Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline.

There is a lack of knowledge regarding the effect of peginterferon (PEG-IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty-two HBeAg-positive and 67 HBeAg-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG-IFN therapy were studied. After PEG-IFN therapy, HBeAg-negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg-positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post-treatment, 7 (13%) HBeAg-positive and 9 (14%) HBeAg-negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post-treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg-negative CHB): 71% vs 5% for HBeAg-positive (P < 0.001) and 60% vs 16% for HBeAg-negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg-positive and HBeAg-negative CHB, respectively). In conclusion, PEG-IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.

Renal function during treatment with adefovir plus peginterferon alfa-2a vs either drug alone in hepatitis B/D co-infection.

Long-term safety of treatment with hepatitis B virus (HBV) polymerase inhibitors is a concern. Adefovir dipivoxil (ADV) therapy has previously been associated with impairment of renal function. Limited data are available on the safety of combination therapy with nucleos(t)ide analogues and interferon alfa (IFNα). The aim of this analysis was to assess the renal function during combination therapy with peginterferon alfa-2a (PegIFNα-2a) plus ADV vs either drug alone in patients with hepatitis B/D co-infection. We performed a retrospective analysis of renal function data of patients treated in the Hep-Net/International Delta Hepatitis Intervention Trial 1(HIDIT-1-trial), a European multicenter study to investigate the efficacy of 48 weeks of therapy with PegIFNα-2a+ADV vs either drug alone in 90 patients with chronic hepatitis B/D co-infection. Glomerular filtration rates (GFR) were calculated by Cockcroft-Gault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After 48 weeks of therapy GFR values were significantly lower in patients receiving adefovir-containing treatment vs PegIFNα-2a alone [mean difference 16.1 mL/min (CG) and 10.2 mL/min (MDRD), respectively, P < 0.05] while no differences were observed between patients receiving adefovir alone vs combination treatment. Twenty-four weeks after treatment GFR values did not differ between treatment arms. A decrease in GFR ≥ 20% was observed more often in patients during adefovir-containing treatment vs PegIFNα-2a alone (P < 0.05) which was confirmed by Kaplan-Meier analysis. Adefovir-containing but not PegIFNα-2a treatment was associated with a decrease in GFR values in about one-fifth of patients. Combination treatment of PegIFNα-2a+ADV in chronic hepatitis B/D co-infection did not lead to any further impairment of kidney function.

A short course of add-on adefovir dipivoxil treatment in lamivudine-resistant chronic hepatitis B patients.

The aims of the study were to investigate the efficacy of rescue therapy with lamivudine (LAM) and adefovir (ADV) combination for 6 months followed by ADV monotherapy in lamivudine-resistant chronic hepatitis B (LAM-R CHB) patients, and to analyze the frequency of ADV resistance mutant development in such patients. A total of 170 consecutive LAM-R CHB patients (male/female: 130/40, mean age: 42.9+/-13.4 years) with viral breakthrough under LAM therapy were analyzed. A total of 68 had HBeAg-positive. Patients received rescue therapy with LAM [100 mg (qd)]+ADV [10 mg (qd)] for 6 months after which LAM was discontinued. HBV-DNA was assessed with the HBV-DNA 3.0 bDNA assay. ADV-resistant mutations were identified by sequencing the reverse transcriptase region. The median duration of rescue therapy was 24 months. Cumulative probability of becoming HBV-DNA undetectable was 33.8%, 59.6% and 68.2% after 24, 48 and 96 weeks of treatment, respectively. These figures were 43.2%, 58.0% and 73.1% for ALT normalization. Among 68 HBeAg-positive CHB patients, 10 patients had an e-antigen seroconversion. Low baseline HBV-DNA level (<10(7) copies/mL) was a significant predictor of response to ADV treatment (P<0.01). Cumulative probability of ADV resistance was 1.2%, 15.1% and 37.3% at 12, 24 and 36 months of therapy, respectively. By multivariate analysis, baseline high viral load and primary nonresponse to treatment at week 24 predicted ADV resistance. The data indicate that a time limited add-on strategy does not provide benefit over the switch strategy with respect emergence of ADV resistant mutants in LAM-R CHB patients.

