Experimental Investigations Into the Etiology of Cholangitis Following Operation for Biliary Atresia B y J . Hirsig, O. Kara and P. P. Rickham 9 Experimental operations carried out on young minipigs appear to show that cholangitis does not occur after simple ligation of the bile duct, but develops nearly invariably if the lymphatic drainage from the liver is also interrupted. The so-called "ascending'" cholangitis observed after h e p a t o - p o r t o - e n t e r o anastomosis is probably not ascending at all, but blood-borne. When a hepatic portoenterostomy is carried out for biliary atresia, trauma to the lymphatics in the porta hepatis should be avoided and an additional omento-hepato-portopexy should be done. Recent clinical experience appears to confirm this hypothesis.
infections. For the last 4 yr we have used only the first stage of Sawaguchi's method, s i.e., we drained the porta via an ileal loop opening as a cutaneous ileostomy. In spite of good bile flow and washing out of the loop with antibiotic solutions, repeated cholangitis occurred and we began to wonder whether these infections were in fact "ascending." We therefore performed a number of animal experiments on 8-wk-old minipigs of the G~ttingen strain with an average weight of about 5 kg.
IN DEX W O R D S : Cholangitis; hepatic portoenterostomy; omento- hepato-portopexy.
N SPITE OF much experimental and clinical investigation, the problems connected with the etiology and therapy of biliary atresia have still not been completely solved. In cases where it is possible to correct extrahepatic biliary atresia by operation, follow-up examinations have shown that the long-term prognosis is often poor. 1 Kasai's 2 introduction of hepatic portoenterostomy in 1959 revolutionized the management of those cases that were previously classified as inoperable. However, it soon became apparent that although biliary drainage was possible in a proportion of cases, so-called ascending cholangitis was a frequent complication, and numerous operations to overcome this complication have been proposed. 3-~ It was shown by Hasse 6 that in animals where the thoracic duct was anastomosed with the gastrointestinal tract, subsequent normalization of the raised serum bilirubin level did not prevent biliary cirrhosis, and although other factors may be at work, one of the principal causes for a progressive cirrhosis following operation is undoubtedly the so-called "ascending infection." We have used the Kasai method since 1968 in Liverpool and since 1971 in ZUrich but have been d i s a p p o i n t e d because, in spite of maintenance of the strictest sterility, the postoperative use of long-term antibiotics, and even after obtaining a good flow of bile, we were still confronted with repeated attacks of cholangitic
I
Journal of Pediatric Surgery, Vol. 13, No. 1 (February),1978
MATERIALS AND
METHODS
The operations were carried out under halothane and nitrous oxide/oxygen anesthesia after intubation.
Group 1 The bile duct was ligated and the gallbladder was excised. The results can be seen in Table 1.
Group 2 The lymphatic drainage of the liver was destroyed by resecting and ligating all lymphatic vessels in the region of the porta hepatis, as well as excision of the periportal lymph glands. T h e results can be seen in Table 2.
Group 3 The bile duct was tied and the lymphatic drainage resected. T h e results can be seen in Table 3. As will be seen from Table 1, we originally lost a number of animals soon after operation because of severe gastrointestinal hemorrhage. In order to avoid this complication, we carried out bilateral vagotomy in the next two groups of animals.
Group 4 We ligated the bile duct exactly as in the group 1 animals, but in addition carried out bilateral truncal vagotomy. The results can be seen in Table 4.
From the Department of Paediatric Surgery, University of Ziirich, Z~rich, Switzerland. Presented before the X X I V Annual International Congress of the British Association of Paediatrie Surgeons, Oslo, Norway, August 2-6, 1977. Address reprint requests to J. Hirsig, M.D. Chief Research Assistant, Department of Paediatric Surgery, University of Ziirich, Zi~rich, Switzerland. 9 1978 by Grune & Stratton, Inc. 0022-3468/78/1301-0013501.00/0
55
56
HIRSIG, KARA, AND RICKHAM Table 1. Ligature of the Bile Duct Number of operated animals Animals lost because of massive hemorrhage from gastrointestinal canal Progressive biliary cirrhosis Cholangitis
Table 4. Ligature of the Bile Ducts and Vagotomy 7 5 2 0
Table 2. Destruction of Lymphatic Drainage From the Liver Number of operated animals Lost because of early postoperative complications Progressive biliary cirrhosis Cholangitis
5 1 0 0
Four animals were followed-up regularly for more than 6 mo.
