Chronic Hepatitis Due to Gluten Enteropathy - a Case Report.

BACKGROUND: Celiac disease is an immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. CASE DESCRIPTION: A 45-year-old Caucasian woman presented with severe iron-deficient anemia and mild elevation of liver enzymes. Upper endoscopy was done in the context of evaluation of anemia, which revealed reduced duodenal folds and mosaic pattern of the mucosa, but also grade II esophageal varices and portal hypertensive gastropathy. Duodenal biopsy showed total villous atrophy, diffuse mainly lymphocytic infiltrate, presence of intra-epithelial lymphocytes. Serology test confirmed celiac disease by the typical pattern of high titer positive IgA and IgG antibodies to tissue transglutaminase. Liver biopsy was performed for staging and etiological evaluation, because laboratory screening ruled out common viral, metabolic and autoimmune liver disease. Liver morphology was consistent with chronic hepatitis without findings for extensive fibrosis. Our patient had poor dietary compliance, so we failed to established improvement of liver enzymes and resolution of anemia during follow-up. CONCLUSIONS: We would like to stress on the diverse clinical manifestations of celiac disease and the importance of serologic screening with antibodies to tissue transglutaminase in differential diagnosis of chronic liver disease.

Prevalence of vitamin D deficiency and insufficiency in Bulgarian patients with chronic hepatitis C viral infection.

AIMS: The present pilot study aimed to determine vitamin D status in Bulgarian patients with chronic HCV infection in respect to the severity of liver disease and response to interferon-ribavirin therapy. METHODS: The study encompassed 296 patients: 161 males (54.4%) aged 42.08 ± 14.87 years, 135 females (45.6%) aged 45.72 ± 14.34 years, 86.5% of them infected with HCV genotype 1. Total 25-hydroxyvitamin-D (25OHD) was determined by liquid chromatography/tandem-mass spectrometric detection. RESULTS: The median 25OHD level of the studied cohort was 50.40 nmol/L (range: 29.6-71.05). 25OHD deficient (< 25 nmol/L) were 16% of patients, 33% showed profound insufficiency (25-50 nmol/L), another 33% were in the range 50-80 nmol/L (mild insufficiency), the rest 18% were 25OHD sufficient. Significantly lower 25OHD levels were registered in cases with advanced fibrosis compared to those with mild or absent fibrosis (37.10 nmol/L vs. 53.00 nmol/L, respectively, p < 0.05). This association remained unchanged by seasonal variations in 25OHD levels. Inverse relationship was found between 25OHD and HCV-RNA (p < 0.01). Patients with sustained virological response to therapy had significantly higher 25OHD levels, compared to patients who failed to achieve viral eradication (56.90 nmol/L vs. 45.00 nmol/L, p = 0.012). CONCLUSION: More than 80% of HCV-infected patients were vitamin D-deficient and -insufficient. The inverse relationship between 25OHD levels and viral load, liver fibrosis and treatment outcomes supports the hypothesis that improvement of vitamin D status may have considerable potential to amend the host defense against HCV infection and response to therapy.

Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS: At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS: TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B.

Evoked Potentials in Patients With Wilson Disease.

INTRODUCTION: Wilson disease (WD) is an inherited disorder of copper metabolism presenting with a variety of symptoms but commonly as a liver or neuropsychiatric disease. Abnormal evoked responses are constantly found among patients with neurologic manifestations and sometimes in patients with hepatic presentation or in presymptomatic siblings. The aim of our study was to assess visual and brainstem auditory evoked potentials (BAEP) in patients with various presentation of WD. METHODS: Visual evoked potentials (VEP) were performed in 36 WD patients and BAEP were done in 37 WD patients. RESULTS: Brainstem auditory evoked potentials were normal in patients with isolated hepatic presentation, whereas they were abnormal in 93.5% of patients with neurologic symptoms. There was significant prolongation of the latencies of the III and V waves and of the interpeak III-V and I-V latencies in comparison with the healthy controls (T-test P = 0). Abnormal VEP were observed in 81% of the patients including six of seven neurologically asymptomatic patients. The values of N75, P100, and N145 latencies were significantly longer in all patients than in healthy controls (T-test). CONCLUSIONS: The data showed that VEP and BAEP are more frequently abnormal in WD than previously reported. The abnormal VEP and BAEP even without clinical signs and brain MRI abnormalities point to subclinical involvement of visual and auditory pathways caused by copper toxicity. Because VEP and BAEP are noninvasive and widely available, they should be performed in all patents with WD.

Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS: Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

DNA methylation in patients with colorectal cancer--correlation with some clinical and morphological features and with local tumour invasion.

