Correspondence

Discordant Occurrence of Primary Biliary Cirrhosis in Monozygotic Twins

N Engl J Med 1994; 331:952October 6, 1994

Article

To the Editor:

The cause of primary biliary cirrhosis is unknown but may be associated with an inherited abnormality of immune regulation1,2. It is not known whether abnormal genes alone will cause the disease or whether an additional triggering event is needed. Both a genetic abnormality and a triggering event are needed to cause another chronic liver disease, autoimmune chronic active hepatitis3. We report on a pair of monozygotic twins; one was healthy, and the other had advanced primary biliary cirrhosis.

The first twin, a 58-year-old woman, had had primary biliary cirrhosis for eight years (Figure 1Figure 1Liver-Biopsy Specimen Showing Histologic Evidence of Hepatic Injury in a 58-Year-Old Woman with Primary Biliary Cirrhosis.). Her biochemical tests showed a pattern typical of the disease (Table 1Table 1Biochemical and Serologic Test Results of the Monozygotic Twin Sisters.). She had recently undergone transjugular insertion of an intrahepatic stent to create a portosystemic shunt for treatment of recurrent bleeding from esophageal varices. Both sisters had serum antimitochondrial antibodies (Table 1) and HLA haplotypes A1, B8, DR3, DQ2 and A2, B44, D13, and DQ1. Both had negative results on assays for antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti-smooth-muscle antibodies, anti-parietal-cell antibodies, hepatitis A antibodies, hepatitis B surface antigen, hepatitis B surface antibodies, cytomegalovirus antibodies, and hepatitis C RNA by the polymerase chain reaction.

In primary biliary cirrhosis, the underlying lesion is chronic progressive damage to bile ducts, with prominent lymphocytic infiltrates1. Peripheral-blood lymphocytes may be sensitized to hepatobiliary antigens, because they produce cytokines when exposed to antigens from normal liver and purified liver-specific cell surfaces4. Furthermore, T lymphocytes from the spleen and CD8-positive T cells from patients with primary biliary cirrhosis are cytotoxic to autologous biliary epithelial cells5. These activated lymphocytes cannot be suppressed in vitro by mitogen-stimulated T cells. Approximately 90 percent of patients with primary biliary cirrhosis have impaired function of the suppressor T cells, as do 25 percent of healthy first-degree relatives1.

The sisters we have described were genetically identical. The presence of antimitochondrial antibodies in the healthy sister suggests that she and her affected sister had the same immunologic abnormality. We speculate that some other event may have triggered an immune response in the affected sister that resulted in an attack on the bile-duct epithelial cells by T lymphocytes. The trigger, presumably an infectious agent, drug, or other agent that can cause transient damage to bile ducts, is unknown. A similar mechanism may also explain the rare instances in which primary biliary cirrhosis develops after an episode of hepatitis related to the use of chlorpromazine, a phenothiazine. This hepatitis is usually self-limited.

Marshall M. Kaplan, M.D.
Arthur R. Rabson, M.D.
Young-Mee Lee, M.D.
David L. Williams, M.D., M.D.,
Patricia A. Montaperto, M.D.
Tufts-New England Medical Center, Boston, MA 02111

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Citing Articles (8)

Citing Articles

1. 1

   Pietro Invernizzi. (2011) Human leukocyte antigen in primary biliary cirrhosis: An old story now reviving. Hepatology 54:2, 714-723
   CrossRef

2. 2

   Pietro Invernizzi, Carlo Selmi, Ian R. MacKay, Mauro Podda, M. Eric Gershwin. (2005) From Bases to Basis: Linking Genetics to Causation in Primary Biliary Cirrhosis. Clinical Gastroenterology and Hepatology 3:5, 401-410
   CrossRef

3. 3

   A. Baragiotta, A. Floreani, K. Agarwal, C. Venturi, A. Craggs, D. E. J. Jones, P. T. Donaldson, M. F. Bassendine. (2004) Chemokine receptor 5 and primary biliary cirrhosis: a two-centre genetic association study. Liver International 24:6, 646-650
   CrossRef

4. 4

   Carlo Selmi, Marlyn J. Mayo, Nancy Bach, Hiromi Ishibashi, Pietro Invernizzi, Robert G. Gish, Stuart C. Gordon, Harlan I. Wright, Bruce Zweiban, Mauro Podda, M.Eric Gershwin. (2004) Primary biliary cirrhosis in monozygotic and dizygotic twins: Genetics, epigenetics, and environment. Gastroenterology 127:2, 485-492
   CrossRef

5. 5

   JJ FELD, EJ HEATHCOTE. (2003) Epidemiology of autoimmune liver disease. Journal of Gastroenterology and Hepatology 18:10, 1118-1128
   CrossRef

6. 6

   JASON M ERICKSON, ANTHONY R MAWSON. (2000) Possible Role of Endogenous Retinoid (Vitamin A) Toxicity in the Pathophysiology of Primary Biliary Cirrhosis. Journal of Theoretical Biology 206:1, 47-54
   CrossRef

7. 7

   Kaplan, Marshall M., . (1996) Primary Biliary Cirrhosis. New England Journal of Medicine 335:21, 1570-1580
   Full Text

8. 8

   (1995) More on Primary Biliary Cirrhosis in Monozygotic Twins. New England Journal of Medicine 332:5, 336-336
   Full Text