Diagnostic and management guidelines for biliary atresia in 2025

Abstract

Background

Biliary atresia (BA) is a severe pediatric biliary disorder characterized by the progressive obstruction of liver bile ducts. In the absence of treatment, fibrosis advances rapidly in most affected children. In recent years, there has been significant progress in the management of BA, but many challenges remain. This guideline provides expert opinions on the screening, diagnosis, treatment, and follow-up of BA, aiming to assist and guide clinical practice.

Methods

The guideline steering group, guideline development group, and guideline review group were formed to formulate clinical questions, develop recommendations, and draft guidelines using the GRADE Grid method, nominal group technique (NGT), and Delphi voting method. Three offline meetings were held on November 5, 2022, June 10, 2023, November 10, 2023, and October 27, 2024, respectively, to vote on the recommendations and solicit comments and suggestions from all participating experts. All experts from the United States, Europe, and Asia contributed significantly to this consensus guideline.

Results

After summarizing high-quality literature on clinically encountered issues such as early screening, complementary checkup, treatments, follow-up, vaccinations, growth, development, and neurocognition, 23 observations were made and strength of recommendations were given.

Conclusions

International guidelines for BA can guide surgeons, patients, medical societies, hospital administrators, and relevant community groups in their current practice. The diagnosis and treatment of BA remains controversial internationally and more research evidence is needed.

Highlight box.

Key recommendations

• Application of the stool color card may help in early screening for biliary atresia (BA).

• Serum bilirubin levels and serum gamma-glutamyl transferase levels in liver function testing are important in the diagnosis of BA.

• Postnatal ultrasound is the test of choice for BA diagnosis in patients with prenatal concerns or direct hyperbilirubinemia.

• Surgical exploration and cholangiography to identify bile duct status can be diagnosed intraoperatively by BA and rule out choledochal cyst.

• Postoperative steroid use improves jaundice clearance, but native liver survival results are unknown.

• Postoperative application of ursodeoxycholic acid improves biochemical liver function indices.

• The addition of medium-chain triglyceride feeding after Kasai portoenterostomy is recommended to help the growth and development of the child.

• Regular follow-up is still needed for children whose jaundice clears.

• Cholangitis should be treated aggressively and regularly once diagnosed.

What was recommended and what is new?

• Previous expert consensus recommended diagnostic and treatment approaches for BA, but lacked up-to-date evidence-based medicine and integration of Eastern and Western opinions to provide comprehensive clinical guidance.

• Our proposal provides comprehensive recommendations for the diagnosis, treatment, follow-up, and vaccination of BA.

What is the implication, and what should change now?

• This consensus summarizes the most recent BA literature and brings together 23 comments and recommendations from 50 experts from the East and West.

• Future research topics include early diagnosis of serologic markers that are still unstable, postoperative drug dosage and indications for discontinuation of drugs that are not clear, and whether to perform liver transplantation when jaundice recurs.

Introduction

Biliary atresia (BA) is a rare liver disorder characterized by the underdevelopment, or complete absence, of the intrahepatic and extrahepatic bile ducts (1). BA manifests with hallmark symptoms, such as jaundice dark urine, pale stools, growth retardation, and hepatomegaly (2). BA is diagnosed in the neonatal to infantile period, usually within the first few days to months of life, and is more common in females (3). The incidence of BA ranges from 1 in 5,000 to 1 in 18,000 live births, and geographically, Asian countries have a relatively increased incidence (3-8). However, several factors have been implicated in increasing the risk of developing the disease. These include genetic predisposition, developmental anomalies, ischemic events, environmental factors, and viral infections, all of which may contribute to the pathogenesis of BA and impact newer classification systems (9,10).

Kasai divided BA into three types based on the most proximal level of obstruction: Type I is defined as obstruction at the level of the common bile duct; in Type II the level of obstruction is in the common hepatic duct, with a notably patent right and left hepatic duct; and Type III, which is the most common, is defined as a proximal obstruction at the level of the porta hepatis (11). Davenport’s newer system classifies BA into syndromic BA, cystic BA, cytomegalovirus (CMV) associated BA, and isolated BA. This classification is based on likely common etiological factors (12). In syndromic BA patients manifest with commonly associated conditions like BA splenic malformation syndrome and the cat eye syndrome. Cystic BA is characterized by cyst formation within an otherwise obliterated biliary tract. Patients with BA who are found to have elevated viral titers are defined as having CMV-associated BA. Patients without any of these feature are defined as having isolated BA.

Recent years have witnessed significant advancements in the diagnosis and management of BA. These advancements encompass the utilization of serological markers such as matrix metalloproteinase-7 (MMP-7), machine-learning-enhanced ultrasound imaging, laparoscopic Kasai portoenterostomy (KPE), improved perioperative nutritional strategies, standardized protocols for the diagnosis and treatment of cholangitis, and innovations in living-donor liver transplantation (LT) (13-18). Despite these advancements, challenges persist, including variability in diagnostic and treatment practices and suboptimal therapeutic outcomes. Consequently, the development of clear, reliable, and clinically practical guidelines remains an urgent priority. We present this article in accordance with the RIGHT reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-97/rc).

