Antimitochondrial Antibody-Negative Primary Biliary Cirrhosis

Objectives : We reviewed our experience with patients who had biochemical and histological features of primary biliary cirrhosis in the absence of antimitochondrial antibodies (AMA) to better understand this variant of the syndrome. Methods : During the period between 1976 to 1992, 597 patients with clinical and histological features of primary biliary cirrhosis were seen at the Mayo Clinic. Thirty-five (5.8%) of these patients were negative for antimitochondrial antibody and had normal cholangiographic studies. The records of these patients were reviewed for this study. Results : No difference was found between the two groups with respect to age, gender, or biochemical features. IgM and γ-globulin levels were higher in the antimitochondrial antibody-positive than the antimitochondrial antibody-negative patients. What is more important, 96% of the AMA-negative patients who could be tested were positive for antinuclear antibody or anti-smooth-muscle antibodies. These tests were positive in only 56% of the antimitochondrial antibody-positive group (p < 0.05). The response of five of these patients to ursodeoxycholic acid appeared comparable to the response seen in antimitochondrial antibody-positive patients. Conclusions : Patients with histological features of primary biliary cirrhosis, whether antimitochondrial antibody positive or negative, are quite comparable with respect to clinical and biochemical features. Other autoantibodies, such as antinuclear or anti-smooth-muscle antibodies, are more common in the antimitochondrial antibody-negative group. These two conditions might be part of a spectrum that has been termed "autoimmune cholangitis" and that is characterized by chronic cholestasis, histological features of chronic nonsuppurative destructive cholangitis, and the presence of any of a variety of serum autoantibodies.     

Celiac disease-associated autoimmune cholangitis

There is an association between celiac disease (CD) and primary biliary cirrhosis, but there is little information regarding the association between CD and autoimmune cholangitis (antimitochondrial antibody-negative primary biliary cirrhosis). We describe a case of a 60-yr-old woman with chronic serum liver biochemistry elevations, recent onset of pruritus, and unexplained iron deficiency anemia. Liver biopsy was suggestive of stage 1 primary biliary cirrhosis, but serum antimitochondrial antibody testing was negative. Subsequent evaluation revealed CD based on markedly elevated antiendomysial antibody titers and characteristic histological features on mucosal biopsies. Initiation of a gluten-free diet led to resolution of iron deficiency anemia, pruritus, and elevated serum liver biochemistries. This suggests that CD may play a direct role in the development of autoimmune cholangitis. Additionally, normalization of hepatic biochemistries may be achieved without the use of immunosuppressive agents in some patients. CD should be considered in all patients diagnosed with autoimmune cholangitis as a gluten-free diet may avoid the need for immunosuppressive therapy in affected patients.     

Familial primary biliary cirrhosis and autoimmune cholangitis

AIM: Autoimmune cholangitis has been proposed as a separate disease entity from primary biliary cirrhosis without serum antimitochondrial antibodies. The ultimate answer to the question of whether autoimmune cholangitis and primary biliary cirrhosis are distinct will require detailed comparison of aetiologic factors and pathogenic mechanisms. METHODS AND RESULTS: Two families are described each of which has one member with classical antimitochondrial antibody positive biopsy-proven primary biliary cirrhosis and a first degree relative with antimitochondrial antibody negative but antinuclear antibody positive autoimmune cholangitis (biopsy proven in one case). Study of such families should allow analysis of the contribution of shared genetic risk factors versus varying environmental triggering mechanisms to disease pathogenesis. CONCLUSIONS: We suggest a European registry of families, such as the two described, which are rare within one centre, to facilitate elucidation of pathogenetic factors.     

