Progressive Cholestatic Liver Disease Research Articles

Autoantibodies in primary biliary cirrhosis: Recent progress in research on the pathogenetic and clinical significance

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of the small- and medium-sized intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMA) in the serum. AMA are detected in over 90% of patients with PBC, whereas their prevalence in the general population is extremely low, varying from 0.16% to 1%. Previous studies have shown that the unique characteristics of biliary epithelial cells undergoing apoptosis may result in a highly direct and very specific immune response to mitochondrial autoantigens. Moreover, recent studies have demonstrated that serum from AMA-positive PBC patients is reactive with a number of xenobiotic modified E2 subunits of the pyruvate dehydrogenase complex, which is not observed in the serum of normal individuals. These findings indicate that chemicals originating from the environment may be associated with a breakdown in the tolerance to mitochondrial autoantigens. While it is currently generally accepted that AMA are the most specific serological markers of PBC, more than 60 autoantibodies have been investigated in patients with PBC, and some have previously been considered specific to other autoimmune diseases. This review covers the recent progress in research on the pathogenetic and clinical significance of important autoantibodies in PBC. Determining the pathogenic role of those autoantibodies in PBC remains a priority of basic and clinical research.

Clinical Analysis of 75 Patients with Primary Biliary Cirrhosis

Background and aims: Primary biliary cirrhosis is a chronic and slowly progressive cholestatic liver disease characterized by destruction of interlobular bile ducts, which if untreated, leads to fibrosis, cirrhosis and liver failure. It is more frequent among female patients and is usually diagnosed in the fifth decade of life. This study aims to determine the demographic, clinical, biochemical and serological characteristics and histological stage of patients with primary biliary cirrhosis. Methods: Retrospective analysis of the adult patients diagnosed with primary biliary cirrhosis at our center from January 2005 to December 2013 was performed. Data collection included demographics, clinical features, biochemical and serological markers, and histological stage. Results: 75 patients were diagnosed with primary biliary cirrhosis (mean age: 55 years, range: 19-83), of whom 92.0% were women. The most common symptoms at presentation were fatigue (40.0%), pruritus (40.0%), jaundice (28.0%) and dark urine (26.7%). 20.0% were asymptomatic at diagnosis. 48.0% of patients had cirrhosis at presentation. Positive antimitochondrial antibodies were found in 96% of cases. 34.8% of the patients were positive for antinuclear antibodies. Overlap syndromes were present in 10.6%. Liver biopsy was performed in 45.3% of the patients. Conclusions: The clinical features of primary biliary cirrhosis were similar to those reported in the international literature but with a high percentage of symptomatic and cirrhotic patients at diagnosis.

Erratum to; A Case of Rapidly Progressive Primary Sclerosing Cholangitis Requiring Liver Transplantation

Primary sclerosing cholangitis (PSC) is a slowly progressive cholestatic liver disease. In cases of PSC, liver transplantation is the only effective treatment that can delay the disease`s natural course. We report a case of rapidly progressive PSC requiring liver transplantation. A 52-year-old woman visited our hospital with abdominal pain. There was no evidence of PSC, as there was no elevation in cholestatic liver enzymes at her first visit. Although her total bilirubin was in a normal range at the initial visit, liver dysfunction progressed rapidly. Despite endoscopic procedures and ursodeoxycholic acid intake, total bilirubin levels rose to 18.9 mg/dL, and liver transplantation was performed 17 months after her first visit. PSC was pathologically confirmed after liver transplantation.

BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

A Case of Rapidly Progressive Primary Sclerosing Cholangitis Requiring Liver Transplantation

Primary sclerosing cholangitis (PSC) is a slowly progressive cholestatic liver disease. In cases of PSC, liver transplantation is the only effective treatment that can delay the disease's natural course. We report a case of rapidly progressive PSC requiring liver transplantation. A 52-year-old woman visited our hospital with abdominal pain. There was no evidence of PSC, as there was no elevation in cholestatic liver enzymes at her first visit. Although her total bilirubin was in a normal range at the initial visit, liver dysfunction progressed rapidly. Despite endoscopic procedures and ursodeoxycholic acid intake, total bilirubin levels rose to 18.9 mg/dL, and liver transplantation was performed 17 months after her first visit. PSC was pathologically confirmed after liver transplantation.

Primary biliary cirrhosis and hereditary hemorrhagic telangiectasia: When two rare diseases coexist

Primary biliary cirrhosis is a slowly progressive cholestatic autoimmune liver disease that mainly affects middle-aged women with an estimated prevalence ranging from 6.7 to 402 cases per million. Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal dominant disorder characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations) that can affect many organs, including liver, with a prevalence of 1-2 cases per 10000. We describe the coexistence, for the first time to our knowledge, of these two rare diseases in a 50-year old Caucasian woman. In this setting, the relevance of an accurate medical history, the role of liver histology and the characterization of liver involvement through dynamic imaging techniques can be emphasized.