Methods

The experts who compiled this clinical practice guideline (CPG) do not have conflicts of interest, and no ethical approval was required for this study design. This CPG is registered with the International Platform for Registration of Practice Guidelines (http://www.guidelines-registry.org/) (registration number: PREPARE-2023CN369).

Workgroup development

This guideline is developed under the auspices of The Section of Hepatobiliary Surgery, Branch of Pediatric Surgery, Chinese Medical Association and The Section of Pediatrics, Chinese Chapter of the International Hepato-Pancreato-Biliary Association. An iterative process was designed beginning with development of clinically-relevant questions in the following categories: screening, diagnosis, management, postoperative management, liver transplantation, and follow-up. Practice guidelines were developed following a literature search and synthesis of evidence by a CPG Working Group. The CPG Working Group is comprised of three subgroups (including the Guideline Steering Team, the Guideline Development Team, and the External Review Team) of experts in a variety of disciplines: including 38 pediatric surgeons, 5 pediatric transplant specialists, 1 pediatric infectious disease specialist, 1 pediatric gastroenterologist, 1 pediatric nutritionist, 1 pathologist, 1 radiologist, 1 perinatal medicine specialist, 1 statistician, and 1 expert in evidence-based medicine.

The guideline steering team organized meetings, defined the guideline’s research scope and PICO (Patients, Interventions, Comparisons, Outcomes) questions, oversaw the process of literature searches and systematic reviews, formed the final recommendations, and approved the guideline for publication. The guideline development team drafted PICO questions, synthesized evidence, graded the quality of evidence, and drafted guidelines with preliminary recommendations. The external review team developed the GRADE evidence matrix, reviewed the final recommendations of guidelines, and relevant supporting documents.

Literature search

A systematic literature search was conducted for relevant literature in Chinese databases (including CNKI and Wanfang) and English databases (including PubMed, Embase, and Cochrane Library) using target questions and keywords. Specifically, Medical Subject Headings (MeSH) and their corresponding free words are combined in the search process. Systematic evaluations, meta-analyses, randomized controlled trials (RCTs), other types of original research, case-control studies, observational work and expert consensus were included. The literature search included literature spanning from 1959 to 2024. The specific search method for BA can be found in Appendix 1.

Synthesis of evidence

From the collected information, further refinement was performed, with the goal of including only high-quality systematic reviews and meta-analyses published within the last 5 years. If more recent evidence was published, the guideline development team would combine the new data with previously published data to create a new systematic review. If no systematic review is currently available or the quality of the systematic review is very low, a new systematic evaluation was performed using studies that were verified to be of higher quality. The specific search method for evidence can be found in the supplementary.

Level of evidence and strength of recommendation

The GRADE methodology was used to evaluate the quality of evidence from literature sources to inform recommendations. The GRADE system designates the evidence as high (A), moderate (B), low (C), and very low (D) based on the level of disparity between the true effect value of the study and the estimated effect value, which would be theoretically derived from further study (19). After the GRADE assessment was completed, the Guideline Development Team drafted preliminary recommendations based on a final summary of the evidence. The Guideline Development Team would then designate their recommendations as strong (Grade 1) or weak (Grade 2). The committee reached a consensus on the quality assessment and strength of recommendation using the nominal group technique (NGT) and the Delphi method. The NGT involved face-to-face interactions to discuss and approve the draft of the questions. Delphi method: participants were collected to vote anonymously on controversial comments at an offline meeting. The final draft of the guidelines and their associated recommendations were then evaluated by a total of 13 experts from the Guidelines Steering Team and External Review Team for final approval.

Guidelines

Early screening (Table 1)

Table 1. Indicators for diagnosing BA effectiveness.

Indicator	Diagnostic modality	Sensitivity	Specificity	AUC
Early screening	SCC (20)	79.6%	99.9%	–
	prenatal ultrasound (21)	90.0%	82.5%	0.862
	DB levels shortly after birth (20)	100.0%	98.8%	–
Complementary checkup	DB (22)	87.6%	59.4%	0.834
	GGT (22)	81.5%	72.1%	0.839
	MMP-7 (22)	91.5%	84.3%	0.968
	Postnatal ultrasonography (22)	58.1%	92.9%	0.943
	SWE (23)	88.0%	85.0%	0.929
	Liver needle biopsy (24)	96.7%	86.7%	–
	Ultrasound guided percutaneous cholecystocholangiography (22)	100%	87.0%	0.940

AUC, area under the curve; BA, biliary atresia; DB, direct bilirubin; GGT, gamma-glutamyl transferase; MMP-7, matrix metalloproteinase-7; SCC, stool color card; SWE, shear wave elastography.

