Non-invasive and invasive brain stimulation in alcohol use disorders: A critical review of selected human evidence and methodological considerations to guide future research.

INTRODUCTION: Alcohol use disorder (AUD) ranks among the leading causes of decrements in disability-adjusted life-years. Long-term exposure to alcohol leads to an imbalance of activity between frontal cortical systems and the striatum, thereby enhancing impulsive behaviours and weakening inhibitory control. Alternative therapeutic approaches such as non-invasive and invasive brain stimulation have gained some momentum in the field of addictology by capitalizing on their ability to target specific anatomical structures and correct abnormalities in dysfunctional brain circuits. MATERIALS AND METHODS: The current review, covers original peer-reviewed published research on the use of brain stimulation methods for the rehabilitation of AUD. A broad and systematic search was carried out on four electronic databases: NCBI PubMed, Web of Science, Handbooks and the Cochrane Library. Any original article in English or French language, without restrictions of patient age or gender, article type and publication outlet, were included in the final pool of selected studies. RESULTS: The outcomes of this systematic review suggest that the dorsolateral prefrontral cortex (DLPFC) is a promising target for treating AUD with high frequency repetitive transcranial magnetic stimulation. Such effect would reduce feelings of craving by enhancing cognitive control and modulating striatal function. Existing literature also supports the notion that changes of DLPFC activity driven by transcranial direct current stimulation, could decrease alcohol craving and consumption. However, to date, no major differences have been found between the efficacy of these two non-invasive brain-stimulation approaches, which require further confirmation. In contrast, beneficial stronger evidence supports an impact of deep brain stimulation reducing craving and improving quality of life in AUD, effects that would be mediated by an impact on the nucleus accumbens, a central structure of the brain's reward circuitry. Overall, neurostimulation shows promise contributing to the treatment of AUD. Nonetheless, progress has been limited by a number of factors such as the low number of controlled randomized trials, small sample sizes, variety of stimulation parameters precluding comparability and incomplete or questionable sham-conditions. Additionally, a lack of data concerning clinical impact on the severity of AUD or craving and the short follow up periods precluding and accurate estimation of effect duration after discontinuing the treatment, has also limited the clinical relevance of final outcomes. CONCLUSION: Brain stimulation remains a promising approach to contribute to AUD therapy, co-adjuvant of more conventional procedures. However, a stronger therapeutic rational based on solid physio-pathological evidence and accurate estimates of efficacy, are still required to achieve further therapeutic success and expand clinical use.

[Abstinence from cocaine after long-term addiction]. / Abstinence à la cocaïne après un parcours de dépendance.

BACKGROUND: Experimental data strongly suggest that in animal and probably in man, noradrenergic and serotoninergic become uncoupled during repeated consumption of drugs of abuse, strongly suggesting that different drugs share common mechanisms for drug-dependence. Using cocaine-dependence as model of strong addiction we speculate that careful analysis of psychic adjustments in patients who experience prolonged abstinence could be a useful tool for patient's care. AIM: The aim of this retrospective study was first to establish similarities in patients' histories concerning modes of entrance, circumstances favouring the stopping, and modality of withdrawal. Secondly, we analysed the different ways used by subjects to substitute their cocaine-dependence. PATIENTS AND METHODS: Cocaine-dependent subjects who had succeeded in supporting abstinence for at least 12 months without consumption were evaluated retrospectively by a face-to face interview. RESULTS: We obtained a list of circumstances associated with entries and exit from cocaine-dependence. Second, when seeking for similarities in addictive behaviour, before and after, between cocaine users, we proposed to classify patients according to the strength in their addictive dominant trait between strong, moderate, mild, or absence of addictive behaviour. For didactic aims, purposes are illustrated by clinical vignettes. CONCLUSIONS: This retrospective study allows us to clear arbitrarily four types of psychical modifications associated with prolonged abstinence in cocaine-dependent patients. Prospective clinical studies are clearly needed to standardize and to validate these clinical criteria.

Inhibitory effects of cyclosporine on human regulatory T cells in vitro.

