Osteopontin is involved in the formation of epithelioid granuloma and bile duct injury in primary biliary cirrhosis

Recently, it was shown that osteopontin (OPN) is involved as a chemoattractant cytokine in the recruitment of macrophages and T lymphocytes in the granulomas of diverse etiologies and also plays an important role in the production of autoantibodies and development of autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by immune-mediated bile duct damage with frequent epithelioid granulomas. In this study, the expression of OPN was immunohistochemically examined in 25 PBC and 52 control livers. Epithelioid cells within granuloma in PBC expressed OPN variably. These cells were also positive for CD68, suggesting their histiocyte/macrophage lineage. In addition, strong expression of OPN was seen in the cytoplasm of mononuclear cells infiltrating around granulomas and also damaged bile ducts in PBC. The number of such positive mononuclear cells and the ratio of OPN-positive cells/total infiltrating cells in portal tracts were higher in PBC than in controls. The majority of these OPN-positive cells were found to be IgG- or IgM-producing plasma cells. These suggest that in PBC, OPN is an important immune molecule in portal tracts, and contributes to the recruitment of mononuclear cells into epithelioid granuloma and also participates in bile duct injury via B-cell differentiation and plasma cell expansion.     

Molecular mechanisms of cholangiopathy in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is histologically characterized by chronic nonsuppurative destructive cholangitis (CNSDC) and the progressive loss of intrahepatic small bile ducts. Cellular immune mechanisms involving T-cell reaction are thought to be significantly involved in the formation of CNSDC and bile duct loss. In inflamed portal tracts of PBC, CD4⁺ T cells of Th1 type expressing IFN-γ or CXCR3 are aggregated and more commonly detected around injured bile ducts than Th2-type CD4⁺ T cells expressing IL-4 or CCR4, indicating that Th1-dominant cellular immunity plays a more-prominent role in recruitment of memory T-cell subsets in PBC and may be responsible for the progressive bile duct damage. Biliary epithelial apoptosis is demonstrated to be a major pathogenic process of bile duct loss in PBC. In CNSDC, several biliary apoptotic cells, an aberrant expression of Fas antigen (proapoptotic molecule) and decreased expression of bcl-2 and mcl-1 (antiapoptotic molecules) are found, although interlobular bile ducts express bcl-2 and mcl-2 but lack Fas. In addition, the upregulation of WAF1 and p53 related to biliary apoptosis is found in biliary epithelial cells of PBC, which may be due to cell senescence in response to genotoxic damage such as oxidative stress. Several steps and mechanisms during induction and progression of cholangitis and biliary apoptosis followed by bile duct loss are now being proposed in PBC, but future analysis of an etiopathogenesis to explain the characteristic histopathogenesis of PBC is required.     

Factors producing bile infarction and bile duct proliferation in biliary obstruction

To clarify the factors producing bile infarction and bile duct proliferation in obstructive jaundice, the incidence of the hepatic lesions and the serum levels of the bile constituents were examined in three rat models. (1) Ligation of the common bile duct induced bile infarction, bile duct proliferation, retention of bile in the liver, and elevation of the serum levels of total bilirubin and total bile acids. (2) The rats treated by choledochotomy had bile in the abdominal cavity, but there was no retention of bile in the liver. The degree of development of bile infarction was similar to that of the common bile duct ligation group, but bile duct proliferation was not found: the serum levels of total bilirubin and total bile acids were elevated. (3) In the rats subjected to partial bile duct ligation, bile infarction and bile duct proliferation were seen only in the lobes with ligation of the hepatic ducts: only slight or no elevation of the serum levels of total bilirubin and total bile acids was found. These data suggest that bile infarction is caused by the toxic action of bile constituents other than bilirubin and bile acids, absorbed into the blood from the obstructed biliary system, and that bile duct proliferation is due to mechanical factors following bile retention or direct actions of retained bile in the liver.     