AIM: To study quantitatively the promoter methylation of hMLH1, p16INK, TIMP3 and TPEF genes in patients with colorectal cancer and synchronous polyps, and correlate it with some clinicomorphological features. METHODS: DNA was extracted from all studied tumours and the corresponding normal mucosa. Microsatellite instability was analysed using two mononucleotide (BAT 25 and BAT 26) and three dinucleotide markers (D2S123, D5S356, D17S250) and automated DNA sequencing. Quantitative analysis of methylation was performed using DNA bisulfite modification, PCR with biotinylated primers, visualisation by 2% agarose gel electrophoresis and pyrosequencing. RESULTS: High methylation levels of hMLH1 and p16INK were found in elderly patients (mean age 73.8 +/- 9.5 years and 65.7 +/- 16.6 years, p < 0.03, t-test). Proximal tumours were more often associated with microsatellite instability (p < 0.05, Fisher's test) and higher level of methylation of hMLH1, p16INK and TIMP3 (p < 0.02, Kruskal-Wallis test), while tumours with poor differentiation tended to have higher methylation of the p16INK gene (p < 0.02, Kruskal-Wallis test). Local tumour invasion was correlated with the level of methylation of hMLH1, TIMP3 and the CpG island methylator phenotype (CIMP) status. Tumours with liver metastases showed a lower level of TIMP3 methylation than tumours with no systemic invasion (p < 0.05, Kruskal-Wallis test). We found concordance of methylation in 56% of the cases with colonic cancer and synchronous adenomas; the remaining 44% were discordant. CONCLUSIONS: Tumours with microsatellite instability, high level methylation and CIMP have distinctive clinical and morphological features. The level of hMLH1 and TIMP3 methylation and CIMP status can be correlated with the local tumour invasion. Different mechanisms, even for one and the same patient, can be responsible for the development of more than one third of the synchronous polyps and carcinomas.

Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study.

AIM: To make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. METHODS: This was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed. RESULTS: A total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm. CONCLUSION: Efficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.

Wilson's disease in association with anetoderma.

BACKGROUND: Wilson's disease is an autosomal recessive disorder of copper homeostasis with predominantly hepatic and neuropsychiatric involvement. Anetoderma is a rare benign condition with focal damage of dermal elastic tissue. Previous reports described this skin disorder in association with prolonged D-Penicillamine therapy. CASE PRESENTATION: A 26-year-old male was referred for evaluation of asymptomatic elevation of aminotransferase levels. Investigations showed negative markers for chronic viral and autoimmune hepatitis, low ceruloplasmin level, and increased copper urinary excretion. Liver biopsy revealed chronic hepatitis with moderate activity and severe bridging fibrosis. Mutation analysis found a compound heterozygote genotype and supported a diagnosis of Wilson's disease. At the time of the primary physical exam, skin lesions were also observed, consisting of numerous white to pale papules less than 7-8 mm in diameter with central protrusion located at the upper part of the body. Primary anetoderma was established based on presentation and skin biopsy findings. Therapy with D-Penicillamine at a daily dose of 1500 mg was started, and, during 12-month follow-up, aminotransferase decreased to normal and skin lesions remained unchanged. CONCLUSION: In our opinion the case is a first reported association between Wilson's disease and primary anetoderma. The possible mechanism behind this relationship is discussed.

High initial dose combination regimen with interferon-alpha and ribavirin in chronic hepatitis C.

BACKGROUND/AIMS: Combination of interferon-alpha and ribavirin becomes the antiviral therapy of choice for chronic hepatitis C. The aim of this trial was to assess the efficacy of two combination treatment strategies: standard regimen Interferon-alpha 3 MU three times per week (group A) and initial high dose Interferon 6 MU daily for 2 weeks followed by intermittent administration 3 MU three times per week (group B), plus Ribavirin in naive and relapsed patients with chronic hepatitis C. METHODOLOGY: Twenty-four patients (group A, 6; group B, 18) received medication for median 6 months (range, 5-12) and followed for 6 months. Primary end-point of therapy was a sustained virologic response. Statistical analysis was performed with a t test or non-parametric Mann-Whitney and chi-square test. RESULTS: At the end of the follow-up the overall sustained response rate was 42%: 6 of 18 (33.3%) patients with induction and 4 of 6 (66.6%) with standard regimen. Patients with sustained virologic response received higher interferon dose (423.7 +/- 102.2 MU) at extended duration of therapy (9.8 +/- 2.9 months) versus patients with non-sustained response (p < 0.05). The difference in sustained response rate in both treatment regimens was nonsignificant. CONCLUSIONS: High initial dose therapy does not enhance virologic response, compared to standard combination regimen.

Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B.

Emtricitabine (FTC) is approved for the treatment of human immunodeficiency virus. FTC and clevudine (CLV) have activity against hepatitis B virus (HBV). This report summarizes the results of a double-blind, multicenter study of patients with chronic hepatitis B who had completed a phase 3 study of FTC and were randomized 1:1 to 200 mg FTC once daily (QD) plus 10 mg CLV QD or 200 mg FTC QD plus placebo for 24 weeks with 24 weeks of follow-up. One hundred sixty-three patients were treated (82 with FTC plus CLV [FTC+CLV] and 81 with FTC); 72% were men, 53% were Asian, 47% were Caucasian, and 52% were hepatitis B e antigen positive, and the median baseline HBV DNA level was 6 log(10) copies/ml. After 24 weeks of treatment, 74% (FTC+CLV) versus 65% (FTC alone) had serum HBV DNA levels of <4,700 copies/ml (P = 0.114) (Digene HBV Hybrid Capture II assay). Twenty-four weeks posttreatment, the mean change in serum HBV DNA levels from baseline was -1.25 log(10) copies/ml (FTC+CLV), 40% had undetectable viremia (versus 23% for FTC alone), and 63% had normal alanine aminotransferase levels (versus 42% for FTC alone) (P < or = 0.025 for all endpoints). The safety profile was similar between arms during treatment, with less posttreatment exacerbation of hepatitis B in the combination arm. In summary, after 24 weeks of treatment, no significant difference between arms was observed, but there was a significantly greater virologic and biochemical response 24 weeks posttreatment in the FTC+CLV arm.