Biliary atresia: new concepts of management

BILIARY ATRESIA: NEW CONCEPTS OF MANAGEMENT DANIEL M. HAYS, M.D. KEN KIMURA, M.D.

0011-3840/81/09-539-606506.50 9

Year Book Medical Publishers, Inc.

TABLE OF CONTENTS SELF-AssESSMENT QUESTIONS . BACKGROUND

.

.

.

.

.

.

. .

ETIOLOGY AND PATHOLOGY

. .

. .

. .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. .

.

.

.

541

.

.

.

546

9. . . .

552

DIAGNOSTIC PROCEDURES

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

558

SURGICAL PROCEDURES

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

565

.

.

.

.

578

ASCENDING CHOLANGITIS, TIlE PARAMOUNT POSTOPERATIVE PROBLEM . . . . . . . . . . . . . . . . . . .

.

582

PORTAL HYPERTENSION .

RESULTS

.

.

.

.

.

. .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

591

HEPATIC FIBROSIS AND CIRRHOSIS ASSOCIATED WITII BILIARY ATRESIA . . . . . . . . .

.

.

.

.

.

.

593

SECONDARY OPERATIONS: ANASTOMOTIC REVISIONS AND LIVER TRANSPLANTATION . . . . . . .

.

.

.

.

.

596

ACCEPTANCE OF THE KASAI APPROACH IN NORTH AMERICA AND EUROPE . . . . . . . . . .

.

.

.

.

.

597

LONG-RANGE SURVIVORS

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

599

SELF*AssESSMENT ANSWERS

.

.

.

.

.

.

.

.

.

.

.

.

.

.

606

542

SELF-ASSESSMENT QUESTIONS 1. Outcome in the treatment of biliary atresia is influenced to a major degree by all except one of the following factors: a. The age of the patient at operation. b. The degree of histologic alteration in liver cells, which may or may not reflect the age. c. The height of total serum bilirubin levels reached prior to surgery. d. The presence or absence of microscopically visible ductal structure in the transected end of the fibrous mass at the

porta hepatis. 2. The etiology of biliary atresia is unknown. All but one of the following statements are true in respect to possible etiologic factors: a. Biliary atresia frequently occurs in the same "sibship" with infants that have the "neonatal hepatitis" syndrome. b. The incidence of biliary atresia has an association with the occurrence of polysplenia, and splenic hypoplasia. c. Elevated titers of antibodies against a number of specific viral agents are prevalent in patients with biliary atresia, but not in those with hepatitis. d. The cholangiographic and pathologic findings in biliary atresia grossly resemble a process that might be termed "sclerosing cholangitis." 3. In the differential diagnosis of neonatal cholestatic jaundice, all except one of the following studies are effectively employed: a. Percutaneous transhepatic cholangiography. b. Serum levels of a-fetoprotein. c. Duodenal intubation with the analysis of intraluminal content. d. Hepatobiliary imaging employing N-substituted iminoo diacetic acids (IDA, HIDA, and PIPIDA). 4. With respect to distinguishing biliary atresia from "neonatal hepatitis" prior to surgery, patients that formerly fell into the latter category have more recently been found to have one of the following diagnoses. All except one are correct: a, a-l-Antitrypsin deficiency. b, Hepatitis secondary to eytomegalovirus. c, Jaundice secondary to Gilbert's disease. d. Hepatitis secondary to rubella infection. 5. The diagnosis of biliary atresia, as established by the sur543

geon at operation, is ordinarily based on only one of the following factors: a. Liver biopsy with rapid section histologic studies. b. Observation of the gross structure of the gallbladder and cystic duct. c. Dissection of the porta hepatis structures. d. Transhepatic cholangiography. 6. Following successful hepatic portoenterostomy for biliary atresia, the postoperative complication that is.more significant than all others combined is: a. Portal hypertension with variceal hemorrhage. b. Febrile episodes, referred to as 'r cholangitis." c. Chronic ascites. d. Growth failure and developmental retardation. 7. In respect to the significance of early operative intervention for patients with biliary atresia, one of the following statements is true: a. There is a sharp decline in survival among patients operated on later than 100 days of age. b. Beyond the initial 60 days of life, survival rates are progressively lower, without any specific age at which survival falls rapidly. c. Patients in which the appearance of jaundice is delayed do not appear to have a corresponding delay in the progression of hepatic changes. d. There are no long-range survivors among patients operated upon after 90 days of age. 8. During episodes of ~'ascending cholangitis" in jaundice-free patients following hepatic portoenterostomy for biliary atresia, all except one of the following signs and]or symptoms are frequently observed: a. Temperature elevations with tachycardia. b. Massive gastrointestinal hemorrhage. c. Elevations in total serum bilirubin and in SGOT, SGPT, and LDH. d. The appearance of acholic stool. 9. In respect to the traditional r and ~'noncorrectable" forms of biliary atresia, all but one of the following statements are correct: a. This distinction no longer plays a major role in determining prognosis. b. These two types are treated by distinctly different types of surgical procedures by surgeons concerned with biliary atresia. c. The ~'correctable" form of biliary atresia is regarded by many surgeons as a form of choledochal cyst. d. The definition of a '~correctable" form of biliary atresia 544

may include the criterion that the cyst wall include welldefined mucosal and muscularis layers. 10. With respect to the postoperative course following Kasaitype procedures for biliary atresia, all except one of the following statements are correct: a. It is probable that portal hypertension exists in all patients; but in the majority, it is not a major clinical problem. b. Some degree of hepatic fibrosis is present throug.hout their subsequent lives. c. A significant group of patients have demonstrable biliary excretion for a prolonged period, but never become completely jaundice free. d. Patients who become completely jaundice free rarely have episodes of "ascending cholangitis." 11. Considering the long-range survivors following Kasai-type procedures for biliary atresia, when this group is defined as those who are jaundice-free for five years or more following surgery, the following statements are correct: a. The results of liver function studies lie within the normal range. b. More than 80% of these patients are attending school or employed. c. More than 85% of these patients do not restrict their physical activity in any way, and participate actively in sports, etc. d. Episodes of "ascending cholangitis" are uncommon. 12. Until approximately 1975, the results of therapy for biliary atresia in several centers in Japan were distinctly better than those in hospitals in the West. This might be attributed to all but one of the following factors: a. A radical new approach in surgical management was developed there. b. Patients with biliary atresia are concentrated in specialized centers resulting i n relatively large series of patients there. c. The form of biliary atresia found in Japan is unique and more amenable to therapy than that seen in the West. d. A major concentration of effort has been made in specific centers there, directed at both the basic and clinical research aspects of the management of biliary atresia. Answers are listed at the end of the article.

545

is a Professor of Surgery at the University of Southern California School of Medicine, Los Angeles, California. Training in surgery and pathology included periods at The New York Hospital, Peter Bent Brigham Hospital, University of California (San Francisco) Hospital, and the Boston Children's Hospital. In 1975-1976 he was the Chairman of a U.S. Committee for the International Study of Biliary Atresia, working with a counterpart committee of Japanese pediatric surgeons. In 1977-1978 he was awarded a Fogarty International Fellowship for the study of biliary atresia in Japan, resulting in a Commonwealth Fund publication on this subject. His research interests, in addition to biliary atresia, include hepatic regeneration and total parenteral nutrition. He has been active in cooperative group studies of pediatric solid tumors.

is the head of Pediatric Surgery, Kobe Children's Hospital. He is a graduate of Kobe University School of Medicine, Kobe, Japan and completed residency training in pediatric surgery at Boston Floating Hospital, Tufts-New England Medical Center, Boston. Doctor Kimura has had a long-standing interest in introducing the exhaustive studies on biliary atresia achieved by Japanese investigators to the audience in Western culture areas. His primary research interests are in the areas of basic and clinical aspects in biliary atresia and gastrointestinal physiology and surgery in infants and children.

T E N YEARS AGO surgeons regarded biliary atresia as a congenital anomaly from which a minority (< 10%) of patients survived following attempts at surgical correction. E ven most of this min o r ity did not fully recover following t he conventional anastomosis of the cystic r e m n a n t s of the biliary t r a c t to the intestine. Most patients received only simple laparotomy and liver biopsy, without an a t t e m p t at therapy. A major concern 546

among pediatricians was to avoid operation, and the thrust of their efforts during this period was toward the development of diagnostic procedures that would avoid laparotomy in patients without structural obstruction. The current and still controversial concepts of the management of biliary atresiaoriginated as a result of the activity of Morio Kasai in Sendai (Japan), who began working in this area during the decade 1955-1965 and developed a unique approach to this disease that may represent the most significant technical contribution originating in Japan in any field of surgery. The original Kasai procedure (1955-1957) was a standard Roux-enY biliary-intestinal connection, but it included a novel dissection of the porta hepatis structures and an entirely new concept of the overall pathologic changes in the biliary ductal system and their significance. In addition to the fact that a sizable group of apparently successfully treated cases soon appeared in his clinic, and subsequently elsewhere in Japan, this approach provided specimens of the intact extrahepatic biliary tract that could be studied for the first time during the early phases of what Kasai described as a dynamic, rather than static, disease. These specimens revealed the presence of an inflammatory process and microscopically visible ductal structures, observations that have been confirmed by pathologists in Western countries. Acceptance of Kasai's concepts and approach took approximately a decade in Japan and almost an additional decade in Western surgical circles. Concepts of therapy of most of the surgeons treating biliary atresia in the United States have gradually come closer to those of Japanese surgeons who have achieved the greatest success with this approach, and the results in some U.S. series are comparable to those obtained in Japan. Once sizable numbers of jaundice-free survivors were available for study following Kasai-type procedures, "ascending cholangitis" came to be recognized as the major postoperative complication. This condition is of such significance that it has dominated subsequent study of biliary atresia and has led to development of a group of specific techniques for its evaluation, the widespread use of postoperative prophylactic antibiotic regimens, and the trial of a diverse group of surgical procedures designed solely to reduce its incidence. Improvement in survival of patients with biliary atresia in all countries has been associated with a decrease in patient age at the time of operation. The major factors that affect the prognosis in patients with biliary atresia at present are: (a) age at the time of operation; (b) the degree of histologic alterations in the liver cells, which may not be merely a reflection of age; (c) the presence (or absence) of microscopically demonstrable ducts in the fibrous tissue structures at the porta hepatis; (d) the tech547

nique of the surgical procedure and experience of the surgeon; and (e) the incidence of postoperative "ascending cholangitis," and, to a lesser degree, the complications of portal hypertension. This monograph is an attempt to view the developments of the past decade in this field in perspective, with emphasis on the surgical techniques utilized and the results of therapy. BACKGROUND

The first comprehensive review of this subject was published by John Thompson1 of the Royal Hospital for Sick Children, Edinburgh, in 1882. Thompson diagramed the findings at autopsy in 49 cases of neonatal obstruction of the biliary tract, which were reported in the European literature during the prior 50 years. These diagrams may be viewed in the library of the Royal Academy of Medicine (London) and suggest that there has been no significant change in the gross forms of this disease in the past century. The question of therapy was not even raised in Thompson's discourse. J. B. Holmes2 of Johns Hopkins made a similar review of the English language literature in 1916 and provided diagrams of 82 gross variants of "congenital biliary atresia," as it was termed in early reports. Holmes made the remarkable prediction that 16% of patients with this disease could be saved by a biliary-intestinal anastomosis, although such a procedure never had been performed successfully. Holmes' cases were divided into a number of categories on the basis of the form of the residual structures seen, but his basic separation of the series into those that were "correctable" or "noncorrectable" provided the only widely used classification of these patients for the next half century. The realization of Holmes' prediction regarding the size of the group of salvageable patients was not achieved until after 1960. Ladd s reported the first successful anastomosis to the intestinal tract for biliary atresia in 1928. The initial brief period of optimism was not supported by subsequent results either at the Boston Children's Hospital, the center of pediatric surgery at that time, or elsewhere in the United States; only occasional instances of survival beyond infancy were reported during the subsequent three decades among patients with well-established atresia. Bill 4 found only 52 reported successes in the Western literature (1927-1970), and in most of these the periods of postoperative observation were brief. The rates of survival in the United States were summarized in the report of the Surgical Section of the American Academy of Pediatrics (1966), 5 which included patients seen during the period 1954-1964. Although 10-20% of the 843 infants treated by members of this organization appeared to have "correctable" forms of biliary atresia, in retrospect the rate of long-range survival probably was less than 548

5%. The results in European, Canadian, and Japanese clinics (except Kasai's) during this era were similar. 6-8 All large series contained occasional patients in whom the jaundice cleared and extended survival was achieved. All of these were infants with "correctable" forms of atresia and followed an anastomosis between a visible cystic structure in the hepatoduodenal ligament, external to or at the margin of the liver surface, and an intestinal segment (usually duodenum). Although cholangiograms were described by Ericsson and Rudhe 9 in 1954, most early.procedures included no consistent attempt to establish a connection between these biliary cystic structures and the intrahepatic ductal system, either before or after the anastomosis. Biliary atresia was reported in Japan as early as 1893, and 88 cases were collected from the Japanese literature by Kasai et al. 1~ in 1957. Kasai began his life-long study of this disease in 1955 with the observation that when the remnants of the extrahepatic biliary tract at the porta hepatis was excised, a demonstrable bile flow from this area could be anticipated. He then carried out more detailed dissections of the fibrous hepatic hilar structures and observed that the remnant of the extrahepatic biliary tract, at the level of the porta hepatis, contained microscopically visible ductal structures, when no ducts could be seen on the cut surface. Prior to 1957, Kasai operated on three infants with "noncorrectable" biliary atresia. These procedures were unique in that the remnant of the extrahepatic tract was transected at the level of the liver surface and an anastomosis was made there. This group includes the initial long-range survivor (> 25 years) with "noncorrectable" biliary atresia. Six additional procedures were carried out in 1957, utilizing a Roux-en-Y jejunal loop for the intestinal connection, resulting in a second long-range survivor. In the United States and Europe during this era, a major emphasis was on the development of diagnostic procedures to identify patients who had the "inspissated bile syndrome" or "neonatal hepatitis" and would not require operation, n-13 The latter included a wide variety of patients with diseases now falling in the category of neonatal cholestatic icterus, including alpha-lantitrypsin deficiency and specific viral infections. The poor results of operation in patients with neonatal jaundice were recognized by pediatricians who were reluctant to refer patients for operation until a battery of studies," frequently serial and timeconsuming, had been performed. This resulted in patients frequently coming to operation at a time when secondary hepatic changes probably would preclude survival even when anastomosis to a biliary cyst was technically feasible. A minority of American surgeons and pediatricians always advocated "early" operation for biliary atresia, which usually implied operative intervention prior to the third month of life." 549

