Search

Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.

New treatments for primary biliary cholangitis (PBC) are progressively emerging, including first and second generations of farnesoid X receptor and peroxisome proliferator-activated receptors agonists. Even though ursodeoxycholic acid monotherapy remains the standard of care treatment for PBC, these additional therapeutic options, already or soon to be available, lead us to revise our priorities and strategies with respect to future clinical trials. The present article is a personal view of where we currently stand in this field and where and how we should be going to achieve new progress.

Pruritus is a frustrating and sometimes debilitating symptom that commonly accompanies primary biliary cholangitis (PBC). The mechanism by which this symptom manifests remains elusive but extensive research has now shown that the itch is not just “weak pain” as had been the commonly held belief for decades. As this research now shines a light on the many diverse paths by which pruritus might be experienced, the necessity for a comprehensive approach to the symptom becomes clear. Understanding the interplay between the pathophysiology of PBC and delicately balanced neural circuitry is paramount to guiding the search for definitive treatment. Most relevant to providers today is the efficacy of currently available treatments and the side effects that may accompany them. Anion exchange resins, while remaining an important element in therapy, are no longer the only available medication to arrest pruritus. Rifampin, opioid antagonists, and other adjunctive therapies have quickly become a mainstay. Newer therapies such as the molecular adsorbent recycling system now also have a role in treatment. Increased recognition of these modalities may serve to alleviate the often debilitating pruritus experienced by patient suffering from PBC and might ultimately allow them to live more meaningful lives.

Primary biliary cirrhosis is a rather uncommon, slowly progressive, cholestatic liver disease that predominantly affects middle-aged women. Apart from the changes in the gut microbiome that have been described in liver disease in general, little is known of the composition of the microbiome in primary biliary cirrhosis. Nevertheless, epidemiological, clinical, and some experimental evidence points to the possible role of a bacterium (or bacteria) in the initiation of the autoimmune process that leads to the development of this unique clinical phenotype.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune destruction of small to medium size intrahepatic bile ducts. The etiology of PBC remains unknown and pathogenesis features immune-mediated biliary injury, alongside the consequences of chronic cholestasis. PBC is strongly associated with the loss of immune tolerance against mitochondrial antigens and the subsequent presence of an articulated immunologic response that involves both humoral and cellular responses. Both environmental factors and genetic variants increase PBC susceptibility. Biliary epithelial cells have often been considered a passive target of the immune attack in PBC; however, cholangiocyte dedifferentiation, senescence, stress, and deoxyribonucleic acid damage have been recognized to play an active role in the pathogenesis of PBC. This review highlights and discusses the most relevant pathogenetic mechanisms in PBC, focusing on the key factors that lead to the onset of cholestasis and immune activation.

Although ursodeoxycholic acid remains the only approved pharmacotherapy for patients with primary biliary cirrhosis, the better characterization of factors responsible for the poor response to this drug and the emergence of several new putative therapeutic targets now offer significant opportunities to improve the management of patients and our capacity to treat them more efficiently. The availability of novel treatment options, such as fibrates, budesonide, and obeticholic acid, all capable of improving prognostic markers, invites us to reconsider our management and treatment strategies. Early identification of high-risk patients should remain a priority to deliver adjunctive therapies to appropriately selected populations and increase their chances of success. Given the absence of comparative trials, the choice between second-line treatments should be dictated by the biochemical, histological, and expected tolerance profiles. Here the author presents a brief overview of what should be known in this field and proposes a practical approach to facilitate decision making.

Cholangiocytes, the epithelial cells lining the biliary tree, represent only a small portion of the total liver cell population (3–5%), but they are responsible for the secretion of up to 40% of total daily bile volume. In addition, cholangiocytes are the target of a diverse group of liver diseases affecting the biliary tract, the cholangiopathies; for most of these conditions, the pathological mechanisms are unclear. MicroRNAs (miRNAs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, it is not surprising that altered miRNA profiles underlie the dysregulation of several proteins involved in the pathobiology of the cholangiopathies, as well as showing promise as diagnostic and prognostic tools. Here the authors review recent work relevant to the role of miRNAs in the etiopathogenesis of several of the cholangiopathies (i.e., fibroinflammatory cholangiopathies and polycystic liver diseases), discuss their value as prognostic and diagnostic tools, and provide suggestions for further research.

Epigenomics, the study of modifications to genetic material that do not alter the underlying DNA sequence, is generating increasing interest as a means to help clarify disease pathogenesis and outcomes. Although genome-wide association studies have identified several potential candidate genes that may be implicated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it is estimated that these genes explain less than 20% of the heritability of these diseases. Thus, to date, the origins of “missing heritability” for PBC and PSC remain elusive. The epigenome may provide a potentially elegant solution to this phenomenon, as it can be modified by both internal and external exposures (coined the “exposome”). This may explain differences in disease presentation, treatment response, and rates of progression between individuals. Epigenetic changes may also provide a framework for discovering potential biomarkers for diagnosis and screening of PBC and PSC. Importantly, because the epigenome is modifiable, it may also highlight novel pathways for therapeutic discovery and interventions of these diseases.

