World J. Surg., 2, 561-569, 1978
Bile Duct and Liver Pathology in Biliary Atresia Joel E. H a a s , M.D. Department of Pathology, Children' s Orthopedic Hospital and Medical Center and University of Washington School of Medicine, Seattle, Washington, U.S.A.
Progression to cirrhosis despite restoration of bile flow by successful portoenterostomy suggests that factors other than obstruction alone are operative in biliary atresia. This paper describes pathologic changes at all levels of the hepatobiliary secretory apparatus from hepatocyte to common duct, exhibited in liver biopsies, resected portions of liver adjacent to the porta hepatis, and extrahepatic duct remnants from 17 patients operated upon for relief of biliary atresia. In both intra- and extrahepatic bile ducts, there were epithelial changes interpreted as occurring in a sequence of vacuolar degeneration, necrosis, inflammatory infiltration, and proliferative epithelial repair that precede obliterative fibrosis. From their distribution, it is inferred that these cytopathologic changes may not be simply due to distal obstruction. These ductal epithelial changes are similar to those that occur in livers of some patients with severe viral hepatitis. The association of these changes with giant cell transformation in all cases suggests that they reflect a common etiology for ductal and hepatocellular damage in the neonatal hepatitis-biliary atresia spectrum. The persistence of these changes in liver biopsies following portoenterostomy suggests that they may be of pathogenetic significance in the progressive liver disease seen in most patients with biliary atresia.
this unsatisfactory situation is to be changed. Concepts of the pathogenesis of biliary atresia h a v e been slow to change. As early as 1901, it was suggested that atresia might not be due to a n o m a l o u s d e v e l o p m e n t of the bile ducts, but occurs as a result of " d e s c e n d i n g cholangitis" [3]. N o t until the last 15 years have critical observations been made linking biliary atresia and neonatal hepatitis. Landing proposed the term "infantile obstructive cholangiopa t h y " to include these two entities in a disease spectrum characterized by c o m m o n clinical, laboratory, and pathologic features [4]. In short, Landing proposed that neonatal hepatitis and biliary atresia are different m o d e s o f b e h a v i o r of the same disease and that the entity k n o w n as biliary atresia is an acquired disease involving inflammation and progressive ductal obliteration, rather than a d e v e l o p m e n tal anomaly. This p a p e r describes the cellular pathology in liver and bile ducts o f a group of patients with biliary atresia. The o b s e r v e d changes are interpreted as reflecting a primary disease process with the potential for progression, despite relief o f obstruction to bile flow.
Almost all infants who survive an operation for the relief of biliary atresia develop chronic liver disease, even w h e n bile flow is restored [1]. Since relief of obstruction to bile flow and control of postoperative cholangitis [2] are not completely curative, other pathogenetic factors m u s t be identified if
Materials and Methods Histologic sections were p r e p a r e d f r o m wedge liver biopsies, tissue r e m o v e d from liver adjacent to the porta hepatis (PH), and resected r e m n a n t s o f extrahepatic ducts ( E H D ) of 17 patients who had K a s a i p o r t o e n t e r o s t o m i e s for biliary atresia b e t w e e n July,
Reprint requests: Joel E. Haas, M.D., Children's Orthopedic Hospital and Medical Center, 4800 Sand Point Way N.E., Seattle, Washington 98105, U.S.A.
0364-2313/78/0002-0561 $01.80 9 1978 Soci6t6 Internationale de Chirurgie 561
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World J. Surg. Vol. 2, No. 5, September, 1978
Table 1. Clinical follow-up of 17 patients undergoing portoenterostomy for biliary atresia.
Case no.
Age at surgery (weeks)
Sex
1
4
F
2 3 4 5 6 7 8 9 10 11
6 6 7 7 7 8 8 9 9 10
F M F F F F M F F F
12
11
M
13 14 15 16 17
11 11 13 13 24
F F F M M
Postoperative survival (months)
Outcome
21/2 11 Unknown 44 6 6 21/2 3 32 5 Unknown 69* 14 8 6 Unknown 13
Dead Dead Lost to follow-up Splenomegaly; bilirubin 3.8 mg/dl Cirrhosis; bilirubin 13.0 mg/dl Dead Dead Dead Cirrhosis; bilirubin 12.9 mg/dl Cirrhosis; bilirubin 3.4 mg/dl Lost to follow-up Cirrhosis; portal hypertension Cholangitis; bilirubin 1.8 mg/dl Cirrhosis; bilirubin 7.8 mg/dl Dead Lost to follow-up Dead
*Segmental EHD obstruction with patent proximal ducts 1972 and August, 1977. F o u r t e e n specimens were fixed in 10% formalin and blocked completely in paraffin. Step and serial sections that were 6/z thick were stained with hematoxylin and eosin or trichrome techniques. Sections of glycol methacrylate-embedded tissue that were 1/x thick were prepared from the 3 most recent specimens. Follow-up liver biopsies obtained from 5 patients were similarly processed. All levels of the biliary duct system were observed for evidence of pathologic change. Intrahepatic duct radicles were distinguished according to criteria defined in a standard textbook of histology [5]. Features of neonatal hepatitis corresponded to those generally accepted by pediatric pathologists [6]. Medical records of all surviving patients were examined for evidence of chronic liver disease. P o s t m o r t e m records and sections were examined in 3 cases.
mation, and extramedullary hematopoiesis (Fig. 1). All biopsies exhibited portal fibrosis, edema, and variable acute and chronic portal triaditis. In 9 there was cirrhosis. Six o f these specimens were from patients less than 12 weeks of age (Cases 1, 3, 4, 7, 11, and 13). The intrahepatic ducts exhibited remarkable changes in all biopsies. Excessive numbers of tortuous biliary channels or stratification of duct lining epithelium was present in all specimens (Fig. 2). This occurred in both Hering and interlobular ducts in 8 specimens, in Hering ducts alone in 3 specimens (Cases 6, 10, and 13), in interlobular ducts alone in 6 specimens (Cases 2, 8, 12, 15, 16, and 17), and did not appear to correlate with age. The duct epithelium was focally altered by a spectrum of celTable 2. Liver in biliary atresia based on studies of 17 specimens obtained at time of portoenterostomy. Number %
Results
Five male and 12 female patients were operated on as early as 4 weeks and as late as 24 weeks of age (Table 1). Three patients were lost to follow-up. Seven have survived periods of from 5 months to 5 years and 9 months, but all have chronic liver disease.