The interest of surgeons in Western countries was largely confined to those patients having "correctable" forms of biliary atresia. The more prevalent (approximately 85%) infants with "noncorrectable" forms were viewed as having obstruction of all of the intrahepatic biliary tract structures and no therapeutic surgical procedures were attempted. Some patients with "noncorrectable" disease had rather prolonged survival, but the mean was 19 months. 1~ In less t h a n 1% of this total group, a form of spontaneous recovery would occur, which usually .was explained on the basis of misdiagnosis; i.e., the patient had unrecognized "neonatal hepatitis." Experimental surgical procedures in "noncorrectable" biliary atresia included those of Absolon, Rikkers, and Aust, 16 demonstrating that serum bilirubin levels could be reduced, frequently to the normal range, by external drainage of hepatic lymph via the thoracic duct. It was believed by m a n y clinicians and pathologists during this era that in most patients with biliary atresia, including both "correctable" and "noncorrectable" types, the intrahepatic ducts frequently were occluded or "absent," constituting what was referred to as intrahepatic biliary atresia, and t h a t repair of the extrahepatic tract usually was a futile exercise, even when feasible. Some suggested that all surgical successes in infants with biliary atresia were the result of misdiagnoses. In autopsy studies from several clinics, the development of a state of ~'correctability" in infants in whom no dilated extrahepatic biliary structure was found at the initial operation was reported. 1~ Others described "second-look" procedures in which "correctable" lesions were found in patients who had been explored previously and found to be "noncorrectable. ''is These experiences, although infrequent, led to the concept t h a t patients with biliary atresia became more amenable to surgical correction as their course continued. It was believed that despite the progression of cirrhosis, the possibility of forming an effective connection with the intrahepatic biliary tract improved with the passage of time. Studies from Australia suggested that the incidence of "correctability" found at operation or autopsy might be increased with advancing age but that this did not increase survival duration. 19"20 This concept was precisely opposite to that held by m a n y investigators in this field in J a p a n in the 1970s. The Japanese believed t h a t the changes in the extrahepatic biliary tract, as well as in the liver, usually were progressive and that the chance of achieving a successful anastomosis became more rem o t e w i t h the passage of time because of changes in both the liver parenchyma and the extrahepatic tract. The surgeons in the United States and Australia undoubtedly were correct, in that with the passage of time a cystic biliary ductal structure 550

occasionally does emerge from the porta hepatis in biliary atresia. Japanese investigators, on the other hand, were concerned with the microscopic ductal structures seen in the fibrous tissue in the porta hepatis of the majority of these patients; and these structures undergo progressive obliteration, at least beyond the third month. An approach routinely used in some institutions in the United States during the decade 1960-1970, but rarely reported, consisted of the excision of cores or segments of liver tissue from the general area of the porta hepatis, with the formation of an anastomosis between a relatively extensive area of exposed hepatic parenchyma and the intestinal tract. The results of these procedures at times were encouraging, jaundice clearing completely. Within months, however, the area of the hepatointesfinal anastomosis became occluded by scar tissue, as obstruction, and progressive cirrhosis developed. These patients at times were operated on repeatedly, with secondary periods of relief from jaundice, b u t the ultimate results were disappointing. During the period 1958-1970, Kasai concentrated the research effort of his department at Tohoku on biliary atresia. The size of biliary ducts in infants with diverse diseases was examined and measured using serial section techniques. Studies of the histopathology of the liver and of the extrahepatic biliary tract remnants in infants with biliary atresia were started (Fig 1) and were continued in the 1970s. 2'' 22 Ductal structures in biliary tract tissue were measured by microscopic techniques and the influence of the presence and size of these ducts on prognosis observed. A spectrum of active inflammatory changes in the remnants of the extrahepatic tract in biliary atresia was described, which will be discussed in the next section. The concept that patient age at the time of operation was a major factor in outcome (Fig 2) appeared in a report in 1961. The lethal febrile episodes that followed operation for biliary atresia were first noted and the term "ascending cholangitis" used in this connection for the first time in Kasai's reports. Kasai's concept of the nature of the histologic changes taking place in biliary ductal structures, both external and within the liver, was unique. His operative approach was even more radical. He believed that when the occluded extrahepatic ductal system was isolated and dissected to the level of the liver surface (or beyond), the remnant ordinarily could be identified as a discrete structure about which a precise anastomosis to an intestinal segment could be formed. It was not an area of denuded liver tissue to be covered by the lumen of the intestine. External biliary tract cysts might have ductal connections with the intrahepatic ductal system, but he believed that the excision of such structures ordinarily was preferable to forming an anastomosis 551

~I-b,-V Fig. 1.--Three-dimensional reconstruction of biliary ducts in the fibrous mass at the porta hepatis in a patient with biliary atresia prepared by a macroserial section technique (Chiba). At the lower right is a diagram of the complete surgical specimen removed during hepatic portoenterostomy in this infant, with that portion, which is the subject of the serial section studies, circled. The large central diagram is the detailed analysis of the circled portion of the specimen; that is, the portion at the porta hepatis. At the distal (lower) portion of this principal diagram there is a small irregular oval indicating the distal plane of transection of the fibrous mass. Immediately above this is a large ductal structure that does not communicate with either the intrahepatic or the extrahepatic system. Thus, an anastomosis at this transection site woutd, in the opinion of the investigators who developed this technique, result in ineffective biliary flow. The larger irregular oval at the top of the diagram illustrates the level of proximal transection of the most proximal portion of the fibrous mass. Here, in contrast to the previous site, many small transected ducts are seen in the reconstruction, some of which probably communicate with intrahepatic biliary radicles. Thus, it is believed by the investigators that transection at this level should result in biliary excretion, and this proves to be true in this case. This is a study of a surgical specimen, not an autopsy study, as in Figures 2 and 3. (From Kasai M., Suzuki H., Ohashi E., et al.~, Copyright by the Societ~ Internationale de Chirurgie.)

external to the liver surface. Thus, the "correctable" and ~noncorrectable" forms in most instances were treated almost identically. Kasai's optimism in respect to the function of an anastomosis to ductal structures that were visible (if at all) only microscopically was based on experimental studies. His group had observed that the smaller intrahepatic biliary ducts frequently were less involved in the sclerotic process, which was characteristic of biliary atresia, than were either the extrahepatic ducts or the larger intrahepatic ducts close to the porta hepatis. As an alternative hypothesis, this process might be more frequently reversible in the smaller intrahepatic ducts. It was postulated that if drainage could be established early i n the course, these intrahepatic ductal structures would retain normal function. 552

130 120~ lie

MEAN AGE AT TIME CI= 100 OPEFIATION 90 (~I 80

60 50

T

I

I

I

!

I

I

!

I

I

I

|

t

I

|

Yeor. 1965 '66 '6"7 '68 '69 ~70 '71 72 '73 s74 'T5 '76 'T7 '7e '79 '80 No. of Patients: 9 12 6 12 9 8 8 8 6 II 9 II 12 12 8 8 -I oi -I -I -I -I Fig 2 . - - M e a n age at the time of the definitive operative procedure for biliaryatresia in patients w h o have undergone hepatic porioenterostomy (or hepatic portocho I lecystostomy) in the Tohoku series (1965-1980). This illustrates the progressive trend toward earlier operation. Six patients excluded from calculations of the m e a n because of advanced age are indicated in the lowest line.The ages of these patients at the time of operation were (left to right): 239, 204, 227, 109, 128, and 160 days of age, respectively. (R. Ohi, Tohoku; personal communication.)

During the period of this development (1955-1965), concepts of management in the United States and Europe were moving in an opposite direction. Preservation of the remnant ductal structures was stressed, with the hope that spontaneous resolution of the process might occur. It was widely believed that the exploratory laparotomy per se increased the postoperative mortality and the severity of subsequent cirrhosis in patients with "neonatal hepatitis ''23 and that the chances of performing a successful anastomosis were extremely small. At operation, the approach was conservative, with a scrupulous attempt at preserving existing ductal structures, no matter how minute. The aim of operation in the West was to identify a subhepatic biliary cyst and, if this was not possible, to preserve intact the existing ductal remnants. Despite this care, a number of patients developed subhepatic bile collections or other evidences of hepatic bile flow following operation, which might be expected to occur if microscopic ductal structure at the porta hepatis had been divided. The dichotomy thus was complete, as Kasai had by this time evolved an operative approach that deliberately sacrificed the entire extrahepatic biliary system in all cases of biliary atresia, i.e., both "correctable" and "noncorrectable," whereas, in the United States and Europe, surgeons scrupulously preserved these structures during operations carried out for precisely the same condition. Acceptance of Kasai's concepts and methods was slow in Japan, except among surgeons trained by him, and it was not until

553

approximately 1969 that this type of procedure became general in Japanese surgical centers. Suruga played a major role in drawing the attention of surgeons abroad to what was taking place in Japan, although his reports in Western countries initially were viewed with skepticism bordering on hostility. The concepts that had been developed by Kasai (1955-1965) and were accepted generally in Japan by 1969 had little influence on the management of infants with cholestatic jaundice in the United States and Europe until the 1970s. Since that time, information regarding the Japanese experience with biliary atresia has become available throughout the world, and surgical procedures of this type have been performed in all developed countries. The initial procedure of the Kasai type was carried out in France in 1969, 24 and by 197625 a series of 49 patients had been operated on at the H6pital St. Vincent de Paul (Paris). Valayer, from Paris, visited Sendal during this period and his operative approach was modeled directly after that of Kasai. In the United States, a systematic study of hepatic portoenterostomy for biliary atresia, including patients from both the Children's Hospital National Medical Center, Washington, D.C., and the University of Colorado Medical Center was begun in the early 1970s, and initially reported in 1975. 26-29 In these institutions, Kasai-type procedures were performed routinely for biliary atresia, and patients underwent systematic and extensive study afterward. National interest in this approach followed. Initial results in some clinics were extremely poor,3~ and the significance of this contribution was questioned by many United States investigators. At least limited success in patients with "noncorrectable" biliary atresia was reported by most surgeons by 1977, and the reported results have improved progressively since that time. There is no evidence that biliary atresia is more prevalent among the Japanese than among Western populations, ~1but the concentration of these patients in a relatively small group of institutions there resulted in series of 50-100 infants during the decade 1965-1975. Such series contained many variants not described previously, and communication among such institutions led to a classification more precise than the traditional one based on a concept of "correctability," which no longer was relevant. After a series of national meetings, the Japanese Society of Pediatric Surgery established a complex classification now generally used there (Fig 3). ETIOLOGY AND PATHOLOGY

The etiology of biliary atresia is not known. Prior to 1965 it usually was described as a ~'birth defect," suggesting a failure in early organogenesis with an embryologic explanation similar to 554

1. PRINCIFALTYPES Type I: Atresia of ~

~ . : . ~'.

~le duct

Type I: AITesk]of common hepoilcduct

~':~:"

__Type~: Atresioof bile ducts at the p~to I'ep~tis

~ ,"F

~"

~;

2. SUBTYPES /~O:)RDING TO STRUCTURE OF DISTAL BILE DUCT a p~tent ~

b.

bile duct

fibrous common

bile ducl

c. aplosia of common

~,~

bi~e duct

~..,.~

SUBTYPES ACCORDINGTO THE STRUCTURES FOUND AT TIE PORTAHEPATIS

d,.: dilated hepatic ducts (internal diameter )trnm)

,/~: hypoplasfic hePatic ducts (internal diome~r <1ram)

bile lake (t:o epithelial lining)

.F

m:

fibrous hepatic "c(xds"

Fig 3.--This classification of the forms of bitiary atresia was adopted by the Japanese Society of Pediatric Surgeons (JSPS) in 1976 and has been translated by M. Kasai. It now is used in the major teaching centers in Japan. The principal types--Types I, 11, and Ill=reflect the status of the biliary ductal system in reference to the site of functional obstruction of the entire tract. The second category--Types a, b, and c--describe the status of the common bile duct remnant. The latter is of significance in reference to the possibility of performing hepatic portocholecystostomy. The third category, subtypes according to the structures found at the porta hepatis, describes the gross (not microscopic) status of the structures found at this level. In many institutions, the first and third categories only are used. For example, "Type IIl-m" probably is the most common form of biliary atresia.

P n:

fibrous mass

O:

oplosio of hepatic structures

i 555

that of duodenal atresia. In early reports, the word "congenital" was used routinely in the diagnosis. Surgeons have regarded biliary atresia as primarily a disease of the major extrahepatic biliary ducts when "correctable" or of both the extrahepatic and intrahepatic ducts when "noncorrectable." However, its pathology has been predominantly described in terms of changes in hepatic tissues obtained from peripheral portions of the liver. These have been readily available (by biopsy) whereas, prior to the routine use of Kasai-type procedures, specimens of the extrahepatic biliary tree (available only at autopsy) usually were distorted by postoperative scar tissue, altered by progression of the disease process, and obscured by the advanced changes of hypertrophic cirrhosis about the porta hepatis. Although Kasai's concepts of pathogenesis were derived from independent study of the new specimens that his approach afforded, a number of pathologists and other investigators in North American, Australian, and European centers had suggested from the limited material available to them, prior to the introduction of this new technique, that the changes in the intrahepatic and extrahepatic ductal systems in biliary atresia inFig 4.--Studies of the structure of the intrahepatic ducts in two infants with biliary atresia as determined by the step serial section technique (2-3 mm intervals). The lower margin of the diagram is the level of the porta hepatis and the study extends upward into the center of a liver lobe. At the top of the diagram are central interlobular ducts. These two studies illustrate arborization of the major ducts into smaller biliary radicles as they approach the fibrous mass at the level of the liver surface. (From Chiba T., Kasai M., Sasano N.=)

-! 556

i

cluded an inflammatory process. 32'33 Some noted that biliary atresia had an unusual association (among siblings) with "neonatal hepatitis"; others postulated that both of these processes might be manifestations of the same etiologic factors.3~ The nature of the disease process now is believed to be best described as a sclerosing cholangitis, which may involve the entire extrahepatic and intrahepatic biliary ductal systems but frequently is also segmental in its severity and may be so localized as to leave some segments relatively unaffected. K.asai's concept that the intrahepatic ductal structures, excluding those immediately adjacent to the porta hepatis, usually are less affected than the extrahepatic ducts (Fig 4) has been widely accepted. However, in some infants, this clearly is not the case, and the small and moderate-sized intrahepatic ducts are also, apparently permanently, occluded (Fig 5). Thus, occlusion in any given biliary ductal segment may be complete or incomplete, may result in dilatations (cysts measuring several centimeters in diameter), or may open and have ductal connections with eiFig 5.--Structure of the intrahepatic biliary system in nine autopsy studies of infants with bitiary atresia in which serial section techniques were used to produce three-dimensional models. The infants with biliary atresia in this study fell in two patterns: A, those patients with large visible ducts at the level of transection at the porta hepatis, which connected with the intrahepatic ductal systems (Cases 1 and 2), and B, patients with many microscopically visible ducts at the level of transection at the porta hepatis, which connected either with large intrahepatic ducts (Cases 3, 4, and 6) or to smaller intrahepatic ducts (Cases 5 and 9). If the term "noncorrectable" biliary atresia has practical meaning at present, it would refer to those falling in the categor, of Cases 5 and 9. (From Chiba T., Kasai M., Sasano N.~ Basic pattern

A

Intrahepatic bile ducts of porto hepatis and tnterlobular bile ducts

/)

Cases 1~2 "

B

.~

Case/4

Case 3

Case 5

Case 6

Case 9 557

ther the intestinal tract or portions of the intrahepatic ductal system. Some evidence of inflammation is apparent in most specimens; and, in exceptional cases, the entire extrahepatic system is fixed to surrounding structures by an edematous inflammator:~ process. It it postulated by Kasai and others that this represents an "early" phase o f the disease, through which all patients pass, but with great variation in its length and severity. It is postulated that this acute or subacute process is follow.ed by a phase in which those ductal structures that have been affected most severely become completely fibrotic and occluded. In such patients, remnants of ductal structures, as well as most of the inflammatory cells, are absent. This is a frequent finding at autopsy, in uncorrected cases, as most patients live for approximately 16 months after the diagnosis is established. 15 A progression of histologic changes in the intrahepatic and extrahepatic biliary ducts, which was not affected by restoration of bile flow following portal enterostomy, has been described by Haas 35 from a study of surgical and autopsy specimens. He suggests that these changes are similar to those found in severe viral hepatitis. Serologic studies of viral antibodies, however, have not shown impressive elevation in infants with biliary atresia. CHANGES FOLLOWING OPERATION.raThe majority of patients with biliary atresia do not have grossly visible ducts in the area of transection of the fibrous mass at the porta hepatis, but microscopic ductal structures usually are present there (Fig 6). Following successful hepatic portoenterostomy for biliary atresia, what is the nature of these ductal structures in subsequent years? This is an unresolved question. Following a study of 32 patients from the Colorado Medical Center series, as well as observations at Tohoku, Ohi concluded that recanalization of the ductal structures in the fibrous mass resulted in two ducts, one from each lobe, and these are what one ultimately finds following a successful procedure. This view is shared by those who have studied the series at Juntendo. The alternative point of view maintains that the multiple microscopic ductules continue to provide drainage of the intrahepatic ductal system for a prolonged period (perhaps indefinitely), although eventually they may coalesce into a single duct or two. This view is held by Kasai, and the same conclusion was reached by Okamoto from studies of the Hyogo series. This is of practical importance because if the former concept is true, particular attention should be directed to include the extreme lateral aspects of the fibrous mass within the anastomosis. A study of autopsy specimens of the porta hepatis region by 558

* " - ' , ~ B i m C ~ B r"

t

~,-'T~

.

. .

9

- ~ - ~ , ~ m ~ t r "

' -: .,ta~"~il

Fig 6.--Microscopically visible ductal structures. Photomicrograph (X130) taken from the hepatic side of the fibrous mass at the porta hepatis in a patient with biliary atresia. Liver tissue is above and the fibrous remnants of the extrahepatic biliary tract below. Numerous ductal structures with epithelial lining are seen both in the fibrous mass and at the periphery of the liver. Bile plugs are seen in ductules. (Kobe series.)