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13–16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

In primary biliary cirrhosis (PBC), the breach of tolerance that leads to active disease involves a disruption in several layers of control, including central tolerance, peripheral anergy, a "liver tolerance effect," and the action of T regulatory cells and their related cytokines. Each of these control mechanisms plays a role in preventing an immune response against self, but all of them act in concert to generate effective protection against autoimmunity without compromising the ability of the host immune system to mount an effective response to pathogens. At the same time, genetic susceptibility, environmental factors, including infection agents and xenobiotics, play important roles in breach of tolerance in the development of PBC.

Primary biliary cirrhosis (PBC) has been considered a multifactorial autoimmune disease presumably arising from a combination of environmental and genetic factors, with genetic inheritance mostly suggested by familial occurrence and high concordance rate among monozygotic twins. In the last decade, genome-wide association studies, new data on sex chromosome defects and instabilities, and initial evidence on the role of epigenetic abnormalities have strengthened the crucial importance of genetic and epigenetic factors in determining the susceptibility of PBC. High-throughput genetic studies in particular have revolutionized the search for genetic influences on PBC and have the potential to be translated into clinical and therapeutic applications, although more biological knowledge on candidate genes is now needed. In this review, these recent discoveries will be critically summarized with particular focus on the possible steps that may transfer genetic and epigenetic knowledge to direct health benefits in patients with PBC. Copyright © 2014 by Thieme Medical Publishers, Inc.

Antimitochondrial, anti-gp210, anti-sp100, and anticentromere antibodies are specifically detected in primary biliary cirrhosis (PBC). In clinical practice, they are useful for the diagnosis of PBC or for evaluating disease severity, clinical phenotype, and long-term outcome. In the typical or classical form of PBC which shows slow progressive loss of small bile ducts with a parallel increase in liver fibrosis, anti-gp210 antibodies are a strong risk factor for progression to jaundice and hepatic failure, whereas the presence of anticentromere antibodies is a risk factor for progression to cirrhosis and portal hypertension. Of note, the autoimmune repertoire, which is established during the early stage of the disease process, can influence the clinical phenotype and the long-term prognosis of PBC. Because the natural course of PBC is being altered by treatment with ursodeoxycholic acid, the clinical significance of these PBC-specific autoantibodies awaits re-evaluation in various ethnicities., Seminars in Liver Disease, 34(3), pp.334-340; 2014

In this article, the authors use the term "overlaps" to refer to the coexistence of primary biliary cirrhosis (PBC) with another autoimmune condition that involves the liver or extrahepatic organs. Diagnosing PBC-autoimmune hepatitis (PBC-AIH) overlap syndrome remains a challenge, especially because there is still no consensus on the most appropriate diagnostic criteria. The prevalence of this condition varies considerably among series of PBC patients, and its treatment demands a combination of ursodeoxycholic acid and immunosuppressive drugs. Overlap syndrome between PBC and primary sclerosing cholangitis is described in exceptional cases. About one in three PBC patients have a concomitant extrahepatic autoimmune disease, which may include rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions. Overlaps raise several questions, about whether they share much the same genetic susceptibility, as is generally assumed. The pathogenesis of these conditions includes the production of both innate and adaptive immune responses targeting cholangiocytes as well as different extrahepatic tissues. In this sense, overlaps in PBC represent a continuous spectrum of autoimmunity involving liver and extrahepatic tissues.

Our understanding of the natural history of primary biliary cirrhosis (PBC) has been evolving especially following the introduction of ursodeoxycholic acid (UDCA). A clearer understanding of disease pathophysiology and earlier diagnosis with increased prevalence of the disease worldwide has led to increased interest and improved outcomes in patients with PBC. In this article, the authors touch briefly on features of the disease and describe the natural history of PBC prior to and after the introduction of UDCA.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by selective destruction of intrahepatic cholangiocytes. Mechanisms underlying the development and progression of the disease are still controversial and largely undefined. Evidence suggests that PBC results from an articulated immunologic response against an immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2); characteristics of the disease are also the presence of disease-specific antimitochondrial autoantibodies (AMAs) and autoreactive CD4 and CD8 T cells. Recent evidence suggests that cholangiocytes show specific immunobiological features that are responsible for the selective targeting of those cells by the immune system. The immune reaction in PBC selectively targets small sized, intrahepatic bile ducts; although a specific reason for that has not been defined yet, it has been established that the biliary epithelium displays a unique heterogeneity, for which the physiological and pathophysiological features of small and large cholangiocytes significantly differ. In this review article, the authors provide a critical overview of the current evidence on the role of cholangiocytes in the immune-mediated destruction of the biliary tree that characterizes PBC.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, which in the majority of patients progresses to liver transplantation or death. To date, no medical treatment has been proven to be of benefit, although ursodeoxycholic acid is widely used. The etiopathogenesis of PSC is unclear, although it is associated with inflammatory bowel disease. Various hypotheses have been suggested, which have led to different therapeutic strategies. Recent studies have suggested that the microbiome may play a role in PSC, raising the possibility of efficacy of antibiotics and fecal microbiota transplantation. Gut-homing T cells may be important in the pathogenesis of PSC, and several agents are in development, targeting various receptors, integrins, and ligands on this pathway, including VAP-1, MAdCAM-1, α4β7, and CCR9. Nuclear receptor agonists such as obeticholic acid and fibrates hold promise, as do other therapies that alter bile acid composition such as norUDCA. Antifibrotic agents such as Loxl2 inhibitors are also being assessed. In conclusion, it is likely that an effective drug therapy for PSC will become available over the next decade.

