Isao Shirahase

Surgical techniques and innovations in living related liver transplantation.

The authors successfully performed a series of 33 living related liver transplantations (LRLT) on children (15 males and 18 females, ranging from 7 months to 15 years of age) from June 1990 to May 1992, with the informed consent of their parents and the approval of the Ethics Committee of Kyoto University. Before operation, six of the children required intensive care, another 14 were hospitalized, and 13 were homebound. Donors (12 paternal and 21 maternal) were selected solely from the parents of the recipients on the basis of ABO blood group and graft/recipient size matching determined by computed tomography scanning. Procurement of graft was performed using ultrasonic aspirator and bipolar electrocautery without blood vessel clamping and without graft manipulation. All donors subsequently had normal liver function and returned to normal life. The left lateral segment (16 cases), left lobe (16 cases), or right lobe (one case) were used as grafts. The partial liver graft was transplanted into the recipient who underwent total hepatectomy with preservation of the inferior vena cava using a vascular side clamp. Twenty-seven of 33 recipients are alive and well with the original graft and have normal liver function. The patient survival rate was 89% (24/27) in elective cases and 50% (3/6) in emergent cases. The other six recipients had functioning grafts but died of extrahepatic complications. Complications of the graft were minimal in all cases. Hepatic vein stenosis, which occurred three times in two cases, was successfully treated by balloon dilatation. In cases with sclerotic portal vein, the authors anastomosed the portal vein of the graft to the confluence of the splenic vein and the superior mesenteric vein without a vascular graft, after experiencing a case of vascular graft thrombosis. After hepatic artery thrombosis occurred in one of the initial seven recipients whose arterial anastomosis was done with surgical loupe, microsurgery was introduced for hepatic artery reconstruction. There has been no occurrence of thrombosis since then. The current results with LRLT suggested that the meticulous management of surgical factors at each stage of the LRLT procedure is crucial for successful outcome. Living related liver transplantation is a promising option for resolving the graft shortage in pediatric liver transplantation and may be regarded as an independent modality to supplement cadaver donation.

Infectious Complications in Living Related Liver Transplantation

During the last 31 months, 50 children between 3 months and 15 years of age have undergone living related liver transplantation (LRLT) for end-stage liver diseases (39 biliary atresia, 2 Budd-Chiari syndrome, 2 progressive intrahepatic cholestasis, 3 liver cirrhosis, 1 Wilson disease, 1 protoporphyria, 1 tyrosinemia, and 1 fulminant hepatitis). Combined FK-506 and low-dose steroids were routinely used for immunosuppression. There were seven deaths, two of which were related to infection (Candida pneumonia and Epstein-Barr virus [EBV]-associated lymphoproliferative syndrome [LPS]). Five patients had a bacterial infection, all of which were associated with surgical complications. Three patients had Candida infection, all of which were malnourished, had biliary atresia, and had been managed with prolonged antibiotics against obstinate ascending cholangitis. There were 14 symptomatic viral infections (1 herpes simplex virus, 1 herpes zoster virus, 5 cytomegalovirus [CMV], 6 EBV, and 1 EBV-associated LPS). Three of the five CMV infections appeared in patients whose graft was ABO-incompatible, who were managed with prophylactic OKT-3. Most of the viral infections (except 1 EBV-associated LPS) were minor and were treated successfully. The low incidence and successful treatment of CMV infection are related to the high compatibility and low incidence of allograft rejection in LRLT. Bacterial and fungal infections can be decreased by greater refinement of surgical technique and more aggressive preoperative management. Treatment of EBV infection is still an unsolved problem.