Gautier et al. ~6 (Paris) suggested that transection of the fibrous mass resulted in enlargement of the microscopic or macroscopic ductal structures in all cases; i.e., irrespective of the type of anastomosis performed or its success or failure. Attempts to produce an experimental model for biliary atresia have been largely unsuccessful. Interruption of the blood supply of the common bile duct by Pickett and Briggs 3~ and of the common hepatic duct by Okamoto3s has resulted in perhaps the nearest approximation to the gross and microscopic pathology found in the human. Intrauterine ligation of the common bile duct, recently carried out by Spitz 39 in fetal lambs, produced a lesion that resembled "correctable" biliary atresia, although ductal lining epithelium was either totally or partially absent in the blind end proximal to the obstruction. Most experimental ligations of biliary ducts, or ligations with sclerotic injection, result in lesions that are closer to choledochal cysts than to biliary atresia. Recent studies by Miyano4~suggest that there is an increased incidence of abnormally high junction of the common bile and pancreatic ducts, i.e., a long "common channel," as well as a poorly developed sphincter musculature, in infants with biliary atresia. The concept is advanced that the reflux of pancreatic 559

enzymes may play a part in the origin of this disease, as well as in choledochal cysts. Biliary atresia initially was described as notably unassociated with (other) congenital anomalies. Although this may be true relative to the syndromes of anomalies that connect the genitourinary, cardiovascular, etc. systems there unquestionably is a higher incidence of anomalies than in the general population. In the author's 31 survey of 84 long-range survivors there were six patients with other major disease states, including .Turner's syndrome, craniostosis, cerebral palsy, pectus excavatum, and jejunal and ileal atresia. Lilly41 describes an increased incidence of major anomalies of the hepatic vasculature. Biliary atresia may have a specific association with polysplenia, 42 or the polysplenia syndrome, and splenic hypoplasia. 43 DIAGNOSTIC PROCEDURES Infants with cholestatic jaundice are evaluated by a reasonably standard group of procedures developed over the past two decades."' 45 Current interest in the United States has centered on scanning studies with a new class of hepatobiliary imaging compounds and, in Japan, on percutaneous transhepatic cholangiography, duodenal intubation, and computerized multiple variant analyses of the significance of different factors in reaching an accurate diagnosis. STUDIES OF BLOOD COMPONENTS.--Determinations of relevant serum components are made, often largely by automated panels (Table 1). Studies usually also include alpha-l-antitrypsin activity and determinations of levels of alpha-fetoprotein and lipoprotein X. Alpha-l-antitrypsin deficiency is of major significance in the United States, where it appears that a third of the patients in the clinical category of "neonatal hepatitis," and previously operated on to distinguish them from those infants with biliary atresia, had this familial condition. Alpha-l-antitrypsin levels in serum now can be determined and operation avoided in these patients. Despite extensive efforts, this condition has not been identified in Japan. Serum levels of alpha-fetoprotein have not been of major clinical significance in distinguishing biliary atresia from neonatal hepatitis. "Lipoprotein X" determinations are believed to be positive (or high) in patients with biliary atresia and usually negative (or lower) in patients with neonatal hepatitis. 46'47 When standards are set at a relatively low level, all patients with biliary atresia will be "positive," as well as approximately onethird of the patients with neonatal hepatitis. This test is widely used in the United States and Japan despite its limitations. 4s Patterns of serum bile acids in neonatal cholestatic conditions 560

TABLE

I.--STUDIES U S E D IN THE EVALUATION OF THE INFANT WITH N E O N A T A L

CHOLESTATICJAUNDICE URINE STUDIES (a) Urine amino acid analysis (tyrosinosis) Co) Culture for cytomegalovirus (c) Urobilinogen FECESSTUDIES (a) Bilirubin (b) '3'I-rose bengal differential excretion

X-RAY STUDmS (a) Hepatic scintigraphy (HIDA, PIPIDA) (b) Sonography (ultrasound) (c) Upper gastrointestinal series (d) Bone age Listed are studies carried out in one or more medical centers. No single institution uses all of these studies routinely or in all patients

SERU]~ISTUDIES (a) Coagulation screen: Prothrombin time; partial thromboplastin time; platelet count (b) Plasma protein fractions: Total protein; albumin]globulin ratio; alphas, alpha 2, beta, and gamma globulins; alpha-fetoprotein (c) Serum enzymes: Lactic dehydrogenase; glutamic oxaloacetic transaminase; glutamic pyruvic transaminase; 5' nucleotidase; alkaline phosphatase; RBC galactoseuridyl transferase (d) Miscellaneous: Parent's blood type; total cholesterol; serum phospholipids and triglycerides; calcium and phosphorus, serum creatinine and blood urea nitrogen; blood cultures; Coombs test; glucose, amino acid levels; bilirubin, total/ direct; blood sugar (e) Bile acid profile (f) Hepatitis B surface antigen (g) Infant serologic studies for toxoplasmosis and syphillis; maternal and infant serologic studies for rubella, cytomegalovirus, herpes simplex and other infections (~rORCH* screen") (h) Serum colloidal reactions (CF, ZT, T.T.), lipoprotein-X determination, alpha-1antitrypsin activity determination

*Refers to serologic tests on mother and infant that can identify the significant congenital infections, i.e., toxoplasmosis (T), rubella (R), cytomegalovirus (C), herpes (H), etc.

have been studied in detail in the United States 49 and other countries, but have not been used routinely as clinical diagnostic procedures. BILE EXCRETION IN INTESTINAL C O N T E N T S . - - T h e differential (gut vs. kidney) excretion of 131I-labeled rose bengal (or BSP) still is used in many institutions. A total excretion through the intestinal tract of 7-10% of the label in 72 hours is regarded as an indication of patency of biliary ducts. This study is techni561

cally difficult because absolute separation of stool and urine specimens must be maintained. In many centers it has been abandoned in favor of scanning studies. There has been a revival of interest in duodenal intubation to obtain intraluminal content for bile analysis. 5~ Fluoroscopic control in placing the duodenal tube, the development of specifically designed rigid tubes, and the introduction of small amounts of concentrated (25%) magnesium sulfate via the tube are refinements now widely utilized. In some institutions the tube is left in place and aspiration carried out .~erially. When this study is positive for bilirubin, it appears to exclude the diagnosis of biliary atresia, but an appreciable group of patients with severe forms of hepatocellular cholestatic jaundice also give negative results. The results of this study are immediately available; i.e., it does not delay operation. Studies of stool for bilirubin and urine for urobilinogen are standard but not conclusive. PREOPERATIVE PERCUTANEOUS BIOPSY.--In many hospitals this procedure has been regarded as definitive in making the distinction between biliary atresia and neonatal hepatitis, and an accuracy as high as 95% has been reported. 53 In most series, the results are equivocal in a significant proportion of patients studied. 13'54 In Japanese centers, percutaneous biopsy is used primarily in situations in which the presumptive clinical diagnosis is neonatal hepatitis. It would appear that this study is more accurate when the disease process is well established, i.e., in older patients, which detracts from its usefulness. The lack of enthusiasm for this procedure in Japan may reflect the younger age of the patients studied there. RADIOGRAPHIC STUDIES.--Many institutions have directed a major research effort toward the development of specific radiographic techniques for infants with neonatal cholestatic jaundice. Percutaneous transhepatic cholangiography (PTC), a technique widely used in adults with obstructive jaundice, has been utilized in some institutions in the study of the jaundiced neonate. It has been used following operations (Kasai-type procedures) in patients who had recurrent cholangitis or evidence of Fig 7.--Intrahepatic ductal system in biliary atresia. Preoperative percutaneous transhepatic cholangiogram (PTC) in a patient with biliary atresia, clearly demonstrating an intrahepatic ductal system. This was a 60-day infant undergoing diagnostic studies for cholestatic jaundice. Obstruction of the intrahepatic ductal system at the general level of the porta hepatis is seen in both the anteroposterior (A) and lateral (B) projections. Both small and medium-sized intrahepatic bile ducts are visibie. (Courtesy of Professor J. Yura, First Department of Surgery, Nagoya City University Hospital, from Hays D.M., Kimura K?') 562

563

anastomotic obstruction,5~ it has also been used as a preoperative diagnostic procedure (Fig 7). By this technique it is possible to identify the intrahepatic ductal system in approximately 50% of patients with biliary atresia and the same percentage of those with the neonatal hepatitis syndrome.~6 When used as a preoperative study, if the intrahepatic system fills with contrast material, not only can the diagnosis be clearly established but the form of structures within the liver and at the porta hepatis are delineated (Fig 8) and operation can be carried out promptly. The procedure has not been associated with major 'complications, but inadvertent injection of the intrahepatic portal venous system or the hepatic lymphatic system is common, resulting in striking visualization of these networks. PTC studies are successful in demonstrating the intrahepatic system in more than 70% of patients following a surgical procedure for biliary atresia. 56 Scintiscans of liver and spleen using 99~technetium sulfur colloid have no features distinguishing biliary atresia from any of the forms of neonatal hepatitis, l~lI-rose bengal radionuclide initially was used in serial scanning of the abdomen to identify the presence of biliary excretion. Techniques subsequently were refined and the duration of studies extended for several days to permit the identification of patients with complete obstruction of the biliary tract. This study in most instances clearly identified patients with biliary atresia, but at least 20% of infants with intrahepatic cholestasis also failed to secrete detectable amounts of 13~I-rose bengal. 57 A new category of hepatobiliary imaging agents, the N-substituted iminodiacetic acids (IDA), have been evaluated since 1975. These are characterized by rapid extraction of the labeled agent by the hepatocytes and prompt excretion into the biliary tree. 5s Using a 99~technetium label, sufficient activity to permit excellent gamma camera imaging is achieved. This family of compounds includes an H-substituted iminodiacetic acid (HIDA) and

Fig 8.--Preoperative PTC in a patient who initially appeared to have a "correctable" form of biliary atresia. This study was performed prior to laparotomy in a threemonth-old infant with cholestatic jaundice. The point of the needle is seen in the principal left intrahepatic bile duct and contrast material is shown filling the left and right ductal systems. Note the fine connecting duct extending inferiorly from the junction of the right and left intrahepatic bile ducts to a "cyst" located in the subhepatic areas, presumably at the liver surface or in the hepatoduodenal ligament. At operation, the cyst was identified at the location indicated in this film and all of the other structures seen in this PTC study were outlined by direct injection of media into this cyst. This case is of interest because if it were regarded as a "correctable" form of bifianj atresia on the basis of the presence of the bile-containing subhepatic cyst and if transection and anastomosis had been performed at this level, the result probably would have been unsuccessful because of the small caliber of the connecting duct. In this instance, however, the cyst was completely excised during the course 564

ntrahepatic iiles

"% . .duct.. SUbshtepatic- /~.'.

ff

of hepatic portoenterostomy and anastomosis performed at a higher ievel close to the confluence of the right and left hepatic ducts. This resulted in adequate biliary excretion. (Courtesy of Professor J. Yura, First Department of Surgery, Nagoya City University Hospital, from Hays D.M., Kimura K?') 565

a paraisopropyl iminodiacetic acid (PIPIDA), both of which have been used in series of children with cholestasis. 59'6o In these studies, tracer is accumulated in the liver within the initial five minutes after injection and the gallbladder may, be visualized within 15 minutes. Activity ordinarily is detected in the proximal small bowel after 30 minutes, and after six hours the tracer is largely in the colon. Miller, Sinatra, and Thomas 6~ used PIPIDA and found excretion absent in eight patients with biliary atresia, prior to operation, as well as in two patients with biliary atresia in whom the hepatic portoenterostomy failed to function. Ten patients with intrahepatic cholestasis showed excretion, as did three patients with biliary atresia and successful portoenterostomy. There was one subsequent misdiagnosis (unpublished) in this series, in which a patient who was more than 90 days of age at the time of the study was incorrectly identified as having biliary atresia, suggesting t h a t in patients with advanced cirrhosis, PIPIDA m a y not be excreted. Radiation received is less with PIPIDA t h a n with 1~1I studies. 6~ Majd, Reba, and Altman sl correctly identified ten patients with biliary atresia using PIPIDA. In 12 patients with intrahepatic cholestasis (not atresia), however, initial definitive excretion was seen in five, questionable excretion in two, and no demonstrable excretion in five. After five days of phenobarbital therapy, five of seven patients with questionable or no excretion had definitive excretion. Two procedures that require intervention under general anesthesia recently have been proposed for the study of infants with neonatal cholestatic jaundice. The first of these is endoscopic retrograde cholangiography, a procedure well established in adults, which has been used in infants in both the United States and Japan. The papilla of Vater has been visualized and retrograde injection has been possible, establishing a diagnosis of biliary atresia. 62 A more invasive approach consists of laparoscopy with liver biopsy and a cholangiogram performed by transhepatic puncture of the gallbladder. If the gallbladder cannot be identified or punctured, a laparotomy is carried out under the same anesthesia, e~ Both of these procedures require significant technical skill. GENERAL COMMENTS.--The wide variety of differential diagnostic signs and tests have been assembled by some clinicians into systems of differential diagnosis, weighing each item relative to its contribution to the diagnosis. 64 A computerized multiple regression analysis utilizing 38 variable items has been used (42 patients) and, with this system, four of seven incorrect clinical impressions were corrected, s5 The differential diagnosis of neonatal cholestatic jaundice has 566

been simplified by the recognition of the importance of alpha-1antitrypsin deficiency and the use of the toxoplasmosis, rubella, cytomegalovirus, herpes, etc. (TORCH) screening procedures to identify specific viral infections that may produce "neonatal hepatitis." Although the percentage of patients with neonatal hepatitis subjected to "unnecessary" laparotomy was greater than 25% in many earlier studies, at present it is ordinarily less than 10%. Following operation there would appear to be little chance of error in making the distinction between biliary atresia and the neonatal hepatitis syndrome, as examination of the specimen of the entire extrahepatic biliary system is routine and clearly indicates the basic nature of the disease process. In some institutions, these specimens are semiserially sectioned to identify and calibrate ductal structures. The long-range prognostic value of the results of the preoperative studies of hepatic function in biliary atresia has been evaluated in several studies. Although patients with depressed serum protein levels and elevated serum turbidity determination prior to operation appear to have relatively low survival rates, these factors are difficult to separate from the influence of the patient's age at operation. SURGICAL PROCEDURES INTRAOPERATIVE STUDIES.--The traditional laparotomy in the United States to establish the diagnosis of biliary atresia begins with an open liver biopsy and an attempt to perform a gallbladder cholangiogram. This procedure may be performed through a relatively small subcostal incision, and if this is the extent of the operative procedure, its duration should be short (< 1 hour) and the secondary effects of anesthesia and operation, minimal. In approximately 25% of the patients with biliary atresia, one can identify a gallbladder lumen and perform some type of cholangiogram through it. In the other 75% there will be either no distinguishable gallbladder lumen or a small cystic cavity, filled with relatively clear fluid, and no ductal connections. Among those patients in whom a cholangiogram is possible, most show an intact (but possibly distorted) gallbladder, cystic duct, and common bile duct, with free flow of contrast material into the duodenum, but the common hepatic duct and intrahepatic ductal system are not seen. In a very small group, the flow will be in the opposite direction; that is, it will fill the gallbladder, cystic duct, common hepatic duct, and (possibly) the intrahepatic radicles, with no flow into the common duct or duodenum. This is the only possible demonstration of a "correctable" form of biliary atresia by gallbladder cholangiogram and is uncommon (< 2% of laparotomies). 567

If the major portions of both the intrahepatic and extrahepatic system are seen but the ducts are extremely small, a diagnosis of biliary hypoplasia is established. In these cases, the liver radicles of the intrahepatic system frequently are incompletely filled by the cholangiogram. When a gallbladder cholangiogram is obtained in which occlusion is demonstrated in the area of the common hepatic duct, attempts are made to repeat the study with the distal choledochal area occluded by pressure. In rare instances, this has resulted in the filling of the common hepatic duct and the intrahepatic system or (more commonly) in the identification of a "hypoplastic" intrahepatic system. In the majority of patients with biliary atresia, the diagnosis is not made by a cholangiogram but simply by examining the rudimentary gallbladder. This ordinarily is a strand of fibrous tissue without a demonstrable lumen. At this point, the surgeon may commence hepatic portoenterostomy for biliary atresia without further studies. When "cysts" or ductal dilatations are encountered in the hepatodu.odenal ligament or at the surface of the liver, they are injected with contrast material and an attempt made to identify their connection with the intrahepatic ductal system. Ordinarily, this is an academic exercise, as all such structures will be excised in the course of the routine Kasai-type procedure and can be examined in more detail in the surgical specimen. THE "CORRECTABLE" FORMS OF BILIARY A T R E S I A . - - T h e s e cystic structures in the hepatoduodenal ligament are regarded by many experienced surgeons as providing an easy but rather uncertain answer to problems of neonatal biliary tract obstruction; their use in an anastomosis is fraught with problems. Many of these cysts are not connected with the intrahepatic ductal system. In others, the connection is small and probably will not function effectively. The routine connection of such cysts to the intestinal tract, as practiced previously, was followed by a reasonably successful initial outcome in approximately 50% of infants so treated. 66The rate of ascending cholangitis and secondary obstruction was high. Numerous instances now have been described in which a primary point of complete obstruction was recognized in the choledochus or common hepatic duct, as well as a secondary point of partial obstruction proximally at the porta hepatis. Cysts must be distinguished from "bile leaks," which are thought to be bile extravasations, and identified by the lack of a muscular wall or epithelial lining. In the event that there is a connection between the cyst and the intrahepatic system, it is contended that this may be occluded by continuation of the basic inflammatory 568

process and that it is preferable for the surgeon to establish a connection with an intestinal segment at the level of the porta hepatis, even when the ductal structures there are much smaller; i.e., not visible without magnification. It is recognized t h a t in a patient with a large subhepatic cyst that has a demonstrated widely patent connection with the intrahepatic ductal system a simple cystenteric anastomosis still is a reasonable procedure. Some authorities (Saito, Tokyo University) would insist that before this procedure is considered, the cyst wall must be known to have a muscularis, as well as a mucosal lining, and be large enough to form a wide anastomosis. Some surgeons would identify such structures as "choledochal cysts" and would excise them as such. Thus, the operative therapy for most surgeons, whether it is called a "choledochal cyst" or a "correctable" form of biliary atresia, would be Similar; i.e., excision during the course of performing hepatic portoenterostomy. THE ORIGINAL I ~ S A I