Expression of bcl-2 in ductular proliferation is related to periportal hepatic stellate cell activation and fibrosis progression in patients with autoimmune cholestasis

AIM: To study bcl-2 expression in ductular proliferation cholangiocytes and hepatic stellate cell activation in liver biopsies from patients with autoimmune cholangitis and primary biliary cirrhosis. MATERIALS AND METHODS: Twenty-four primary biliary cirrhosis patients and 11 autoimmune cholangitis patients were included. Thirty-four females, average age: 52.5+/-12.6 years. We studied the presence of ductular proliferation, cholestasis, florid ductal lesion, granulomata, ductopenia and histologic stage. Patients were classified in primary biliary cirrhosis or autoimmune cholangitis according to antimitochondrial antibodies, antinuclear antibodies, smooth muscle antibody, antiGP210 and antiSP100 autoantibodies. We studied the presence of bcl-2 by monoclonal antibcl-2 antibody (clon 100, BioGenex). The presence of activated (specific antialpha-actin antibodies) and independent lobular, periportal and portal hepatic stellate cell was assessed using a semiquantitative scale. RESULTS: Interlobular ducts bcl-2 was seen in 18 (51.4%) patients. Activated periportal hepatic stellate cell correlated with Ludwig's stage (r=0.43; n=35; p=0.01). Ten out of 15 (66.6%) patients with ductular proliferation showed positive interlobular ducts bcl-2 while bcl-2 was negative in 8 out of 20 (40%) patients without ductular proliferation; p<0.05. Bcl-2 positive patients in ductular proliferation showed a more advanced Ludwig's stage (2.33+/-0.77 versus 1.26+/-1.05; p<0.05) and a higher periportal hepatic stellate cell activation index (0.83+/-0.78 versus 0.23+/-0.43; p=0.009). No relationship was found among periportal hepatic stellate cell activation and the presence of florid ductal lesion, cholestasis, granulomata or biliary erosive necrosis. Hepatic stellate cell activation was similar in patients with either autoimmune cholangitis or primary biliary cirrhosis. CONCLUSIONS: Periportal hepatic stellate cell activation seems to play a main role in fibrosis progression in patients with autoimmune cholestasis. Bcl-2 expression in ductular proliferation may promote hepatic stellate cell activation and fibrosis.     

Recurrence of primary biliary cirrhosis, autoimmune cholangitis and primary sclerosing cholangitis after liver transplantation

Given the usually prolonged natural history of primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis, and the relatively recent introduction of orthotopic liver transplantation, our understanding of recurrence of these autoimmune diseases after orthotopic liver transplantation has been slow to evolve. Present data suggest that after orthotopic liver transplantation, patients with primary biliary cirrhosis will have persistence of serum antimitochondrial antibodies, develop histologic lesions suggestive of recurrent primary biliary cirrhosis with a frequency in the 8% to 16% range at 2 to 5 years after orthotopic liver transplantation, but will demonstrate little if any symptomatic disease as a consequence. Although data are extremely limited, autoimmune cholangitis patients will have a similar post-transplant course (without antimitochondrial antibodies). Recurrence of primary sclerosing cholangitis remains the most controversial, however, these patients probably develop nonanastomotic intrahepatic and extrahepatic strictures more frequently than patients without primary sclerosing cholangitis, with a frequency in the 20% to 25% range at 3 to 5 years. With longer patient follow-up and additional studies, it is hoped that our understanding of recurrent autoimmune biliary diseases will grow considerably in the future.     

The Overlap Syndromes of Autoimmune Hepatitis

Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7–13 %, and the frequency of overlap with primary sclerosing cholangitis is 8–17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4-associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13–15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied.     

Overlap syndromes

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.     

Histopathologic comparison of anti-mitochondrial antibody-positive primary biliary cirrhosis and autoimmune cholangiopathy

The present study aimed to investigate whether antimitochondrial antibody (AMA)-positive primary biliary cirrhosis (PBC) and AMA-negative PBC with autoantibodies differ histologically, especially with respect to infiltrating cells in portal tracts involved by chronic non-suppurative destructive cholangitis. Liver specimens were stained from 15 primary biliary cirrhosis with AMA (group 1), nine patients consistently negative for AMA but positive for antinuclear antibodies (ANA) (group 2). Group 2 showed overlapping features of PBC and autoimmune hepatitis type 1, in a pattern recently termed autoimmune cholangiopathy (AIC). We analyzed the cell population, including lymphocytes, plasma cells, large histiocytes, eosinophils and neutrophils, which had infiltrated portal tracts involved by destructive lesions. Although serum immunoglobulin M levels were higher in group 1 compared to those in group 2 (P=0.0282), patients of both groups were broadly comparable with respect to clinical features and laboratory data. Histologically, the number of plasma cell and its percentage among inflammatory infiltrating cells in the portal tract were higher in group 2 than in group 1 (P=0.0015, P=0.0070, respectively). The percentage of lymphocyte infiltration among inflammatory infiltrating cells in the portal tract were higher in group 1 than in group 2 (P=0.0052). The percentage of plasma cell infiltration among inflammatory infiltrating cells in the portal tract was correlated to immunoglobulin G levels in group 2 (r=0.949, P=0.0016). In conclusion, AMA-positive PBC and AIC showed differences in inflammatory cell population in involved portal tracts in this preliminary study.     