Operative Liver Biopsies Table 2 indicates that all 17 original specimens exhibited giant cell transformation (GCT) and other changes of neonatal hepatitis, such as focal hepatocellular degeneration, necrosis, pseudoacinous for-
Giant cell transformation and hepatitis Hering duct changes Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Interlobular duct changes Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Portal fibrosis and inflammation Cirrhosis Cholestasis Hepatocytes, duct epithelium, and lumens Hepatocytes alone
17
100
17 17 11
100 100 64
16 16 14 17 9
94 94 82 100 53
12 5
71 30
J.E. Haas: Hepatobiliary Pathology in Biliary Atresia
563
Fig. 1. Giant cell transformation in liver biopsy at time of portoenterostomy. The size of multinucleated "giant" hepatocytes (G) can be compared to ordinary hepatocytes at the bottom of the photograph. Inflammatory cells are present in adjacent portal region. (Methacrylate section x 380)
lular changes in all specimens (Figs. 2 and 3). The earliest change was an intracellular vacuole displacing the nucleus. Flattened or condensed cells with pyknotic nuclei appeared to be necrotic. Cells with large granular nuclei and scant cytoplasm appeared to be regenerating. Occasional cells were in mitosis. Hering ducts in all biopsies and interlobular ducts in 16 biopsies exhibited these changes. The changes were focal, usually not involving the entire duct circumference, and were accompanied by discrete infiltrates of polymorphonuclear (PMN) leukocytes. These inflammatory cells were scattered among degenerating and necrotic cells but were rare in duct lumens. Bile was usually prominent in hepatocytes and dilated canaliculi. Normal and abnormal ducts contained bile in 12 of 17 specimens. Granules of bile were frequent within the cytoplasm of unaltered duct epithelial cells and those of proliferated Hering ducts. Bile was occasionally seen in vacuolated cells described above.
Porta Hepatis (PH) Ducts greater than 200/~ in diameter were present in only 5 specimens (Cases 2, 6, 8, 13, and 16). In the remainder, fibrotic profiles of obliterated large
ducts lacking a lumen or lining could be distinguished. Cellular and inflammatory changes identical to those in intrahepatic ducts altered the linings of persisting smaller ducts and glands in a high proportion of PH specimens (Table 3). Additional features here were masses of proliferated lining cells nearly occluding duct lumens (Fig. 4), large areas of epithelial ulceration, and distortion of duct walls and contour by nodules of fibrous tissue within lumens or concentric layers of fibrous tissue surrounding ducts. Bile was rarely present in persisting ducts, but never in macrophages or free in fibrous tissue. Hepatic fibrosis and cirrhosis were always more severe in the PH than in peripheral biopsies obtained simultaneously.
Extrahepatic Duct (EHD) Remnants One specimen was composed of vessels and nerves. Three consisted of a fibrous cord with a vague fibrotic duct outline, unaccompanied by inflammatory cells or periductular glands. Thirteen specimens contained a lumen remnant adjacent to atretic segments or persistent periductular glands in regions of obliterated lumens. In all 13, cellular changes identical to those described above were ap-
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World J. Surg. Vol. 2, No. 5, September, 1978
Fig. 2. Liver biopsy at time of portoenterostomy. Proliferating Hering ducts extend from the periphery of the liver lobule into the fibrotic portal triad. Duct cells exhibit focal vacuolation (arrows) and duct walls contain polymorphonuclear leukocyte infiltrates, some of which are circled. (Methacrylate • 360)
Fig. 3. Liver biopsy at time of portoenterostomy. Cytoplasmic vacuolar change (arrows) and nuclear pyknosis are present in cells of the interlobular duct in the center and Hering duct cells at the periphery of the liver lobule. (Methacrylate • 960)
J.E. Haas: Hepatobiliary Pathology in Biliary Atresia
565
Table 3. Porta hepatis in biliary atresia based on studies of 16 specimens. Number Duct diameter greater than 200tx Duct and gland changes Epithelial cellular changes Inflammatory infiltration Epithelial proliferation Periductal fibrosis
Table 4. Extrahepatic duet remnant in biliary atresia based on studies of 17 specimens.
%
5
33
16 14 12 15
lO0 88 75 94
parent (Fig. 5). Epithelial ulceration and proliferation were frequently less severe, but inflammatory infiltrates accompanied the cellular changes in 11 specimens (Table 4). In 2 specimens where the point of obstruction was near the liver, and in 1 segmentally stenotic specimen, the epithelial lining of the distal lumen and periductular glands exhibited these same cellular and inflammatory changes (Fig. 6). Obliterated segments were usually composed of focally inflamed scar tissue. In 3 specimens, a mass of granulation tissue or subepithelial fibrosis obstructed or severely distorted the lumen contour. In the remainder, a tapering lumen contour adjacent to the obliterated segment could be attributed to periductal fibrosis. Only 1 E H D remnant contained bile, that one being an example of segmental E H D ob-
Nerve and vessel only, no ducts seen Fibrous cord with vague duct outline Lumen or periductal glands remaining Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Fibrosis
Number
%
1 3 13 13 11 11 12
--100 85 85 92
struction with patent ducts in the proximal biliary system.
Follow-up Liver Biopsies Ten liver biopsies from 5 survivors exhibited persistence or progression of changes present in original specimens. Focal GCT persisted in 3 biopsies obtained at intervals of 11/2, 2, and 31/2 months after p o r t o e n t e r o s t o m y (Cases 10, 5, and 14). In 1 case (Case 14), GCT was extreme at the initial biopsy and the 31/z-month follow-up biopsy exhibited extraordinary cirrhosis. One other case (Case 5) progressed to cirrhosis during a 2-month postoperative interval. Cellular, inflammatory, and proliferative
Fig. 4. Duct at the porta hepatis. The lumen is nearly occluded by lining epithelium. Binucleate cells (arrows) are evidence of cellular proliferation. Cellular vacuoles, pyknotic cells, and polymorphonuclear leukocyte infiltrates are also present. (Methacrylate x 340)
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Fig. 5. Extrahepatic duct remnant at site of fibrous obliteration. Concentric fibrosis accompanies these periductular glands which exhibit epithelial changes similar to those seen in ducts at the porta hepatis and in liver biopsies. (Methacrylate x 380). changes in the duct epithelium persisted in biopsies from 4 patients; all had multiple episodes of cholangitis but were biopsied when free of symptoms (Cases 5, 10, 13, and 14). In 1 case (Case 13), the cellular and inflammatory changes were absent after a postoperative interval of 101/2 months, but interlobular ducts were no longer visible in the severely fibrotic portal triads. In 3 biopsies from the longest survivor (Case 12), portal and interlobular duct inflammatory infiltrates persisted at intervals of 3 and 11 weeks after portoenterostomy, but were absent in a biopsy done 5 years and 9 months later.
