Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

Current management of long-term survivors of biliary atresia: over 40 years of experience in a single center and review of the literature

Introduction

Owing to several therapeutic advancements, more patients with biliary atresia now survive into adulthood while retaining their native liver. However, the optimal strategy for long-term management of such patients remains unclear.

Methods

Aiming to establish the current management strategies, we reviewed previous reports of long-term outcome of BA who underwent surgery at our institution as well as the relevant literature, focusing particularly on the treatment of late complications.

Results

Approximately 30–40% of long-term survivors of biliary atresia who retain their native liver exhibit late sequelae such as cholangitis and portal hypertension. Early and appropriate intervention with Kasai portoenterostomy is essential for ensuring long-term survival with good quality of life. In our hospital, the current standard for Kasai portoenterostomy involves dissecting the fibrous remnants along the porta hepatis, just on the level of the liver capsule. Cholangitis is an important late complication in biliary atresia, and the possibility of mechanical obstruction of the biliary drainage route or deformity of the intrahepatic bile ducts with or without gallstones should be thoroughly evaluated in patients with intractable cholangitis. Regarding portal hypertension, appropriate interventions such as endoscopic variceal treatment and partial splenic embolization are considered to provide good quality of life when hepatic function is preserved.

Conclusion

Appropriate therapeutic management is strongly recommended in selected patients with late complications.

     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

A review of long-term outcome and quality of life of patients after Kasai operation surviving with native livers

Biliary atresia (BA) is a rare neonatal cholestatic disease which leads to progressive obliterative cholangiopathy, resulting in biliary obstruction and jaundice. The standard surgical treatment is hepatoportoenterostomy (Kasai operation). Although approximately 50% of the affected infants would require liver transplantation within the first 2 years of life, the other 50% of the patients can live for years with their native liver, despite the progression of cirrhosis and chronic liver disease. Many of these patients will be affected by long-term complications such as repeated cholangitis, portal hypertension, variceal bleeding, growth problems, biochemical abnormalities, and hepatic osteodystrophy. These morbidities impose a huge impact on the quality of life of the patients and their families. Herein, we performed a comprehensive review on the clinical status and quality of life of long-term survivors of biliary atresia with their native livers, to facilitate meticulous longitudinal follow-up of these patients, and alert caregivers the probable complications to be aware of.     

Liver disease in autosomal recessive polycystic kidney disease

Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.     

Late complications in long-term survivors of biliary atresia.

Ninety patients with biliary atresia surviving more than 5 years were analysed with respect to late complications occurring after the age of 4 years. Thirty-five had complications including cholangitis, portal hypertension, hypersplenism, gastrointestinal bleeding, and esophageal varices. These complications occurred at various times. The background factors of late complications were past history of cholangitis soon after the operation, advanced age at operation, re-operation, high portal pressure at initial operation, and a long interval before disappearance of jaundice after surgery. These factors are mostly related to the first operation and its postoperative course. Therefore, we stress that late complications can be prevented by intensive treatment of the patient at the time of the first operation.     

