[Secondary cholangitis of the critically ill]. / Sekundär sklerosierende Cholangitis bei kritisch Kranken.

Sclerosing Cholangitis of the Critically Ill (SC-CIP) is a relatively new entity within the spectrum of secondary cholangitis that develops in the wake of intensive care therapy with mechanical ventilation and catecholamine treatment. It is caused by ischemic or immunologic injury to small bile ducts that becomes self-aggravating and persists beyond the end of the intensive care stay. Early clinical and laboratory findings show acute cholangitis with elevated CRP, gamma GT, AP, and bilirubin. ERCP shows damaged intrahepatic bile ducts with irregular calibers and biliary casts. The following phase is chronic and oligosymptomatic. Still, all laboratory parameters will stay mildly elevated and ERCP and MRCP will show progressive loss of small bile ducts. Long-term prognosis is poor. Even with UDCA therapy, most patients will develop liver cirrhosis within months or years.

Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration.

BACKGROUND & AIMS: Pegylated interferon-alpha (PegIFNα) remains an attractive treatment option for chronic hepatitis B virus (HBV) infection because it induces higher rates of antigen loss and seroconversion than treatment with polymerase inhibitors. Although early HBsAg decline is recognised as the best predictor of sustained response to IFN-based therapy, it is unclear whether immune cell functions are required to induce significant antigenemia reduction in the first weeks of treatment. Aim of the study was to investigate whether PegIFNα can induce sustained human hepatocyte responsiveness and substantial loss of circulating and intrahepatic viral antigen loads in a system lacking immune cell functions. METHODS: HBV-infected humanized uPA/SCID mice received either PegIFNα, entecavir (ETV), or both agents in combination. Serological and intrahepatic changes were determined by qRT-PCR and immunohistochemistry and compared to untreated mice. RESULTS: After 4 weeks of treatment, median viremia reduction was greater in mice treated with ETV (either with or without PegIFNα) than with PegIFNα. In contrast, levels of circulating HBeAg, HBsAg, and intrahepatic HBcAg were significantly reduced (p = 0.03) only in mice receiving PegIFNα alone or in combination, as compared to mice receiving ETV monotherapy. Progressive antigen reduction was also demonstrated in mice receiving PegIFNα for 12 weeks (HBeAg = Δ1log; HBsAg = Δ1.4log; p < 0.0001). Notably, repeated administrations of the longer-active PegIFNα could breach the impairment of HBV-infected hepatocyte responsiveness and induce sustained enhancement of human interferon stimulated genes (ISG). CONCLUSIONS: The antiviral effects of PegIFNα exerted on the human hepatocytes can induce sustained responsiveness and trigger substantial HBV antigen decline without claiming the involvement of immune cell responses.

Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation.

UNLABELLED: No specific drugs are currently available against hepatitis delta virus (HDV), a defective virus leading to the most severe form of chronic viral hepatitis in man. The lack of convenient HDV infection models has hampered the development of effective therapeutics. In this study, naïve and hepatitis B virus (HBV) chronically infected humanized uPA/SCID mice were employed to establish a small animal model of HBV/HDV coinfection and superinfection. For preclinical antiviral drug evaluation, the GMP version of the myristoylated preS-peptide (Myrcludex-B), a lipopeptide derived from the pre-S1 domain of the HBV envelope, was applied to prevent de novo HBV/HDV coinfection in vivo. Virological parameters were determined at serological and intrahepatic level both by real-time polymerase chain reaction (PCR) and by immunohistochemistry. Establishment of HDV infection was highly efficient in both HBV-infected and naïve chimeric mice with HDV titers rising up to 1 × 10E9 copies/mL. Notably, HDV superinfection led to a median 0.6log reduction of HBV viremia, which although not statistically significant suggests that HDV may hinder HBV replication. In the setting of HBV/HDV simultaneous infection, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, confirming that HDV can replicate intrahepatically also in the absence of HBV infection. Furthermore, the increase of HBV viremia and intrahepatic cccDNA loads was significantly slower than in HBV mono-infected mice. Treatment with the HBV entry inhibitor Myrcludex-B, efficiently hindered the establishment of HDV infection in vivo. CONCLUSION: We established an efficient model of HBV/HDV infection to exploit mechanisms of viral interference in human hepatocytes and to test the efficacy of an HDV-entry inhibitor in vivo.

Hepatitis B virus limits response of human hepatocytes to interferon-α in chimeric mice.

BACKGROUND & AIMS: Interferon (IFN)-α therapy is not effective for most patients with chronic hepatitis B virus (HBV) infection for reasons that are not clear. We investigated whether HBV infection reduced IFN-α-mediated induction of antiviral defense mechanisms in human hepatocytes. METHODS: Human hepatocytes were injected into severe combined immune-deficient mice (SCID/beige) that expressed transgenic urokinase plasminogen activator under control of the albumin promoter. Some mice were infected with HBV; infected and uninfected mice were given injections of human IFN-α. Changes in viral DNA and expression of human interferon-stimulated genes (ISGs) were measured by real-time polymerase chain reaction, using human-specific primers, and by immunohistochemistry. RESULTS: Median HBV viremia (0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 hours after each injection of IFN-α, but increased within 24 hours. IFN-α activated expression of human ISGs and nuclear translocation of signal transducers and activators of transcription-1 (STAT1) in human hepatocytes that repopulated the livers of uninfected mice. Although baseline levels of human ISGs were slightly increased in HBV-infected mice, compared with uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA, MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice. IFN-α did not induce nuclear translocation of STAT1 in HBV-infected human hepatocytes. Administration of the nucleoside analogue entecavir (for 20 days) suppressed HBV replication but did not restore responsiveness to IFN-α. CONCLUSIONS: HBV prevents induction of IFN-α signaling by inhibiting nuclear translocation of STAT1; this can interfere with transcription of ISGs in human hepatocytes. These effects of HBV might contribute to the limited effectiveness of endogenous and therapeutic IFN-α in patients and promote viral persistence.

Calculated Antibiosis of Acute Cholangitis and Cholecystitis.

BACKGROUND: The aim of this article is to present the most recent suggestions for the therapy of acute cholangitis and cholecystitis based on a review of the current literature. METHODS: We performed a systematic literature search in the Medline, PubMed, and Google Scholar databases using the keywords mentioned above. This article is strongly influenced by the publication of the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07, TG13) in 2007 and 2013. These were the first practical guidelines targeting diagnosis and treatment of acute cholangitis and cholecystitis. These guidelines are based on the best published evidence and a consensus conference of international experts in the field. RESULTS AND CONCLUSION: Acute cholangitis and acute cholecystitis are common conditions that may result in progressively severe infection and death when not treated appropriately. Beside supportive therapy and antiobstructive measures, therapy with antimicrobial agents is an important component in the management of affected patients. Here, we discuss the use of antimicrobial agents that are suitable for the first-line management of these infections. Empirical therapy depends upon the knowledge of local microbial epidemiology and patient-specific factors affecting the selection of appropriate agents.