Potential Roles for Infectious Agents in the Pathophysiology of Primary Biliary Cirrhosis: What’s New?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease serologically characterized by the presence of high-titer antimitochondrial antibodies and, histologically by chronic nonsuppurative cholangitis and granulomata. The aetiology of the disease remains elusive, although genetic, epigenetic, environmental, and infectious factors have been considered important for the induction of the disease in genetically prone individuals. The disease shows a striking female predominance and becomes clinically overt at the fourth to sixth decade. These characteristics have prompted investigators to consider infections that predominate in women at these ages as the likely candidates for triggering the disease. Recurrent urinary tract infections due to Escherichia coli were the first infections to be considered pathogenetically relevant. Over the years, several other microorganisms have been linked to the pathogenesis of PBC owing to epidemiological, immunological, microbiological, or experimental findings in animal models. Recent studies have provided data supporting the pathogenic role of Novosphingobium aromaticivorans and betaretroviruses. Several reports have linked other organisms to the induction of the disease and/or the maintenance of the auto-aggressive responses that are perpetuated over the course of the disease. This review highlights the findings of the most recent studies investigating the link between infections and PBC. We also discuss the close interplay of the infectious agents with other environmental and genetic factors, which may explain the multifaceted nature of this puzzling disease.

Rheumatoid Arthritis and Primary Biliary Cirrhosis: Cause, Consequence, or Coincidence?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized serologically by cholestasis and the presence of high-titre antimitochondrial antibodies and histologically by chronic nonsuppurative cholangitis and granulomata. PBC patients often have concomitant autoimmune diseases, including arthropathies. This raises the question as to whether there are shared features in the pathogenesis of those diseases with the pathogenesis of PBC. Epidemiological and large case studies have indicated that although the incidence of rheumatoid arthritis (RA) is not significantly raised in PBC patients, there appears to be a higher rate of RA in PBC patients and their relatives. Genetic studies have demonstrated that several genes implicated in PBC have also been implicated in RA. Epigenetic studies provided a wealth of data regarding RA, but the findings on epigenetic changes in PBC are very limited. As well, certain infectious agents identified in the pathogenesis of PBC may also play a role in the pathogenesis of RA. These data suggest that although RA is not significantly present in PBC, some individuals with certain genetic traits and environmental exposures may develop both conditions. This concept may also apply to other concomitant diseases found in PBC patients.

Popular and unpopular infectious agents linked to primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the autoimmune destruction of the biliary epithelial cells of the small and medium-size bile ducts. The disease affects middle aged women and usually affects more than one member within a family. The pathognomonic serological hallmark of the disease is the presence of circulating anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies. Susceptibility genes and environmental risk factors such as infections and smoking have been reported as important for the development of the disease. Among the environmental agents, infectious triggers are the best studied. Most of the work published so far has investigated the role of infections caused by Novosphingobium aromaticivorans and Escherichia coli. This review will discuss the popular and unpopular infectious agents causatively linked to PBC. It will also examine reports investigating the epidemiological aspects of the disease and their direct or indirect implications to bacterial-induced PBC.

Abcb11 Deficiency Induces Cholestasis Coupled to Impaired β-Fatty Acid Oxidation in Mice

The bile salt export pump (BSEP) is an ATP-binding cassette transporter that serves as the primary system for removing bile salts from the liver. In humans, deficiency of BSEP, which is encoded by the ABCB11 gene, causes severe progressive cholestatic liver disease from early infancy. In previous studies of Abcb11 deficiency in mice generated on a mixed genetic background, the animals did not recapitulate the human disease. We reasoned that ABCB11 deficiency may cause unique changes in hepatic metabolism that are predictive of liver injury. To test this possibility, we first determined that Abcb11 knock-out (KO) C57BL/6J mice recapitulate human deficiency. Before the onset of cholestasis, Abcb11 KO mice have altered hepatic lipid metabolism coupled with reduced expression of genes important in mitochondrial fatty acid oxidation. This was associated with increased serum free-fatty acids, reduced total white adipose, and marked impairment of long-chain fatty acid β-oxidation. Importantly, metabolomic analysis confirmed that Abcb11 KO mice have impaired mitochondrial fatty acid β-oxidation with the elevated fatty acid metabolites phenylpropionylglycine and phenylacetylglycine. These metabolic changes precede cholestasis but may be of relevance to cholestatic disease progression because altered fatty acid metabolism can enhance reactive oxygen species that might exacerbate cholestatic liver damage.