The demography of primary biliary cirrhosis in Ontario, Canada

The demographics of primary biliary cirrhosis in Ontario, Canada, are described. Two hundred and twenty-five primary biliary cirrhosis patients were identified by 85 of 502 gastroenterologists (or internists) practicing in Ontario acute care hospitals that have 150 or more beds. Two hundred and six patients were verified as being antimitochondrial antibody-positive, resulting in an incidence of 3.26 per million per year and a prevalence of 22.39 per million. Questionnaire data were obtained on 88.5% of these patients. Twenty-nine percent of the patients were found to be asymptomatic. Geographical clustering and racial predisposition were not seen. No increase in breast cancer prevalence was noted. By the time the diagnosis of primary biliary cirrhosis was established, the patients had consulted a median number of 3.5 physicians. Fatigue was reported as the most disabling symptom. The diagnosis of primary biliary cirrhosis in patients referred from across the province of Ontario was independently confirmed by us, using standard criteria (antimitochondrial antibody testing and liver biopsy), and was found to be reliable.     

Chronic hepatitis C and autoimmune cholangitis: a case study and literature review

We present a case of a chronic hepatitis C with damage of bile ducts resembling primary biliary cirrhosis. The immunological profile (negative antimitochondrial antibodies and positive anti-nuclear antibody) was characteristic of the autoimmune cholangitis. One year of treatment with ursodeoxycholic acid returned the liver tests to the normal range but the liver lesions remained unchanged.     

Anti-Sp100 and anti-Gp210 in the diagnosis of primary biliary cirrhosis in patients with autoimmune cholangitis

We describe 2 women with features of autoimmune cholangitis. Serum biochemical studies showed cholestasis and increased immunoglobulin M with negative antimitochondrial antibodies. Markers of hepatitis B and C viruses were absent. Both had positive antinuclear antibodies. One had a speckled pattern (multiple nuclear dots) and the other a perinuclear pattern (pore nuclear). In the first case anti-Sp100 was positive by EIA and in the second anti-Gp210 was detected by immunoblot. Diagnosis of primary biliary cirrhosis was made and the patients were treated with UDCA. Current knowledge indicates that determination of anti-Sp100 and anti-Gp210 substantially improves diagnosis of primary biliary cirrhosis as these ANA are highly specific for this disease. These autoantibodies may lead to the classification of different groups of patient included in autoimmune cholangitis. All patients with autoimmune cholangitis should be tested for anti-Sp100 and anti-Gp210.     

Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis

Murine models of autoimmunity allow the study of the earliest events in disease pathogenesis. Our laboratory has developed a xenobiotic induced model of primary biliary cirrhosis (PBC) following immunization of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA), an antigen selected following quantitative structure-activity relationship analysis of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the immunodominant autoantigen of PBC. Recent data in humans with PBC has suggested that a major component of liver pathology is due to activation of innate immunity. We took advantage of our 2-OA-BSA model and immunized mice with and without the addition of α-galactosylceramide (α-GalCer), an invariant natural killer T cell activator. Importantly, we report herein that 2-OA-BSA-immunized mice exposed to α-GalCer develop a profound exacerbation of their autoimmune cholangitis, including significant increases in CD8(+) T-cell infiltrates, portal inflammation, granuloma formation, and bile duct damage. Furthermore, such mice produce increased levels of antimitochondrial antibodies and have evidence of fibrosis, a feature not previously reported in the murine models of PBC. CONCLUSION: Our data suggests a primary role of innate immunity in the exacerbation of autoimmune cholangitis and also become a logical explanation for the recurrence of PBC following liver transplantation in the absence of major histocompatability complex compatibility. We submit that PBC begins with loss of tolerance to PDC-E2 and a multilineage antimitochondrial response in which autoreactive CD8(+) T cells are critical. However, the perpetuation of disease and its exacerbation will also be modulated by innate immune mechanisms.     