PROCEDURE (HEPATIC PORTOENTEROS-

TOMY).--Kasai referred to his original procedure in 1959 as "hepatic portoenterostomy" to distinguish it from anastomotic connections to areas of exposed hepatic tissue in the region of the porta hepatis, an operation referred to by him (and others) at that time as "hepatic enterostomy.''6~-69 The important feature of this approach, and its only unique aspect, is the concept and technique of dissection of the porta hepatis structures with the identification and preservation of the rudimentary ductal system there for anastomosis with an intestinal segment (Fig 9). Excision of the entire extrahepatic biliary tract is incidental, although it provides a specimen of intense interest to the histopathologist concerned with atresia. Kasai contended that the planes of dissection in the region of the porta hepatis may be obscured by the inflammatory process associated with atresia. Because of this, he recommended that the dissection be commenced distally by mobilizing the gallbladder and the rudimentary choledochus. When the cystic and common ducts were patent, he began the dissection over the distal common hepatic duct remnant. He believed that from these sites, which usually are not areas of the most severe inflammatory reaction, a plane of dissection can be established (immediately anterior to the portal vein) that will bring the surgeon to the bifurcation of the portal vein at the level best suited to identify correctly the porta hepatis fibrous mass. Kasai transects this fibrous mass at the level of the posterior wall of the portal vein branches (Fig 10) whereas others have other points of reference (see next section). The other aspect of this operation, i.e., the connection of the distal end of the intestinal conduit with the 569

Gallbladder

Drain

Step 1

Branches of Portal Vein

9

On

:in

Step 2

570

Fibrous Mass

Step 3

Fig 9.--Details of the Kasai procedure. Technique of dissection of the hilar structures and anastomosis at the porta hepatis in biliary atresia as used by Kasai and others. Step 1 illustrates the structures in the region of the porta hepatis. The entire rudimentary extrahepatic bitiary tract, including the gallbladder, has been elevated superiorly and its posterior aspect is in view. The fibrous mass (common hepatic duct) here widens into a fan-shaped structure arising from the angle formed by the major branches of the portal vein. In Step 2, a series of small veins running from the fibrous mass into the portal veins are illustrated. The presence of these vessels in large numbers is peculiar to biliary atresia and may reflect the inflammatory process involved. The line of proposed transection of the fibrous mass, lying at the level of t h e posterior aspect of the portal vein, comes into view following division of these veins. Step 3 illustrates the anastomosis in progress, with sutures passing through the hepatic tissue about the fibrous mass but not through its substance. At operation, the ductal structures that appear in this diagram on the cut surface of the transected fibrous mass ordinarily are not seen without magnification. (From Hays D.M., Surgical Rounds, July, 1980.)

intestinal tract or its exteriorization, has been carried Out in multiple ways by Kasai, as well as other surgeons, and is in no sense specific to this operative procedure. Perhaps unfortunately, the latter aspect, i.e., the form of the distal connection of the conduit, is the basis for present naming of the operative ap571

Fig 10.--Illustration of Kasai's concept that the fibrous mass at the porta hepatis should be transected at the level of the posterior aspect of the major portal vein branches. (A) The segment of intestine used to form the anastomoses (B) turned posteriorly rather than superiorly. The relative size of the fibrous mass at the porta hepatis in this illustration is enlarged for clarity. The ductal structures ordinarily are not seen on the transected fibrous mass. (From Kasai M., Suzuki H., Ohashi E., et al.~ Copyright by the Societ~ Internationale de Chirurgie.)

proaches to biliary atresia. All current procedures utilize the basic Kasai approach to the dissection of the porta hepatis, although it may be described in different terms. The original Kasai procedure used a standard Roux-en-Y intestinal connection. Although at one time the term "hepatic portoenterostomy" was restricted to this original (Kasai I) operation, it now is applied to any one of a variety of procedures that include this basic dissection of the porta hepatis but many different forms of anastomosis to the intestinal tract or exteriorization. Thus, "hepatic portoenterostomy" now has become a general term, and the original procedure is referred to as the Kasai I, to differentiate it from modifications from his clinic since that time, i.e., Kasai II, etc. (Fig 11). This procedure, i.e., the Kasai I, has been performed more frequently than all the other surgical procedures for "noncorrectable" biliary atresia combined, omitting exploratory laparotomy. It was the original approach during the early years in almost all

Fig 11.--Variations of hepatic portoenterostomy. The "first generation" of Kasaitype operative procedures for biliary atresia. All of the techniques diagramed in this and Figure 12 include a similar dissection of porta hepatis structures, followed by the formation of these different connections between the remnants of the biliary tract at the porta hepatis and the intestinal tract of the anterior abdominal wall. All except the original procedure (Kasai I) were developed for the purpose of preventing ascending cholangitis. The initial Kasai procedure (Kasai I), described in Japanese in 1957 and in English in 1968, was the first procedure performed in almost all institutions in Japan and has been carried out in more than 600 patients. The length of the 572

KASAI I (19r

~

l (~968)

UEDA (1972)

KASAI I (1972)

YURAI

IKEDA 1

(1973)

(B75)

SURt.IGAI (tg'to)

SURUGA]I

KASAI-GALLBLAD~R

intestinal segment between the porta hepatis and the Roux-en-Y division has varied from 20 to 80 cm in different series. Akiyama, at the National Children's Hospital, who has the largest current successful experience with this procedure, uses a segment more than 40 cm in length. The Sawaguchi procedure (1968) completely diverted biliary flow to an abdominal wall stoma. This was followed by a double-barreled stoma, described by Suruga in 1970. Biliary conduit systems that were not completely diverting but provided a stoma for decompression of the conduit system were utilized by Kasai (Kasai II) and Ueda (1972). Because of excessive fluid loss from the biliary stoma, Suruga modified his first procedure to include an inlying tube for the reintroduction of bile into the intestinal tract (Suruga 11),which couId be performed in the patient's home. Surgical procedures that did not utilize a stoma were used by Yura (1973) and Ikeda (1975). Yura's technique included enterostomy tubes that permitted obtaining cultures and irrigation of the area of the porta hepatis and the anastomosis with antibiotic solutions. The Ikeda I (1975) was the first of a series of operative techniques utilizing a gastric tube as the biliary outflow conduit. In these procedures (Figs 11 and 12), the approximate length of the intestinal segments used is indicated in centimeters on the diagram. The use of the gallbladder as a conduit (lower right), termed hepatic portocholecystostomy, was described by Kasai and has been widely utilized. Rotation of the gallbladder and cysticduct to the porta hepatis is carried out with care to preserve arterial and venous connections and to avoid cystic duct kinking. 573

institutions and has been performed in approximately 600 patients in Japan alone. The results of this procedure, however, cannot be compared with the overall results of later modifications. Because of its long history, its use in multiple institutions, the fact that initially it was used in an era prior to the development of modern therapeutic techniques (including the use of broad-spectrum antibiotics), or even recognition of the significance of "ascending cholangitis," the overall results of this procedure are relatively poor by contemporary standards. On the other hand, the Kasai I still is used by Akiyama in one of the largest current series, very much as it was described originally. 7~ The relative success in this large series suggests that the Kasai I procedure remains a standard against which the results of all innovative surgical approaches must be evaluated. Akiyama's series is also unique in respect to the intensity of the prophylactic antibiotic regimen utilized, including ampicillin for two years after operation. The intestinal conduit segment is longer (> 40 cm) than described initially by Kasai. A revival of interest in the Kasai I procedure, with a long (up to 80 cm) segment between the liver and the first Roux-en-Y anastomosis, is now under way in Japan. OPERATIVEPROCEDUREDESIGNEDTO PREVENTASCENDINGCHOLANGITIS.--The first goal of therapy for biliary atresia always had been to achieve a jaundice-free state, and initially there was little planning beyond this point. After the first decade of experience with the Kasai-type procedure, however, a secondary goal developed. It was recognized that a large group of infants who became anicteric after hepatic portoenterostomy did not live, primarily because of the syndrome of febrile episodes termed "ascending cholangitis." At least a third of the patients in the early successful series with Kasai-type procedures died following such febrile episodes. Recognition of this second problem led to the development of a diverse group of surgical procedures (Figs 11 and 12). All of these used the basic features of the Kasai-type of dissection of

Fig 12.--Additional "second generation" operative procedures for biliary atresia. Lilly and Altman used a double-barreled stoma of a true Mikulicz type, in which the spur was crushed to minimize bile loss. In B, an attempt was made by Kasai both to use a decompressing stoma and to return biliary drainage to the duodenum (Kasai III). This procedure was abandoned at Tohoku because of the high incidence of postoperative ascending cholangitis. It is used in Niigita, where an intestinal segment 50 cm in length is placed between the two Roux-en-Y anastomoses. In C (Yura II), developed at Nagoya, an attempt is made to establish the flow of gastroduodenal contents past the anastomosis at the porta hepatis. In D, an additional modification of the double-barreled enterostomy developed (1976-1977) in Kobe in an effort to prevent excessive fluid loss is illustrated. The conduit illustrated in E is formed from a tube graft (pedicle) of gastric wall carrying the biliary outflow to the duodenum. 574

A

B

C

D

E

F

G

H

I

J

K

This has been used in the Kyushu series. Additional attempts to return the biliary outflow to the upper gastrointestinal tract are seen in F and G, two procedures developed (1977-1978) that utilize an isolated jejunal segment to connect the porta hepatis to the duodenum (F), or to the gastric antrum (G). In both of these procedures, the jejunal segment and the duodenum (or stomach) are joined longitudinally for a distance of 6 - 8 cm and the muscular layer in the septum separating these two structures is partially excised for a distance of 4 - 6 cm proximal to their intraluminal connections. This is an effort to limit the amount of reverse flow of gastroduodenal content into the biliary conduit. These procedures have been used in the Hyogo series and in eight cases in Osaka. Perhaps the ultimate attempt to isolate the biliary intestinal anastomosis from the flora of the lower gastrointestinal tract is found in H, in which one end of an isolated conduit is connected to the gastric lumen and the other to an abdominal stoma (Kyushu). Procedure I (Yura III) was designed to increase the acidity of the enteric content passing the level of the anastomosis at the porta hepatis, altering the flora at this level. It has been used in Nagoya and Ehime. Procedures J and K utilize isolated jejunal loops to connect the porta hepatis to the gastric lumen (J) or the duodenum (K). J has been used in the Kyushu and Hyogo series and K at Ehime and Hyogo. All of the procedures illustrated have been used in from six to seven hundred infants and are diagramed here to provide a background for surgeons who may plan additional innovations in this field. 575

the porta hepatis, and each was developed in an attempt to protect the intrahepatic ductal structures from ascending cholangitis. Some of these procedures produced a temporary complete diversion of the biliary outflow (Sawaguchi). 71 Others used a temporary stoma for decompression of the hepatic limb of the hepatobiliary intestinal connection. Some of the patients with stomas had sufficient biliary output to produce acute fluid and electrolyte losses, and both Suruga and Kasai developed modifications designed to return the major part of the biliary flow to the intestinal tract (see Figs 11 and 12). Most procedures that now are used for biliary atresia include an abdominal stoma, either as a form of complete diversion or to decompress the biliary drainage system. Initially, these were closed early in the course, but the duration has been progressively lengthened and at present many are maintained for two to three years. Most series contain patients in whom the stoma has been closed and then reopened when severe episodes of cholangitis'followed initial closure. Even patients with complete diversion of the biliary tract have episodes of ascending cholangitis. In an analysis by Sawaguchi (1978) of the National Children's Hospital series, among 24 patients treated by his complete diversion during the period 1966-1977, 11 (46%) had clinical episodes of ascending cholangitis, although in six of these cholangitis was seen only following stoma closure. In general, the stomas have not been closed in those infants who do not achieve an anicteric state and continue to have febrile episodes. At times, the presence of a stoma has resulted in disturbing clinical symptoms from hemorrhage from the stomal veins as portal hypertension develops or from recurrent intestinal fluid losses requiring hospitalization. A surgical approach in many clinics has been to return the biliary output from the porta hepatis to the duodenum or stomach (see Figs 11 and 12). These procedures always were carried out in attempts to keep the lower intestinal flora away from the biliary tract and to utilize gastric acidity to reduce potential bacterial contamination. None of these procedures have been altogether effective in eliminating ascending cholangitis. DISSECTION OF THE PORTA HEPATIS STRUCTURES.--Because of the wide variety of different forms of biliary-intestinal tract connection (or exteriorization), attention has been centered on this aspect of the procedure. The dissection of the porta hepatis structures and the anastomosis with biliary remnants undoubtedly are of greater significance in determining the ultimate clinical outcome. During the 1960s in Japan, it appeared that successively deeper dissections into hepatic tissue were made in an attempt to secure bile drainage. The results in several studies21, 72 (Fig 13) suggested that the preferable site for tran576

DISSECTION CUT SURFACE SUPRAPORTAL

~i::ii::

a.':~iii!i~' . . . . . .

9 :::.

PORTAL .....

..~.........

c . ~ ?

INFRAPORTAL

'::!i!!!:!:!:!:!:!!!!!!!!!!!!i;'!!!::::::::::::.

