The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice.

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.

Renal grafts from anti-hepatitis B core-positive donors: a quantitative review of the literature.

BACKGROUNDS AND AIMS: Organ shortage is a major problem in transplantation. The use of organs from hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive donors could significantly increase the donor pool. However, little information is available about the impact of HBcAb status of renal donors on viral transmission to recipients. To address this issue, the present quantitative review of relevant studies has been performed. MATERIALS AND METHODS: Electronic databases including Medline, EMBASE, ISI, and Scopus were systematically searched for studies that evaluated risk of hepatitis B virus (HBV) transmission through renal transplantation from HBsAg-/HBcAb+ donors. Eligible studies were identified according to predefined criteria. The final outcome was one of HBV markers seroconversion defined as HBsAg, hepatitis B surface antibody (HBsAb), or HBcAb detection in previously seronegative end-stage renal disease (ESRD) patients after transplantation, and without other identified major sources of infection. RESULTS: Nine studies with 1385 eligible kidney recipients were included. In total, 45 subjects showed seroconversion of HBV markers as follows: HBsAg (n = 4) (0.28%; 95% confidence interval [CI] 0.006; 0.57), HBcAb (n = 32), HBsAb (n = 5), and either HBcAb or HBsAb (n = 4). The total rate of seroconversion after renal transplantation was calculated to be 3.24% (95% CI: 2.31-4.18). CONCLUSION: Our review indicates that the risk of HBV transmission from HBcAb-positive kidney donors is extremely low. Therefore, kidneys from these donors can be transplanted safely into ESRD patients.

[Direct antiviral treatment strategies in chronic hepatitis C]. / Direkt antivirale Therapieansätze bei der chronischen Hepatitis C.

The standard antiviral therapy for chronic hepatitis C is pegylated interferon-alfa (PegIFN) and ribavirin since about 10 years. This treatment regimen leads to a sustained virological response (SVR) in 40-50 % of patients infected with HCV genotype 1 and in approx. 80 % of those infected with HCV genotype 2 or 3. In recent years, many direct antiviral agents (DAA) have been developed and are being explored in clinical studies. These antiviral agents target different viral proteins that are central for HCV replication, incl. the NS3/4A protease, NS5B polymerase, and the NS5A protein. The protease inhibitors telaprevir and boceprevir have recently been approved for the treatment of chronic HCV genotype 1 infection in combination with PegIFN and ribavirin. These triple therapies increase the SVR rates in HCV genotype 1 patients from 40-50 % to approx. 70 %. Other DAAs will likely be approved in the near future and may result in an IFN-free antiviral therapy.

Weight loss and severe jaundice in a patient with hyperthyroidism.

BACKGROUND: Thyrotoxicosis may significantly alter hepatic function and is associated with autoimmune disorders of the liver. CASE REPORT: We report the case of a thyrotoxic patient with Graves' disease and histologically established cholestatic hepatitis. Medical treatment of hyperthyroidism normalized liver function tests. CONCLUSIONS: In patients with elevated liver function parameters and jaundice of unknown origin, thyroid function should generally be tested. Moreover, medical treatment of hyperthyroidism with thyrostatics may cause severe hepatitis whereas untreated hyperthyroid patients are at risk of developing chronic liver failure.

Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide.

Constipation, one of the major side effects of opiates used in palliative care, can impair patients' quality of life to a point where it prevents sufficient pain control. Methylnaltrexone is a novel µ-receptor antagonist, which does not pass the blood brain barrier. It is licensed to treat opiate induced constipation for patients with advanced diseases. This review article presents an overview of pharmacology and safety of its application, evidence of its efficacy and economic aspects of its use in clinical practice. Available data are limited but strongly suggest that methylnaltrexone causes laxation in less than 24 hours for at least half of those patients over the first two weeks of usage without impairing pain control or causing serious adverse effects. To avoid danger of gastrointestinal perforation it is contraindicated for patients at risk for that complication. More research is needed to evaluate its long-term efficacy and economic impact.

[A rare cause of an indistinct liver lesion in an elderly woman]. / Seltene Ursache einer unklaren Leberläsion bei einer 76-jährigen Patientin.

HISTORY: A 76-year-old woman was admitted with a two-months history of pain in the right upper abdomen and nausea. There was no disease or premedication in her history. INVESTIGATIONS: Labaratory tests revealed a normocytic anemia, elevated liver enzymes and signs of cholestasis. An MR of the abdomen showed a hyperperfused tumor in the liver segments IV, V and VIII, likely to be a hepatocellular carcinoma. However, tumor markers including AFP were not elevated. A liver biopsy revealed the final diagnosis of angiosarcoma. THERAPY AND COURSE: Because the tumor was not resectable transarterial chemoembolisation (TACE) with doxorubicin was performed with palliative intent. Six weeks later a CT scan revealed extensive tumor progression. Therefore no further causal tretament was performed. With best supportive care the patient died within 4 weeks after she had been discharged. Occupational history revealed that the woman had been exposed to polyvinylchloride for six years when she had worked in a factory producing varnish aerosol cans 44 years ago. CONCLUSION: Angiosarcomas of the liver are rare, highly malignant and diffuse infiltrating vascular tumors with rapid growth and poor prognosis. In patients who have been exposed to polyvinylchloride and present with an indistinct lesion of the liver an angiosarcoma should be considered.