The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation.

BACKGROUND: Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. AIM: To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. METHODS: Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. RESULTS: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. CONCLUSION: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.

Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study.

The present study was designed to determine the seroprevalence of hepatitis B and C virus (HBV, HCV) infections and risk factors in the Turkish general population. Participants were enrolled from urban and rural areas of the predetermined 23 EUROSTAT NUTS 2 region. A two-stage stratified sampling method was used to select participants from these regions (n = 5460; 50.9% females; mean (SD) age: 40.8 (14.7) years). Sociodemographics, clinical characteristics and risk factors were recorded at home visits. The seropositivity rates for hepatitis B surface antigen (HBsAg), anti-HCV, anti-HBs and anti-HBc total were 4.0%, 1.0%, 31.9% and 30.6%, respectively. Among HBsAg-positive cases, 94.5% were anti-HBe-positive, 70.2% were HBV-DNA-positive and 2.8% were anti-HDV total positive; 99.1% of HBV infections were of genotype D. Close contact with a hepatitis patient (OR 3.24; 95% CI 2.25-4.66; p < 0.001), living in the southeastern region (OR 2.74; 95% CI 1.7-4.45; p < 0.001), male gender (OR 1.77; 95% CI 1.28-2.46; p < 0.001), being married (OR 1.62; 95% CI 1.02-2.57; p 0.038), educational level less than high school (OR 1.53; 95% CI 1.04-2.26; p 0.03), orodental interventions (OR 1.54; 95% CI 1.01-2.35; p 0.047) and a history of non-disposable syringe use (OR 1.4; 95% CI 1.01-1.96; p 0.045) were significant determinants of HBsAg positivity. Age ≥50 years (OR 2; 95% CI 1.09-4.3; p 0.026) was the only significant predictor of anti-HCV positivity. In conclusion, our findings revealed an HBsAg positivity in 4% and anti-HCV positivity in 1% of the adult population and at least one-third of the population has been exposed to HBV infection in Turkey.

Coexistence of hereditary hemorrhagic telangiectasia and fibropolycystic liver disease.

This is a case report of a 43-year-old woman who received a transplant for end-stage liver disease due to hereditary hemorrhagic telangiectasia and fibropolycystic liver disease. This is an uncommon association of two autosomal-dominant conditions with defined genetic and molecular defects. The liver showed extensive vascular malformations of arteries and veins as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. This case raises interesting questions about the possible relationship of these genes and their gene products, both of which are related to cell-matrix interactions and are strongly associated with blood vessels, one of them being expressed on endothelial cells and the other being developmentally important in blood vessels.

Importance of concomitant viral infection during late acute liver allograft rejection.

We have determined accompanying events and reviewed the management and outcome of late acute cellular rejection episodes in 384 consecutive liver recipients. A significant proportion of patients experienced concomitant viral infection (group 1, n = 15 [41%]), with CMV infection comprising the largest group and smaller contributions from other viruses (CMV, 30%; HSV, 5%; EBV, 3%; varicella zoster virus, 3%). Thirteen (35%) patients (group 2) developed late rejection associated with low maintenance immunosuppression, and in a further 10 patients (group 3), no accompanying factor could be identified. Refractory rejection was higher in late compared with early rejection episodes in our series (29% vs. 9.2%, P < 0.05). Antiviral chemotherapy administered in rejection episodes with concomitant viral infection, either as sole treatment in cases with accompanying hepatitis or as adjunctive therapy to further supplemental immunosuppression in episodes of steroid-resistant rejection, controlled the rejection process in all treated patients.

Hypogonadism is not related to the etiology of liver cirrhosis.

