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Regulation of CC chemokine receptor 5 in hepatitis G virus infection

INTRODUCTION: Epidemiological data demonstrate an association between hepatitis G virus (HGV) co-infection and improved survival of HIV-positive individuals. However, the mechanism by which HGV affects progression of HIV disease remains unclear. As down-regulation of CC chemokine receptor 5 (CCR5) delays HIV progression, we investigated whether CCR5 expression is altered by exposure of lymphocytes to HGV proteins. METHODS: A cross-sectional analysis of CCR5 expression was carried out on CD4 and CD8 T lymphocytes of 11 HGV-positive and 12 HGV-negative persons, who were homozygous for the CCR5 wild-type gene. Binding of the HGV E2 protein to CD81 was analysed by flow cytometry. Lymphocytes were stimulated with immobilized HGV E2, anti-CD81 or serum proteins from HGV-infected subjects and changes in CCR5 expression and CC chemokine secretion were determined. RESULTS: We demonstrate that the HGV envelope protein E2 specifically binds to CD81 on T lymphocytes. This interaction induces a dose-dependent release of RANTES and down-regulation of CCR5 surface expression with concomitant intra-cellular accumulation of CCR5 proteins. This effect of HGV E2 on CCR5 expression was confirmed when lymphocytes were incubated with serum proteins from HGV-infected subjects. Finally, our cross-sectional analysis revealed CCR5 expression to be reduced by 53% and 36% on CD4 and CD8 lymphocytes of HGV-infected subjects, respectively (P < 0.01). CONCLUSIONS: Our results demonstrate that an interaction of HGV E2 with CD81 leads to increased RANTES secretion and decreased CCR5 surface expression. This mechanism might contribute to the delayed progression of HIV-infection in HGV-coinfected patients.     

Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases

The contribution of the acute phase inducer interleukin 6 (IL-6) in the pathogenesis of liver diseases is yet unclear. Our analysis showed enhanced expression of IL-6 in livers derived from patients with acute and chronic liver diseases. Additionally, IL-6 plasma levels were significantly increased in patients with chronic liver diseases and showed an inverse correlation with biochemical markers of liver function and a positive correlation with inflammatory markers, signs of portal hypertension, and the degree of liver fibrosis. To prove the relevance of these clinical findings, we applied the tetrachlorcarbonide (CCl(4)) model to conditional knockout animals (Cre/loxP system) for gp130, the common signal transducer of IL-6 family cytokines. Cre recombinases were expressed through a hepatocyte (AlfpCre) and a ubiquitous (MxCre) control element. Gp130 deleted mice had a totally abolished STAT3 activation and acute phase response induction, but gp130 deletion had no effect on the degree of acute liver injury and subsequent hepatocyte proliferation. In contrast, during chronic liver injury induced by biweekly application of CCl(4), deletion of the gp130 receptor in nonparenchymal liver cells and not hepatocytes resulted in fibrosis progression. In conclusion, our experiments indicate an involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (Hepatology 2003;38:218-229).     

Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression in fulminant hepatic failure

BACKGROUND/AIMS: Inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) have important functions in inflammation and vasoregulation but their role in fulminant hepatic failure (FHF) is not well understood. METHODS: Intrahepatic in situ staining and semi-quantification of iNOS and eNOS by immunohistochemistry in 25 patients with FHF, in 40 patients with chronic liver diseases (CLD) and in ten normal controls (NC). RESULTS: Expression patterns of iNOS and eNOS differed. While in NC only faint iNOS expression was found in some Kupffer cells/macrophages and hepatocytes, eNOS was expressed constitutively in sinusoidal and vascular endothelial cells. In CLD, iNOS expression was induced in Kupffer cells/macrophages and hepatocytes, representing the main iNOS expressing cell types. Additionally, bile ducts, vascular endothelial cells and lymphocytes also expressed iNOS (P = 0.001). In contrast, no differences were found between eNOS expression in CLD and NC (P = 0.64). The same cell types expressed eNOS and iNOS in FHF but numbers of both were significantly enhanced, exceeding the levels seen in CLD (P < 0.001, P = 0.017). CONCLUSIONS: Our data demonstrate that iNOS and eNOS are differently regulated in physiologic conditions and in liver disease. While eNOS seems to be involved in the physiological regulation of hepatic perfusion, strong upregulation of iNOS might contribute to inflammatory processes in FHF.     

