Outcomes of liver transplantation for Alagille syndrome after Kasai portoenterostomy: Alagille Syndrome with agenesis of extrahepatic bile ducts at porta hepatis.

BACKGROUND: Alagille syndrome (ALGS) is an autosomal dominant disorder, characterized by a paucity of intrahepatic bile ducts, resulting in significant cholestasis, and peculiar extrahepatic features. Some ALGS patients show a considerable overlap with biliary atresia (BA), and they can undergo Kasai procedure. The purpose of this study is to show the manifestations of BA overlapped ALGS cases in our institution, and to compare the outcomes of ALGS patients following liver transplantation (LT) between those who previously underwent Kasai surgery (ALGS-Kasai group) and those who did not (ALGS-non-Kasai group). METHODS: Medical records of ALGS patients who underwent LT in Kyoto University Hospital, Japan from January 1992 to March 2018 were analyzed. ALGS diagnosis was determined according to physical, radiologic, and histopathological findings. RESULTS: Thirty-one patients were ascertained (ALGS-Kasai: 4 males and 5 females vs. ALGS-non-Kasai: 14 males and 8 females, p = 0.43). Of 31 ALGS patients, 96.8% of children had pulmonary artery stenosis, 54.8% showed facial features, 29% revealed skeletal anomalies and 9.7% demonstrated ocular anomalies. The age at LT was significantly younger in ALGS-Kasai than ALGS-non-Kasai group (1.47 [interquartile range (IQR), 0.75-1.92] vs. 5.1 [IQR, 1.4-9.29] years; p = 0.038). Overall patient survival did not significantly differ between ALGS-Kasai (88.9%) and ALGS-non-Kasai patients (86.4%) (p = 0.84). Furthermore, the 1-year, 5-year, and 10-year patient survival rates for ALGS-Kasai group were 100%, 88.9%, and 88.9%, respectively, whereas those for ALGS-non-Kasai group were 90.9%, 90.9%, and 86.4%, respectively, with p-values of 0.36, 0.90, and 0.84, respectively. CONCLUSIONS: BA overlapped ALGS cases had neonatal progressive cholestasis which prompted Kasai procedure, and early liver dysfunction after Kasai led to performing LT. The ALGS-Kasai patients undergo LT at earlier ages than the ALGS-non-Kasai patients, however, overall patients' survival rates are similar between groups. Overall ALGS patients' survival rate after LT is considered high. LEVELS OF EVIDENCE: Level III; Case-control study or Retrospective comparative study.

Characteristics and outcome of liver transplantation in children with Alagille syndrome: a single-center experience.

BACKGROUND: This study was carried out in Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan, with the aim of reviewing the characteristics and the outcome of liver transplantation (LT) in children with Alagille syndrome (AGS). METHODS: We performed a retrospective analysis of transplant records of children diagnosed with AGS and undergoing LT between 1987 and 2010. RESULTS: Nine patients underwent living donor LT. Cholestasis and characteristic facies were seen in all patients. Posterior embryotoxon was seen in 4/9 (44.4%), butterfly vertebrae in 3/9 (33.3%), heart defect (pulmonary stenosis in 2) in 3/9 (33.3%), and renal disease in 2/9 (22.2%) patients. Five cases had cholestasis prior to the age of 60 days, whereas four cases had cholestasis after 60 days of age. Iminodiacetic acid scans showed no excretion of isotope into the bowel in four cases and suggested a false diagnosis of biliary atresia. All patients underwent diagnostic laparotomy and liver biopsy. Results of liver biopsy showed characteristic features of paucity of interlobular bile ducts in all patients. Kasai portoenterostomy was not performed in any patient prior to being referred for LT. The mean age at the time of LT was 4.6 years. The 5-year overall survival rate after living donor LT was 88.9%. CONCLUSION: Our conclusion is that the clinical features of AGS are informative. In addition, histological confirmation is important in the diagnosis. AGS children with severe liver disease had good prognoses with LT.

