Primary Biliary Cirrhosis

Definition

Autoimmune disorder in middle-age females where there is chronic non-suppurative destruction of bile ducts resulting in cirrhosis. Antimitochondrial antibody to M2 component of pyruvate dehydrogenase is found in 90% of the cases.

Clinical Features

Nearly 10× more frequent in females than males
Usually insidious onset starting with pruritus

Pathogenesis

Considered to be autoimmune:
- often other autoimmune disorders
- proof strong, but only indirect and circumstantial1

Gross Pathology

Basic lesion:
- chronic, nonsuppurative, destructive cholangitis:
  - possibly ending in cirrhosis2

Histopathology

Early Stage

Involves ducts 40–80μm diameter:
- i.e. segmental and larger interlobular ducts
- size may be difficult to estimate because some enlarge apparently through:
  - damage to basement membrane
  - reactive hyperplasia of lining epithelium3
Lesions:
- focal in liver
- segmental within duct system
Affected duct segments:
- epithelial swelling or eosinophil condensation
- possibly stratification
- infiltration by lymphocytes and plasma cells
- damage of basement membrane may lead to rupture
- inflammatory cells accumulate beside or around duct (Fig. 1
  Fig. 1: Granulomatous cholangitis in primary biliary cirrhosis (PBC). Detail from a portal tract with dense lymphoplasmacytic infiltrate and lymphoid aggregate (left). The interlobular bile duct (center) shows a focal rupture of its cholangiocytic lining, at the site of an adjacent epithelioid granuloma. (H&E)
  ):
  - mainly lymphocytes:
    - sometimes aggregated in lymphoid follicle with germinal center
  - may be:
    - abundant plasma cells
    - quite prominent eosinophils
    - neutrophils
    - single or small clusters of epithelioid cells:
      - sometimes epithelioid granulomas close to or surrounding bile duct
Smaller ducts:
- may be surrounded by edema or fibrosis:
- presumably result of more distal obstruction
May be parenchymal changes:
- lobular infiltration by scattered lymphocytes
- nodular regenerative hyperplasia:4
  - together with narrowing of portal vein branches,5 may explain development of portal hypertension before development of fibrosis and cirrhosis
- lesions of chronic cholestasis absent or minimal

Histologic Progression

Most cases within 2 years:
- 20% remain histologically stable
- sustained regression in 2%6
Extension beyond limits of portal tract
Increasing:
- fibrosis
- disturbance of lobular architecture
Appears to be driven by:
- periportal and architectural changes of chronic cholestasis
- lymphocytic interface hepatitis (piecemeal necrosis):7,8
  - intralobular ‘invading’ lymphocytes play role in development of septal fibrosis 9 (Fig. 2
    Fig. 2: Primary biliary cirrhosis, stage 3. The picture shows portal–portal septal fibrosis (septal stage 3), portal inflammation with lymphoid aggregate, absence of interlobular bile duct (ductopenia), and cholate stasis in periportal and periseptal parenchyma. (H&E)
    )
  - may be variable degree of intralobular necroinflammation10
May be liver cell dysplasia of large and small cell type11
Progressive ductopenia

Advanced Cases

Portal lymphoid aggregates mark site of disappeared bile ducts (see Fig. 2)
Cholestatic and hepatitic features result in progressive fibrosis with:
- portal–portal septum formation
- additional portal–central septa9
Resulting cirrhosis:
- biliary type when cholestatic features predominate
- more macronodular type when predominance of hepatitic features
- may be any combination of two patterns
Hepatitic-type lesions appear most important for progression of fibrosis12

Special Stains and Immunohistochemistry

Antimitochondrial antibodies:
- in >90% of patients1
- most specific against M2 component of pyruvate dehydrogenase complex
Aberrant expression of cytokeratin 7 in hepatocytes (Fig. 3
Fig. 3: Primary biliary cirrhosis. Detail of portal tract and surrounding parenchyma. This cytokeratin 7 immunostain highlights an increase in the number of ductular structures at the portal tract periphery; expression of cytokeratin 7 in periportal hepatocytes (early stage of cholate stasis), and a few scattered, small cytokeratin 7 positive cells at some distance from the portal tract (presumed hepatic progenitor cells). (Immunostain for cytokeratin 7)
) may be marker for:
- degree of cholestasis
- progression13

Diagnosis

Liver biopsy:
- important in diagnosis and staging14
- characteristic bile duct lesions not always seen:
  - due to sampling variability
  - prevents firm histologic diagnosis
A florid bile duct lesion in PBC can be categorized as:
- lymphocytic
- pleomorphic
- granulomatous cholangitis (see Fig. 1):
  - most diagnostic feature15

Differential Diagnosis

Select up to 2 differential diagnoses to compare with Primary Biliary Cirrhosis

Chronic hepatitis, especially viral hepatitis C:
- in viral hepatitis C, affected duct segment shows:
  - vacuolization and stratification of cholangiocytes
  - preservation of basement membrane16
  - no cholestatic features
Drug-induced bile duct damage:
- usually ducts of smaller caliber than in PBC
- clinical history comprises episode of jaundice17
Conditions characterized by bile duct damage and granulomas:
- fascioliasis
- sarcoidosis:
  - may be difficult because may lead to:
    - ductopenia
    - chronic cholestatic liver disease
  - final diagnosis requires consideration of clinical context and laboratory data
Immune cholangitis18 or autoimmune cholangiopathy:19
- clinically, biochemically, and histologically similar to PBC, but antimitochondrial antibodies negative
- represents antimitochondrial antibody-negative PBC:20
  - but reactivity to recombinant mitochondrial antigens by immunoblotting in about 75% of such patients21
Autoimmune hepatitis–PBC overlap syndrome:22
- rare
- clinical, biological, and histologic features of PBC and autoimmune hepatitis, simultaneously or sequentially
- higher degrees of ‘hepatitic component’ of PBC, which responds to corticosteroid therapy23

Staging/grading

Several systems proposed for staging2,24–26
Most popular applicable to any vanishing bile duct disease:24
- distinguishes four stages:
  - stage 1:
    - portal
  - stage 2:
    - periportal
  - stage 3:
    - septal fibrosis
  - stage 4:
    - cirrhosis
Staging in small needle biopsy specimens valuable if interpreted with caution:
- considerable variability in degree of fibrosis in different parts of liver27

References

1 Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev. 2000;174:210–225.