Heterogeneity of antimitochondrial antibodies with the M2-M4 pattern by immunofluorescence as assessed by Western immunoblotting and enzyme linked immunosorbent assay.

Seventy seven sera with antimitochondrial antibody exhibiting the M2-M4 pattern in immunofluorescence (56 from primary biliary cirrhosis (PBC), 21 from non-primary biliary cirrhosis patients) were studied by the combined use of Western immunoblotting with beef heart mitochondria and an enzyme linked immunosorbent assay (ELISA) with beef heart submitochondrial particles. Forty seven sera (10 without autoantibodies and 37 with different auto-antibodies) were included as controls. By immunoblotting, seven mitochondrial peptides reacting with antimitochondrial antibody positive sera were detected. These were of molecular weight 74 kD, 58 kD, 55 kD, 52 kD, 51 kD, 46 kD, and 43 kD. All primary biliary cirrhosis sera and 71% of antimitochondrial antibody-positive non-primary biliary cirrhosis sera reacted with one or more of these peptides, while none of the 47 antimitochondrial antibody negative sera reacted in immunoblotting. The 74 kD band was the most frequently detected (84% of primary biliary cirrhosis and 57% of non-primary biliary cirrhosis cases). All the primary biliary cirrhosis sera which failed to react with this peptide, showed a positive reaction with that of molecular weight 52 kD. 67/77 (87%) immunofluorescence antimitochondrial antibody positive sera reacted in the ELISA test (93% of primary biliary cirrhosis and 71% of non-primary biliary cirrhosis cases). All the 47 immunofluorescence antimitochondrial antibody negative sera were confirmed negative by ELISA. The ELISA values correlated with the immunofluorescence titres (p less than 0.05). By comparison of the results obtained by these two techniques, it emerged that the ELISA test (using our preparation of submitochondrial particles) was not able to detect the antibody directed against the mitochondrial peptide of 52 kD, which thus seems to be different from the other specificities.     

Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis

An antinuclear immunofluorescence pattern displaying a thin ring confined to the nuclear envelope was assessed in sera from 38 patients with primary biliary cirrhosis and in sera from a control group of 277 patients with other antinuclear antibody-positive diseases. This rim-like antinuclear reactivity was present in sera from 20 primary biliary cirrhosis patients (52.6%) but in only two patients from the control group (0.7%) (p less than 0.001). Furthermore, this autoantibody was present in three of four primary biliary cirrhosis patients without antimitochondrial antibodies. Presence of this rim-like pattern in primary biliary cirrhosis did not correlate with the presence of associated autoimmune diseases nor with other clinical, biochemical, nor histological features of the disease. The antigenic specificity of sera displaying this antinuclear immunofluorescence pattern was characterized by Western blot analysis using an antigenic extract containing nuclear envelope proteins purified from rat liver. Sixteen of the 20 positive sera showed a common pattern of reactivity with a set of nuclear envelope-associated proteins approximately 200 kD in size. In conclusion, sera from primary biliary cirrhosis patients showing a rim-like fluorescent nuclear pattern have antinuclear autoantibodies that react specifically with components of the nuclear envelope. The high specificity of these new autoantibodies in primary biliary cirrhosis indicate that they might be a serological marker of the disease, particularly useful in patients without antimitochondrial antibodies.     

Relationship between apoptasis, tumour necrosis factor, cell proliferation in chronic cholestasis