We investigated the clinical and laboratory findings of hypogonadism and feminization in male patients with viral or alcoholic cirrhosis to determine whether chronic liver disease plays a primary role in the development of sexual dysfunction and hormonal changes. Two groups of male patients with liver cirrhosis (23 alcoholic, 33 viral) age- and Child's grade-matched, and 20 age-matched healthy men, as a control group, were included in this study. Clinical signs of hypogonadism and feminization were examined in the cirrhotic patients. Follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free testosterone, estradiol, androstenedione, dehydroepiandrosterone sulfate, and sex hormone-binding globulin were estimated in all groups. Seminal fluid was also analyzed in 7 alcoholic and 15 viral cirrhotics. Serum levels of estradiol, androstenedione, and sex hormone-binding globulin were significantly higher, and free testosterone and dehydroepiandrosterone sulfate levels were significantly lower in both groups of cirrhotics compared with the control group. Child's C patients in both groups of cirrhotics were found to have higher estradiol and lower free testosterone levels than child's A and B patients. Alcoholic and viral cirrhotics had markedly reduced sperm motility and density. The differences between alcoholic and viral cirrhotic patients in the clinical signs of hypogonadism, serum levels of sex steroids, and the results of seminal fluid analysis were not statistically significant. These findings suggest that liver cirrhosis per se, independent of etiology, causes hypogonadism and feminization, and that the degree of hypogonadism and feminization correlates well with the severity of liver failure.

Spontaneous ascitic infection in different cirrhotic groups: prevalence, risk factors and the efficacy of cefotaxime therapy.

OBJECTIVE: To investigate the prevalence of spontaneous ascitic infection (SAI) in different cirrhotic groups, the risk factors for development of SAI, and the efficacy of cefotaxime therapy. DESIGN: A prospective study. SETTING: In-patient clinic of a university hospital. PATIENTS: Eighty cirrhotic patients with ascites were assigned to four groups: hepatitis B or D virus-related 34, alcoholic 18, hepatitis C virus-related 14, miscellaneous 14. INTERVENTIONS: Paracentesis was performed on 80 patients during 92 consecutive hospitalizations. Ascitic fluid was cultured by the method of bedside inoculation of blood culture bottles with ascites. The patients with SAI were treated with cefotaxime (2 g, three times daily, intravenously) for 5 days. MAIN OUTCOME MEASURES: Frequency of SAI in cirrhotic groups; clinical, bacteriological and biochemical findings of SAI; rate of recovery-from infection. RESULTS: Twenty SAI episodes (22%) were found in 16 patients; 8 episodes were spontaneous bacterial peritonitis, 2 bacterascites, and 10 culture-negative neutrocytic ascites. SAI occurred more frequently in patients with hepatitis B or D virus-related liver cirrhosis (32%) than in the alcoholic (6%, P < 0.05), hepatitis C virus-related (14%) or miscellaneous (14%) cirrhotic groups in multivariate analysis, independent predictive factors associated with the development of SAI are chronic hepatitis B virus infection, ascitic fluid total protein and serum bilirubin. Escherichia coli was obtained in 5 of 10 positive ascitic fluid cultures. Cure of the infection was achieved in 95% of episodes. Hospitalization mortality rate in infected patients was 20%. CONCLUSION: Spontaneous ascitic infection occurs in approximately 20% of cirrhotic patients hospitalized with ascites. The patients with low ascitic protein concentration, high serum bilirubin level or hepatitis B virus cirrhosis are more predisposed to SAI. Cefotaxime may be an effective first-choice antibiotic for ascitic fluid infection.

Tuberculous peritonitis--reports of 26 cases, detailing diagnostic and therapeutic problems.

OBJECTIVE: To evaluate the clinical presentation, biochemical (ascites and serum) and laparoscopic findings, and to assess the efficacy of triple antituberculous therapy without rifampicin for 6 months in patients with tuberculous peritonitis. METHODS: Twenty-six tuberculous peritonitis patients (11 male, 15 female) with a mean age of 34.8 +/- 3.4 years (range 14-77) were assessed with regard to diagnostic and therapeutic features. RESULTS: The most common symptoms and signs were abdominal pain (92.3%) and ascites (96.2%), respectively. Tuberculin skin test (TST) was positive in all patients. An abnormal chest radiography suggestive of previous tuberculosis was present in five patients (19.2%), and two patients (7.7%) had extra-peritoneal (cerebral, pericardial) active tuberculous involvement. In 24 of the 25 patients who underwent laparoscopy with directed biopsy, whitish nodules suggested tuberculous peritonitis; 76% of the biopsy specimens revealed caseating, 20% non-caseating granulomatous inflammation, and 4% non-specific findings. The ascitic fluid of one patient (3.8%) was positive for acid-resistant bacilli, and culture was positive in two patients (7.7%). Twenty-four of the patients were treated for 6 months with isoniazid, streptomycin (total dose 40 g) and pyrazinamide (for the first 2 months and then substituted with ethambutol). Eighteen patients also received methyl prednisolone, initially 20 mg/day, for 1 month. The follow-up period was 19 +/- 1.7 months after the end of therapy (range 6-36). Ascites and abdominal pain abated earlier in patients on steroid therapy. All but two of the 24 patients responded to treatment. CONCLUSION: Non-invasive tests such as acid-fast stain and culture of the ascitic fluid are usually insufficient, hence invasive laparoscopy and peritoneal biopsy are necessary for the diagnosis of tuberculous peritonitis if non-invasive tests such as ascites adenosine deaminase activity measurement are not easily available. Triple therapy without rifampicin for 6 months is sufficient to treat tuberculous peritonitis.