2 Rubin E, Schaffner F, Popper H. Primary biliary cirrhosis: Chronic non-suppurative destructive cholangitis. Am J Pathol. 1965;46:387–407.

3 Nakanuma Y, Tsuneyama K, Gershwin ME, Yasoshima M. Pathology and immunopathology of primary biliary cirrhosis with emphasis on bile duct lesions: recent progress. Semin Liver Dis. 1995;15:313–328.

4 Colina F, Pinedo F, Solis JA, Moreno D, Nevado M. Nodular regenerative hyperplasia of the liver in early histological stages of primary biliary cirrhosis. Gastroenterology. 1992;102:1319–1324.

5 Nakanuma Y, Ohta G, Kobayashi K, Kato Y. Histological and histometric examination of the intrahepatic portal vein branches in primary biliary cirrhosis without regenerative nodules. Am J Gastroenterol. 1982;77:405–413.

6 Locke GR, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology. 1996;23:52–56.

7 Nakanuma Y, Saito K, Unoura M. Semiquantitative assessment of cholestasis and lymphocytic piecemeal necrosis in primary biliary cirrhosis: a histologic and immunohistochemical study. J Clin Gastroenterol. 1990;12:357–362.

8 Portmann B, Popper H, Neuberger J, Williams R. Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology. 1985;88:1777–1790.

9 Nakanuma Y. Pathology of septum formation in primary biliary cirrhosis: a histological study in the non-cirrhotic stage. Virchows Arch [A]. 1991;419:381–387.

10 Nakanuma Y. Necroinflammatory changes in hepatic lobules in primary biliary cirrhosis with less well-defined cholestatic changes. Hum Pathol. 1993;24:378–383.

11 Nakanuma Y, Hirata K. Unusual hepatocellular lesions in primary biliary cirrhosis resembling but unrelated to hepatocellular neoplasms. Virchows Arch [A]. 1993;422:17–23.

12 Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology. 1999;29:1007–1012.

13 Yabushita K, Yamamoto K, Ibuki N, Okano N, Matsumura S, Okamoto R, et al. Aberrant expression of cytokeratin 7 as a histological marker of progression in primary biliary cirrhosis. Liver. 2001;21:50–55.

14 Desmet VJ. Histopathology of chronic cholestasis and adult ductopenic syndrome. Lindor KD, Dickson ER editor. Clinics in liver disease, vol. 2, no. 2. Primary biliary cirrhosis, primary sclerosing cholangitis and adult cholangiopathies. Philadelphia: W.B. Saunders; 1998.

15 Ludwig J. New concepts in biliary cirrhosis. Semin Liver Dis. 1987;7:293–301.

16 Christoffersen P, Poulsen H, Scheuer PJ. Abnormal bile duct epithelium in chronic aggressive hepatitis and primary biliary cirrhosis. Hum Pathol. 1972;3:227–235.

17 Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol. 1997;26 (Suppl 1):31–35.

18 Brunner G, Klinge O. Ein der chronisch-destruierenden nicht-eitrigen Cholangitis ähnliches Krankheitsbild mit antinukleären Antikörpern (Immuncholangitis). Dtsch Med Wochenschr. 1987;112:1454–1458.

19 Ben Ari Z, Dhillon AP, Sherlock S. Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic active hepatitis. Hepatology. 1993;18:10–15.

20 Heathcote EJ. Autoimmune cholangitis. Lindor KD, Dickson ER editor. Clinics in liver disease, vol. 2, no. 2. Primary biliary cirrhosis, primary sclerosing cholangitis and adult cholangiopathies. Philadelphia: W.B. Saunders; 1998.

21 Miyakawa H, Tanaka A, Kikuchi K, Matsushita M, Kitazawa E, Kawaguchi N, et al. Detection of antimitochondrial autoantibodies in immunofluorescent AMA-negative patients with primary biliary cirrhosis using recombinant autoantigens. Hepatology. 2001;34:243–248.

22 Woodward J, Neuberger J. Autoimmune overlap syndromes. Hepatology. 2001;33:994–1002.

23 Poupon R, Chazouillères O, Poupon RE. Chronic cholestatic diseases. J Hepatol. 2000;32 (Suppl 1):129–140.

24 Ludwig J, Dickson ER, McDonald GSA. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch [A]. 1978;379:103–112.

25 Popper H, Schaffner F. Nonsuppurative destructive chronic cholangitis and chronic hepatitis. In: Popper H, Schaffner F editor. Progress in liver diseases. vol. III:New York: Grune and Stratton; 1970.

26 Scheuer PJ. Primary biliary cirrhosis. Proc R Soc Med. 1967;60:1257–1260.

27 Garrido MC, Hubscher SG. Accuracy of staging in primary biliary cirrhosis. J Clin Pathol. 1996;49:556–559.

Last updated: 23 Nov 2006