BACKGROUND: Inevitable hepatitis C virus (HCV) recurrence after liver transplantation is a major barrier to the survival of a transplanted liver. It may be promoted by immunosuppression and the emergence of CD4+CD25+ regulatory T cells (Treg). Treg cells can mediate the induction and maintenance of immunological self-tolerance as well as transplant tolerance. We investigated the effects of cyclosporine (CsA), a widely used immunosuppressive agent, on human CD4+CD25+ Treg cells. METHODS: Human CD4+CD25+ cells isolated from healthy donors were cultured in the presence of 40 or 400 ng/mL CsA. The suppressive activity of Treg was assessed in mixed leukocyte reactions (MLR) using CD25+ and autologous activated peripheral blood mononuclear cells (PBMC). Phenotype analysis (flow cytometric, Q-PCR) and cytokine production (ELISA) of Treg cells were then performed on cultures. RESULTS: CsA (40 or 400 ng/mL) inhibited the proliferative capacity of PBMC and CD4+CD25+ Treg in a dose-dependent manner. Interestingly, addition of 40 ng/mL CsA in MLR impaired the suppressive activity of CD4+CD25+ cells, whereas a higher dose of CsA had no effect on Treg function. It appears that a therapeutic dose of CsA (40 ng/mL) did not change the phenotype of CD4+CD25+ T cells, but altered Treg activity by switching the regulatory to an inflammatory cytokine profile. CONCLUSION: CsA significantly impaired the function of CD4+CD25+ Treg cells by inducing interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) secretion. The present studies suggested that CsA may block the induction of immune tolerance and decrease the risk of hepatitis C recurrence.

Increased expression of regulatory Tr1 cells in recurrent hepatitis C after liver transplantation.

Immune response failure during HCV infection has been associated with the activity of regulatory T cells. Hepatitis C-related cirrhosis is the main reason for liver transplantation. However, 80% of transplanted patients present an accelerated recurrence of the disease. This study assessed the involvement of regulatory T-cell subsets (CD4+CD25+ cells: 'Treg' and CD49b+CD18+ cells: 'T regulatory-1' cells), in the recurrence of HCV after liver transplantation, using transcriptomic analysis, ELISA assays on serum samples and immunohistochemistry on liver biopsies from liver recipients 1 and 5 years after transplantation. Three groups of patients were included: stable HCV-negative recipients and those with mild and severe hepatitis C recurrence. At 5 years, Treg markers were overexpressed in all HCV+ recipients. By contrast, Tr1 markers were only overexpressed in patients with severe recurrence. At 1 year, a trend toward the overexpression of Tr1 was noted in patients evolving toward severe recurrence. IL-10 production, a characteristic of the Tr1 subset, was enhanced in severe recurrence at both 1 and 5 years. These results suggest that Tr1 are enhanced during severe HCV recurrence after liver transplantation and could be predictive of HCV recurrence. High levels of IL-10 at 1 year could be predictive of severe recurrence, and high IL-10 producers might warrant more intensive management.

Low density lipoprotein receptor transcripts correlates with liver hepatitis C virus RNA in patients with alcohol consumption.

Alcohol consumption has a major impact on the natural history of chronic hepatitis C virus (HCV) infection, although the underlying mechanisms are still debated. We designed a clinical study to evaluate the impact of alcohol abuse on both viral load and expression of low-density lipoprotein receptor (LDLR) and CD81 expression. Thirty-eight consecutive HCV-infected patients were enrolled. Group 1 (n = 18), < or =10 g alcohol/day, group 2 (n = 8), < or =30 g alcohol/day, group 3 (n = 12), >or =30 g alcohol/day. Receptors expression was measured by flow cytometry analysis in peripheral blood mononuclear cells (PBMC) and by specific real-time retrotranscription polymerase chain reaction (RT-PCR) in the liver. Serum viral load was evaluated by quantification of both HCV genomic RNA and total core antigen. The hepatic viral load was assessed by real-time RT-PCR. Serum HCV-RNA and total core antigen were significantly correlated, and were higher, albeit not significantly, in group 3 than in group 1. Alcohol consumption had no effect on expression of HCV putative receptors in PBMC, except for CD81, which was upregulated on monocytes in group 2. In the liver, viral load and levels of LDLR transcripts were significantly higher in group 3 than in group 1. Remarkably, a significant positive correlation was found between LDLR transcripts and HCV-RNA (r2 = 0.83, P < 10(-3)). Finally, in vitro experiments suggested that the effect of ethanol on LDLR expression was indirectly mediated by both tumour necrosis factor-alpha and interleukin-1beta. In conclusion, this study is the first to support a role for LDLR in the natural infection by HCV in man.