A rare complication of endoscopic injection sclerotherapy: thrombosis of subclavian vein.

A 28-year-old man with compensated cirrhosis of the liver (Child B) and after 4 episodes of esophageal variceal bleeding received prophylactic endoscopic variceal sclerotherapy in our Gastroenterology Clinic for 8 consecutive months. Sclerotherapy of the esophageal varices had been performed at monthly intervals until variceal obliteration was achieved. Both the intravariceal and paravariceal injection techniques were used and injections were repeated periodically as necessary. On the 8th month, 1 week after the 4th sclerotherapy procedure, the patient complained of swelling on his right shoulder and on his right arm. There was jugular congestion and swelling of his right arm and right shoulder. The patient was hemodynamically stable. An X-ray of brachial venography revealed an obstruction of the vena subclavia dextra. During follow-up, the jugular congestion and swelling of his right arm gradually subsided spontaneously over a 6-month period without any need for medication. There has been no recurrence of his symptoms during the 1-year follow-up period. Now, he is still well clinically. This experience suggests that endoscopic injection sclerotherapy may cause thrombosis of the subclavian vein which have been never seen before.

Crohn's disease; analysis of 105 patients.

In this paper, 105 patients with Crohn's disease, (47 M, 58 F), mean age 37.4 +/- 42 years were evaluated clinically, demographically and epidemiologically. Mean age of patients at the time of diagnosis was 26.5 +/- 10.9 years. Follow-up period was 2.7 +/- 2.1 years on average. On admission, symptoms or signs were as follows: right lower quadrant pain 90.5%, abdominal mass 18.1%, enterocutaneous fistula 11.4% and subileus 9.5%. Diagnosis of Crohn's disease was established during appendectomy in 14 patients (13.3%). Family history of inflammatory bowel disease was determined only in six patients (5.7%). Intestinal localization were as follows: ileo colonic 52%, ileal 38%, colonic 10%. Clinical forms were inflammatory (68%), fistulous (23%) and obstructive (9%). Sacroiliitis (7.6%), ankylosing spondylitis (4.7%), erythema nodosum (2.9%), pyoderma gangrenosum (1%) were detected as extraintestinal manifestations. Of the patients, 12.4% underwent surgical intervention due to abscess drainage in 6.6%, fistulectomy in 3.8%, stricture resection in 1.9%. Medical therapy alone was sufficient in 75.3% of patients. As a result, our cases mentioned in this paper reflect the general characteristics of Crohn's disease and prominence of regular visits and treatment.

Persistently normal alanine transaminase levels in chronic C hepatitis: what does it tell us?