Early screening is important for prompt disorder recognition and early intervention. Recent meta-analysis studies have concluded that newborns should be screened for BA within 30 days to ensure timely diagnosis and treatment (25). One screening tool includes the use of a stool color card (SCC). SCC is a simple, cost-effective, and non-invasive early screening method. Additionally, this resource can be easily accessed as it can be attached to the maternal and child health handbooks (26). Children with BA often present with pale stools, and parents can use the SCC to compare their infant’s stool color to this control, thus facilitating the early detection of suspected BA or other infantile cholestatic disorders (27). In recent years, advancements in information technology and artificial intelligence have led to the development of mobile applications that offer a simple, convenient, and rapid method for parents to perform a variety of screening tests for BA. However, further research is needed to validate the reliability of these applications, particularly in addressing the issue of chromatic aberration (28,29).

Ultrasound is a versatile tool in the medical field with various applications. In prenatal ultrasound, the presence of microcysts at the hepatic hilum, a dilated right hepatic artery, and sero-peritoneum may suggest BA, although there is a paucity of supporting research; further investigation is required to validate its diagnostic accuracy (30,31).

Evaluating direct bilirubin (DB) levels shortly after birth is another method of screening for BA. Heel blood screening for raised DB levels occurs within 60 hours of birth. The first screening is considered positive for DB levels >3.4 µmol/L (0.04 mg/dL), and a second serum bilirubin screening is then recommended within 2 weeks of birth (32). The second screening is deemed positive if DB levels are greater than 17.1 µmol/L (0.19 mg/dL), in which case BA is suspected and further testing is indicated (33). Studies conducted in the United Kingdom, Japan, and the United States have demonstrated that DB screening can facilitate early detection of BA; however, it is less cost-effective and more invasive compared to the SCC method (26).

Complementary checkup (Table 1)

During early follow-up appointments, patients should have their serum markers for liver function evaluated. BA is suspected when serum DB is elevated to ≥17.1 µmol/L and when DB accounts for more than 20% of the total bilirubin (TB) (33). Serum gamma-glutamyl transferase (GGT), functioning as an indicator of biliary obstruction, has a critical value of greater than 100 U/L, in which the diagnosis of BA is considered, and greater than 300 U/L indicates a high suspicion of BA (34,35).

Another serum marker that may offer utility in the diagnosis of BA is the evaluation of serum MMP-7. The serum MMP-7 assay is currently the most promising indicator for early diagnosis of BA (35). In multicenter studies, serum MMP-7 levels were found to be significantly elevated in children with BA compared to those with normal neonatal profiles, α1-antitrypsin deficiency (AATD), and Alagille syndrome (ALGS), lending to its ability to differentiate BA from other liver diseases (13,36,37). Another multicenter prospective study evaluated the diagnostic efficacy of MMP-7 at different time points in children, demonstrating that neonatal serum MMP-7 has high diagnostic accuracy (38). However, the current lack of a consistent diagnostic threshold for MMP-7 limits its clinical application (39,40).

Postnatal ultrasonography is an effective preliminary imaging modality to differentiate jaundiced children with BA from those without BA. Key ultrasonographic findings include the triangular cord sign, hepatoportal fibrous plaques, absence of the common bile duct, gallbladder wall abnormalities, abnormal gallbladder morphology, and an increased diameter of the hepatic artery (41). Ultrasound has been recommended as the imaging modality of choice for BA due to its noninvasiveness, ease of use, and superior diagnostic accuracy. Additionally, shear wave elastography (SWE) is a specific ultrasound technique that measures liver stiffness and has been shown to be effective in diagnosing BA, as evidenced by a meta-analysis demonstrating good diagnostic performance (42). Furthermore, a multicenter study found that machine-learning-enhanced ultrasonography outperformed general ultrasonography in the early diagnosis of BA, which can be particularly beneficial for identifying BA in primary care settings (14).

Preoperative liver biopsy is a valuable tool in the diagnosis of BA (43). Histologic findings suggestive of BA include bile thrombus formation in the portal tracts, peri-portal edema, portal fibrosis, and bile duct proliferation (44). However, it is important to note that these histologic changes are not exclusive to BA, and a small number of children with BA may not exhibit significant bile ductule proliferation early in life (45).

Ultrasound-guided percutaneous cholecystocholangiography is an operation performed under either general anesthesia or using local anesthesia (22). It is highly suggestive of BA when the intrahepatic bile ducts fail to fill with contrast, serving as an adjunct test for suspected BA following initial ultrasound evaluation. However, the procedure is technically challenging, the contrast agent poses potential risks, and the specificity of the test is limited (46). This modality can be clinically utilized to identify biliary dysplasia when BA is suspected. This is also true for endoscopic retrograde cholangiography (ERCP) when facilities and experience are available (47).

The presence of hepatic subcapsular spider-like telangiectasis (HSST) on surgical exploration in children with suspected BA is associated with the diagnosis (48). BA is diagnosed when exploration reveals atrophy of the gallbladder and absence of bile. If the gallbladder has bile, an intraoperative cholangiogram is required to rule out choledochal cysts (CC) (49). The diagnostic flow chart is depicted in Figure 1.

