Lack of Concomitant Expression of ICAM-1 and HLA-DR on Bile Duct Cells from Patients with Primary Sclerosing Cholangitis and Primary Biliary Cirrhosis

In both primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) prominent infiltrates of lymphocytes surround the bile ducts, on which an abberrant expression of major histocompatibility complex class II antigens has been found, suggesting that the immune system is involved in the biliary destruction. Since the lymphocytes presumably must adhere to the bile ducts to initiate a cell-to-cell-mediated destruction, we have studied the expression of the lymphocyte function-associated antigen-1 (LFA-1) together with its ligand, the intercellular adhesion molecule-1 (ICAM-1), and the expression of HLA-DR, using immunoperoxidase staining of cryostat sections from patients with PBC (n = 10), PSC (n = 13), and normal healthy controls (n = 6). Most lymphocytes expressed LFA-1. ICAM-1 expression was found on hepatocytes from 9 of 10 PBC and 10 of 13 PSC patients but was not seen on hepatocytes from the controls. Hepatocytes expressing HLA-DR were only found in one patient with PBC. None of the septal bile ducts expressed ICAM-1, and only one PSC patient and three PBC patients expressed ICAM-1 on their interlobular bile ducts. The bile ducts in 22 of 23 patients, however, expressed HLA-DR. Proliferating bile ductules from two PBC patients and three PSC patients showed a concomitant expression of ICAM-1 and HLA-DR. None of the bile ducts from the controls expressed ICAM-1 or HLA-DR. Thus, since most bile ducts involved in the disease process of both PBC and PSC lack expression of ICAM-1, other adhesion molecules must be involved if a cell-to-cell-mediated destruction accounts for the biliary destruction in these two disease states. Furthermore, the lack of concomitant expression of HLA-DR and ICAM-1 on the bile ducts in PBC and PSC indicates that other regulatory mechanisms exist in the biliary epithelium than in most other epithelial cells.     

Expression of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 protein and messenger RNA in primary biliary cirrhosis

OBJECTIVE: This study examined the role of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) in the autoimmune process of bile duct destruction in the early stages of primary biliary cirrhosis (PBC). MATERIALS AND METHODS: Ten PBC liver samples and five control samples were studied. Immunohistochemical studies of ICAM-1 and LFA-1, and Western blot of ICAM-1 were performed. Immunoelectron microscopy was conducted using immunoglobulin-gold and silver staining. Human ICAM-land LFA-1 peptide nucleic acid probes were used for in situ hybridization. RESULTS: In PBC liver samples, immunohistochemistry showed aberrant ICAM-1 expression on bile duct epithelial plasma membrane and also luminal sites of endothelial plasma membrane of terminal portal venules. Western blot confirmed ICAM-1 protein expression. LFA-1-positive lymphocytes were associated with epithelial cells of septal and interlobular bile ducts. Immunoelectron microscopy localized ICAM-1 on the luminal and basal surfaces as well as on lymphocytes around damaged bile duct epithelial cells, and LFA-1 on lymphocytes around damaged bile ducts. Messenger RNA expression of ICAM-1 was demonstrated in bile ducts, and LFA-1 in lymphocytes around bile ducts. CONCLUSION: De novo expression of ICAM-1 and LFA-1 at protein and mRNA levels in PBC may imply an inductive role of ICAM-1 through binding with its ligand LFA-1 in the extravasation of activated lymphocytes and lymphocyte-mediated bile duct destruction.     

Expression of adhesion molecules on mature cholangiocytes in canal of Hering and bile ductules in wedge biopsy samples of primary biliary cirrhosis