BACKGROUND/AIMS: We evaluated the demographic, clinical, histological and serological characteristics of chronic hepatitis C infection with persistently normal serum alanine transaminase levels and compared the results with those obtained in a group of chronic hepatitis C infection with serum alanine transaminase levels above normal. METHODOLOGY: Twenty-one patients who had chronic hepatitis C infection with normal alanine transaminase during the follow-up period and 34 patients who had chronic C infection with serum alanine transaminase levels above normal were included in this study. Demographic, clinical, histological and serological parameters of these two groups were evaluated. RESULTS: There were no significant differences in age, gender, known route of infection, viral load and genotype distribution between the two groups (P > 0.05). The gamma-glutamyltransferase and gamma-globulin levels were significantly higher in the serum alanine transaminase levels above normal group (P < 0.01 and P < 0.05). Among the patients with normal alanine transaminase, liver biopsy findings were normal in eight patients (38%). None of the patients with serum alanine transaminase levels above normal had normal liver biopsy findings. Histologic activity index was significantly higher in serum alanine transaminase levels above normal group (9.7 +/- 2.2 vs. 6.4 +/- 1.9; P < 0.001). Histologic activity index and alanine transaminase levels correlate with the stage of the disease (P < 0.05). CONCLUSIONS: For a definite diagnosis in patients with HCV-RNA+ and normal alanine transaminase liver biopsy is necessary and significant liver disease may be present in such patients irrespective of viral load, genotype and alanine transaminase levels.

Genes of major histocompatibility complex class II influence chronic C hepatitis treatment with interferon in hemodialysis patients.

UNLABELLED: The prevalence of anti-HCV among patients on hemodialysis is consistently higher than in the general population, indicating that patients on hemodialysis programs are at risk of acquiring HCV infection. The response to interferon alpha 2b (IFN -alpha 2b) therapy in chronic C hepatitis depends on viral and host factors. We treated 22 chronic C hepatitis uremic patients with IFN -alpha 2b (3 MU three times a week) and compared interferon responsive and unresponsive patients with regard to HLA II genes. HLA II genes were investigated by PCR-SSP low resolution, anti-HCV with ELISA II and HCV-RNA with reverse transcriptase "nested" PCR. FINDINGS: HLA DRB1*13 is 50% positive in the non-responder group (four women, four men, mean age; 28.8+/-11.9 years) and 7% in the responder group (five women, nine men, mean age; 32.2+/-7.8 years) (p<0.05). There was no difference with respect to HLA genes between controls (six women, eight men, mean age; 29.5+/-12.8 years) and patients (nine women, 13 men, mean age; 31.0+/-9.3 years) (HLA DRB1*13 is 28% and 22% positive, respectively). We conclude that major histocompatibility complex class II genes influence the outcome of chronic C hepatitis treatment with IFN -alpha 2b.

Polymorphisms of HLA-DP are associated with response to peginterferon in Caucasian patients with chronic hepatitis B.

BACKGROUND: Polymorphisms of the HLA-DP gene are associated with the natural clearance of the hepatitis B virus in Asian patients. AIM: To investigate the association of HLA-DP polymorphisms with response to peginterferon (PEG-IFN) in Caucasian chronic hepatitis B (CHB) patients. METHODS: We studied 262 Caucasian chronic hepatitis B patients infected with HBV genotype A or D, treated with PEG-IFN for 1 year in two randomised controlled trials (HBV 99-01 and PARC study). Response was defined as an HBV DNA <2000 IU/mL at 6 months post-treatment. Variations at HLA-DPA1 and HLA-DPB1 were genotyped. RESULTS: Of the 262 patients, 58% was HBeAg-positive and HBV genotype A and D was observed in 32% and 68%, respectively. At 6 months post-treatment, 57 (22%) patients had achieved an HBV DNA <2000 IU/mL. HLA-DPB1 was independently associated with virological response [adjusted odds ratio (OR) 1.8, 95% confidence interval (CI):1.1-3.0, P = 0.025], and with an undetectable HBV DNA (adjusted OR 2.4 95% CI: 1.2-4.7, P = 0.015) when adjusted for HBeAg status and other known response modifiers. In HBeAg-positive patients, combined HBeAg seroconversion with HBV DNA <2000 IU/mL was increasingly observed with each addition of an HLA-DPB1 G-allele (adjusted OR 2.7, 95% CI: 1.2-5.9, P = 0.012). Furthermore, HLA-DPA1 and HLA-DPB1 haplotype block GG showed comparable results for virological and combined response. CONCLUSION: In this large cohort of Caucasian chronic hepatitis B patients infected with HBV genotypes A or D, polymorphisms of HLA-DP are independently associated with both virological and serological response to PEG-IFN therapy at 6 months post-treatment.

Importance of cytochrome P-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients.

