monotherapy, serum b2m levels at three months of treatment, compared with baseline levels, are good predictors of risk for virological breakthrough.

Large Intestine Histopathology of Pegylated-Interferon-Alpha Plus Ribavirin Treated Chronic Hepatitis C Patients

Gastrointestinal disorders (especially diarrhea) are observed in a proportion of patients treated with the currently approved combination treatment for chronic hepatitis C (CHC), pegylated-interferon alpha (PEG-IFNa) plus ribavirin (RIB) [1]. Several reports suggest that the presence of inflammatory bowel disease (IBD) is not a contraindication for interferon-alpha- (IFNa-) based treatments [2, 3]. Furthermore, a randomised placebo-controlled trial of PEG-IFNa in patients with active ulcerative colitis concluded that PEG-IFNa is safe but not effective treatment for these patients [4]. On the contrary, several reports [5, 6, 7, 8] revealed that treatment of chronic viral hepatitis with IFNa or PEG-IFNa with or without RIB was related with the onset of clinically and histologically confirmed acute colitis of the IBD type. To our knowledge the effect of chronic hepatitis C virus (HCV) infection or PEG-IFNa plus RIB combination treatment on large intestine histopathology has not been investigated, within a clinical trial. The principal aim of our study was to investigate the effect of PEG-IFNa plus RIB treatment on the large intestine histology of treated CHC patients. Twenty-four treatment-naive CHC patients with serologically (antiHCV-positive, Abbott Laboratories, Abbott Park, Ill, USA), virologically (serum HCV-RNA detection, Cobas Amplicor HCV test, version 2, Roche Diagnostics, Branchburg, NJ, USA), and histologically (liver biopsy-Ishak scoring system) confirmed CHC and no contraindication of receiving combination treatment with PEG-IFNα2b and RIB were enrolled in this pilot study. All patients were treated with weight-based dosing of pegylated interferon-a2b (Peg-Intron, 1.5μg/kg/week) and genotype-related ribavirin dose (Rebetol, 800 mg/day for genotype 2/3 and 1000–1200 mg/day for genotype 1/4-infected patients, depending on baseline body weight < or ≥ 85 kg, resp.) for 24 weeks. Patients were evaluated for the presence of gastrointestinal symptoms, by receiving a detailed history, before the beginning of treatment, during the treatment period and at week 24 of treatment. The study population underwent recto-sigmoidoscopic examination prior to the beginning of the treatment schedule. Three to five biopsy specimens were taken from the rectosigmoid area. Histological findings characteristic of inflammation as well as the presence of architectural disorders and the quantity of mucus production, the presence of ulcerations and Paneth cells as well as the numbers of lymphoid follicles in every biopsy specimen were evaluated. Fifteen patients underwent the same procedure after the completion of 24-week treatment course and three of them were also evaluated during treatment because of diarrhea. Ten age-, sex-, and BMI-matched healthy subjects (control group) underwent recto-sigmoidoscopic examination and biopsy. All controls had no history of inflammatory bowel disease or other gastrointestinal diseases, did not receive any medication and did not report symptoms from the gastrointestinal tract. Written informed consent was obtained from each participant for his or her participation in the study. The study conformed to the ethical guidelines of the 1975 Declaration of Helsinki. No pathological macroscopic (endoscopic) findings were identified at baseline as well as in endoscopic re-evaluation in either patients or controls. CHC patients had no statistically significant difference in the presence of bowel inflammatory infiltration compared to controls as shown in Table 1. It is important to note that a respectable proportion of CHC patients exhibited architectural disorder and decreased mucus production (25%) as well as presence of Paneth cells (16.7%), compared to controls, but this does not reach statistical significance possibly due to the small sample size of the study population. This finding needs further investigation because of the documental lymphotropism of HCV and the well-known HCV-related autoimmune manifestations. Table 1 Comparison of epidemiological and large intestine histopathology data between untreated CHC patients and controls. No patient reported diarrhea before the initiation of treatment whereas 3 patients reported diarrhea during the treatment course. In particular, the first patient reported diarrhea at week 6 of treatment, the second one at week 12, and the third one at week 14. Baseline histology was normal in all three patients. Histopathological evaluation of the large intestine at the onset of symptoms revealed mild chronic nonspecific colitis in the first patient (Figure 1) and normal large intestine histology in the other two patients, respectively. The same findings were repeated in these patients in the histological re-evaluation at week 24 of treatment. Diarrhea spontaneously resolved in all of them within 5–7 days and none of them followed treatment discontinuation. Figure 1 Histopathological evaluation of the large intestine at baseline (a) and at the onset of symptoms (b) revealed normal large intestine histology and mild chronic nonspecific colitis in the first patient with diarrhea, respectively. There was no statistically significant difference between the percentage of patients with large intestine inflammation before the initiation and at week 24 of treatment (66.7% versus 53.3% resp., P = .71). Particularly, 6/15 patients exhibited mild inflammatory infiltration before the initiation as well as at week 24 and 3/15 exhibited absence of inflammation both before and at week 24 of treatment. Moreover, 4/15 positive patients for the presence of inflammation before treatment had normal large intestine histology at week 24 and finally, 2/15 patients had no findings of inflammation before treatment but exhibited mild nonspecific inflammatory lesions at week 24. No statistically significant differences were observed before the beginning and at week 24 of combination treatment regarding architectural disorder and decrease of mucus production (P = .70), presence of Paneth cells (P = .10), and the number of lymphoid follicles in every biopsy specimen (P = .97) as shown in Table 2. Interestingly none of 4 patients with detectable Paneth cell at baseline evaluation exhibits presence of them at week 24. This finding needs further investigation in large-scale studies because of the proposed importance of these multifaceted cells in the pathophysiology of IBD [9]. Table 2 Comparison of large intestine histopathology and diarrhea data of CHC patients before and after 24 weeks of treatment. In conclusion, according to the preliminary results of our pilot study, it seems that the immunomodulatory-antiviral treatment of CHC with PEG-IFNa2b plus ribavirin for 24 weeks possibly does not significantly affect the large intestine histology of treated patients, despite the appearance of symptoms from the gastrointestinal tract in a subgroup of them. The effect of chronic HCV infection in the intestine histopathology needs further investigation.