AIM: To examine the expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) expression on canals of Hering (CoH) and bile ductules associated with the autoimmune process of bile duct destruction in primary biliary cirrhosis (PBC). METHODS: Ten wedged liver biopsies of PBC (five cases each of stages 2 and 3) were studied. The liver specimens were processed for transmission electron microscopy. Immunohistochemistry was performed using anti-ICAM-1 and anti-LFA-1 mouse mAbs. In situ hybridization was done to examine the messenger RNA expression of ICAM-1 in formalin-fixed, paraffin-embedded sections using peptide nucleic acid probes and the catalyzed signal amplification (CSA) technique. Immunogold-silver staining for electron microscopy was performed using anti-ICAM and anti-LFA-1 mouse mAbs. The immunogold particles on epithelial cells of bile ductules and cholangiocytes of CoH cells were counted and analyzed semi-quantitatively. Western blotting was performed to confirm ICAM-1 protein expression. RESULTS: In liver tissues of PBC patients, immunohi-stochemistry showed aberrant ICAM-1 expression on the plasma membrane of epithelial cells lining bile ductules, and also on mature cholangiocytes but not on hepatocytes in CoH. LFA-1-positive lymphocytes were closely associated with epithelial cells in bile dcuctules. ICAM-1 expression at protein level was confirmed by Western blot. In situ hybridization demonstrated ICAM-1 mRNA expression in bile ductules and LFA-1 mRNA in lymphocytes infiltrating the bile ductules. By immunoelectron microscopy, ICAM-1 was demonstrated on the basal surface of epithelial cells in bile ductules and on the luminal surfaces of cholangiocytes in damaged CoH. Cells with intermediate morphology resembling progenitor cells in CoH were not labeled with ICAM-1 and LFA-1. CONCLUSION: De novo expression of ICAM-1 both on mature cholangiocytes in CoH and epithelial cells in bile ductules in PBC implies that lymphocyte-induced destruction through adhesion by ICAM-1 and binding of LFA-1-expressing activated lymphocytes takes place not only in bile ductules but also in the CoH.     

Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1

BACKGROUND/AIMS: Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been implicated in the susceptibility to a range of inflammatory diseases, including inflammatory bowel disease (IBD). Primary sclerosing cholangitis (PSC) is an immune-mediated chronic cholestatic liver disease associated with IBD. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts in late stage PSC and serum levels of soluble intercellular adhesion molecules are increased in PSC. The aim of this study was to analyse ICAM-1 gene polymorphisms in PSC patients. METHODS: In this study, 104 patients with PSC and 213 healthy controls were recruited from Oxfordshire Caucasians. PCR with sequence-specific primers (PCR-SSP) was used to detect both ICAM-1 biallelic polymorphisms G241R and K469E. The results were controlled for the HLA haplotypes associated with PSC. RESULTS: The E/E frequency of K469E in PSC was 12% (12/104), significantly lower than that in controls (24%, 51/213;P = 0.009; Pc = 0.02; OR, 0.41). The occurrence of the haplotype G241-E469/G241-E469 in PSC was 4% (4/104), significantly lower than the control group (13%, 28/213; P = 0.01; Pc = 0.04; OR, 0.26). There was no difference between PSC and control groups in the frequencies of the genotype R241G or in allele frequencies of K469E. CONCLUSIONS: The E469E homozygote status for ICAM-1 is associated with protection against PSC.     

Is the intercellular adhesion molecule-1/leukocyte function associated antigen 1 pathway of leukocyte adhesion involved in the tissue damage of alcoholic hepatitis?

Alcoholic hepatitis is characterised histologically by an intense inflammatory cell infiltrate made up predominantly of neutrophils but including other cell types, particularly lymphocytes. Leukocyte cytotoxicity requires cell adhesion, which is mediated via receptors on the leukocyte surface including leukocyte function associated antigen-1 (LFA-1) which binds to the ligand intercellular adhesion molecule-1 (ICAM-1) on the target cell. The distribution of ICAM-1 and LFA-1 expression in liver biopsy specimens from patients with alcoholic liver disease was examined to ascertain whether this pathway of leukocyte adhesion is involved in the tissue damage of alcoholic hepatitis. Specimens were stained for ICAM-1 and LFA-1 by a three step immunoalkaline-phosphatase method using monoclonal antibodies against ICAM-1 and LFA-1. LFA-1 staining on portal tract inflammatory cells and parenchymal inflammatory cells and ICAM-1 staining on liver components were examined. ICAM-1 expression on hepatocytes was significantly greater in alcoholic hepatitis compared with fatty liver (p less than 0.001) and normal controls (p less than 0.01). ICAM-1 expression correlated with the histological degree of hepatocellular damage (tau = 0.79; p = 0.0005) and parenchymal inflammation (tau = 0.65; p less than 0.001, and with LFA-1 expression on parenchymal leukocytes (tau = 0.63; p = 0.01). The ICAM-1/LFA-1 pathway may therefore be involved in leukocyte mediated tissue damage during alcoholic hepatitis.     

