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Neonatal Jaundice and Biliary Atresia
Symposium on Hepatic Surgery
Neonatal Jaundice and Biliary Atresia Alfred A. de Lorimier, M.D.*
The differential diagnosis of jaundice in the newborn remains a difficult problem. Many disease entities are eliminated when the serum bilirubin fraction is almost exclusively the indirect, unconjugated form. However, cholestatic jaundice, associated with direct, conjugated hyperbilirubinemia, is not exclusively due to bile duct obstruction. Approximately 30 per cent of infants with cholestatic jaundice have primary hepatocellular disease, with patent bile ducts. Therefore, careful clinical and laboratory evaluation of the infant is required before he is surgically explored to treat presumed biliary atresia. In the past, only 5 per cent of infants were found to have a "curable" form of biliary atresia. Currently, a newer operative approach of hepatic portoenterostomy has been advocated to enhance the curability of biliary atresia. This article reviews the differential diagnosis of jaundice in the newborn, and the operative treatment of biliary atresia.
NEONATAL JAUNDICE Persistent jaundice in infancy after the first 3 weeks oflife, in which the direct bilirubin accounts for more than 30 per cent of the total bilirubin level, suggests bile duct obstruction requiring surgical attention. However, there are a number of nonsurgical diseases producing abnormally high serum conjugated bilirubin levels, and the differential diagnosis is important. Causes of prolonged cholestatic jaundice include: 1. Infections; viral, bacterial or parasitic 2. Genetic-metabolic diseases; alpha anti-trypsin deficiency, galactosemia, hereditary fructosemia, hereditary tyrosinemia, cystic fibrosis, Niemann-Pick disease 3. Neonatal hepatitis (idiopathic cholestatic jaundice of infancy) 4. Intrahepatic biliary atresia and hypoplasia 5. Extrahepatic biliary atresia and hypoplasia 6. Choledochal cyst 7. Bile duct stricture
Tables 1 and 2, taken from Sass-Kortsak, identify some of the features that characterize infections and genetic-metabolic causes of jaundice in infancy.1s 'Associate Professor of Surgery, Pediatric Surgery Service, University of California, San Francisco, School of Medicine, San Francisco, California
Surgical Clinics of North America-Vol. 57, No.2, April 1977
429
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Table 1. Infections Leading to Conjugated Hyperbilirubinemia in Early Infancy SCREENING TESTS IN BOTH
USUAL MODE OF AGENT
INFECTION
Cytomegalovirus
Transplacental
Rubella virus
Transplacental
Hepatitis B virus
Intrapartum, transfusion
Herpes simplex
Intrapartum or immediate post partum
OTHER MANIFESTATIONS
Low birth weight, micro- or hydrocephaly, intracranial calcifications, chorioretinitis, enteritis, pneumonitis, thrombocytopenia, . hemolytic anemia, myocarditis. Low birth weight, congestive heart disease, cataracts, microphthalmia, glaucoma, deafuess, bone lesions, microcephaly, thrombocytopenia, anemia. No other systemic involvement reported as yet in young infants. Skin or mucous membrane vesicles, encephalitis, cerebral calcifications, chorioretinitis, keratoconjunctivitis, pneumonitis, thrombocytopenia, coagulopathy.
MOTHER AND INFANT
DEFINITIVE DIAGNOSIS
CF antibody in serum
Isolation from urine and from liver. Demonstration of virus in liver by IF. Specific IgM antibody.
CF and HI antibodies, in serum
Isolation of virus from nasopharyngeal secretions of liver. Demonstration of virus in liver by IF. Specific IgM antibody.
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Hepatitis B antigen in infant, antigen and antibody in mother. Perinatal herpes in mother, or attendants. Serology and demonstration of virus in herpeslike lesions.
As for screening + demonstration ofHB antigen in liver by IF and EM.
Isolation or demonstration of virus from superficial lesions and liver. Specific IgM antibody.
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Coxsackie B virus
Transplacental
Meningoencephalitis, myocarditis, thrombocytopenia.
Varicella-zoster virus
Transplacental
Varicella rash, pneumonitis, other visceral involvement.
Bacterial sepsis (E. Coli, other enteric bacteria, staphylococcus, etc.) Treponema pallidum Toxoplasma gondii
Intrapartum or postnatal
Lethargy, labile temperature, fever, weight loss, pallor, anemia, vomiting, diarrhea, pyuria, meningitis, etc.
Abbreviations:
Serology of very limited value. Isolation from respiratory secretions and feces. CF antibody in serum. Demonstration of virus in superficial lesions. High white blood cell count, shift to left, pyuria, anemia without reticulocytosis.
Isolation of virus from liver.
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Rhinitis, rash, bone lesions, lymphadenopathy, anemia. Micro- or hydrocephaly, intracranial calcifications, chorioretinitis, microphthalmia, thrombocytopenia, anemia, skin hemorrhages.
CF = complement fixing HI = hemagglutination inhibition IF = immunofluorescence microscopy EM = electronmicroscopy.
VDRL or TPI, particularly in mother. CF antibody in serum, SabinFeldman dye test, titre in excess of 1:1000.
Dark field examination of exudates for treponema. Rising antibody titres in infant. Isolation by culture from liver, CSF, eye. Specific IgM antibody.
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Table 2. Genetic-Metabolic Diseases Leading to Conjugated Hyperbilirubinemia in Early Infancy MODE OF
ADDITIONAL
CONDITION
INHERITANCE
CLINICAL MANIFESTATIONS
Alpha, antitrypsin deficiency
Autosomal recessive
Neonatal hepatitis syndrome.
Galactosemia (transferase deficiency)
Autosomal recessive
Hereditary fructose intolerance
Autosomal recessive
Hereditary tyrosinemia
Autosomal recessive
Fibrocystic disease
Autosomal recessive
Failure to thrive, gastrointestinal symptoms. Cataracts, renal tubular defect, hypoglucosemia. Onset of vomiting, diarrhea, weight loss with introduction of fructose (fruit and/or sucrose) in diet. Renal tubular defects. Hypoglucosemia. Failure to thrive, vomiting, diarrhea, rickets, renal tubular defects, hypoglucosemia. Failure to thrive, meconium ileus, malabsorption, pulmonary infections. Failure to thrive, cherry-red spots, CNS later.
Nieman-Pick's disease, Type A & B
Autosomal recessive
SCREENING TESTS
DEFINITIVE DIAGNOSIS
Serum protein electrophoresis: absent alpha globulin peak.
Protease inhibitor typing. Quantitative a, AT measurement in serum. Red cell galactose-I-P0 4 uridyl transferase assay. .
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Reducing sugar in urine identifiable as galactose while patient on milk feeding. Reducing sugar in urine identifiable as fructose while patient receives fructose or sucrose.
Fructose tolerance test (dangerous). Liver fructose-I-PO. aldolase activity.