[Personalized medicine 2011]. / Individualisierte Medizin 2011.

Molecular and cell biology have not only greatly advanced our understanding of the pathogenesis of numerous human diseases but at the same time contributed to their diagnosis, therapy and prevention. Based on modern genetic as well as epigenetic and biochemical analyses it is possible to identify on the one hand point mutations and single nucleotide polymporphisms (SNPs) as well as epigenetic modifications. On the other hand, using high throughput array technologies, it is possible to analyze thousands of genes simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (personalized medicine).

[Personalized medicine]. / Individualisierte Medizin 2011.

Molecular and cell biology have revolutionized not only diagnosis, therapy and prevention of human diseases but have also greatly contributed to the understanding of their pathogenesis. Based on modern molecular and biochemical methods it is possible to identify on the one hand point mutations and single nucleotide polymorphisms. On the other hand, using high throughput array technologies, it is possible to analyze thousands of genes simultaneously, resulting in an individual gene or gene expression profile (signature). These data increasingly allow to define the individual risk for a given disease and to predict the individual prognosis of a disease as well as the efficacy of therapeutic strategies (personalized medicine). In this review recent advances of predictive medicine and its clinical relevance will be addressed.

[Genome-wide association studies]. / Genomweite Assoziationsstudien.

Genome-wide association studies (GWAS) are aimed to identify genetic markers of complex human diseases and individual traits. In this context more than 150 gene loci have been found to be associated with about 60 different diseases and personal characteristics. A recent example is the relevance of a polymorphism in the interleukin 28B gene for the natural course of hepatitis C virus infection and the efficacy of antiviral therapy. It is to be expected that GWAS will increasingly contribute to the understanding of the pathogenesis and consquently improve prediction, prevention, diagnosis and therapy of human diseases and eventually will become part of clinical practice.

[A patient with chronic diarrhoe, head pigmentation and alopecia. Cronkhite-Canada syndrome]. / Patient mit chronischer Diarrhoe, Pigmentierungsstörung und Haarausfall. Cronkhite-Canada Syndrom.

HISTORY AND FINDINGS ON ADMISSION: A 70-year-old man with a 14 month history of chronic severe diarrhea treated with budenosid and mesalazin was admitted because of peripheral oedema and weight loss of about 26 kg. INVESTIGATIONS AND DIAGNOSIS: A general pigmentation of the skin, especially on scull and hands, as well as dystrophic nail changes and alopecia of scalp and facial hair were seen. The tests showed a slight macrocytotic, normochromic anemia. Total protein and the clotting factors were decreased. Endoscopy revealed multiple sessile polyps in the stomach and duodenum in appearance to colon and rectum. Endoscopic removal of a polyp showed histologically cystic dilatation of foveolae and oedematous mucosa. The histological features, the wide distribution of the polyps together with the skin changes, lead to the diagnosis of Cronkhite-Canada syndrome (CCS). TREATMENT AND COURSE: The patient was initially treated with prednisolon 60 mg/d i. v. for 2 weeks, resulting in a marked improvement of symptoms and weight gain. He is at present in good health under prednisolon 20 mg/d per os and is followed up in our outpatient department. CONCLUSION: CCS is in up to 14 % of the cases associated with a carcinoma of the gastrointestinal tract. At present there are only reports about a successful treatment by steroids, prophylactic gastrectomy and proctocolectomy. Typical myopathic lesions of CCS have not been described to date, but the demonstrated improvement of creatinin kinase with successful treatment suggests a common pathophysiological mechanism.

New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with significant morbidity and mortality. Since there is evidence for an interaction of NS5A with c-Raf we studied whether the c-Raf inhibitor sorafenib affects HCV replication. METHODS: HCV replicating HuH7.5 cells were treated with sorafenib and examined for HCV RNA titres by northern blotting or real time polymerase chain reaction (PCR), for core, NS3 and NS5A expression by immunostaining, and for replication by luciferase reporter assays. RESULTS: Here we demonstrate that in cells replicating infectious HCV particles, NS5A recruits c-Raf to the replicon complex resulting in the activation of c-Raf. Therefore, we studied the effect of inhibition of c-Raf on HCV replication using the anti-tumour drug sorafenib that is known to inhibit c-Raf with high specificity. Sorafenib efficiently blocks HCV replication and viral gene expression. In addition, in HCV-replicating cells sorafenib decreased the hyperphosphorylated form of NS5A and resulted in the formation of additional hypophosphorylated forms. Further, sorafenib caused a rapid dissociation of lipid droplets. We provide evidence that the antiviral effect of sorafenib indeed is caused by inhibition of c-Raf. By contrast, inhibition of targets downstream of c-Raf or inhibition of tyrosine kinases by sunitinib did not affect HCV replication. CONCLUSION: Our data demonstrate that the well-characterised anti-tumour drug sorafenib efficiently blocks HCV replication in vitro. This novel effect of sorafenib should be further explored as an antiviral strategy for patients with chronic HCV infection.