Decreased anion exchanger 2 immunoreactivity in the liver of patients with primary biliary cirrhosis

Chloride-bicarbonate anion exchanger 2 (AE2) is expressed in a variety of tissues, including the liver and salivary glands, where it may participate in the generation of hydroionic fluxes into secretions. We have previously reported decreased hepatic levels of AE2 messenger RNA in patients with primary biliary cirrhosis (PBC), a cholestatic condition frequently associated with pluriglandular exocrine failure. Here we investigated the expression of AE2 protein in the liver of PBC patients. Using a monoclonal antibody against an AE2 peptide, immunohistochemistry was performed on liver biopsy specimens from subjects with normal liver (n = 7), patients with PBC (n = 13), and patients with cirrhosis or cholestasis other than PBC (n = 17 and 11, respectively). Immunostaining was graded from 0 to 7, according to its intensity and distribution. AE2 immunoreactivity was observed in normal livers, as previously reported, and in many pathological liver biopsy specimens, being mainly restricted to canaliculi and the luminal membrane of terminal and interlobular bile ducts. Canalicular and ductular scores were significantly reduced in the PBC group compared with each control group (normal liver and cirrhosis or cholestasis other than PBC), whereas no differences in immunoreactivity scores were observed among control groups. When four patients with primary sclerosing cholangitis (PSC) were analyzed, they also differed from those with PBC. These results suggest that PBC is characterized by diminished expression of AE2 in the liver. Reduced levels of this transporter protein might be involved in the pathogenesis of cholestasis in PBC.(Hepatology 1997 Jan;25(1):12-7)     

Increased gall bladder volume in primary sclerosing cholangitis.

BACKGROUND: The diagnosis of primary sclerosing cholangitis (PSC) requires invasive procedures such as liver biopsy and endoscopic retrograde cholangiography (ERC). Sonographic measurement of fasting gall bladder volume, which has been reported to be enlarged in PSC, could serve as a non-invasive screening test. METHODS: Fasting gall bladder volume was studied in patients with PSC (n = 24), primary biliary cirrhosis (PBC, n = 13), liver cirrhosis due to other causes (n = 18), ulcerative colitis (n = 15), and healthy controls (n = 23). Meal induced gall bladder emptying was studied in patients with PSC, patients with PBC, and healthy controls. RESULTS: In patients with PSC gall bladder volume was greatly enlarged (72.9 (SEM 3.7) ml) compared with healthy controls (25.4 (1.7) ml, and patients with PBC (30.9 (2.7) ml), liver cirrhosis (31.3 (4.0) ml) or ulcerative colitis (25.8 (2.0) ml) (p < 0.0005 v all). In four patients with PSC the gall bladder wall was irregularly thickened (> 4 mm) as previously described in PSC. Postprandial residual fractions (% of fasting volume) were comparable between patients with PSC (17.5 (3.7)%) and those with PBC (23.6 (7.1%) and healthy controls (12.7 (2.3)%) Although gall bladder emptying seems normal, increased biliary pressure in patients with PSC cannot be excluded. CONCLUSION: Apart from wall thickening, patients with PSC often present with enlargement of the gall bladder. Sonographic determination of fasting gall bladder volume may be a useful, non-invasive, and easy to perform tool in the evaluation of patients suspected of having PSC.     

Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis

The expression of HLA class I (HLA-A, B, C) and class II (HLA-DR) antigens on the biliary epithelium of 10 patients (nine men) with primary sclerosing cholangitis (PSC) was investigated using an immunoperoxidase technique on cryostat sections. Five patients were staged as grade II and five grade III on hepatic histology. None were cirrhotic. as grade II and five grade III on hepatic histology. None were cirrhotic. Controls were nine patients with primary biliary cirrhosis (PBC), five with extra hepatic biliary obstruction, 15 with other forms of chronic liver disease and six with normal livers. Bile ducts from the normal subjects and patients with chronic liver disease did not express HLA-DR antigens. In contrast, all 10 of the PSC biopsies showed varying degrees of HLA-DR staining of the biliary epithelium. Expression of DR antigens was also found on the bile ducts of all five patients with extra hepatic biliary obstruction and in six of nine patients with PBC. Expression of HLA class I antigens was seen on the biliary epithelium of all the biopsies examined. Increased numbers of helper and suppressor T-cells were seen in the portal tracts of all the PSC patients. This study has confirmed that aberrant expression of HLA-DR may occur on the biliary epithelium of some, but not all, patients with PBC. In addition, the study has shown that aberrant expression of HLA-DR always occurs in PCS at an early stage of histological liver damage. While this may be important in the pathogenesis of PSC, the aberrant expression in extra hepatic biliary obstruction suggests that it may be a secondary phenomenon.     

Diagnostic approach to primary sclerosing cholangitis: open questions.

Over the last ten years the incidence of primary sclerosing cholangitis (PSC) presented a progressive increase, showing an association with chronic inflammatory bowel disease (IBD) in 50-70% of the cases. Nowadays, however, the prevalence of PSC is still unknown, mainly because of its difficult identification. In contrast to primary biliary cirrhosis (PBC), which is strongly associated with the presence of anti-mitochondrial antibodies (AMA) in serum, a similar reliable diagnostic marker has not yet been demonstrated in PSC. In this review we tried to investigate the controversial diagnostic aspects which may interfere with the initial assessment of PSC syndrome. Alkaline phosphatase (ALP) and endoscopic retrograde cholangiography (ERC) are actually the two cornerstones of the clinical setting, but if alone, they do not seem to provide sufficient accuracy. Furthermore, liver biopsy, perhaps more sensitive but not always specific, is generally performed too late. In our opinion, epidemiologic studies are needed in Italy and elsewhere in order to evaluate PSC prevalence. Moreover, the analysis of these results might lead to an earlier detection of the disease and, perhaps, favourably modify its natural history.     

Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis

BACKGROUND/AIMS: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) has been implicated in the aberrant homing of intestinal lymphocytes to the liver in primary sclerosing cholangitis (PSC). Intercellular adhesion molecule-1 (ICAM-1) has also been implicated in the pathogenesis of PSC and the E/E genotype of the K469E polymorphism has been reported to be associated with PSC susceptibility. The aims of this study were to determine if MAdCAM-1 polymorphisms or the K469E polymorphism of ICAM-1 are associated with PSC in Scandinavia. METHODS: Seven single nucleotide polymorphisms (SNPs) in MAdCAM-1 and the G421R and K469E ICAM-1 SNPs were genotyped in 365 PSC patients from Norway and Sweden. 327 Norwegian ulcerative colitis (UC) patients and 368 Norwegian bone marrow donors served as controls. RESULTS: No significant association with PSC was found for any of the MAdCAM-1 or ICAM-1 SNPs. Allele frequencies for these polymorphisms were not significantly different between PSC patients with UC, UC patients and healthy controls. CONCLUSIONS: Polymorphisms in MAdCAM-1 are not likely to significantly affect PSC susceptibility. In addition, the E/E genotype of the K469E in ICAM-1 does not influence PSC susceptibility in Scandinavia.     

