Primary biliary cirrhosis and primary sclerosing cholangitis

Primary biliary cirrhosis and primary sclerosing cholangitis are the most common chronic cholestatic liver diseases in adults that lead to biliary cirrhosis and its inherent complications such as portal hypertension and liver failure. Although important advances in the understanding of the pathogenesis of these conditions have been accomplished in the last two decades, much work is needed to uncover the interaction of genetic and immunologic mechanisms involved in their pathogenesis. Ursodeoxycholic acid at dosage of 13 to 15 mg/kg/d is the only agent that can currently be recommended in the treatment of PBC. No medical therapy aimed at disrupting disease progression is available for patients with primary sclerosing cholangitis, although several agents with different properties are currently under evaluation. Liver transplantation is the treatment of choice for patients with primary biliary cirrhosis and primary sclerosing cholangitis with end-stage liver disease.     

Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 microm in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P <.0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases.     

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.     

Primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune cholangitis

Primary biliary cirrhosis (PBC), and autoimmune cholangitis are presumed to be autoimmune cholestatic diseases, but the relevant antigens are unknown. Primary biliary cirrhosis is diagnosed by a positive serum mitochondrial antibody test. It usually affects women and has a very long course, culminating in liver transplantation or death. Ursodeoxycholic acid is probably the appropriate treatment. Primary sclerosing cholangitis (PSC) is marked by progressive destruction of extrahepatic and intrahepatic bile ducts. There is no specific diagnostic test or treatment. Cholangiocarcinoma is the dreaded complication and precludes liver transplantation, the only chance of a cure. Autoimmune cholangitis overlaps PBC and autoimmune chronic hepatitis. It is a rare condition, resembling PBC but with a negative serum mitochondrial antibody test; however, serum antinuclear antibodies and smooth muscle antibodies are present in high titers.     

Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND/AIMS: Former studies reported a high prevalence of depression in patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These studies hypothesized that the presence of depression could explain the fatigue experienced by these patients. METHODS: Our aim was to study the prevalence of depression in a Dutch population with PBC and PSC. In addition, to investigating the effects of using an additional diagnostic structured psychiatric interview, after screening with the Beck Depression Inventory (BDI), a self-report severity scale instrument used in former studies. Patients with PBC and PSC (n=92) completed the BDI. Patients with scores of 10 or higher (n=39) were interviewed using a structured psychiatric interview. Patients with scores lower than 10 were at random (30/53, 57%) also interviewed using a structured psychiatric interview. RESULTS: Of the 92 patients that were included 42% had depressive symptoms according to the BDI. However, of these patients only 3.7% had a depressive syndrome according to the DSM-IV criteria as assessed with the structured psychiatric interview. CONCLUSIONS: The prevalence of a depressive disorder in patients with PBC and PSC is not higher than in the general population. Fatigue in patients with PBC and PSC cannot be explained by depression.     

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.     

HLA DPB Polymorphism in primary sclerosing cholangitis and primary biliary cirrhosis

In recent years there has been an increasing interest in the link between susceptibility to autoimmune liver disease and genes of the HLA system, although the role of the DPB1 locus in British patients has only been investigated in autoimmune hepatitis. The aim of the current study was to determine the distribution of DPB1 alleles in a large series of British patients with the two other autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, and compare the allele frequencies obtained with those of a geographically matched control group. Polymerase chain reaction sequence-specific oligonucleotide probing was used to assign 18 DPB1 alleles in 82 patients with primary biliary cirrhosis (PBC), 71 patients with primary sclerosing cholangitis (PSC), and 103 controls. The frequencies of the DPB1 alleles were not significantly different comparing patients and controls. However, two important observations were made. Firstly, in primary sclerosing cholangitis, the previously reported association with the haplotype A1-B8-DR3-DQ2 does not extend to the DPB1 locus, suggesting that the genetic determinants of susceptibility for this disease lie closer to the DRB loci. Secondly, in primary biliary cirrhosis there is evidence that the reported association with DR8-DQB110402 includes the DPB110301 allele. The weak HLA association reported here is in contrast with recent data from Japan, where susceptibility is strongly linked to a particular amino acid residue encoded by the DPB110501 allele. These data clearly demonstrate that the alleles of the DPB1 locus are not associated with susceptibility to or protection from either primary biliary cirrhosis or primary sclerosing cholangitis in British patients.     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.     

Adhesion molecule expression in primary sclerosing cholangitis and primary biliary cirrhosis.

There are conflicting reports regarding intercellular adhesion molecule-1 (ICAM-1) expression in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Expression of adhesion molecules ICAM-1, lymphocyte adhesion molecule-1 (LFA-1), vascular cell adhesion molecule (VCAM), and E-selectin was examined together with HLA-DR in 16 liver biopsy specimens showing PSC and 12 specimens showing PBC. These were compared with biopsy specimens showing large duct obstruction (n = 7), chronic active hepatitis (n = 4), alcoholic liver disease (n = 4), and normal liver histological results (n = 5). ICAM-1 was detected on biliary epithelium in five of seven PSC specimens of histological stage 3 or 4, but not in nine early PSC specimens or in specimens from disease controls. In PBC, ICAM-1 was positive on three of 12 cases, two stage 2, and one stage 3. Nine of 16 PSC specimens (three of nine early, six of seven late disease) and six of 10 PBC specimens (three early, three late disease) were positive for HLA-DR. LFA-1 stained infiltrating inflammatory cells in PSC, PBC, and disease controls. In conclusion, ICAM-1 expression on biliary epithelium in PSC occurs mainly in late stage disease and therefore may be secondary to previous events inducing inflammation rather than of primary pathogenic importance. ICAM-1 expression in PBC is less common and not clearly associated with a particular disorder. Previous reports of ICAM-1 prevalence may have been biased towards end stage, pre-transplantation biopsy specimens.     

