Ryoji Ohi

Long-term follow-up after surgery for patients with biliary atresia☆

Long-term results after surgery for biliary atresia (BA) in 48 patients, ranging in age from 10 to 33 years, were examined. There were 19 males and 29 females. Twelve had correctable type BA and 36 had the noncorrectable type. Forty-one cases had no jaundice; seven did. Thirty-seven of the 48 cases were leading normal lives. Among them, six cases were enjoying their lives after overcoming sequelae, such as portal hypertension. The main morbidities of the remaining 11 long-term survivors were jaundice and portal hypertension. The growth of most cases were comparable to those of the normal Japanese population. The data of liver function tests were variable and disclosed a moderate degree of abnormality in patients mainly complicated by cholangitis. Eleven cases, including six jaundice cases, required treatment for esophageal varices and/or hypersplenism. In conclusion, the cured states of most cases without jaundice are satisfactory and these former patients have achieved a favorable quality of life. Early operations are essential to obtain good short-term results as well as good long-term results.

Surgical limitation for biliary atresia: indication for liver transplantation

Of 245 patients undergoing corrective operations for biliary atresia, jaundice was cleared in 113. In January 1988, 84 of them were living and free of jaundice and the other 19 were alive with jaundice. A vast majority of long-term survivors showed normal growth and development, and were leading normal lives for their respective ages. Portal hypertension, a common late complication, improved spontaneously or after sclerotherapy in jaundice-free patients. Therefore, liver transplantation is not recommended for jaundice-free patients even with esophageal varices. Patients with persistent severe jaundice (serum bilirubin over 10 mg/dL) and those with moderate jaundice (serum bilirubin 5 to 10 mg/dL) and severe esophageal varices require liver transplantation. Patients with moderate jaundice having no or slight varices should be carefully followed. When varices become worse or serum bilirubin rises, liver transplantation is indicated. Patients with mild jaundice (serum bilirubin lower than 5 mg/dL) have a possibility of improvement in their condition before the age of 15 years, and are not recommended for liver transplantation. The high value of the lowest postoperative bilirubin level suggests the necessity of liver transplantation in early childhood. Liver transplantation as the primary treatment for biliary atresia may be indicated only for patients over 120 days of age with an enlarged and hard liver.

Surgical treatment of congenital dilatation of the bile duct with special reference to late complications after total excisional operation

The surgical treatment of 100 cases with congenital dilatation of bile duct with special reference to late complications was analyzed. There were no deaths nor occurrences of malignancy. Among 91 patients who had undergone the standard operation, namely total excision of the dilated extrahepatic bile duct and reconstruction after Roux-en-Y hepaticojejunostomy, there were one early complication (pancreatic juice leakage) and five late complications (four intrahepatic gallstones and one liver abscess). The cause of intrahepatic gallstone formation after a total excisional operation was attributed to the remaining intrahepatic bile duct dilatation and the stenosis located between the intrahepatic bile duct dilatation and the common hepatic duct. Accordingly, these results support the total excisional procedure for this condition; however, with regard to the cases associated with cystic dilatation of intrahepatic bile ducts, completely free bile drainage from the dilated intrahepatic biliary system should be performed at the radical operation.

Portal hypertension after successful hepatic portoenterostomy in biliary atresia

From 1953 through 1984, we have operated on 225 cases of biliary atresia, and 95 patients are presently surviving. Portal hypertension with esophageal varices was endoscopically confirmed in 26 of 66 patients (39%) examined, 14 with and 52 without jaundice. All these patients except two had had frequent episodes of postoperative cholangitis. Eight patients have undergone treatment for portal hypertension. The treatment for variceal bleeding in jaundice-free infants with biliary atresia should be initiated conservatively, including endoscopic sclerotherapy. The results of our experience, however, justifies the employment of shunt procedures for patients older than 6 or 7 years of age.

Changes of portal vein pressure and intrahepatic blood vessels after surgery for biliary atresia

The portal vein pressure was measured and biopsies of the liver were taken during the corrective operation in 31 patients with biliary atresia and during relaparotomy in 16 patients free from jaundice 4 mo to 9 yr after a successful corrective operation. Because the portal vein pressure was higher than 200 mmH2O in about 70% of patients during the corrective operation, portal hypertension appears to have already developed in most of the patients with biliary atresia at 2-4 mo of age. In the patients who had had frequent episodes of postoperative cholangitis, the portal vein pressure was elevated and the amount of interstitial tissue in the liver was markedly increased at reoperation compared with those at the corrective operation. These results showed that postoperative cholangitis aggravated portal hypertension and fibrosis of the liver. On the contrary, the portal vein pressure declined in patients in whom active bile drainage had persisted and cholangitis had not been complicated after operation. An early corrective operation and prevention of postoperative cholangitis are of the greatest important for prevention of development of the portal hypertension and cirrhosis of the liver in long-term survivors after surgery for biliary atresia.