BACKGROUND: Target of the immune response in chronic autoimmune cholestasis, is the bile duct epithelium. Lymphocytic infiltration and apoptosis have both been suggested to mediate the destruction of hepatocytes and biliary epithelium in primary biliary cirrhosis. AIMS: To further address this issue in two cholestatic liver diseases characterized by an autoimmune pathogenesis and, furthermore, evaluate the relationship between apoptosis and both tumour necrosis factor alpha and cell proliferation. METHODS: Liver tissue specimens from 16 patients with primary biliary cirrhosis, 15 with primary sclerosing cholangitis, and 16 with chronic hepatitis C (controls) were evaluated. DNA-fragmentation of apoptotic cells was ascertained by the TdT-mediated deoxyuridine triphosphate nick-end labelling method. Tumour necrosis factor alpha expression and cell proliferation (Ki-67 antigen) were assayed by immunohistochemistry. RESULTS: Hepatocytes with DNA fragmentation were observed in 75% of patients with primary biliary cirrhosis, in 66.6% with primary sclerosing cholangitis, and in 43.7% with chronic hepatitis C. Biliocytes showed apoptosis in only 3 cases of primary biliary cirrhosis. Biliocytes showed a strong cytoplasmic expression in 4 cases (1 primary biliary cirrhosis, 2 primary sclerosing cholangitis and 1 chronic hepatitis C). A few intralobular and portal inflammatory mononuclear cells expressing tumour necrosis factor alpha were observed in 62.5% of patients with primary biliary cirrhosis, 46.1% with primary sclerosing cholangitis, and 56.2% with hepatitis C virus chronic hepatitis. The amount of intraportal mononuclear cells expressing Ki-67 antigen was significantly higher in primary biliary cirrhosis specimens than in primary sclerosing cholangitis (p<0.001) or hepatitis C virus-related chronic hepatitis (p<0.03). No correlation was found within the 3 groups of patients between the Ki-67 histological score and the severity of liver disease. Moreover, no relationship was found between TdT-mediated deoxyuridine triphosphate nick-end labelling and either tumour necrosis factor alpha or Ki-67 staining. CONCLUSIONS: Apoptosis is a phenomenon which frequently involves hepatocytes in chronic autoimmune cholestasis. This process is apparently parallel, but unrelated to cell proliferation. Cell proliferation mainly involves mononuclear cells in portal tracts of primary biliary cirrhosis specimens. The finding of tumour necrosis factor alpha expression in biliocytes deserves further study to establish whether this cytokine is involved in triggering bile duct lesions.     

Reactivities and clinical relevance of antimitochondrial antibodies to four mitochondrial inner membrane proteins in sera of patients with primary biliary cirrhosis

Antimitochondrial antibodies are characteristically detected in sera of patients with primary biliary cirrhosis. The antigens to which the antimitochondrial antibodies in primary biliary cirrhosis sera react have been located in the mitochondrial inner membrane. We have reported on four mitochondrial inner membrane proteins, extracted from beef heart, which reacted with antimitochondrial antibodies of primary biliary cirrhosis. These four proteins had molecular weights of 70, 54, 51 and 45 kd. Forty-six of the 50 PBC sera tested were positive with rat kidney and stomach specimens by the indirect immunofluorescent method. All sera of 50 primary biliary cirrhosis patients were positive with at least one and as many as four of the mitochondrial proteins extracted from beef heart using immunoblotting. Forty-seven primary biliary cirrhosis sera (94%) had IgG antibodies (antimitochondrial antibodies) to the antigen proteins, 43 patients (86%) IgM antimitochondrial antibodies and 38 patients (76%) IgA antimitochondrial antibodies. Seventy per cent of patients had antimitochondrial antibodies in all three immunoglobulin classes. In a few primary biliary cirrhosis sera, antimitochondrial antibodies were represented by only one class of immunoglobulin. The major antigenic proteins of mitochondrial inner membrane to which the antimitochondrial antibodies react were the 70 and 51 kd proteins. All primary biliary cirrhosis sera containing antibodies to the 54 and/or 45 kd proteins reacted with 70 kd as well. Patients with an elevation of serum bilirubin over 2 mg per dl were often found to produce antimitochondrial antibodies reactive with the 54 kd in addition to the 70 kd protein. No significant association was found between histological classifications and reactive patterns of antimitochondrial antibodies.     