Figure 1.

Flow chart. BA, biliary atresia; DB, direct bilirubin; KPE, Kasai portoenterostomy; SCC, stool color card; TB, total bilirubin.

Overall, the early diagnosis of BA is of the utmost importance to ensure prompt treatment and the most optimal long-term prognosis. At the same time, it is also important to ensure the correct diagnosis is made and the appropriate treatment is enacted. There are multiple conditions that present in a similar manner to BA, therefore systematic evaluations of a broad differential diagnosis are equally important. Similar diseases include: progressive familial intrahepatic cholestasis (PFIC), neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), inborn errors of bile acid synthesis (IEBAS), AATD, alagille syndrome (ALGS), CC, and idiopathic infantile cholestasis. Before proceeding with a management strategy for BA we recommend that these conditions should be considered and ruled out.

Treatments

Treatment in reference centers

As are many neonatal cholestatic diseases, BA is a rare and complex disease that requires unique medical and surgical knowledge and expertise. For this reason, the treatment of these patients should be centralized in reference centers linked by national and international networks. In addition, diagnostic and therapeutic algorithms must become optimized and unified. Additionally, the generation of patient registries to ensure long-term follow-up are important for improved patient outcomes (50).

Neoadjuvant therapy

In patients with obstructive jaundice and suspected BA, attention must be paid to bleeding caused by vitamin K deficiency, especially in those countries where vitamin K prophylaxis is not generally recommended for all newborns. Patients with cholestatic conditions are at increased risk of malabsorption of fat-soluble vitamins, like vitamin K. Therefore, it is recommended to take vitamin K 1–2 hours before surgery to reduce the risk of intraoperative bleeding (51).

KPE surgery

KPE is not indicated in the presence of the following conditions: (I) when the 2D-SWE indicates severe liver fibrosis [meta-analytic studies have shown that Aixplorer’s 2D-SWE mean thresholds of 12.2 kPa (range, 10.8–13.5 kPa) and 18.7 kPa (range, 15.7–24.4 kPa) were used to predict advanced fibrosis (F3–F4) and cirrhosis (F4) in infants with BA (23)]; (II) when there are associated fetal malformations, such as severe cardiac defects, which significantly increase the risk of intraoperative morbidity or mortality; and (III) in cases of liver failure accompanied by severe hemorrhagic and coagulation dysfunction.

With the continuous development of laparoscopic surgical techniques in pediatric surgery, KPE can be safely performed laparoscopically. Recently, multiple studies have shown that the jaundice clearance rate and the 2-year native liver survival (NLS) rate of laparoscopic KPE are comparable to those of open surgery, allowing surgical providers to select the method based on experience (52-54). Additionally, research comparing the length of the retained jejunal biliary limb found that there was no significant difference in the incidence of cholangitis or NLS between short intestinal limbs, determined by the distance from the hilum to the umbilicus, and the conventional long intestinal limbs (55). Robotic-assisted KPE has also been introduced as a surgical modality for the treatment of BA (56). While the emergence of laparoscopic KPE is promising, long-term comparative studies between open and laparoscopic surgery are still needed to compare long-term outcomes (56).

The insertion of an anti-reflux valve in the biliary branch, in order to minimize the reflux of chyme into the biliary branch, has demonstrated a reduction in postoperative cholangitis as a result (7). However, since the diagnosis of cholangitis remains ambiguous, the effectiveness of the anti-reflux valve should be interpreted with caution.

Children who achieve adequate bile drainage after an initial KPE procedure followed by a sudden cessation of bile flow are the best candidates for redoing the KPE procedure, but only one re-KPE procedure should be performed in this group (57-59). Reoperation should also be performed in children with uncontrollable bleeding, anastomotic fistula, or intestinal obstruction after KPE. Despite this, the clinical feasibility of reoperation and the decision on whether to change the surgeon remain subjects of ongoing debate.

Postoperative medical management, after KPE (Table 2)

Table 2. Pharmacologic management of BA.

Treatment	Category	Promotes clearance of jaundice	Prevention of cholangitis	Improving autologous liver survival
Neoadjuvant therapy	Vitamin K	/	/	/
Postoperative medical management	Steroid (60-64)	+	/	−
	UDCA (65)	+	/	−
	Antibiotics (66)		−	−
	Anti-CMV (67,68)	+	/	+

+, beneficial; −, no clear benefit; /, not yet studied. BA, biliary atresia; CMV, cytomegalovirus; UDCA, ursodeoxycholic acid.