A 56-year-old white male painter, with a history of major electrocution and deep thermal injury, developed mental status changes initially ascribed to an acute neurological event. Unexpectedly, magnetic resonance imaging (MRI) of the head showed areas of high signal intensity in the basal ganglia, which can be observed in advanced liver disease. An electroencephalogram (EEG) suggested metabolic encephalopathy and coexistent elevation of ammonia, indicative of significant liver disease. The patient had had a long history of right upper quadrant pain and fluctuation in liver tests following the electrocution trauma. For these symptoms, he underwent surgery 7 years prior to his current presentation of portosystemic encephalopathy, and was found to have a gangrenous acalculous cholecystitis. Intraoperative cholangiogram suggested possible strictures within the right hepatic ducts. Multiple liver biopsies, however, showed only steatosis. Current evaluation including liver biopsy, MRI, magnetic resonance angiography (MRA), and magnetic resonance cholangiopancreatography (MRCP), revealed progression to biliary cirrhosis with large bile duct obstruction, and hepatic artery thrombosis/occlusion with evidence of left lobe atrophy and right lobe compensatory hypertrophy. The pathobiology of ischemic bile duct injury is discussed herein. The case is an example of serious late sequelae of an occupational injury.

An asymptomatic 70-year-old Hispanic woman with type 2 diabetes was found in 2004 to have an AST of 132 U/L, ALT 146 U/L, alkaline phosphatase 1107 U/L, total serum bilirubin 3.5 mg/dL, and albumin 2.9 g/dL. Viral hepatitis testing was negative. Serum IgG, IgA, and IgM were all elevated, antimitochondrial antibody was weakly positive, and antinuclear antibody was negative. Liver biopsy was reported to show "evolving cirrhosis with marked lymphoid hyperplasia." Although the indication was nowhere stated, she was prescribed ursodeoxycholic acid 500 mg b.i.d, on which her biochemical tests initially improved. One year later she developed itching and jaundice. Imaging studies revealed multiple gallstones. An MRCP was suggestive of cirrhosis with a questionable common bile duct stricture, and she underwent ERCP with removal of gallbladder and common bile duct stones and placement of a biliary stent. A periampullary mass, which proved to be a somatostatinoma, was excised in 2006 via an open laparotomy, at which the stent was removed and a second liver biopsy performed. It was reported as showing chronic active hepatitis, activity stage 2, and fibrosis grade 3 with bridging. Her subsequent course was complicated by recurrent bleeding from small bowel arteriovenous malformations. Seen for the first time at Columbia University Medical Center in January 2007, she complained of continuing pruritus. AST was 69 U/L, ALT 43 U/L, alkaline phosphatase 491 U/L, and total bilirubin 3.3 mg/dL. Serum albumin was 2.6 g/dL. Antinuclear antibodies, negative in 2004, were now positive at 1:320, and antimitochondrial M2 antibodies were strongly positive. Serum IgG and IgA, but NOT IgM, were elevated. Review of her outside liver biopsies revealed features of primary biliary cirrhosis (PBC) in the first, and of both PBC and autoimmune hepatitis (AIH) in the second. The patient exhibits an overlap syndrome, in which both histologic and serologic features of AIH evolved in a setting initially most suggestive of PBC alone. The phenomenon of autoimmune overlap syndromes is discussed.

The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.

Patients with primary biliary cirrhosis (PBC) generate a variety of autoantibodies, which are primarily directed against mitochondrial antigens (AMA). However, a subgroup of patient sera are also positive for antibodies to nuclear components (ANAs). At indirect immunofluorescence (IIF), PBC sera mostly produce homogeneous, nuclear dot, speckled, centromere, or rim-like patterns. During the last two decades, a number of nuclear structures have been recognized as specific targets of ANA in PBC. These include Sp100 and promyelocytic leukemia proteins, which generate a nuclear dot IIF pattern, and two components of the nuclear pore complex specifically associated with a perinuclear pattern (i.e., gp210 and p62). In recent years, the clinical significance of ANA in PBC has been widely investigated and data indicate that, unlike AMAs, PBC-specific ANAs correlate with disease severity and may therefore be a marker of poor prognosis.