Primary biliary cirrhosis: a multi‐faced interactive disease involving genetics, environment and the immune response

Primary biliary cirrhosis (PBC) is considered a model autoimmune disease based on several features, including the presence of a highly directed and very specific immune response to mitochondrial autoantigens, a female predominance, a targeted destruction of the biliary epithelium, and homogeneity between patients. It is essentially a chronic progressive cholestatic liver disease characterized by immune-mediated destruction of small- and medium-sized intrahepatic bile ducts. There is considerable variation in the incidence and prevalence of the disease between regions of the world, although such differences likely reflect not only a true disparity in disease but also differences in awareness; for example, in the United States, PBC is often detected in an asymptomatic stage based on multi-phasic clinical testing. There has been considerable progress at defining the immune response in this disease, including quantitation of autoreactive T cells against PDC-E2, the major mitochondrial autoantigen. The overwhelming data suggests that patients develop PBC based on a genetic predisposition and loss of tolerance to one or more environmental agents. In this review, we will present an updated overview of PBC and place it in the context of autoimmunity.

Twelve-Year-Old Girl with Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a slowly progressive cholestatic liver disease of autoimmune etiology. The initial presentation of PBC is varies from asymptomatic, abnormal liver biochemical tests to overt cirrhosis. Unlike other autoimmune liver diseases, PBC has rarely been reported in childhood. We report a case of primary biliary cirrhosis in a 12-year-old girl. In addition to characteristic histology features, strongly positive antimitochondrial antibodies, increased liver enzyme levels, increased serum quantitative immunoglobulin M levels, and cholestasis were discovered. She had been treated with ursodeoxycholic acid. In the world literature, we found only few pediatric patients of primary biliary cirrhosis. Aetiology, pathogenesis, the long-term natural history, and prognosis remain obscure. Due to increased awareness of early-onset PBC, rather than typical older ones, further pediatric cases may be discovered.

Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterized by circulating antimitochondrial antibodies (AMAs) as well as disease-specific antinuclear antibodies, cholestatic liver function tests, and characteristic histological features, including granulomas. A variety of organisms are involved in granuloma formation, of which mycobacteria are the most commonly associated. This has led to the hypothesis that mycobacteria may be involved in the pathogenesis of PBC, along with other infectious agents. Additionally, AMAs are found in a subgroup of patients with mycobacterial infections, such as leprosy and pulmonary tuberculosis. Antibodies against species-specific mycobacterial proteins have been reported in patients with PBC, but it is not clear whether these antibodies are specific for the disease. In addition, data in support of the involvement of the role of molecular mimicry between mycobacterial and human mitochondrial antigens as triggers of cross-reactive immune responses leading to the loss of immunological tolerance, and the induction of pathological features have been published. Thus, antibodies against mycobacterial heat shock protein appear to cross-recognize AMA-specific autoantigens, but it is not clear whether these autoantibodies are mycobacterium-species-specific, and whether they are pathogenic or incidental. The view that mycobacteria are infectious triggers of PBC is intriguing, but the data provided so far are not conclusive.

The Current Endeavors to Understand the Pathogenesis of Intractable Liver Diseases

The death due to liver diseases accounts for more the 35,000 cases every year in Japan for decades. Among these liver diseases, the Ministry of Health, Labor, and Welfare of Japan has named both fulminant hepatitis and primary biliary cirrhosis (PBC) as intractable liver diseases, since the precise mechanism of these diseases are unclear. Accordingly, there are no effective medical treatments other than liver transplantation toward these diseases. However, still the number of the liver transplantation performed in Japan is small. Thus, we have focused on the pathogenesis of these two intractable conditions. The fulminant hepatitis is a distinct form of acute hepatitis, and hepatitis B virus infection accounts for 20~30% of this lethal condition. Only tiny proportions of patients with acute HBV infection develop fulminant hepatitis (less than 10%). It has been widely believed both viral and host factors contribute for fulminant hepatitis, although still unknown factors are expected to be involved. On the other hand, PBC is a chronic progressive cholestatic liver disease. Clinical features of PBC include female predominance (80 to 90%), the presence of antimitochondrial antibody (up to 95%), and elevated serum levels of immunoglobulin M. Eventually, patients with PBC will develop liver failure due to biliary cirrhosis in spite of medical interventions. Immune-mediated processes are believed to be responsible for the pathogenesis, although the precise mechanism is yet to be determined. In this review article, our endeavors to understand the mechanism of these intractable liver diseases are discussed.