Post-operatively, steroids administration is known to inhibit associated inflammation (69), promote enterohepatic recycling of bile acids and reduce bile acid synthesis (70). However, clinical studies have shown that steroid therapy does not decrease the incidence of cholangitis (71) and carries several drawbacks, including an increased risk of infections, gastrointestinal damage, and impaired growth and development (72,73). In children receiving high-dose postoperative steroid therapy (methylprednisolone >4 mg/kg/day), significant growth impairment and developmental delays have been observed, persisting up to 6 years of age. The use of steroid therapy postoperatively remains controversial. While high-quality European meta-analyses and multiple RCT trials do not support the use of steroids to improve jaundice clearance and NLS after KPE, two RCTs have found contrary results and found improved outcomes (60-64). Additionally, there is still no clear consensus on the appropriate timing for discontinuing steroid therapy.

Despite undergoing KPE, some children continue to experience ongoing cholestasis and progressive hepatic fibrosis. Consequently, bile acid-modulating medications, such as ursodeoxycholic acid (UDCA), are commonly prescribed to enhance bile flow and improve liver function following surgery (65). Currently, the use of these medications is largely empirical, with different medical facilities adopting varying dosing schedules. There are no definitive guidelines on when to discontinue treatment (74,75).

Studies have produced conflicting results on the effectiveness of antibiotics in preventing postoperative cholangitis after KPE (76-79). A meta-analysis, evaluating a mix of retrospective and cross-sectional studies, concluded that the current evidence does not support the use of prophylactic antibiotics to reduce the risk of postoperative cholangitis after KPE, indicating the need for more prospective studies to generate more definitive evidence on the issue (66). The typical prophylactic regimen involves a postoperative intravenous infusion of third-generation cephalosporins, or a combination of third-generation cephalosporins with nitroimidazoles, for at least 2 weeks. This is followed by alternating oral administration of third-generation cephalosporins and sulfonamides every 2 weeks for 3–6 months after the infusion has been discontinued (76,77,79,80).

Multiple studies have demonstrated that children who suffer from BA and are co-infected with certain viruses, particularly with CMV, tend to have shorter NLS and have less effective jaundice clearance (67,81,82). A large-scale study in mainland China revealed that viral testing remains important for predicting NLS (83). The patients were considered CMV positive if CMV-IgM was detected in serum and/or CMV-DNA was detected in urine or blood (84-86). Antiviral treatment is beneficial for children who test positive for serum CMV-IgM, polymerase chain reaction (PCR) urine CMV-DNA, or PCR CMV-DNA in serum/plasma/whole blood (68). Some European centers have reported that discontinuing antiviral therapy is advisable once blood CMV-DNA levels fall below 250 IU/mL, though further studies are needed to validate this approach (86,87).

Nutrition support and nutrition management

Children who have BA have increased energy requirements but limited fluid tolerance. To meet their nutritional needs, they often require formulas with energy densities of 80–100 kcal/100 mL, achieved through the use of fortified breast milk, high-calorie infant formulas, and the addition of carbohydrates or medium-chain triglyceride (MCT) components. These interventions help these children by promoting catch-up growth or acting to maintain an appropriate growth rate (88,89). In the absence of breast milk, hydrolyzed formulas with added MCT are preferred postoperatively due to their easier tolerance and absorption. For children who are intolerant of enteral feedings or who fail to achieve sufficient growth despite optimized tube feeding, parenteral nutritional (PN) support may be considered (15).

Malnutrition is a common complication in children with BA, necessitating regular testing for fat-soluble vitamins and micronutrients, with supplementation of deficits as needed, as outlined in Table 3 (90). Protein intake should be targeted at 130–150% of the recommended requirements based on the child’s age, with a goal of approximately 2–5 g/kg/day (90,91). For children with cholestasis, formulas enriched with MCT (>30% of total fat) are recommended, while ensuring that at least 20% of energy intake comes from long-chain triglycerides (LCT) to prevent essential fatty acid deficiency (EFAD) (91).

Table 3. Nutritional management of children with BA.

Energy/nutrient	Recommendations	Recommended strategies
Caloric	130–150% of recommended energy requirements for ideal body weight	- Use a metabolic cart to assess energy needs when available
		- If significant weight gain deficit exists, energy supply needs to be adjusted promptly to provide additional energy
		- Failure to achieve goal orally within two weeks requires NG/NJ tube feeding
Lipids	30–50% of total calories, starting at 30% of MCT and at least 20% of energy from LCT	- MCT can be supplemented via MCT formulas or MCT components
		- Monitor for EFAD
Protein	130–150% of age requirement or 2–5 g/kg/d	- Monitor for losses secondary to indigestion/ malabsorption
		- Ensure that the minimum age requirement for protein intake is met
Carbohydrates	40–60% of total calories	- Insulin resistance can lead to hyperglycemia or hypoglycemia
Vitamin A	Patients ≤10 kg: 5,000 IU/d; patients >10 kg: 10,000 IU/d	- Serum retinol and retinol-binding protein levels are monitored and adjusted according to the results of monitoring
		- Monitoring frequency is 3–6 months
Vitamin D	Vitamin D3 intake: 2,000–5,000 IU/d	- Monitor serum 25(OH)D levels; <75 nmol/L (30 ng/mL) is considered insufficiency, and <50 nmol/L (20 ng/mL) is considered deficiency
		- PTH, calcitonin, and calcium and phosphorus levels should also be monitored
Vitamin E	TPGS (water-soluble vitamin E) supplementation: 15–25 IU/(kg·d)	- Adjustment based on results of laboratory monitoring with a frequency of 3–6 months
Vitamin K	2–5 mg/d	- Monitor INR
		- Intravenous or intramuscular injection of 1–10 mg if vitamin K deficiency-induced protein (PIVKA II) is >3 ng/mL
Iron	Meet the DRI for that age	- Note that iron overdose can cause hepatotoxicity; clinicians should carefully consider whether IV iron is needed
Calcium	Meet the DRI for that age	- Monitoring bone health with laboratory monitoring of 25(OH)D, INR, serum calcium, magnesium and phosphorus levels and PTH