High plasma tyrosine + methionine, aminoaciduria, tyrosyluria. Digestive enzymes in feces or duodenal juice.
p-Hydroxyphenylpyruvic acid oxidase in liver?
Foam cells in bone marrow.
Sphingomyelinase assay in leukocytes, cultured fibroblasts, liver tissue.
Sweat chloride concentration.
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NEONATAL JAUNDICE AND BILIARY ATRESIA
433
Our inability to identify the specific causes and the pathogenesis for idiopathic cholestatic jaundice, intrahepatic and extrahepatic biliary atresia and hypoplasia, and choledochal cyst accounts for a great deal of confusion about these entities. There are probably many causative agents, and a number of the currently known infections and metabolic diseases were formerly in the group referred to as neonatal hepatitis. In our efforts to simplify matters it is appealing to consider a unifying concept that links neonatal hepatitis, intrahepatic and extrahepatic biliary atresia or hypoplasia as a clinical spectrum of the same phenomenon. 1o The reasons for this include: (1) the difficulty in defining each entity biochemically and histologically, and (2) some patients, who had "neonatal hepatitis" and intact bile ducts initially, subsequently developed intrahepatic or extrahepatic biliary atresia later in the course of the disease.
BILIARY ATRESIA Definition Intrahepatic atresia is associated with intact and patent extrahepatic bile ducts, but liver biopsy shows minimal inflammatory reaction and fibrosis, and markedly diminished or absent intrahepatic bile ducts. These children tend to live for a prolonged time (3-20 years) with lowgrade or intermittent jaundice. They have high serum bile salt, cholesterol, and alkaline phosphatase levels, and they develop intense pruritis. In time subcutaneous xanthomata appear in the skin creases of the extremities and face. Confusion occurs here, because some patients with extrahepatic biliary atresia will develop the same clinical and histologic features described above. Extrahepatic biliary atresia is characterized by a fibrous replacement of the normal bile duct channels in the hepatoduodenalligament and within the liver. Varying degrees oflow-grade inflammatory reaction are usually present in the fibrous strands and adjacent tissues. Very rarely, the process involves only a short segment of the distal bile ducts. More commonly, the ducts proximal to the cystic duct are obliterated, and the gallbladder, cystic duct, and common bile duct are patent. The most frequent finding is complete replacement of the ducts by a dense fibrous, desmoplastic reaction from the duodenum to the liver hilus, including the gallbladder. The bile duct epithelium is either absent or in isolated strands. No muscular cells are seen. Extrahepatic biliary atresia is a misnomer, because the obliterative, fibrous process invariably affects the ducts within the liver. "Correctable" biliary atresia exists when there are patent hepatic ducts extending into the liver. 7 If the hepatic ducts are not patent, the lesion has been considered "incorrectable."5 Again confusion arises, because in many instances of apparently "correctable" biliary atresia, a bile duct-enteric anastomosis may not result in any bile drainage, no doubt because of extensively obliterated intrahepatic ducts. Kasai has shown that in many cases of apparently "incorrectable" biliary atresia, totally obliterated extrahepatic ducts have had excellent drainage by anastomosing bowel to the porta hepatis. 9
434
ALFRED A. DE LORIMIER
Extrahepatic biliary hypoplasia is characterized by cholestatic jaundice, but the bile ducts are patent and very narrow. Usually the bile duct walls are fibrotic. In Kasai's histologic studies of resected "incorrectable" bile duct specimens, he found that bile excretion occurred where the resected specimen showed isolated ductal structures greater than 200 micra in diameter. 9 Therefore, it might be said that these are examples of biliary hypoplasia rather than atresia. Choledochal cyst with biliary atresia may be found in 10 to 30 per cent of these infants. The common bile and/or hepatic ducts are large and dilated with atresia distally. The duct walls have the thick, fibrous, and inflammatory reaction, as described above. However, these infants, who are jaundiced from early infancy, usually develop the same clinical course as seen in biliary atresia, and they do not have the more uncomplicated course of choledochal cyst found in later infancy and childhood. There is extensive intrahepatic fibrosis which seems to progress with time. Therefore, these patients should be considered to have biliary atresia with dilated extrahepatic bile ducts, and not choledochal cyst disease. Clinical Evaluation A history should be elicited from the parents of infants with jaundice about hepatitis, familial diseases or active genital infection. The findings of Down's syndrome or trisomy 17-18 may be associated with biliary atresia or neonatal hepatitis. 2 The Porter-Alagille syndrome of hepatic duct hypoplasia is associated with characteristic facies, vertebral and cardiac malformations, and retarded development. I. 13 Biliary atresia is also associated with other congenital malformations in 10 to 30 per cent of cases, such as congenital heart lesions, myelomeningocele, and the polysplenia syndrome. 5-14 The physical finding that suggests biliary duct obstruction is the presence of an enlarged, firm liver with a blunt, slightly irregular margin. The enlarged liver associated with other causes has a relatively soft, sharp edge in the first several months of life. Laboratory tests usually do not clearly establish the cause for the jaundice. The stools should be observed for evidence of bile excretion which would indicate intrahepatic, not extrahepatic, cholestasis. However, pigment in foods will obscure the lack of bile pigment in the stools. In biliary atresia the total serum bilirubin is usually in excess of 8 mg per cent, but less than 15 mg per cent. The direct bilirubin is usually less than 5 mg per cent in infants with intrahepatic cholestasis. A very high serum alkaline phosphatase or cholesterol level suggest biliary duct obstruction, but these elevated values usually occur after 4 to 5 months of age. The transaminases, lactic dehydrogenase, and leucine aminopeptidase values suggest hepatitis when they are markedly elevated. Some newer tests have been advocated which might help differentiate intrahepatic cholestasis, and above this level identify the likelihood of biliary atresia. 15 The presence of lipoprotein X in the serum has been associated with biliary atresia, particularly if it does not diminish following 2 weeks of orally administered cholestyramine. 4 Further experience with these tests will be required before they can be advocated.
435
NEONATAL JAUNDICE AND BILIARY ATRESIA
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Figure 1. Correlation of the severity of portal fibrosis and age in liver biopsy specimens taken from infants with biliary atresia and hepatitis.
