The role of osteopontin and tumor necrosis factor alpha receptor-1 in xenobiotic-induced cholangitis and biliary fibrosis in mice.

Proinflammatory and profibrotic cytokines such as osteopontin (OPN) and tumor necrosis factor-alpha receptor-1 (TNFR(1)) may be critically involved in the pathogenesis of cholangiopathies and biliary fibrosis. We therefore aimed to determine the role of genetic loss of either OPN or TNFR(1) in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a model of xenobiotic-induced sclerosing cholangitis with biliary-type liver fibrosis using respective knock-out mice. OPN and TNFR(1) knock-out mice were fed a 0.1% DDC-supplemented diet for 4 weeks and compared with corresponding wild-type (WT) controls. Liver morphology (H&E staining), serum markers of liver injury and cholestasis (ALT, AP, bilirubin), markers of inflammation in liver (CD11b and F4/80 immunostaining, mRNA expression of iNOS, MCP-1, IL-1beta, INF-gamma, TNF-alpha and OPN), degree of ductular reaction (immunohistochemistry with morphometric analysis and western blotting for cholangiocyte-specific marker keratin 19) and degree of liver fibrosis (Sirius-red staining, hepatic hydroxyproline content for quantification) were compared between groups. DDC feeding in OPN and TNFR(1) knock-out mice and respective WT controls resulted in comparable extent of liver injury, inflammatory response, ductular reaction and liver fibrosis. Our data indicate that genetic loss of neither OPN nor TNFR(1) significantly effects on the pathogenesis of DDC-induced sclerosing cholangitis, ductular reaction and resulting biliary fibrosis.

Vasculitis of the gallbladder: case report and spectrum of disease.

Polyarteritis nodosa and microscopic polyangiitis involve small and medium-sized blood vessels. The majority of patients with microscopic polyangiitis have perinuclear antineutrophil cytoplasmic antibodies, usually antimyeloperoxidase (anti-MPO) antibodies. This report describes the first case of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) associated vasculitis presenting as, and manifesting predominantly with, cholecystitis. We review the spectrum of disease in small and medium-sized vessel arteritis of the gallbladder from localized arteritis that may not require treatment other than careful observation for the development of systemic disease to multiorgan involvement requiring aggressive immunosuppressive therapy.

18F-FDG PET/CT in an Atypical Case of Relapsed IgG4-Related Disease Presenting as Inflammatory Pseudotumor in Gall Bladder Fossa With Extensive Disease Involvement.

Immunoglobulin G4-related disease (IgG4-RD) with multisystem involvement is known to mimic various malignancies and can be diagnosed with high clinical suspicion. We hereby report an atypical case of IgG4-RD, who presented as an inflammatory pseudotumor resembling gall bladder malignancy with hepatic, omental, and subcutaneous involvement. The characteristic tracer uptake pattern described on FDG PET/CT may not be always present in IgG4-RD, especially in the setting of postabdominal surgery. FDG PET/CT revealed the disease progression despite glucocorticoids and aided in response evaluation after second-line drug, rituximab.

Epithelial Inclusions in Gallbladder Specimens Mimic Parasite Infection: Histologic and Molecular Examination of Reported Cystoisospora belli Infection in Gallbladders of Immunocompetent Patients.

Recent publications have described epithelial cytoplasmic vacuoles and inclusions incidentally noted within gallbladder epithelium and concluded that they represent coccidian parasite infection, in particular, Cystoisospora belli. We identified 8 gallbladder specimens from our institution in the past 3 years in which this diagnosis was suggested or in which similar epithelial alterations were prominent. Molecular analysis was performed on the 8 gallbladder specimens and on 3 positive control specimens: small bowel biopsies from acquired immunodeficiency syndrome patients with diarrhea. Polymerase chain reaction using primers designed to amplify an internal transcribed spacer (ITS2) in the C. belli ribosomal gene cluster was performed on the DNA samples. All 8 gallbladder specimens were negative for amplification, while a product consistent with C. belli was amplified from all 3 positive controls. Histologically, the gallbladder cytoplasmic inclusions stained diffusely positive for Grocott-Gomori's methenamine silver and Periodic acid-Schiff with diastase. In contrast, sections from a positive control small bowel biopsy demonstrated organisms that were negative for Grocott-Gomori's methenamine silver and showed a distinct capsular and punctate internal staining on Periodic acid-Schiff with diastase in various parasite forms. Together, the lack of molecular evidence of C. belli and the distinct morphologic and special staining patterns in these gallbladders compared with positive control small bowel suggest that these epithelial changes do not represent true C. belli infection. Our results suggest that gallbladders of immunocompetent patients may occasionally show epithelial changes that can morphologically mimic C. belli infection. Pathologists should be aware of this histologic variant to minimize unnecessary treatment, testing, and patient anxiety.