Postmortem Findings The livers of 3 patients (Cases 1, 7, and 15) examined at postmortem performed, respectively, at 21/2, 21/2, and 6 months following portoenterostomy all exhibited severe biliary cirrhosis. Bands of fibrous tissue were frequently greater in width than nodules of surviving bile-stained hepatocytes. Large numbers of Hering duct profiles persisted. These occasionally contained bile but also exhibited atrophy. Interlobular duct profiles were sparse. Ascending cholangitis was a clinical feature in each case, and the amount of inflammatory infiltrates in fibrous tissue and in intrahepatic ducts was greater than that seen at the time of portoenterostomy. In some areas polymorphonuclear leukocytes formed abscesses
within intrahepatic ducts. The surface of the liver exposed at the time of portoenterostomy exhibited marked fibrosis. Cystically dilated duct profiles here frequently contained bile; others were filled with granulation tissue, rich in both foamy and bileladen macrophages. Bacteria were present within cleft-like spaces thought to be lymphatics. Discussion
The Kasai operation for biliary atresia has provided unique specimens for histopathologic examination and an opportunity to study early events in the natural history of biliary atresia [7]. Descriptions of such specimens have correlated morphology with outcome, attempting to provide prognostic information [8, 9]. Other reports have also described ductular fibrosis and inflammatory infiltrates in EHD specimens, but have generally attributed these changes to distal duct obstruction, rather than considering them as part of a primary disease process [8-12]. In this and a previous paper from this institution [7], early cellular pathologic changes are described at every level of the biliary tree, including the smallest intrahepatic branches. We believe from the distribution of these changes in the original specimens and their persistence after corrective surgery that they may not be the result of obstruction alone.
J.E. Haas: Hepatobiliary Pathology in Biliary Atresia
567
Fig. 6. Extrahepatic duct remnant lumen distal to site of fibrous obliteration. Cellular pyknosis and necrosis in both duct lumen and gland epithelium (arrows) are accompanied by polymorphonuclear leukocytes in adjacent tissue. (Paraffin x 380) Traditionally, pathologic changes in the liver, in PH specimens, and in EHD remnant specimens from patients with biliary atresia have been attributed to distal duct obstruction. However, bile was never conspicuous in PH specimens in this study. The only E H D specimens containing bile both here and in the literature [8, 9] are examples of sharply localized E H D obstruction where proximal hepatic ducts are patent. In the liver of patients with biliary atresia, it has been shown that bile stasis may be limited to hepatic cells and canaliculi [7]. This finding strengthens the proposal by Landing [4] that the bile secretory defect that occurs in neonatal hepatitis also occurs in biliary atresia. Several features documented in this paper and by others support the concept that the ductal cellular changes in biliary atresia may not be secondary to obstruction. First, epithelial degeneration and inflammation are present in the lumens of 3 EHD specimens distal to regions of complete obstruction (Fig. 6). Second, in biliary atresia, intrahepatic changes may sometimes progress despite surgical relief of obstruction, as indicated here and elsewhere [13]. Third, the literature indicates that intrahepatic duct epithelial changes similar to those described here in biliary atresia also occur in liver diseases not associated with large duct obstruction.
Duct cellular changes of vacuolar swelling, flattening, focal necrosis, infiltration by PMN leukocytes, and epithelial proliferation have been described in acute viral hepatitis [14, 15], severe hepatocellular failure [16, 17], primary biliary cirrhosis [18, 19], and in livers of 35-40% of patients with chronic aggressive hepatitis [20]. Thus, these cellular changes seen in biliary atresia cannot be viewed only as a nonspecific response to ductal obstruction. An extraordinary proliferation of ductular epithelial cells in the liver of biliary atresia has been said to participate in compression and obliteration of the larger interlobular ducts [21]. The nature and significance of such "cholangiolar proliferation" has been controversial [15]. These structures are referred to here as Hering ducts because of their continuity with parenchymal cells [5]. Others have termed them cholangioles, branches of interlobular ducts, or pseudoducts reflecting regeneration of damaged peripheral lobular hepatocytes [15]. Regardless of their nature, they are seen as frequently in toxic or viral hepatitis as they are in association with extrahepatic duct obstruction [15], although not usually to the same degree. Ductular proliferation in a small proportion of cases of neonatal hepatitis is said to be the reason for occasional er-
568
roneous needle biopsy diagnosis of biliary atresia [6]. Therefore, it is possible that ductular proliferation is part of a basic cholangiopathic process, rather than being solely due to obstruction. The cirrhosis in biliary atresia may not be solely due to extrahepatic obstruction. It is characterized by more fibrosis [3, 22], a lack of hepatic regenerative activity [22], more rapid progression [3], and more periductal fibrosis, when compared to other forms of obstructive cirrhosis [22]. The presence of GCT in all cases, and the association of severe neonatal hepatitis with rapidly appearing cirrhosis in 1 case (Case 14), support the suggestion that the unusually severe cirrhosis in atresia is due, at least in part, to primary hepatocellular destruction [22]. Previous studies of the liver in atresia document the occurrence of GCT in as few as 15% and as many as 90% of cases, the higher incidence generally being seen in more recent studies [4]. The severity of cirrhosis and periductal fibrosis in all PH specimens, in contrast to that in the peripheral portions of the liver, corroborates an earlier postmortem description of the liver in biliary atresia. In that report, this centrally concentrated fibrosis was interpreted as the source of a progressive process extending towards the periphery of the liver [22]. Previous descriptions [8, 13] of surgical