Needle biopsy of the liver has also been used to distinguish biliary atresia and cholestatic syndrome. The distinguishing features of biliary atresia are: (1) proliferation of bile ductules in the periportal areas, and (2) periportal fibrosis. Infants with various forms of neonatal hepatitis, including idiopathic cholestatic jaundice, may show a large number of giant cells which probably develop from a coalescence of individual hepatocytes. However, approximately 40 per cent of infants with biliary atresia will show typical hepatic giant cells on biopsy specimens. In our experience, the histologic changes typical for biliary atresia seem to become more evident beyond 2 months of age, and the diagnosis should be clarified before this time (Figs. 1 and 2).6 An experienced pediatric pathologist is required for interpretation. In one series of needle biopsy specimens the pathology diagnosis correlated with the operative findings in 60 per cent of cases; it was equivocal in 16 per cent and in error in 24 per cent. 8 Interpretation of open liver biopsy performed during BIL.E DUCT PROLIFERATION
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436
ALFRED A. DE LORIMIER
abdominal exploration gave a correct diagnosis in 61 per cent; it was equivocal in 39 per cent and in error in 9 per cent of cases. 8 If one of the infections or genetic-metabolic diseases outlined in Tables 1 and 2 is suspected, needle biopsy may be helpful, but in other circumstances it must be interpreted with caution. Percutaneous hepatic cholangiograms might be considered. However, this procedure requires a general anesthetic in infants. In most instances, the bile ducts in infants with either cholestatic jaundice or biliary obstruction are too small to cannulate biliary radicals when they are present. Quantitative studies of bile excretion can be obtained by using radioiodinated Rose Bengal injected intravenously. In normal infants, 75 percent of the isotope is recovered from the stools within 3 days following the injection. Practically none of the infants with biliary atresia excrete more than 10 per cent of the isotope into the bowel, and only 10 per cent of infants with hepatitis excrete less than 10 per cent of the isotope in the bile. 15 This test requires collecting urine and stool over a 72-hour interval after inj ecting radioiodinated Rose Bengal. The isotope is re adily excreted in the urine. Therefore, careful nursing attention is necessary to keep urine and stool specimens separated, and catheterized drainage of the bladder in girls is necessary.
Surgical Treatment Diagnostic laparotomy is indicated in those infants who do not have evidence of an infectious or metabolic cause for the jaundice, and in whom there is persistent lack of bile excretion as indicated by consistent elevation of serum direct bilirubin, lack of pigment in the stool (other than that produced by ingestion of colored foods), and an abnormally low excretion of radio iodinated Rose Bengal in the stool. The time of the exploration should be as early as possible after the discovery of the persistent j aundice to minimize progressive liver damage from the ductal obstruction. Preoperatively, these infants usually have abnormal clotting factors, and they require vitamin K, 2 mg given intramuscularly each day, until the prothrombin time is normal. The infant should not have feedings withheld for more than 5 hours prior to anesthesia to prevent hepatic glycogen depletion. The operative procedure must be conducted expeditiously. An indwelling venous catheter should be placed to infuse 5 per cent dextrose in Ringer's lactate solution to run at a rate of 10 ml per kg per hour during the course of the procedure. This fluid infusion compensates for intra-abdominal third space losses. The baby is given a general anesthetic through an endotracheal tube, and he is positioned over an x-ray film cassette changer. A nasogastric tube should be placed in the stomach. A right upper abdominal transverse incision is preferred, and it should be placed above the edge of the liver. On entering the abdomen the gallbladder is cannulated and aspirated to see ifbile is present. Contrast medium, such as 50 per cent Hypaque, is diluted to one-third the original concentration, and it is instilled into the gallbladder. The volume required is no more than 3 ml, and it should not be forced under high pressure. If the infant has hepatitis, it might minimize hepatic injury by using dilute solution, and it should not be extravasated into hepatic parenchyma. A
NEONATAL JAUNDICE AND BILIARY ATRESIA
437
roentgenogram is obtained immediately after injection, and the presence of intact intrahepatic and extrahepatic ducts is ascertained. While the film is being developed, a wedge biopsy of the liver is obtained. If bile is present in the gallbladder and if the contrast medium has flowed into the duodenum, extrahepatic biliary obstruction is not present, and the abdomen is closed. If there is no bile in the gallbladder, and the contrast medium flows into the duodenum, but does not reflux into the intrahepatic ducts, it will be necessary to repeat the study with a soft, bull-dog clamp placed on the common duct to see if the contrast medium can be refluxed into the intrahepatic ducts. Failure to identify the intrahepatic ducts indicates extrahepatic biliary atresia. In the past fibrous obliteration of the common bile duct, but patency of the right, left, or common hepatic ducts was considered the only form of "correctable" biliary atresia. This finding was described in less than 20 per cent of cases. Most infants were considered incurable, because only fibrous scar and no patent ducts were found grossly. In 1959 Dr. Morio Kasai introduced a more enthusiastic approach in the surgical treatment of biliary atresia. 9 Because of the favorable results described by him and others, the current operative procedure is to dissect all fibrous and ductule tissue in the hepatoduodenalligament off of the portal vein and hepatic artery. The gallbladder and cystic duct are mobilized and the resection of the obliterated ducts extends from the duodenum to the hilum of the liver. This specimen is fixed in its normal relationship and serial sections are obtained for microscopic study at a later time. A Roux-en-Y hepatic portojejunostomy is constructed. The jejunum is transected close to the ligament of Treitz and the distal end is oversewn. An end-to-side porta hepatis anastomosis is made by suturing the jejunum to the liver capsule with an inner layer of continuous, fine, absorbable sutures and an outer layer of interrupted fine silk. The proximal end of the jejunum is then anastomosed to the side of the jejunum 30 cm from the porta hepatis anastomosis (Fig. 3). Some surgeons transect the tissue at the capsule of the liver,- and others remove a core ofliver parenchyma at the porta hepatis. It remains to be documented whether superior long-term results are achieved by dissecting into the liver parenchyma. In an extensive series of patients from various centers in Japan, 40 per cent of these patients had clearing of jaundice. 9 The success of the procedure seems to be dependent upon the size of the bile ducts in the fibrous tissue resected and the age of the patient when operated upon. With rare exception, good excretion of bile occurred only when the bile ducts were greater than 200 micra in diameter within the excised specimen at the porta hepatis. 9 Bile excretion was confined to those infants less than 4 months old, and it was highest when the infants were less than 3 months 01d. 9
Prognosis There are two significant problems following operative repair. First, a major complication is recurrent ascending cholangitis. Second, as these infants are followed for a prolonged period of time, progressive cirrhosis,
438
ALFRED A. DE LORIMIER
KASAl
SURUGA
Figure 3. Two methods for bile drainage in the surgical treatment of biliary atresia. 9 The original procedure by Kasai is shown on the left and the Suruga operation is on the right.
hepatic failure, and portal hypertension continue even though good bile excretion is maintained. In infants, ascending cholangitis is characterized by intermittent high fever, with recurrent or increasing jaundice, abdominal distention, and hepatosplenomegaly. Laboratory tests show leukocytosis with shift to the left, anemia, and deterioration of liver function. There is usually no respiratory or urinary infection, and blood cultures mayor may not grow enteric organisms. The onset of cholangitis occurs within days to months postoperatively, and it usually recurs at a later time following response to antibiotic treatment. Needle biopsy of the liver for bacterial culture has helped in identifying the infecting organism. The cholangitis is frequently fatal, and autopsy reveals numerous intrahepatic bile duct abscesses containing enteric organisms such as E. coli, Klebsiella, Proteus, streptococci, and candida. The problem of recurrent cholangitis prompted some surgeons to modify the standard Roux-en-Y hepatic portojejunostomy. Many surgeons divide the afferent jejunal loop to drain the bile directly to the abdominal wall with the hope of preventing reflux of enteric organisms into the biliary radicals (Fig. 3).9.11 Several months later the external fistula can be taken down and anastomosed to the efferent jejunal limb. The external fistula can be a problem because of considerable fluid, electrolyte, and bile salt loss if good bile drainage is established. On some occasions the secretions have been collected and replaced into the distal jejunal limb. Whether these procedures prevent recurrent cholangitis remains to be proven. There are a number of long-term survivors who have had hepatico-duodenostomy with no more complications of cholangitis than when a Roux-en-Y jejunostomy is used.