Tumor markers carbohydrate antigens CA 19-9 and CA-50 and carcinoembryonic antigen in pancreatic cancer and benign diseases of the pancreatobiliary tract.

Sera from patients with diseases in the pancreas, gallbladder, and bile duct were analyzed for the tumor markers CA 19-9, CA-50, and carcinoembryonic antigen. In particular CA 19-9 and CA-50 appear to be valuable in differentiating malignant from benign disease in these organs. Our sample of 72 patients with pancreatic cancer also indicates that CA 19-9 and CA-50 complement each other in 21% of the cases. They are also shown to be reliable for monitoring disease: following radical surgery for pancreatic cancer low levels of CA 19-9 and CA-50 were noted, while progressive rises of these tumor markers were related to disease progression.

Localized vasculitis of the gastrointestinal tract.

We studied the clinical and pathologic findings of 63 patients with localized vasculitis of the gastrointestinal tract, including 35 partial bowel resections, 14 cholecystectomies, five partial pancreatectomies, six appendectomies, one omentectomy, one gastrectomy, and one esophagectomy. Vasculitis was classified histologically as polyarteritis (n = 33), phlebitis (n = 12), Churg-Strauss angiitis (n = 8), small-vessel vasculitis (n = 6), Buerger's disease (n = 2), and giant-cell arteritis (n = 1). Nineteen of 33 cases of polyarteritis affected the small bowel or gallbladder, and nine patients with polyarteritis had elevated serum antinuclear antibodies or rheumatoid factor. Eight of 12 cases of phlebitis affected the right colon; there were giant cells in four of these 12 cases, a history of medication use in seven of eight cases, and no evidence of serum autoantibodies. Short-term follow-up (mean, 5 years) demonstrated that systemic disease developed in six of 23 patients with polyarteritis (four of whom had elevated serum rheumatoid factor or antinuclear antibodies), the patient with giant-cell arteritis, and one of two patients with Buerger's disease. Systemic vasculitis did not develop in patients with other types of vasculitis. We conclude that patients with gastrointestinal phlebitis, polyarteritis without serum autoantibodies, and small-vessel vasculitis have a low short-term risk for the development of systemic disease.

[Visible venous bloodflow in real-time abdominal sonography, possibly a sign of hepatitis B virus-induced, compensated immune hemolysis]. / Real-time hasi ultrahang vizsgálat során látható vénás vérkeringés, amely B-hepatitis vírus által indukált, kompenzált immun-haemolysis sonographiás jele lehet.

In 15 patients examined for the suspicion of hepatobiliary disease the venous blood flow was visible by the permanent circulation of soft particles in both the systemic and the portal veins with abdominal real-time ultrasonography. In order to clarify the background of the phenomenon there were extended laboratory examinations carried out. In the course of them the infectedness of the patients with Hepatitis-B virus, immune haemolysis and the disorder of the cellular immunity could be demonstrated. Similar visual phenomenon was found only in one patient suffering only from immune haemolysis, but no hepatic disease. The hepatic patients generally do not show the phenomenon. On the basis of these it is presumed that visible venous flow in real-time abdominal ultrasonography may be a sign of compensated immune haemolysis induced by Hepatitis-B virus infection.

[Immunoreactivity of patients with pathology of the liver, gallbladder and biliary tract]. / Immunoreaktivnost' u bol'nykh s patologiei pecheni, zhelchnogo puzyria i zhelchevyvodiashchikh putei.

In a work, the comparative analysis of the state of immunological reactivity in 25 patients with pathology of the liver, gallbladder and bile ducts and in 25 healthy subjects is presented. In patients, T-lymphocytopenia, impaired ratio of subpopulations of the helpers and suppressors, increase in the absorptive and metabolic activity of neutrophilic granulocytes, lysozyme activity of the blood serum, decrease in the immunoglobulin G content are observed.

Antibodies to Escherichia coli and anti-adhesive activity in paired serum, hepatic and gall bladder bile samples.

Human bile contains a mixture of immunoglobulins excreted through the liver and produced in the biliary tract. This study examines the specific antibody activity of the biliary immunoglobulins against Escherichia coli antigens. Paired samples of serum, hepatic bile, and gall bladder bile were obtained from 23 patients with gallstones and five patients with healthy gall bladders. Antibody activity against E. coli antigens was found in all the sera and most of the bile samples. The levels of IgA, IgM, IgG, and secretory component (SC)-combined antibodies were lower in bile than in serum. Selective treatment of IgA by the liver was suggested by the finding of a correlation between the serum and the bile IgA antibody activity. IgG antibodies were only found in inflamed gall bladders. The bile was shown to have antibacterial activity against E. coli, i.e. an ability to inhibit the attachment to epithelial cells, but the inhibitory activity was not restricted to the immunoglobulin fraction of the bile.

Antigen Dd reactivity in selected diseases.