Three-dimensional reconstruction of biliary pathways in primary biliary cirrhosis: a computer-assisted study

Bile ducts and ductules were traced by means of computerized three-dimensional reconstruction in seven patients with primary biliary cirrhosis, three of them in the early asymptomatic stage and four of them with late disease. A patient with cryptogenic cirrhosis was also studied. Loss of bile ducts was confirmed, and was greater in the late stages as expected. Reconstruction demonstrated amputation of bile ducts of various sizes ranging from less than 40 micron to more than 80 micron in external diameter. Amputation was sometimes seen in relation to granuloma formation. The main or side branches of ducts could be traced to zones of proliferated ductules which, in turn, often communicated with liver-cell plates. Clusters of atypical ductules could be seen to communicate with liver-cell plates but not with ductules and ducts. We concluded that proliferation of 'typical' ductules with well-defined lumens, characteristically seen in primary biliary cirrhosis, probably represents a means whereby bile continues to be drained from the liver in spite of interruption of ducts. Computerized three-dimensional reconstruction proved to be a rapid and accurate way of accumulating the necessary data.     

Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss

The pathogenesis of progressive bile duct loss in primary biliary cirrhosis remains unclear. In this study, the involvement of cellular senescence of biliary epithelial cells was examined in liver tissue samples from patients with primary biliary cirrhosis (n = 33), and compared with control diseased and normal livers (n = 83). In addition, cellular senescence was induced by oxidative stress in cultured mouse biliary epithelial cells. Biliary epithelial cells in small bile ducts in primary biliary cirrhosis, especially those in patients presenting with chronic non-suppurative cholangitis, frequently expressed senescence-associated beta-galactosidase, and senescence-associated p16(INK4) and p21(WAF1/CIP). In contrast, senescence-associated markers were rarely expressed in small bile ducts in control livers. The infiltration of myeloperoxidase-positive inflammatory cells into biliary epithelial cell layers was closely associated with the cellular senescence of biliary epithelial cells in early-stage PBC. Cellular senescence of cultured mouse biliary epithelial cells was induced by treatment with H2O2 via the p38MAPK-dependent pathway and nitric oxide-augmented H2O2-induced cellular senescence. Oxidative stress- and nitric oxide-mediated cellular senescence may be involved in bile duct lesions, which are followed by progressive bile duct loss in primary biliary cirrhosis.     

The enigma of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure (1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.     

Circulating activated B cells in primary biliary cirrhosis

Since patients with primary biliary cirrhosis (PBC) have evidence of abnormal function of the humoral immune system, we determined if B cells from patients with this disease show evidence of activation and can be stimulated by polyclonal activators. Using a reverse hemolytic plaque assay, it was found that patients with PBC had a significant increase in the number of circulating immunoglobulin-secreting cells, compared to normal controls and patients with chronic type B hepatitis virus (HBV) infection. However, the total number of activated cells was less than 1% of the total circulating B-cell population. Furthermore, we were unable to detect an increase in the expression of transferrin receptors, a membrane receptor associated with B-cell activation, in the majority of B cells in patients with PBC. In other studies, immunoglobulin production by lymphocytes from patients with PBC, when stimulated with the polyclonal activators pokeweed mitogen and Epstein-Barr virus (EBV), was reduced. This hyporesponsiveness was not due to a decrease in the number of B cells, as determined by staining with the monoclonal antibody anti-Leu 12. Furthermore, the decreased response of B cells to polyclonal activation in PBC patients was not due increased suppressor T-cell function, since EBV-stimulated cultures of lymphocytes from patients with PBC demonstrated diminished suppression of immunoglobulin-secreting cells after 14 days of culture compared to controls. These findings suggest that the humoral abnormalities in PBC are due to the activation of a small subpopulation of B cells rather than to generalized B-cell hyperactivity.     

