Antonino Picciotto

Chronic hepatitis induced by Jin Bu Huan

BACKGROUND/AIMS Jin Bu Huan and other Chinese herbal products are widely taken remedies. They have been developed as a natural alternative to traditional drugs in the treatment of various ailments. Their ability to induce several side effects such as acute hepatitis has already been described. We report a case of chronic hepatic damage following administration of Jin Bu Huan Anodyne tablets. METHODS The patient, a 49-year-old man, developed biochemical signs of liver damage 2 months after beginning Jin Bu Huan intake (3 tablets/daily) including biopsy-proven chronic hepatitis with moderate fibrosis. Virological, autoimmune, metabolic or other hepatotoxic causes were excluded. Liver function impairment was resolved by discontinuing Jin Bu Huan intake. CONCLUSIONS This case reinforces the already known hepatotoxicity of this product and should make us think more about the uncontrolled use of alternative products.

Is hepatic ultrasonography a valid alternative tool to liver biopsy? report on 507 cases studied with both techniques

In order to evaluate the diagnostic potential of liver ultrasonography (US), the charts of 23 cases with normal liver, 424 patients with chronic widespread, and 60 patients with focal hepatic diseases, who had undergone both US and liver biopsy, were reviewed. The positive predictive value of US was good in all hepatic disorders (range 86.9–96.5%), while its negative predictive value was very low (range 14.1–42.5%) in the various forms of widespread liver disease and suitable for screening purposes (74%) in focal lesions. Of the 507 cases, 39 with an ultrasonically suspected liver mass also underwent an echo-guided fine-needle aspiration, which showed a high sensitivity (85%) in the 27 biopsy-proved malignant lesions and excluded tumor cells in the remaining 12 cirrhotic cases. As regards US tissue diagnosis, hepatic tumors, fatty infiltration, and fibrosis were detected in 88%, 60%, and 49% of cases, respectively. Fat and fibrous content on biopsy were similarly and significantly correlated with both echo pattern and sound attenuation. Overall results suggest that in the group of widespread hepatic disorders the usefulness of US is greatly reduced by the fact that the patients actual condition is not likely to be negative if US examination is normal and by the impossibility of differentiating fat from fibrosis. In focal lesions, the diagnostic value of US appears high and the method may frequently provide conclusive proof of the tumor if a positive cytodiagnosis on echoguided aspirated material is done.

Activating NK cell receptor expression/function (NKp30, NKp46, DNAM‐1) during chronic viraemic HCV infection is associated with the outcome of combined treatment

Specific NK cell killer inhibitory receptor (KIR):HLA haplotype combinations have been associated with successful clearance of acute and chronic HCV infection. Whether an imbalance of activating NK cell receptors also contributes to the outcome of treatment of chronic HCV infection, however, is not known. We studied peripheral NK cell phenotype and function in 28 chronically viraemic HCV genotype I treatment‐naïve patients who underwent treatment with pegylated IFN‐α and ribavirin. At baseline, chronically infected patients with sustained virological response (SVR) had reduced CD56brightCD16+/− cell populations, increased CD56dullCD16+ NK cell proportions, and lower expression of NKp30, DNAM‐1, and CD85j. Similarly, reduced NK cell IFN‐γ production but increased degranulation was observed among nonresponding (NR) patients. After treatment, CD56brightCD16+/− NK cell numbers increased in both SVR and NR patients, with a parallel significant increase in activating NKp30 molecule densities in SVR patients only. In vitro experiments using purified NK cells in the presence of rIL‐2 and IFN‐α confirmed upregulation of NKp30 and also of NKp46 and DNAM‐1 in patients with subsequent SVR. Thus, differences in patient NK cell receptor expression and modulation during chronic HCV‐1 infection are associated with subsequent outcome of standard treatment. Individual activating receptor expression/function integrates with KIR:HLA genotype carriage to determine the clearance of HCV infection upon treatment.

Circadian reduction of chromium in the gastric environment

Samples of gastric juice from variously treated subjects efficiently reduced hexavalent chromium and decreased its mutagenicity. Chromium reduction was due to thermostable components of gastric secretions and was favoured by the acidity of the intragastric environment. The circadian monitoring of pH and of chromium reduction, as assessed by colorimetric analysis at hourly intervals, showed a basal activity (less than 10 micrograms/ml gastric juice) during the night and interdigestive periods, and peaks (tens of micrograms/ml) during the 3-4-h periods after each meal. Assays in the Ames reversion test confirmed that the decrease in mutagenicity of sodium dichromate produced by gastric juice was significantly enhanced after meals. This physiological mechanism is expected to provide an important protective barrier against the oral toxicity of this metal, and may explain its lack of oral carcinogenicity.