We have investigated the importance of cytochrome P-450IIIA enzyme activity in influencing dosage of the immunosuppressive drugs FK 506 and cyclosporine after liver transplantation. Cytochrome P-450IIIA enzyme activity in vivo was measured 1 yr postoperatively in 37 stable orthotopic liver graft recipients (21 receiving FK 506 and 16 given cyclosporine) by the erythromycin breath test and the production of monoethylglycinexylidide from lignocaine. A strong correlation existed between FK 506 dose and erythromycin breath test results (r = 0.583, p < 0.007), but no corresponding relationship with monoethylglycinexylidide production was observed. The FK 506 dose (14 to 196 micrograms/kg/day) also correlated closely with circulating predose levels of the drug in both plasma and blood (r = 0.538 and 0.731, p = 0.015 and < 0.001, respectively). Although no correlation existed between cyclosporine dose (0.254 to 0.494 mg/kg/day) and trough blood levels, a relationship was demonstrated when erythromycin breath test results were included in the derived equation: Drug dose/cytochrome P-450IIIA activity alpha drug level (p = 0.011 vs. 0.175 without erythromycin breath test). A corresponding enhancement was demonstrated with erythromycin breath test results to relate FK 506 dose and plasma levels (p = 0.006 versus 0.015 without erythromycin breath test results), although breath test results and FK 506 levels were highly discordant (p > 0.8). The use of monoethylglycinexylidide test results as an alternative measure of cytochrome P-450IIIA activity provided no comparable increase in correlation for FK 506 or cyclosporine.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of cyclosporin A absorption in rat small bowel and the effect of bile.

1. Cyclosporin A absorption was examined after the instillation of approximately 2 mg/kg into four segments (mean length 15 cm) of rat small bowel, isolated in situ in fed Wistar female rats: SI (duodenum and proximal jejunum distal to the common bile duct); SII (distal jejunum); SIII (proximal ileum) and SIV (distal ileum). 2. Cyclosporin A concentrations in whole blood were assayed by an enzyme-mediated immunoassay for up to 4 h in samples drawn from the femoral vein and used to determine the following pharmacokinetic parameters: the area under the blood cyclosporin A concentration versus time curve (AUC, 0-4 h), the maximum blood concentration of cyclosporin A (Cmax.), the time to reach Cmax. (tmax.), the absorption half-life (t1/2a), the elimination half-life (t1/2 lambda), and the mean residence time (MRT). 3. Cyclosporin A absorption in SI (AUC, 991 micrograms l-1 h) was nearly double that in more distal segments and decreased progressively (SII, 533 micrograms l-1 h; SIII, 470 micrograms l-1 h; SIV, 419 micrograms l-1 h). There were corresponding differences in Cmax.: 327 micrograms/l in SI and 201 micrograms/l, 169 micrograms/l and 151 micrograms/l in SII, SIII and SIV, respectively. Tmax. was shorter in SIV (0.9 h) than in other segments (1.3-1.5 h), but there were no significant differences between the segments for t1/2a, t1/2 lambda or MRT. 4. In the presence of continuous bile flow (diverted via a cannula for SIV), cyclosporin A absorption significantly increased by 23% in SI and by 50% in SIV, but the differential between absorption in SI and SIV was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial measurements of serum transaminases in renal transplant recipients with chronic hepatitis C: do they reflect disease severity?