BA, biliary atresia; DRI, dietary reference intake; EFAD, essential fatty acid deficiency; INR, international normalized ratio; LCT, long-chain triglycerides; MCT, medium-chain triglyceride; PTH, parathyroid hormone; TPGS, tocopheryl polyethylene glycol succinate.

LT

Indications for LT after KPE include poor bile drainage and unresolved jaundice, poor bile flow in the early stages, advanced development of cirrhosis despite good bile flow. Patients who have been diagnosed with BA late and there is severe damage to the liver, primary LT is indicated. In patients with intractable nutritional deficits including severe malnutrition, growth retardation requiring aggressive nutritional support, or metabolic bone disease leading to fracture, these patients may benefit from LT. In patients who suffer from recurrent infections including bacterial biliary cholangitis despite the application of appropriate antibiotic therapy, patients with cholangitis secondary to multi-drug resistant microorganisms, or life-threatening sepsis, LT may be an option. Additionally, patients who require recurrent hospitalizations affecting quality of life suffer from complications of portal hypertension, who have refractory variceal bleeding, marked ascites, and spontaneous episodes of bacterial peritonitis may indicate a decline in liver function and may benefit from LT. Other clinical manifestations of declining liver function include, symptomatic thrombocytopenia, severe pruritus, pulmonary vascular disease, hepatopulmonary syndrome, portal hypertension, or hepatorenal syndrome. Finally, in patients with hepatobiliary malignancies including hepatocellular carcinoma or cholangiocarcinoma, LT may be indicated (15,88).

In patients who fail to have adequate biliary clearance after KPE, surveillance of TB levels should help guide whether LT is warranted. If TB levels remain >100 µmol/L three months after KPE, an evaluation for LT should be considered. For cases where TB levels are between 34–100 µmol/L or not elevated, preoperative evaluation for LT is warranted if biliary cirrhosis or portal hypertension fails to respond adequately to conservative treatment during long-term follow-up (88,92).

The optimal time for LT in children 12 years of age or younger is when the Pediatric End-Stage Liver Disease (PELD) score is between 15 and 25. While a PELD score above 25 indicates a more urgent need for transplantation, the extent of liver failure and the co-morbid effects increase perioperative risks significantly (88). For children younger than 12 years of age, organ allocation should be guided by the PELD scoring system (93). For those aged 12 years and older, the optimal time for LT is when the Model for End-Stage Liver Disease (MELD) score exceeds 20, with organ allocation based on the MELD score (93).

The preoperative evaluation for LT should include a thorough history and physical examination (94). In patients with nutritional deficits enteral nutritional (EN) support before LT is ideal in children with BA, if well tolerated (95). In children with end-stage liver disease (ESLD) and malnutrition who have failed to tolerate enteral feeding, PN should be considered to improve and/or resolve malnutrition before LT (96). Careful identification and management of children with elevated bilirubin levels, portal vein thrombosis, ventilator dependence, or those weighing ≤10 kg can help reduce preoperative mortality associated with LT (97).

Follow-up

A regular follow-up system should be established for children with BA after KPE, as effective follow-up can significantly improve prognosis. The recommended time-frame for follow-up is monthly during the first postoperative year, every 3 months during the second year, every 6 months in the third year, and then monitoring at the fifth and tenth postoperative years. The specific details and frequency of follow-up visits are outlined in Table 4 (91). Studies have shown that complications such as delayed cholangitis, portal hypertension, hepatic deterioration, and hepatic malignancy can occur in children who have been followed for more than 20 years after KPE (98,99). Long-term follow-up is particularly crucial for children with severe fibrosis, as monitoring for complications such as portal hypertension may help improve NLS (100). A 20-year follow-up study reports 5- and 10-year NLS rates of 51.3% and 46.5%, respectively, with overall survival rates of 91.5% and 90.5% at the same intervals (50).

Table 4. Principles of follow-up for children with BA.