The diagnosis and treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease of autoimmune etiology. The initial presentation of PBC is various from asymptomatic, abnormal liver biochemical tests to overt cirrhosis. The diagnosis of PBC is based on cholestatic biochemical liver tests, presence of antimitochondrial antibody and histologic findings of nonsuppurative destructive cholangitis. Although the diagnosis is straightforward, it could be underdiagnosed because of its asymptomatic presentation, or underrecognition of the disease. UDCA in a dose of 13-15 mg/kg is the widely approved therapy which can improve the prognosis of patients with PBC. However, one-third of patients does not respond to UDCA therapy and may require liver transplantation. Every effort to diagnose PBC in earlier stage and to develop new therapeutic drugs and clinical trials should be made.     

The limitations and hidden gems of the epidemiology of primary biliary cirrhosis

Epidemiology is expected to provide important clues to our understanding of the enigmatic etiopathogenesis of primary biliary cirrhosis (PBC). First, a systematic review of population based studies indicated a wide range in the yearly incidence (0.33–5.8/100.000) and point prevalence (1.91–40.2/100.000) rates. Though different ethnic representations may also contribute it is likely that methodological issues, based on the retrospective survey of diagnosed cases, and time trend play a major role, also in view of the prolonged asymptomatic period of the disease. Of note, the highest prevalence rates (35–40/100.000) were found in areas characterized by high medical awareness and easier access to healthcare. Second, the search for serum AMA in unselected population sera may identify the largest possible number of patients who have or will develop the disease. Indeed, a surprisingly high AMA prevalence rate, ranging between 0.43 and 1%, appears likely in the general population despite the lack of adequate work-up in most studies. Third, the median female to male ratio for PBC is classically accepted as 9–10:1 but is significantly lower for AMA prevalence (2.5:1), death certificates for PBC (4.3:1) and liver transplantation (6:1), thus suggesting that PBC in men may be underdiagnosed in early stages or manifest a more severe progression. Lastly, studies of both PBC and serum AMA prevalence among family members and monozygotic twins strongly support the role played by genetic factors in the etiopathogenesis of the disease. In conclusion, PBC epidemiology is far from being a closed case and the numerous open issues will be solved through a collaborative effort and powerful data mining tools.     

Complement profile in primary biliary cirrhosis

PBC is a chronic progressive liver disease of unknown etiology. Several abnormalities found in PBC support the hypothesis that it may be considered an autoimmune disease. Despite the complex and interesting relationship that exists between autoimmune disorders and the complement system, very few reports on the level of the serum complement component in PBC have been published, and most of these comprised only a few patients or analyzed only a scant number of the complement components. In the present study, sera of 73 PBC patients were analyzed for the levels of 10 complement components. It was found that the levels of most of the serum complement components, including C1q, C2, C3, C5, C7, properdin and factor B were significantly elevated in patients with PBC in comparison to healthy controls. The level of C4 was slightly lower than that of the normal controls (p = 0.019), while the levels of C6 and C8 were within the normal range. The number of PBC patients with serum levels of C4 and C6 < 60% of normal pooled serum was higher than in the respective control groups (6/69 compared with 0/26 and 4/71 compared with 0/27, respectively). However, the difference was not statistically significant. Thus, our study shows alterations in the levels of most complement components in PBC, the reasons for which are discussed.     

Surgical treatment of primary biliary cirrhosis and primary sclerosing cholangitis

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are progressive cholestatic liver diseases of supposed auto-immune etiology. The clinical course is unpredictable and, in many patients, leads to end-stage liver disease or a poor quality of life. Conservative therapy only has a limited effect on the natural history, but orthotopic liver transplantation (OLT) offers a definitive therapeutic option. Retrospective analysis was performed for 38 patients with PBC and 17 patients with PSC who underwent OLT between January 1986 and June 2003 at our institution. Median follow-up after OLT was 72 mo. Cumulative survival at 5 yr post-OLT was 84% in the PBC group and 73% in the PSC group. Compared with OLT for other benign diseases, actuarial survival rates at 5 and 10 yr post-OLT were significantly better for patients with PBC, whereas there was no difference in survival after OLT for patients with PSC. Survival rate at 5 yr post-OLT was significantly increased for patients with PBC who had a Child-Pugh B liver cirrhosis (93%) compared with those who had Child-Pugh C cirrhosis (60%). Retransplantation rate was 18.2% (resulting from biliary complications in three cases). Surgical techniques had no effect on outcome after OLT in both groups. We concluded that liver transplantation represents a safe and beneficial therapy for patients with end-stage PBC. Cirrhotic patients with PSC also benefit from OLT, with an outcome comparable to that of liver cirrhosis of other etiologies.     