Biliary Atresia Revisited

Extrahepatic biliary atresia (EHBA) is an inflammatory fibrosing process affecting the extrahepatic and intrahepatic biliary tree resulting in fibrous obliteration of the extrahepatic biliary tract, ductopenia of intrahepatic bile ducts, and biliary cirrhosis. EHBA is divided into a correctable and a noncorrectable type with focal patency of the otherwise atretic biliary tree in the former and no patency of the biliary tree in the noncorrectable type. EHBA is divided in a fetal, prenatal or embryonic, and a more common, perinatal, acquired form. The symptoms of the former start shortly after birth and there is frequently an association with a variety of congenital anomalies. Children with the perinatal form become jaundiced several weeks after birth; no associated congenital anomalies are present. Morphologically, an inflammatory and fibrosing process of the extrahepatic biliary tree leads to complete lumenal obliteration. The liver is characterized by a nonspecific giant cell transformation, and portal expansion by fibrous connective tissue with marked ductular proliferation. With time, ductopenia and biliary cirrhosis develop. The diffential diagnosis with other conditions with similar microscopic patterns such as as alpha-1 antitrypsin deficiency, total parental nutrition, obstruction by a choledochal cyst, arteriohepatic dysplasia, familial progressive intrahepatic cholestasis, and alteration of the bile acid metabolism is discussed. In the fetal group, abnormalities in different genes seem to play a role; ductal plate malformation is another possibility. Different etiologies have been postulated in the perinatal form of EHBA: genetic susceptilibility, vascular factors, toxins, and infections mainly by rotavirus and reovirus. The pathogenesis is complex. EHBA is a heterogenous disease, resulting from a combination of genetic factors, insults, and activition of different genetic and immunologic pathways. The treatment of EHBA is surgical, with anastomosis between the biliary tree and the intestine in the correctable type and a hepatic portoenterostomy (HPE) for the noncorrectable group. HPE is a temporizing treatment allowing the infant to develop and grow, followed in the majority of the patients by liver transplantation.     

先天性胆总管囊肿合并门脉高压症

目的 探讨先天性胆总管囊肿（ＣＣ）合并门脉高压的原因、类型及转归。方法 将１７例ＣＣ合并门脉高压与１３例ＣＣ不合并门脉高压者进行比较,项目包括病程、胆源性发热、胆总管囊肿的最大前后径、胆道压力、肝组织病理变化、病理图像分析,对门脉高压患儿进行随访。结果 门脉高压组（ＰＨ）胆源性发热发生率高,胆道压力高于非门脉高压组（ＮＰＨ）,门脉高压组肝组织病理观察发现：１４例肝小叶完整,门静脉及肝静脉分支走行正     

Long-term prognosis in biliary atresia after hepatic portoenterostomy: analysis of 35 patients who survived beyond 5 years of age

The long-term prognosis in 35 patients with biliary atresia, who had undergone successful hepatic portoenterostomy and survived beyond 5 years of age, was studied. Eighteen (51%) patients developed ascending cholangitis after surgery. Jaundice recurred or increased in half of the patients, mainly as a result of ascending cholangitis. Another serious problem was the development of portal hypertension. Esophageal varices developed in 16 (46%) patients, with rupture and massive hemorrhage in seven. Leukopenia resulting from hypersplenism was common. Eighteen patients had WBC counts less than 5000/microliter. Thrombocytopenia was less common than leukopenia. Height was slightly below normal, although weight was within the normal range. Three patients died of hepatic failure; all had previously had ascending cholangitis. These observations indicate that ascending cholangitis is critical in the long-term and short-term prognoses in patients who have undergone successful repair of biliary atresia.     

Biliary atresia and the Kasai operation: continuing care

Surgical intervention utilizing the Kasai hepatic portoenterostomy has improved the outcome of patients with biliary atresia and provided a population of patients with unique health problems. The clinical course of 21 children followed for three years or longer was reviewed, focusing on their medical management. Ten (47.6%) had successful bile drainage following surgery and experienced a number of specific problems including recurrent cholangitis, nutritional and growth deficiencies, delayed developmental landmarks, portal hypertension, osteomalacia and osteoporosis, and social and psychiatric difficulties. These complications responded to aggressive medical therapy and support. Although the overall three-year survival of this series was 38.1%, in children who were operated upon prior to 2 months of age and in whom the enteric conduit was externalized the three-year survival rate was 66.7%.     

