Successful sealing of benign esophageal leaks after temporary placement of a self-expanding plastic stent without fluoroscopic guidance.

INTRODUCTION: We report on our experience with the temporary use of a self-expanding plastic stent (SEPS) in the treatment of non-malignant esophageal leaks. MATERIAL AND METHODS: Between November 2001 and May 2005 ten patients with iatrogenic esophageal perforations (n = 4), post-surgical leaks (n = 5) and esophago-mediastinal fistulas after caustic injury (n = 1) were treated by temporary SEPS placement. In eight out of ten patients SEPS placement was done without fluoroscopy due to the emergency setting. Stent removal was performed with a rat-toothed forceps. RESULTS: Leaks were located in the proximal (n = 1), middle (n = 6) and distal (n = 3) parts of the esophagus. The mean leakage size was 2 cm. Stent placement without fluoroscopy was always successful. The median duration of stent therapy was 55.5 days (range 15,438). In 7/10 cases the SEPS was readily removed, showing complete healing of the former leak. Four patients died during the follow-up. However, their deaths were not related to the stent therapy. DISCUSSION: The temporary use of the SEPS represents a safe method for sealing benign esophageal leaks. In the emergency-setting SEPS placement without fluoroscopy is feasible and the stent can be easily removed. In contained perforations without severe mediastinitis of the mid esophagus the SEPS should be discussed as a gentle first-line therapy.

Crohn's disease-induced non-alcoholic fatty liver disease (NAFLD) sensitizes for severe acute hepatitis B infection and liver failure.

Non-alcoholic fatty liver disease (NAFLD) commonly is associated with chronic inflammatory bowel disease (CIBD) and usually is considered to be stable and benign. However, NAFLD -- and in particular its subset, non-alcoholic steatohepatitis (NASH) -- may lead to progressive liver disease. Moreover, NAFLD sensitizes the liver to injury and increases the risk of developing acute-on-chronic liver failure following a "third hit". We here present one patient with NASH, as probably induced by long-standing Crohn's disease in the absence of ethanol consumption or abuse. The patient acquired an acute HBV infection and died from complications. As based on the clinical and histological findings, Crohn's disease appears to be a risk factor for developing NAFLD and thus to contribute to the progression into NASH. In conclusion, we suggest that Crohn's disease-related NAFLD may increase the vulnerability of the liver, which indicates that patients with a known history of CIBD merit special attention.

Dark lumen magnetic resonance colonography: comparison with conventional colonoscopy for the detection of colorectal pathology.

BACKGROUND: The purpose of this study was to assess the feasibility and usefulness of a new magnetic resonance (MR) colonography technique for the detection of colorectal pathology in comparison with conventional colonoscopy as the standard of reference. PATIENTS AND METHODS: A total of 122 subjects with suspected colorectal disease underwent "dark lumen" MR colonography. A contrast enhanced T1w three dimensional VIBE sequence was collected after rectal administration of water. The presence of colorectal masses and inflammatory lesions were documented. Results were compared with those of a subsequently performed colonoscopy. RESULTS: MR colonography was found to be accurate regarding detection of clinically relevant colonic lesions exceeding 5 mm in size, with sensitivity and specificity values of 93%/100%. CONCLUSION: Dark lumen MR colonography can be considered as a promising alternative method for the detection of colorectal disease. In addition, it allows assessment of extraluminal organs.

Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A metabolism in a patient after liver transplantation.

Immunosuppressive therapy in patients after liver transplantation requires careful monitoring of blood levels for immunosuppressive agents such as cyclosporin A. A variety of drugs are capable of interfering with the metabolism of cyclosporin A. We observed a 63-year-old patient who received a liver allograft for cryptogenic liver cirrhosis in 1998. This patient developed severe acute rejection 14 months after transplantation which was associated with a sudden drop in cyclosporin A levels. Two weeks previously, he had started taking the herbal drug Hypericum perforatum (2 x 900 mg/day) for increasing episodes of depression. The cyclosporin A dosage later had to be doubled, which caused some side effects. Finally, an assessment of oral cyclosporin A resorption suggested an enhanced cyclosporin A metabolism. Hypericum perforatum was stopped. Both cyclosporin A dosage and blood levels immediately returned to normal. The liver function recovered completely. In conclusion, this observation is a previously undescribed drug interaction of a widely used herbal drug (Hypericum perforatum, i.e. St. John's wort) in a patient after liver transplantation.