A valved hepatic portoduodenal intestinal conduit for biliary atresia

Forty-six consecutive patients with biliary atresia were operated on at our institution during the 11-year period between 1978 and 1989. Their ages at operation ranged from 18 to 153 days (mean, 59 days). After dissecting the porta hepatis structures by Kasai operation, a biliointestinal anastomosis was constructed with a valved hepatic portoduodenal intestinal conduit in all cases. The intestinal valve is an intussuscepted muscular valve. Valvular function was examined radiologically. The upper gastrointestinal series demonstrated no reflux of contrast material into the conduit proximal to the valve and liver scintigraphy demonstrated that radioactive isotope drained readily into the duodenum through the valve. Thirty-nine of the forty-six patients (85%) had bile drainage after initial operation. At present 30 patients (65%) are alive without jaundice, 6 (13%) are alive with jaundice, and 10 (22%) are dead. The 5-year jaundice-free survival rate was 64%. Cholangitis occurred in 9 of 39 patients (23%) who had obtained apparent bile drainage: 5 had tractable cholangitis and 4 had refractory cholangitis. Reoperation restored bile flow in 2 of 8 patients who abruptly ceased to have bile drainage without cholangitis. In conclusion, with a valved hepatic portoduodenal intestinal conduit, the incidence of cholangitis was decreased, its medical control became easier, and the survival rate was improved.

Immunohistochemical demonstration of collagen types III and IV and myofibroblasts in the liver of patients with biliary atresia

To clarify the pathogenesis of pericholangitis in biliary atresia, immunohistochemical and ultrastructural methods were used to quantify the amount of collagen types III and IV, and alpha-smooth muscle actin-positive myofibroblast present in the pericholangial tissue. Patients were divided into two groups: the early-stage group (n = 7; 15 to 30 days old at the time of the Kasai operation), and the advanced-stage group (n = 14; 8 months to 6 years old at the time of liver transplantation). The liver specimen was harvested at the time of the Kasai operation in the early-stage group, and during liver transplantation in the advanced-stage group. Liver tissue from the donor was used as the control. The specimen was visually inspected and classified into three grades to express the extent of proliferation. An increase of collagen types III and IV, and myofibroblast in the pericholangial area was seen even in 2- to 4-week-old patients, which became marked with the progression of the fibrotic disease process. This suggests that pericholangitis occurs in the very early stage of biliary atresia, perhaps before the development of bile duct obstruction.

Increased deposition and serum level of type IV collagen in patients with extrahepatic biliary atresia

Increased deposition of fibrous connective tissue has been demonstrated in extrahepatic biliary atresia (EHBA). We have focused on type IV collagen, a major component of the perisinusoidal wall of the liver. We attempted to localize tyep IV collagen in liver specimens with monoclonal antibodies. Ultrastructural changes of the liver were observed by electronmicroscopy. Serum amount of type IV collagen was estimated by a recently developed sandwich enzyme immunoassay (EIA) method. Serum laminin and prolyl 4-hydroxylase were also determined by EIA for comparison with type IV collagen. Increased deposition of type IV collagen in the perisinusoidal wall was evident in the area with so-called sinusoidal capillarization. Electronmicroscopy showed a basement membrane structure underlying the endothelial cells in Disses space. Serum type IV collagen increased in EHBA patients before living-related liver transplantation (LRLT), and returned to normal within 5 weeks after LRLT, except for some patients with postoperative complications. Serum laminin and prolyl 4-hydroxylase showed the same propensity, although less prominently so. It is suggested that the immunoassay of serum type IV collagen adopted in this study has potential application in estimating collagen synthetic activity of the liver and in monitoring the postoperative states of patients after LRLT.

Changes in portal vein hemodynamics after hepatic portoenterostomy in biliary atresia

Portal vein (PV) shrinkage sometimes eliminates the possibility of liver transplantation in biliary atresia patients after hepatic portoenterostomy. To determine the factors leading to PV shrinkage, we performed a serial sonographic study of the portal venous system in 21 children. Cross-sectional PV area and mean portal venous velocity (PVV) were reduced in patients with refractory cholangitis and those with gastroesophageal varices and cholangitis. Although the reduction in cross-sectional PV area was greater in patients with four-time laparotomy than single laparotomy, the mean PVV was not reduced by repeated laparotomy. Patients with varices were lower in age, weight, mean PVV, cross-sectional PV area for age, and had higher serum total bilirubin levels. In conclusion, refractory cholangitis is a significant factor in shrinking the PV. With active bile drainage, varices spontaneously regress, the PV increases in both caliber and total length per unit hepatic volume, and PVV normalizes. It is suggested that pulsed Doppler PV sonography can help to determine the optimal time for liver transplantation referral in biliary atresia patients with progressive cirrhosis.