[Management of psychological disorders in patients with chronic hepatitis C]. / L'hépatologue, le psychiatre et les patients ayant une hépatite C.

BACKGROUND: Chronic hepatitis C remains a public heath problem. In France, 400,000 to 500,000 subjects are chronically infected with HCV. LITERATURE FINDINGS: The purpose of this review was first to summarize the clinical aspects of the disease and the guidelines and results of antiviral treatment. The authors focus on the psychiatric side effects of antiviral treatment, and discuss the importance of good patient-provider interaction in patient's satisfaction, highlighting the mandatory role of the dynamic management of patients by hepatologists and psychiastrists. CONCLUSION: Multidisciplinary approaches have to be set up to better treat these patients.

[Management of cirrhosis complications in HIV patients coinfected with hepatitis B or C virus]. / Prise en charge des complications de la cirrhose chez les patients VIH co-infectés par une hépatite virale B ou C.

Cirrhosis is a serious complication of viral hepatitis, and its incidence is increasing in HIV patients coinfected with HCV or HBV as they live longer, thanks to effective antiretroviral treatment (Haart). HIV coinfection accelerates the progression of fibrosis in hepatitis. To implement preventive measures, prompt diagnosis of cirrhosis is important, either by liver biopsy or the noninvasive tests for fibrosis now under wide study (FibroTest, FibroScan, etc.). Afterwards, assessment of the severity of cirrhosis and screening for complications are both necessary: testing for liver failure (Child-Pugh and MELD scores), portal hypertension (upper gastrointestinal endoscopy), and hepatocellular carcinoma (ultrasound and alpha fetoprotein assay). Careful consideration of drug prescriptions and possible interactions is essential. Specific treatment for hepatitis B or C virus is possible at this stage of cirrhosis, although more difficult, especially for HCV (results influenced by genotype, additional risk of complications by lactic acidosis or hepatic decompensation). Management of the complications of portal hypertension must be planned, as for those without HIV infection. Treatment of hepatocellular carcinoma is still disappointing, and liver transplantation, although possible in these patients, must be evaluated.

Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas.

A link between chronic hepatitis C virus (HCV) infection and low-grade B-cell lymphomas has been suggested by epidemiological studies. Marginal zone lymphomas (MZLs) including splenic lymphomas with villous lymphocytes are among the most frequently reported subgroups in the setting of chronic HCV infection. In this study, we examined the effect of antiviral treatment in eight patients with HCV-associated MZL. We found that five out of eight patients have responded to interferon alpha and ribavirin. In some cases, hematologic responses were correlated to virologic responses. In addition, we report a case of large granular lymphocyte leukemia occurring in association with MZL and HCV, and responding to interferon and ribavirin. We suggest that there is an etiologic link between HCV and antigen-driven lymphoproliferative disorders.

[Cholestatic icterus induced by the administration of fusidic acid in a cirrhotic patient]. / Ictère cholestatique induit par la prise d'acide fucidique chez un patient cirrhotique.

INTRODUCTION: Fucidic acid is an antibiotic essentially used to treat staphylococcal infections. Its chemical structure is very similar to that of bilary acids and hence implies competitive mechanisms between their elimination and metabolization. OBSERVATION: A patient with a past history of alcohol-induced cirrhosis was treated with fucidic acid for a Staphylococci aureus urinary infection. On day 2 of treatment a conjugate bilirubine icterus appeared. There was no argument to suggest a decompensation of the icterus. The icterus disappeared on suspension of fucidic acid. COMMENTS: The occurrence of an icterus in a cirrhotic patient may evoke decompensation of the hepatopathy and an extensive exploration must be made. A thorough survey of all drug administration must be made. Notably, the possibility of the occurrence of a connective bilirubin icterus during treatment with fucidic acid must be known. The icterus always regresses on withdrawal of treatment and this etiology must be evoked before conducting invasive examinations.

Effects of bile acids on the humoral immune response: a mechanistic approach.