UNLABELLED: Chronic hepatitis C infection is a common problem in renal allograft recipients, this study was designed to investigate the association of serum aminotransferase levels with liver histology, in renal transplant patients with chronic hepatitis C virus (HCV) infection, in the long term. METHODS: In this study, 82 HCV-infected renal allograft recipients, who were followed up with functioning grafts for at least 6 months, were analyzed. Patients were classified according to their transaminase values as persistently normal, intermittently abnormal, or continuously abnormal liver function tests. Serum transaminase levels exceeding at least 1.5 times the upper limit of normal (40 IU) for periods longer than 1 month were taken as abnormal. Patients with abnormal liver function tests owing to HCV unrelated causes (drugs, alcohol, or other toxic substances, other viruses, etc.) were excluded from the study. Forty-eight of these patients underwent at least one liver biopsy. RESULTS: Of the 82 patients, 34 (41.5%) had persistently normal (liver biopsy revealed normal or minimal changes in 77.0%, chronic persistent hepatitis in 15.3%, chronic active hepatitis in 7.7%; no patient had cirrhosis), 29 (35.3%) intermittently abnormal (liver histology was consistent with minimal changes in 50%, chronic persistent hepatitis in 27.8%, chronic active hepatitis in 16.7%, cirrhosis in 5.5%), 19 (23.2%) persistently abnormal (liver biopsy showed minimal changes in 41.1%, chronic persistent hepatitis in 17.6%, chronic active hepatitis in 35.3%, cirrhosis in 5.9%) transaminase values. CONCLUSION: Although continuously or intermittently elevated transaminases do not always indicate morphologically advanced disease, the normal course of serum transaminases is mostly accompanied by normal, or near-normal, liver histology, in HCV-infected renal transplant patients. Liver biopsy is not indicated in deciding disease severity in these patients unless clinical findings dictate otherwise.

After the eradication of Helicobacter pylori infection, relapse is a serious problem in Turkey.

Eradication of Helicobacter pylori (Hp) infection is strongly recommended in duodenal and gastric ulcer. In developed countries the recurrence rate is low; however, in Turkey, the Hp recurrence rate is suspected to be high as the prevalence of Hp infection is--as high as 70-80% in the asymptomatic population. We planned this study to determine the relapse rate of Hp infection after successful eradication therapy in Turkey. Fifty-two cases including 24 patients with duodenal ulcer and 28 patients with nonulcer dyspepsia were examined in this study. The eradication regimen was omeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg three times a day for 1 week. All patients underwent upper gastrointestinal tract endoscopy. At least four samples from antrum and corpus were taken to enable histologic diagnosis of Hp infection. After the eradication therapy, endoscopy was repeated at 1, 3, 6, and 12 months, and Hp-positive patients were dropped from study. With the use of this regimen, the Hp eradication rate was 92.3% (48/52). After the eradication of Hp infection, relapse rates were 6.97%, 27.5%, and 11.11% at 3, 6, and 12 months, respectively. The cumulative relapse rate for 1 year was 41.46%. The results of this study revealed that after the eradication of Hp infection, recurrence is encountered very often as a problem in Turkey. We concluded that hygienic and environmental factors can affect these high relapse rates.

Is severe cryptogenic chronic hepatitis similar to autoimmune hepatitis?

BACKGROUND/AIMS: It has been reported that severe cryptogenic chronic hepatitis may be a subgroup of autoimmune hepatitis. The aims of this study were to investigate the clinical features, liver function tests, human leukocyte antigens and response to immunosuppressive therapy in severe cryptogenic chronic hepatitis, and to compare the findings in such patients with those in patients with autoimmune hepatitis. METHODS: History of alcohol and hepatotoxic drug intake, markers of metabolic liver disease, autoantibodies (antinuclear antibody, smooth muscle antibody, antibody to liver/kidney microsome type 1), and viral markers (HBsAg, HBV DNA, anti-HCV, HCV RNA) were negative in all severe cryptogenic chronic hepatitis patients (histological activity index > 9 and alanine aminotransferase level > 2 x normal). Fifteen cryptogenic patients (13 women; mean age, 33 +/- 16 years) and seven autoimmune patients (seven women; mean age, 28 +/- 3.9 years; five type 1; two type 2a) received prednisolone and azathioprine for at least 2 years. RESULTS: Cryptogenic chronic hepatitis patients were similar to patients with autoimmune hepatitis with respect to age, sex, clinical presentation, liver function tests and Knodell scores at admission. HLA phenotype frequencies were comparable between cryptogenic and autoimmune groups: BW6 (77% vs. 100%), DR4 (62% vs. 57%), and HLA B8 (15% vs. 43%). The rates of complete and partial remissions achieved during therapy were 87% vs. 57% and 13% vs. 29%, respectively (p > 0.05). CONCLUSIONS: The clinical, biochemical and HLA phenotypic features, and the responsiveness to immunosuppressive therapy in severe cryptogenic chronic hepatitis support the idea that it may be an autoimmune liver disease similar to autoimmune hepatitis.