NEONATAL JAUNDICE AND BILIARY ATRESIA
439
When an intact gallbladder and distal common duct are present, Kasai has preferred anastomosing the gallbladder to the porta hepatis. 9 The procedure would seem to prevent cholangitis, but Odievre et al. have had problems with bile leak and peritonitis in four of ten infants following this procedure. 12 Because cholangitis is a significant problem, these infants should be treated with antibiotics prophylactically, beginning immediately preoperatively, and continuing for at least 7 days postoperatively. Odievre et al. have given ampicillin for 1 year in a number of their patients. Gentamicin, kanamycin, polymixin, colistin, ampicillin, sulfamethoxazole-trimethoprim and cephalosporins or combinations of these have been effective agents. Frequently, cholangitis recurs upon discontinuing the antibiotics, and continued prophylaxis with oral antibiotics is not always effective. Choleretic agents have been tried, without distinct success. Correctable forms of biliary atresia do not have simple distention of intrahepatic ducts such as seen in older patients with common bile duct stones or stricture. The bile ducts in biliary atresia are distinctly abnormal with alternating areas of constriction and dilatation (Fig. 4). Following operative decompression of the ducts, constriction of the ductules probably occurs, resulting in focal areas of stagnation and abscess formation. In addition to the Japanese investigations, Lilly describes sustained bile drainage in 22 of 34 patients treated from 1972 to 1975.11 Odievre, Valayer, and others have operated upon 49 infants and 31 had good bile
Figure 4. Cholangiogram of a "correctable" form of biliary atresia. No contrast flows into the duodenum. The intrahepatic ducts are abnormal with alternating areas of constriction and dilatation.
440
ALFRED A. DE LORIMIER
flOW. 12 Bile excretion occurred within 2 weeks postoperatively in 14 infants and between 15 and 45 days postoperatively in the others. All the survivors have had cholangitis and/or progressive cirrhosis with portal hypertension. However, Campbell has treated 13 infants, several of whom had transient diminution of bilirubin levels, and bile excretion was not sustained in any ofthem.4 We have performed Kasai's operation in 12 infants before 3 months of age. Three died of cholangitis. Nine have had varying improvement in serum bilirubin levels, but they all have active hepatocellular disease and progressive fibrosis. With the exception of Campbell, most reports indicate improved and prolonged survival in infants treated by these current procedures.4. 11. 12 The longest reported survival is 25 years following hepatic duct duodenostomy.3 This patient and two of four of our own, followed for more than 6 years, have had recurrent cholangitis and intrahepatic calcium bilirubinate stones. Even though numerous complications of ongoing liver disease continue in these patients, hepatic portoenterostomy should be performed, because there is no alternative treatment and long-term survival can be achieved. Liver transplantation should be considered in those patients who develop significant hepatic insufficiency manifested by cholestasis with severe pruritis, progressive cirrhosis with portal hypertension and ascites, and growth failure.
REFERENCES 1. Alagille, D., Odievre, M., Gautier, M., et al.: Hepatic ductularhypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development and cardiac murmur. J. Pediat., 86:63-72,1975. 2. Alpert, L. 1., Strauss, L., and Hirschorn, K.: Neonatal hepatitis and biliary atresia associated with trisomy 17-18 syndrome. N. Eng. J. Med., 280:16-20,1969. 3. Berenson, M. M., Garde, A. R, and Moody, F. G.: Twenty-five year survival after surgery for complete extrahepatic biliary atresia. Gastroenterology, 66:260-263,1974. 4. Campbell, D. P.: Hepatic portoenterostomy. Indicated or not in the treatment of biliary atresia. Am. J.-Dis. Child., 129:1427-1428,1975. 5. Chandra, R. S.: Biliary atresia and other structural anomalies in the congenital polysplenia syndrome . .T. Pediat., 85:649-655, 1974. 6. de Lorimier, A. A., and Witzlebin, C. L.: Unpublished observations. 7. Gross, R E.: Obstructive jaundice in infancy. In: The Surgery ofInfancy and Childhood. Philadelphia; W .. B. Saunders Co., 1953. p. 512. 8. Hays, D. M., Wooley, M. M., Snyder, W. H., et al.: Diagnosis of biliary atresia: Relative accuracy of percutaneous liver biopsy, open liver biopsy and operative cholangiography. J. Pediat., 71 :598-607, 1967. 9. Kasal, M. : Treatment of biliary atresia with special reference to hepatic porto-en terostomy and its modifications. In Bill, A. H., and Kasal, M. (eds.): Biliary Atresia and Choledochal Cyst. New Concepts of Cause and Treatment, Progress in Pediatric Surgery, Vol. 6. Munchen-Berlin-Wien, Urban and Schwarzenberg, 1974, pp. 5-52. 10. Landing, B. H.: Considerations of pathogenesis of neonatal hepatitis, biliary atresia, and choledochal cyst-The concept of infantile obstructive cholangiography. In Bill, A. H., and Kasal, M. (eds.): Biliary Atresia and Choledochal Cysts. New Concepts of Cause and Treatment. Progress in·. Pediatric Surgery, Vol. 6. Munchen-Berlin-Wien, Urban and Schwarzenberg, 1974, pp. 113-"139. 11. Lilly, J. R, Altman, P., Schroter, G., et al.: Surgery of biliary atresia-Current status. Am. J. Dis. Child., 129:1429-1431, 1975. 12. Odievre, M., Valayer, J., Razmon-Pinta, M., et al.: Hepatic porto-enterostomy in the treatment of extrahepatic biliary atresia. J. Pediat., 88 :774-779, 1976.