Whereas bile acids in excess depress the cell-mediated immune response, their effects on the humoral response have been little investigated. The aim of this study was to investigate the effects of bile acids on immunoglobulin production. Human peripheral blood mononuclear cells were stimulated for 5 days by Staphylococcus aureus Cowan I (SAC-I). Immunoglobulins were measured in the supernatants and cell lysates using ELISA. We found that bile acids inhibited IgM production in a dose-dependent manner. The inhibitory effects of 50 microM chenodeoxycholic acid (CDCA) and its glyco- and tauro-conjugates (62, 53 and 51%, respectively) were stronger than those of ursodeoxycholic acid (UDCA) and its conjugates (45, 40 and 34%, respectively). The inhibition of IgG production by CDCA and UDCA was weak (23 and 12%, respectively, at 50 microM). IgA production was not modified. The inhibition of intracellular IgM concentration paralleled that observed in the secreted compartment. By contrast, CDCA enhanced intracellular concentration of IgG. In the absence of significant necrosis or apoptosis, CDCA-mediated inhibition of SAC-I-induced IgM production was significantly correlated to the ability of the bile acid to inhibit cell proliferation (r=0.98; p<0.05). In conclusion, we showed that hydrophobic bile acids strongly depress the primary humoral response. This effect resulted from both an inhibition of cell proliferation, and to a lesser extent from a deficient exocytosis of immunoglobulins.

Activation of the interferon-inducible protein kinase PKR by hepatocellular carcinoma derived-hepatitis C virus core protein.

Hepatitis C virus (HCV) is a major etiological agent of chronic liver disease and hepatocellular carcinoma (HCC). We demonstrate herewith that HCV core proteins encoded by sequences isolated from HCC tumor tissues, but not those derived from their non-tumor counterparts in the same liver, co-localise in vitro and in vivo and co-immunoprecipitate with PKR in hepatocytic Huh7 cells. We show that this association in fact augments the autophosphorylation of PKR and the phosphorylation of the translation initiation factor eIF2alpha, which are two markers of PKR activity. The present study therefore identifies a novel model of virus-cell interactions whereby a viral protein, the HCV core, activates PKR activity.

[Liver transplantation for alcoholic liver disease]. / Transplantation hépatique pour maladie alcoolique du foie.

Alcoholic cirrhosis is a major public health issue in France. The prevalence of alcoholic cirrhosis and the number of potential candidates for liver transplantation is unknown but certainly underestimated. Despite physicians' ethical reserves concerning this self-inflicted disease and the public's misgivings, liver transplantation for alcoholic cirrhosis can provide survival rates comparable with those observed for other chronic liver diseases. in this indication, liver transplantation if often associated with a low risk of acute rejection and a high rate cancer of the upper respiratory and digestive tracts. The risk of recurrent alcoholism after liver transplantation is also a major problem. Its prevalence varies from 10 to 50%, depending on the assessment criteria, and the rate recurrent risk for the liver graft (alcohol intake>40 g/d) is to the order of 10%. These figures illustrate the importance of careful management and support for these patients. At least 6 months weaning from alcohol is a commonly accepted selection criterion for transplantation candidates. Criteria for liver transplantation generally include patients aged under 65 years, weaned for more than 6 months, with Child C cirrhosis or less, uncontrollable digestive tract hemorrhage, spontaneous severe infection, hepatorenal syndrome, hepatopulmonary syndrome, or multifocal hepatocellular carcinoma if the largest nodule measures less than 3 cm. Acute alcoholic hepatitis is a severe disease, fatal in 50% of the cases, and resistant tot corticosteroid therapy. Liver transplantation in this subpopulation of often young patient who have not achieved weaning merits further evaluation.

Expression of hepatitis C virus NS5A natural mutants in a hepatocytic cell line inhibits the antiviral effect of interferon in a PKR-independent manner.

The impact of hepatitis C virus NS5A protein mutations on interferon alfa (IFN-alpha) signaling pathway, cell proliferation, and viability is an important issue that is still under debate. We have therefore combined transient and stable expression in a human hepatocytic cell line (Huh7) of 3 full-length NS5A sequences, isolated from patients with or without response to IFN-alpha therapy. Expression of all 3 NS5A-reduced IFN-alpha global antiviral activity on both vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) replication. We did not show, however, an effect of these 3 NS5A proteins on double-stranded RNA-dependent kinase (PKR) expression and activity as well as colocalization and coimmunoprecipitation between NS5A and PKR. We also failed to show an effect of the 3 NS5A mutants tested on cell proliferation and viability. Overall, our results support an important role of NS5A in controlling IFN-alpha antiviral activity; they show, however, that PKR-independent mechanisms are implicated, at least in liver-derived cells.