Surgical reconstruction of peripheral pulmonary artery stenosis in Williams and Alagille syndromes.

OBJECTIVES: Peripheral pulmonary artery stenosis is a rare congenital heart defect frequently found in association with Williams and Alagille syndromes. Controversy exists regarding the optimal treatment of peripheral pulmonary artery stenosis, with most centers favoring catheter-based interventions. In contrast, we have preferentially used surgical reconstruction of peripheral pulmonary artery stenosis. The purpose of the present study was to review our experience with surgical reconstruction of peripheral pulmonary artery stenosis. METHODS: We performed a retrospective review of patients who underwent surgical reconstruction of peripheral pulmonary artery stenosis. A total of 16 patients were identified: 7 had Williams syndrome, 6 had Alagille syndrome, and 3 had no identifiable syndrome. Detailed pulmonary angiography was performed in all patients to define stenoses at the main, branch, lobar, and segmental arterial levels. The mean preoperative right ventricular/left ventricular pressure ratio was 0.88 ± 0.07. The surgical approach was a median sternotomy with cardiopulmonary bypass. All peripheral stenoses were augmented with pulmonary artery homograft tissue. The median age at surgery was 14 months, and concomitant procedures were performed in 9 of the 16 patients. RESULTS: There was 1 operative mortality (6%). The mean right ventricular/left ventricular pressure ratio decreased to 0.40 ± 0.04 postoperatively (P < .005), representing a 55% reduction compared with the preoperative values. The patients were followed up for a median of 5 years. No late mortality occurred and reoperation was not required. CONCLUSIONS: The data have demonstrate that this comprehensive surgical approach to the treatment of peripheral pulmonary artery stenosis was associated with low early and no late mortality. Surgical reconstruction of the peripheral pulmonary artery stenosis resulted in a significant decrease in right ventricular pressure. We hypothesize that this reduction in right ventricular pressures will confer a long-term survival advantage for this cohort of patients.

Living donor liver transplantation in children with cholestatic liver disease: a single-center experience.

OBJECTIVES: Cholestatic liver disease (CLD) is the main indication for liver transplantation in children. This retrospective study evaluated the outcomes of living donor liver transplantation (LDLT) in children with CLD. METHODS: One hundred fifty-nine children with CLD who underwent 164 LDLT between May 2001 and May 2011 were evaluated. Their original diseases were biliary atresia (n=145, 91%), Alagille syndrome (n=8, 5%), primary sclerosing cholangitis (n=2), and the others (n=4). The mean age and body weight of the recipients at LDLT was 42±53 months and 14.0±11.0 kg, respectively. RESULTS: Parents were living donors in 98%. The left lateral segment was the most common type of graft (77%). There were no reoperations and no mortality in any living donor. Recipients' postoperative surgical complications consisted mainly of hepatic arterial problems (7%), hepatic vein stenosis (5%), portal vein stenosis (13%), biliary stricture (18%), intestinal perforation (3%). The overall rejection rate was 31%. Cytomegalovirus infection and Epstein-Barr virus disease were observed in 26% and 5%, respectively. Retransplantation was performed five times in four patients; the main cause was hepatic vein stenosis (n=3). Four patients died; the main cause was gastrointestinal perforation (n=2). The body height of Alagille syndrome patients less than 2 years old significantly improved compared with older patients after LDLT. The 1-, 5-, and 10-year patient survival rates were 98%, 97%, and 97%, respectively. CONCLUSIONS: LDLT for CLD is an effective treatment with excellent long-term outcomes.

Orthotopic liver transplantation for adults with Alagille syndrome.

