Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy.

Background & Aims: Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce. Methods: We retrospectively describe a cohort of 38 patients with PFIC3 with a median age at last follow-up of 19.5 years (range 3.8-53.8). Results: Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplant at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with positive (normal or decreased) canalicular MDR3 expression in the native liver and had prolonged native liver survival (NLS; median 12.4 years [range 3.8-53.8]). In contrast, in patients with severe genotypes (no missense variation), there was no detectable canalicular MDR3 expression, symptom onset and cirrhosis occurred earlier, and all underwent liver transplantation (at a median age of 6.7 years [range 2.3-10.3]). The latter group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed an improvement in liver biochemistry in response to UDCA. Biliary phospholipid levels over 6.9% of total biliary lipid levels predicted response to UDCA. Response to UDCA predicted NLS. Conclusions: Patients carrying at least one missense variation, with positive canalicular expression of MDR3 and a biliary phospholipid level over 6.9% of total biliary lipid levels were more likely to respond to UDCA and to exhibit prolonged NLS. Impact and implications: In this study, data show that genotype and response to ursodeoxycholic acid therapy predicted native liver survival in patients with PFIC3 (progressive familial intrahepatic cholestasis type 3). Patients carrying at least one missense variation, with positive (decreased or normal) immuno-staining for canalicular MDR3, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to ursodeoxycholic acid therapy and to exhibit prolonged native liver survival.

Efficacy and Safety of Endoscopic Primary Prophylaxis of Bleeding in Children With High-Risk Gastroesophageal Varices.

OBJECTIVES: Primary prophylaxis of bleeding is debated in children with gastroesophageal varices; one of the reasons is the limited number of studies concerning its efficacy and safety. We report our experience with endoscopic primary prophylaxis. METHODS: From 2006 to 2019, 145 children (median age, 3.5 years; cirrhosis, n = 116) with high-risk gastroesophageal varices underwent primary prophylaxis (banding, n = 114; sclerotherapy n = 31, primarily in smaller children). RESULTS: We observed the eradication of varices in 93% of children after a mean of 6 months, at least one recurrence of varices in 45% after eradication, and gastrointestinal bleeding in 17% of children. Irrespective of the cause of portal hypertension, grade 3 esophageal varices, presence of gastric varices along the cardia and a lower composite score of endoscopic severity were associated with a worse probability of eradication, a longer time to eradication and a lower risk of a first recurrence and of bleeding following the procedure, respectively. Ten-year probabilities of overall survival and of bleeding-free survival were 95% and 75%, respectively. CONCLUSIONS: Endoscopic primary prophylaxis of variceal bleeding is reasonably effective and safe in children with high-risk gastroesophageal varices. Worse results are observed in children with more advanced endoscopic features. This pleads for endoscopic screening in children with portal hypertension and early detection of varices warranting primary prophylaxis.

A Model for Early Endoscopic Detection of High-Risk Gastroesophageal Varices in Children With Biliary Atresia.

OBJECTIVE: In children with biliary atresia and portal hypertension, progression to gastroesophageal varices carrying a risk of bleeding depends on age, total serum bilirubin concentration and initial endoscopic features. We report an attempt to use these factors for early detection of high-risk varices (HRVs). METHODS: Based on different combinations of these factors, a model was set to estimate the probabilities of emergence of HRVs at various time intervals. A 10% probability was chosen to set the date of the next endoscopy in children who did not display HRVs initially. A total of 113 children without HRVs who underwent their first endoscopy before age 8 in 2013-2020 were included. A comparison was made with children seen during the period 1990-2012 when this model was not used. RESULTS: In all, 65 of the 113 children underwent one to five additional endoscopies at dates set according to the model. The emergence of HRVs was recorded in 22 children after a mean interval of 14 months and was managed by endoscopic primary prophylaxis in all but one who underwent liver transplantation. Three other children bled before the next planned endoscopy. Compared with 175 children of the same age ranges without HRVs in the period 1990-2012, the use of the model was associated with a faster detection of HRVs with a lower number of endoscopic procedures (P  = 0.0022 and P  = 0.023, respectively). CONCLUSION: The results suggest that the model reported may be a useful tool for the early detection of HRVs to allow primary prophylaxis of bleeding.