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13. Porter, S. D., Soper, R. T., and Tidrick, R. T.: Biliary hypoplasia. Ann. Surg., 167:602-608, 1968. 14. Pickham, P. P.: Neonatal biliary obstruction. In Pickham, P. P., and Johnston, J. M., (eds.): Neonatal Surgery. New York, Appleton, Century-Crofts, 1963, p. 427. 15. Sass-Kortsak, A.: Management of young infants presenting with direct-reacting hyperbilirubinemia. Ped. Clin. N. Am., 21 :777-799, 1974. Pediatric Surgery Service University of California, San Francisco, School of Medicine San Francisco, California 94143
Neonatal Jaundice and Biliary Atresia Alfred A. de Lorimier, M.D.*
The differential diagnosis of jaundice in the newborn remains a difficult problem. Many disease entities are eliminated when the serum bilirubin fraction is almost exclusively the indirect, unconjugated form. However, cholestatic jaundice, associated with direct, conjugated hyperbilirubinemia, is not exclusively due to bile duct obstruction. Approximately 30 per cent of infants with cholestatic jaundice have primary hepatocellular disease, with patent bile ducts. Therefore, careful clinical and laboratory evaluation of the infant is required before he is surgically explored to treat presumed biliary atresia. In the past, only 5 per cent of infants were found to have a "curable" form of biliary atresia. Currently, a newer operative approach of hepatic portoenterostomy has been advocated to enhance the curability of biliary atresia. This article reviews the differential diagnosis of jaundice in the newborn, and the operative treatment of biliary atresia.
NEONATAL JAUNDICE Persistent jaundice in infancy after the first 3 weeks oflife, in which the direct bilirubin accounts for more than 30 per cent of the total bilirubin level, suggests bile duct obstruction requiring surgical attention. However, there are a number of nonsurgical diseases producing abnormally high serum conjugated bilirubin levels, and the differential diagnosis is important. Causes of prolonged cholestatic jaundice include: 1. Infections; viral, bacterial or parasitic 2. Genetic-metabolic diseases; alpha anti-trypsin deficiency, galactosemia, hereditary fructosemia, hereditary tyrosinemia, cystic fibrosis, Niemann-Pick disease 3. Neonatal hepatitis (idiopathic cholestatic jaundice of infancy) 4. Intrahepatic biliary atresia and hypoplasia 5. Extrahepatic biliary atresia and hypoplasia 6. Choledochal cyst 7. Bile duct stricture
Tables 1 and 2, taken from Sass-Kortsak, identify some of the features that characterize infections and genetic-metabolic causes of jaundice in infancy.1s 'Associate Professor of Surgery, Pediatric Surgery Service, University of California, San Francisco, School of Medicine, San Francisco, California
Surgical Clinics of North America-Vol. 57, No.2, April 1977
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Table 1. Infections Leading to Conjugated Hyperbilirubinemia in Early Infancy SCREENING TESTS IN BOTH
USUAL MODE OF AGENT
INFECTION
Cytomegalovirus
Transplacental
Rubella virus
Transplacental
Hepatitis B virus
Intrapartum, transfusion
Herpes simplex
Intrapartum or immediate post partum
OTHER MANIFESTATIONS
Low birth weight, micro- or hydrocephaly, intracranial calcifications, chorioretinitis, enteritis, pneumonitis, thrombocytopenia, . hemolytic anemia, myocarditis. Low birth weight, congestive heart disease, cataracts, microphthalmia, glaucoma, deafuess, bone lesions, microcephaly, thrombocytopenia, anemia. No other systemic involvement reported as yet in young infants. Skin or mucous membrane vesicles, encephalitis, cerebral calcifications, chorioretinitis, keratoconjunctivitis, pneumonitis, thrombocytopenia, coagulopathy.
MOTHER AND INFANT
DEFINITIVE DIAGNOSIS
CF antibody in serum
Isolation from urine and from liver. Demonstration of virus in liver by IF. Specific IgM antibody.
CF and HI antibodies, in serum
Isolation of virus from nasopharyngeal secretions of liver. Demonstration of virus in liver by IF. Specific IgM antibody.
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Hepatitis B antigen in infant, antigen and antibody in mother. Perinatal herpes in mother, or attendants. Serology and demonstration of virus in herpeslike lesions.
As for screening + demonstration ofHB antigen in liver by IF and EM.
Isolation or demonstration of virus from superficial lesions and liver. Specific IgM antibody.
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Coxsackie B virus
Transplacental
Meningoencephalitis, myocarditis, thrombocytopenia.
Varicella-zoster virus
Transplacental
Varicella rash, pneumonitis, other visceral involvement.
Bacterial sepsis (E. Coli, other enteric bacteria, staphylococcus, etc.) Treponema pallidum Toxoplasma gondii
Intrapartum or postnatal
Lethargy, labile temperature, fever, weight loss, pallor, anemia, vomiting, diarrhea, pyuria, meningitis, etc.
Abbreviations:
Serology of very limited value. Isolation from respiratory secretions and feces. CF antibody in serum. Demonstration of virus in superficial lesions. High white blood cell count, shift to left, pyuria, anemia without reticulocytosis.
Isolation of virus from liver.
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Transplacental Transplacental
Rhinitis, rash, bone lesions, lymphadenopathy, anemia. Micro- or hydrocephaly, intracranial calcifications, chorioretinitis, microphthalmia, thrombocytopenia, anemia, skin hemorrhages.
CF = complement fixing HI = hemagglutination inhibition IF = immunofluorescence microscopy EM = electronmicroscopy.
VDRL or TPI, particularly in mother. CF antibody in serum, SabinFeldman dye test, titre in excess of 1:1000.
Dark field examination of exudates for treponema. Rising antibody titres in infant. Isolation by culture from liver, CSF, eye. Specific IgM antibody.
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Table 2. Genetic-Metabolic Diseases Leading to Conjugated Hyperbilirubinemia in Early Infancy MODE OF
ADDITIONAL
CONDITION
INHERITANCE
CLINICAL MANIFESTATIONS
Alpha, antitrypsin deficiency
Autosomal recessive
Neonatal hepatitis syndrome.
Galactosemia (transferase deficiency)
Autosomal recessive
Hereditary fructose intolerance
Autosomal recessive
Hereditary tyrosinemia
Autosomal recessive
Fibrocystic disease
Autosomal recessive
Failure to thrive, gastrointestinal symptoms. Cataracts, renal tubular defect, hypoglucosemia. Onset of vomiting, diarrhea, weight loss with introduction of fructose (fruit and/or sucrose) in diet. Renal tubular defects. Hypoglucosemia. Failure to thrive, vomiting, diarrhea, rickets, renal tubular defects, hypoglucosemia. Failure to thrive, meconium ileus, malabsorption, pulmonary infections. Failure to thrive, cherry-red spots, CNS later.
Nieman-Pick's disease, Type A & B
Autosomal recessive
SCREENING TESTS
DEFINITIVE DIAGNOSIS
Serum protein electrophoresis: absent alpha globulin peak.
Protease inhibitor typing. Quantitative a, AT measurement in serum. Red cell galactose-I-P0 4 uridyl transferase assay. .
j
Reducing sugar in urine identifiable as galactose while patient on milk feeding. Reducing sugar in urine identifiable as fructose while patient receives fructose or sucrose.
Fructose tolerance test (dangerous). Liver fructose-I-PO. aldolase activity.
High plasma tyrosine + methionine, aminoaciduria, tyrosyluria. Digestive enzymes in feces or duodenal juice.
p-Hydroxyphenylpyruvic acid oxidase in liver?