PH specimens have emphasized fibrosis but not ductal epithelial or inflammatory changes. Others have described excessive numbers of glands in EHD remnants near the porta hepatis [9]. These structures were interpreted as reflecting an adaptive or reparative response in specimens lacking a lumen. Glands seen in EHD specimens in the present study (Fig. 5) were thought not to be excessive but, instead, to represent persistent structures normally present in extrahepatic duct walls [5]. One other study of EHD remnants described focal duct epithelial necrosis not accompanied by inflammation [12]. Another described inflammatory cells accompanying glands and focal duct lining defects [9]. Each study cited these changes as possibly leading to large duct obliteration. Others have described inflammatory infiltrates in EHD remnants, but have attributed this to distal obstruction [10]. The etiology of the bile duct cellular changes described here is not apparent. Cholestasis alone cannot satisfactorily explain them, since they may occur and progress in its absence [7, 13, 20]. The similarity of ductal epithelial changes in biliary atresia to those occurring in some patients with severe viral and immunologically mediated hepatitis is interesting. The emerging consensus is that such changes in hepatitis are due to direct damage by the hepatitis virus [16, 17, 20], despite their similarity to changes usually attributed to large duct obstruction. As in biliary atresia, hepatitis patients with these
World J. Surg. Vol. 2, No. 5, September, 1978
duct epithelial changes develop cirrhosis more frequently and rapidly than those whose livers lack such changes [20]. Virus-mediated duct damage and ductal disappearance is well documented in other forms of childhood cholestasis [23]. The "virus-like particles" described by others in the nuclei of duct epithelial cells in EHD remnants [12] must be viewed with caution. Critical examination of these electron microscopic images suggests that they are a manifestation of cellular reaction to injury rather than of viral origin [24]. In summary, this paper describes changes occurring in intra- and extrahepatic ducts in patients with biliary atresia. It is suggested that these changes are analogous to those occurring within the cells of the liver in neonatal hepatitis reflecting a common etiology for both parenchymal and duct cell injury. It is further proposed that these changes occur in a sequence of degeneration, necrosis, inflammatory infiltration, and epithelial proliferation that precedes obliteration of the ducts. These changes, like giant cell transformation, may not be a response to obstruction, but may be a manifestation of a specific disease process. Regardless of their etiology, the continuation of these intrahepatic changes, in spite of surgery for relief of obstruction, is thought to be the explanation for the progressive liver disease seen in many patients with biliary atresia.
Acknowledgments
I am deeply indebted to Doctors Alexander H. Bill and J. Bruce Beckwith for their generous support, encouragement, and constructive criticism.
R~sum~
L'aggravation de la cirrhose apr~s une h6paticoent6rostomie r6tablissant l'6coulement de bile sugg6re que la pathog6nie de l'atr6sie biliaire n'est pas uniquement faite d'obstruction biliaire. Nous d6crivons les 16sions observ6es, chez 17 malades oper6s d'atr6sie biliaire, aux divers 6tages de l'arbre biliaire, depuis l'h6patocyte jusqu'au chol6doque (biopsies h6patiques, fragments de tissu h6patique pr61ev6s dans le hile, r6sidus de l'arbre biliaire extra-h6patique). Tant dans les canaux biliaires intra- qu'extra-h6patiques, on trouve des alt6rations 6pith61iales que l'on peut interpr6ter comme une succession de d6g6n6rescence vacuolaire, n6crose, infiltrat inflammatoire, prolif6ration 6pith61iale r6paratrice et finalement fibrose oblit6rante. La distribution de ces 16sions cytologiques indique qu'elles ne sont peut-6tre pas dues unique-
J.E. Haas: Hepatobiliary Pathology in Biliary Atresia
m e n t a une obstruction distale. Les altrrations de l ' r p i t h r l i u m des canalicules biliaires r e s s e m b l e n t ce que l ' o n o b s e r v e dans la foie de certains cas d ' h r p a t i t e virale. Darts tous les cas, les 16sions s ' a c c o m p a g n e n t de formation de cellules grantes, ce qui sugg~re une 6tiologie c o m m u n e aux 16sions canalaires et hrpatocellulaires de l ' h r p a t i t e n r o n a tale et de l'atrrsie biliaire. L a persistance des 16sions dans les biopsies p r r l e v r e s apr~s hrpatic o e n t r r o s t o m i e indique qu'elles p e u v e n t j o u e r un r r l e p a t h o g r n e dans la p r o g r e s s i o n de l'atteinte hrpatique o b s e r v r e dans la majorit6 des cas d ' a t r r s i e biliaire.
569
10.
11.
12. 13. 14.
References
1. Odirvre, M., Valayer, J., Razemon-Pinta, M., Habib, E.C., Alagille, D.: Hepatic portoenterostomy or cholecystostomy in the treatment of extrahepatic biliary atresia. J. Pediatr. 88:774, 1976 2. Odi~vre, M.: Long-term results of surgical treatment of biliary atresia. World J. Surg. 2:589, 1978 3. Rolleston, H.D., Hayne, L.B.: A case of congenital hepatic cirrhosis with obliterative cholangitis. Br. Med. J. 1:758, 1901 4. Landing, B.H.: Considerations of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst. The concept of infantile obstruction cholangiopathy. In Progress in Pediatric Surgery, Volume 6, A.H. Bill and M. Kasai, editors. Baltimore-LondonTokyo, University Park Press, 1974, pp. 113-139 5. Jones, A.L., Spring-Mills, E.: The liver and gall bladder. In Histology, 4th edition, L. Weiss and R.O. Greep, editors. New York, McGraw-Hill Book Co., 1977, pp. 701-746 6. Brough, A.J., Bernstein, J.: Conjugated hyperbilirubinemia in early infancy: a reassessment of liver biopsy. Hum. Pathol. 5:507, 1974 7. Bill, A.H., Haas, J.E., Foster, G.L.: Biliary atresia: histopathologic observations and reflections upon its natural history. J. Pediatr. Surg. 12:977, 1977 8. Kasai, M,: Treatment of biliary atresia with special reference to hepatic portoenterostomy and its modifications. In Progress in Pediatric Surgery, Volume 6, A.H. Bill and M. Kasai, editors. Baltimore-LondonTokyo, University Park Press, 1974, pp. 5-52 9. Gautier, M., Jehan, P., Odirvre, M.: Histologic study of biliary fibrous remnants in 48 cases of extra-
15. 16. 17. 18.
19.