重建外周免疫耐受抑制原发性胆汁性肝硬化的实验研究

目的 以原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)自身抗原诱导PBC小鼠重建外周免疫耐受,探索PBC免疫治疗的新途径.方法 将M2蛋白与新生小鼠的脾淋巴细胞及交联剂1-乙基-3(3-二甲基氨阿基)碳化二亚胺(ECDI)共培养,形成抗原负载的淋巴细胞,随后通过尾静脉注入小鼠体内诱导免疫系统对PBC自身抗原的免疫耐受,同时注射聚肌苷酸胞苷酸(polyI:C)诱导PBC病变,对照组注射与牛血清白蛋白(BSA)共培养的脾细胞,16周后观察小鼠的各项实验室指标,分析重建PBC小鼠外周免疫耐受是否能够有效地阻止病变产生或缓解病程.结果 抗线粒体抗体(AMA):免疫耐受组与BSA对照组、模型对照组相比阳性率显著降低,差异有统计学意义(P=0.007,P=0.003);BSA对照组和模型对照组间无明显差异(P=0.74);免疫耐受组、BSA对照组、模型对照组的碱性磷酸酶(AKP)水平分别为(80.5±9.8)U/L、(93.8±15.7)U/L、(92.5±17.7)U/L;其中BSA组和模型组差异无统计学意义(P=0.83),而免疫耐受组低于BSA组(P=0.0095)和模型对照组(P=0.029);免疫耐受组、BSA对照组、模型对照组的胆管阳性浸润率分别为42.67%±12.30%、57.07%±11.35%、51.53%±9.96%;其中免疫耐受组阳性浸润率低于模型对照组,差异有统计学意义(P=0.039),同时显著低于BSA对照组(P=0.0024),而且BSA对照组和模型对照组比较差异无统计学意义(P=0.167).结论 本实验通过重建外周免疫耐受,在一定程度上抑制了PBC小鼠的病变程度,为今后进一步研究PBC的免疫治疗提供思路.

Abstract：

Objective To investigate a new therapeutic pathway for primary biliary cirrhosis (PBC) by immune tolerance reestablishment in a PBC mouse model. Methods Spleenic cells from naive mice were incubated with M2 in the presence of ECDI and the ceils were injected into caudal vein of the mice which would be used for development of PBC model. Spleenic cells incubated with bovine serum albumin (BSA) were injected as controls. 16 weeks later, anti-mitoehondrial antibody (AMA) , alkaline phosphatase(AKP) and portal inflammation were assayed for evaluating the prevention effect. Results AMA positive rate in tolerance group was lower than that in BSA and PBC groups ( P = 0. 007, P = 0. 003 ). The difference between BSA and PBC was not significantly. Serum AKP levels in tolerance, BSA and PBC group were (80.5 ±9.8) U/L, (93.8 ±15.7) U/L and (92.5 ±17.7) U/L, separately. The level in tolerance group was lower than that in BSA and PBC groups (P =0.0095, P =0.029). The rates of portal areas with cell infiltration were 42. 67% ± 12. 30% , 57. 07% ± 11. 35% and 51. 53% ± 9. 96% , separately. The number of infiltrated portal tracts in tolerance group was less than that in PBC group (P = 0.039) and BSA group (P = 0. 0024). Conclusion PBC was prevented to some extent by reestablishing immune tolerance to M2 autoantigen. This provides clues for finding a better treatment proposal.     