= LIVER p"~--I=PORTAL FIBROUS MASS

Fig 13.~A division of the possible sites of surgical transection of the porta hepatis fibrous mass into three categories, following a retrospective study of 37 operative cases at Kobe (K. Kimura). In those infants in whom the "supraportar' site was used, dissection was carried beyond the fibrous mass into the liver parenchyma. In those in whom an "infraportal" dissection was carried out, the major portion of the fibrous mass remained above the line of transection; that is, toward the liver. Division of the fibrous mass at either of these sites produced unsatisfactory biliary drainage. In contrast, active biliary excretion was obtained when transection was carried out through the "portal" level by one of the three types of excision of the mass depicted (a, b, c). (From Kimura K., Tsugawa C., Kubo, M.~

section of the fibrous mass was no deeper than the level of the surface of the liver and that by deeper dissection the functional ductal structures could be completely excised or obscured. All surgeons carrying out hepatic portoenterostomy remove small anterior or lateral segments of liver tissue during the procedure in order to visualize the fibrous mass more clearly or to facilitate the anastomosis about it, but this does not directly affect the level of transection. Okamoto stresses a wide base at the porta hepatis, permitting access to lateral areas where right and left hepatic ducts may be located (Fig 14). It has been recognized from histologic studies, however, that ductal structures may also exist in the midline of the porta hepatis. In his dissection of the porta hepatis structures, Kasai advocates turning posteriorly within the angle formed by the branching of the portal vein to reach a level for transection that is parallel to the posterior aspect of these branches (see Fig 10), creating an anastomosis that faces posteriorly rather than superiorly. 69 He believes that the transection should extend laterally following the fibrous mass until the level is reached where the portal vein branches are completely surrounded by adherent liver tissue. This is also the level at which the right and left hepatic arteries become adherent to liver tissue. Some surgeons 577

Fig 14.--Variation in the Kasai procedure..A step in the formation of the anastomosis during hepatic portoenterostomy for biliary atresia as visualized by Okamoto. A particularly wide transection of the porta hepatis mass, extending to the ligamentum teres on the left, is emphasized in this technique. Okamoto believes that it is from these lateral segments of the fibrous mass that biliary excretion ordinarily develops. Other aspects of the dissection and transection are similar to those illustrated in Figure 9. (From Okamoto E.r~)

.lig.teres hepatis

routinely include a thin strip of hepatic tissue in the specimen. Ueda finds that the most satisfactory level of transection of the fibrous mass is at the level of the first major branch of the right or left hepatic artery. Akiyama describes the preferred site of transection as the border of the liver parenchyma. Okamoto recommends the excision of a triangular piece of portal fibrous mass with its apex in the midline at the deepest point of dissection. v3 The unusual width of his excision is unique (see Fig 14). All surgeons identify and divide the venous drainage from the mass into the portal veins (Fig 15). Most surgeons do not use either cautery or sutures to control hemorrhage following transection of the porta hepatis mass, believing that ductal structures may be destroyed by either technique. Suruga believes that use of the dissecting microscope makes electrocautery precise and without danger. 74 Irrigation and compression for as long as 30 minutes is used routinely to control hemorrhage rather than any form of mechanical hemostasis. Rapid section histologic technique for detecting the presence or absence of bile ductules in the porta hepatis tissue at the (proposed) line of transection has been used at one time in almost all centers, and continues to be used in some.~5 It is not used routinely in many of the most successful series. Surgeons in these institutions believe that the level of transection is,determined by the gross anatomical structures encountered and that their decision as to the site would not be altered by the presence 578

I

/'

artery

fibrous cord

~

}~f"

~''-~--

Fig 15.--An additional illustration of the dissection of the porta hepatis structures in carrying out hepatic portoenterostomy for biliary atresia, emphasizing the veins running from the fibrous mass into the portal system. Division of a number of these usually is required to reach the appropriate level for transection. Some authors also divide segmental r e ~ c tor hepatic vessels on either right and left9 (From Kimura K., Tsugawa C., Kubo M.~)

drain

or absence of ducts in a single specimen from the porta hepatis. There are long-range survivors in whom the sections of the fibrous mass showed few or no ducts. The rapid section technique in effect is a sampling procedure. On the other hand, the prognostic significance of the presence of ducts in t h e - p e r m a n e n t (multiple, even serial) sections of the mass, near the level of transection, is universally appreciated. Although the depth of dissection at the porta hepatis and the level of transection are both controversial matters, the principles of the form of anastomosis about these structures are well established. The opening in the intestinal segment should be small, encompassing only the fibrous mass, and the sutures supporting the anastomosis should be placed in surrounding structures, not the fibrous mass. If there is a grossly visible duct or ducts at the site of transection, care is taken to place the sutures at least several millimeters distant from these openings, b u t otherwise the procedure is the same. 9 H E P A T I C P O R T O C H O L E C Y S T O S T O M Y . - - W h e n the gallbladder is to be used as a biliary conduit (see Fig 11), dissection o f the porta hepatis structures is identical. Mobilization of the gallbladder from its bed must be carried out with great care to preserve the cystic artery and vein. The dome of the gallbladder then is used in the anastomosis precisely as a segment of intestine. If the gallbladder lumen is long, a segment of the fundus m a y be excised to prevent folding. This variant of biliary atresia, in which the gallbladder and cystic and common bile ducts 579

are patent, has a variation in incidence in different institutions (5-20%). Hepatic portocholecystostomy is widely used 69'76 because the incidence of postoperative ascending cholangitis is negligible. Other complications are frequent. It appears that in some cases the occlusive process continues in the cystic or common hepatic duct, producing postoperative obstruction. This may be reflected in anastomotic disruptions and excessive biliary drainage or increasing jaundice. The indications for re-exploration and replacing the gallbladder with an intestinal loop are liberal in most centers, and this type of revision has been carried out successfully in most series. A completely different approach is possible when the gallbladder has a direct connection with the common hepatic duct and intrahepatic system. In this instance, it is possible to mobilize the gallbladder and form a direct anastomosis with the duodenum or to an intestinal segment. This procedure appears to have a particularly high rate of ascending cholangitis, and usually has been replaced later by some form of hepatic portoenterostomy at the porta hepatis. 66 HYPOPLASIA OF THE BILIARY TRACT.--Hypoplasia of t h e extra-

hepatic and intrahepatic biliary tract is regarded by some as a separate clinical entity. Division of the minute distal choledochus with implantation into the duodenum has been advocated for this condition (Longmire). Although there may be an area of selective stenosis at the distal end of the choledochus, ordinarily the entire system is equally "hypoplastic." Some surgeons have believed that this is a form of biliary atresia for which the Kasai procedure is applicable. Most do not regard this as a problem requiring surgical intervention and wait for spontaneous resolution following diagnosis by cholangiogram at laparotomy. Patients with this condition frequently develop lethal cirrhosis with or without associated continuing icterus. RESULTS

In evaluating the results of the group of operative procedures that have been called hepatic portoenterostomy, although some of the connections are to the stomach or duodenum, a variety of criteria are used. The first of these is the achievement of biliary excretion (Table 2). This is readily measurable in patients with a completely diverting intestinal limb, and both volume and bile content (concentration) can be determined. Formerly, measurements of this output were imprecise, but now have been quantified. Using the present procedures (1981), it would appear that approximately 580

U 0 r

m~

2.

r~ 0 r-,.l

0

r

o z

0

*

% O~ . ~ o

oO

0

o

~z 0

,o

I I

~mb-

I I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

I

C.~ I:1., ,.-1

r.. 0

I;::=

I "t3 ,--1

z o

~

~

~

581

75% of infants achieve a biliary output that is sufficient to lower bilirubin levels significantly. In patients without a stoma (Kasai I), or with a nondiverting stoma, this evaluation, based on stool color (or analysis), is not precise. The second criterion of a successful result is the complete clearing of jaundice and achievement of normal serum bilirubin levels. In most early series, this group consisted of < 30% of total patients operated on, b u t progressive improvement in this respect has been noted, and rates of 3 5 - 6 0 % have been reported from several clinics. 77' 7s In all large series there are patients with obvious active biliary excretion in whom the serum bilirubin levels fall b u t never return to normal values. In the National Children's Hospital (Japan) series, this group is approximately 10% of the total. These marginally improved patients remain moderately icteric, and during episodes of ascending cholangitis, elevations of serum bilirubin are seen. Biliary outflow usually stops eventually, and these patients die before five years of age. Another variant course is seen in patients in whom there is a prolonged delay before establishment of initial biliary excretion but who ultimately achieve a jaundice-free state. This delay may be as long as five months, and it is assumed that residual hepatic fibrosis in such patients is severe. Improvement in results has been directly associated with a declining patient age at the time of the operative procedure (Figs 2 and 16) and m a n y infants now are explored between 30 and 40 days of age (Table 3). There also has been continuing improvement in results beginning during the period 1970-1975 in most institutions in J a p a n (see Table 2) and somewhat later i.n other countries. The two largest series in the United States are at the University of Colorado Medical Center and at the Children's Hospital National Medical Center. Among 43 patients operated on at the latter (1972-1978), 29 had extended bile drainage and 16 were jaundice-free in 1978, in addition to five additional surviving patients with jaundice. Two patients in this series, dying of unrelated causes were free from jaundice at the time of death. 75 Subgroups of patients with specific characteristics have a prognosis that is significantly better or worse than the total series. For example, in a statistical study of the University of Colorado Medical Center series (41 patients), it was found that the patients who were (a) < 10.5 weeks of age at operation, (b) had a duct in the fibrous mass at the porta hepatis with a diameter > 150 ~, and (c) attained a concentration of bilirubin in bile > 8.8 mg/100 ml following operation had a four-year survival rate of 89%. 79 Among the Japanese series, which are confined to patients < 60 days of age at operation, rates of bile excretion are approximately 90%. In contrast, in series in which 582

IO0 A = Under 2mos o = 2-:5 mos * = Over 3mos

~, -J >

,-..

co .....................

t--

z

40

A

.,.

~_

i'Y tlj

a_ 20 0 0

I

t

!

!

I

!

)

)

1

I

I

2

5

4

5

6

7

8

9

I0

T I M E (yeers) Fig 16.--Survival influenced by age at time of definitive operation in 565 patients with biliary atresia treated by Kasai-type procedures by members of the Surgical Section of the American Academy of Pediatrics (1970-1980) and reported 19781980. These actuarial curves of survival reflect the result of an annual questionnaire sent to all members of the Section, making reporting of fatalities significantly delayed. (Courtesy of Dr. John Lilly.)

the age at operation is high, such as t h a t reported by Odievre, s~ in which 26 of 111 patients with noncorrectable types of biliary atresia were operated on before four months of age, only 30% had some degree of restoration of bile flow t h a t continued for at least one year. The influence of the presence of ductal structures in the porta hepatis tissue has a direct influence on bile excretion and survival (Fig 17 and Table 4). It is of interest, however, t h a t some TABLE 3.--RESULTS OF THERAPY RELATED TO AGE AT OPERATION FOR BILIARY ATRESIA (1965--1977, INCLUSIVE)* (The National Children's Hospital, Tokyo) AGE (DAYS) AT OPERATION

NUMBER OF PATIENTS

STOOL PIGMENTNOTED

31-60 61-90 91-100 101-120 > 120

16 [1] 47 5 8 [1] 14

10 31 4 6 ~

9 30 2 5

71 2 5f 1| 4/

57 (63.3%)

48 (53.3%)

37

TOTAL 9

90

DISAPPEARANCE ALIVEf OF JAUNDICE v~TrHOUTJAUNDICE 32

(50.7%)

5 (18.5%)

(41.1%)

*From Akiyama, Saeki, and O g a t a J ~ t T e n m o n t h s to 13 years following hepatic portoenterostomy (20 patients > 5 yr). [ ] Anastomosis to visible hepatic duct a t the porta hepatis. 583

BILIARYATRESIA:DUCTHISTOLOGY& POST-OP.BILEDRAINAGE No. of 20 Patients ~ . ~ Bile Drainagq

15

[ ~ N o Drainage

10

0

---3 !

II DuctType

III CHNMC

Fig 17.--Biliary duct histology and postoperative bile drainage. Airman has divided patients with biliary atresia into three categories on the basis of the microscopic findings in the ductal remnants at the site of transection (porta hepatis). In Type I (eight patients), ductal lumen sizes of 150 i~ are reached. In Type II (25 patients), ductal structures measured 30-100 p., and in Type Ill (nine patients) there was no identifiable biliary epithelium. As noted, there is a correlation between the presence and size of ductal structures and achieving bile drainage. However, one patient, without ducts seen at the transection site, excreted bile. (From Airman R.P. 7s)

patients survive who had very minute or apparently absent ducts in the tissue sectioned. The overall survival rates are very similar in all of the groups and subgroups in the Japanese Society of Pediatric Surgeons (JSPS) classification (Table 5). This is of significance because it emphasizes that there is no "noncorrectable" type of biliary atresia, which can be recognized by the surgeon at the operating table. A previously common operative finding, described as "no ductal structures," no longer is seen in centers in which biliary atresia is encountered frequently.~5 There may be an almost complete absence of some portions of the remnant ductal structures, particularly in the area of the common hepatic duct "cord," but a "fan" of fibrous tissue almost always is present at the area of portal vein branching. It is significant that there are long-range survivors (see Table 5) among patients who had a hypoplastic ductal system with only a fibrous strand available at the porta hepatis (JSPS, minor subtype o). ASCENDING CHOLANGITIS, THE PARAMOUNT POSTOPERATIVE PROBLEM The initial group of failures following hepatic portoenterostomy for biliary atresia consisted of infants in whom there was insufficient biliary excretion to achieve a jaundice-free state. U1584

T A B L E 4.--RELATIONSHIP OF SIZE (MICROSCOPIC) OF THE BILIARY DucrAL STRUCTURES AT THE PORTA HEPATIS TO PROGNOSIS (EHIME SERIES) 1968--77"

ALIVE SIZE OF BILIARY DUCTAL STRUCTURE (p.) 1,000

TOTAL PATIENTS

DEAD

Poor Biliary Excretion

Adequate Biliary Excretion

Lost to Follow-up

-

2

1

500 -

5 2

1

-

3

2

-

5

2

100 OTOTAL

10 4 31

4 1 11

3 2

1

1"-0

*From Prof. S. Kimura (Ehime), personal communication.

timately this is lethal and still occurs in approximately 30% of all patients who are operated on for biliary atresia. Among those patients who become temporarily or permanently jaundice-free, more than 50% will be affected by the second major problem, termed ascending cholangitis. Paradoxically, Lilly states that this can be found in all patients in whom biliary excretion is achieved and constitutes the "hallmark" of a successful anastomosis. 8. All of the complex surgical biliary-intestinal connections that have been developed during the past two decades (see Figs 11 and 12) are attempts to eliminate or reduce the incidence of this syndrome. The significance of this complication cannot be overemphasTABLE 5.--SURVWAL RATES A/%IONGINFANTS WITH BILIARYATRESIAIN DIFFERENT CATEGORIES OF TItE J S P S CLASSIEICATION* (The National Children's Hospital, 1967-1971) MAJOR GROUPS I II ]II TOTAL SURVIVAL BY MINOR GROUP

(MINOR GROUPS) "/ ~t u

ct

~

0/4 2/2 0/1

2/5 0/2 0/2

0/1 1/6

7/29

2/7

3/10

1/7

7/29

o

TOTAL SURVIVAL? BY MAJORGROUP

3/10

3/15

219 3/6 14/63 (22%)

3/10

3/15

19/78 (24%)

*From S. Sawaguchi; presentation, Japanese Society of Pediatric Surgery, May, 1976. t > 5 years. 585

ized. In many early series, as high as 80% of patients were affected within two months of the initial surgical procedure. Mortality from this complication early in the course frequently was as high as 25%, and this did not include those who died subsequently following recurrent episodes. This clearly is the most important factor affecting the survival of patients who become anicteric following a Kasai-type procedure. In most large series, it would appear that the number of deaths due to this entity is approximately one-half the number of deaths due to simple failure of bile excretion, but the two factors clearly are interrelated in many patients. THE ETIOLOGIC FACTORS IN ASCENDING CHOLANGITIS.--Ascend-

ing cholangitis is a syndrome rather than a disease entity, and it has not been clearly shown to be "ascending" or even obviously "cholangitis." It is possible that it represents a variety of processes with different etiologies. In most institutions treating biliary atresia regularly, "ascending cholangitis" is the label applied to any febrile episode that occurs following an operative procedure for atresia, for which no other explanation is apparent. Some investigators believe that the hepatic lymphatic or portal venous routes may play a major role in the introduction of the organisms that are responsible for this syndrome and that the intraluminal connection of the intestine is less significant. However, cultures of the intrahepatic bile obtained by percutaneous transhepatic cholangiogram (PTC) with drainage during febrile episodes matched closely those obtained simultaneously by stomal aspiration. 55 It is generally believed that the organisms responsible for ascending cholangitis arise in the intestinal tract, and both (a) blood cultures that have been obtained during such episodes, including portal blood, and (b) cultures of the site of hepatointestinal anastomoses, obtained either through stomas or directly at secondary operative procedures, indicate that a wide spectrum of intestinal organisms are involved. Etiologic relationships are difficult to establish. Some investigators stress the importance of establishing biliary flow in preventing ascending cholangitis. Others believe that a considerable component of the early postoperative biliary output actually is lymph and that the avenue of entry of organisms may be via the lymphatic system, although conceding that reduced bile flow is also a factor. Patients who develop no postoperative biliary flow rarely have ascending cholangitis. 81 However, patients with "correctable" types ofbiliary atresia, i.e., with visible ducts at the porta hepatis, have high rates of ascending cholangitis, particularly when they are treated by simple cystenterostomy. Drainage of the lymphatic system at the porta hepatis into 586

intestinal segments in states of chronic biliary obstruction was investigated by Fonkalsrud 82 and others. The lymph drainage of almost the entire liver passes through the area of the porta hepatis and it has been observed, both experimentally and clinically, that when the biliary tract is obstructed, lymphatics from the region of the port~i hepatis to the thoracic duct enlarge, carrying pigment-laden lymph from the intrahepatic biliary system into the thoracic duct and general circulation. This influenced the development of surgical procedures in the early history of the treatment of biliary atresia, s3 Experimental studies h a v e suggested that disruption of this lymphatic drainage system is a significant factor in the development of postoperative ascending cholangitis, and it has been recommended that this drainage be augmented by attaching the omentum to the dissected areas in the region of the porta hepatis in all operations for biliary atresia, s4 However, if clinical ascending cholangitis is related to disruption of the perihilar lymphatics by surgical dissection, it is difficult to explain the high incidence of this condition in patients with "correctable" forms of biliary atresia treated by simple cystduodenostomy or Roux-en-Y enterostomy, in which hilar dissection usually is minimalJ ~ In one series, ten of 15 patients died as a result of ascending cholangitis after a simple cystduodenostomy. Ascending cholangitis is not confined to any of the major types or subtypes of biliary atresia in the JSPS classification (see Fig 3). The incidence clearly is inversely related to patient age at the time of operation and also correlates directly with the degree of hepatic fibrosis found. That is, the more advanced the intrahepatic fibrotic processes the greater will be the frequency and severity of ascending cholangitis encountered postoperatively. Of major interest is the effect of the diverse operative approaches to biliary-intestinal drainage on the incidence of ascending cholangitis (Table 6), as all of these procedures were developed with control of this condition as a specific goal. At present there seems to be no surgical procedure in general use (see Figs 11 and 12) that reduces the incidence of this syndrome below 25-30% of the total number of jaundice-free patients, and, in most series, the incidence is higher than this. One notable exception is hepatic portocholecystostomy, but this procedure can be performed in only 10-20% of patients with biliary atresia; i.e., those in whom the gallbladder, cystic duct, and choledochus are patent. Following this procedure, the incidence of ascending cholangitis is extremely low, but there are other significant problems. "Early" ascending cholangitis has been defined as that form 587

TABLE 6.--INCIDENCE OF ASCENDING CHOLANGITIS: INFLUENCE OF TYPE OF SURGICAL PROCEDURE* PERIOD OF STUDY

AUTIIOR

1971-77

Kasai

1967-78

Kimura, S.

