Current Concepts in Liver Disease: An Update, Part 2
Moderator: Dr. Linda D. Ferrell
Section 1 -
Update on Primary Biliary Cirrhosis & Primary Sclerosing Cholangitis
Swan N. Thung
Professor of Pathology, and Gene & Cell Medicine
Mount Sinai School of Medicine
New York, NY
Primary biliary cirrhosis (PBC)
and primary sclerosing cholangitis (PSC)
biliary duct diseases, which progress eventually to biliary cirrhosis. Their etiology is unknown, but
both are probably immune–mediated disorders. Patients with PBC or PSC often present with elevated
canalicular enzyme (alkaline phosphatase and gamma-glutamyl transferase) activities with or without
The rest of the clinical picture and laboratory test results of patients with PBC or PSC are
characteristic, and the differentiation between the two is often not difficult. In some patients,
however, they are less typical and liver biopsy is needed. The clinical and pathologic differential
diagnoses are described.
Evidence suggests the role of genetic, immunologic, and infective factors in the development of both
PBC is associated with autoimmune conditions such as thyroid disease, sicca complex, rheumatoid
arthritis, dermatomyositis, systemic lupus erythematosus, CREST syndrome, and autoimmune hemolytic
anemia; and with the presence of anti-mitochondrial antibodies (AMA), which are directed at the E2
component of pyruvate dehydrogenase (PDC-E2), located on the inner mitochondrial membrane. The
relationship of mitochondrial antigens and antibodies to the pathogenesis of PBC has always been
speculative. PDC-E2 complex has been expressed on the bile duct epithelium of patients with early PBC
. Injection of AMA M2 autoantigen into a mouse model produced AMA M2 autoantibodies and bile duct
degeneration in these mice . Furthermore, spontaneous autoimmune biliary disease, which serologically
and pathogenetically mimicked PBC was recently described in NOD.c3c4 congenic mice . The latter mouse
model in addition to the deficient CD4+CD25+ regulatory T cells (Tregs) in patients with PBC as well as
in their daughters and sisters, support a genetic factor in the pathogenesis of PBC . PBC has been
reported in sisters, twins, mothers and daughters. In addition, there is increased prevalence of
HLA-DRw8 and C4A-QO in patients with PBC in the US. The prevalence of circulating AMA is increased in
relatives of patients. The AMA in patients with PBC cross-reacts with subcellular constituents of
Gram-negative and positive organisms, and the etiological role of enterobacterial antigens in intestinal
infection and Gram negative urinary infections have been suggested .
PSC is associated with ulcerative colitis (UC) in 70% of patients. Rarely, it is associated with
regional ileitis. The manifestation of PSC may precede that of ulcerative colitis. The prevalence of
PSC among patients with UC is about 5%. An increased prevalence of certain HLA haplotypes (A1, B8, DR3,
DR4, and DRW52A)
is seen .
Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in
majority of patients. Increased intercellular adhesion molecule-1 concentration in the serum also
suggests activation of patients' immune system . Increases in serum levels of circulating immune
complexes and in complement metabolism, in addition to their association with other autoimmune diseases,
such as thyroiditis and type1diabetes, further support the role of immunologic factors in PSC. It is,
however, unclear whether these immunologic changes actually cause PSC or are simply epiphenomena.
Infection of the biliary tree by microsporidium or Cryptosporidium results in cholangiographic and
histologic changes of PSC. This suggests that UC, which may cause leakage of bacteria or bacterial
products through damaged intestinal epithelium to the portal vein, may have the same effect.
Ninety percent of patients with PBC are women, usually 40-60 years of age. Patients
may be asymptomatic or may complain of pruritus, fatigue, or right upper quadrant pain. Hepatomegaly,
skin xanthomas, scratching marks on the skin, complains of backache and pain over the ribs from bone
changes associated with chronic cholestasis, and bleeding duodenal varices may be observed. Immune
mediated diseases as mentioned earlier are frequently associated with PBC
PSC affects predominantly men between 25-45 years, but can also occur in children as young as 2 years
It is no longer accurate to regard PSC as rare in children. Childhood PSC usually presents
in mid-childhood to early adolescence . Patients may be asymptomatic or experiencing fatigue, right
upper quadrant pain, pruritus and intermittent jaundice. Symptoms indicate advanced disease. Most
children present with nonspecific symptoms and in approximately 80% do not present with jaundice. Serum
alkaline phosphatase activity is persistently elevated, even in asymptomatic patients. Fever with or
without jaundice accompanies ascending cholangitis, which complicates biliary surgery, endoscopy or
occurs spontaneously. The ductal disease progresses eventually to biliary cirrhosis with its
complications, i.e. portal hypertension and/or hepatocellular failure .