Group 5 Finally, we carried out the same operation as in the group 3 animals, namely tying off the bile duct and destroying the lymphatic drainage from the liver; in addition we performed a bilateral truncal vagotomy. The results can be seen in Table 5. We found that the bigger and the more radical the operations, the higher the early postoperative mortality. This explains the relatively numerous early postoperative deaths in group 5. During the follow-up period, all animals had liver biopsies taken by laparoscopy at intervals of about 10 days. One biopsy was taken for histology and one biopsy was sent for bacterial culture. At the same time, blood was obtained for determination of hemoglobin, leucocyte count, serum bilirubin, alkaline phosphatase, and transaminases.
DISCUSSION
These experiments seem to indicate that at least in the minipig (that, as far as its abdominal organs are concerned, is very similar to man), the chances of postoperative cholangitis are very much increased if the lymphatic drainage from the liver is at least partially destroyed. How the cholangitis develops in these cases is as yet unknown. Various bacteria were cultured. Streptococcus viridans, streptococcus hemolyticus, and staphylococcus aureus were often found. Occasionally E. coli and Klebsiella were discovered. We believe that this infection is hematogenous in origin and is probably Table 3. Ligature of the Bile Duct and Destruction of Lymphatic Drainage Number of operated animals Lost because of early complications Progressive biliary cirrhosis Cholangitis and hepatic abscesses Five of 7 animals suffered from histologically and, bacteriologically proven cholangitis, some with hepatic abscesses within 5 wk after operation.
Number of operated animals Lost because of early complications Lost because of colon perforation during laparoscopy 3 wk later Progressive biliary cirrhosis Cholangitis
7 1 1 5 0
brought about by interfering with the resistance of the hepatic reticuloendothelial system by destroying the lymphatic drainage. The infection was found only in the liver; no other organs were involved. From the clinical point of view, it seems logical that in order to prevent this dreaded complication we should avoid any operative injury to the lymphatics when dissecting the porta hepatis during a Kasai operation. The extraordinarily good results achieved by Suruga et al. r when performing hepatic portoenterostomy using an operating microscope could be explained by assuming that when microsurgery is employed, fewer lymph vessels will be destroyed. We suggest that interruption of the lymphatic drainage from the liver is chiefly responsible for recurrent attacks of postoperative cholangitis. Therefore, we have recently performed an omento-hepato-portopexy in addition to a hepatic p o r t o e n t e r o s t o m y . Our colleague, Professor Ishiis from Hiroshima, who helped us with these animal experiments, has performed the same operation three times since his return to Japan. In these four cases, no postoperative cholangitis has so far occurred. We therefore believe that an atraumatic preparation of the porta hepatis and an omento-hepato-portopexy should be performed in all cases of hepatic portoenterostomy. ACKNOWLEDGMENT
We thank Dr. J. Briner, pediatric pathologist at the Ztirich University Children's Hospital, for his help in interpreting the histology of the liver biopsies. The results of this work will be reported in more detail later on. Table 5. Ligature of the Bile Duct, Destruction of Lymphatic Drainage and Vagotomy Number of operated animals Lost because of early complications Progressive biliary cirrhosis Cholangitis and hepatic abscesses
22 7 15 13
ETIOLOGY OF CHOLANGITIS
57 REFERENCES
1. Kasai M: Treatment of biliary atresia with special reference to hepatic porto-enterostomy and its modification. Prog Pediatr Surg 6:5, 1974 2. Kasai M, Suzuki S: A new operation for "non-correctabLe" biliary atresia: Hepatic porto-enterostomy. Shujutsu 13:733, 1959 3. Sawaguchi S, Nakajo T, Hori T, et al: Staged reconstruction of biliary tract for congenital biliary atresia. Sixty-eighth Annual Meeting of the Japanese Society of Surgery, Kanasawa, Japan 4. Suruga K: Operations for biliary atresia. Shujutsu 24:543, 1970 5. Kasai M, Asakura Y, Suzuki H, et al: Modifications of
hepatic porto-enterostomy to prevent postoperative ascending cholangitis. Fifth Annual Meeting of the Pacific Association of Pediatric Surgeons, Tokyo, Japa~ 1972 6. Hasse W: Experimentelle untersuchung zum Problem der chirurgischen Behandlung yon Saiiglingen mit Gallengangsatresie, in Pompino HJ (ed): Kinderchirurgie, Neve Wege in Diagnostik und Therapie. Munich, Urban & Schwarzenberg, 1974 p 249 7. Suruga K, Kono S, Myano T, et al: Treatment of biliary atresia: Microsurgery for hepatic portoenterostomy. Surgery 80:558, 1976 8. Ishii T: Personal communications, 1977
infections. For the last 4 yr we have used only the first stage of Sawaguchi's method, s i.e., we drained the porta via an ileal loop opening as a cutaneous ileostomy. In spite of good bile flow and washing out of the loop with antibiotic solutions, repeated cholangitis occurred and we began to wonder whether these infections were in fact "ascending." We therefore performed a number of animal experiments on 8-wk-old minipigs of the G~ttingen strain with an average weight of about 5 kg.