20. 21. 22. 23. 24.
hepatic biliary atresia: correlation with postoperative bile flow restoration. J. Pediatr. 89:704, 1976 Miyano, T., Suruga, K., Tsuchiya, H., Suda, K.: A histopathological study of the remnant of extrahepatic bile duct in so-called uncorrectable biliary atresia. J. Pediatr. Surg. 12:19, 1977 Chiba, T., Kasai, M., Sasano, N.: Histopathological studies in intrahepatic bile ducts in the vicinity of porta hepatis in biliary atresia. Tohoku J. Exp. Med. 118:199, 1976 Scotto, J.M., Stralin, H.G.: Congenital extrahepatic biliary atresia. Arch. Pathol. Lab. Med. 101:416, 1977 Altman, R. P., Chandra, R., Lilly, J.: Ongoing cirrhosis after successful porticoenterostomy in infants with biliary atresia. J. Pediatr. Surg. 10:685, 1975 Scheuer, P.J.: Liver Biopsy Interpretation, 2rid edition. Baltimore, Williams and Wilkins, 1973, pp. 5665 Gall, E.A., Dobrogorski, O.: Hepatic alterations in obstructive jaundice. Am. J. Clin. Pathol. 41:126, 1964 Schmid, M., Cueni, B.: Portal lesions in viral hepatitis with submassive hepatic necrosis. Hum. Pathol. 3:209, 1972 Desmet, V.J., DeGroote, J., Van Damme, B.: Acute hepatocellular failure. Hum. Pathol. 3:167, 1972 Christofferson, P., Poulsen, H., Scheuer, P.J.: Abnormal bile duct epithelium in chronic aggressive hepatitis and primary biliary cirrhosis. Hum. Pathol. 3:227, 1972 Desmet, V.: Chronic hepatitis (including primary biliary cirrhosis). In The Liver, E.A. Gall and F.K. Mostofi, editors. Baltimore, Williams and Wilkins, 1973, pp. 286-341 Poulsen, H., Christofferson, P.: Abnormal bile duct epithelium in chronic aggressive hepatitis and cirrhosis. Hum. Pathol. 3:217, 1972 Oh'i, R., Kasai, M.: Intrahepatic biliary obstruction in congenital bile duct atresia. Tohoku J. Exp. Med. 99:129, 1969 MacMahon, H.E.: A variant of obstructive biliary cirrhosis. Am. J. Pathol. 60:271, 1970 Heathcote, J., Deodhar, K.P., Scheuer, P.J., Sherlock, S.: Intrahepatic cholestasis in childhood. N. Engl. J. Med. 295:801, 1976 Yunis, E.J., Hashida, Y., Haas, J.E.: The role of electron microscopy in the identification of viruses in human disease. In Pathology Annual, Part I, Volume 12, S.C. Sommers and P.P. Rosen, editors. New York, Appleton-Century-Crofts, 1977, pp. 311-330
Bile Duct and Liver Pathology in Biliary Atresia Joel E. H a a s , M.D. Department of Pathology, Children' s Orthopedic Hospital and Medical Center and University of Washington School of Medicine, Seattle, Washington, U.S.A.
Progression to cirrhosis despite restoration of bile flow by successful portoenterostomy suggests that factors other than obstruction alone are operative in biliary atresia. This paper describes pathologic changes at all levels of the hepatobiliary secretory apparatus from hepatocyte to common duct, exhibited in liver biopsies, resected portions of liver adjacent to the porta hepatis, and extrahepatic duct remnants from 17 patients operated upon for relief of biliary atresia. In both intra- and extrahepatic bile ducts, there were epithelial changes interpreted as occurring in a sequence of vacuolar degeneration, necrosis, inflammatory infiltration, and proliferative epithelial repair that precede obliterative fibrosis. From their distribution, it is inferred that these cytopathologic changes may not be simply due to distal obstruction. These ductal epithelial changes are similar to those that occur in livers of some patients with severe viral hepatitis. The association of these changes with giant cell transformation in all cases suggests that they reflect a common etiology for ductal and hepatocellular damage in the neonatal hepatitis-biliary atresia spectrum. The persistence of these changes in liver biopsies following portoenterostomy suggests that they may be of pathogenetic significance in the progressive liver disease seen in most patients with biliary atresia.
this unsatisfactory situation is to be changed. Concepts of the pathogenesis of biliary atresia h a v e been slow to change. As early as 1901, it was suggested that atresia might not be due to a n o m a l o u s d e v e l o p m e n t of the bile ducts, but occurs as a result of " d e s c e n d i n g cholangitis" [3]. N o t until the last 15 years have critical observations been made linking biliary atresia and neonatal hepatitis. Landing proposed the term "infantile obstructive cholangiopa t h y " to include these two entities in a disease spectrum characterized by c o m m o n clinical, laboratory, and pathologic features [4]. In short, Landing proposed that neonatal hepatitis and biliary atresia are different m o d e s o f b e h a v i o r of the same disease and that the entity k n o w n as biliary atresia is an acquired disease involving inflammation and progressive ductal obliteration, rather than a d e v e l o p m e n tal anomaly. This p a p e r describes the cellular pathology in liver and bile ducts o f a group of patients with biliary atresia. The o b s e r v e d changes are interpreted as reflecting a primary disease process with the potential for progression, despite relief o f obstruction to bile flow.
Almost all infants who survive an operation for the relief of biliary atresia develop chronic liver disease, even w h e n bile flow is restored [1]. Since relief of obstruction to bile flow and control of postoperative cholangitis [2] are not completely curative, other pathogenetic factors m u s t be identified if
Materials and Methods Histologic sections were p r e p a r e d f r o m wedge liver biopsies, tissue r e m o v e d from liver adjacent to the porta hepatis (PH), and resected r e m n a n t s o f extrahepatic ducts ( E H D ) of 17 patients who had K a s a i p o r t o e n t e r o s t o m i e s for biliary atresia b e t w e e n July,
Reprint requests: Joel E. Haas, M.D., Children's Orthopedic Hospital and Medical Center, 4800 Sand Point Way N.E., Seattle, Washington 98105, U.S.A.
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Table 1. Clinical follow-up of 17 patients undergoing portoenterostomy for biliary atresia.
Case no.