Similar T-Cell Oligoclonality in Antimitochondrial Antibody-Positive and -Negative Primary Biliary Cirrhosis

Approximately 5% of patients with clinical and histological features suggestive of primary biliary cirrhosis do not have anti-mitochondrial antibodies that can be detected by current methodologies. Although the role of these autoantibodies in the pathogenesis of liver disease is uncertain, T lymphocytes within the portal tracts are felt to be important mediators of bile duct destruction. In order to investigate the hypothesis that a similar T-cell process may be involved in both antimitochondrial antibody-positive and -negative primary biliary cirrhosis, we characterized the oligoclonally expanded T cells in both types of patients by analysis of complementarity determining region 3 length in peripheral blood mononuclear cells. The distribution of oligoclonally expanded T cells was similar in both groups. This finding does not support a distinct T-cell-mediated pathogenesis for anti-mitochondrial antibody-positive and -negative primary biliary cirrhosis but rather suggests that similar processes may be involved in the immunopathogenesis of both.     

Immunohistochemical analysis of inflammation in primary sclerosing cholangitis.

OBJECTIVES: There are only limited data about the nature of the mononuclear infiltrate surrounding the affected biliary canaliculi in primary sclerosing cholangitis (PSC). The aim of this study was to characterize the composition of the mononuclear infiltrate and to detect signs of activation/ proliferation among the various subpopulations involved. Furthermore the putative role of the biliary epithelium as antigen presenting cells (APC) was assessed. METHODS: Liver biopsies of 14 PSC patients were analysed. Seven liver specimens of non-inflammatory liver disease (NIL) patients with hepatocellular carcinoma or metastasis from colorectal carcinoma, as well as eight liver biopsies of primary biliary cirrhosis (PBC) patients, served as controls. Paraffin embedded material was stained with GB7, anti-CD3, anti-CD20, anti-CD45RO. Deep frozen sections were stained with anti-CD4, anti-CD8, anti-CD25, anti-CD86, anti-HLA-DR, anti-IFNgamma, anti-IL4, anti-ICAM1 and anti-alpha4beta7. Stainings were scored by two pathologists using a semiquantitative scale. RESULTS: The portal infiltrate was found to consist mainly of CD3+CD45RO+ cells. Few cells expressed activation or proliferation markers in any of the liver specimens. In the PSC-material, significantly more of the infiltrative lymphocytes were positive for the integrin alpha4beta7, as compared to hardly any positive cells in the NIL-group (P < 0.001) and < 10% in the PBC-specimens (P < 0.01). Variable HLA-DR expression of the biliary epithelium was observed in all groups, however, without co-expression of ICAM1 or B7.2. CONCLUSIONS: The portal infiltrate in PSC liver histology specimens appears to consist mainly of non-activated memory T-lymphocytes, a substantial proportion of which expresses the gut-homing integrin alpha4beta7. An antigen-presenting role for the biliary epithelium could not be demonstrated.     

Prevalence of autoimmune liver disease in Alaska Natives

OBJECTIVE: There is limited information on the prevalence of autoimmune liver disease in nonwhite populations. We conducted a population-based study on the prevalence of autoimmune liver diseases in Alaska natives. METHODS: Clinical records from 1984 to July, 2000 were reviewed to identify Alaska natives with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, autoimmune cholangitis, and overlap syndromes of two of the above. AIH was defined as definite or probable, based on criteria established by the International Autoimmune Hepatitis Group. The diagnosis of PBC was based on a positive antimitochondrial antibody of > or = 1: 40, biochemical evidence of cholestasis, and compatible liver biopsy. Autoimmune cholangitis was defined as PBC but without a positive antimitochondrial antibody. Primary sclerosing cholangitis was diagnosed on the basis of cholangiogram. RESULTS: Seventy-seven patients with possible autoimmune liver disease were identified. Of these, 42 had definite and seven probable AIH. At presentation, 34.7% of patients with AIH presented with acute icteric hepatitis, and 65.3% were asymptomatic. Persons presenting with mild or no symptoms were more likely to have moderate to severe fibrosis on liver biopsy than those presenting with jaundice. Eighteen persons were diagnosed with PBC, five with autoimmune cholangitis, five with overlap syndrome, and none with primary sclerosing cholangitis. The combined point prevalence of AIH Alaska natives was 42.9/100,000 (95% CI = 31-57.7). The prevalence of PBC was 16/100,000 (95% CI = 12.9-25.4). CONCLUSIONS: This population-based study demonstrates that the prevalence rates of AIH and PBC in Alaska natives are comparable with reported rates in other populations.