Apoptosis and cell proliferation in biliary atresia

Biliary atresia (BA), which is thought to result from progressive destruction of the bile ducts by a necroinflammatory process, is the most common cause of obstructive jaundice in infancy. Abnormalities in the cell turnover of remodelling ductal plates are considered one of the important aetiological factors in this disorder, but little work has been done on this topic. Programmed cell death or apoptosis was therefore examined by TdT‐mediated dUTP biotin nick end labelling (TUNEL) and cell proliferation by Ki67 immunostaining in 34 cases of BA. The results were compared with normal control liver (five cases) and congenital dilatation of the bile ducts (CDB, five cases) in order to study the cell turnover or tissue dynamics of BA. The TUNEL labelling index (LI) in bile ducts (48·9±13·2 per cent) was significantly higher than that of the control normal liver (3·6±2·8 per cent) and of CDB (2·5±5·1 per cent). The Ki67 LI in the bile ducts of BA (15·0±5·57 per cent) was also significantly higher than that of CDB (8·6±5·4 per cent). No significant differences of the TUNEL and Ki67 LIs in hepatocytes were, however, observed between BA, CDB, and normal liver. The TUNEL LI was significantly higher than the Ki67 LI in the bile ducts of BA. BA is therefore associated with increased and disorganized cell turnover of the bile ducts, which is related to malformation of the ductal plate or abnormal bile duct development. Copyright

CD8+ T cells infiltrating into bile ducts in biliary atresia do not appear to function as cytotoxic T cells: a clinicopathological analysis

It is speculated that immune mechanisms are involved in bile duct damage in biliary atresia (BA), as in primary biliary cirrhosis (PBC). In BA, however, no reports have described the in situ distribution of cytotoxic T lymphocytes (CTLs) using specific markers, nor has the clinical association been clarified. The present study describes the immunohistochemical distribution of CD8+ T cells and the relevant markers [perforin, granzyme B, FasL (CD95L)] in 47 cases of BA operated upon at days 12–79. The results were compared with those of PBC. In BA, CD8+ T cells infiltrated bile ducts in a way similar to that observed in PBC. However, in sharp contrast to PBC, none of the inflammatory cells infiltrating into the bile ducts in BA expressed cytotoxic markers such as perforin, granzyme B, or Fas ligand (FasL). Clinical follow‐up of patients with BA revealed that a greater degree of infiltration of bile ducts by CD8+ T cells is associated with better liver function. Taken together, these data suggest the absence of direct CTL activity against bile ducts in BA in the postnatal period. Copyright

In situ expression of fibrogenic growth factors and their receptors in biliary atresia: comparison between early and late stages.

Progressive fibrosis, despite successful surgical treatment, is one of the serious complications of biliary atresia. To understand the mechanism of this fibrosis, the in situ expression of fibrogenic growth factors (TGF‐β and PDGF) and their corresponding receptors was studied by immunohistochemistry using frozen sections. The results were compared between the early (n=12) and late (n=6) stages. The early stage was characterized by abundant expression of all ligands and receptors, together with type I procollagen (PC‐I). The major cellular sources were activated fibroblasts/myofibroblasts distributed mostly in the portal tracts. Macrophages also expressed all the ligands and the receptors, but to a lesser degree. Bile duct cells strongly expressed TGF‐β RI and RII and PDGF AA and BB, but focally expressed TGF‐β. All of these decreased in the late stage of biliary atresia. These results suggest that TGF‐β and PDGF play important roles in the fibrogenesis of biliary atresia, especially in its early stage, acting either by autocrine or paracrine mechanisms involving activated fibroblasts/myofibroblasts, bile duct cells, and macrophages. Copyright

Immunocytochemical characterization of supporting cells in the enteric nervous system in Hirschsprung's disease

The enteric nervous system (ENS) is composed of two distinct neural components, extrinsic and intrinsic, and its supporting cells uniquely possess some characteristics of both central nervous system (CNS) astrocytes and peripheral nervous system (PNS) Schwann cells. To provide further insight into the neural defects in Hirschsprungs disease, the supporting cells in biopsied normal gut, ganglionic, and aganglionic segments from six cases of Hirschsprungs disease were investigated immunocytochemically for localization of three neuroglial markers, glial fibrillary acidic protein (GFAP), S-100 protein, and glutamine synthetase (GS), by the avidin-biotin-horseradish peroxidase complex method applied to free-floating thick cryostat sections. In normal control gut and ganglionic segments of Hirschsprungs colon, all of the GFAP, S-100, and GS were expressed strongly by the supporting cells of the myenteric and submucosal plexuses, interconnecting nerve fiber bundles of the plexuses, and fine nerve strands in the muscular layer. The nerve bundles of the subserosa merging into the muscular layer were also immunoreactive for GFAP and S-100, but negative or only faintly positive for GS. On the other hand, aberrantly proliferated nerve bundles in the aganglionic segment of the Hirschsprungs colon were accompanied by supporting cells strongly positive for GFAP and S-100, but negative or faintly positive for GS. These results indicate that the supporting cells of the enteric neurons proper, enteric glia, express GFAP, S-100, and GS, whereas the supporting cells of the extrinsic components, which accompany PNS axons, are negative or very weakly positive for GS. Thus, GS immunocytochemistry may delineate intrinsic and extrinsic neural components in the ENS, and may provide an important clue for differential diagnosis of Hirschsprungs disease.

In biliary atresia duct histology correlates with bile flow

Three basic types of microscopic biliary structures at the portahepatis were distinguishable in infants with biliary atresia: bile ducts, collecting ductules of biliary glands, and biliary glands. Correlation between the type of biliary structure and the quantity and quality of post-operative bile flow was possible in 23 instances. At 2 weeks after operation, the 11 patients in whom a bile duct was identified had a daily bile flow of 68.0 +/- 11.5 mL. Bilirubin concentration in the bile was 13.6 +/- 3.3 mg/dL and total daily bilirubin excretion was 8.77 +/- 2.74 mg. In contrast, bile flow in 12 patients having only collecting ductules and/or biliary glands in the porta hepatis was 19.1 +/- 3.9 mL and bilirubin concentration in bile was 1.7 +/- 0.3 mg/dL. Thus, total daily bilirubin excretion was 0.34 +/- 0.08 mg (P less than 0.001). Postoperative cholangitis occurred only in patients with ducts. It is concluded that only bile ducts communicate with the intrahepatic biliary system and drain bile after hepatic portoenterostomy.