The etiopathogenesis of primary biliary cirrhosis (PBC), an autoimmune disease characterized by the progressive destruction of intrahepatic bile ducts, is still enigmatic. There is growing evidence that suggests that the disease results from a combination of genetic and environmental factors. PBC should be regarded as a peculiar, yet representative autoimmune disease. For example, the relative risk for siblings and the concordance rate in monozygotic twins in PBC are among the highest reported in autoimmune conditions. Association studies for specific genes have provided weak associations, which often are limited to specific geographical areas. Interestingly, PBC epidemiology also presents a geographical pattern; it is more common in the northern parts of Europe and United States. In this article, we critically review available evidence regarding genetics and geoepidemiology in PBC. We also submit possible interpretations of data, new developments and theories, and attempt to indicate directions for future research efforts.

Because the etiopathogenesis of PBC is incompletely defined, curative therapies have not been identified, and the focus has been on prevention of disease progression. Ursodeoxycholic acid retards progression and is likely to be combined with newer therapies in future trials. Advances in our understanding of the roles of retroviral infection and autoimmune responses of T and B cells to PBC-specific autoantigens provides rationales for studies of the safety and efficacy of antiretroviral, immunosuppressive, and immunomodulatory agents in PBC. Promising options include inhibition of (1) T-cell activation and proliferation; (2) transendothelial migration and activation of effector cells; (4) cytokine and immunoglobulin effector mechanisms; and (5) inflammation and oxidation. Depletion and immunomodulation of T and B cells may provide opportunities to thwart re-emergence of effector mechanisms. Induction of tolerance in susceptible people before onset of disease or of hyporesponsiveness in established disease is increasingly feasible, as is prevention of biliary fibrosis.

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.

Hepatic formation of bile is critical to survival and is one of the most easily disrupted liver functions. Liver biopsy is performed to obtain a definitive diagnosis of cause, to exclude potential etiologies, or simply to assist in development of a differential diagnosis. Parenchymal changes of cholestasis (feathery degeneration of hepatocytes, dilated bile canaliculi with retained bile, Kupffer cell phagocytosis of bile that has leaked into the sinusoidal space) are nonspecific and may be seen with both nonobstructive and obstructive cholestasis. The portal tract changes of obstruction are characteristic: bile ductular proliferation, inspissated bile in bile ducts, portal tract edema, neutrophilic inflammation, and cholate stasis of periportal hepatocytes. Uncorrected obstruction incites robust fibrogenesis by portal tract myofibroblasts, engendering a characteristic jigsaw pattern of fibrous septa. Diseases with specific histological features include primary biliary cirrhosis, primary sclerosing cholangitis, biliary atresia, and graft-versus-host disease. However, the pathologist is cautioned not to overinterpret the cholestatic liver biopsy and to apply rigorous criteria for specific causal diagnoses. Most of the histological features of cholestasis are nonspecific. Hence, both practicing physician and pathologist should have sound knowledge of the pathology of cholestasis.

Although the autoantigens of antimitochondrial antibodies (AMA) have been defined and epitope mapped for both autoreactive B and T cells, the pathogenesis of primary biliary cirrhosis (PBC) still remains a mystery. The data gathered so far address several important aspects of this intriguing puzzle. First, biliary epithelial cells (BECs) seem to be immunologically active because they express molecules such as major histocompatibility complex (MHC) antigens, and adhesion and costimulatory molecules. Second, although pyruvate dehydrogenase complex (PDC)-E2, the major autoantigen in PBC, is upregulated in BECs when examined immunohistochemically, this abnormal staining seems to be secondary to immune complexes of AMA bound to PDC-E2 present in the BECs. Third, in addition to CD4(+) T cells, CD8(+) T cells also recognize the inner lipoyl domain of PDC-E2. Fourth, modification of mitochondrial antigens by xenobiotics may lead to the induction of the disease. These findings help to clarify the pathogenic mechanism of PBC and suggest that (l) induction may be secondary to a primary response to a xenobiotic that is normally metabolized in an estrogen-dependent pathway and (2) pathology is mediated by and orchestrated by a highly directed and specific CD4, CD8 and autoantibody response to the lipoyl domain of the mitochondrial autoantigens, with tissue destruction based on the immunoglobulin A (IgA) receptor, apoptosis, and the mucosal organization of biliary and salivary duct cells.

Despite the presumed immunological pathogenesis of primary biliary cirrhosis, no clear or even harmful consequences resulted from some specific treatments addressed to modify the immunological condition. However, ursodeoxycholic acid (UDCA; 13–16 mg/kg/d) has clear favorable effects not only by improving biochemical cholestasis, but also by delaying the histological progression. Long -term treatment with UDCA is associated with excellent survival, free of transplantation in cases showing biochemical response at one year. In the remaining patients, data on the effect of fibrates, budesonide, or obeticholic acid are encouraging. Pruritus is usually managed using resins; further steps are needed in resistant cases with the use of rifampicin, naltrexone, sertraline, or invasive procedures such as albumin dialysis. Osteoporosis, which is highly prevalent in patients with deep and prolonged cholestasis, improves with bisphosphonates; current data indicate that both weekly alendronate and monthly ibandronate increase bone mass in patients with osteoporosis. Nutritional and fat-vitamin supplementation is also mandatory in patients with severe cholestasis.