Foam cells in bone marrow.
Sphingomyelinase assay in leukocytes, cultured fibroblasts, liver tissue.
Sweat chloride concentration.
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NEONATAL JAUNDICE AND BILIARY ATRESIA
433
Our inability to identify the specific causes and the pathogenesis for idiopathic cholestatic jaundice, intrahepatic and extrahepatic biliary atresia and hypoplasia, and choledochal cyst accounts for a great deal of confusion about these entities. There are probably many causative agents, and a number of the currently known infections and metabolic diseases were formerly in the group referred to as neonatal hepatitis. In our efforts to simplify matters it is appealing to consider a unifying concept that links neonatal hepatitis, intrahepatic and extrahepatic biliary atresia or hypoplasia as a clinical spectrum of the same phenomenon. 1o The reasons for this include: (1) the difficulty in defining each entity biochemically and histologically, and (2) some patients, who had "neonatal hepatitis" and intact bile ducts initially, subsequently developed intrahepatic or extrahepatic biliary atresia later in the course of the disease.
BILIARY ATRESIA Definition Intrahepatic atresia is associated with intact and patent extrahepatic bile ducts, but liver biopsy shows minimal inflammatory reaction and fibrosis, and markedly diminished or absent intrahepatic bile ducts. These children tend to live for a prolonged time (3-20 years) with lowgrade or intermittent jaundice. They have high serum bile salt, cholesterol, and alkaline phosphatase levels, and they develop intense pruritis. In time subcutaneous xanthomata appear in the skin creases of the extremities and face. Confusion occurs here, because some patients with extrahepatic biliary atresia will develop the same clinical and histologic features described above. Extrahepatic biliary atresia is characterized by a fibrous replacement of the normal bile duct channels in the hepatoduodenalligament and within the liver. Varying degrees oflow-grade inflammatory reaction are usually present in the fibrous strands and adjacent tissues. Very rarely, the process involves only a short segment of the distal bile ducts. More commonly, the ducts proximal to the cystic duct are obliterated, and the gallbladder, cystic duct, and common bile duct are patent. The most frequent finding is complete replacement of the ducts by a dense fibrous, desmoplastic reaction from the duodenum to the liver hilus, including the gallbladder. The bile duct epithelium is either absent or in isolated strands. No muscular cells are seen. Extrahepatic biliary atresia is a misnomer, because the obliterative, fibrous process invariably affects the ducts within the liver. "Correctable" biliary atresia exists when there are patent hepatic ducts extending into the liver. 7 If the hepatic ducts are not patent, the lesion has been considered "incorrectable."5 Again confusion arises, because in many instances of apparently "correctable" biliary atresia, a bile duct-enteric anastomosis may not result in any bile drainage, no doubt because of extensively obliterated intrahepatic ducts. Kasai has shown that in many cases of apparently "incorrectable" biliary atresia, totally obliterated extrahepatic ducts have had excellent drainage by anastomosing bowel to the porta hepatis. 9
434
ALFRED A. DE LORIMIER
Extrahepatic biliary hypoplasia is characterized by cholestatic jaundice, but the bile ducts are patent and very narrow. Usually the bile duct walls are fibrotic. In Kasai's histologic studies of resected "incorrectable" bile duct specimens, he found that bile excretion occurred where the resected specimen showed isolated ductal structures greater than 200 micra in diameter. 9 Therefore, it might be said that these are examples of biliary hypoplasia rather than atresia. Choledochal cyst with biliary atresia may be found in 10 to 30 per cent of these infants. The common bile and/or hepatic ducts are large and dilated with atresia distally. The duct walls have the thick, fibrous, and inflammatory reaction, as described above. However, these infants, who are jaundiced from early infancy, usually develop the same clinical course as seen in biliary atresia, and they do not have the more uncomplicated course of choledochal cyst found in later infancy and childhood. There is extensive intrahepatic fibrosis which seems to progress with time. Therefore, these patients should be considered to have biliary atresia with dilated extrahepatic bile ducts, and not choledochal cyst disease. Clinical Evaluation A history should be elicited from the parents of infants with jaundice about hepatitis, familial diseases or active genital infection. The findings of Down's syndrome or trisomy 17-18 may be associated with biliary atresia or neonatal hepatitis. 2 The Porter-Alagille syndrome of hepatic duct hypoplasia is associated with characteristic facies, vertebral and cardiac malformations, and retarded development. I. 13 Biliary atresia is also associated with other congenital malformations in 10 to 30 per cent of cases, such as congenital heart lesions, myelomeningocele, and the polysplenia syndrome. 5-14 The physical finding that suggests biliary duct obstruction is the presence of an enlarged, firm liver with a blunt, slightly irregular margin. The enlarged liver associated with other causes has a relatively soft, sharp edge in the first several months of life. Laboratory tests usually do not clearly establish the cause for the jaundice. The stools should be observed for evidence of bile excretion which would indicate intrahepatic, not extrahepatic, cholestasis. However, pigment in foods will obscure the lack of bile pigment in the stools. In biliary atresia the total serum bilirubin is usually in excess of 8 mg per cent, but less than 15 mg per cent. The direct bilirubin is usually less than 5 mg per cent in infants with intrahepatic cholestasis. A very high serum alkaline phosphatase or cholesterol level suggest biliary duct obstruction, but these elevated values usually occur after 4 to 5 months of age. The transaminases, lactic dehydrogenase, and leucine aminopeptidase values suggest hepatitis when they are markedly elevated. Some newer tests have been advocated which might help differentiate intrahepatic cholestasis, and above this level identify the likelihood of biliary atresia. 15 The presence of lipoprotein X in the serum has been associated with biliary atresia, particularly if it does not diminish following 2 weeks of orally administered cholestyramine. 4 Further experience with these tests will be required before they can be advocated.
435
NEONATAL JAUNDICE AND BILIARY ATRESIA
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HEPATITIS • BILIAR.Y ATRESIA
PORTAL FIBROSIS
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Figure 1. Correlation of the severity of portal fibrosis and age in liver biopsy specimens taken from infants with biliary atresia and hepatitis.