The efficacy of surgical shunts to treat severe portal hypertension after a Kasai procedure for biliary atresia.

BACKGROUND: To assess the outcome of patients with biliary atresia (BA) who underwent a surgical shunt (SS) for severe portal hypertension (PH) following a Kasai procedure. METHODS: We collected and analyzed the data and outcomes of patients with BA who underwent SS for severe PH following a Kasai procedure between 1974 and 2014, focusing on complications related to the procedure, overall survival (OS), and transplant-free survival (TFS). RESULTS: SS was performed at a median age of 5.5 years [2-13.5] in 38 patients. Conjugated bilirubin level (cBL) was ≤20 µmol/l in 24 patients at time of SS. Median follow-up was 15 years [1-32]. OS at 5 and 10 years was 91% and 87% respectively. TFS at 5 and 10 years was 84% and 70% respectively. Long-term complications included hepatic encephalopathy in 9 patients, and hepatopulmonary syndrome in 3. At last follow-up, 10/14 patients without LT and 18/ 24 who had a delayed LT at a median delay of 11 years [1.5-22] were alive. CONCLUSION: Surgical shunt for severe portal hypertension in biliary atresia may delay the need for liver transplantation. However complications are indications for transplantation. LEVEL OF EVIDENCE: Type of study: Therapeutic. Level of evidence III.

Portal hypertension in children: High-risk varices, primary prophylaxis and consequences of bleeding.

BACKGROUND & AIMS: Primary prophylaxis of bleeding is debated for children with portal hypertension because of the limited number of studies on its safety and efficacy, the lack of a known endoscopic pattern carrying a high-risk of bleeding for all causes, and the assumption that the mortality of a first bleed is low. We report our experience with these issues. METHODS: From 1989 to 2014, we managed 1300 children with portal hypertension. Endoscopic features were recorded; high-risk varices were defined as: grade 3 esophageal varices, grade 2 varices with red wale markings, or gastric varices. Two hundred forty-six children bled spontaneously and 182 underwent primary prophylaxis. The results of primary prophylaxis were reviewed as well as bleed-free survival, overall survival and life-threatening complications of bleeding. RESULTS: High-risk varices were found in 96% of children who bled spontaneously and in 11% of children who did not bleed without primary prophylaxis (p<0.001), regardless of the cause of portal hypertension. Life-threatening complications of bleeding were recorded in 19% of children with cirrhosis and high-risk varices who bled spontaneously. Ten-year probabilities of bleed-free survival after primary prophylaxis in children with high-risk varices were 96% and 72% for non-cirrhotic causes and cirrhosis respectively. Ten-year probabilities of overall survival after primary prophylaxis were 100% and 93% in children with non-cirrhotic causes and cirrhosis respectively. CONCLUSION: In children with portal hypertension, bleeding is linked to the high-risk endoscopic pattern reported here. Primary prophylaxis of bleeding based on this pattern is fairly effective and safe. LAY SUMMARY: In children with liver disease, the risk of bleeding from varices in the esophagus is linked to their large size, the presence of congestion on their surface and their expansion into the stomach but not to the child's age nor to the cause of portal hypertension. Prevention of the first bleed in children with high-risk varices can be achieved by surgery or endoscopic treatment, and decreases mortality and morbidity.

Survey on Clinical Practice of Primary Prophylaxis in Portal Hypertension in Children.

Primary prophylaxis in portal hypertension in children is controversial, because there are few studies documenting its efficacy on the risk of bleeding. Twenty-eight centres out of the 38 we contacted returned a completed questionnaire about their clinical practices. More than 75% of the centres use endoscopy to screen patients diagnosed with portal cavernoma, biliary atresia, cystic fibrosis, and other fibrotic chronic liver diseases with suspected portal hypertension. In cases of grade 2 varices with red marks and grade 3 varices >90% of centres perform sclerotherapy or endoscopic variceal ligation. Noncardioselective beta-blockers were used by approximately 20% of centres. In conclusion, despite the absence of scientific recommendations there is a tacit consensus concerning the need to screen children with clinical signs of portal hypertension, and to provide primary prophylaxis in cases of endoscopic patterns of high-risk varices.