Evaluation of a new hepatitis C virus sequencing assay as a routine method for genotyping

The determination of HCV genotypes, subtypes and isolates has been helpful in understanding the evolution and the epidemiology of the virus, and is an important factor in the pre‐treatment evaluation. A new simpler and automated sequencing based system has been developed recently, the Visible Genetics TruGene™ Hepatitis C Assay. The aim of the study was to compare this new genotyping assay with reverse hybridization based Innogenetics INNO‐LiPA HCV II assay that is used most commonly. Eighty‐eight HCV‐RNA positive patients were enrolled and divided in four groups: 26 hemodialysed patients, 30 untreated patients with chronic HCV hepatitis, 12 IFN non‐responder patients with chronic HCV hepatitis, 20 asymptomatic HCV positive subjects. The 5′‐UTR region was amplified by RT‐PCR and the nucleotide sequences determined by the TruGene™ assay. In parallel, the amplicons were also tested by INNO‐LiPA. Concordant results were obtained in 80 out of 88 cases (90.9%). The new assay allowed to genotype 2 samples not typed by LiPA as 1b and 2a/c. The new system also allowed the subtyping of 3 untypable samples, classified as genotype 1 by INNO‐LiPA, as genotype 1b (1 sample) and, as genotype 4 (2 samples). The difference between these genotype 4 isolates and the closest genotype 1 isolate was 6 nucleotides. One LiPA genotype 1a sample was typed as 1b and 2 genotype 1b samples were all typed as 1a by the sequence analysis. In conclusion, the new assay is a sensitive and rapid method that is suitable for accurate large‐scale genotyping. J. Med. Virol. 63:17–21, 2001.

Sustained virological response to pegylated interferon and ribavirin is maintained during long-term follow-up of chronic hepatitis C patients

Aliment Pharmacol Ther 31, 502–508

Behavior of soluble HLA class I antigens in patients with chronic hepatitis C during interferon therapy: An early predictor marker of response?

Soluble HLA class I antigens (sHLA-I),β2-microglobulin (β2-μ.) and alanine aminotransferase (ALT) serum levels have been evaluated in 16 patients affected by chronic hepatitis C treated for six months with recombinant interferon-α (rIFN-α, 3 MU three times a week). The predictor role of sHLA-I and ALT modifications with respect to the response to rIFN-α therapy was also evaluated. Six patients responded (group 1), five patients relapsed following an initial response (group 2), and five did not respond to rIFN-α treatment (group 3). The baseline serum levels of sHLA-I andβ2-μ were significantly higher in all three groups of HCV-positive patients with respect to HCV-negative controls (P<0.05). A significant increase of sHLA-I serum level with respect to baseline value (P<0.001) was observed in group 1 patients after two weeks of rIFN-α treatment. sHLA-I serum level then decreased, although remaining steadily and significantly increased with respect to baseline (P values ranging from 0.05 to 0.01) in the following five months and then returned to baseline one month after the end of rIFN-α administration. No significant variations ofβ2-μ serum levels were detected throughout the observation period. In group 1 patients ALT serum levels significantly decreased after two weeks of rIFN-α treatment (P<0.001) and then remained in the normal range throughout the observation period. In the other two groups of patients no relevant variations of sHLA-I andβ2-μ serum levels were found during and after rIFN-α therapy. The modifications of sHLA-I serum levels discriminate, as a single marker, group 1 patients from group 2 and 3 patients after two weeks of rIFN-α treatment (P<0.003). The association of sHLA-I and ALT modifications improves the discriminant power and leads to a complete differentiation of the three groups of patients after four weeks of rIFN-α treatment (P<0.0001). If confirmed in a larger series of patients, these results will provide a useful marker to predict which patients affected by chronic hepatitis C will respond to treatment and will help to avoid their ineffective treatment with an expensive and potentially harmful drug.

Non‐Antigen‐Specific CD8+ T Suppressor Lymphocytes in Diseases Characterized by Chronic Immune Responses and Inflammation

Abstract: Recent studies on regulatory lymphocytes demonstrate that CD8+ T suppressor (Ts) cells may have great relevance in controlling immune system homeostasis and avoiding development of chronic inflammatory diseases. Among the three subpopulations of CD8+ Ts cells so far recognized in humans, the type 2 (non‐antigen‐specific) cell is characterized by the capacity to inhibit both T cell proliferation and cytotoxic T lymphocyte activity through secretion of soluble factors. Previous work has shown the impairment of in vitro generation of type 2 CD8+ Ts cells from the peripheral blood of relapsed patients with multiple sclerosis, systemic lupus erythematosus, or systemic sclerosis. Here, similar findings are demonstrated for patients with human immunodeficiency virus or chronic hepatitis C virus infection. Furthermore, the presence of type 2 CD8+ Ts cells infiltrating diseased tissues in patients with autoimmune thyroiditis or cancer is shown. Collectively, these findings suggest that type 2 CD8+ Ts cells may be involved in the control of pathologic chronic immune responses, contributing in some cases to the pathogenesis of the disease.

Predictive value of on-treatment response during full-dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension.

Objective.  Therapy with full‐dose pegylated interferon (PEG‐IFN) and weight‐based ribavirin has been evaluated in limited series of patients with hepatitis C virus (HCV) and advanced disease. In this study, we evaluated the efficacy and tolerability of full‐dose antiviral therapy in patients with compensated, fully developed cirrhosis, and assessed the predictive value of on‐treatment virological response.

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Despite the excellent efficacy of direct‐acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance‐associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real‐life DAA failures.