Age at surgery (weeks)
Sex
1
4
F
2 3 4 5 6 7 8 9 10 11
6 6 7 7 7 8 8 9 9 10
F M F F F F M F F F
12
11
M
13 14 15 16 17
11 11 13 13 24
F F F M M
Postoperative survival (months)
Outcome
21/2 11 Unknown 44 6 6 21/2 3 32 5 Unknown 69* 14 8 6 Unknown 13
Dead Dead Lost to follow-up Splenomegaly; bilirubin 3.8 mg/dl Cirrhosis; bilirubin 13.0 mg/dl Dead Dead Dead Cirrhosis; bilirubin 12.9 mg/dl Cirrhosis; bilirubin 3.4 mg/dl Lost to follow-up Cirrhosis; portal hypertension Cholangitis; bilirubin 1.8 mg/dl Cirrhosis; bilirubin 7.8 mg/dl Dead Lost to follow-up Dead
*Segmental EHD obstruction with patent proximal ducts 1972 and August, 1977. F o u r t e e n specimens were fixed in 10% formalin and blocked completely in paraffin. Step and serial sections that were 6/z thick were stained with hematoxylin and eosin or trichrome techniques. Sections of glycol methacrylate-embedded tissue that were 1/x thick were prepared from the 3 most recent specimens. Follow-up liver biopsies obtained from 5 patients were similarly processed. All levels of the biliary duct system were observed for evidence of pathologic change. Intrahepatic duct radicles were distinguished according to criteria defined in a standard textbook of histology [5]. Features of neonatal hepatitis corresponded to those generally accepted by pediatric pathologists [6]. Medical records of all surviving patients were examined for evidence of chronic liver disease. P o s t m o r t e m records and sections were examined in 3 cases.
mation, and extramedullary hematopoiesis (Fig. 1). All biopsies exhibited portal fibrosis, edema, and variable acute and chronic portal triaditis. In 9 there was cirrhosis. Six o f these specimens were from patients less than 12 weeks of age (Cases 1, 3, 4, 7, 11, and 13). The intrahepatic ducts exhibited remarkable changes in all biopsies. Excessive numbers of tortuous biliary channels or stratification of duct lining epithelium was present in all specimens (Fig. 2). This occurred in both Hering and interlobular ducts in 8 specimens, in Hering ducts alone in 3 specimens (Cases 6, 10, and 13), in interlobular ducts alone in 6 specimens (Cases 2, 8, 12, 15, 16, and 17), and did not appear to correlate with age. The duct epithelium was focally altered by a spectrum of celTable 2. Liver in biliary atresia based on studies of 17 specimens obtained at time of portoenterostomy. Number %
Results
Five male and 12 female patients were operated on as early as 4 weeks and as late as 24 weeks of age (Table 1). Three patients were lost to follow-up. Seven have survived periods of from 5 months to 5 years and 9 months, but all have chronic liver disease.
Operative Liver Biopsies Table 2 indicates that all 17 original specimens exhibited giant cell transformation (GCT) and other changes of neonatal hepatitis, such as focal hepatocellular degeneration, necrosis, pseudoacinous for-
Giant cell transformation and hepatitis Hering duct changes Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Interlobular duct changes Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Portal fibrosis and inflammation Cirrhosis Cholestasis Hepatocytes, duct epithelium, and lumens Hepatocytes alone
17
100
17 17 11
100 100 64
16 16 14 17 9
94 94 82 100 53
12 5
71 30
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563
Fig. 1. Giant cell transformation in liver biopsy at time of portoenterostomy. The size of multinucleated "giant" hepatocytes (G) can be compared to ordinary hepatocytes at the bottom of the photograph. Inflammatory cells are present in adjacent portal region. (Methacrylate section x 380)
lular changes in all specimens (Figs. 2 and 3). The earliest change was an intracellular vacuole displacing the nucleus. Flattened or condensed cells with pyknotic nuclei appeared to be necrotic. Cells with large granular nuclei and scant cytoplasm appeared to be regenerating. Occasional cells were in mitosis. Hering ducts in all biopsies and interlobular ducts in 16 biopsies exhibited these changes. The changes were focal, usually not involving the entire duct circumference, and were accompanied by discrete infiltrates of polymorphonuclear (PMN) leukocytes. These inflammatory cells were scattered among degenerating and necrotic cells but were rare in duct lumens. Bile was usually prominent in hepatocytes and dilated canaliculi. Normal and abnormal ducts contained bile in 12 of 17 specimens. Granules of bile were frequent within the cytoplasm of unaltered duct epithelial cells and those of proliferated Hering ducts. Bile was occasionally seen in vacuolated cells described above.
Porta Hepatis (PH) Ducts greater than 200/~ in diameter were present in only 5 specimens (Cases 2, 6, 8, 13, and 16). In the remainder, fibrotic profiles of obliterated large
ducts lacking a lumen or lining could be distinguished. Cellular and inflammatory changes identical to those in intrahepatic ducts altered the linings of persisting smaller ducts and glands in a high proportion of PH specimens (Table 3). Additional features here were masses of proliferated lining cells nearly occluding duct lumens (Fig. 4), large areas of epithelial ulceration, and distortion of duct walls and contour by nodules of fibrous tissue within lumens or concentric layers of fibrous tissue surrounding ducts. Bile was rarely present in persisting ducts, but never in macrophages or free in fibrous tissue. Hepatic fibrosis and cirrhosis were always more severe in the PH than in peripheral biopsies obtained simultaneously.
Extrahepatic Duct (EHD) Remnants One specimen was composed of vessels and nerves. Three consisted of a fibrous cord with a vague fibrotic duct outline, unaccompanied by inflammatory cells or periductular glands. Thirteen specimens contained a lumen remnant adjacent to atretic segments or persistent periductular glands in regions of obliterated lumens. In all 13, cellular changes identical to those described above were ap-
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Fig. 2. Liver biopsy at time of portoenterostomy. Proliferating Hering ducts extend from the periphery of the liver lobule into the fibrotic portal triad. Duct cells exhibit focal vacuolation (arrows) and duct walls contain polymorphonuclear leukocyte infiltrates, some of which are circled. (Methacrylate • 360)
Fig. 3. Liver biopsy at time of portoenterostomy. Cytoplasmic vacuolar change (arrows) and nuclear pyknosis are present in cells of the interlobular duct in the center and Hering duct cells at the periphery of the liver lobule. (Methacrylate • 960)
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565
Table 3. Porta hepatis in biliary atresia based on studies of 16 specimens. Number Duct diameter greater than 200tx Duct and gland changes Epithelial cellular changes Inflammatory infiltration Epithelial proliferation Periductal fibrosis
Table 4. Extrahepatic duet remnant in biliary atresia based on studies of 17 specimens.