Primary prophylaxis of variceal bleeding in children and the role of MesoRex Bypass: Summary of the Baveno VI Pediatric Satellite Symposium.

UNLABELLED: Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11-12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. CONCLUSION: There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta-blockade in children was proposed.

Progression to high-risk gastroesophageal varices in children with biliary atresia with low-risk signs at first endoscopy.

OBJECTIVES: Biliary atresia carries a risk of bleeding because of portal hypertension. Our goal was to define the factors associated with the emergence of endoscopic signs carrying a high risk of bleeding in children who did not display these signs at the first upper gastrointestinal endoscopy. METHODS: From 1989 to 2013, a total of 225 children with low-risk signs at the first endoscopic examination underwent ≥2 upper gastrointestinal endoscopic examinations. The emergence of high-risk gastroesophageal varices was observed in 76 children in the 10 years following the first endoscopic examination. A survival study using the occurrence of high-risk varices as an event was performed to identify factors related to the emergence of these varices and to describe the probability of their emergence in 2 groups of children ages older than 18 months and 18 months or younger at the time of the first endoscopy. RESULTS: High total serum bilirubin concentration, young age, and high number/grade of esophageal varices at the first endoscopy were significantly related to the emergence of high-risk varices. The probability of the emergence of high-risk signs was higher and these signs appeared faster in infants 12 months of age or younger and/or when the first endoscopic examination displayed >1 grade 1 or grade 2 varices. Progression to high-risk varices was also related to bilirubinemia in children older than 18 months at the first endoscopy. CONCLUSIONS: The results allow defining a program of repeat endoscopies to detect high-risk varices and to discuss endoscopic primary prophylaxis of bleeding or hasten liver transplantation when these signs are found.

Portopulmonary Hypertension in Liver Disease Presenting in Childhood.

OBJECTIVE: Portopulmonary hypertension (POPH) is a known complication of cirrhosis in adults, but there is little information on its incidence and outcome in children with liver disease. We report 14 patients with POPH and present a synthesis of the medical literature. METHODS: Diagnosis of POPH in the 14 patients was based on right-sided heart catheterization displaying mean pulmonary artery pressure (mPAP) >25 mmHg, indexed pulmonary vascular resistances >3 Wood units · m, and pulmonary wedge pressure <15 mmHg. A literature review added 84 patients. RESULTS: In our unit, POPH was found in 0.5% of the children with portal hypertension, 0.9% of the children with end-stage liver disease awaiting transplantation, and 3 children with congenital portosystemic shunts (CPSSs). Analysis of 98 reported patients, including the 14 presented here, showed the cause of liver disease to be chronic liver disease or portal cavernoma in 76 instances (34 with a history of surgical portosystemic shunt) and CPSS in 22 instances. There was a precession with proven hypoxemia caused by hepatopulmonary syndrome in 6 patients. Median survival was 3 months in 56 untreated patients. An 80% 5-year probability of survival in 42 patients was treated by CPSS closure, pulmonary vasodilators, and/or liver transplantation. Mean pretransplant mPAP was 34 and 49 mmHg in transplant survivors and nonsurvivors, respectively. CONCLUSIONS: POPH is a rare but extremely severe complication of childhood liver disease. Portosystemic shunts, whether congenital or acquired, likely play an important causative role. Early diagnosis is crucial and requires systematic screening by echocardiography in children at risk.

Experience with endoscopic management of high-risk gastroesophageal varices, with and without bleeding, in children with biliary atresia.

