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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.

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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.

     

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.     

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.     

A case of primary biliary cirrhosis accompanied with fibrinogen storage disease

We report the first case of primary biliary cirrhosis (PBC) accompanied by fibrinogen storage disease (FSD). A 50-year-old Japanese woman had been treated for numbness of her right-side extremities for 5 years. Mildly elevated serum levels of alkaline phosphatase and gamma-glutamyl transferase were detected. The titers of both anti-mitochondrial (x 320) and anti-mitochondrial M2 (x 84) antibodies were elevated. The biopsied liver specimen showed mononuclear cell infiltrate densely encircling the bile ducts, poorly developed epithelioid cell granuloma, and loss of integrity of bile duct organization, which permitted a diagnosis of stage I PBC according to Scheuer's histologic classification. In addition, round to oval, eosinophilic, homogenous intracytoplasmic inclusions, several microm in average size, with a surrounding halo were found in the vast majority of hepatocytes. These inclusions were negative for the periodic acid-Schiff reaction. In immunohistochemistry, the inclusions were positive for fibrinogen and complement C3c, but not for HBs antigen and alpha1-antitrypsin. These findings were identical to FSD. To investigate the mechanism(s) of abnormal fibrinogen storage, immunostaining for heat shock protein 70 and ubiquitin was performed. The former was detected in all intracytoplasmic inclusions, whereas the latter was detected in only some inclusions, suggesting a partial loss of ubiquitin expression.     

Chromolipid-induced portal lymphadenopathy in primary biliary cirrhosis

Yellow or brown granules of chromolipid, often called Hamazaki-Wesenberg bodies, have previously been described in the sinuses of lymph nodes. They have been seen in normal nodes and nodes showing non-specific reactive changes; particular interest has been shown in a suggested association with sarcoidosis. We describe two patients, both with primary biliary cirrhosis, in whom the accumulation of large numbers of such bodies in the sinuses of lymph nodes of the porta hepatis led to a prominent lymphadenopathy.     

Primary liver lymphoma associated with primary biliary cirrhosis

We describe a case of a primary polymorphic centroblastic–centrocytic B-cell lymphoma of the liver developing in a patient with primary biliary cirrhosis—an association which has not previously been reported.
We would like to thank Dr C.Fisher, Department of Histopathology, The Royal Marsden Hospital, Fulham Road, London. UK, for his expert help with this case.     

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).     

The value of antinuclear antibodies in primary biliary cirrhosis

Objective

Although autoantibodies have been used for the diagnosis of primary biliary cirrhosis (PBC), their role has not been clarified. In this study, we try to explore the value of gp210 antibody and anti-centromere antibodies (ACA) in PBC.

Methods

Anti-gp210 and ACA were tested in 140 PBC patients by ELISA and indirect immunofluorescence respectively. Their association with clinical, pathological data and prognosis was analysed.

Results

30.5% of PBC patients had positive anti-gp210 antibody and 29.2% had ACA. The anti-gp210 antibody positive group had higher Mayo risk scores and lower serum albumin levels compared to the negative one. Patients with positive anti-gp210 antibody were more likely to develop hepatic failure (p < 0.05, OR = 9.8460, 95% CI: 1.067–90.901) than patients with negative anti-gp210 antibody. More patients with positive ACA developed portal hypertension than patients with negative ACA (p < 0.05, OR = 9.259; 95% CI: 1.027–88.410). Furthermore, concurrent Sjögren’s syndrome (SjS) and PBC was significantly more likely in the ACA positive group than in the negative ones (68.4% in ACA positive group, 20.7% in ACA negative group p < 0.001).

Conclusions

Both anti-gp210 antibody and ACA are related to severe disease course and poor prognosis. For PBC patients with positive ACA, further examinations should be made to detect underlying SjS.

     

Infection as a risk factor in the pathogenesis of primary biliary cirrhosis: pros and cons

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that may eventually lead to cirrhosis and liver failure. Evidence suggests cardinal roles for both environmental factors and genetic susceptibility. Nevertheless, the absolute etiology of PBC is unclear, despite recent well-designed case-control studies that reported environmental risk factors, including infectious agents, for PBC. Of the reported infectious agents, some of them are not reproducible and remain controversial. However, infection is no doubt one of the major risks among the environmental factors. This is supported by the fact that infectious agents in autoimmune diseases express antigens resulting in molecular mimicry and xenobiotics that play a role in breaking tolerance. Taken together, recent findings from genome wide assays as well as novel animal models may enable us to better understand the mechanism of pathogenesis responsible for this disease.     

Pathology of septum formation in primary biliary cirrhosis: A histological study in the non-cirrhotic stage

Summary Bridging or incomplete septum formation, an important step leading to cirrhosis in various chronic progressive liver diseases, was examined in 231 liver biopsy specimens of primary biliary cirrhosis (non-cirrhotic stage). Incomplete septa from the enlarged portal tracts and portal to portal bridges were frequent and appeared first, while portal to central ones appeared subsequently and became frequent in the liver specimens with changes resembling cirrhosis. These septa were divided into four types histologically: ductular, lymphocytic, loose connective tissue and fibrous type. More than one type was usually found in the same specimen. The pathology of the first three types was similar to and frequently continuous with that of neighbouring periportal regions, suggesting that most of these septa were formed by the extension of periportal destructive processes. The fibrous type might be an advanced form of the other three types. Incomplete septa seemed to pinch off part of the hepatic parenchyma in a hepatic lobule; this was followed by an unusual enlargement of the portal tracts and an approximation of portal tracts and central veins. There were perivenular hepatocellular necroses on occasion. Progression of periportal hepatocellular damage may lead to septum formation and finally progress to cirrhosis, in primary biliary cirrhosis. The significance of perivenular necroses remains speculative.     

Anti-mitochondrial antibody IgG subclass distribution and affinity in primary biliary cirrhosis.

We have studied the total IgG subclass and anti-mitochondrial antibody (AMA) specific IgG subclass distribution in primary biliary cirrhosis (PBC) sera. In order to solve the problems caused by the differing affinities of subclass specific monoclonals and the competitive inhibition of antibodies in a whole serum assay, six sera were separated into subclass-specific fractions by affinity-depletion chromatography. AMA subclass distribution of 20 further sera from patients with PBC was assessed using conventional methods and the results were calibrated against one of the fractionated sera. Light chain distribution and AMA functional affinity were also assessed for the fractionated subclasses. Total amounts of IgG3 were significantly increased compared with normal controls. AMA were found in all IgG subclasses and not restricted predominantly to IgG3 as previously described. The functional affinity of IgG3 AMA is generally lower as compared with that of other subclasses. No light chain restriction was found.