1971-77

Kasai

1967-78 1971-77

Kimura, S.

1971-77 1973-78

Kasai Lilly

1973-78 1967-78

Lilly Akiyama

Kasai

PROCEDURE

Hepatic portoenterostomy (Kasai I) Hepatic portoenterostomy (Kasai I) Hepatic portoduodenostomy (Kasai III) Hepatic portoduodenostomy Hepatic portoenterostomy (Kasai II) Hepatic portocholecystostomy Mikulicz double-barreled enterostomy Hepatic portocholecystostomy Hepatic portoenterostomy (Kasai I)

PATIENTS WITH ASCENDING CHOLANGITIS? 15/22 (68%) 9/14 (66%) " 11/12 (92%) 6/12 (50%) 6117 (35%) 0/8 (0%) 10/10 (100%) 0/4 (0%) 22/37 (60%)

*From Kasai et a1.69; S. Kimura et a1.11~ Lilly and HitchS~; Akiyama et al. 7~ tOnly patients achieving an anicteric state are included in these series.

occurring during the first month following operation (Akiyama). This is particularly lethal, perhaps because it occurs in the setting of administration of broad-spectrum antibiotics. CLINICAL

ASPECTS

OF

THE

ASCENDING

CHOLANGITIS

SYNDROME.--The acute form of this syndrome, occurring following Kasai-type procedures for biliary atresia, is recognized by elevations in temperature, tachycardia, acholic stools, at times abdominal distention, and usually an increased icterus. Leukocytosis, an elevated sedimentation rate, and an increase in serum levels of GOT, GPT, and LDH, as well as increased BSP retention, usually are seen. Anemia and malnutrition are later developments. Before the use of effective antibiotic therapy, the course in these patients frequently was short, ending fatally. At present, most such acute episodes can be controlled. Both acute and recurring forms of ascending cholangitis occur in jaundice-free infants. They also occur in patients who, after operation, have shown active biliary excretion and a decline in serum bilirubin levels, but not to a normal range. The occurrence of a series of febrile episodes in the latter group may initiate the beginning of a slow rise in serum bilirubin levels and general deterioration. This sequence of eventg is attributed to functional obliteration of the bile ductules secondary to infection after initial relief from obstruction by hepatic portoenterostomy. 588

These patients may not die for many years, but their ultimate hepatic decompensation is attributed to the early episodes of cholangitis. MANAGEMENT OF ASCENDING CHOLANGITIS AND PROPHYLACTIC

REGIMENS.--Patients with symptoms of ascending cholangitis are admitted to the hospital for diagnostic studies and intensive parenteral therapy. Blood cultures taken during these episodes usually are negative, but, if positive, reveal a wide variety of predominantly intestinal bacterial forms, including E. coli and species of Klebsiella, Proteus, Pseudomonas, and Candida. Cultures of fluid in the intestinal loop from the area of the anastomosis at the porta hepatis obtained via stomas or at operation reveal the same spectrum of organisms. In addition to routine laboratory determinations and studies of liver function, in some institutions PTCs or intrahepatic ductal drainage 55 are performed routinely if cholangitis occurs (Figs 18 and 19). In this situation, the PTC technique usually is successful in demonstrating the intrahepatic biliary tract, which may be somewhat dilated but usually not actually mechanically obstructed. The procedure is also used to obtain cultures and to decompress the intrahepatic biliary tract. At Kobe, a fine plastic catheter has been left in the intrahepatic system for several weeks, for biliary drainage and cultures, interrupted by the introduction of antibiotic solutions, in the management of ascending cholangitis. ~ Acute episodes of ascending cholangitis may be lethal, but a dramatic response to antibiotic therapy is common and some response, expected. The type of antibiotic therapy may be directed by the results of cultures, but the acute nature of this illness requires that it usually be empirical. Under most circumstances it consists of cephalosporin and an aminoglycoside. Ampicillin and other penicillins, tobramycin, and chloramphenicol also are used to achieve a broad spectrum of antibiotic activity. Infants with ascending cholangitis are in the hospital for weeks or even months, on continuous parenteral antibiotic therapy, and discharged on oral prophylactic regimens for at least several additional weeks. When patients become jaundice-free and then repeated episodes of ascending cholangitis occur, an aggressive approach is adopted in many institutions, which frequently leads to surgical re-exploration of the anastomotic area. Initial procedures may include serial percutaneous liver biopsies (for tissue and culture), percutaneous transhepatic cholangiography and drainage, and endoscopic visualization of the hepatobiliary intestinal anastomosis through the intestinal loop. In patients with an exteriorized loop, it may be possible to demonstrate obstruction (or 589

~

.-..~y,~ . site of 1 ~1~" anastomosis j

~.,,r 747~. intestinal .,~ -~'_~~:~--.~;!~-" conduit 590

the absence of obstruction) at the anastomosis by contrast studies carried out through the loop (Fig 20); but this procedure is performed infrequently because of the danger of introducing intrahepatic infection. The findings of the PTC frequently lead to laparotomy and anastomotic revision. PROPHYLACTIC ANTIBIOTIC MANAGEMENT.--In many institutions, to avert cholangitis, antibiotics are given prior to hepatic portoenterostomy. Some use a standard intravenous antibiotic regimen for several days; others use oral antibiotics. Intensive antibiotic regimens are utilized during the immediate postoperative period in almost all centers, and the period of this therapy has been lengthened in recent years. Common therapeutic regimens include kanamycin or another aminoglycoside and a cephalosporin. A third antibiotic, such as tobramycin or carbenicillin, has been used in some series prophylactically. After several months, most patients are placed on oral ampicillin or Bactrim (trimethoprim and sulfamethoxazole), and this is continued for several years. Controlled studies justifying the use of this intensive prophylactic antibiotic approach never have been possible. By all reports, prior to its use, the incidence of lethal ascending cholangirls was extremely high. Basic to the theoretical reason for its use is the concept that the gradual development of biliary flow is the most significant feature in the initial weeks following a potentially successful portoenterostomy for biliary atresia and that establishing such flow ultimately is the only means of preventing ascending cholangitis. Thus, it is postulated that during this specific period, a strenuous antibiotic regimen might prevent such infection. If ascending cholangitis is not controlled during this initial period, its effects will diminish biliary flow and lead to a cycle of continued infection and bile stasis. The postoperative period is viewed as an interval during which a deadly race takes place between the development of biliary flow and the propensity for ascending cholangitis in the stagnant content of the intrahepatic biliary ductules, which have been exposed for the first time to the intestinal flora. Evaluation of the importance of the development of secondary infections induced by this intensive use of antibiotics is confused

Fig 18.--Postoperative percutaneous transhepatic cholangiogram. PTC performed two years after hepatic portoenterostomy for biliary atresia because of ascending cholangitis. The point of the needle is located in the right intrahepatic ductal system and injected contrast material moves readily into both lobes and also through the anastomotio site at the porta hepatis and into the jejunal conduit. Thus, obstruction was not demonstrated. (From Hashimoto T., Yura J., et al., Jpn. J. Pediatr. Surg. 9:105, 1977.) 591

~

~Esite

-p-,-?

"~i~

of

conduit

Fig 19.--Additional PTC in a patient with ascending cholangitis performed one year following hepatic portoenterostomy for biliary atresia. The point of the needle is seen in the right intrahepatic duct, which is moderately dilated. This patient had noted recurrent febrile episodes, and the delayed emptying, observed in this cholan. giogram, suggested a mild stenosis at the site of the anastomosis. (From Hashimoto T., Yura J., et al., Jpn. J. Pediatr. Surg. 9:105, 1977.) 592

by the recurrent nature of ascending cholangitis. As noted, blood and bile cultures obtained by needle aspiration, etc., are positive for almost all common intestinal organisms, and all large series include cases in which forms of Pseudomonas and Candida predominate. Steroid therapy has been a part of the management of ascending cholangitis for a decade, and is used for varying intervals after operation, but usually terminated within several weeks. Stimulation of the bile flow with choleretic agents during .the postoperative period is practiced in many centers with the use of intravenous dihydrocholic acid for a brief period, followed by oral administration of the same drug for prolonged periods. Phenobarbital also is given on a long-range basis to some patients. In the past, the human gamma globulin preparations have been used in the prophylaxis of ascending cholangitis. ASCENDING CHOLANGITIS AS A LATE C O M P L I C A T I O N . - - E p i s o d e s

of ascending cholangitis may occur several years after the clearing of jaundice in some patients. Lilly and Hitch 8~ regard this form as usually secondary to mechanical obstruction and an indication for operative intervention. In general, patients who have gone four years from the time of their initial procedure, and are jaundice-free, have no further episodes of ascending cholangitis21 Laboratory research in this area includes studies of the flora of the blood, "loops," biliary ducts, and liver under different clinical conditions. 85 Animal studies of the histopathology of tissues adjacent to the biliary-intestinal anastomosis and of the flora and flow characteristics of the hepatic lymphatic drainage system in the presence of an obstructed biliary tract, continue.31 PORTAL HYPERTENSION Portal hypertension undoubtedly is present to some degree in all patients with biliary atresia. Portal vein pressures, measured at the time of the initial hepatic portoenterostomy (Kasai), were > 200 mm H20 in 68% of 31 patients. 69'86 In 16 patients who became jaundice-free, the pressure was again determined at secondary procedures four months to nine years later. In five of six patients in whom there had been no interval ascending cholangitis there was a drop in portal pressure of 44-135 mm whereas among patients with recurrent cholangitis pressures remained > 200 mm H20 in eight of ten, with increases of 71-150 mm. Other studies confirmed the general elevation of pressures in patients with atresia. 8~ Clinically, evidence of portal hypertension and its complications is apparent in all series, but the significance of this appears to be highly variable. A high incidence of complications 593

B

abdominal wall stoma :,:~ ~

. ~ g .;intrahepatic &'& ..~:~-~"" radicles '~,~" site of .~," anastomosis

Fig 20.--Contrast study through an abdominal stoma illustrating the biliary-intestinal anastomosis following a Kasai-type procedure for biliary atresia (Kobe series). This infant had undergone a Ueda procedure (Fig 11) for biliary atresia. The indication for performing this study was the reflux of jejunal content through the stoma two 594

was reported by Altman and by Ueda whereas in the series from Tohoku it was an infrequent clinical problem. Among 83 infants with extrahepatic biliary atresia treated by a Kasai I procedure by Akiyama at the National Children's Hospital (1967-1977), 31 became anicteric and 30 were alive in 1980. s7 Periodic endoscopic examinations were carried out in all jaundice-free patients beginning in 1972. Among 28 of the 31 jaundice-free patients, esophageal varices were identified in 12 (43%) and six had esophageal bleeding. Varices were found in 20% of the patients operated on before 70 days of age and in 50% of the patients operated on after 70 days of age. In the Osaka and Hyogo series, the incidence of bleeding varices was relatively high. Among 23 patients subjected to radical surgery for biliary atresia (Hyogo), 14 of 17 jaundice-free survivors (1977) had clinical evidence of portal hypertension, including nine with bleeding varices, and six required operation. 8s It would appear that many patients have minor bleeding episodes associated with the varices resulting from atresia that are not severe enough to require a surgical procedure. A compilation of approximately 749 patients "at risk" (combined Japanese institutions, 1978) revealed that only 26 of these had undergone a major procedure for portal hypertension. These operations included 11 esophageal transections, eight portosystemic shunts (mesocaval or splenorenal), and seven miscellaneous procedures. 3~ Although portosystemic shunts frequently were utilized prior to 1975, 89 because of concern regarding hepatic encephalopathy, most of the operative procedures carried out for portal hypertension since that time have been forms of direct approach, usually esophageal transection. 9~ A direct relationship between the occurrence and severity of variceal hemorrhage and the incidence of postoperative episodes of ascending cholangitis is noted in reports from several series. 8~ HEPATIC FIBROSIS A N D CIRRHOSIS ASSOCIATED WITH BILIARY ATRESIA

Biliary atresia always is a precirrhotic condition, and affected patients have some hepatic cell damage, which begins during or prior to the neonatal period and results in residual fibrosis. The natural history of the disease, as revealed in liver tissue, has been studied in detail (by serial biopsy) and shows a month-bymonth progression of intrahepatic changes in those infants who months after the original procedure, but similar studies have been used in the evaluation of infants with recurrent ascending cholangitis. This patient's subsequent course was unremarkable. (From Hays D.M., Kimura K?1) 595

are not operated on successfully.92 In these studies, bile duct proliferation is prominent between two and six months of age and declines thereafter. Bile ducts are barely visible after 18 months of age. Hepatic giant-cell formation is prominent between two and four months of age. A striking increase in the size of the periportal areas of fibrosis begins at approximately two months of age. In those infants in whom delayed clinical appearance of the disease is seen, i.e., late appearance of jaundice, the progressive hepatic changes appear to be similarly delay.ed. In the past, it was proposed that patients with "intrahepatic" atresia had a longer life expectancy than those with uncorrected extrahepatic atresia. It now is believed that the disappearance of bile ducts in advanced disease accounts for the long survival in patients with "intrahepatic biliary atresia"; i.e., the older surviving patients have few (if any) visible bile ducts. 93 The most important clinical question is how this progression of hepatic cell changes is affected by the new operations performed for biliary atresia. Those patients (40-50%) who never achieve sufficient biliary excretion to achieve a jaundice-free state following operation have continued progressive fibrosis similar to those in whom no procedure is performed. When jaundice clears initially but then returns permanently the changes are delayed but also are progressive to death. Among patients who become anicteric there is a correlation between frequency of episodes of subsequent ascending cholangitis and the progression of fibrosis in the liver. Causal relationships here are not clear, as it has been demonstrated that patients with advanced cirrhosis at the time of their initial procedure have more frequent episodes of ascending cholangitis. This is attributed to stasis and low bile flow. As noted, intrahepatic bile duct proliferation is a standard feature of the pathologic process in biliary atresia. In patients in whom hepatic portoenterostomy results in active bile excretion, proliferation of bile ducts appears to halt at approximately the time of the successful operation. Subsequently, the number of these structures in the portal areas gradually decreases. Interlobular bile ducts are identifiable in younger patients with biliary atresia, according to Kasai, but if the hepatic portoenterostomy is not successful, these disappear by the fourth or fifth month. 94 He believes that this constitutes the limiting factor in the "correctability" of biliary atresia; i.e., after the ,disappearance of the intralobular ducts, effective biliary excretory function is not possible. Studies of the larger series of patients with biliary atresia, apparently successfully treated by hepatic portoenterostomy, suggest that the hepatic alterations improve, although there are exceptions.VS. 95 In the Tohoku series, ten patients who are jaundice-free for two to 17 years following surgery have undergone 596

serial postoperative liver biopsies. 91'9~ These were performed at the time of secondary operation or by percutaneous techniques. In the majority of these patients, improvement in the histologic appearance of the hepatic tissue obtained at successive samplings was evident, although there was a wide range in the degree of improvement. The results are similar in several smaller series. In those series that note histologic improvement there is a disappearance of bile plugs, a gradual diminution in the number of areas of bile duct proliferation, and a return to normal architectural arrangement of hepatic cells. Improvement in the degree of hepatic fibrosis is inversely related to the incidence of postoperative ascending cholangitis in several series. In one, the histologic improvement could be directly correlated with improvement in the results of postoperative liver function studies, but, in others, improvement in histology of the liver was not seen despite a striking improvement in the liver function profile. In many studies, severity of the hepatic histologic changes at the time of the initial surgical procedure has been used as a prognostic indicator. The degree of alteration in liver tissue can be used to predict with some accuracy the probability of achieving bile excretion, an anicteric state, and of survival, although in all large series there are some patients who follow a completely unpredictable course in this regard. The evidence is clear that a major portion, if not all, of longrange survivors have residual hepatic fibrosis. Among 30 survivors (> 5 years) in the series from the National Children's Hospital (Japan), 26 had palpable livers, but some of these were minimally so21 A substantial majority of these children were completely asymptomatic and had no other signs of hepatic disease. Liver fibrosis in this group had not resulted in sufficient portal hypertension to produce demonstrable splenomegaly or hemorrhage, nor was their general activity or school performance significantly affected. These children had occult liver disease with no indication of progression. This is not uniformly so, as one patient in the National Children's Hospital series died of hepatic decompensation ten years after hepatic portoenterostomy, remaining jaundice-free almost until the time of death. These patients appear to be abnormally sensitive to common viral infections, which may produce temporary or permanent hepatic dysfunction in the period after operation. Ascites is uniformly seen in patients who do not achieve biliary excretion or a jaundice-free state. Among those who become anicteric, its incidence is extremely low (< 2%). sl Mild abnormalities in some hepatic function studies, however, are seen among long-range survivors at any age. Persistent elevation of serum alkaline phosphatase is the most common deviation from normal, noted in patients with otherwise unremarkable liver function, by standard studies. 597