IN DEX W O R D S : Cholangitis; hepatic portoenterostomy; omento- hepato-portopexy.
N SPITE OF much experimental and clinical investigation, the problems connected with the etiology and therapy of biliary atresia have still not been completely solved. In cases where it is possible to correct extrahepatic biliary atresia by operation, follow-up examinations have shown that the long-term prognosis is often poor. 1 Kasai's 2 introduction of hepatic portoenterostomy in 1959 revolutionized the management of those cases that were previously classified as inoperable. However, it soon became apparent that although biliary drainage was possible in a proportion of cases, so-called ascending cholangitis was a frequent complication, and numerous operations to overcome this complication have been proposed. 3-~ It was shown by Hasse 6 that in animals where the thoracic duct was anastomosed with the gastrointestinal tract, subsequent normalization of the raised serum bilirubin level did not prevent biliary cirrhosis, and although other factors may be at work, one of the principal causes for a progressive cirrhosis following operation is undoubtedly the so-called "ascending infection." We have used the Kasai method since 1968 in Liverpool and since 1971 in ZUrich but have been d i s a p p o i n t e d because, in spite of maintenance of the strictest sterility, the postoperative use of long-term antibiotics, and even after obtaining a good flow of bile, we were still confronted with repeated attacks of cholangitic
I
Journal of Pediatric Surgery, Vol. 13, No. 1 (February),1978
MATERIALS AND
METHODS
The operations were carried out under halothane and nitrous oxide/oxygen anesthesia after intubation.
Group 1 The bile duct was ligated and the gallbladder was excised. The results can be seen in Table 1.
Group 2 The lymphatic drainage of the liver was destroyed by resecting and ligating all lymphatic vessels in the region of the porta hepatis, as well as excision of the periportal lymph glands. T h e results can be seen in Table 2.
Group 3 The bile duct was tied and the lymphatic drainage resected. T h e results can be seen in Table 3. As will be seen from Table 1, we originally lost a number of animals soon after operation because of severe gastrointestinal hemorrhage. In order to avoid this complication, we carried out bilateral vagotomy in the next two groups of animals.
Group 4 We ligated the bile duct exactly as in the group 1 animals, but in addition carried out bilateral truncal vagotomy. The results can be seen in Table 4.
From the Department of Paediatric Surgery, University of Ziirich, Z~rich, Switzerland. Presented before the X X I V Annual International Congress of the British Association of Paediatrie Surgeons, Oslo, Norway, August 2-6, 1977. Address reprint requests to J. Hirsig, M.D. Chief Research Assistant, Department of Paediatric Surgery, University of Ziirich, Zi~rich, Switzerland. 9 1978 by Grune & Stratton, Inc. 0022-3468/78/1301-0013501.00/0
55
56
HIRSIG, KARA, AND RICKHAM Table 1. Ligature of the Bile Duct Number of operated animals Animals lost because of massive hemorrhage from gastrointestinal canal Progressive biliary cirrhosis Cholangitis
Table 4. Ligature of the Bile Ducts and Vagotomy 7 5 2 0
Table 2. Destruction of Lymphatic Drainage From the Liver Number of operated animals Lost because of early postoperative complications Progressive biliary cirrhosis Cholangitis
5 1 0 0
Four animals were followed-up regularly for more than 6 mo.