BACKGROUND & AIMS: Biliary atresia, the most common cause of childhood cirrhosis, increases the risks for portal hypertension and gastrointestinal bleeding. We report the results from a single-center study of primary and secondary prophylaxis of bleeding in children with portal hypertension and high-risk varices. METHODS: We collected data from 66 children with major endoscopic signs of portal hypertension, including grade 3 esophageal varices or grade 2 varices with red wale markings and/or gastric varices, treated consecutively from February 2001 through May 2011. Thirty-six children (mean age, 22 mo) underwent primary prophylaxis (sclerotherapy and/or banding, depending on age and weight). Thirty children (mean age, 24 mo) who presented with gastrointestinal bleeding received endoscopic treatment to prevent a relapse of bleeding (secondary prophylaxis). RESULTS: In the primary prophylaxis group, a mean number of 4.2 sessions were needed to eradicate varices; no bleeding from gastroesophageal varices was observed after eradication. Varices reappeared in 37% of children, and 97% survived for 3 years. In the secondary prophylaxis group, a mean number of 4.6 sessions was needed to eradicate varices. Varices reappeared in 45%, and 10% had breakthrough bleeding; 84% survived for 3 years. There were no or only minor complications of either form of prophylaxis. CONCLUSIONS: Endoscopic therapy as primary or secondary prophylaxis of bleeding appears to be well tolerated and greatly reduces the risk of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices. However, there is a risk that varices will recur, therefore continued endoscopic surveillance is needed.

Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding.

BACKGROUND & AIMS: Biliary atresia is the most common cause of childhood cirrhosis. We investigated prospectively the development of portal hypertension in 139 children with biliary atresia, the risk of gastrointestinal (GI) bleeding in the first years of life, and associations between endoscopic patterns of varices and risk. METHODS: Children with clinical or ultrasonographic signs of portal hypertension underwent upper GI endoscopy examinations (n = 125, median age of 13 months). Information was recorded about esophageal varices and grade, red wale markings on the variceal wall, gastric varices along the cardia, and portal hypertensive gastropathy. A second endoscopy examination was performed in 64 children after a mean interval of 51 months to study their progression or regression. RESULTS: At the first endoscopy examination, 88 of 125 children had esophageal varices, including 74 who were younger than 2 years. Grade II and III varices, red markings, gastric varices, and signs of gastropathy were present in 29, 30, 24, and 27 children, respectively. At the second endoscopy examination, progression, stability, and regression of endoscopic signs were observed in 37, 18, and 9 of the 64 children, respectively. Twenty-eight children had GI bleeding at a median age of 17 months. Multivariate analysis showed that red markings, and most importantly gastric varices, were independent factors associated with bleeding. CONCLUSIONS: Children with biliary atresia have a high risk of portal hypertension in the first years of life. Spontaneous regression of varices is rare. Children with a combination of esophageal varices and red markings and/or gastric varices along the cardia should receive primary prophylaxis of bleeding.

Prophylactic endoscopic sclerotherapy of large esophagogastric varices in infants with biliary atresia.

BACKGROUND: Esophageal varices-related GI bleeding occurs frequently and early in life in children with biliary atresia and it may be life threatening. OBJECTIVE: We report the results of prophylactic sclerotherapy in 13 infants with biliary atresia and large varices. PATIENTS: Mean age was 13 months, mean weight was 8.2 kg, mean total serum bilirubin was 258 mumol/L, and mean prothrombin time was 78%. Esophageal varices were grade III (11 patients) or II (2 patients), with red signs in all infants and gastric varices in 12. None had GI bleeding. INTERVENTION: Sclerotherapy was performed with the patient under continuous intravenous octreotide therapy in 7 infants. RESULTS: In 8 children a complete or almost complete eradication of varices was obtained; none of these children bled later, 4 underwent liver transplantation, 3 are alive without liver transplantation, and 1 died of sepsis after 9 months awaiting liver transplantation. In 4 children a partial eradication was obtained and liver transplantation was performed. None of these children bled. One other child bled to death after 2 sessions of sclerotherapy. LIMITATIONS: Four ulcers and 2 stenoses occurred in 6 children with no octreotide versus no ulcer and 1 stenosis in 7 children receiving octreotide. CONCLUSION: These results (1) indicate that primary prevention of GI bleeding by sclerotherapy of esophageal varices is technically feasible and fairly effective in infants with biliary atresia and large varices, even in those with end-stage liver disease, (2) suggest that decreasing the risk of bleeding may allow liver transplantation under better conditions, and (3) further suggest that octreotide associated with sclerotherapy lowers the rate of complications.