Effects of bile salts and aliphatic ionic surfactants on human lymphocyte proliferation.

BACKGROUND: The molecular mechanisms involved in the immunosuppressive properties of bile salts are partly unknown. METHODS: The aim of the study was to compare the effects of bile salts to those of various compounds with a steroid structure, or straight-chain hydrocarbons of different lengths and polar groups in the human mixed lymphocyte reaction. RESULTS: We showed a significant correlation between the effects of bile salts and a low critical micellar concentration, a high surface activity index, and the absence of conjugation. In addition to mixed lymphocyte reaction (MLR) inhibition, chenodeoxycholate (CDC) inhibit ConA-induced IL2 production without any effect on IL2 R expression. Fusidate, a negatively charged steroid, with physical properties comparable to those of deoxycholate, had similar effects. Cetyltrimethylammonium bromide (CTAB), which exhibited a very low critical micellar concentration, inhibited mixed lymphocyte reaction in an extent comparable to cyclosporin A. In contrast, aliphatic compounds with critical micellar concentrations in the same range as bile salts but with a lower molecular area had no effect. CONCLUSIONS: Amphiphilic negatively charged molecules inhibit T-cell proliferation to an extent that is dependent upon their hydrophobicity. These results may be explained, at least in part, by a modification in the cell membrane lipid bilayer structure.

Bile acids modulate the interferon signalling pathway.

We have previously shown that cholestasis and bile acids inhibit 2', 5' oligoadenylate synthetase (OAS) activity in the liver and in primary hepatocyte cultures. Here, we assessed the influence of bile acids on interferon (IFN) pathway activation in three hepatoma cell lines. In HepG2 cells, bile acids (100-200 micromol/L) inhibited IFN-induced 2',5' OAS activity to an extent depending on their surface activity index. In Western blot analysis, IFN-induced expression of two major antiviral proteins, MxA and OAS p100, was reduced by 54% +/- 8% and 44% +/- 12%, respectively, when cells were preincubated for 4 hours with 100 micromol/L chenodeoxycholic acid (CDCA). In the same conditions, CDCA did not modify the IFN-induced signal transducers and activators of transcription (STAT)s tyrosine phosphorylation. In contrast, it reduced IFN-induced MxA promoter activity by 60%. The inhibitory effect of CDCA was not mediated by a 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA)-sensitive protein kinase C (PKC)-dependent pathway. Finally, using CHO cells stably expressing a functional human bile acid carrier (Na+-dependent taurocholate cotransporting polypeptide [NTCP]), we found that bile acid inhibition of the IFN pathway occurred in the range of more physiological concentrations (12-50 micromol/L). In summary, our results provide strong evidence that bile acids inhibit the induction of proteins involved in the antiviral activity of IFN. This might partly explain the lack of responsiveness to IFN therapy in some patients with advanced chronic viral liver diseases.

High doses of hydroxyethyl starch and human albumin have similar effects on monocyte function and oncotic pressure.

The accumulation of hydroxyethyl starches (HES) in monocytes/macrophages has raised concern over their potential detrimental effects on host defences. We assessed prospectively the function of circulating monocytes isolated from patients treated with plasma exchange (PE) using HES. The study was carried out in the medical intensive care unit of a university hospital. Eight patients underwent PE for neurological disorders. Each patient underwent three PEs, 48 h apart. The total exchange volume was 4 L per PE. Only 4% human albumin was used for the first PE. In the second and third PEs, the plasma substitute was 2 L of HES (200,000/6%/0.62) and 2 L of albumin. Mononuclear cells were collected before and immediately after each PE and 48 h after the last PE. They were placed in suspension culture and incubated with lipopolysaccharide (LPS). Monocyte function was assessed in terms of procoagulant activity (PCA) and tumour necrosis factor alpha (TNF-alpha) production. LPS-stimulated PCA increased after the first PE (P < 0.05). Stimulated TNF-alpha production increased, but not significantly so. Similar effects were observed after the second and third PE (P < 0.05 for stimulated TNF-alpha). Values 48 h after the last PE were similar to those obtained before the second PE, suggesting that repeated infusions of HES had no detrimental effect on monocyte function. Furthermore, plasma oncotic pressure was preserved after PE with HES. These results support the partial replacement of costly human albumin with HES during repetitive PE, and suggest that HES might be a safe plasma expander in septic patients.