Within the last decade, several mouse models that manifest characteristic features of primary biliary cirrhosis (PBC) with antimitochondrial antibodies (AMAs) and immune-mediated biliary duct pathology have been reported. Here, the authors discuss the current findings on two spontaneous (nonobese diabetic autoimmune biliary disease [NOD.ABD] and dominant negative transforming growth factor-β receptor II [dnTGFβRII]) and two induced (chemical xenobiotics and microbial immunization) models of PBC. These models exhibit the serological, immunological, and histopathological features of human PBC. From these animal models, it is evident that the etiology of PBC is multifactorial and requires both specific genetic predispositions and environmental insults (either xenobiotic chemicals or microbial), which lead to the breaking of tolerance and eventually liver pathology. Human PBC is likely orchestrated by multiple factors and hence no single model can fully mimic the immunopathophysiology of human PBC. Nevertheless, knowledge gained from these models has greatly advanced our understanding of the major immunological pathways as well as the etiology of PBC.

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease. Susceptibility to PBC probably arises from a combination of genetic and environmental factors. The prevalence of PBC varies both on an international and a regional level. This can be explained, in part, by differences in clinical practice and case-finding activity. It is likely, however, that substantive geographical differences exist both in terms of genetic susceptibility and environmental factors that potentially trigger the disease in genetically susceptible individuals. The study of the epidemiology of PBC has strongly supported the concept of an environmental triggering factor, but as yet no specific agent has been identified. Ongoing work to discover the environmental agent, as well as the mechanism that causes the disease will answer key questions as to the epidemiology of this complex autoimmune disease as well as providing useful information for other autoimmune conditions.

Viral hepatitis and malignancy frequently recur after transplantation, but recurrence of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis is controversial. Differences in study design, number of patients, immunosuppressive treatment, length of follow-up, and criteria for recurrence account for discrepant results. Most patients with suspected recurrent disease are asymptomatic after transplantation. In patients transplanted for PBC, antimitochondrial antibodies frequently persist and do not correlate with disease recurrence; liver biopsy remains the gold standard for diagnosis. Exclusion of other disorders that can mimic PBC is paramount prior to making a diagnosis of recurrent disease. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies will be necessary to address the impact of disease recurrence on the allograft. Due to lack of a diagnostic gold standard, a diagnosis of recurrent PSC after transplantation is difficult to make. An accurate diagnosis of PSC recurrence requires well-defined cholangiographic and histologic criteria. Other disorders that can produce biliary strictures after transplantation should be excluded. As with PBC, the effects of immunosuppression may modify or delay disease expression within the graft; medium-term patient and graft survival is excellent. Recurrence of autoimmune hepatitis is based on clinical, biochemical, serologic, and histologic criteria. As in patients transplanted for PBC and PSC, other conditions that can mimic autoimmune hepatitis require exclusion prior to making a diagnosis of recurrence. Most adult recipients respond to an increase in immunosuppression, whereas pediatric recipients do not respond as well. A cautious approach to withdrawal of immunosuppression is warranted in all patients transplanted for autoimmune hepatitis and the consequences of recurrent disease within the graft will require prolonged follow-up. Future studies should focus on preventive and therapeutic strategies for recurrent autoimmune diseases after transplantation.

In patients with primary biliary cirrhosis (PBC), ursodeoxycholic acid (ursodiol) improves laboratory test markers of cholestasis and hepatic inflammation as well as some hepatic histological features; it also delays histological progression in the early stages of PBC. Ursodiol is well tolerated and safe. Less well substantiated are that ursodiol either improves the quality of life or prevents liver transplantation or that it prolongs survival without transplantation. There are favorable trends for ursodiol in preventing transplantation and prolonging survival, but in the absence of randomized, placebo-controlled trials of sufficient duration, there remain impressions rather than statistically proved, strong conclusions.

Primary biliary cirrhosis (PBC) is an immunologically mediated disease in which activated T lymphocytes attack and destroy epithelial cells in the small intralobular bile ducts of genetically susceptible patients. This article reviews the results of treatment of PBC with immunomodulatory agents. Results with drugs such as glucocorticoids, azathioprine, and chlorambucil have been disappointing because of either limited efficacy (azathioprine), toxicity (chlorambucil), or both (glucocorticoids). Colchicine improved tests of liver function in three prospective studies and was associated with improved survival for up to 4 years. However, survival benefits were lost at 8 years. Colchicine appears to slow the rate of progression of PBC but not to stop it. Preliminary results suggest that colchicine may have synergistic effects if used together with ursodeoxycholic acid, particularly in patients who are only partially responsive to ursodeoxycholic acid. Results with cyclosporine have been disappointing because of limited efficacy and predictable toxicity. The modest improvement in tests of liver function and survival are counterbalanced by the development of hypertension in some and worsening renal function in most. There is little beneficial effect on symptoms or histology. Results with methotrexate are promising. There are improvements in symptoms and tests of liver function that are equal to those seen with ursodeoxycholic acid and significant improvement in liver histology. Some patients, particularly those with striking inflammation and granulomas in portal triads, appear to have achieved sustained remission while on methotrexate. The effects of methotrexate are additive to those of ursodeoxycholic acid in patients whose blood tests have responded only partially to ursodeoxycholic acid. The most effective treatment of PBC will most likely use a combination of drugs such as ursodeoxycholic acid, colchicine, and methotrexate.