Detection of male DNA in the liver of female patients with primary biliary cirrhosis

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by progressive inflammatory destruction of bile ducts, with eventual hepatic fibrosis and cirrhosis. Since primary biliary cirrhosis affects predominantly middle-aged women and has pathological similarities to hepatic graft-versus-host-disease, we investigated whether fetal cell microchimerism might be involved in the development of this disease. METHODS: The presence of Y-chromosome-specific sequences was analyzed by polymerase chain reaction using peripheral blood mononuclear cells from women with primary biliary cirrhosis (n=18) and healthy (control) women (n=18), and by in situ hybridization of liver biopsy sections from women with primary biliary cirrhosis (n=19) and women with chronic hepatitis C or alcoholic liver disease (n=20). RESULTS: Male cells were detected in liver biopsy specimens of 8 of 19 patients (42%) with primary biliary cirrhosis. Y-chromosome-containing cells were not seen in any of the liver biopsy specimens from women with chronic hepatitis C or alcoholic liver disease. Male cells were detected in peripheral blood mononuclear cells from one healthy control at a level of 1 male cell per 10(6) female cells, but were not detected in peripheral blood mononuclear cells of women with primary biliary cirrhosis. CONCLUSIONS: The presence of male cells in the liver of women with primary biliary cirrhosis raises the possibility that fetal cell microchimerism may be involved in the pathogenesis of this chronic liver disease.     

Myeloperoxidase-positive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions

Previous studies have suggested that increased nitric oxide (NO)-mediated products are found in the livers of subjects with primary biliary cirrhosis (PBC), but the mechanisms involved remain enigmatic. We took advantage of immunohistochemistry and several unique monoclonal antibodies to study inflammatory cells responsible for the generation of NO, the enzymes responsible for NO production, the expression of 3-nitrotyrosine, and the presence of CD68(+) and/or myeloperoxidase (MPO)(+) cells. We examined a total of 113 liver specimens, including 64 with PBC, 19 with primary sclerosing cholangitis (PSC), 6 with non-A, non-B hepatitis, 6 with alcoholic liver disease, 4 with cryptogenic cirrhosis, 4 with biliary atresia, and 10 normal subjects. Twenty-two percent of PBC had elevated expression of 3-nitrotyrosine in their bile duct epithelial cells (BECs) (P =.0316). Furthermore, the BECs in PBC also demonstrated apoptotic changes. MPO-positive inflammatory cells were also noted adjacent to the basement membrane. In contrast, the liver of normal subjects showed few apoptotic changes in the bile ducts, with no evidence of MPO staining in the portal area. Furthermore, sections from livers of subjects with stage I or stage II PBC demonstrated significantly increased inflammatory cell infiltration (P =.0064) and elevated 3-nitrotyrosine expression in BECs (P =.0246) compared with stage III and IV. The presence of 3-nitrotyrosine was closely associated with infiltrating CD68- and/or MPO-positive cells. There was also a stage-associated difference in the presence of bile duct infiltrating cells and 3-nitrotyrosine in PBC with an increase dominant in early stage disease. In conclusion, NO and reactive oxygen species, collectively determined as 3-nitrotyrosine, are associated with bile duct destruction in PBC and are particularly prevalent in early stage disease.     

Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 microm in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P <.0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases.     

Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P < .0001) and histological (0.79, P < .0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F) > or =2, 0.95 for F > or =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed F > or =2, F > or =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.     

Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis

Reovirus type 3 (Reo-3) infection has recently been implicated in the pathogenesis of certain idiopathic, cholestatic liver diseases of newborns. In the present study, antibody titres to Reo-3 virus (anti-Reo-3) were determined in sera from 43 adults with idiopathic cholestatic liver disease, including 34 patients with primary biliary cirrhosis (PBC) and 9 patients with primary sclerosing cholangitis (PSC). Seventy-four adults with various other causes of chronic liver disease and 16 healthy volunteers served as controls. Geometric mean titres of anti-Reo-3 were significantly higher in PBC and PSC sera than chronic liver disease and healthy controls (P less than 0.005). Mean antibody titres for all patient groups, however, were within the 95% confidence limits for normals. Seven of 34 (21%) PBC patients and 3/9 (33%) PSC patients had elevated titres of anti-Reo-3, as compared to only 4/74 (5%) chronic liver disease (P less than 0.05) and 0/16 (0%) healthy control subjects (P less than 0.05) (Fisher's Exact Test). Antibody titres to five other common viruses were normal in patients with high anti-Reo-3 titres when compared to age- and sex-matched controls with liver disease. Immunoperoxidase staining for Reo-3 viral markers and cultures of liver biopsy material for Reo-3 virus were negative in both patients and controls. The results of this study indicate that, although patients with PBC and PSC have higher anti-Reo-3 antibody titres than patients with other forms of chronic liver disease or healthy volunteers, only a minority of these patients have titres that exceed the 95% confidence limits for normals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis

Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis (PBC). However, the benefit from UDCA therapy on the progression of PBC from its early stage towards extensive fibrosis and cirrhosis has not been clearly shown. The aim of this study was to assess the effect of UDCA therapy on liver fibrosis progression in PBC. A Markov model was used to analyze the progression rates between early and late histologic stages in 103 patients with PBC enrolled in a randomized, double-blind, placebo-controlled trial of UDCA. Early stage was defined by the presence of portal and periportal lesions without extensive fibrosis, whereas late stage was defined by the presence of numerous septa, bridging fibrosis, or cirrhosis. A total of 162 pairs of liver biopsy specimens were studied. The model accurately described the observed data. UDCA therapy was associated with a 5-fold lower progression rate from early stage disease to extensive fibrosis or cirrhosis (7% per year under UDCA vs. 34% per year under placebo, P <.002), but was not associated with a significant difference in regression rates (3% per year under both UDCA and placebo). At 4 years, the probability of UDCA-treated patients to remain in early stage disease is 76% (95% confidence interval: 58%-88%), as compared with 29% (15%-52%) in placebo-treated patients. In conclusion, UDCA therapy significantly delays the progression of liver fibrosis in PBC. Markov modeling should prove useful in assessing the efficacy of future medical treatments in clinical trials involving histologic endpoints.     

Autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome in adults: report of three cases

Overlap syndromes are cases of liver diseases that share clinical, serological, histological and radiological criteria of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). No definitions have been fully established and therefore there is no solid evidence on the diagnosis and treatment. This article presents the cases of three adult patients with overlapping features of AIH and PSC. Orthotopic liver transplantation was considered the best therapeutic alternative due to advanced disease progression in one patient, while medical treatment was provided in the remaining two patients.     

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected.IgM and IgG-positive plasma cells were counted in each sample.RESULTS:A predominance of IgG-positive plas...     

Increased prevalence of primary biliary cirrhosis near Superfund toxic waste sites

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are uncommon liver diseases of unknown etiology. Reported clustering of PBC cases may be due to environmental factors. Individuals with PBC have a high prevalence of thyroid disease and thyroid disease is reportedly more prevalent near Superfund toxic waste sites (SFS). The objective of this study was to examine the prevalence and potential clustering of individuals with PBC and PSC near SFS. De-identified clinical and demographic data were used to determine the observed prevalence for each New York City zip code (n = 174) and borough (n = 5) of patients with PBC (PBC-OLT) or PSC (PSC-OLT) who were listed for liver transplantation. The expected prevalence was calculated using Organ Procurement and Transfer Network (OPTN) and U.S. Census data. Both PBC-OLT patients and patients not listed for liver transplantation (PBC-MSSM) were included in the cluster analysis. Prevalence ratios of PBC-OLT and PSC-OLT cases were compared for each zip code and for each borough with regard to the proximity or density of SFS, respectively. SaTScan software was used to identify clusters of PBC-OLT cases and PBC-MSSM cases. Prevalence ratio of PBC-OLT, not PSC-OLT, was significantly higher in zip codes containing or adjacent to SFS (1.225 vs. 0.670, respectively, P = .025). The borough of Staten Island had the highest prevalence ratio of PBC-OLT cases and density of SFS. Significant clusters of both PBC-OLT and PBC-MSSM were identified surrounding SFS. In conclusion, toxin exposure may be a risk factor influencing the clustering of PBC cases.     

Role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model

Intercellular adhesion molecule-1 (ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti-ICAM-1 and anti-LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r =.58, P <.05) between day 3 and 28. Treatment with anti-ICAM-1 (but not anti-LFA-1) decreased both the mean grades of portal inflammation (P =.003) and NSDC (P =.002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti-ICAM-1 and anti-LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti-ICAM-1, alone (P =.02). Anti-ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P <.01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti-ICAM-1 nor anti-LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC.