In 1977 we advocated surgical correction for infants with extrahepatic biliary atresia.1 In the ensuing 8 years it has been established that bile drainage can be accomplished for most infants operated on before the age of 3 months. Unfortunately, the prediction that the provision of bile drainage does not necessarily translate into cure has also been confirmed. We will review here the results of surgical treatment for 100 patients having Kasai's portoenterostomy for biliary atresia emphasizing the essentials of diagnosis and surgery, the problem of postoperative cholangitis, and the importance of meticulous attention to the nutritional and metabolic aspects of patient care.
It is important to distinguish, in an expeditious and costeffective way, those infants with biliary atresia from those with jaundice secondary to intrahepatic cholestasis. With the application of newer imaging modalities the recognition of the infant with extrahepatic biliary atresia is not difficult. Although there has been a proliferation of diagnostic studies purporting to distinguish between obstruction and cholestasis, in fact, no test nor combination of studies is absolutely reliable.2 In our center, isotope scanning with ^sup 99m^Tc-IDA has become the "gold standard" diagnostic study (Figures 1A, 1B). Pretreatment with phenobarbital (5mg/kg/d, for 5 to 7 days) enhances excretion of isotope in infants with cholestasis and increases the accuracy of the study.3 Using correlative percutaneous needle biopsy of the liver, the diagnosis of extrahepatic biliary atresia or cholestatic syndrome can be established in virtually every instance. For the infant with persistent hyperbilirubinemia (direct bilirubin > 2 mg/ dl for over 2 weeks) in whom the common metabolic and infectious etiologies have been excluded, we have adopted the protocol outlined in the Table. All patients are screened for alpha, antitrypsin deficiency since it is known that this inherited metabolic condition can present in infancy as mixed jaundice.4
The histopathology of the obliterative process, biliary atresia, accounts for the success of Kasai's operation.5 The bile ducts are not absent. Rather, they are present as fibrous cords. Usually, but not always, the entire extrahepatic duct system is identifiable. Even if there is discontinuity of these structures there always remains fibrous tissue at the porta hepacis which invests microscopically patent biliary ductules.6 These minutely patent structures in turn communicate with the intrahepatic duct system. Transecting this fibrous tissue opens these channels. By anastomosing a segment of intestine (jejunum) to the periductal connective tissue, bile can flow from the liver through these ductules into the conduit. The surgically created biliary conduit is usually vented externally, at least temporarily, on the premise that reflux of intestinal content is diminished and the risk of cholangitis lessened. Many surgical venting procedures have been devised.7 None is completely protective.
Particularly during the first 2 years following the Kasai operation, cholangitis occurs in over half the patients and deterioration of liver function with progression to cirrhosis is accelerated by repeated bouts of inflammation and infection in the biliary system.8 The diagnosis of the typical case of cholangitis is not difficult: the patient develops fever, usually spiking, and is irritable and lethargic. Anorexia, increased abdominal distention, ascites, and deepening jaundice can develop in a matter of days. Elevation of the alkaline phosphatase, transaminases and gamma-glutamyl transpeptidase above baseline, leukocytosis and high ESR are frequently present and help confirm the diagnosis. Blood cultures are often negative, although the patients may appear septic.
The diagnosis can be confirmed by percutaneous needle biopsy of the liver. The pathologie/histologie features include acute inflammatory infiltrates in the portal and periportal areas including involvement of the biliary duct epithelium and, in the more severe cases, microabscess formation. Biopsies are not performed routinely and have not always yielded the infective organism. Enteric gram-negative and anaerobic bacteria have been isolated most frequently.9 The mechanism of invasion of the liver remains unclear but may be related to decreased reticuloendothelial system function from the underlying cirrhosis or from the abnormal liver perfusion and/or compromised lymphatic drainage. Treatment consists of broad spectrum intravenous antibiotic coverage, usually Ampicillin, plus an aminoglycoside with or without Clindamycin. l0 Depending upon the severity of the illness and the degree of recurrent cholestasis, a brief course of steroids has been tried empirically in an attempt to diminish the edema at the anastomosis and, perhaps, minimize the damage to the liver parenchyma. The use of steroids in this context has never been critically evaluated and remains an empiric measure.
Figure 1. At Normal ^sup 99m^Tc-IDA scan. At 35 minutes the gallbladder is seen (arrow). Radionuclide has been excreted from the liver into the intestine before I hour. Bt There has been no excretion of isotope from the liver into the gastrointestinal tract. This finding, after suitable treatment with phenobarbital has almost invariably been diagnostic of biliary atresia.
CHOLESTASIS VS. BILIARY ATRESIA
Consequent to recurrent or refractory infection, bile flow diminishes and in some instances may cease completely. Obstruction to bile flow secondary to inflammation and scar at the portal anastomosis takes its toll on the liver and accelerates hepatic decompensation. Intervention by endoscopic debridement through the vented conduit or by laparotomy with resectional debridement and revision of the portoenterostomy anastomosis has succeeded in rescuing several patients in whom there was cessation of bile flow consequent to cholangitis.11,12 We advocate anastomotic debridement for the patient in whom the initial operation succeeds in establishing bile flow and the bilirubin returns to normal or near normal levels. We are less enthusiastic about reoperation for the patient in whom an initial operation, properly performed, fails to provide bile drainage or for the patient in whom bile flow is established but the volume is scanty and the bilirubin remains elevated.
MANAGEMENT CONSIDERATIONS IN BILIARY ATRESIA
During the immediate postoperative period attention is focused on the resumption of bile flow. In most patients the serum bilirubin concentration actually increases after surgery and it may take 2 or 3 weeks for it to return to preoperative levels. When the operation succeeds, bile flow is established by the time the patient leaves the hospital, usually within 10 to 14 days. During this time the parents are instructed in the technique of returning the bile into the efferent intestinal loop if an exteriorized conduit was created. Normalization of the serum bilirubin does not occur for several months and elevated transaminases and gamma glutamyl transpeptidase persists for months or years after surgery in the majority of patients. The major concerns in the longterm management of patients with corrected biliary atresia are: 1) maintenance of nutritional state; 2) stimulation of bile flow by pharmacologic means; and 3) prevention of cholangitis.
Somewhat surprising is the observation that most infants with biliary atresia gain weight normally in the weeks preceding diagnosis. No major differences are noted between infants consuming breast milk or a proprietary formula, suggesting that in the early stages both butterfat and vegetable oil are reasonably well absorbed. This may reflect the progressive nature of the process since about one- third of the patients excrete bile pigment initially before the stools become consistently clay colored.
Subsequent weight gain can be more of a problem even if adequate bile flow is established.13 Attempts to improve caloric intake with the use of a medium chain triglyceride (MCT)-containing formula or with MCT supplements have been disappointing in our experience, although others have expressed more enthusiasm.14 Most infants refuse to ingest the formula, perhaps because of its unpleasant flavor. Early introduction of cereal and other carbohydrate-rich foodstuffs is better tolerated and is encouraged. We routinely administer aqueous preparations of the fat soluble vitamins A (5,000 IU daily) and D (Ergocalciferol, vitamin D2 5,000 to 10,000 IU daily).
An appreciation of the importance of vitamin E in preventing neurologic sequelae in children with chronic cholestasis has led to more careful monitoring of this vitamin. 15 To assess vitamin E status in the presence of elevated serum lipids (cholesterol, phospholipids, and triglycerides) the ratio of serum vitamin E concentration to total lipids is preferred. Determination of vitamin E concentrations in adipose tissue obtained by a simple needle aspiration technique has allowed more accurate evaluation of vitamin E status. Nerve conduction abnormalities are detectable well before clinical signs of deficiency are apparent and confirmation of the diagnosis of chronic viramin E neuropathy can be obtained by peripheral nerve biopsy. ,6 The earliest sign of vitamin E deficiency is the loss of tendon reflexes and proprioceptive sense. In more advanced cases eye muscle paralysis, blindness, and ataxia develop. If effective treatment is undertaken before the age of 3 years these abnormalities can be prevented and in some instances reversed. After age 3 the damage may not be reversible.
When the biliary conduit has been exteriorized measured volumes of 300 to 800ml/day are not unusual. A systematic evaluation of the effects of biliary diversion on the physicochemical properties of bile and the nutritional consequences of biliary diversion has been carried out in five patients. Despite good bile flow in all subjects, total bile salt output varied widely during the day and was often below the minimum micellar concentration. Bile is generally returned to the intestine immediately before a feeding, but even with the theoretic advantage of having bile present for fat digestion and absorption, poor weight gain was the rule. Following closure of the enterostomy a dramatic improvement in weight gain, as seen in Figure 2, was demonstrated in four of the five patients. The advantages of exteriorized drainage in decreasing postoperative cholangitis must be weighed against the nutritional consequences of bile diversion.
Pharmacologic Stimulation of Bile Flow
It is commonly accepted that phenobarbital stimulates the bile-salt independent fraction of bile flow. 17 As mentioned earlier, advantage is taken of this effect in order to optimize the yield of the diagnostic IDA scan. Phenobarbital has also been found useful in the treatment of cholestasisassociated pruritus in an occasional patient.18 Unfortunately, the effect can be transient and unpredictable. Whether the systemic relief is due to the sedative effect of the medication or to its choleretic properties is difficult to establish, particularly since no biochemical marker has been found which correlates with pruritus or explains its cause.
Studies in our patients with cutaneous enterostomies have failed to demonstrate a stimulatory effect of phenobarbital. 19 The underlying pathology in the liver, with chronic cholestasis as reflected by persistently abnormal biochemical indices can account for this inability to augment bile flow. Considering the multitude of other effects of phenobarbital on the central nervous system and the hepatic microsomal enzyme systems, routine use of this medication in patients with biliary atresia should be reconsidered. The beneficial effect of phenobarbital in decreasing jaundice and improving disabling pruritus has been more consistent in cases of intrahepatic biliary hypoplasia.
From 1974 to 1985, 100 patients had surgical correction of biliary atresia. Extended bile drainage was accomplished in 81. The remaining 19 had temporary or no bile flow, and all of these patients have expired. Among those having extended bile flow, the bilirubin returned to normal in 33 infants. Thirty of this group followed from between I and 9 years are alive and jaundice free at this time. Among the remaining patients in whom bile drainage was accomplished, about one-half have died with progressive liver disease and complications of portal hypertension. Two have received liver transplants and the rest are living but remain jaundiced and have a guarded outlook.
Thus we have learned that in some patients hepatic fibrosis is progressive despite bile drainage.20 For these, and for patients in whom the operation fails to provide bile drainage, hepatic transplantation is the final alternative for salvage. With the availability of the immunosuppressant cyclosporine-A the results of transplantation have improved dramatically. The 1-year survival rate now approaches 70%. Systemic hypertension, opportunistic infections, and rejection remain the major concerns after transplantation. Almost one-third of the children in Starzl's reported experience have required retransplantation.21 The family needs extensive support and guidance in preparation and after the transplant. Unfortunately, one of every five patients evaluated dies while awaiting scarce donor organs. Public education to emphasize the critical need for organs and organ donation is vital if we are to improve survival for this group of patients.
Figure 2. Growth Following Biliary Ostomy Closure. Effect of closure of the cutaneous enterostomy on weight gain in a patient with biliary atresia. Bile output averaged I50cc/day and the bilirubin remained elevated (1.5 to 3.6mg/dl) after her initial surgery and following the stoma closure. Note the marked "catch up" growth which resulted.
1. Altman RP: Recent developments in hepatobiliary surgery. Pediatr Ann 1977; 6:3%.
2. Chiba T. Kasai M: Differentiation nf biliary atresia from neonatal hepatitis by routine clinical examinations. Tokoku J Exp Med 1975; 115.
3. Majd M. Reha RC. Altman RP: Effect of phenobarbital on ^sup 99m^Tc-IDA scintigraphy in the evaluation of neonatal jaundice. Semin Nuc Med 1981; 11(3).
4. Talamo RC: Basic and clinical aspects of the alpha, antitrypsin. Pediatrics 1975;56:91.
5. Kasai M, Kimura S, Asakura Y, et al: Surgical treatment of biliary atresia. J Pediatr Surg 1968; 3:665.
6. Chandra RS. Altman RP: Ductal remnants in extrahepatic biliary atresia: A histopathologic study with clinical correlation. J Pediatr 1978; 93: 1%.
7. Kobayashi A, Utsunomiya T, Yoshior O, et al: Ascending cholangitis after successful surgical repair of biliary arresta. Arch Dis Child 1973; 48:697.
8. Lilly JR. Hitch DC: Postoperative ascending cholangitis following portoenteroMomy for biliary atresia: Measures fiw control. World) Surg 1978; 2:581.
9. Hitch DC, Lilly JR. Reucr LB. et al: Biliary flora and antimicrobial concentrations after Kasai's operation. JPediatr Surg 1979; 14:648.
10. Brook 1. Altman RP: The significance of anaerobic bacteria in biliary tract infection after hepatic piwtoenterostomy for biliary atresia. Sundry 1984; 95:281.
11. Cracvc AH. Volpicelli N. Kotlotkc AM: Endoscopic recanaliiation of a portoentemstomy. JPediatr Surg 1982; 17:901.
1 2 . Altman RP, Anderson KD: Surgical management of intractable cholangitis following successful Kasai procedure. J Pediatr Surg 1982; 17:894.
13. Rarkin M, Lilly JR: Biliary atresia and the Kasai operation: Continuing care. J Pediatr 1980; 96:1015.
14. Cohen MI. Gartner LM: The use of medium-chain triglycerides in the management of biliary atresia. J Pediatr 1971; 79:379.
15. Rosenblum JL, Keating JP. Prensky AL, et al: A progressive ncunilogic syndmme in children with chronic liver disease. N Engl J Med 1981; 304:503.
16. Guggenheim MA, Ringel SP, Silverman A, et al: Pn>gressivc neuromuscular disease in children with chninic cholestasis and vitamin E deficiency: Diagnosis and treatment with alpha Tocopherol. J Pediatr 1982; 100:51.
17. Capnm JP. Erlinger S: Barbiturates and biliary function. Digestion 1975; 12:43.
18. Stiehl A. Thaler MM. Admirand WH: The effects of phenobarbital on bile salts and bilirubin in patients with intrahepatic and exttahepatic cholestasis. N Engl J Med 1972; 286:858.
19. Levy J. Altman RP. Palmer PH: Effect of phenobarbital on bile acid excretion in infants with biliary atresia. Hepathology 1984; 4:1059.
20. Altman RP: The portoenterostomy procedure for biliary atresia: A five-year experience. Ann Surg 1978. 188:351.
21. Gartner JC Jr. Zitelli BJ, Malatack JJ. et al: Orthotopic liver transplantation in children: Two-year experience with 47 patients. Pediatr 1984; 74:140.
CHOLESTASIS VS. BILIARY ATRESIA