Pyruvate dehydrogenase complex (PDC), 2-oxo-glutarate dehydrogenase complex (OGDC), and the branched-chain 2-oxoacid dehydrogenase complex (BCOADC) constitute the 2-oxoacid dehydrogenase family of multienzyme complexes. These complexes, which are larger than ribosomes and which consist of multiple copies of E1, E2, and E3 subunits together with regulatory kinases and phosphatases and, in the case of PDC, an E3-binding protein (protein X), each play an important role in oxidative metabolism in mitochondria. Primary biliary cirrhosis (PBC) is associated with a high incidence of autoantibodies directed at mitochondrial autoantigens (the antimito-chondrial antibodies), identified as the E2 components of PDC, OGDC, and BCOADC, together with protein X and the E1 alpha and E1 beta subunits of PDC. The dominant B-cell autoepitope in PBC has been identified as the inner lipoic acid binding domain of PDC-E2, with the lipoic acid co-factor, which plays a critical role in E2 enzymatic activity, playing a role in autoantibody binding to antigen. Autoreactive CD4+ T cells specific for human PDC-E2 are also present in both the peripheral blood and liver mononuclear cell infiltrates of PBC patients. The mechanism of break-down of B-cell and T-cell self-tolerance to these ubiquitous mitochondrial antigens in such an organ-specific manner remains unclear. The apparent importance of autoreactive responses to these self-antigens does, however, raise the possibility that antigen-specific immunotherapy may offer a novel route to therapy in PBC.

The primary function of the immune system is protection and defense against infection. However, the maintenance of normal immune function is a very intricate process, and the failure of these processes to establish and maintain tolerance to self results in autoimmunity. The damage that results from autoimmune disease can be extensive and can be directed at any tissue in the body. One of the major issues in autoimmunity is whether this is a natural or an unnatural phenomenon. Although there have been numerous and exciting theories proposed to explain the autoimmune response, the basic underlying risk factors remain unclear. Both genetic and environmental factors have been incriminated, but the highly variable expression of autoimmune disease and the multiple genetic and environmental determinants make conclusions difficult. Primary biliary cirrhosis is considered a model autoimmune disease because it reflects a highly directed and highly specific response to an identified target, the biliary epithelium. In this review we attempt to place these issues in perspective both from the generic perspective of autoimmunity and from the specific perspective of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that has a prevalence of 1 in 1000 women over the age of 40. Treatment is presently limited to ursodeoxycholic acid, a hydrophilic bile acid that has nonspecific, choleretic, effects in cholestatic liver disease. PBC has strong autoimmune features, including highly specific loss of tolerance to a ubiquitous mitochondrial antigen. Both environmental and genetic factors are considered important in the pathogenesis of disease. Prior to the advent of genome-wide association studies, only class II human leucocyte antigen (HLA) loci (HLA-DRB1*08, *11, and *13) had been reproducibly shown to associate with disease. Non-HLA loci were suggested for several genes (e.g., CTLA-4, MDR3), but often inconclusively replicated. With the application of genome-wide technology, HLA was confirmed as the strongest association and many other risk loci have been identified, with equivalent effect size to HLA, including IL12A, IL12RB2, STAT4, IRF5-TNPO3, 17q12.21, MMEL1, SPIB, and CTLA-4. These collectively support an important role for innate and adaptive immunity in development of disease. Further insights are predicted as studies with larger cohorts are assembled, and different approaches are taken to further discover common and uncommon gene variants associated with disease. Disease subphenotypes such as response to therapy, clinical progression, and symptoms remain additional areas for further dedicated studies, and in which different genetic risk factors may be relevant. Identification of risk loci associated with disease has the potential to aid development of rational, disease-specific, therapies in the future.

Bone disease occurring in the setting of chronic liver disease is being recognized increasingly often. The osteopenia may be an important cause of morbidity in these patients, particularly as effective treatments become available for the liver diseases and especially if these treatments actually worsen the coexistent bone disease. Although no specific treatments are of proven benefit for the bone disease in most instances, adequate exercise and calcium intake as well as vitamin D supplementation when deficiencies are present are recommended for all patients. Information is lacking about specific treatment for patients with PSC, hemochromatosis, and alcoholic liver disease. For patients with PBC, other than the above general measures, preliminary information suggests that supplemental estrogens in postmenopausal women and the use of calcitonin may offer promise; both measures are deserving of further study in this group of patients.

Autoimmune liver diseases (ALD) are characterized by immune-mediated injury of bile ducts or hepatocytes, thus including cholangiopathies such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and autoimmune hepatitis. Further, ALD variants manifesting with both hepatocellular and cholangiocellular damage are becoming more common. Serum autoantibodies, together with imaging and histology, are critical to the diagnostic process when ALD is suspected. Because an early diagnosis can influence prognosis, the development of sensitive and specific tests for serum autoantibodies should be a priority for researchers to ensure a more efficient noninvasive workup. Little prognostic value has been observed for any of the ALD serum hallmarks, and a vigorous effort to investigate new and old markers should therefore be undertaken in longitudinal studies as in the recent paradigm of PBC-specific antinuclear antibodies. We review herein the numerous ALD screening tests available in routine and specialized laboratories and comment on their significance in clinical practice.

The principle of therapy for chronic inflammatory liver diseases is the removal of causal agents. For autoimmune liver diseases, however, total removal of causal agents and immune cells is impossible. Therefore, autoimmune liver diseases are presently treated by suppression of the immune response. Autoimmune hepatitis is characteristically responsive to corticosteroids, often used in combination with azathioprine to obtain a steroid-sparing effect. For primary biliary cirrhosis, ursodeoxycholic acid is safe and is the first choice for treatment. Treatment of this autoimmune liver disease should also address various symptoms and complications arising from any associated autoimmune diseases, particularly cholestasis and cirrhosis-related complications. For primary sclerosing cholangitis there are no established immunomodulatory therapies, but medical, endoscopic, and surgical treatments are applicable to this disease. Liver transplantation becomes indicated during the eventual end stages of each of these immune-mediated liver diseases.

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease characterized by the presence of high titer antimitochondrial autoantibodies (AMAs) and destruction of intrahepatic small bile ducts. Despite vigorous efforts in the characterization of autoantibodies and bile duct histopathology, the etiology of this disease is unclear. Although there is no correlation between the titer of AMAs and disease severity, the presence of AMAs usually occurs before symptoms of liver abnormalities. We believe that the production of AMAs is not an epiphenomenon, and an understanding of the mechanism of AMA induction will shed light on the etiology of PBC. Recent studies have suggested that the induction of PBC is multifactorial, in which the primary player involves the xenobiotics modification of mitochondrial proteins or exposure to xenobiotic-modified bacterial mitochondrial protein homologs, leading to breaking of tolerance to the human mitochondrial autoantigens and eventually liver pathology in genetic susceptible individuals. We discuss the immunophysiological characteristics of biliary epithelial cells, biochemistry of the 2-oxo-acid dehydrogenase complex, and environmental and genetic factors relevant to PBC.

Similar to other autoimmune diseases, there are intense humoral and cellular responses to intracytoplasmic antigens in primary biliary cirrhosis (PBC). The autoantigens against antimitochondrial antibodies (AMAs) in PBC are located on the inner mitochondrial membrane and are identified as members of the 2-oxo-acid dehydrogenase complexes (2-OADCs), of which the E2 subunit of pyruvate dehydrogenase complex (PDC-E2) is the major autoantigen; AMAs are is present in approximately 90 to 95% of PBC sera. An orchestrated immune response against the intrahepatic biliary epithelial cell (BEC) through 2-OADC-specific CD4 (+) helper T cells and CD8 (+) CTL are thought to be the major players in the immunological destruction of BECs in PBC. We believe that a prior/primary event of specific intrahepatic BEC malfunction (possibly caused by environmental insults such as xenobiotics and microorganisms) is responsible for the breaking of self-tolerance to 2-OADC and leads to BEC destruction. The generation of 2-OADC-specific T cells further accelerates the damage of BEC. In addition, immunoglobulin A AMAs may participate in the destruction of BECs by damaging mitochondria.

The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.

The case discussed is of a 38-year-old African-American woman who developed upper abdominal symptoms and liver test abnormalities. She underwent cholecystectomy for presumed gallstone disease. This was followed by a worsening of her condition, with the development of jaundice in the next 2 weeks. Results of reevaluation included transaminases around 1000 IU/L with minimal elevation of alkaline phosphatase (ALP), an antimitochondrial antibody (AMA) titer of 1:320, and an elevated immunoglobulin M (IgM). The antinuclear antibodies (ANA) level was positive, but titers were not obtained. There was no suggestion of bile duct obstruction. Liver biopsy findings were believed to be consistent with primary biliary cirrhosis (PBC). She was therefore started on, but failed treatment with, ursodeoxycholic acid. She was transferred to a transplant center 8 weeks later after a brief episode of encephalopathy and hypoglycemia. The clinical findings were consistent with subfulminant hepatic failure secondary to autoimmune hepatitis (AIH) with an ANA titer of 1:1280, an anti-smooth muscle antibody (SMA) titer of 1:40, and an elevated IgG. Review of the biopsy showed panlobular inflammation and bridging necrosis consistent with severe AIH. On imaging, she had ascites and a nodular appearance of the liver. An immediate drop in transaminases followed corticosteroid therapy, but her disease was already irreversible, and she underwent successful liver transplantation. The explanted liver was shrunken and noncirrhotic with massive hepatocellular collapse and contained multiple regenerating nodules, explaining the ultrasonographic appearances. The inflammatory component had greatly diminished compared with the earlier biopsy. The case illustrates the importance of knowledge of the natural course of a specific disease and the careful interpretation of clinical data, including autoimmune markers. PBC would rarely cause liver failure in a young woman; it is not a rapidly progressive disease. The original clinical diagnosis was unduly swayed by a positive AMA, which can be seen in up to 20% of patients with AIH. Markedly elevated transaminases with minimal elevation of ALP and positive ANA in a young woman should have pointed toward AIH at an earlier stage. The academic discussion of AMA-positive AIH versus PBC/AIH overlap syndrome remains intriguing, but prompt institution of aggressive immunosuppressive therapy aimed at the AIH component should not be deferred. In retrospect, an opportunity was missed.