%
5
33
16 14 12 15
lO0 88 75 94
parent (Fig. 5). Epithelial ulceration and proliferation were frequently less severe, but inflammatory infiltrates accompanied the cellular changes in 11 specimens (Table 4). In 2 specimens where the point of obstruction was near the liver, and in 1 segmentally stenotic specimen, the epithelial lining of the distal lumen and periductular glands exhibited these same cellular and inflammatory changes (Fig. 6). Obliterated segments were usually composed of focally inflamed scar tissue. In 3 specimens, a mass of granulation tissue or subepithelial fibrosis obstructed or severely distorted the lumen contour. In the remainder, a tapering lumen contour adjacent to the obliterated segment could be attributed to periductal fibrosis. Only 1 E H D remnant contained bile, that one being an example of segmental E H D ob-
Nerve and vessel only, no ducts seen Fibrous cord with vague duct outline Lumen or periductal glands remaining Epithelial cellular change s Inflammatory infiltration Epithelial proliferation Fibrosis
Number
%
1 3 13 13 11 11 12
--100 85 85 92
struction with patent ducts in the proximal biliary system.
Follow-up Liver Biopsies Ten liver biopsies from 5 survivors exhibited persistence or progression of changes present in original specimens. Focal GCT persisted in 3 biopsies obtained at intervals of 11/2, 2, and 31/2 months after p o r t o e n t e r o s t o m y (Cases 10, 5, and 14). In 1 case (Case 14), GCT was extreme at the initial biopsy and the 31/z-month follow-up biopsy exhibited extraordinary cirrhosis. One other case (Case 5) progressed to cirrhosis during a 2-month postoperative interval. Cellular, inflammatory, and proliferative
Fig. 4. Duct at the porta hepatis. The lumen is nearly occluded by lining epithelium. Binucleate cells (arrows) are evidence of cellular proliferation. Cellular vacuoles, pyknotic cells, and polymorphonuclear leukocyte infiltrates are also present. (Methacrylate x 340)
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Fig. 5. Extrahepatic duct remnant at site of fibrous obliteration. Concentric fibrosis accompanies these periductular glands which exhibit epithelial changes similar to those seen in ducts at the porta hepatis and in liver biopsies. (Methacrylate x 380). changes in the duct epithelium persisted in biopsies from 4 patients; all had multiple episodes of cholangitis but were biopsied when free of symptoms (Cases 5, 10, 13, and 14). In 1 case (Case 13), the cellular and inflammatory changes were absent after a postoperative interval of 101/2 months, but interlobular ducts were no longer visible in the severely fibrotic portal triads. In 3 biopsies from the longest survivor (Case 12), portal and interlobular duct inflammatory infiltrates persisted at intervals of 3 and 11 weeks after portoenterostomy, but were absent in a biopsy done 5 years and 9 months later.
Postmortem Findings The livers of 3 patients (Cases 1, 7, and 15) examined at postmortem performed, respectively, at 21/2, 21/2, and 6 months following portoenterostomy all exhibited severe biliary cirrhosis. Bands of fibrous tissue were frequently greater in width than nodules of surviving bile-stained hepatocytes. Large numbers of Hering duct profiles persisted. These occasionally contained bile but also exhibited atrophy. Interlobular duct profiles were sparse. Ascending cholangitis was a clinical feature in each case, and the amount of inflammatory infiltrates in fibrous tissue and in intrahepatic ducts was greater than that seen at the time of portoenterostomy. In some areas polymorphonuclear leukocytes formed abscesses
within intrahepatic ducts. The surface of the liver exposed at the time of portoenterostomy exhibited marked fibrosis. Cystically dilated duct profiles here frequently contained bile; others were filled with granulation tissue, rich in both foamy and bileladen macrophages. Bacteria were present within cleft-like spaces thought to be lymphatics. Discussion
The Kasai operation for biliary atresia has provided unique specimens for histopathologic examination and an opportunity to study early events in the natural history of biliary atresia [7]. Descriptions of such specimens have correlated morphology with outcome, attempting to provide prognostic information [8, 9]. Other reports have also described ductular fibrosis and inflammatory infiltrates in EHD specimens, but have generally attributed these changes to distal duct obstruction, rather than considering them as part of a primary disease process [8-12]. In this and a previous paper from this institution [7], early cellular pathologic changes are described at every level of the biliary tree, including the smallest intrahepatic branches. We believe from the distribution of these changes in the original specimens and their persistence after corrective surgery that they may not be the result of obstruction alone.
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Fig. 6. Extrahepatic duct remnant lumen distal to site of fibrous obliteration. Cellular pyknosis and necrosis in both duct lumen and gland epithelium (arrows) are accompanied by polymorphonuclear leukocytes in adjacent tissue. (Paraffin x 380) Traditionally, pathologic changes in the liver, in PH specimens, and in EHD remnant specimens from patients with biliary atresia have been attributed to distal duct obstruction. However, bile was never conspicuous in PH specimens in this study. The only E H D specimens containing bile both here and in the literature [8, 9] are examples of sharply localized E H D obstruction where proximal hepatic ducts are patent. In the liver of patients with biliary atresia, it has been shown that bile stasis may be limited to hepatic cells and canaliculi [7]. This finding strengthens the proposal by Landing [4] that the bile secretory defect that occurs in neonatal hepatitis also occurs in biliary atresia. Several features documented in this paper and by others support the concept that the ductal cellular changes in biliary atresia may not be secondary to obstruction. First, epithelial degeneration and inflammation are present in the lumens of 3 EHD specimens distal to regions of complete obstruction (Fig. 6). Second, in biliary atresia, intrahepatic changes may sometimes progress despite surgical relief of obstruction, as indicated here and elsewhere [13]. Third, the literature indicates that intrahepatic duct epithelial changes similar to those described here in biliary atresia also occur in liver diseases not associated with large duct obstruction.