In the overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis, the
aminotransferase activities are higher, and the autoimmune hepatitis component usually responds to
immunosuppressive treatment . Autoimmune hepatitis is an important "atypical" clinical picture of
childhood PSC, frequently with elevated IgG, and positive anti-nuclear antibodies (ANA) and anti-smooth
muscle antibodies (ASMA), in addition to features of cholestasis and bile duct disease. Clinical
response to corticosteroids in childhood PSC may be equivocal or incomplete .
Bile canalicular enzymes, e.g. alkaline phosphatase and gamma-glutamyl transferase are elevated in the
serum in both conditions. Serum copper, ceruloplasmin and liver copper content are also increased owing
to chronic cholestasis. Serum IgM is almost always elevated in PBC and in 50% of patients with PSC.
Bilirubin values are normal in the beginning and will rise at later stages of the disease. Low titers of
ANA and ASMA are present in both diseases. AMA with titers above 1:40 is characteristic for PBC, while
pANCA is found in at least two-thirds of patients with PSC .
PSC is readily diagnosed by the appearance on endoscopic retrograde
cholangiopancreatography (ERCP) as areas of irregular stricture formation and dilatation (beading)
involving the intrahepatic and/or extrahepatic bile ducts . If the disease involves only the small
bile ducts (small duct PSC), the ERCP appearance is similar to that of PBC, which is normal. Magnetic
cholangiopancreatography is also considered diagnostic technique for this disease ,
but its interpretation may be difficult in smaller children.
The histological appearances of PBC have been divided into 4 stages: stage 1 florid duct lesion;
stage 2 ductular reactions; stage 3 scarring (septal fibrosis and bridging);
stage 4 cirrhosis .
Staging of PBC, however, has its shortcomings, because the changes in the liver are focal, the different
stages may overlap, and there is no good correlation between the clinical picture and the stage. The
only diagnostic histological finding is the florid duct lesion (stage 1), in which the bile duct
epithelial cells are swollen or exhibit eosinophilic degeneration, irregular and the underlying basement
membrane is disrupted . This damaged bile duct is surrounded by a cellular reaction, which includes
lymphocytes, plasma cells, histiocytes and some eosinophils. Granulomas may be observed around the
ruptured bile ducts and in the lobules. Following the destruction, the bile ducts disappeared and the
bile ductules begin to proliferate (stage 2). Hepatic arterial branches can be identified without the
accompanying bile ducts. Loss of bile ducts results in changes of prolonged cholestasis e.g. increased
copper and copper-binding protein, cholate-stasis (ballooning), and Mallory hyalin in periportal
hepatocytes. Fibrosis extends from and connects adjacent portal tracts (stage 3). With increased
fibrosis, the inflammatory cells will decrease. Eventually, fibrous septa surround regenerative nodules
(stage 4). There may be variable degree of interface hepatitis and lobular inflammation. When they are
significant, an overlap of PBC and autoimmune hepatitis has to be considered. Nodular regenerative
hyperplasia has been described even in early stages of PBC.
Liver changes, especially in the earlier stages of PSC are non-specific and may be difficult to
differentiate from chronic hepatitis. Biopsy specimens show fibrosis and lymphocytic infiltration of
portal tracts with atrophy of bile ducts. The portal inflammation is always less than what is seen in
PBC. PSC is a fibro-inflammatory disease of bile ducts, resulting in periductal "onion-skin" fibrosis,
bile duct scars, and cholangiectases . Other changes secondary to the chronic bile duct disease and
cholestasis are similar to those seen in PBC, i.e. cholestasis, cholate-stasis, increased levels of
copper and copper-binding protein in periportal and periseptal hepatocytes, ductular reaction and
eventually biliary cirrhosis. Acute cholangitis may complicate PSC.