Immunohistochemical analysis of adhesion molecules in the micro-environment of portal tracts in relation to aberrant expression of PDC-E2 and HLA-DR on the bile ducts in primary biliary cirrhosis

We have examined immunohistochemically the expression of adhesion molecules in the micro-environment of portal tracts and their relationship to the expression of the pyruvate dehydrogenase E2 complex (PDC-E2) and HLA-DR in liver biopsy specimens. Ten cases of primary biliary cirrhosis (PBC) and 19 controls were examined, including four cases of extrahepatic biliary obstruction, six of chronic viral hepatitis, and nine normal livers. In PBC, the damaged small bile ducts demonstrated an increased expression of PDC-E2 and an aberrant expression of HLA-DR; about half of these damaged bile ducts also expressed intercellular adhesion molecules (ICAM)-1 and a few expressed vascular adhesion molecule (VCAM)-1. In addition, lymphocyte function-associated antigen (LFA)-1 and very late antigen (VLA)-4 were expressed on infiltrating lymphocytes around these bile ducts. In contrst, in control livers, these alterations in antigen expression on the bile ducts were either not observed or were only focal and weak, when present. These findings suggest that ICAM-1/LFA-1 and also VCAM-1/VLA-4 linkages between the damaged bile ducts and lymphocytes may facilitate antigen-specific reactions such as the presentation of antigens, possibly PDC-E2, to the periductal lymphocytes in PBC. ICAM-1, VCAM-1, and E-selectin were strongly expressed on the endothelial cells of some vessels in the portal tracts in PBC, suggesting the facilitation of the recruitment of lymphocytes around the of some vessels in the portal tracts in PBC, suggesting the facilitation of the recruitment of lymphocytes around the bile ducts of PBC. VCAM-1, a member of the immunoglobulin superfamily, has not hitherto been reported on bile ducts.     

Infectious agents in the pathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria, Escherichia Coli, and Nosphingobium aromaticivorans are the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.     

Severe hypercholesterolemia and phytosterolemia with extensive xanthomas in primary biliary cirrhosis: Role of biliary excretion on sterol homeostasis

Primary biliary cirrhosis (PBC) is an autoimmune, chronic, cholestatic liver disease that affects primarily women. PBC is commonly associated with hypercholesterolemia that has been associated with cholestasis. We report an exceptionally high blood cholesterol and phytosterols with just mild cholestasis indicating a selective defect in sterol biliary secretion in a patient with PBC.     

Solving the primary biliary cirrhosis puzzle: The emerging image of immunopathology in primary biliary cirrhosis

The role of adaptive as well as innate immune responses in the pathology of primary biliary cirrhosis (PBC) has been a major subject of investigation. Primary biliary cirrhosis is an autoimmune liver disease involving the destruction of small bile ducts, which eventually leads to liver cirrhosis. Adaptive immune responses involving autoantibody production by B cells and autoreactive T cells have been labeled as the most probable mediators of tissue destruction. Autoantibody production against mitochondrial antigens is used as a key diagnostic marker in PBC, being present in 90-95% of patient sera. Besides blood, these antimitochondrial antibodies are found in liver, bile, saliva, and urine of patients and target mitochondrial autoantigens that are well conserved between species. One possible mechanism of antibody-mediated tissue destruction is via the transcytosis of immunoglobulin A antimitochondrial antibodies through biliary epithelium. Another mechanism may involve the recognition by antimitochondrial antibodies of the mitochondrial autoantigens abnormally expressed on patient biliary epithelium. The second component of the adaptive immune response in PBC involves T cells, which comprise a large fraction of infiltrating leukocytes in diseased livers. Autoreactive CD4⁺ and CD8⁺ T cells recognizing mitochondrial antigens targeted by antimitochondrial antibodies have been isolated with specificity for epitopes that overlap with those of B cells. Cytokines production of such infiltrates indicates the involvement of both T_H1 and T_H2 responses in the diseased tissue. Besides adaptive responses, innate immunity effector mechanisms involving eosinophils, macrophages, and B cells hyperresponsive to bacterial DNA CpG motifs has been implicated in the pathology of PBC. Despite research efforts, the etiology of PBC still remains elusive, although theories involving the participation of genetic factors, molecular mimicry due to microorganisms, and a role for modification of native autoantigens by xenobiotics have been proposed.     

Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)

Summary Staging of liver biopsy specimens from patients with chronic non-suppurative destructive cholangitis (CNDC or syndrome of primary biliary cirrhosis) has become an important part of clinical studies that are currently done in many centers. Therefore, staging methods should be based on uniform criteria that are applicable to all specimens and are easily reproducible. Most pathologists staging CNDC use the system proposed by Scheuer and modified slightly by Popper and Schaffner; and generally these methods serve well. But the features relied upon as characteristic of the earlier phases of CNDC (namely, inflammatory destruction of intrahepatic bile ducts and proliferation of ductules) are not always present in biopsy specimens from early cases, and occasionally they coexist with more advanced lesions, such as bridging necrosis.We suggest a new staging system, based on our experience with 219 individual biopsy specimens from 101 patients with well established CNDC. Our proposed criteria are: stage I — portal hepatitis; stage II — periportal hepatitis; stage III — septal fibrosis or bridging necrosis, or both; and stage IV — cirrhosis. In most instances, we found these features easy to recognize, and one or another of them was always present. Intra-observer and interobserver variations were small. Experience with the proposed staging system indicates that stages III and IV are encountered 3 or 4 times as commonly as stages I and II. Incidence of inflammatory bile duct destruction seemed to vary little from stages I to II. Cholestasis and positive copper stains were most common in stages III and IV.

---

Zusammenfassung Die histologischen Stadien der chronisch-destruierenden, nichteitrigen Cholangitis (CNDC oder Syndrom der primÄren biliÄren Zirrhose) müssen genau bestimmt werden, um (1) den Krankheitsablauf zu verfolgen und damit — in weiten Grenzen — die Lebenserwartung einzelner Patienten zu bestimmen, und (2) um den Erfolg von Behandlungsversuchen an Patientengruppen zu bewerten. Die histologischen Stadien der CNDC werden meist nach der Methode von Scheuer oder, in leichter Abwandlung, nach der von Popper und Schaffner bestimmt. Diese Methoden funktionieren ausgezeichnet, wenn die für die Frühstadien namengebenden VerÄnderungen (entzündliche Gallengangszerstörung und Proliferation der GallenkanÄlchen) im PrÄparat sichtbar sind. Leider ist das in manchen FÄllen nicht so, oder die histologischen VerÄnderungen, die die Frühstadien kennzeichnen sollen, kommen gemeinsam mit den Merkmalen spÄterer Stadien vor.Auf Grund unserer Erfahrungen mit 219 LeberbiopsieprÄparaten von 101 Patienten mit nachgewiesener CNDC möchten wir eine neue Stadieneinteilung vorschlagen. Die Einteilungskriterien sind: Stadium I — portale Hepatitis; Stadium II — periportale Hepatitis; Stadium III — septale Fibrose oder Brückennekrose, oder beides; und Stadium IV — Zirrhose. Die namengebenden histologischen VerÄnderungen waren leicht zu erkennen und in jedem PrÄparat vorhanden. Die Einteilungsergebnisse waren gut reproduzierbar, sowohl vom gleichen Untersucher als auch von 2 verschiedenen Untersuchern. Die Stadien III und IV fanden sich in unserem Material drei- bis viermal hÄufiger als die Stadien I und II. Entzündliche Gallengangszerstörung fand sich in den Stadien I und II mit etwa gleicher HÄufigkeit. FÄrbbares Gallen- und Kupferpigment war am hÄufigsten in den Stadien III und IV.