Duct cellular changes of vacuolar swelling, flattening, focal necrosis, infiltration by PMN leukocytes, and epithelial proliferation have been described in acute viral hepatitis [14, 15], severe hepatocellular failure [16, 17], primary biliary cirrhosis [18, 19], and in livers of 35-40% of patients with chronic aggressive hepatitis [20]. Thus, these cellular changes seen in biliary atresia cannot be viewed only as a nonspecific response to ductal obstruction. An extraordinary proliferation of ductular epithelial cells in the liver of biliary atresia has been said to participate in compression and obliteration of the larger interlobular ducts [21]. The nature and significance of such "cholangiolar proliferation" has been controversial [15]. These structures are referred to here as Hering ducts because of their continuity with parenchymal cells [5]. Others have termed them cholangioles, branches of interlobular ducts, or pseudoducts reflecting regeneration of damaged peripheral lobular hepatocytes [15]. Regardless of their nature, they are seen as frequently in toxic or viral hepatitis as they are in association with extrahepatic duct obstruction [15], although not usually to the same degree. Ductular proliferation in a small proportion of cases of neonatal hepatitis is said to be the reason for occasional er-
568
roneous needle biopsy diagnosis of biliary atresia [6]. Therefore, it is possible that ductular proliferation is part of a basic cholangiopathic process, rather than being solely due to obstruction. The cirrhosis in biliary atresia may not be solely due to extrahepatic obstruction. It is characterized by more fibrosis [3, 22], a lack of hepatic regenerative activity [22], more rapid progression [3], and more periductal fibrosis, when compared to other forms of obstructive cirrhosis [22]. The presence of GCT in all cases, and the association of severe neonatal hepatitis with rapidly appearing cirrhosis in 1 case (Case 14), support the suggestion that the unusually severe cirrhosis in atresia is due, at least in part, to primary hepatocellular destruction [22]. Previous studies of the liver in atresia document the occurrence of GCT in as few as 15% and as many as 90% of cases, the higher incidence generally being seen in more recent studies [4]. The severity of cirrhosis and periductal fibrosis in all PH specimens, in contrast to that in the peripheral portions of the liver, corroborates an earlier postmortem description of the liver in biliary atresia. In that report, this centrally concentrated fibrosis was interpreted as the source of a progressive process extending towards the periphery of the liver [22]. Previous descriptions [8, 13] of surgical PH specimens have emphasized fibrosis but not ductal epithelial or inflammatory changes. Others have described excessive numbers of glands in EHD remnants near the porta hepatis [9]. These structures were interpreted as reflecting an adaptive or reparative response in specimens lacking a lumen. Glands seen in EHD specimens in the present study (Fig. 5) were thought not to be excessive but, instead, to represent persistent structures normally present in extrahepatic duct walls [5]. One other study of EHD remnants described focal duct epithelial necrosis not accompanied by inflammation [12]. Another described inflammatory cells accompanying glands and focal duct lining defects [9]. Each study cited these changes as possibly leading to large duct obliteration. Others have described inflammatory infiltrates in EHD remnants, but have attributed this to distal obstruction [10]. The etiology of the bile duct cellular changes described here is not apparent. Cholestasis alone cannot satisfactorily explain them, since they may occur and progress in its absence [7, 13, 20]. The similarity of ductal epithelial changes in biliary atresia to those occurring in some patients with severe viral and immunologically mediated hepatitis is interesting. The emerging consensus is that such changes in hepatitis are due to direct damage by the hepatitis virus [16, 17, 20], despite their similarity to changes usually attributed to large duct obstruction. As in biliary atresia, hepatitis patients with these
World J. Surg. Vol. 2, No. 5, September, 1978
duct epithelial changes develop cirrhosis more frequently and rapidly than those whose livers lack such changes [20]. Virus-mediated duct damage and ductal disappearance is well documented in other forms of childhood cholestasis [23]. The "virus-like particles" described by others in the nuclei of duct epithelial cells in EHD remnants [12] must be viewed with caution. Critical examination of these electron microscopic images suggests that they are a manifestation of cellular reaction to injury rather than of viral origin [24]. In summary, this paper describes changes occurring in intra- and extrahepatic ducts in patients with biliary atresia. It is suggested that these changes are analogous to those occurring within the cells of the liver in neonatal hepatitis reflecting a common etiology for both parenchymal and duct cell injury. It is further proposed that these changes occur in a sequence of degeneration, necrosis, inflammatory infiltration, and epithelial proliferation that precedes obliteration of the ducts. These changes, like giant cell transformation, may not be a response to obstruction, but may be a manifestation of a specific disease process. Regardless of their etiology, the continuation of these intrahepatic changes, in spite of surgery for relief of obstruction, is thought to be the explanation for the progressive liver disease seen in many patients with biliary atresia.
Acknowledgments
I am deeply indebted to Doctors Alexander H. Bill and J. Bruce Beckwith for their generous support, encouragement, and constructive criticism.
R~sum~
L'aggravation de la cirrhose apr~s une h6paticoent6rostomie r6tablissant l'6coulement de bile sugg6re que la pathog6nie de l'atr6sie biliaire n'est pas uniquement faite d'obstruction biliaire. Nous d6crivons les 16sions observ6es, chez 17 malades oper6s d'atr6sie biliaire, aux divers 6tages de l'arbre biliaire, depuis l'h6patocyte jusqu'au chol6doque (biopsies h6patiques, fragments de tissu h6patique pr61ev6s dans le hile, r6sidus de l'arbre biliaire extra-h6patique). Tant dans les canaux biliaires intra- qu'extra-h6patiques, on trouve des alt6rations 6pith61iales que l'on peut interpr6ter comme une succession de d6g6n6rescence vacuolaire, n6crose, infiltrat inflammatoire, prolif6ration 6pith61iale r6paratrice et finalement fibrose oblit6rante. La distribution de ces 16sions cytologiques indique qu'elles ne sont peut-6tre pas dues unique-
J.E. Haas: Hepatobiliary Pathology in Biliary Atresia
m e n t a une obstruction distale. Les altrrations de l ' r p i t h r l i u m des canalicules biliaires r e s s e m b l e n t ce que l ' o n o b s e r v e dans la foie de certains cas d ' h r p a t i t e virale. Darts tous les cas, les 16sions s ' a c c o m p a g n e n t de formation de cellules grantes, ce qui sugg~re une 6tiologie c o m m u n e aux 16sions canalaires et hrpatocellulaires de l ' h r p a t i t e n r o n a tale et de l'atrrsie biliaire. L a persistance des 16sions dans les biopsies p r r l e v r e s apr~s hrpatic o e n t r r o s t o m i e indique qu'elles p e u v e n t j o u e r un r r l e p a t h o g r n e dans la p r o g r e s s i o n de l'atteinte hrpatique o b s e r v r e dans la majorit6 des cas d ' a t r r s i e biliaire.
569
10.
11.
12. 13. 14.
References
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