Anti-neutrophil cytoplasmic antibodies in a rat model of trinitrobenzenesulphonic acid-induced liver injury.

BACKGROUND: In sera from patients with autoimmune liver diseases, e. g. primary sclerosing cholangitis (PSC) and autoimmune hepatitis, anti-neutrophil cytoplasmic antibodies (ANCAs) can be found. Until now, no animal model of ANCA induction in liver disease has been described. In this study, we describe a novel rat model of acute liver injury and subsequent ANCA production. MATERIALS AND METHODS: The hapten reagent 2,4,6-trinitrobenzenesulphonic acid (TNBS) was injected into the portal vein of female Lewis rats. Two experimental groups were studied: group A (TNBS/ethanol) received different TNBS concentrations; control animals of group B (ethanol) were injected with 10% (v/v) ethanol/0.9% (w/v) NaCl. RESULTS: A dose-dependent acute necrotizing liver injury occurred after injection of TNBS. Histopathological examination revealed acute hepatic injury with confluent parenchymal necrosis, mild bile duct proliferation and periportal infiltration. The periportal infiltration consisted mainly of macrophages and T lymphocytes. ANCAs were found in an allogenic test system between 1 and 8 weeks after TNBS injection in 11 out of 28 (39%) TNBS-treated rats (group A) and did not correlate with the extent of liver injury or TNBS dose. Autoantibody specificities of IgG type were directed against catalase (29%), myeloperoxidase (14%) and actin (7%), as detected by enzyme-linked immunosorbent assay and Western blotting. Moreover, autoantibodies against the asialoglycoprotein receptor were observed. Peripheral blood mononuclear cells and spleen lymphocytes from TNBS-treated rats were shown to produce ANCAs. CONCLUSION: In summary, we were able to show that intraportal administration of the hapten reagent TNBS induces an acute necrotizing liver injury with subsequent ANCA production in Lewis rats. ANCA specificities were mainly directed against catalase, an autoantigen that has recently been identified in sera from patients with primary sclerosing cholangitis and autoimmune hepatitis. This animal model offers the opportunity to study the pathomechanisms of ANCA production in necrotizing liver injury.

[Littoral-cell angioma--a rare differential diagnosis on splenic tumors]. / Uferzellangiom--eine seltene Differentialdiagnose von Milztumoren.

UNLABELLED: HISTORY AND PRE-ADMISSION FINDINGS: Routine abdominal sonography of a 51-year-old man 6 years after removal of the right testis and radiotherapy for a seminoma revealed a 3 cm mass within the spleen. INVESTIGATIONS: All biochemical tests were normal. Computed tomography (CT) and magnetic resonance imaging confirmed the tumour which had not been present on the CT before the seminoma had been treated. No other space-occupying lesions were found in the thorax and abdomen. TREATMENT AND COURSE: A splenectomy was performed because a metachronous metastasis of the seminoma was suspected. The operation and subsequent course were uneventful. At operation the tumour had been diagnosed as an haemangioma because of its gross appearance, but histological and immunohistochemical examination revealed a littoral cell angioma. CONCLUSION: The littoral cell angioma is a benign vascular lesion in the red pulp of the spleen, which may be caused by different stimuli such as chronic infection or tumours. This case illustrates, that this tumour should be considered in the differential diagnosis of an unclear neoplasm in the spleen.

Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells.

Endotoxin is physiologically present in portal venous blood at concentrations of 100 pg/ml to 1 ng/ml. Clearance of endotoxin from portal blood occurs through sinusoidal lining cells, i.e., Kupffer cells, and liver sinusoidal endothelial cells (LSEC). We have recently shown that LSEC are fully efficient APCs. Here, we studied the influence of endotoxin on the accessory function of LSEC. Incubation of Ag-presenting LSEC with physiological concentrations of endotoxin lead to >/=80% reduction of the accessory function, measured by release of IFN-gamma from CD4+ T cells. In contrast, conventional APC populations rather showed an increase of the accessory function after endotoxin treatment. Inhibition of the accessory function in LSEC by endotoxin was not due to lack of soluble costimulatory signals, because neither supplemental IL-1beta, IL-2, IFN-gamma, or IL-12 could rescue the accessory function. Ag uptake was not influenced by endotoxin in LSEC. However, we found that endotoxin led to alkalinization of the endosomal/lysomal compartment specifically in LSEC but not in bone marrow macrophages, which indicated that Ag processing, i.e., proteolytic cleavage of protein Ags into peptide fragments, was affected by endotoxin. Furthermore, endotoxin treatment down-regulated surface expression of constitutively expressed MHC class II, CD80, and CD86. In conclusion, it is conceivable that endotoxin does not alter the clearance function of LSEC to remove gut-derived Ags from portal blood but specifically affects Ag processing and expression of the accessory molecules in these cells. Consequently, Ag-specific immune responses by CD4+ T cells are efficiently down-regulated in the hepatic microenvironment.