Evidence for a deficiency of interferon response in mononuclear cells from hepatitis C viremic patients.

BACKGROUND/AIMS: The pathophysiology of chronic hepatitis C and the mechanisms of resistance to interferon alpha are poorly understood. The aim of this work was to assess the influence of HCV infection and the viral genotype on lymphocyte production of 2',5' oligo-adenylate synthetase activity and monocyte production of TNF alpha and IL1 beta. METHODS: Mononuclear cells from 50 consecutive patients were studied after 6 months of interferon treatment. Patients with persistent viremia (PCR-positive, elevated ALT, n = 39) were compared with the PCR-negative patients with normal ALT activity (n = 11) of similar age and sex ratio. RESULTS: Cells from the viremic patients showed lower basal and stimulated 2',5' oligo-adenylate synthetase activity, and a lower in vitro response capacity to human recombinant interferon. In contrast, no difference was observed in basal and stimulated TNF alpha or IL1 beta production between the two groups. In the PCR-positive patients the viral genotype had no significant influence on the response of mononuclear cells to interferon or endotoxin. CONCLUSIONS: These results show that the presence of HCV in blood is associated with an elective defect in interferon system activation, independently of the viral genotype.

Bile acid inhibition of interferon activity in human lymphocytes: no evidence of oxidative stress.

Cholestasis and bile acids are two factors involved in resistance to interferon therapy in patients with chronic hepatitis C. As bile acids inhibit the biological activity of this cytokine in vitro and are capable of generating oxidative stress in hepatocytes, we investigated the potential involvement of such a mechanism in human lymphocytes. Thus, we evaluated (a) the effects of bile acids (0-200 mumol L-1) on lymphocyte reduced glutathione content and malondialdehyde production and (b) the ability of antioxidants to prevent the inhibitory effect of chenodeoxycholic acid on interferon-induced lymphocyte 2',5'-oligoadenylate synthetase activity, an index of the biological activity of interferon. We found that treatment of lymphocytes with bile acids for 24 h did not induce malondialdehyde release or significantly modify cellular reduced glutathione content. Synthetic precursors of glutathione (N-acetylcysteine and S-adenosylmethionine) and antioxidants (superoxide dismutase and catalase) had no preventive influence on the inhibitory effect of chenodeoxycholic acid on interferon-induced 2',5'-oligoadenylate synthetase activity. These negative results do not provide evidence for the use of glutathione precursors in cholestatic conditions associated with viral diseases.

Effect of cholestasis and bile acids on interferon-induced 2',5'-adenylate synthetase and NK cell activities.

BACKGROUND/AIMS: The mechanisms involved in resistance to interferon alfa in patients with chronic hepatitis C are unclear. Both cirrhosis and cholestasis have been shown to be predictive of resistance. The aim of this study was to evaluate the influence of cholestasis and bile acids on 2',5'-oligoadenylate synthetase and natural killer activities, which are both involved in the antiviral activity of interferon. METHODS: 2',5'-Oligoadenylate synthetase activity was evaluated in spleen, liver, and isolated hepatocytes from bile duct-ligated rats, and the effect of bile acids in vitro on interferon-induced 2',5'-oligoadenylate synthetase and natural killer activities was examined in fresh mononuclear cells from healthy subjects. RESULTS: Cholestasis had a time-dependent inhibitory effect on 2',5'-oligoadenylate synthetase activity in liver, spleen, and isolated hepatocytes from cholestatic rats (-70%, 86%, and 70% relative to baseline, respectively). In vitro, endogenous bile acids had a concentration-dependent inhibitory effect on interferon-induced 2',5'-oligoadenylate synthetase and natural killer activities, which was related to their structure. This inhibitory effect correlated with the surface activity index. CONCLUSIONS: Cholestasis and bile acids diminish the biological activity of interferon and natural killer activity. The results suggest a decrease in the antiviral defenses in cholestatic conditions.