Evaluations	Pertinent findings/metrics	Follow-up frequency
Subjective content provided by parents	Skin color, urine color, and stool color	All follow-up nodes were monitored
Basic information about the child	Height, weight, head circumference, feeding status	All follow-up nodes were monitored
Serological examination	Complete blood counts, complete metabolic panel and liver function tests	All follow-up nodes were monitored
	Coagulation testing and blood ammonia levels	Monitoring every 6 months for the first 3 years and then at all follow-up nodes
Fat-soluble vitamins	Retinol/retinol-binding protein ratio (vitamin A)	Year 1 is monitored every 3 months, and all subsequent follow-up nodes are monitored
	Serum 25-hydroxyvitamin D (vitamin D)
	Alpha tocopherol/total lipid ratio (vitamin E)
	Prothrombinogen and international normalized ratio (vitamin K)
Echography	Liver and spleen size, presence of ascites, degree of liver fibrosis and cirrhosis, and presence of intrahepatic cysts	Year 1 is monitored every 3 months, and all subsequent follow-up nodes are monitored

BA, biliary atresia.

Cholangitis is the most common complication following KPE, with an incidence rate ranging from 40% to 93% (101). Cholangitis should be strongly suspected in children who present postoperatively with fever of unknown origin, absence of bile-colored stools, irritability, and abnormal laboratory findings (16,102). The management of cholangitis after KPE generally involves antibiotic therapy graded by the severity of the condition. Empiric antibiotic treatment typically begins with third-generation cephalosporins, or a combination of third-generation cephalosporins with metronidazole administered intravenously. If the fever persists for more than 24 hours despite antibiotic treatment, the regimen may be escalated to intravenous carbapenem antibiotics (79). If no improvement in body temperature is observed after 48–72 hours of initial treatment, the antibiotic regimen should be adjusted based on clinical response and blood culture sensitivity results. Once the fever is controlled, the patient can be discharged with a prescription for oral third-generation cephalosporins. For refractory cholangitis, a course of carbapenem antibiotics for 2–4 weeks is recommended, with adjustments made according to blood culture results until the infection is controlled. In cases of frequent cholangitis, enterococcal infection should be considered, with vancomycin or linezolid as the preferred treatment options. If high fever and negative blood cultures persist despite adjustments to antibiotic therapy, fungal infections should then be suspected, and a combination of antifungal medications may be warranted (80,103). Unsatisfactory treatment results should be tested for metagenomic next-generation sequencing (mNGS) (104). In children who have survived for many years without jaundice but then experience episodes of cholangitis, it is essential to investigate the possibility of Roux loop obstruction. Timely release of the Roux loop obstruction can help preserve the child’s native liver (105).

Long-term complications such as portal hypertension may arise from chronic hepatobiliary inflammation leading to progressive cirrhosis. This condition can cause portal hypertension, which in turn may result in esophageal varices and ascites (106). The presence of portal hypertension is typically assessed through physical examination, laboratory tests, and ultrasound during postoperative follow-up. Endoscopy in the fourth year after KPE is also recommended for further evaluation (99). Prompt identification and early intervention in children presenting with clinical and ultrasound indicators of portal hypertension can include the utilization of prophylactic endoscopic variceal ligation for those at elevated risk of variceal bleeding (107,108).

Vaccinations

Children with BA can typically follow the routine vaccination schedule, as long as there are no clear contraindications (Table 5). However, if a child has severe coagulation abnormalities or is progressing toward hepatic failure, vaccination should be postponed. Vaccination can be resumed once the child’s condition has improved and stabilized. Live attenuated vaccine given one year after surgery. For children undergoing LT, it is advisable to complete vaccinations prior to the procedure, taking into consideration the potential effects of postoperative immunosuppression on vaccine efficacy (109,110).

Table 5. Principles of vaccination for children with BA.

Treatment	Inactivated vaccine	Attenuated live vaccine
High-dose steroid therapy† ≥14 d	Vaccination should be given at least 2 weeks before treatment or after stopping steroid therapy	Vaccination should be given at least 4 weeks apart before treatment or 4 weeks after stopping steroid therapy
High-dose steroid therapy† <14 d	Routine vaccination	Vaccination is not recommended during treatment, vaccination can occur 2 weeks after cessation of steroid therapy
Low-dose steroid therapy‡	Routine vaccination	Vaccination may be given as appropriate after assessment
KPE	Vaccination should be given at least 2 days before surgery	Vaccination should be given at least 21 days before surgery
LT	Vaccination should be given at least 2 weeks before surgery	Vaccination should be given at least 4 weeks before surgery

^†, prednisone ≥20 mg/d or prednisone >2 mg/(kg·d) for those who weigh <10 kg. ^‡, prednisone <20 mg/d or prednisone <2 mg/(kg·d) for those weighing <10 kg, or equivalent steroid therapy on alternate days. BA, biliary atresia; KPE, Kasai portoenterostomy; LT, liver transplantation.

