Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with endstage liver disease and yields excellent long-term survival in both groups.     

Cirrhosis and autoimmune liver disease:Current understanding

Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.     

Overlap syndromes

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

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis（AIH）,primary biliary cirrhosis（PBC） and primary sclerosing cholangitis（PSC）.Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis（AMA-negative PBC） overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.     

Liver transplantation in autoimmune liver disease--selection of patients

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune liver diseases, which are good indications for orthotopic liver transplantation (OLT). While there is effective treatment for AIH (steroids with or without azathioprine) and PBC (Ursodesoxycholic acid) no such treatment is currently established for PSC. The need for transplantation can be delayed for AIH and PBC with appropriate therapies, while treatment options for PSC are still controversially discussed. Although the time point for liver transplantation can be roughly estimated for AIH by failure of immunosuppressive therapy and for PBC by prognostic models, the prediction of survival in patients with PSC is more difficult, and further complicated through the risk of developing cholangiocellular carcinoma (CCC). Long-term (5-year) outcome after liver transplantation approaches 80-90% for autoimmune liver diseases unless CC complicates PSC at the time of OLT. The risk of disease recurrence has been recognized for each of these entities although its clinical relevance is controversial. This gets more important as long-term survival can be achieved for most of these patients today. In this review the natural course of autoimmune liver disease will be discussed and prognostic models will be presented, which are helpful for finding the optimal time point for liver transplantation.     

Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis

Opinion statement Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients’ well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.     

Liver transplantation in PBC and PSC: indications and disease recurrence

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent major indications for liver transplantation (LT). Despite the steady increase in the incidence and prevalence of PBC, the number of liver transplants for PBC has fallen in recent years, whereas the number of transplants for PSC has remained stable. Indications for LT for PBC and PSC are no different from those of other causes of chronic liver disease, apart from some disease-specific indications. PBC and PSC have more favourable outcomes after LT, compared to viral hepatitis and alcohol-associated liver disease. Numerous studies have clearly demonstrated that PBC and PSC recur after LT. The diagnosis of recurrent disease should be made on agreed criteria. The impact of recurrent disease on survival is unclear. Study of recurrent PBC and PSC may provide a better understanding of the mechanisms of these diseases in the native liver.     

Recurrence of cholestatic liver disease after living donor liver transplantation

End-stage liver disease, due to cholestatic liver diseases with an autoimmune background such as primary biliary cirrhosis （PBC） and primary sclerosing cholangitis （PSC）, is considered a good indication for liver transplantation. Excellent overall patient and graft outcomes, based mostly on the experience from deceased donor liver transplantation （DDLT）, have been reported. Due to the limited number of organ donations from deceased donors in most Asian countries, living donor liver transplantation （LDLT） is the mainstream treatment for end-stage liver disease, including that resulting from PBC and PSC. Although the initial experiences with LDLT for PBC and PSC seem satisfactory or comparable to that with DDLT, some aspects, including the timing of transplantation, the risk of recurrent disease, and its long-term clinical implications, require further evaluation. Whether or not the long-term outcomes of LDLT from a biologically related donor are equivalent to that of DDLT requiresfurther observations. The clinical course following LDLT may be affected by the genetic background shared between the recipient and the living related donor.     

Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels

Background Bezafibrate is a commonly used medicine for hyperlipidemia, and recently several reports have suggested the efficacy of bezafibrate for the treatment of primary biliary cirrhosis (PBC). To assess its efficacy for other liver diseases, we administered bezafibrate to patients with various categories of hepatobiliary impairment. Methods Bezafibrate (400 mg/day) was orally administered to 67 patients with chronic liver disease [22 with PBC, six with primary sclerosing cholangitis (PSC), 20 with chronic liver disease associated with hepatitis C virus (HCV) infection (CLD-C), seven with auto immune hepatitis (AIH), ten with alcoholic liver injury, and two with drug-induced liver injury]. Results The levels of biliary enzymes, such as alkaline phosphatase and γ-glutamyltranspeptidase, decreased promptly and dramatically. The abnormally high level of alanine aminotransferase also showed a gradual decrease over 6 months in five of the eight PBC patients, all three PSC patients, eight of the 17 CLD-C patients, and all seven alcoholic liver injury patients. The level of immunoglobulin M showed a gradual decrease in 17 of the 22 PBC patients. Conclusions Bezafibrate significantly reduced the level of biliary enzymes in various chronic liver diseases and may be useful for the treatment of certain liver disease subsets.     