Comparison of hepaticoantrostomy and hepaticojejunostomy for biliary reconstruction after resection of a choledochal cyst

Twelve infants operated upon for choledochal cyst (CC) are reviewed with emphasis on the operative technique of biliary tract reconstruction, incidence of cholangitis, postoperative hypergastrinemia, biliary excretion, and upper gastrointestinal (GI) motility in a follow-up of 24 to 35 months. In 7 patients biliary reconstruction was performed with a Roux-en-Y hepaticojejunostomy (HJ), and in 5 with a hepaticoantrostomy (HAST). In the HJ group 4 patients had recurrent episodes of cholangitis and intermittent diarrhea and serum gastrin levels were significantly elevated in 5. Hepatobiliary scintigraphy showed unobstructed excretion of labelled bile through bile ducts into the Roux-en-Y loop, but with significantly delayed emptying of bile into the distal jejunum in all patients. Gastric emptying and upper intestinal passage were normal. In the HAST group no episode of cholangitis occurred and serum gastrin levels were within the normal range. Scintigraphically, hepatobiliary excretion, and duodenojejunal passage of labelled bile was normal, except in 1 patient who developed a postoperative stenosis of the left hepatic duct. Upper GI contrast studies demonstrated normal gastric emptying without reflux into the biliary system. These results suggest that biliary reconstruction with HAST can be performed safely with a low incidence of complications HAST offers a more physiologic method of biliary reconstruction after resection of a CC that allows bile to drain directly into the duodenum.     

Biliary atresia with a “cyst at porta”: management and outcome as per the cholangiographic anatomy

The purpose of this study is to classify biliary atresia (BA) with a "cyst at porta" according to the cholangiographic anatomy and to define management strategy and outcome in each group. A cyst at porta was identified in 13 of 58 babies (22.4%) with BA at first presentation. The cholangiographic anatomy was classified as; Group A (n = 7), type III BA with extrahepatic cyst; Group B (n = 2), type I or II BA with extrahepatic biliary cyst; and Group C (n = 4), type I or II BA with both extrahepatic and intrahepatic biliary cysts. The remaining 45 patients were comprised of type III BA without a cyst. A Kasai's portoenterostomy (PE) was performed for all Group A patients. Groups B and C were treated by hepaticojejunostomy (n = 5) or portoenterostomy (n = 1). All 45 patients with type III BA without a cyst were treated by a Kasai's PE. The median age at surgery was 92 days (ranges 28-342 days). There were three early post-operative deaths, all in patients with type III BA without cyst. Overall 18/55 (32.7%) patients achieved a jaundice free state. In Group A, 5/7 (71.4%) patients had bile flow, 2/7 (28.6%) are anicteric and 2/7(28.6%) had 1-2 episodes of post-operative cholangitis. In Group B, both patients are anicteric and none had post-operative cholangitis. In Group C, all four babies had bile flow but, significant morbidity because of recurrent severe cholangitis. Only one patient reached a jaundice free state. Of the remaining 42 patients with type III BA without a cyst, 27 (64.3%) had bile flow, 13 (31%) became jaundice free and 14 (33.3%) have had 1-2 episodes of post-operative cholangitis. In conclusion, thirteen of 58 (22.4%) babies with BA had a "cyst at porta" at first presentation in this series. The outcome was most satisfactory in type I BA without intrahepatic cystic dilatation (Group B) in terms of achieving a jaundice free state and freedom from recurrent cholangitis. However, intrahepatic biliary cysts (Group C) were associated with recurrent severe cholangitis and a poor eventual outcome despite a good initial bile flow. The outcome in type III BA with extrahepatic cyst was comparable to type III BA without cyst.     

Intrahepatic biliary tract abnormalities in children with corrected extrahepatic biliary atresia

Three children with surgically corrected extrahepatic biliary atresia developed recurrent cholangitis associated with bile lakes that failed to drain via the hepatoportoenterostomy. Surgical or percutaneous drainage of these cysts was followed by both resolution of the infection and spontaneous internal drainage. We postulate that the ongoing inflammatory process resulted in intrahepatic biliary obstruction, which caused cholangitis and bile cysts. Successful treatment required not only antibiotics but drainage of the bile lakes. Development of bile cysts is a new cause of recurrent cholangitis seen in extrahepatic biliary atresia.     