Anti asialoglycoprotein receptor antibodies and soluble interleukin-2 receptor levels as marker for inflammation in autoimmune hepatitis.

Circulating anti asialoglycoprotein receptor antibodies (anti-ASCPR) and soluble interleukin-2 receptor levels (sIL-2R) were blindly determined in sera of 23 patients with autoimmune hepatitis and compared to 18 healthy individuals. All patients underwent liver biopsy which was blindly staged and graded. 14 of 23 (61%) patients but none of normal controls showed anti-ASCPR positivity. Eleven of twelve (92%) patients with biopsy-proven grade 3 hepatitis were high-titered anti-ASCPR positive compared to three of eleven patients with grade I hepatitis. Mean levels of sIL-2R +/- standard deviation were 1.175 +/- 663 units/ml in the total number of patients with auto-immune hepatitis comparing to 372 +/- 69 units/ml in healthy controls (p < 0.001). Eleven of twelve patients with grade 3 hepatitis had significant higher sIL-2R levels (1,669 +/- 559) than patients with mild disease (635 +/- 113). Chi-square analysis demonstrated a significant correlation between positive anti-ASCPR titer and elevated sIL-2R values. A follow-up analysis of six patients showed a significant decrease of both anti-ASCPR titer and sIL-2R levels after three to nine months of immunosuppressive therapy. These findings suggest that elevated sIL-2R levels and anti-ASCPR titer are associated in patients with autoimmune hepatitis and- as a function of either T or B cell activation, respectively- could serve as reliable humoral marker for disease-specific activity.

Receptor-mediated entry of hepatitis B virus particles into liver cells.

In previous reports several receptors for either natural hepatitis B virus (HBV) particles or genetically engineered virus have been described, whereby endocytosis represents a putative uptake mechanism for HBV particles. We have found that HBV-particles from viremic carriers could bind to the human asialoglycoprotein receptor (ASGPR), which mediates glycoprotein uptake into liver cells. The HBV-ASGPR interaction was studied in a cell culture system using hepatoma HepG2 and HuH7 cells compared to COS cells as controls. About 50% of HBsAg-secretion into the cell culture supernatant after HBV-inoculation as a function of HBV-uptake could be inhibited by the specific ASGPR-ligand asialofetuin. COS-cells did not show HBsAg-secretion. If the cells were grown as clones, 15% of HepG2-cells demonstrated HBsAg-secretion but only 5% in the presence of asialofetuin. HBV-particle uptake was further confirmed by HBV-DNA analysis using PCR. HBV-ASGPR interaction was studied with purified, biotin-conjugated human ASGPR. Quantitative inhibition with asialofetuin indicated a high-affinity binding of HBV-particles to purified ASGPR. After denaturing polyacrylamid gel electrophoresis and transblotting of isolated HBV-particles a receptor-blotting system was established which identified distinct binding sites for biotinylated receptors. These results suggest that the ASGPR is capable of specifically binding HBV-particles and, moreover, to mediate their hepatic endocytosis which ultimately could be responsible for the HBV-infection of liver cells.

Soluble E-selectin enhances intercellular adhesion molecule-1 (ICAM-1) expression in human tumor cell lines.

E-selectin mediates neovascularization via its soluble form, while its membrane-bound form initiates binding of tumor cells to vascular endothelium. Therefore, it was studied whether soluble E-selectin regulates further adhesion molecules on tumor cells. In tumor cells but not in related nonmalignant cells, intercellular adhesion molecule (ICAM)-1 expression was strikingly increased from 5 to 68% positive cells by in vitro inoculation of a recombinant E-selectin-IgG1 within 24 h, as analyzed by flow cytometry. The absence of changes in the expression of vascular cell adhesion molecule, integrin ligands (CD11a, CD18, integrin alpha 4), and sialyl-Lewis X indicates a specific effect of soluble E-selectin on ICAM-1. A cell adhesion assay revealed that the enhanced adhesion on T-cells to tumor cells mediated by soluble E-selectin-induced ICAM-1 expression was at a maximum after a 12-h incubation period. Therefore, ICAM-1 regulation on tumor cells might be a mechanism of immune escape.