Secondary sclerosing cholangitis presents with the same histopathologic changes as PSC. Secondary
causes, including postoperative biliary stricture, ischemic cholangitis due to intrahepatic
chemoembolization, hepatic arterial thrombosis following liver transplantation, AIDS-related
cholangiopathy, bile duct neoplasm, Langerhans cell histiocytosis, and cystic fibrosis can usually be
excluded by the patient's history, physical examination, and laboratory tests.
The course is variable and unpredictable in both diseases, particularly among the asymptomatic
patients. Prognostic models in PBC are based on Cox's regression analysis, which depends on age, serum
albumin and bilirubin levels, prothrombin time, and the presence or absence of edema .
Hepatocellular carcinoma, lymphoma and breast carcinoma are malignancies sometimes associated with PBC
PSC with involvement of extra-hepatic ducts has a worse prognosis than intra-hepatic alone. PSC with
normal cholangiography (=small duct PSC) gives better overall transplantation-free survival than large
duct PSC. The level of serum bilirubin, histological stage of the fibrosis, age, sex (women have poorer
prognosis than men) and the presence of splenomegaly (portal hypertension) are factors that influence
survival. Sclerosing cholangitis, in addition, is a risk factor for cholangiocarcinoma. A small group
of patients may do well, but the majority of patients suffer from cholestatic jaundice, portal
hypertension with variceal bleeding, liver failure and cholangiocarcinoma. Cholangiocarcinoma may
develop in approximately 10% of patients with PSC.
There is no specific treatment for PBC or PSC. Control of itching and replacement of fat-soluble
vitamins is important in jaundiced patients. Ursodeoxycholic acid (UDCA) has been shown to improve the
biochemical expression of liver damage in patients with cholestatic liver diseases
studies, histology was shown to improve, and treatment for at least 2 years, prolonged survival in one
study . Other treatments using methotrexate, immunosuppressive drugs, colchicine, etc, have been
tried in PBC with little or no benefits
Bacterial cholangitis in PSC is treated with broad-spectrum antibiotics. Local strictures in major
bile ducts may be relieved by introduction of stents, using balloon dilation via
transhepatic or endoscopic routes .
Liver transplantation should be considered for patients with uncontrollable itching, ascites, hepatic
encephalopathy, and bleeding esophageal varices. Timing of liver transplantation is important Results
are excellent in PBC with 1 year survival about 85-90% and a 5 year survival of 60-70%. Recurrence of
PBC in the allografts ranges between 5-35%
Recurrence of PSC in the allograft has been reported
Bile duct problems occur more frequently in PSC than in patients transplanted for other causes.
Other causes of sclerosing cholangitis in allografts, such as ischemic cholangitis or rejection have to
be considered as well in the differential diagnoses.
- Ahrens EH Jr, Payne MA, Kunkel HG, et al. Primary biliary cirrhosis. Medicine 1950; 29: 199.
- Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis: chronic non-suppurative destructive cholangitis. Am J Pathol 1965; 46: 387.
- Kaplan MM, Gershwin ME: Primary biliary cirrhosis. N Engl J med 2005;353:1261.
- Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med 1995; 332: 924.
- Farrant JM, Hayllar KM, Wilkinson ML, et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 1991; 100: 1710.
- Van de Water J, Turchany J, Leung PSC, et al. Molecular mimicry in primary biliary cirrhosis. Evidence for biliary expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2. J Clin Invest 1993; 91: 2653.
- Jiang XH, Zhong RQ, Fang XY, et al: Establishment of a mouse model of primary biliary cirrhosis by AMA M2 autoantigen injection. Zhonghua Gan Zang Bing Za Zhi 2006;14:202..
- Irie J, Wu Y, Wicker LS, et al: NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006;203:1209.
- Lan RY, Cheng C, Lian ZX et al: Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology 2006;43: 729.
- Butler P, Valle F, Hamilton-Miller JMT, et al. M2 mitochondria antibodies and urinary rough mutant bacteria in patients with primary biliary cirrhosis and in patients with recurrent bacteriuria. J Hepatol 1993; 17: 408.
- Mehal WZ, Lo YM, Wordsworth BP, et al. HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis. Gastroenterology 1994; 106: 160.
- Polzien F, Ramadori G. Increased intercellular adhesion molecule-1 serum concentration in cholestasis. J Hepatol 1996; 25: 877.