Group 5 Finally, we carried out the same operation as in the group 3 animals, namely tying off the bile duct and destroying the lymphatic drainage from the liver; in addition we performed a bilateral truncal vagotomy. The results can be seen in Table 5. We found that the bigger and the more radical the operations, the higher the early postoperative mortality. This explains the relatively numerous early postoperative deaths in group 5. During the follow-up period, all animals had liver biopsies taken by laparoscopy at intervals of about 10 days. One biopsy was taken for histology and one biopsy was sent for bacterial culture. At the same time, blood was obtained for determination of hemoglobin, leucocyte count, serum bilirubin, alkaline phosphatase, and transaminases.
DISCUSSION
These experiments seem to indicate that at least in the minipig (that, as far as its abdominal organs are concerned, is very similar to man), the chances of postoperative cholangitis are very much increased if the lymphatic drainage from the liver is at least partially destroyed. How the cholangitis develops in these cases is as yet unknown. Various bacteria were cultured. Streptococcus viridans, streptococcus hemolyticus, and staphylococcus aureus were often found. Occasionally E. coli and Klebsiella were discovered. We believe that this infection is hematogenous in origin and is probably Table 3. Ligature of the Bile Duct and Destruction of Lymphatic Drainage Number of operated animals Lost because of early complications Progressive biliary cirrhosis Cholangitis and hepatic abscesses Five of 7 animals suffered from histologically and, bacteriologically proven cholangitis, some with hepatic abscesses within 5 wk after operation.
Number of operated animals Lost because of early complications Lost because of colon perforation during laparoscopy 3 wk later Progressive biliary cirrhosis Cholangitis
7 1 1 5 0
brought about by interfering with the resistance of the hepatic reticuloendothelial system by destroying the lymphatic drainage. The infection was found only in the liver; no other organs were involved. From the clinical point of view, it seems logical that in order to prevent this dreaded complication we should avoid any operative injury to the lymphatics when dissecting the porta hepatis during a Kasai operation. The extraordinarily good results achieved by Suruga et al. r when performing hepatic portoenterostomy using an operating microscope could be explained by assuming that when microsurgery is employed, fewer lymph vessels will be destroyed. We suggest that interruption of the lymphatic drainage from the liver is chiefly responsible for recurrent attacks of postoperative cholangitis. Therefore, we have recently performed an omento-hepato-portopexy in addition to a hepatic p o r t o e n t e r o s t o m y . Our colleague, Professor Ishiis from Hiroshima, who helped us with these animal experiments, has performed the same operation three times since his return to Japan. In these four cases, no postoperative cholangitis has so far occurred. We therefore believe that an atraumatic preparation of the porta hepatis and an omento-hepato-portopexy should be performed in all cases of hepatic portoenterostomy. ACKNOWLEDGMENT
We thank Dr. J. Briner, pediatric pathologist at the Ztirich University Children's Hospital, for his help in interpreting the histology of the liver biopsies. The results of this work will be reported in more detail later on. Table 5. Ligature of the Bile Duct, Destruction of Lymphatic Drainage and Vagotomy Number of operated animals Lost because of early complications Progressive biliary cirrhosis Cholangitis and hepatic abscesses
22 7 15 13
ETIOLOGY OF CHOLANGITIS
57 REFERENCES
1. Kasai M: Treatment of biliary atresia with special reference to hepatic porto-enterostomy and its modification. Prog Pediatr Surg 6:5, 1974 2. Kasai M, Suzuki S: A new operation for "non-correctabLe" biliary atresia: Hepatic porto-enterostomy. Shujutsu 13:733, 1959 3. Sawaguchi S, Nakajo T, Hori T, et al: Staged reconstruction of biliary tract for congenital biliary atresia. Sixty-eighth Annual Meeting of the Japanese Society of Surgery, Kanasawa, Japan 4. Suruga K: Operations for biliary atresia. Shujutsu 24:543, 1970 5. Kasai M, Asakura Y, Suzuki H, et al: Modifications of
hepatic porto-enterostomy to prevent postoperative ascending cholangitis. Fifth Annual Meeting of the Pacific Association of Pediatric Surgeons, Tokyo, Japa~ 1972 6. Hasse W: Experimentelle untersuchung zum Problem der chirurgischen Behandlung yon Saiiglingen mit Gallengangsatresie, in Pompino HJ (ed): Kinderchirurgie, Neve Wege in Diagnostik und Therapie. Munich, Urban & Schwarzenberg, 1974 p 249 7. Suruga K, Kono S, Myano T, et al: Treatment of biliary atresia: Microsurgery for hepatic portoenterostomy. Surgery 80:558, 1976 8. Ishii T: Personal communications, 1977