Latest and Emerging Therapies for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common causes of chronic cholestatic liver disease in adults. In PBC, therapy with ursodeoxycholic acid (UDCA) is safe and has been associated with tangible biochemical, histologic, and survival benefits. However, a need for different or adjuvant therapies remains for specific subsets of PBC patients, including those who do not respond to UDCA and those who have advanced histologic disease at presentation. Similarly, beneficial therapies for disease-related symptoms that do not typically respond to UDCA (eg, fatigue and pruritus) are still needed. In contrast to PBC, no medical therapy of proven benefit has been identified for patients with PSC. In PBC and PSC, adequate management of complications of chronic cholestasis is important. For both diseases, liver transplantation is the only curative option.     

Autoimmunerkrankungen der Leber

Autoimmune liver diseases are divided into autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). They play an important role in the differential diagnosis of acute and chronic liver diseases. Diagnostic criteria consist of biochemical parameters (liver function tests, immunoglobulins, autoantibodies), imaging (ultrasound, MRCP, ERCP) and histopathologic characteristics. The treatment of choice in AIH is a combined immunosuppressive therapy of prednisolone and azathioprine. Ursodeoxycholic acid is the treatment of choice for PBC and improves liver biochemistry and prolongs transplant-free survival by slowing histological progression in the majority of patients. To date, there is no effective medical treatment option for patients with PSC.     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.     

Liver transplantation and autoimmunity.

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent good indications for orthotopic liver transplantation (OLT). While there is effective treatment for AIH (steroids with or without azathioprine) and PBC (ursodeoxycholic acid) no such treatment is currently established for PSC. The need of transplantation can be delayed for AIH and PBC with appropriate therapies, while treatment options for PSC are still controversially discussed. Although the time point for liver transplantation can be roughly estimated for AIH by failure of immunosuppressive therapy and for PBC by prognostic models, the prediction of survival in patients with PSC is more difficult, and further complicated by the risk of developing cholangiocellular carcinoma. Long term (5-year) outcome after liver transplantation approaches 80 to 90% for autoimmune liver diseases unless cholangiocellular carcinoma complicates PSC at the time of OLT. The risk of disease recurrence has been recognised for each of these entities although its clinical relevance is controversial and not exactly determined today. As survival after liver transplantation is steadily increasing, recurrent autoimmune liver disease may become a clinical problem in the future. Recently de novo autoimmune hepatitis after liver transplantation has been reported from several transplant centres, although its importance still needs to be established.     

Liver transplantation for cholestatic liver disease

Opinion statement Liver transplantation is an effective form of therapy for patients with end-stage cholestatic disease that improves both survival and quality of life. Liver transplantation is very effective for the treatment of intractable pruritus but less effective for the treatment of lethargy. Survival rates are good (more than 70% at 5 years); these patients are at greater risk of developing acute and chronic rejection and are more likely to require long-term immunosuppression. Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) recur in the graft. Recurrent PSC may be difficult to differentiate from secondary sclerosing cholangitis, but it recurs in up to 60% of patients at 5 years and may reduce graft survival. PBC recurrence, noted in up to 40% of patients at 10 years, has little effect on graft survival with respect to cancers. Patients with PSC are at greater risk of both colonic cancer (which may be reduced by ursodeoxycholic acid) and cholangiocarcinoma. Diagnosis of cholangiocarcinoma before transplantation usually contraindicates transplantation. The main challenges facing liver transplantation are the need to expand the donor pool and the need to find immunosuppressive regimens with fewer long-term toxicities.     