Parenchymal and nonparenchymal liver cells and their interaction in the local immune response.

Nonparenchymal liver cells (Kupffer cells, sinusoidal endothelial cells, Ito-cells and liver-associated lymphocytes) interact with hepatocytes and with each other by soluble mediators and direct cell-cell contact. The acute phase response is a nonspecific reaction of the organism to trauma, injury or infection and its main constituents the acute phase proteins are produced by hepatocytes. The profile of acute phase protein production is influenced by the local presence of cytokines with IL-6 as the principal regulator. Nonparenchymal cells (Kupffer cells, sinusoidal endothelial cells and Ito-cells) are a source of IL-6 and therefore participate in the generation of acute phase response. The release of IL-10 by Kupffer cells with consecutive down-regulation of IL-6 production may be a mechanism by which resolution of acute phase response is achieved. Still, the mechanisms underlying chronic inflammation remain unclear. Concerning the antigen-specific immune response nonparenchymal liver cells have a number of important functions. They can act as antigen-presenting cells (Kupffer cells) or mediate effector functions (liver associated lymphocytes). Local interaction of nonparenchymal cells with hepatocytes can be mediated by cytokines and/or adhesion molecule expression which again may lead to mutual influence of immunological functions, e.g. TNF-alpha release by Kupffer cells may enhance MHC-II expression on hepatocytes and consequently augment antigen-presenting capacity leading to an improved antigen-specific immune response. Leukocytes are attracted and home to the liver by mechanisms poorly defined because the initial contact between leukocytes and macrovascular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between autoimmune liver diseases and viral hepatitis: clinical and serological characteristics in 859 patients.

An etiopathological link between hepatitis virus infection and autoimmune liver disease, in particular autoimmune hepatitis has been suggested. In some patients features of both viral and autoimmune disease are present. We have studied 352 patients with autoimmune liver disease and 507 patients with viral hepatitis for diagnostic characteristics as well as for evidence of an etiological connection. 38 of the 201 patients with hepatitis C (19%) and 42 of the 306 patients with hepatitis B (14%) had significant titres of autoantibodies (ANA, SMA or LKM). SLA autoantibodies were found exclusively in patients with autoimmune liver disease. LKM auto-antibody was found in only one of the 201 HCV patients. Evidence of past or present hepatitis B virus and past hepatitis A virus infection was most common in the hepatitis C virus patients and least common in autoimmune hepatitis. 28 of the 352 patients with autoimmune liver diseases tested positive in the second generation anti-HCV ELISA, but only five patients (two with autoimmune hepatitis, one with primary sclerosing cholangitis and two with primary biliary cirrhosis) were positive in confirmatory anti-HCV assays, and only in these could HCV-RNA be isolated. Autoimmune hepatitis patients had significantly higher transaminase, GLDH and IgG levels. HLA-B8, HLA-DR3 and HLA-DR4 were significantly more common in autoimmune hepatitis. Distinction between autoimmune liver disease and viral hepatitis C could be made reliably on clinical and laboratory grounds. Our data show that a link between hepatitis A, B, or C virus infection and autoimmune liver diseases is highly unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune hepatitis following hepatitis A virus infection.

A 7-year-old patient is reported who suffered from fatigue and jaundice due to chronic hepatitis. He had acquired hepatitis A virus infection in his community and communicated the disease to his German family 4 weeks later. While the other family members recovered from acute viral hepatitis A, the patient presented 10 weeks after the onset of hyperbilirubinemia (12 mg/dl) with the histology of chronic hepatitis, absence of markers for viral persistence, presence of autoantibodies against smooth muscle (1:320) and the asialoglycoprotein receptor (1:600), and marked hypergammaglobulinemia (3700 mg/dl), leading to the diagnosis of autoimmune hepatitis. The patient received immunosuppressive therapy, symptoms of liver disease disappeared, and autoantibodies cleared from circulation. The case is discussed in the context of a putative virus-induced autoimmune hepatitis in childhood. Autoimmune hepatitis may be induced by an external trigger. Hepatitis A virus infection is one of probably several triggers that may induce autoimmune hepatitis in predisposed individuals.