The distribution of detectable antibodies against antigen Dd has been studied in rheumatoid arthritis, goitre, nephrotic syndrome, cirrhosis, gastrointestinal tract diseases, neurological diseases, liver and gall bladder diseases, breast cancer, respiratory diseases and cardiovascular diseases. Except in rheumatoid arthritis, breast cancer and nephrotic syndrome, where the incidence of antigen Dd-reactivity did not differ much from that in the control group, in all other disease it was significantly lower.

Relationship between colorectal liver metastases and CEA levels in gallbladder bile.

While computerized tomographic (CT) scanning and intraoperative exploration are both considered accurate measures of liver involvement with metastatic disease, 10% to 30% of colorectal liver metastases remain undetected. Attempting to improve current methods for detecting colorectal liver metastases, CEA levels in gallbladder bile and serum from patients with known liver metastases were determined. One hundred per cent of patients with single and multiple metastases of various dimensions were observed to have gallbladder bile CEA levels strikingly higher than serum values (4.7 to 259 times greater, p = 0.0009). Linear regression analysis of estimated tumor volume and surface area versus gallbladder bile CEA levels predicted that very small tumors (less than or equal to 1 cm3 in volume) might produce detectable levels (9 to 41 ng/mL) of biliary CEA. For this reason, patients who lack clinical and radiologic evidence of distant metastases at the time of primary colorectal resection but who do have elevated gallbladder bile CEA levels (greater than or equal to 10 ng/mL) are being followed for the appearance of occult hepatic metastases.

Bile secretory immunoglobulin A in biliary infection and cholelithiasis.

Bile samples from 71 patients with cholelithiasis and a control group of 10 subjects without hepatobiliary diseases were cultured for bacteria and measured for secretory immunoglobulin A (SIgA) using enzyme immunoassay specific for SIgA. The results of bile bacterial culture were all positive in patients with primary bile duct pigment stones, and significantly lower bile SIgA levels were observed than in normal controls (P less than 0.005). It was also shown that the constitutent ratios of SIgA to total bile immunoglobulin and the bile-serum ratio of SIgA were markedly lower in these patients than in normal controls (P less than 0.001, P less than 0.001). In patients with cholecystolithiasis, bile SIgA concentrations of patients with biliary infections were remarkably lower than those of patients without biliary infection (P less than 0.01) and those of normal controls (P less than 0.01). These results suggest a close relationship between biliary tract infection and low concentrations of bile SIgA.

Anatomical and immunological responses of rabbit gallbladders to bacterial infections.

To study the sequential morphological and immunological response of the rabbit gallbladder to bacterial infection and to compare the inflammatory responses with different pathogens, gallbladders were infected with Streptococcus faecalis and two strains of Escherichia coli, one of which produced enterotoxin. Gallbladder infection was produced either by intravenously injecting bacteria into rabbits with a small liver infarct or by injecting bacteria directly into the gallbladder of normal rabbits. The percentage of gallbladders infected intravenously with a nonenterotoxigenic E. coli strain was 86% at 1 week, 70% at 3 weeks, and 15% at 6 weeks. Epithelial necrosis and leukocyte infiltration were prominent 1 week after infection. At 3 and 6 weeks after infection, there was crypt distortion and increased mucus secretion in the epithelium as shown by periodic acid-Schiff staining. The lamina propria was infiltrated with mononuclear cells, many of which were plasma cells. Myofibroblasts (contractile fibroblasts) were also identified on transmission microscopy, In addition to these changes, toxigenic E. coli produced subepithelial capillary dilation in the villus core. Morphological changes (excluding toxin-associated changes) were related to the duration of infection rather than to the specific species of infecting bacteria. Infected gallbladders studied by immunofluorescence had a greater than 50-fold increase in plasma cells compared with control cells. In addition, the number increased with the duration of infection. Immunoglobulin A cells were the major cell type in gallbladders infected by intravesical injection, whereas immunoglobulin G cells predominated in gallbladders infected intravenously. The gallbladder appears to mount a local immune response to bacterial infection.

Asialoglycoprotein receptor in human isolated hepatocytes from normal liver and its apparent increase in liver with histological alterations.

We have characterized a binding site for galactosyl terminal glycoproteins in hepatocytes isolated from human biopsies. The binding of asialoorosomucoid on hepatocytes previously treated by Triton X-100 was saturable, calcium-dependent and highly affine (Ka = 1.11 +/- 0.87.10(9) M-1) thus corresponding to a ligand-receptor binding. The total number of receptors in the normal human liver was 140,000 +/- 65,000 sites per cell. This corresponded to the value obtained in the human hepatoma cell line HepG2, but was significantly lower than for isolated rat hepatocytes. Furthermore, in hepatocytes isolated from livers with histological features of either fibrosis, cirrhosis, hepatocarcinoma with cirrhosis or nodular regenerative hyperplasia, the number of asialoglycoprotein receptors per cell was increased, while the binding affinity was unchanged.