Sonographical diagnosis of pneumoretroperitoneum as a result of retroperitoneal perforation

A retroperitoneal perforation is a rare incident. It can occur as a complication of ERCP with papillotomy (0.2-0.5%). Leakage of contrast agent during endoscopy raises the suspicion that this complication has occurred but doesn't always give sufficient information about the leakage extent. In the case of extreme gas emission, a plain abdominal X-ray shows classic pneumoretroperitoneum. The abdominal CT scan can display small amounts of free air which is why it is used for diagnosis in such cases. Ultrasonography also provides a reliable diagnosis and is a good method for monitoring the progression of the condition. Alternative causes of pneumoretroperitoneum can be: trauma, inflammation, infection, tumor as well as ERCP and other interventional procedures, especially endoscopies. Presacral retroperitoneal pneumoradiography was used for the diagnosis of retroperitoneal tumors in the 70 s but is no longer used today. Perforations into the retroperitoneal space come from several locations in the gastrointestinal tract. In the different types of lesions the gas can penetrate the compartments and reach as far as the mediastinum, the intraabdominal cavity, subcutaneum (cervical) or the scrotal compartment (compartment shift). Based on 11 cases (7 perforations during ERCP, 2 perforation during colonoscopy, 2 cases with damage of the distal esophagus), we show the most extensive presentation of the sonographical picture of pneumoretroperitoneum. Typical signs on abdominal ultrasound are an increased echogenicity around the right kidney ("overcasted" or "covered" kidney), air dorsal to the gallbladder, around the duodenum and the head of the pancreas and especially ventral to the great abdominal vessel which can lead to the picture of "vanishing" vessels. The extent of free air is easy to assess. Even very small amounts are detectable ventral to the right kidney. In most cases, a conservative approach with no oral intake, antibiotic coverage, and analgesia in close gastroenterological-surgical cooperation is indicated. Especially after ERCP abscess formation is repeatedly described, sometimes even with a lethal outcome. Sonography is a suitable method for detecting free air in the retro-peritoneum. Pneumoretroperitoneum following bowel-perforation can be effectively shown by ultrasound, it is possible to assess the extent of free air, and sonographic monitoring of the treatment is possible and successful.     

Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience

Acute hepatitis B progresses to liver failure with the need of liver transplantation in about 1% of cases. We treated patients with severe acute or fulminant hepatitis B with lamivudine in an attempt to prevent hepatitis B virus (HBV) reinfection after potential liver transplantation. Since September 2000, 17 patients with severe acute or fulminant HBV infection were treated with 100 or 150 mg lamivudine daily once we had evidence for a severe course as indicated by an INR >2.0. These were compared to a historic control from our unit and to external patients. Fourteen of the 17 patients (82.4%) survived with full recovery without liver transplantation. All these 14 individuals cleared HBsAg on lamivudine within less than 6 months. Twelve patients recovered quickly as indicated by a normalized prothrombin time within 1 week while two patients had a more prolonged course. None of the patients showed an adverse event. Three patients requiring transplantation despite lamivudine therapy had more advanced disease on admission, of whom one had additionally ingested paracetamol (acetaminophen) while the second was already HBV-DNA negative by polymerase chain reaction on admission. The lamivudine treated patients had significant higher frequency of survival without liver transplantation 82.4 vs 20% (4/20) in the historic control (P < 0.001). Similar data were derived from external centres using lamivudine (15/20, 75%). Lamivudine is safe in patients with severe acute or fulminant hepatitis B, leading to fast recovery with the potential to prevent liver failure and liver transplantation when administered early enough.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Health effects and sources of indoor air pollution. Part I

Since the early 1970s, the health effects of indoor air pollution have been investigated with increasing intensity. Consequently, a large body of literature is now available on diverse aspects of indoor air pollution: sources, concentrations, health effects, engineering, and policy. This review begins with a review of the principal pollutants found in indoor environments and their sources. Subsequently, exposure to indoor air pollutants and health effects are considered, with an emphasis on those indoor air quality problems of greatest concern at present: passive exposure to tobacco smoke, nitrogen dioxide from gas-fueled cooking stoves, formaldehyde exposure, radon daughter exposure, and the diverse health problems encountered by workers in newer sealed office buildings. The review concludes by briefly addressing assessment of indoor air quality, control technology, research needs, and clinical implications.     

Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: Epidemiological data indicate that hepatitis C virus (HCV) infection runs a more rapid and severe course of disease in HIV-coinfected patients, probably because of an altered immune response. DESIGN: We investigated whether HCV-specific cytokine responses are affected by HIV coinfection. METHODS: Using triple colour flow cytometry on peripheral blood lymphocytes after stimulation with the four major immunodominant HCV core T cell epitopes, CT1-CT4, we determined intracytoplasmic production of IFN-gamma, IL-2, IL-4, IL-10 and CD30 expression, a putative surrogate marker of type 2 cells. Fifteen patients with asymptomatic HIV/HCV coinfection (group A), 15 patients with chronic HCV infection (group B) and 10 HIV-infected patients without hepatitis C (group C) were included in the study. RESULTS: In group A, HCV antigens induced significantly higher IL-2 and IFN-gamma production than groups B and C (P < 0.05). Groups A and B showed a similar induction of CD30, which was significantly higher than in group C (P < 0.001). Remarkably, in group A HCV antigens induced IL-4 production in addition to IL-10 and IFN-gamma in the CD30 subset, whereas in groups B and C no IL-4 induction was observed in this T cell subset (P < 0.002). CONCLUSION: Our data suggest that asymptomatic HIV coinfection importantly alters the HCV-specific cytokine response towards a greater production of proinflammatory type 1 cytokines. Moreover, the antiviral activity of type 1 cytokines may be modified by an increased production of type 2 cytokines in the CD30 subset. The altered cytokine pattern may contribute to the adverse natural course of hepatitis C in HIV coinfection.