Needle biopsy of the liver has also been used to distinguish biliary atresia and cholestatic syndrome. The distinguishing features of biliary atresia are: (1) proliferation of bile ductules in the periportal areas, and (2) periportal fibrosis. Infants with various forms of neonatal hepatitis, including idiopathic cholestatic jaundice, may show a large number of giant cells which probably develop from a coalescence of individual hepatocytes. However, approximately 40 per cent of infants with biliary atresia will show typical hepatic giant cells on biopsy specimens. In our experience, the histologic changes typical for biliary atresia seem to become more evident beyond 2 months of age, and the diagnosis should be clarified before this time (Figs. 1 and 2).6 An experienced pediatric pathologist is required for interpretation. In one series of needle biopsy specimens the pathology diagnosis correlated with the operative findings in 60 per cent of cases; it was equivocal in 16 per cent and in error in 24 per cent. 8 Interpretation of open liver biopsy performed during BIL.E DUCT PROLIFERATION
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436
ALFRED A. DE LORIMIER
abdominal exploration gave a correct diagnosis in 61 per cent; it was equivocal in 39 per cent and in error in 9 per cent of cases. 8 If one of the infections or genetic-metabolic diseases outlined in Tables 1 and 2 is suspected, needle biopsy may be helpful, but in other circumstances it must be interpreted with caution. Percutaneous hepatic cholangiograms might be considered. However, this procedure requires a general anesthetic in infants. In most instances, the bile ducts in infants with either cholestatic jaundice or biliary obstruction are too small to cannulate biliary radicals when they are present. Quantitative studies of bile excretion can be obtained by using radioiodinated Rose Bengal injected intravenously. In normal infants, 75 percent of the isotope is recovered from the stools within 3 days following the injection. Practically none of the infants with biliary atresia excrete more than 10 per cent of the isotope into the bowel, and only 10 per cent of infants with hepatitis excrete less than 10 per cent of the isotope in the bile. 15 This test requires collecting urine and stool over a 72-hour interval after inj ecting radioiodinated Rose Bengal. The isotope is re adily excreted in the urine. Therefore, careful nursing attention is necessary to keep urine and stool specimens separated, and catheterized drainage of the bladder in girls is necessary.
Surgical Treatment Diagnostic laparotomy is indicated in those infants who do not have evidence of an infectious or metabolic cause for the jaundice, and in whom there is persistent lack of bile excretion as indicated by consistent elevation of serum direct bilirubin, lack of pigment in the stool (other than that produced by ingestion of colored foods), and an abnormally low excretion of radio iodinated Rose Bengal in the stool. The time of the exploration should be as early as possible after the discovery of the persistent j aundice to minimize progressive liver damage from the ductal obstruction. Preoperatively, these infants usually have abnormal clotting factors, and they require vitamin K, 2 mg given intramuscularly each day, until the prothrombin time is normal. The infant should not have feedings withheld for more than 5 hours prior to anesthesia to prevent hepatic glycogen depletion. The operative procedure must be conducted expeditiously. An indwelling venous catheter should be placed to infuse 5 per cent dextrose in Ringer's lactate solution to run at a rate of 10 ml per kg per hour during the course of the procedure. This fluid infusion compensates for intra-abdominal third space losses. The baby is given a general anesthetic through an endotracheal tube, and he is positioned over an x-ray film cassette changer. A nasogastric tube should be placed in the stomach. A right upper abdominal transverse incision is preferred, and it should be placed above the edge of the liver. On entering the abdomen the gallbladder is cannulated and aspirated to see ifbile is present. Contrast medium, such as 50 per cent Hypaque, is diluted to one-third the original concentration, and it is instilled into the gallbladder. The volume required is no more than 3 ml, and it should not be forced under high pressure. If the infant has hepatitis, it might minimize hepatic injury by using dilute solution, and it should not be extravasated into hepatic parenchyma. A
NEONATAL JAUNDICE AND BILIARY ATRESIA
437
roentgenogram is obtained immediately after injection, and the presence of intact intrahepatic and extrahepatic ducts is ascertained. While the film is being developed, a wedge biopsy of the liver is obtained. If bile is present in the gallbladder and if the contrast medium has flowed into the duodenum, extrahepatic biliary obstruction is not present, and the abdomen is closed. If there is no bile in the gallbladder, and the contrast medium flows into the duodenum, but does not reflux into the intrahepatic ducts, it will be necessary to repeat the study with a soft, bull-dog clamp placed on the common duct to see if the contrast medium can be refluxed into the intrahepatic ducts. Failure to identify the intrahepatic ducts indicates extrahepatic biliary atresia. In the past fibrous obliteration of the common bile duct, but patency of the right, left, or common hepatic ducts was considered the only form of "correctable" biliary atresia. This finding was described in less than 20 per cent of cases. Most infants were considered incurable, because only fibrous scar and no patent ducts were found grossly. In 1959 Dr. Morio Kasai introduced a more enthusiastic approach in the surgical treatment of biliary atresia. 9 Because of the favorable results described by him and others, the current operative procedure is to dissect all fibrous and ductule tissue in the hepatoduodenalligament off of the portal vein and hepatic artery. The gallbladder and cystic duct are mobilized and the resection of the obliterated ducts extends from the duodenum to the hilum of the liver. This specimen is fixed in its normal relationship and serial sections are obtained for microscopic study at a later time. A Roux-en-Y hepatic portojejunostomy is constructed. The jejunum is transected close to the ligament of Treitz and the distal end is oversewn. An end-to-side porta hepatis anastomosis is made by suturing the jejunum to the liver capsule with an inner layer of continuous, fine, absorbable sutures and an outer layer of interrupted fine silk. The proximal end of the jejunum is then anastomosed to the side of the jejunum 30 cm from the porta hepatis anastomosis (Fig. 3). Some surgeons transect the tissue at the capsule of the liver,- and others remove a core ofliver parenchyma at the porta hepatis. It remains to be documented whether superior long-term results are achieved by dissecting into the liver parenchyma. In an extensive series of patients from various centers in Japan, 40 per cent of these patients had clearing of jaundice. 9 The success of the procedure seems to be dependent upon the size of the bile ducts in the fibrous tissue resected and the age of the patient when operated upon. With rare exception, good excretion of bile occurred only when the bile ducts were greater than 200 micra in diameter within the excised specimen at the porta hepatis. 9 Bile excretion was confined to those infants less than 4 months old, and it was highest when the infants were less than 3 months 01d. 9
Prognosis There are two significant problems following operative repair. First, a major complication is recurrent ascending cholangitis. Second, as these infants are followed for a prolonged period of time, progressive cirrhosis,
438
ALFRED A. DE LORIMIER
KASAl
SURUGA
Figure 3. Two methods for bile drainage in the surgical treatment of biliary atresia. 9 The original procedure by Kasai is shown on the left and the Suruga operation is on the right.
hepatic failure, and portal hypertension continue even though good bile excretion is maintained. In infants, ascending cholangitis is characterized by intermittent high fever, with recurrent or increasing jaundice, abdominal distention, and hepatosplenomegaly. Laboratory tests show leukocytosis with shift to the left, anemia, and deterioration of liver function. There is usually no respiratory or urinary infection, and blood cultures mayor may not grow enteric organisms. The onset of cholangitis occurs within days to months postoperatively, and it usually recurs at a later time following response to antibiotic treatment. Needle biopsy of the liver for bacterial culture has helped in identifying the infecting organism. The cholangitis is frequently fatal, and autopsy reveals numerous intrahepatic bile duct abscesses containing enteric organisms such as E. coli, Klebsiella, Proteus, streptococci, and candida. The problem of recurrent cholangitis prompted some surgeons to modify the standard Roux-en-Y hepatic portojejunostomy. Many surgeons divide the afferent jejunal loop to drain the bile directly to the abdominal wall with the hope of preventing reflux of enteric organisms into the biliary radicals (Fig. 3).9.11 Several months later the external fistula can be taken down and anastomosed to the efferent jejunal limb. The external fistula can be a problem because of considerable fluid, electrolyte, and bile salt loss if good bile drainage is established. On some occasions the secretions have been collected and replaced into the distal jejunal limb. Whether these procedures prevent recurrent cholangitis remains to be proven. There are a number of long-term survivors who have had hepatico-duodenostomy with no more complications of cholangitis than when a Roux-en-Y jejunostomy is used.