INTRODUCTION: Alagille syndrome (AGS) is an inherited multisystem disorder, and liver transplantation (LT) may be required in pediatric patients with AGS (P-AGS). There are limited data regarding the outcomes of LT in adults with AGS (A-AGS). AIM: To determine and compare the outcomes of LT in A-AGS vs. P-AGS as well as A-AGS vs. adults with biliary atresia (A-BA). METHODS: Adults (>18 yr), with AGS and BA, and children (≤18 yr), with AGS who underwent isolated first LT between 10/1987 and 5/2008, were identified from the UNOS database. RESULTS: Forty-four of 79,400 adults transplanted for AGS were compared with 407 P-AGS and 56 A-BA, respectively. A-AGS patients had a significantly higher rate of encephalopathy, lower serum albumin, and higher serum creatinine in comparison with P-AGS. One- and five-yr patient and graft survival in A-AGS who underwent LT were not significantly different in comparison with either P-AGS or A-BA (A-AGS patient survival: 95.5%, 90.9%, P-AGS: 88. 7%, 86.2%, A-BA: 89.3%, 87.5%; A-AGS graft survival: 84.1%, 79. 5%, P-AGS: 80.3%, 76%. 1%, A-BA: 82.1%, 78.6%, respectively). CONCLUSION: The outcome of first LT in A-AGS is excellent compared with the overall reported adult patient and graft survival. Although A-AGS were sicker than P-AGS at transplant, their outcomes were comparable with that of P-AGS.

Effect of Kasai procedure on hepatic outcome in Alagille syndrome.

OBJECTIVES: Alagille syndrome (AGS) frequently presents with neonatal jaundice and can mimic other causes of high gamma-glutamyl transpeptidase (GGT) cholestasis, most notably biliary atresia. As a result infants with AGS may undergo intraoperative cholangiogram and even Kasai procedure. The aim of the study was to assess the hepatic outcomes of children with AGS who underwent the Kasai procedure. PATIENTS AND METHODS: A retrospective review of the AGS clinical database at the Children's Hospital of Philadelphia was performed to identify clinically defined patients with AGS who underwent a Kasai. A cohort of Alagille control subjects was selected with equivalent symptoms of neonatal jaundice and matched for age and presence of cardiac anomaly. JAGGED1-mutation analysis was performed on available samples. Clinical courses were reviewed. Fisher exact and t tests were used for analysis. RESULTS: Of the 430 patients with AGS, 19 underwent a Kasai procedure (K). The control cohort (C) consisted of 36 patients. Total bilirubin measured between 6 and 10 weeks of age in each cohort was equivalent (K: 9.6 mg/dL, C: 8.7 mg/dL); GGT levels were higher in the control group (K:493.4 U/L, C:574.4 U/L). Of note, the Kasai cohort had a significantly larger number of liver transplants (K: 9 [47.3%], C: 5 [13.9%], P = 0.01) and sustained higher mortality (K: 6 [31.6%], C: 1 [2.8%], P = 0.005). There was no genotype-phenotype correlation between the mutations identified and patients who underwent Kasai. CONCLUSIONS: These data suggest that the Kasai procedure, although appropriate for children with biliary atresia, does not benefit children with AGS and actually appears to worsen outcome. The current data suggest that the Kasai is not a marker for underlying severe liver disease, but the procedure itself may have a detrimental effect on outcome. An appropriate medical evaluation and particular consideration of AGS is essential before surgical referral in infants with high GGT cholestasis.

Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality.

BACKGROUND: Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations in Jagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS. METHODS AND RESULTS: Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort. CONCLUSIONS: The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role for Jagged1 and the Notch signaling pathway in vascular development.

10 years of pediatric liver transplantation.