     

IgA class antibodies to 2-oxo-acid dehydrogenase complex are not predictive markers of histopathological progression in primary biliary cirrhosis

Although antimitochondrial antibody (AMA) is the characteristic serological feature of primary biliary cirrhosis (PBC), its pathogenic role remains unclear. In our previous study, we reported a positive correlation between immunoglobulin (Ig) A class anti-2-oxo-acid dehydrogenase complex (2-OADC) and histopathological stage. To determine whether the appearance of IgA class anti-2-OADC by immunoblotting represents an early marker of more aggressive disease or whether it is late finding during the disease course of PBC, we tested not only the entire IgA class but also IgA1, IgA2 and secretory IgA class anti-2-OADC in serial serum samples from 15 patients with PBC. During the median observation period of 51 months, four cases showed histopathological progression (from stage 1 to 2, stage 1 to 3, stage 1 to 4 and stage 2 to 4). There was no statistically significant correlation between the above IgA class anti-2-OADCs and histopathological progression. There was no significant correlation between histopathological stages and IgA2 class anti-2-OADC or secretory IgA class anti-2-OADC by immunoblotting. IgA class anti-2-OADC was more frequent in stages 3–4 than in stages 1–2 (p = 0.0049), but IgA1 class anti-2-OADC was more frequent in stages 1–2 than in stages 3–4 (p = 0.0232). Our present study demonstrated that serum IgA class 2-OADC was not a predictive marker of histopathological progression but was associated with the histopathological stage of PBC. Although the IgA class AMA may have a specific pathogenic role for PBC, the discrepant results between IgA and IgA1 class anti-2-OADC should be further assessed to investigate different functional activities depending on their molecular form.     

Unusual hepatocellular lesions in primary biliary cirrhosis resembling but unrelated to hepatocellular neoplasms

Summary Structural, cellular and nuclear abnormalities of hepatocytes are a histological hallmark of well-differentiated, small hepatocellular carcinoma (HCC) or its borderline lesion. This study revealed that several hepatocellular abnormalities found in these hepatocellular neoplasms were also found in non-cirrhotic stages of primary biliary cirrhosis (PBC) in which HCC is unlikely to develop. These changes are small cell changes, consisting of the appearance of small hepatocytes arranged in thin trabecular or compact patterns with increased cellularity and basophilic cytoplasm. This was found in 36%, 71% and 100% in specimens of stages 1, 2 and 3, respectively. Large cell changes occurred and consisted of large hepatocytes with large nuclei and prominent nucleoli, found in 27%, 47% and 22% of the stages, respectively. Finally, liver cell rosettes were seen, showing variable acinar formation and present in 0%, 41% and 33% of the stages, respectively. These lesions were identified microscopically as irregularly shaped areas or vague nodules of hepatocytes without a fibrous rim, in the hepatic lobules. They showed an expansive growth or shaggy border against the surrounding hepatic parenchyma. Follow-up studies, including autopsies, failed to show development of HCC or its borderline lesion in PBC cases. Pathologists must make a diagnosis of HCC and its borderline lesion bearing in mind the occurrence of such unusual hepatocellular lesions probably of a reactive nature.     

Isotypic distribution of anti-pyruvate dehydrogenase antibodies in patients with primary biliary cirrhosis and their family members

IgG subclasses of anti-pyruvate dehydrogenase (PDH) antibodies were determined in 72 patients with primary biliary cirrhosis. All isotypes were detected, but IgG3, IgG1, and IgG2 predominated independently or in association. An average of 33.3±19.1% of the anti-PDH IgG was IgG1 (mean optical density, 0.863±0.783, vs 0.053±0.038 in the normal controls), 25.0±17.8 IgG2 (0.652±0.656 vs 0.062±0.030), 39.5±23.4% IgG3 (1.140±0.917 vs 0.010±0.023), and 2.4±7.4% IgG4 (0.060±0.182 vs 0.012±0.007). Anti-PDH IgG were restricted to IgG1 in the family members of patients (0.180±0.403).