Long-term outlook in biliary atresia

The oldest survivors from the Kasai portoenterostomy originate in Sendai, Japan and are approaching their 60th birthday. These represent the tip of an expanding cohort of adults born with this previously fatal condition. Increasingly transition to adult-biased hepatologists and physicians will be the expectation of many with this condition. However unlike their usual patients with alcohol, drugs, virally mediated liver disease these are different with different expectations of health and quality of life. Cure is not on the cards for most of these and they survive still with impaired bile flow and increased liver fibrosis and cirrhosis with the threat of cholangitis and portal hypertension still apparent.We review the reported statistics on long-term survival essentially from Japan and Western Europe (such as the UK and France) and the range of complications that may still beset this group.     

Long-term survival after Kasai's operation for biliary atresia

Long-term survival of biliary atresia patients after Kasai hepaticoportoenterostomy is being increasingly reported. Prognostic factors indicative of a favorable long-term outcome consist of: (1) early age at operation; (2) bilirubin excretion of at least 6 mg daily 1 month after operation; (3) favorable hepatic histology at the time of operation; and (4) low incidence of postoperative cholangitis. Jaundice-free long-term survival is now attained in from one-fourth to one-third of patients undergoing Kasai hepaticoportoenterostomy by experienced surgeons in the Western hemisphere. In many long-term survivors there is normalization of liver function, improvement in hepatic histology, and resolution of the complications of portal hypertension. Most patients in this category have made a normal adjustment to their disease and lead active adolescent and adult lives. Offprint requests to: B. A. Stewart     

Long-term prognosis of patients with extrahepatic biliary atresia successfully treated with surgery. Our experience

The long-term prognosis of extrahepatic biliary atresia after surgical restoration of bile flow is still controversial. An ongoing process of cirrhosis and the development of portal hypertension continue to create frequent and frustrating management problems. Clinical features, hepatic function, echotomography aspect, calcium-phosphorus metabolism and serum levels of 25-OH-D-3 were evaluated in 12 anicteric patients with extrahepatic biliary atresia successfully treated in a period from 1974 through 1987. Seven of these children had a total of 21 episodes of cholangitis. In five patients liver biopsy, obtained at the time of the external diversion closure, showed a biliary cirrhosis. Growth, development and hepatic function were normal in all children studied; one patient had esophageal varices. The serum levels of 25-OH-D3 in patients without oral supplementation of vitamin D are lower than normal. This deficit can be corrected by oral administration of vitamin D. Our study revealed that the children with successful portoenterostomy appeared to thrive normally and that they tolerated the relatively mild liver damage. We believe that Kasai operation should be done in all patients with extrahepatic biliary atresia and that the liver transplantation is to be reserved only in those with unsuccessful Kasai. In our experience external diversion was not useful to prevent cholangitis and moreover it complicates the hepatectomy in case of transplantation.     

Sclerosing cholangitis with neonatal onset

Sclerosing cholangitis is characterized by irregular narrowing of extrahepatic or intrahepatic bile ducts, and in adults is defined mainly by radiologic findings. We describe eight children with cholestasis from the first week of life, followed by early cirrhosis and portal hypertension. Histologic examination of the liver showed absence of interlobular bile ducts in the early cholestatic phase in two patients and biliary cirrhosis later in all patients. Radiologic examination by percutaneous cholecystography under ultrasound guidance, carried out at age 8 months to 9 years, disclosed abnormal intrahepatic bile ducts with rarefaction of segmental branches, stenosis, and focal dilation. The extrahepatic ducts were involved in six patients. No intestinal disease has been found in these patients.     

Intrahepatic biliary cysts after hepatic portoenterostomy in four children with biliary atresia

We report our experience with 4 cases of cystic dilatation of intrahepatic bile ducts following hepatic portoenterostomy for biliary atresia. Two of the cases did not achieve satisfactory bile excretion and all four cases developed recurrent cholangitis after hepatic portoenterostomy. The attacks of cholangitis seemed to be associated with the presence of intrahepatic cysts. Although one case resulted in death from hepatic failure, three other cases are now outpatients. Patients who develop recurrent cholangitis following hepatic portoenterostomy, should be examined to exclude the presence of intrahepatic biliary cysts. Ultrasonography, computed tomography and percutaneous transhepatic cholangiography were all effective in detecting cysts and provided valuable information for planning treatment. Percutaneous transhepatic or surgical drainage of the bile ducts was effective in reducing jaundice, and recurrent cholangitis.     

