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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3182307cb9
Invited Commentaries

Biliary Atresia: New Lessons Learned From the Past

Muraji, Toshihiro

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Department of Pediatric Surgery, Ibaraki Children's Hospital, Ibaraki, Japan.

Address correspondence and reprint requests to Toshihiro Muraji, MD, PhD, Department of Pediatric Surgery, Ibaraki Children's Hospital, 3-3-1 Futabadai, Mito, Ibaraki 311-4145, Japan (e-mail:

Received 14 June, 2011

Accepted 31 July, 2011

The author reports no conflicts of interest.

See “Toll-like Receptor mRNA Expression in Liver Tissue From Patients With Biliary Atresia” by Saito et al on page 620.

The etiology of biliary atresia (BA) remains an enigma. It has been 30 years since the first article to propose an immune-mediated mechanism was written by Hadchouel et al (1). This article suggested the involvement of humoral immunity, whereby immunoglobulin M (IgM), with or without IgG, was deposited in the basement membrane of glandular structures in the fibrous remnant of the porta hepatis in one-third of 128 patients with BA. In the 3 decades since the article, researchers have focused on adaptive immunity, especially the activation of cell-mediated immunity, as the mechanism of biliary epithelial cell destruction (2).

In an attempt to clarify the role of the innate immune response in BA, Saito et al (3) examines in this issue of JPGN the mRNA expression levels of Toll-like receptors (TLRs) in liver biopsy specimens. They report that the activation of the innate immune system via the TLR8 pathway may be responsible for the pathogenesis of BA, and that the TLR3 innate immune response may affect the prognosis. It is suspected that the activated TLR3 in BA explains the ongoing cirrhosis of the liver even after a Kasai procedure results in successful bile drainage.

Looking at the Japanese proverb “visiting the old, learn the new,” it tells us to remember what has been done so we may learn and obtain true insight. Kasai (4) wrote an insightful article in 1981, the same year as the Hadchouel group's publication. He measured the portal vein pressure at the time of initial portoenterostomy in 31 patients (median age 65 days), demonstrating that the pressure was >150 mmH2O in all of the cases. He concluded that portal hypertension appeared to have already developed in patients with BA, even in the youngest infant (40 days old), who presumably had minimal distortion of the lobular architecture of the liver. This raises the question as to whether the portal hypertension seen in BA is pre- or postsinusoidal. The expression of co-stimulatory factor, the second signal to T lymphocytes that emerged through cross-talk between innate and adaptive immunity, was found in the biliary epithelium and in the vessels and sinusoids of the liver in patients with BA, particularly those with portal hypertension (5). Regardless of the primary insult mechanism of the disease, the portal hypertension may well be sinusoidal, with the sinusoidal endothelium being primarily involved. In other words, it is hypothesized that portal hypertension in an early phase of the disease is not secondary to biliary epithelial damage but may be a presenting feature in conjunction with the biliary damage before the development of the nodular regeneration. Consequently, locating upregulated TLRs will be an important next step toward clarifying the role of TLRs in the etiopathogenesis and later progressive fibrosis of BA.

Another intriguing observation is the positive correlation between the TLR7 mRNA level and the patient's age at the time of the Kasai procedure. Whether an earlier Kasai procedure improves the prognosis remains controversial. This is because the clinical outcome is influenced greatly by a surgical technique and episodes of cholangitis, which exacerbate the initial insult. These data would be important in that delaying the operation may induce the upregulation of TLR7 in the liver because of longer exposure to enteral bacteria. This observation lends support to the concept that performing a Kasai procedure earlier could improve the prognosis.

To continue “visiting the old,” in 1974, Shim et al (6) demonstrated a difference in the incidence of BA among various ethnic groups living in Hawaii. The incidence of Japanese in Hawaii was 0.8/1000 live births, compatible with that of Japanese in Sendai, Japan, whereas the incidence of whites was 0.6 ± 0.2. The incidence of Filipinos in Hawaii is 2.0 ± 0.9, which is fewer than the incidence among French Polynesian (3.2/10,000 live births). They implied that race is a more important influence on the occurrence of BA than geographic location or differences in environment. This ethnic diversity may be explained by parents’ allele disparity for common phenotypes or the degree of human leukocyte antigen diversity found in a genetic pool of each ethnicity (7). One could get insight into the etiopathogenesis of BA when it is explained using our modern research modalities and international cooperation.

Closing this commentary, I would like to expand the report of Saito et al with the concept of maternofetal immune disease (2,8), although I admit that I am “drawing water to my own mill.” TLR8, along with TLR3, -7, and -9, recognizes nucleic acid–based, pathogen-associated molecular patterns, which include not only microorganisms but also similar endogenous ligands. Papadimitraki et al (9) suggest that the necrotic or apoptotic cells activate cytokine production through the TLR9 pathway, driving aberrant B-cell responses in systemic lupus erythematosus. Tournadre et al (10) recently reported that TLR3 and TLR7 are expressed in the inflammatory myopathic tissues in polymyositis/dermatomyositis, a disease that is recognized as one of the possible maternofetal immune diseases (11).

This piece of provocative work provides investigators tackling the etiopathogenesis of BA with important information. We should link our “old” knowledge about BA with modern research modalities, furthering our search for answers.

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1. Hadchouel M, Hugon RN, Odievre M. Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants. Histopathology 1981;5:217–21.

2. Muraji T, Suskind DL, Irie N. Biliary atresia: a new insight into etiopathogenesis. Expert Rev Gastroenterol Hepatol 2009; 3:599–606.

3. Saito T, Hishiki T, Terui K, et al. Toll-like receptor mRNA expression in liver tissue from patients with biliary atresia. J Pediatr Gastroenterol Nutr 2011;53:620–6.

4. Kasai M, Okamoto A, Ohi R, et al. Changes of portal vein pressure and intrahepatic blood vesels after surgery for biliary atresia. J Pediatr Surg 1981; 16:152–159.

5. Kobayashi H, Li Z, Yamataka A, et al. Role of immunologic costimulatory factors in the pathogenesis of biliary atresia. J Pediatr Surg 2003; 38:892–896.

6. Shim WK, Kasai M, Spence MA, et al. Racial influence on the incidence of biliary atresia. Prog Pediatr Surg 1974; 6:53–62.

7. Irie N, Muraji T, Hosaka N, et al. Maternal HLA class I compatibility in patients with biliary atresia. J Pediatr Gastroenterol Nutr 2009; 49:488–492.

8. Stevens A. Do maternal cells trigger or perpetuate autoimmune diseases in children? Pediatr Rheumatol 2007; 5:9.

9. Papadimitraki ED, Choulaki C, Koutala E, et al. Expansion of Toll-like receptor 9-expression B cells in active systemic lupus erythematosus. Arthritis Rheum 2006; 54:3601–3611.

10. Tournadre A, Lenief V, Miossec P. Expression of Toll-like receptor 3 and Toll-like receptor 7 in muscle is characteristic of inflammatory myopathy and is differentially regulated by Th1 and Th17 cytokines. Arthritis Rheum 2010; 62:2144–2151.

11. Arlett CM, Ramos R, Jimenez SA, et al. Chimeric cells of maternal origin in juvenile idiopathic inflammatory myopathies. Childhood Myositis Heterogeneity Collaborative Group. Lancet 2000; 356:2155–2156.

Copyright 2011 by ESPGHAN and NASPGHAN


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