SECONDARY OPERATIONS: ANASTOMOTIC REVISIONS AND LIVER TRANSPLANTATION

Hepatic portoenterostomy is a complex technical procedure and may be followed by all of the standard complications of major abdominal surgery.31 Many of these patients require staged closure of stomas, and surgical intervention for the complications of portal hypertension is common. Many patients with recurrent ascending cholangitis, following Kasai I or similar procedures without a stoma, have been converted to a procedure with a stoma, or a stoma revised, in an attempt to avoid further episodes. In addition, there are some specific indications for anastomotic revision in patients with biliary atresia. As an experimental procedure in several institutions, all patients who did not have postoperative bile excretion were explored routinely. In most instances, this consisted of a deeper dissection in an attempt to reach biliary radicles not drained by the initial operation. The results of these procedures have been disappointing, although there has been an occasional (< 10%) success with this approach. In contrast to these experimental procedures, most surgeons will electively explore patients in whom a well-defined sequence of events occurs following hepatic portoenterostomy. This includes: (a) an initial active bile flow for a number of days or weeks, followed by (b) a relatively sudden cessation of flow. As noted previously, in patients treated by hepatic portocholecystostomy, an indication for revision would include any failure in bile excretion during the initial month. Anastomotic disruption in the initial days following the procedure also is an indication for revision. The results of these secondary procedures are remarkably good: Among 38 collected patients in whom an anastomotic revision for specific indications was performed in Japan, 31 14 are jaundice-free survivors for five or more years. In Altman's series, reoperation has been carried out in 18 patients, eight of whom initially were explored in other institutions. 9~ Nine of these patients had active postoperative biliary excretion and a return of serum bilirubin to the normal range. Other series. describe a comparably favorable experience with anastomotic revision for definite iiidiCations. " In all series Of patients with biliary atresia there are many who survive for many months or years w i t h a p p a r e n t l y obstructed biliary ducts and a hopeless prognosis. Many of these patients have no (other ?) anomalies or significant extrahepatic disease. If deterioration is not rapid, they should be considered candidates for hepatic transplantation. The first human hepatic transplant for biliary atresia was performed by Starzl in 1963, and many of his longest-surviving liver transplant patients had this disease. 9~ 598

Children with biliary atresia are among the most favorable candidates for liver transplantation. In a series of 48 children in whom this procedure has been performed for atresia (Starzl), 33% have survived for more than one year and it appears that approximately one-half of these will survive for five years. 9s"99 Hepatic transplantation is not an alternative to performing hepatic portoenterostomy (any Kasai-type procedure) in the treatment of biliary atresia, but it is used after failure of the latter. The anastomotic connections that are formed in a Kasai-type procedure actually are of help at the time of orthotopic liver transplantation, and the additional age that may be reached, after even a temporarily successful hepatic portoenterostomy, provides larger vessels for the anastomoses involved in carrying out the transplantationJ ~176 ACCEPTANCE OF THE KASAI APPROACH IN NORTH AMERICA AND EUROPE During the past decade there has been a continuing controversy in the United States and Europe over the significance of the Japanese contribution. 28'3o,31,8o There would also appear to be much uncertainty, if not misunderstanding, in respect to the practical application of the new concepts. Because of these problems associated with evaluation and application, a survey of the attitudes of surgeons toward the management of biliary atresia in Japan and in the United States and Canada was carried out by one of the authors (19771978)J ~ A questionnaire of 24 items, including diagrams of operative situations, was prepared and completed by 53 Japanese surgeons (during a personal interview) and by 60 UnitedStates and Canadian surgeons by interview or mail, including those who had published reports on the management of biliary atresia in all three countries. The conclusions of this survey may be summarized as follows. (a) Some Japanese surgeons have had a volume of personal experience (> 200 cases) with Kasai-type procedures that is unparalleled in the West, but several North American institutions75, s~ are developing series at a rate that will make them comparable within several years. (b) Japanese surgeons and North American surgeons approach the problem of differential diagnosis in neonatal jaundice similarly and recognize the importance of identifying nonobstructive hepatic disease prior to (preferable) or, if necessary, at operation. (c) Japanese surgeons stress the gross appearance of the gallbladder and the cholangiogram, if it is possible to perform one, as definitive in making the diagnosis of biliary atresia and pro599

ceed with a Kasai-type procedure once these factors indicate the diagnosis. Details of the structure of the extrahepatic biliary remnant, i.e., the presence of small cysts, are of academic interest but do not alter their basic surgical approach. They do not regard their procedures as an exploration of the porta hepatis; rather, they excise all of the porta hepatis biliary remnant structures in the course of the Kasai-type procedure. North American surgeons are inclined to describe the procedure they perform as an exploration of the porta hepatis. This may not be entirely a semantic distinction, as the philosophical approach here is somewhat different. (d) Most Japanese surgeons in large institutions perform the Kasai-type procedure for all variants of biliary atresia whereas many North American surgeons continue to use small subhepatic cysts in forming a cystenterostomy or cystduodenostomy. The advantage of complete excision of the extrahepatic biliary tract in all types of biliary atresia, however, is recognized by a sizable group of North American surgeons, including those who have treated the largest number of patients. (e) Japanese surgeons, as well as some surgeons in the United States, perform secondary revisions of hepatobiliary anastomoses more frequently than surgeons generally in North America. These Japanese surgeons have well-established indications for re-exploration. The concept that radical surgical procedures for biliary atresia are "last resort" operations that ordinarily should end the surgical experience of a given infant is not prevalent among these surgeons. (f) Descriptions of the general findings at operation and of the biliary tract remnants by pathologists reveal no essential differences in these countries. A hypertrophic variant of biliary atresia may be more prevalent in Japan. 31 (g) "Unnecessary" laparotomies for neonatal cholestatic jaundice, in which patent extrahepatic and intrahepatic ducts are demonstrated, were performed less frequently in Japan than in North America prior to 1977-1978. This may reflect the fact that Some of the diseases that simulate biliary atresia are less common in Japan. al (h) It would appear that there are differences in the interpretation of current concepts or at least of their application to specific situations in Japan and North America. Some surgeons in North America appear to accept the Kasai approach in principle, but, in practice, their clinical decisions have been dictated by more traditional concepts of therapy. It should be stated that some Japanese surgeons have a similar approach. In contrast, in both countries, surgeons who work in institutions in which the largest group of patients with biliary atresia are treated have developed remarkably similar responses to most of the problems presented by the operative management of this disease. 60o

This survey T M already has the perspective of a historical rather than a current review, as the attitude of surgeons in the United States since 1978 has moved perceptively toward acceptance of these new approaches. In this regard, the same sequence of events occurred in the United States that was seen in Japan a decade earlier. Smaller series usually had initially relatively poor results whereas those with the largest experience evolved a technique in which biliary excretion was achieved in a majority of patients. Investigators in the latter institutions then became concerned with the secondary aspects of the therapy of this condition; i.e., ascending cholangitis, portal hypertension, etc. The concentration of patients in specific centers noted in Japan, resulting in series as large as 200 infants, has not been seen in the United States. Many institutions in Japan had extremely poor results with the Kasai-type procedure up until 1975. Surgeons in many countries, who infrequently carry out any procedure for biliary atresia, have attempted the Kasai approach. Ueda has used the term "pseudo Kasai-procedure" to describe operations carried out by Japanese surgeons in which, although the general goal was the Kasai-type procedure, the execution of details of the technique was highly variable. In the United States it is apparent that better results are obtained in institutions in which a considerable volume of patients are treated. 77'79 Reports suggest that there are many institutions outside Japan in which this approach has achieved relative success.75'so. 1o2.lo3 LONG-RANGE SURVIVORS There have been occasional long-range survivors following cystenterostomy for "correctable" forms of biliary atresia; but in many of these cases, the accuracy of the diagnosis is in question, and others have had multiple operative procedures of diverse types. These patients represent < 1% of patients operated on for biliary atresia in the United States. For the purposes of this review, the term "long-range survivor" will be confined to those patients in whom a Kasai-type procedure was performed. The largest series are in Japan, and Kasai's (Tohoku) is the only one that includes a significant group of patients (> 9) followed for more than a decade. From this clinic, the results of a survey of 14 jaundice-free survivors who had been operated on for "noncorrectable" forms of biliary atresia between 1956 and 1973 were reported in 1975. 91 Serum bilirubin levels in all but one of these patients were within the normal range. Fifty percent (seven) had elevations of serum alkaline phosphatase. Otherwise, liver function "profiles" contained results within the normal range in 11 and included slight abnormalities in at least one study in three. One 601

child with Turner's syndrome and one with craniostenosis were included. With these exceptions, height and weight were slightly above the mean for Japanese children. When reviewed in 1978, this series contained 22 jaundice-free five-year survivors and nine ten-year survivors. 69 In only two had there been evidence of portal hypertension at any time and only one had required operation for bleeding. The long-range survivors in the National Children's Hospital (Tokyo) series were reviewed in 1976 and 1980. T M A total of 102 patients were treated by Kasai-type procedures (1967-1975). Twenty-seven of these were nonicteric five or more years after operation. Three of this group died of hepatic decompensation (with minimal jaundice) between five and 11 years postoperatively. The remaining 24 patients were studied in detail. Body weight rose to within the normal range (+- 2 SD) by 12 months of age but mean body length remained subnormal to age four. Dentition was normal in most and motor development only retarded prior to 18 months of age. Normal speech patterns were found in these patients at all ages. In a study (1978) from the National Children's Hospital (Sawaguchi), the results of hepatic function studies in 19 children (> 5 years of age) were within the normal range or with slight elevations of SGOT or alkaline phosphatase in 50% of the group. The other 50% had a variety of slight to moderate deviations from normal in several liver function studies, and possibly elevations in gamma globulin levels. S e v e n o f these patients had evidence of hypersplenism, and splenectomy had been performed for this reason in two. In the University of Colorado series, ~~ ten of 21 patients had satisfactory biliary drainage and had been followed for from three to five and one-half years. All ten had ascending cholangitis at some time (one to seven episodes). Osteomalacia was noted in five. Major retardation in development was not seen, following recovery from the initial operation and hospitalizations, in any of these patients. LONG-RANGE SURVIVORS IDENTIFIED BY THE A U T H O R S . - - D u r i n g

1977-1978, the authors identified 85 living patients in Japan who were treated by hepatic portoenterostomy prior to 1973 (> 5 years). 31 Although all of these patients had Kasai-type procedures, six probably would have been described as having a "correctable" type of atresia. These patients had been operated on at 15 different institutions, with the largest groups from Tohoku (23) and the National Children's Hospital (22). Excluded from consideration were any cases in which cystenterostomy or cystduodenostomy had been performed and also those for which detailed information could not be obtained. Data was obtained by visiting the institutions involved and obtaining information di6O2

rectly from surgeons and other physicians responsible for care of the patients. Medical records were examined and slides from the porta hepatis reviewed when possible. Twenty-four percent of the patients were personally examined by us and others contacted by telephone. The sources of data, then, were the patient and family, the surgeon and his associates, and hospital medical records. Seventy-nine percent of the patients had been examined within one year of the date of the review and 95% within two years. Correlation between data obtained from the medical records and subsequently directly from the patient (or by examining the patient) was extremely high (> 95%). Five of these patients had other congenital defects and one had cerebral palsy. Sixty of these patients had been subjected to the Kasai I procedure, reflecting the fact that this was the initial operation in all institutions in Japan. Excluding simple stoma closures, 14 of these patients had undergone secondary operative procedures of some type following the initial hepatic portoenterostomy for atresia. Five were anastomotic revisions and the remainder included a variety of operations for portal hypertension. Fortyeight of the long-range survivors had at least one postoperative hepatic biopsy and three had three or more biopsies. The majority of these demonstrated a reduction in the severity of the histologic alterations in successive biopsies. As noted by S. Kimura, T M there may be great variation in the severity of cirrhosis in different parts of the same liver following operation, which may explain the divergent opinions on the results of these biopsies. Of major interest is the fact that 95% of these patients were asymptomatic relative to their basic disease process. Seventytwo were known to be attending regular schools and two attend special schools. Two patients were employed at the time of the survey and had excellent work records. Sixty patients were active in athletics and > 85% did not restrict their physical ac.tivity in any way. The boys participated in the most active and strenuous sports. The oldest survivor in this series (25 years) had been a probation officer for more than three years. REFERENCES 1. Thompson J.: On congenital obliteration of the bile ducts. Edinburgh Med. J. 37:523, 604, 724, 1892. 2. Holmes J.B.: Congenital obliteration of the bile ducts: Diagnosis and suggestions for treatment. Am. J. Dis. Child. 11:405, 1916. 3. Ladd W.E.: Congenital atresia and stenosis of the bile ducts. J.A.M.A. 91:1082, 1928. 4. Bill A.H.: Biliary atresia: Introduction. World J. Surg. 2:557, 1978. 5. Izant R.J. Jr., Akers D.R., Hays D.M., et al.: Biliary atresia survey. Surg. Sec. Am. Acad. Pediatr., 1966. 603

6. Pellerin D., Aicardi J., Nezelof C.: Les ictdres de type retentionnel du nourrisson. Ann. Pediatr. 42:2676, 1966. 7. Welte W.: Diagnostische und therapeutische problems bei der gallengangsatresia. Dtsch. Med. Wochenschr. 96:899, 1971. 8. Ishida M.: Causes of unsatisfactory outcome of surgery for the noncorrectable type of biliary atresia. J. Jpn. Soc. Pediatr. Surg. 5:460, 1969. 9. Ericsson N.O., Rudhe V.: Cholangiography in infancy as an aid in operative diagnosis of biliary obstruction. Acta Chir. Scand. 107:275, 1954. 10. Kasai M., Watanabe K., Yamagata A., et al.: Surgical treatment of biliary atresia. Nihon-~ji-shinpo 15:1730, 1957. 11. Harris R.C., Anderson D.H., Day R.L.: Obstructive jaundice in infants with normal biliary tree. Pediatrics 13:293, 1954. 12. Ghadimi H., Sass-Kortsak A.: Evaluation of the radioactive rose-bengal test for the differential diagnosis of obstructive jaundice in infants. N. Engl. J. Med. 265:351, 1961. 13. Hays D.M., Woolley M.M., Snyder W.H. Jr., et aI.: Diagnosis of biliary atresia: Relative accuracy of percutaneous liver biopsy, open liver biopsy, and operative cholangiography. J. Pediatr. 71:598, 1967. 14. Kiesewetter W.B., Koop C.E., Farquahr J.D.: Surgical jaundice in infancy. Pediatrics 15:149, 1955. 15. Hays D.M., Snyder W.H. Jr.: Life span in untreated biliary atresia. Surgery 54:373, 1963. 16. Absolon K.B., Rikkers H., Aust J.B.: Thoracic duct lymph drainage in congenital biliary atresia. Surg. Gynecol. Obstet. 120:123, 1965. 17. Lad(] W.E.: Congenital obstruction of the bile ducts. Ann. Surg. 102:742, 1935. 18. Carlson E.: Salvage of the "noncorrectable" case of congenital extrahepatic biliary atresia. A.M.A. Arch. Surg. 81:893, 1960. 19. Danks D.M., Campbell P.E.: Extrahepatic biliary atresia: Comments on the frequency of potentially operable cases. J. Pediatr. 69:21, 1966. 20. Danks D.M., Clarke A.M., Jones P.G., et al.: Extrahepatic biliary atresia: Further comments on operable cases. J. Pediatr. 3:584, 1968. 21. Ohi R., Kasai M., Takahashi T.: Intrahepatic biliary obstruction in congenital bile duct obstruction. Tohoku J. Exp. Med. 99:129, 1969. 22. Chiba T., Kasai M., Sasano N.: Histopathological studies on intrahepatic bile ducts in the vicinity of porta hepatis in biliary atresia. Tohoku J. Exp. Med. 118:199, 1976. 23. Thaler M.M., Gellis S.S.: Studies in neonatal hepatitis and biliary atresia. Am. J. Dis. Child. 116:257, 1968. 24. Alagille D.: Clinical aspects of neonatal hepatitis. Am. J. Dis. Child. 123:287, 1972. 25 Odievre M., Valayer J., Razemon-Pinta M., et al.: Hepatic portoenterostomy or cholecystostomy in the treatment of extrahepatic biliary atresia. J. Pediatr. 88:774, 1976. 26. Lilly J.R.: The Japanese operation for biliary atresia: Remedy or mischief?. Pediatrics 55:12, 1975. 27. Lilly J.R., Altman R.P., Schroter G., et al.: Surgery ofbiliary atresia. Am. J. Dis. Child. 129:1429, 1975. 28. Altman R.P., Lilly J.R.: Technical details in the surgical correction of extrahepatic biliary atresia. Surg. Gynecol. Obstet. 140:953, 1975. 29. Lilly J.R., Altman R.P.: Hepatic portoenterostomy (the Kasai operation) for biliary atresia. Surgery 78:76, 1975. 30. Campbell D.P., Poley J.R., Bhatia M., et al.: Hepatic portoenterostomy--is it indicated in the treatment of biliary atresia? J. Pediatr. Surg. 9:329, 699, 1974. 31. Hays D.M., Kimura K.: Biliary Atresia: The Japanese Experience. Cambridge, Mass., Harvard University Press, 1980. 604