The role of biliary epithelial cell (BEC) antigens in immune recognition and damage of biliary epithelium in primary biliary cirrhosis (PBC) is unknown. The major autoantigen in PBC (the mitochondrial enzyme pyruvate dehydrogenase dihydrolipoamide acetyltransferase [PDC-E2]) is abnormally distributed in the biliary epithelium of patients with PBC relative to controls. The antigen is not only present in mitochondria but also associated with the BEC plasma membrane. This atypical distribution of PDC-E2 is present both in early (stages I-II) and advanced (stages III-IV) disease, suggesting a role for the antigen in progression and/or etiology of PBC. The identity of the plasma membrane antigen remains unknown, but there is evidence to suggest that it is an antigen that cross reacts with antibodies to PDC-E2. Use of BEC purified from human liver may help in deciphering the possible importance of BEC plasma membrane antigens in immune recognition and toxicity toward BEC in PBC.

While fervently studied by several laboratories, the role of T cells in the pathogenesis of primary biliary cirrhosis (PBC) still remains a mystery. The studies concerning cell phenotype, antigen specificity, and major histocompatibility complex (MHC)-T-cell receptor (TCR) interaction gathered thus far all address important aspects of this intriguing conundrum. However, the lack of an animal model and the genetic diversity of the human population with PBC make this task even more difficult. The possibilities regarding immune therapy resulting from such studies are of great importance. Future work concerning the T-cell epitopes--for both the pyruvate dehydrogenase complex (PDC), its related mitochondrial autoantigens, and any as yet unidentified PBC-specific autoantigens--may provide valuable information with regard to disease therapy. In addition, knowledge with regard to TCR usage and MHC association will help to clarify the pathogenic mechanisms of this enigmatic disease.

Immunoreactivity to intra- and extracellular antigens is regulated mainly by two different types of T-helper cells, namely TH1 (producing mainly IFN-gamma and Il-2) and TH2 (producing IL-4, -5, -10). Both types cross-regulate each other. TH1 mechanisms seem to be involved principally in organ-specific autoaggressive disorders, while TH2 response is an expression of allergic conditions characterized by eosinophilic reactions and increased IgE levels. There are only a few reports dealing with cytokine profiles in patients with primary biliary cirrhosis (PBC). From studies analyzing the cytokine gene expression and cytokines in supernatants of nonstimulated and antigen-specific lymphocytes derived from the affected liver or peripheral blood of PBC patients, there is evidence that, in the course of the disease, predominantly TH1 cells are activated. However, in view of the eosinophilic reaction observed especially in patients with early PBC, it may well be that a switch from TH2 to TH1 occurs. Concerning the regulatory function of TH1/TH2 cells, a more refined evaluation of these T-cell subsets could help to provide a new insight into the natural course of PBC.

The natural history of primary biliary cirrhosis (PBC) is one of slowly progressive cholestasis with liver damage, development of cirrhosis with its concomitant complications, and death unless the patient undergoes liver transplantation. Natural history studies have identified several variables associated with a decreased survival in patients with PBC. The course of the disease can be divided into three time periods: (1) a presymptomatic phase, probably lasting up to 20 years; (2) a symptomatic phase, with anicteric or mild jaundice, lasting up to 5 to 10 years; and (3) a preterminal or accelerated phase with marked jaundice, lasting up to 2 years. Since the course of the disease is one of slow progression leading to liver failure and death unless liver transplantation intervenes, several investigators have developed statistical models to predict survival. The ability to predict survival for individual patients with PBC has been valuable in the management of these patients, particularly in patient selection and timing of liver transplantation. In addition, survival estimates can be utilized in education and counseling patients and their families. These models may also be used to evaluate the efficacy of new treatments by comparing natural history survival with the survival achieved by therapeutic effect. Over the past several decades, the natural history models of PBC have been developed in the absence of effective medical therapy. The efficacy of liver transplantation and survival following liver transplantation has now been quantitatively established. Future efforts should be aimed at determining not only survival of patients with primary biliary cirrhosis in the presence of effective medical therapy but also at assessing the quality of life and cost-effectiveness of medical therapy and liver transplantation in the management of patients with primary PBC.