NEONATAL JAUNDICE AND BILIARY ATRESIA
439
When an intact gallbladder and distal common duct are present, Kasai has preferred anastomosing the gallbladder to the porta hepatis. 9 The procedure would seem to prevent cholangitis, but Odievre et al. have had problems with bile leak and peritonitis in four of ten infants following this procedure. 12 Because cholangitis is a significant problem, these infants should be treated with antibiotics prophylactically, beginning immediately preoperatively, and continuing for at least 7 days postoperatively. Odievre et al. have given ampicillin for 1 year in a number of their patients. Gentamicin, kanamycin, polymixin, colistin, ampicillin, sulfamethoxazole-trimethoprim and cephalosporins or combinations of these have been effective agents. Frequently, cholangitis recurs upon discontinuing the antibiotics, and continued prophylaxis with oral antibiotics is not always effective. Choleretic agents have been tried, without distinct success. Correctable forms of biliary atresia do not have simple distention of intrahepatic ducts such as seen in older patients with common bile duct stones or stricture. The bile ducts in biliary atresia are distinctly abnormal with alternating areas of constriction and dilatation (Fig. 4). Following operative decompression of the ducts, constriction of the ductules probably occurs, resulting in focal areas of stagnation and abscess formation. In addition to the Japanese investigations, Lilly describes sustained bile drainage in 22 of 34 patients treated from 1972 to 1975.11 Odievre, Valayer, and others have operated upon 49 infants and 31 had good bile
Figure 4. Cholangiogram of a "correctable" form of biliary atresia. No contrast flows into the duodenum. The intrahepatic ducts are abnormal with alternating areas of constriction and dilatation.
440
ALFRED A. DE LORIMIER
flOW. 12 Bile excretion occurred within 2 weeks postoperatively in 14 infants and between 15 and 45 days postoperatively in the others. All the survivors have had cholangitis and/or progressive cirrhosis with portal hypertension. However, Campbell has treated 13 infants, several of whom had transient diminution of bilirubin levels, and bile excretion was not sustained in any ofthem.4 We have performed Kasai's operation in 12 infants before 3 months of age. Three died of cholangitis. Nine have had varying improvement in serum bilirubin levels, but they all have active hepatocellular disease and progressive fibrosis. With the exception of Campbell, most reports indicate improved and prolonged survival in infants treated by these current procedures.4. 11. 12 The longest reported survival is 25 years following hepatic duct duodenostomy.3 This patient and two of four of our own, followed for more than 6 years, have had recurrent cholangitis and intrahepatic calcium bilirubinate stones. Even though numerous complications of ongoing liver disease continue in these patients, hepatic portoenterostomy should be performed, because there is no alternative treatment and long-term survival can be achieved. Liver transplantation should be considered in those patients who develop significant hepatic insufficiency manifested by cholestasis with severe pruritis, progressive cirrhosis with portal hypertension and ascites, and growth failure.
REFERENCES 1. Alagille, D., Odievre, M., Gautier, M., et al.: Hepatic ductularhypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development and cardiac murmur. J. Pediat., 86:63-72,1975. 2. Alpert, L. 1., Strauss, L., and Hirschorn, K.: Neonatal hepatitis and biliary atresia associated with trisomy 17-18 syndrome. N. Eng. J. Med., 280:16-20,1969. 3. Berenson, M. M., Garde, A. R, and Moody, F. G.: Twenty-five year survival after surgery for complete extrahepatic biliary atresia. Gastroenterology, 66:260-263,1974. 4. Campbell, D. P.: Hepatic portoenterostomy. Indicated or not in the treatment of biliary atresia. Am. J.-Dis. Child., 129:1427-1428,1975. 5. Chandra, R. S.: Biliary atresia and other structural anomalies in the congenital polysplenia syndrome . .T. Pediat., 85:649-655, 1974. 6. de Lorimier, A. A., and Witzlebin, C. L.: Unpublished observations. 7. Gross, R E.: Obstructive jaundice in infancy. In: The Surgery ofInfancy and Childhood. Philadelphia; W .. B. Saunders Co., 1953. p. 512. 8. Hays, D. M., Wooley, M. M., Snyder, W. H., et al.: Diagnosis of biliary atresia: Relative accuracy of percutaneous liver biopsy, open liver biopsy and operative cholangiography. J. Pediat., 71 :598-607, 1967. 9. Kasal, M. : Treatment of biliary atresia with special reference to hepatic porto-en terostomy and its modifications. In Bill, A. H., and Kasal, M. (eds.): Biliary Atresia and Choledochal Cyst. New Concepts of Cause and Treatment, Progress in Pediatric Surgery, Vol. 6. Munchen-Berlin-Wien, Urban and Schwarzenberg, 1974, pp. 5-52. 10. Landing, B. H.: Considerations of pathogenesis of neonatal hepatitis, biliary atresia, and choledochal cyst-The concept of infantile obstructive cholangiography. In Bill, A. H., and Kasal, M. (eds.): Biliary Atresia and Choledochal Cysts. New Concepts of Cause and Treatment. Progress in·. Pediatric Surgery, Vol. 6. Munchen-Berlin-Wien, Urban and Schwarzenberg, 1974, pp. 113-"139. 11. Lilly, J. R, Altman, P., Schroter, G., et al.: Surgery of biliary atresia-Current status. Am. J. Dis. Child., 129:1429-1431, 1975. 12. Odievre, M., Valayer, J., Razmon-Pinta, M., et al.: Hepatic porto-enterostomy in the treatment of extrahepatic biliary atresia. J. Pediat., 88 :774-779, 1976.
NEONATAL JAUNDICE AND BILIARY ATRESIA
441
13. Porter, S. D., Soper, R. T., and Tidrick, R. T.: Biliary hypoplasia. Ann. Surg., 167:602-608, 1968. 14. Pickham, P. P.: Neonatal biliary obstruction. In Pickham, P. P., and Johnston, J. M., (eds.): Neonatal Surgery. New York, Appleton, Century-Crofts, 1963, p. 427. 15. Sass-Kortsak, A.: Management of young infants presenting with direct-reacting hyperbilirubinemia. Ped. Clin. N. Am., 21 :777-799, 1974. Pediatric Surgery Service University of California, San Francisco, School of Medicine San Francisco, California 94143