Recurrence of primary biliary cirrhosis, autoimmune cholangitis and primary sclerosing cholangitis after liver transplantation

Given the usually prolonged natural history of primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis, and the relatively recent introduction of orthotopic liver transplantation, our understanding of recurrence of these autoimmune diseases after orthotopic liver transplantation has been slow to evolve. Present data suggest that after orthotopic liver transplantation, patients with primary biliary cirrhosis will have persistence of serum antimitochondrial antibodies, develop histologic lesions suggestive of recurrent primary biliary cirrhosis with a frequency in the 8% to 16% range at 2 to 5 years after orthotopic liver transplantation, but will demonstrate little if any symptomatic disease as a consequence. Although data are extremely limited, autoimmune cholangitis patients will have a similar post-transplant course (without antimitochondrial antibodies). Recurrence of primary sclerosing cholangitis remains the most controversial, however, these patients probably develop nonanastomotic intrahepatic and extrahepatic strictures more frequently than patients without primary sclerosing cholangitis, with a frequency in the 20% to 25% range at 3 to 5 years. With longer patient follow-up and additional studies, it is hoped that our understanding of recurrent autoimmune biliary diseases will grow considerably in the future.     

Pathogenesis of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune cholangiopathy

Autoimmune liver diseases have much in common with each other, and there are clear associations with genetic haplotypes. Elegant studies have shown autoimmune liver disease induced by viruses and drugs. Although there is evidence for nonimmunological events precipitating immune disease, especially in primary sclerosing cholangitis, the precise pathways, what is bystander and what is essential, have not been determined. This article reviews some of the mechanisms involved in pathogenesis.     

Reovirus type 3 infection in patients with primary biliary cirrhosis and primary sclerosing cholangitis

Reovirus type 3 (Reo-3) infection has recently been implicated in the pathogenesis of certain idiopathic, cholestatic liver diseases of newborns. In the present study, antibody titres to Reo-3 virus (anti-Reo-3) were determined in sera from 43 adults with idiopathic cholestatic liver disease, including 34 patients with primary biliary cirrhosis (PBC) and 9 patients with primary sclerosing cholangitis (PSC). Seventy-four adults with various other causes of chronic liver disease and 16 healthy volunteers served as controls. Geometric mean titres of anti-Reo-3 were significantly higher in PBC and PSC sera than chronic liver disease and healthy controls (P less than 0.005). Mean antibody titres for all patient groups, however, were within the 95% confidence limits for normals. Seven of 34 (21%) PBC patients and 3/9 (33%) PSC patients had elevated titres of anti-Reo-3, as compared to only 4/74 (5%) chronic liver disease (P less than 0.05) and 0/16 (0%) healthy control subjects (P less than 0.05) (Fisher's Exact Test). Antibody titres to five other common viruses were normal in patients with high anti-Reo-3 titres when compared to age- and sex-matched controls with liver disease. Immunoperoxidase staining for Reo-3 viral markers and cultures of liver biopsy material for Reo-3 virus were negative in both patients and controls. The results of this study indicate that, although patients with PBC and PSC have higher anti-Reo-3 antibody titres than patients with other forms of chronic liver disease or healthy volunteers, only a minority of these patients have titres that exceed the 95% confidence limits for normals.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Recurrence of primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation in Japan

Although there was some initial controversy, there is now a consensus that primary biliary cirrhosis (PBC) does indeed recur in both cadaveric and living donated allografts. Recurrence rate after deceased donor liver transplantation (LT) was reported to be 10.9–23% at 5 years. In the present study, we reviewed 221 PBC patients who underwent living-donor liver transplantation (LDLT) in Japan. The 5-year overall survival rate was 79%, and the rate of recurrence based on histological findings was 10% (7/70) after a median time of 36 months. Primary immunosuppression, withdrawal of corticosteroids and human leukocyte antigen matches were not associated with the recurrence. Recurrent PBC appears to have little impact on graft function and survival, but this may become a greater problem with longer follow up.
It is noteworthy that the 10-year survival of primary sclerosing cholangitis (PSC) patients who underwent LDLT wasfound to be only 39.1% in Japan, whereas that of PBC was 72.9%. Factors associated with the poor prognosis include biliary strictures, hepatobiliary and colorectal malignancies, and recurrence of PSC. In our study, we reviewed 66 patients with PSC who underwent LDLT in Japan. The 5-year survival rate was 72%, and the rate of recurrence diagnosed on histological and cholangiographic findings was 25% (11/44). Well-defined diagnostic criteria and longer studies are required to characterize the nature of recurrent PSC and its impact on graft survival in more detail.