Hepatic copper content is normal in early primary biliary cirrhosis and primary sclerosing cholangitis

In previous studies, the majority of patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), had increased hepatic copper (Cu) levels even in early stages of disease. We prospectively measured hepatic copper content by atomic absorption spectrophotometry in 55 patients with PBC, 6 patients with PSC, and 29 patients with other chronic noncholestatic liver diseases. Hepatic Cu content was normal in 22/61 (36%) of patients with PBC or PSC; 18 of the 22 did not have cirrhosis (82%). Hepatic Cu content increased with increasing stage of disease (r=0.61,P<0.001) and was positively correlated with serum total bilirubin (r=0.6,P<0.0001) and alkaline phosphatase (r=0.5,P<0.001). All patients with stage I and II disease had hepatic Cu<150 µg/g dry weight, and all patients with hepatic Cu>150 µg/g dry weight had stage III and IV disease. Hepatic Cu content is normal in early PBC and PSC. Copper accumulation in the liver in these cholestatic liver diseases is secondary to cholestasis rather than a primary phenomenon.Supported by General Research Center grant MOIRR0054 from the National Institutes of Health.     

Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver. METHODS: Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation. RESULTS: In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers. CONCLUSION: These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.     

自身免疫性肝病活检组织病理学特征分析109例

目的:分析比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)及其重叠综合征的组织病理学变化,提高对自身免疫性肝病(AILD)的认识.方法:对27例AIH、67例PBC、4例PSC、1例AIH-PSC重叠综合征和10例AIH-PBC重叠综合征患者的肝穿组织病理资料进行回顾性分析.结果:AILD患者多发于中年女性(73.3%),肝组织病理变化以界面性肝炎为主(77.7%),在重度患者则出现重度界面性肝炎、桥样坏死等.PBC患者早期(Ⅰ、Ⅱ)占28.3%,而晚期(Ⅲ、Ⅳ)占71.7%,肝组织病理变化以小胆管减少甚至消失为主(62.6%).AIH-PBC重叠综合征患者并非罕见,他的肝组织病理学具有AIH和PBC的双重特征.结论:AILD是非病毒性肝病的重要组成部分,其诊断需综合临床表现、生化、免疫指标和组织学变化.     

Autoimmune liver disease: diagnosis and therapy

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndromes of these three disease entities are regarded as autoimmune liver diseases. These conditions are important differential diagnoses of elevated liver function tests as about 10 % of liver transplantations in Europe and North America are for these indications. The diagnosis is often difficult but can be facilitated by sequential measurement of relevant autoantibodies, exclusion of other liver disease, ultrasound, ERCP and liver histology. In AIH immunosuppressive therapy has been shown to prevent or stop the development of cirrhosis and improve the prognosis of the patients decisively. In other autoimmune liver diseases this evidence is missing making individual therapeutic decisions necessary. Ursodesoxycholic acid (UDCA) seems to slow disease progression in particular in early stages of PBC.     

An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection

A case-control study was undertaken to describe the prevalence of Strongyloides stercoralis infection among patients with autoimmune liver diseases, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC). This study covered 4,117 patients who were admitted to hospitals in Okinawa, Japan, between 1988 and 2006. During this period, 538 patients had the following chronic liver diseases: PBC, AIH, PSC, chronic viral hepatitis group, and alcoholic liver disease. The other 3,579 patients who were hospitalized and underwent parasitologic tests served as controls. The frequency of S. stercoralis infection in the autoimmune liver diseases group (1.0%) was lower than that found in the control group (7.0%; P = 0.0063). None of the female patients with PBC born before 1955 had S. stercoralis infection, which was also statistically significant (P = 0.045). We hypothesized that immunomodulation by S. stercoralis infection may lower the incidence of autoimmune liver disease.     

Autoimmune hepatitis and overlap syndromes

Autoimmune hepatitis (AIH) is an immune-mediated, autodestructive liver disease with hepatocytes as target cells, mostly affecting young women. Primary biliary cirrhosis (PBC) is also regarded as an autoimmune liver disease with bile duct epithelia as the target cells, resulting in a continuous loss of bile ducts. Both diseases may occur simultaneously in their full manifestations in about 10% to 20% of cases, thus constituting an overlap syndrome with PBC directing the course of the disease. AIH may also occur simultaneously with primary sclerosing cholangitis (PSC), with a frequency of between 2% and 8% of patients with PSC. In most cases, AIH precedes manifestation of PSC. In children, the overlap syndrome of AIH and PSC seems to make up an entity of its own: autoimmune sclerosing cholangitis.