- Heathcote EJ. Management of primary biliary cirrhosis. Hepatology 2000;31: 1005-1013.
- Prince MI, Jones DE,. Primary biliary cirrhosis: new perspectives in diagnosis and treatment. Postgrad Med J 2000; 76: 199.
- Wilshanski M, Chait P, Wade JA, et al. Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis. Hepatology 1995; 22: 1415.
- El-Shabrawi M, Wilkinson ML, Portmann B, et al. Primary sclerosing cholangitis in childhood. Gastroenterology 1987; 92: 1226.
- Feldstein AE, Perrault J, El-Youssif M, et al: Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 2003;38:210.
- Floreani A, Rizzoto ER, Ferrara F, et al: Clinical course and outcome of autoimmune hepatitis / primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol 2005;100: 1516.
- Lo SK, Fleming KA, Chapman RW. A 2 year follow-up study of anti-neutrophil antibody in primary sclerosing cholangitis: relationship to clinical activity, liver biochemistry and ursodeoxycholic acid treatment. J Hepatol 1994; 21: 974.
- Ludwig J, MacCarthy RL, LaRusso NF. Intrahepatic cholangiectases and large duct obliteration in primary sclerosing cholangitis. Hepatology 1986; 6:560.
- Angulo P, Pearce DH, Johnson CD, et al: Magnetic resonance cholangiography in the evaluation of the biliary tree: its role in patients with primary sclerosing cholangitis. J Hepatol 2000;33:520.
- Ludwig J, Dickson ER, McDonald GS: Staging of chronic non-suppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch Pathol Anat 1978;379:103.
- Nak anuma Y, Tsuneyama K, Gershwin ME, et al. Pathology and immunopathology of primary biliary cirrhosis with emphasis on bile duct lesions: recent progress. Semin Liv Dis 1995;15:313.
- Lefkowitch JH. Primary sclerosing cholangitis. Arch Intern Med 1982; 42:1157.
- Dickson ER, Grambsch PM, Fleming TR, et al. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10:1.
- Tanaka Y, Naitoh M, Yoshiura K, et al. Hepatocellular carcinoma arising in an elderly male with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2000; 2:239.
- Ye MQ, Suriawinata A, Black C, Min AD, Strauchen J, Thung SN. Primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in a patient with primary biliary cirrhosis Arch Pathol Lab Med 2000; 124: 604
- Heathcote EJ, Cauch-Dudek K, Walker V, et al. The Canadian multicenter double-blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19:1149.
- Combes B, Carithers RL Jr, Maddrey WC, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995;22:759.
- Poupon RE, Balkau B, Eschwege E, Poupon R, UDCA-PBC Study Group. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991;324:1548.
- Bach N, Thung SN, Schaffner F. The histologic effects of low-dose methotrexate therapy for primary biliary cirrhosis. Arch Pathol Lab Med 1998;122:342.
- Combes B, Emerson SS, Flye NL, et al: Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 2005;42:1009.
- Linberg B, Arnelo U, Bergquist A, et al: Diagnosis of biliary strictures in conjunction with endoscopic retrograde cholangiopancreatography with special reference to patients with primary sclerosing cholangitis. Endoscopy 2002;34:909.
- Wong PYN, Portmann B, O'Grady JG, et al. Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. J Hepatol 1993;17: 284.
- Esquivel CO, van Thiel DH, Demetris AJ, et al. Transplantation for primary biliary cirrhosis. Gastroenterology 1988;94:1207.
- Hubscher SG, Elias E, Buckels JAC, et al. Primary biliary cirrhosis: Histological evidence of disease recurrence after liver transplantation. J Hepatol 1993;18:173.
- Guy JE, Qian P, Lowell JA, Peters MG: Recurrent primary biliary cirrhosis: peritransplant factors and ursodeoxycholic acid treatment post-liver transplant. Liver Transpl 2005;11:1252.
- Harrison RF, Davies MH, Neuberger JM, et al. Fibrous and obliterative cholangitis in liver allografts: evidence of recurrent primary sclerosing cholangitis ? Hepatology 1994; 20: 356.
- Graziadei IW, Wiesner RH, Marotta PJ, et al. Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis. Hepatology 1999; 30: 1121-1127.