PURPOSE: Pediatric liver transplantation is an accepted therapy for end-stage liver disease, but little long-term data exist. METHODS: From October 1984 to October 1994, 202 patients underwent a total of 225 liver transplantations. There were 98 boys and 104 girls, the average age was 5.1 +/- 4.9 (range, 0.2 to 19.1) years. Thirty (16%) were under 1 year of age. The diseases that required transplantation included biliary atresia (BA) (45%), metabolic liver disease (MLD) (9.9%), acute hepatic failure (6.9%), and Alagille's syndrome (AS) (5.4%). Originally the immunosuppression was cyclosporine- and steroid-based; the later regimens also included azathioprine and antilymphocyte preparations. All reported survival rates were derived from life-table analysis. RESULTS: The patient survival rates at 1, 5, and 10 years were 76%, 70%, and 61%; the retransplantation rate was 11%. The respective graft survival rates were 71%, 63%, and 59%. There were 60 deaths; 48 (81%) occurred in the first year. These first-year deaths were from sepsis (20; 42%), central nervous system problems (5; 11%), intraoperative complications (4; 8%), lymphoproliferative disease (LPD) (2; 4%), rejection (2; 4%), primary nonfunction (2; 4%), and miscellaneous other causes (7; 15%). There were 12 deaths after the first year, from LPD (3; 25%), sepsis (1; 8%), rejection (2; 18%), cancer (1; 9%), secondary hepatic failure (1; 9%), cerebral vascular accident (1; 9%), or pre- or postoperative complications (3; 25%). Compared with the overall survival rate, patients with MLD had a better chance of survival (83%; P <.012) than did those with AS (45%; P < .001). The 5- and 10-year survival rates for patients with BA were 61% and 58%. Over the past 2 years, the survival rate has increased (87% v 72%; P < .05) as early septic deaths have decreased (from 2.6 to 1.0 per year). CONCLUSION: Liver transplantation is effective treatment for end-stage liver disease. Decreasing the number of early septic deaths has improved the chance of survival, and better diagnosis and treatment of LPD would improve the late survival rate.

Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy.

OBJECTIVE: To determine the outcome, in index patients followed at an American Center, of syndromic paucity of interlobular bile ducts (sPILBD; Alagille syndrome), with onset of cholestasis in infancy. DESIGN: Cohort. SETTING: Regional referral center for infants and children with liver disease. RESULTS: During the past 10 years, 26 unrelated children with sPILBD were identified. Fifteen (58%) are alive without liver transplantation at a median age of 12.1 years. Three (11%) died, all before 2 years of age. Eight patients (31%) underwent liver transplantation at a median age of 6.5 years; all eight are alive a median 5.4 years after transplantation. The most common factors contributing to the decision for transplantation were bone fractures, pruritus, and severe xanthoma. The predicted probability of reaching 19 years of age without transplantation is about 50%; however, with transplantation, the predicted probability of long-term survival is 87%. Of 26 patients 4 (15%) have had significant central nervous system disease, and two of them have died of intracranial hemorrhage. Of the four patients who underwent cholecystoportostomy or portoenterostomy, three required liver transplantation. CONCLUSIONS: Children with sPILBD identified in infancy because of cholestasis have a 50% probability of long-term survival without liver transplantation, a worse prognosis than other follow-up studies have reported. In selected patients, liver transplantation provides the opportunity for long-term survival with improved quality of life. Patients with sPILBD are at risk of having intracranial hemorrhage.

[Alagille's syndrome in Cuba. A report of 9 cases]. / El síndrome de Alagille en Cuba. Informe de 9 casos.

Alagille's syndrome or arteriohepatic dysplasia has been described in Cuba in nine patients between nine months and 12 years of age (8 males and one female). Among the clinical features we found five major abnormalities: chronic cholestasis with neonatal jaundice (9/9), peculiar facies (9/9), peripheral pulmonary artery hypoplasia associated with cardiac murmur (6/9), butter-fly-like arch defects (4/9), and posterior embryotoxon (6/7). Two children had a severe xanthomatosis. Laparoscopy showed green hepatomegaly depending on the degree of cholestasis, and only one patient had incipient signs of micronodular cirrhosis. Liver histology showed a paucity of interlobular bile ducts. Survival was of 60%. One patient survived more than 30 years. Four patients died of liver carcinoma (unique report in infants), broncho-pneumonia, acute renal failure, and sudden death respectively. Among the minor features were mental retardation (5/9), a peculiar voice (3/9), growth retardation observed in some of our patients. This is the first report on Alagille's syndrome in Latin America, because so far reports have come only from Europe and North America.