32. Danks D.M.: Prolonged neonatal obstructive jaundice: A survey of modem concepts. Clin. Pediatr. 4:499, 1965. 33. Brent R.L.: Persistent jaundice in infancy. J. Pediatr. 61:111, 1972. 34. Landing B.H.: Considerations of the pathogenesis of neonatal hepatitis, biliary atresia, and choledochal cyst: The concept of infantile obstructive cholangiography. Prog. Ped'mtr. Surg. 6:113, 1974. 35. Haas J.E.: Bile duct and liver pathology in biliary atresia. World J. Surg. 2:561, 1978. 36. Gautier M., Jehan P., Odievre M.: Histologic study of biliary fibrous remnants in 48 cases of extrahepatic biliary atresia: Correlation with postoperative bile flow restoration. J. Pediatr. 89:704, 1976. 37. Pickett L.K., Briggs H.C.: Biliary obstruction secondary to hepatic vascular ligation in the fetal sheep. 4. Pediatr. Surg. 4:95, 1969. 38. Okamoto E., Okasora T., Toyosaka A.: An experimental study on the etiolo ogy of congenital biliary atresia, in Cholestasis in Infancy. Japan Med. Res. Found., University of Tokyo Press, 1980, p. 217. 39. Spitz L.: Ligation of the common bile duct in the fetal lamb: An experimental model for the study of biliary atresia. Pediatr. Res. 14:740, 1980. 40. Miyano T., Suruga K., Kimura K., et al.: A histopathologic study of the region of the ampulla of Vater in congenital biliary atresia. Jpn. J. Surg. 10:34, 1980. 41. Lilly J.R.: Surgical hazards of co-existing anomalies in biliary atresia. Surg. Gynecol. Obstet. 139:49, 1974. 42. Shiraki K.: Polysplenia and congenital biliary atresia: Their association and significance. Jpn. J. Pediatr. Surg. 11:1379, 1979. 43. Maksem J.A.: Polysplenia syndrome and splenic hypoplasia associated with extrahepatic biliary atresia. Arch. Pathol. Lab. Med. 104:212, 1980. 44. Sharp H.L., Leonard A.S.: Extrahepatic biliary atresia, a diagnostic dilemma, in Leevey C.M. (ed.): Diseases of the Liver and Biliary Tract. Basel, S. Karger, 1976. 45. Zeltzer P.M.: Alpha-fetoprotein in the differentiation of neonatal hepatitis and biliary atresia: Current status and implications for the pathogenesis of these disorders. J. Pediatr. Surg. 13:381, 1978. 46. Seidel D., Alaupovic P., Furman R.H.: A lipoprotein characterizing obstructive jaundice. I. Method for quantitative separation and identification of lipoproteins in jaundiced subjects. J. Clin. Invest. 48:1211, 1969. 47. Poley J.R., Smith E.I., Boon D.J., et al.: Lipoprotein-X and the double l~lIrose bengal test in the diagnosis of prolonged infantile jaundice. J. Pediatr. Surg. 7:660, 1972. 48. Simon J.B., Poon R.W.M.: Lipoprotein-X levels in extrahepatic versus intrahepatic cholestasis. Gastroenterology 75:177, 1978. 49. Javitt N.B., Morrissey K.P., Seigel E., et al.: Cholestatic syndromes in infancy: Diagnostic value of serum bile acid pattern and cholestyramine administration. Pediatr. Res. 7:119, 1973. 50. Kawai S., Kobayashi A., Ohbe Y.: Diagnosis of congenital biliary atresia with reference to the differential diagnosis from neonatal hepatitis. Jpn. J. Pediatr. Surg. 10:619, 1978. 51. Hashimoto S., Tsugawa C., Kimura K., et al.: Diagnosis of biliary atresia by duodenal tubing. J. Jpn. Soc. Pediatr. Surg. 14:889, 1978. 52. Greene H.L., Helinek G.L., Moran R., et al.: A diagnostic approach to prolonged obstructive jaundice by 24-hour collection of duodenal fluid. J. Pediatr. 95:412, 1979. 53. Brough A.J., Bernstein J.: Liver biopsy in the diagnosis of infantile ob9structive jaundice. Pediatrics 43:519, 1969. 54. Hays D.M.: Biliary atresia: The current state of confusion. Surg. Clin. North Am. 53:1257, 1973. 55. Kimura K., Hashimoto S., Nishijima E., et al.: Percutaneous transhepatic 6O5

cholangiodrainage after hepatic portoenterostomy for biliary atresia. J. Pediatr. Surg. 15:811, 1980. 56. Hashimoto T., Yura J.: Percutaneous transhepatic cholangiography (PTC) in biliary atresia with special reference to the structure of the intrahepatic bile ducts. J. Pediatr. Surg. 16:22, 1981. 57. Hayden P.W., Rudd T.G., Christie D.L.: Rose bengal sodium I TM studies in infants with suspected biliary atresia. Am. J. Dis. Child. 133:834, 1979. 58. Wistow B.W., Subramanian G., VanHeertum R.L., et al.: An evaluation of ~ T G labeled hepatobiliary agents. J. Nucl. Ivied. 18:455, 1977. 59. Riely C.A., Caride V.J., Lange R.C., et al.: The use of ~TC-HIDA in evaluating pediatric liver disease (abstract). Gastroenterology 75:983, 1978. 60. Miller J.H., Sinatra F.R., Thomas D.W.: Biliary excretion disorders in infants: Evaluation using ~ T C PIPIDA. Am. J. Roentgenol. 135:47, 1980. 61. Maid M., Reba R.C., Altman R.P.: Hepatobiliary scintigraphy with ~ r C PIPIDA in the evaluation of neonatal jaundice. Pediatrics 67:140, 1981. 62. Lebwohl O., Waye J.D.: Endoscopic cholangiopancreatography in the diagnosis of extrahepatic biliary atresia. Am. J. Dis. Child. 133:647, 1979. 63. Hirsig J., Rickham P.P.: Early differential diagnosis between neonatal hepatitis and biliary atresia. J. Pediatr. Surg. 15:13, 1980. 64. Chiba T., Kasai M.: Differentiation of biliary atresia from neonatal hepatitis by routine clinical examinations. Tohoku J. Exp. Med. 115:327, 1975. 65. Sakurai M., Shiraki K.: Quantitative diagnosis of biliary atresia and neonatal hepatitis: Its pathogenesis, diagnosis, and treatment, in Cholestasis in Infancy. Japan Med. Res. Found., University of Tokyo Press, 1980, p. 293. 66. Kimura K., Tsugawa C., Matsumoto Y., et al.: The surgical management of the unusual forms of biliary atresia. J. Pediatr. Surg. 14:653, 1979. 67. Kasai M., Suzuki S.: A new operation for noncorrectable biliary a t r e s i a - hepatic portoenterostomy. Shujutsu 13:733, 1959. 68. Kasai M., Kimura S., Asakura Y., et al.: Surgical treatment of biliary atresia. J. Pediatr. Surg. 3:665, 1968. 69. Kasai M., Suzuki H., Ohashi E., et al.: Technique and results of operative management of biliary atresia. World J. Surg. 2:571, 1978. 70. Akiyama H., Saeki M., Ogata T.: Congenital biliary atresia: Our operative method and the operative results. Jpn. J. Pediatr. Surg. 10:678, 1978. 71. Sawagnchi S., Nakajo T., Hori T., et al.: Reconstruction of the biliary (Sawaguchi procedure) tract in biliary atresia using jejunal conduit. J. Jpn. Surg. Soe. 69:1317, 1968. 72. Kimura K., Tsugawa C., Kubo M.: Technical aspects of hepatic portal dissection in biliary atresia. J. Pediatr. Surg. 14:27, 1979. 73. Okamoto E.: Operative techniques for congenital biliary atresia and its results. Jpn. J. Pediatr. Surg. 10:697, 1978. 74. Suruga K., Kono S., Miyano T., et al.: Treatment for biliary atresia: Microsurgery for hepatic portoenterostomy. Surgery 80:558, 1976. 75. Altman R.P.: The portoenterostomy procedure for biliary atresia: A five year experience. Ann. Surg. 188:351, 1978. 76. Lilly J.R.: Hepatic portocholecystostomy for biliary atresia. J. Pediatr. Surg. 14:301, 1979. 77. Altman R.P.: Invited commentary. World J. Surg. 2:579, 1978. 78. Suruga K.: Treatment of biliary atresia--study on our operative results of the so-called "uncorrectable type" of biliary atresia. Jpn. J. Pediatr. Surg. 11:79, 1979. 79. Hitch D.C., Shikes R.H., Lilly J.R.: Determinants of survival after Kasai's operation for biliary atresia using actuarial analysis. J. Pediatr. Surg. 14:310, 1979. 80. Odievre M.: Long-term results of surgical treatment of biliary atresia. World J. Surg. 2:589, 1978. 606

81. Lilly J.R., Hitch D.C.: Postoperative ascending cholangitis following portoenterostomy for biliary atresia: Measures for control. World J. Surg. 2:581, 1978. 82. Fonkalsrud E.W., Kitagawa S., Longmire W.P. Jr.: Hepatic lymphatic drainage to the jejunum for congenital biliary atresia. Am. J. Surg. 112:188, 1966. 83. Suruga K., Yamazaki Z.,Iwai S., et al.: The surgery of infantile obstructive jaundice. Arch. Dis. Child. 40:158, 1965. 84. Hirsig J., Kara O., Rickham P.P.: Experimental investigations into the etiology of cholangitis following operations for biliary atresia. J. Pediatr. Surg. 13:55, 1978. 85. Ikeda K., Suita S.: Hepatic portogastrostomy using a gastric tube for the treatment of congenital biliary atresia. Z. Kinderchir. 17:360, 1975. 86. Kasai M., Okamoto A., Ohi R., et al.: Changes of portal vein pressure and intrahepatic blood vessels after surgery for biliary atresia. J. Pediatr. Surg. 16:152, 1981. 87. Saeki M., Akiyama H., Ogata T.: Portal hypertension after successful hepatic portoenterostomy for biliary atresia. Jpn. J. Pediatr. Surg. 12:1059, 1980. 88. Toyosaka A.: Portal hypertension followed by successful hepatic portoenterostomy for biliary atresia. Jpn. J. Pediatr. Surg. 11:537, 1979. 89. Altman R.P.: Portal decompression by interposition mesocaval shunt in patients with biliary atresia. J. Pediatr. Surg. 11:809, 1976. 90. Yakabe S., Ikeda K., Kaneko T., et al.: Management of postoperative portal hypertension of biliary atresia. Jpn. J. Pediatr. Surg. 12:1065, 1980. 91. Kasai M., Watanabe I., Ohi R.: Follow-up studies of long-term survivors after hepatic portoenterostomy for "noncorrectable" biliary atresia. J. Pediatr. Surg. 10:173, 1975. 92. Shiraki K., Odawara M., Higurashi M., et al.: Liver in congenital bile duct atresia: Histological changes in relation to age. Pediatr. Univ. Tokyo 12:67, 1966. 93. Landing B.H., Wells T.R., Reed G.B., et al.: Diseases of the bile ducts in children, in Gall E.(ed.): The Liver, Int. Acad. Pathol. Monograph #13. Baltimore, Williams & Wilkins Co., 1972, p. 480. 94. Kasai M., Ohi R., Chiba T.: Intrahepatic bile ducts in biliary atresia: Its pathogenesis, diagnosis and treatment, in Cholestasis in Infancy. Japan Med. Res. Found., University of Tokyo Press, 1980, p. 181. 95. Sondheimer J.M., Shandling B., Weber J.L., et al.: Hepatic function following portoenterostomy for extrahepatic biliary atresia. Can. Med. Assoc. J. 118:255, 1978. 96. Altman R.P.: Results of re-operations for correction of extrahepatic biliary atresia. J. Pediatr. Surg. 14:305, 1979. 97. Starzl T.E., Halgrimson C.G., Schroter G.P.J., et al.: Fifteen years of clinical liver transplantation. Gaslroenterology 77:375, 1979. 98. Lilly J.R., Starzl T.E.: Liver transplantation in children with biliary atresia and vascular anomalies. J. Pediatr. Surg. 9:707, 1974. 99. Starzl T.E., Koep L.J., Schroter G.P.J., et al.: Liver replacement for pediatric patients. Pediatrics 63:825, 1979. 100. Putnam C.W., Halgrimson C.G., Koep L., et al.: Progress in liver transplantation. World J. Surg. 1:165, 1977. 101. Hays D.M.: Differences in attitude toward the management of biliary atresia among surgeons in Japan and in North America. J. Pediatr. Surg. 14:580, 1979. 102. deLorimier A.: Neonatal jaundice and biliary atresia. Surg. Clin. North Am. 57:429, 1977. 103. Howard E.R., Mowat A.P.: Extrahepatic biliary atresia" Recent developments in management. Arch. Dis. Child. 52:825, 1977. 6O7

104. Kobayashi A., Sakai K., Okubo M., et al.: Appraisal of physical growth and development of long-survived patients with successfully repaired biliary atresia. Jpn. J. Pediatr. Surg. 12:1019, 1980. 105. Barkin R.M., Lilly J.R.: Biliary atresia.and the Kasai operation: Continuing care: J. Pediatr. 96:1015, 1980. 106. Kimura S., Tomomatsu S., Joko Y., et al.: Studies on the postoperative changes in the liver tissue on long-term survivors after successful surgery for biliary atresia. Z. Kinderchir. 31:228, 1980. 107. Sawaguchi S., Akiyama H., Nakajo P., et al.: Long-term results of surg/cat treatment of congenital biliary atresia. Geka Chiryo 39:396, 1978. 108. Miyata M., Satani M., Ueda T., et al.: Long-term results of hepatic portoenterostomy for biliary atresia: Special reference to postoperative portal hypertension. Surgery 76:234, 1974. 109. Yura J., Hashimoto T., Tsuruga N.: Treatment of congenital biliary portojejunostomy with gastrojejunostomy. Jpn. J. Pediatr. Surg. 10:665, 1978. 110. Kimura S., Nakarnura A., Inao A., et al.: Our method in dissection of the porta hepatis for biliary atresia and its long-term results. Jpn. J. Pediatr. Surg. 10:691, 1978. 111. Tsunoda A., Yamada T., Matsumoto R.: An evaluation of the result of surgical treatment for congenital biliary atresia. Jpn. J. Pediatr. Surg. 10:713, 1978.

SELF-ASSESSMENT ANSWERS 1. 2. 3. 4. 5. 6.

c c b c b b

608

7. 8. 9. 10. ll.a 12.

b b b d c