Growth, development and neurocognition

The phenotype of children with BA differs from the etiologic mechanisms seen in adult liver diseases, such as alcoholic liver disease and viral hepatitis. This distinction underscores the importance of monitoring growth, development, and neurocognitive transitions as children with BA progress into adulthood (99,111). A multicenter study assessing the quality of life of children with BA aged 2–25 years reveals significantly impaired psychosocial functioning compared to a matched healthy population. The most pronounced differences are observed in school functioning, with slight delays in gross motor and language development being evident (112).

Conclusions

Internationally, the diagnosis and treatment of BA remain controversial, including the choice of different regions or centers to adopt different methods for diagnosis as early as possible, and the dosage and indications for discontinuation of perioperative medications remain controversial. This study shows that there is still a need for non-consensus among experts on most issues. This study provides an important direction for future clinical difficulties in the diagnosis and treatment of BA.

Recommendations

Recommendation 1: Application of SCC may help in early screening for BA (agreement rate =100%) (1B).

Recommendation 2: Sole prenatal ultrasound is not recommended for the diagnosis of BA (agreement rate =89%) (2C). Infants with abnormal prenatal ultrasound should be followed up in the postpartum period (agreement rate =100%) (1B).

Recommendation 3: Heel blood DB measurement is promising for early screening for BA (agreement rate =89%) (1B).

Recommendation 4: Serum bilirubin levels and serum GGT levels in liver function testing are important in the diagnosis of BA (agreement rate =100%) (1B).

Recommendation 5: MMP-7 is a potential indicator for early diagnosis of BA (agreement rate =89%) (2C).

Recommendation 6: Postnatal ultrasound is the test of choice for BA diagnosis in patients with prenatal concerns or direct hyperbilirubinemia (agreement rate =100%) (1A). SWE is useful for BA diagnosis (agreement rate =84%) (2B).

Recommendation 7: Preoperative liver needle biopsy might help in the differential diagnosis of jaundiced children (agreement rate =58%) (2B).

Recommendation 8: Surgical exploration and cholangiography to identify bile duct status can be diagnosed ntraoperatively by BA and rule out CC (agreement rate =89%) (1A).

Recommendation 9: To reduce the risk of intraoperative bleeding complications, it is recommended that 0.2–0.3 mg/kg/dose of vitamin K be administered intravenously before surgery (agreement rate =100%) (1D).

Recommendation 10: Each center can choose either open or laparoscopic-assisted KPE surgery according to their own experience (agreement rate =89%) (1B).

Recommendation 11: Postoperative steroid use improves jaundice clearance, but NLS results are unknown (agreement rate =100%) (2B).

Recommendation 12: Postoperative application of UDCA improves biochemical liver function indices (agreement rate =100%) (2D).

Recommendation 13: In the absence of evidence, postoperative prophylaxis with antibiotics is recommended (agreement rate =84%) (1C).

Recommendation 14: Postoperative anti-CMV therapy helps improve NLS in children with BA combined with CMV infection (agreement rate =79%) (2C).

Recommendation 15: The addition of MCT feeding after KPE is recommended to help the growth and development of the child (agreement rate =95%) (2B). Supplementation of fat-soluble vitamins as needed after KPE (agreement rate =95%) (1B).

Recommendation 16: Three months after KPE, patients with TB level greater than 100 µmol/L should be promptly evaluated for LT (agreement rate =95%) (1B).

Recommendation 17: The PELD score is used as one of the evaluation criteria for children up to 12 years of age to undergo LT. A score of about 10 is considered for LT counseling, while a score of 10–15 is associated with limited clinical benefit and an elevated rate of postoperative complications at >25 (agreement rate =95%) (1C). The MELD is used as one of the evaluation criteria for children with BA to receive LT in children aged 12 years and older, with greater LT benefit seen at >20 points (agreement rate =95%) (1C).

Recommendation 18: Liver function, nutrition and development, cardiopulmonary function, renal function, oral hygiene, risk of anesthesia, vaccinations, and screening for viral infections should be assessed prior to LT (agreement rate =100%) (1C).

Recommendation 19: The number of follow-up visits can be increased during follow-up, depending on the patient’s condition. Regular follow-up is still needed for children whose jaundice clears (agreement rate =100%) (1A).

Recommendation 20: Cholangitis should be treated aggressively and regularly once diagnosed (agreement rate =100%) (1A).

Recommendation 21: Children with gastroesophageal variceal bleeding are recommended to start endoscopic treatment immediately after treatment of acute hemorrhagic shock (agreement rate =84%) (1C). Children at risk of gastrointestinal bleeding should undergo regular endoscopy and treatment (agreement rate =84%) (2C). Echocardiography should be performed in patients with portal hypertension, and the possibility of underlying pulmonary hypertension should also be considered (agreement rate =100%) (1C).

Recommendation 22: When there are no clear contraindications to vaccination in children with BA, vaccination is routinely administered according to schedule in principle (agreement rate =100%) (1C).

Recommendation 23: Perform standardized follow-up including growth and development, neurological and nutritional assessments (agreement rate =100%) (1B).

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.