Diagnostic and therapeutic endoscopic retrograde cholangiopancreatography in children: a large series report

OBJECTIVES: Our goal is to evaluate the indications, findings, therapies, safety, and technical success of endoscopic retrograde cholangiopancreatography (ERCP) in children. METHODS: Our database was searched for patients 17 years of age or younger undergoing ERCP between January 1994 and March 2003. Additional information was obtained by chart review. The safety and technical success of ERCP were examined. Complications were classified by the consensus criteria. RESULTS: A total of 245 patients (95 M, 150 F; mean age 12.3 years) underwent 329 examinations. Indications included biliary pathology (n = 93), pancreatic pathology (n = 111), and chronic abdominal pain of suspected biliary or pancreatic origin (n = 41). The ERCP findings were bile duct stone(s) (n = 29), benign biliary stricture (n = 19), primary sclerosing cholangitis (n = 7), anomalous pancreaticobiliary union (n = 8), choledochal cyst (n = 5), bile duct leak (n = 6), malignant biliary stricture (n = 2), biliary atresia (n = 1), chronic pancreatitis (n = 44), pancreas divisum (n = 26), pancreatic duct stricture with (n = 6) or without (n = 9) leak, pancreatic tumor (n = 1), periampullary adenoma (n = 2), and sphincter of Oddi dysfunction (n = 65). Endoscopic therapies were performed in 71% of the procedures and included sphincterotomy, stone extraction, stricture dilation, endoprosthesis placement, snare papillectomy, and cystoduodenostomy. Thirty-two (9.7%) post-ERCP complications occurred and included cholangitis in 1 patient and pancreatitis in 31. The pancreatitis was graded mild in 24, moderate in 5, and severe in 2. No mortality related to ERCP occurred. CONCLUSIONS: Diagnostic and therapeutic ERCP results are similar in children and adults except for a lower incidence of malignant disease in children. Technical success rates are high. However, ERCP-related pancreatitis is not uncommon, and the risk and benefits should be carefully reviewed before proceeding. Outcome data are necessary and is currently being accumulated at our institution.     

Perioperative factors affecting the outcome following repair of biliary atresia

The records of all patients with biliary atresia seen at the Childrens Hospital of Los Angeles during a 14-year period were reviewed. Of the 41 patients who could be evaluated, 32 were treated with trimethoprim and sulfamethoxazole prophylaxis, five were given other agents, and four received no prophylaxis after surgery. At least one episode of cholangitis occurred in nine patients. With one exception, all patients destined to have cholangitis did so within 9 months of surgery. Of the nine patients, five were receiving prophylaxis at the time the disease developed, but two were no longer receiving any prophylaxis. The other two patients in whom cholangitis developed never received antibiotic prophylaxis. In the 24 patients who had a Kasai type of portoenterostomy, cholangitis developed in three of the five (60%) with a Roux-en-Y limb length less than 40 cm and in two of the 19 (10.5%) with limb lengths greater than 40 cm (P less than .02). When performed earlier than 61 days after birth, surgery resulted in adequate bile flow in 64.7% (11/17) of patients who could be evaluated as compared with 31.8% (7/22) for surgery at 61 days or later (P less than .05). Of the patients with adequate biliary drainage 11 had no apparent liver disease, but only two of the patients with poor drainage were free of clinical liver disease. The conclusion from this series is that a combination of timely surgery, intestinal conduit at least 40 cm in length, and subsequent long-term antibiotic prophylaxis favors the best bile flow and reduces the occurrence of cholangitis, resulting in the best outcome.