Sclerosing Cholangitis in Baboons (Papio spp) Resembling Primary Sclerosing Cholangitis of Humans

Primary sclerosing cholangitis is a chronic and progressive cholestatic liver disease that has been extensively documented in the human literature. Although it shares many features in common with chronic lymphocytic cholangitis in cats, primary sclerosing cholangitis has never been reported in a nonhuman primate. Primary sclerosing cholangitis is characterized by the presence of intrahepatic and/or extrahepatic inflammation and concentric fibrosis of bile ducts, eventually leading to cirrhosis and hepatic failure. The pathogenesis and cause remain unknown, but the disease likely involves a multifactorial mechanism with genetic- and immune-mediated components. The authors report 2 cases that histologically resemble the condition in humans; they consist of 2 adult male baboons with a clinical history of chronic elevated liver enzymes. In both cases, the liver was histologically characterized by thick bands of fibrosis and mild lymphoplasmacytic periportal cholangiohepatitis with concentric periductal fibrosis, resulting in atrophy and loss of bile ducts. Immunohistochemical analysis revealed positivity of hepatocytes to cytokeratin 7. Masson stain demonstrated marked biliary fibrosis. This is the first report that resembles sclerosing cholangitis in a nonhuman primate, and it suggests that the baboon may provide a useful animal model for this condition in humans.

Approaches to the pathogenesis of primary biliary cirrhosis through animal models

Primary biliary cirrhosis (PBC) is a chronic and progressive cholestatic liver disease of unknown etiopathogenesis that mainly affects middle-aged women. Patients show non-suppurative cholangitis with damage and destruction of the small- and medium-sized intrahepatic bile ducts. Characteristically, the disease is strongly associated with autoimmune phenomena such as the appearance of serum antimitochondrial autoantibodies (AMA) and portal infiltrating T cells against the inner lipoyl domain in the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Here we review the major characteristics of a series of inducible and genetically modified animal models of PBC and analyze the similarities and differences to PBC features in humans.

Successful heterozygous living donor liver transplantation for an oxysterol 7α-hydroxylase deficiency in a Japanese patient

Only 2 patients with an oxysterol 7α-hydroxylase deficiency caused by mutations of the cytochrome P450 7B1 (CYP7B1) gene have been reported; for both, the outcome was fatal. We describe the clinical and laboratory features, the hepatic and renal histological findings, and the results of bile acid and CYP7B1 gene analyses for a third patient. This Japanese infant presented with progressive cholestatic liver disease and underwent successful heterozygous living donor liver transplantation. Sources of relevant data included medical records, hepatic and renal histopathological findings, gas chromatography/mass spectrometry analyses of bile acids in serum and urine samples, and analyses of the CYP7B1 gene in the DNA of peripheral blood lymphocytes. Large excesses of 3β-hydroxy-5-cholen-24-oic acid were detected in the patient's serum and urine. Cirrhosis and polycystic changes in the kidneys were documented. The demonstration of compound heterozygous mutations (R112X/R417C) of the CYP7B1 gene led to the diagnosis of an oxysterol 7α-hydroxylase deficiency. After liver transplantation with an allograft from a heterozygous living donor (the patient's mother), the features of decompensated hepatocellular failure abated, and the renal abnormalities were resolved. In conclusion, we report the first Japanese patient with an oxysterol 7α-hydroxylase deficiency associated with compound heterozygous mutations of the CYP7B1 gene; in this patient, liver transplantation with an allograft from a parental donor was effective.

Su1417 The Role of EUS in the Diagnosis of Gallbladder Sludge in Refractory PSC: Could Therapeutic ERCP and Laparoscopic Cholecystectomy Be Helpful? A Single Center Report

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown etiology with no effective medical therapy. Transplantation remains the only life-extending treatment option for patients with end-stage PSC.

Bile acids for primary sclerosing cholangitis

Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients survival and disease outcome has yet been proven. To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded generally from inception through to October 2010. Randomised clinical trials comparing any dose of bile acids or duration of treatment versus placebo, no intervention, or another intervention were included irrespective of blinding, language, or publication status. Two authors extracted data independently. We evaluated the risk of bias of the trials using prespecified domains. We performed the meta-analysis according to the intention-to-treat principle. We presented outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). Eight trials evaluated ursodeoxycholic acid versus placebo or no intervention (592 patients). The eight randomised clinical trials have a high risk of bias. Patients were treated for three months to six years (median three years). The dosage of ursodeoxycholic acid used in the trials ranged from low (10 mg/kg body weight/day) to high (28 to 30 mg/kg body weight/day). Ursodeoxycholic acid did not significantly reduce the risk of death (RR 1.00; 95% CI 0.46 to 2.20); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 1.22; 95% CI 0.91 to 1.64); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.60; 95% CI 0.23 to 1.57). Ursodeoxycholic acid significantly improved serum bilirubin (MD -14.6 µmol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (MD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (MD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (MD -260 IU/litre; 95% CI -315 to -205), but not albumin (MD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was safe and well tolerated by patients with primary sclerosing cholangitis. We did not find enough evidence to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis. However, bile acids seem to lead to a significant improvement in liver biochemistry. Therefore, more randomised trials are needed before any of the bile acids can be recommended for this indication.

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.