Biliary Atresia

Biliary Atresia – 10 Interesting Facts

Biliary atresia is the most common cause of obstructive jaundice in the first 3 months after birth; it is also the most common cause of end-stage liver disease and liver transplant in children worldwide²
It is imperative to differentiate benign causes of jaundice from those that require emergent intervention
Early identification of BA allows for earlier intervention and improved outcomes
Dark urine and acholic stools are distinctive of cholestasis
Elevated direct bilirubin level (greater than 1 mg/dL the first 2 weeks after birth) is diagnostic of neonatal cholestasis
Obtain abdominal ultrasonography to assess for underlying anatomic cause of cholestatic jaundice when direct hyperbilirubinemia is confirmed
Intraoperative cholangiogram is the gold standard diagnostic study for BA
First line treatment for BA is the KPE, which allows bile drainage into the small intestine, thereby decreasing liver injury
Curative treatment for BA is liver transplant
Patients who undergo transplant require lifelong immunosuppression

Alarm Signs and Symptoms

Acholic stools are distinctive of cholestasis and necessitate prompt evaluation to diagnose etiology
Ascites consistent with portal hypertension requires salt and fluid restriction and diuresis
Variceal bleeding, a sign of decompensated liver cirrhosis, requires fluid resuscitation and transfusion. In addition, coagulopathy may require fresh frozen plasma and platelet transfusion
Fever, irritability, and abdominal pain can be consistent with cholangitis and require further workup and broad-spectrum antibiotics

Introduction

BA (biliary atresia) is a neonatal progressive obliterative fibroinflammatory disease of the intra- and extrahepatic biliary tree¹
Cholestasis is defined as reduced bile formation or excretion
Neonatal cholestasis is defined as direct or conjugated bilirubin level above 95% the reference range for laboratory value within the first few days of life or greater than 1 mg/dL 2 weeks after birth
Cholestasis can be caused by various etiologies affecting the formation or excretion of bile at the level of the hepatocyte (hepatocellular cholestasis) or at the level of the biliary tree (obstructive cholestasis)
Cholestasis is always pathologic and characterized by elevation in serum conjugated bilirubin level and bile acids

Background Information

Neonatal cholestasis, although uncommon (1 per 2500 term infants), can be present at birth and is due to impaired bile flow
BA
- Most common cause of obstructive jaundice in the first 3 months after birth
- Most common cause of end-stage liver disease and liver transplant in children worldwide²
Surgical excision of the obliterated extrahepatic biliary tree and reestablishment of bile flow by KPE (Kasai portoenterostomy) are essential for overall native liver survival, with earlier intervention associated with better outcomes³⁴
If untreated, BA is uniformly fatal
Only 20% to 30% of children reach adulthood with their native liver⁵⁶ despite the surgical intervention due to the progressive fibroinflammatory nature of the disease

Epidemiology

Prevalence is 5 to 10 per 100,000 births in the United States⁷
Incidence varies around the globe, which is possibly related to genetics, environmental exposure, viruses, and toxins⁸⁹¹⁰
- Highest incidence in French Polynesia (1-3 per 10,000), followed by Taiwan (1 per 8000), and then Europe and North America (approximately 0.5 per 10,000)³¹¹
More common in females, preterm infants, and Asian and Black people⁷¹²
Seasonal variation has been reported in some studies, with a small increased incidence from August to October¹³ and December to March;¹⁴ the seasonality suggests the possibility of viral-induced etiology⁸
Isolated BA is more common in infants born to mothers with pregestational diabetes (PR [prevalence ratio], 4.94)⁷

Etiology

Figure 1. Multifactorial etiology for BA.BA, biliary atresia; BASM, biliary atresia splenic malformation syndrome.

Onset of disease has been controversial; however, evidence now supports a “fetal disease”⁷¹⁵
Several causative factors, both acquired and genetic, have been reported (Figure 1)
- Viral etiology
  - Clustering of cases during certain seasons can support a viral etiology; however, observing the presence of viruses in babies with BA did not have reproducible outcomes¹⁶
  - Largest body of evidence in support of viral infection pertains to cytomegalovirus¹⁵¹⁷¹⁸¹⁹
  - Other viruses implicated include reovirus and group C rotavirus²⁰²¹
- Toxic etiology
  - Clustering of BA cases in lambs in Australia in 1964, 1988, and 2007 during times of drought, now thought to be related to isoflavonoid toxin isolated from Dysphania plant²²
  - Use of the isoflavonoid, biliatresone, induces cholangiopathy in zebrafish, mice, and human organoids²³²⁴²⁵²⁶
- Genetic etiology
  - More common in some children with BASM subtype (biliary atresia splenic malformation syndrome)
    - Exome sequencing has identified several genes associated with BA
    - JAG1 variants found in BA²⁷
    - CFC1 mutations are 2 times more frequent in children with BASM than in general population²⁸
    - ZIC3 variants, PKD1L1 gene, and ciliary genes are found in some children with BASM²⁹³⁰
  - Genome-wide association studies revealed BA susceptibility loci in children with isolated BA
    - Chromosome 10q24 (downstream of 2 genes XPNPEP1, involved in metabolism of inflammatory mediators, and ADD3, which encodes the protein adducin 3)³¹³²
    - Chromosome 2p16.1 signals intron EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1)³³
    - Chromosome 14q21.3-3’ enhancer region for ARF6 (ADP ribosylation factor 6) (mediates epidermal growth factor receptor] signaling and regulates actin cytoskeletal modeling)³⁴
    - MAN1A2 regulates ciliogenesis; its expression is reduced in the liver of patients with BA³⁵
  - Copy number variants are also found in some patients with BA³⁶
    - Chromosome 2q37: heterozygous deletion found in approximately 10% of patients with BA and only in 0.08% of controls
    - Deletion at 2q37.3 resulted in deletion of 1 copy of GPC1, a gene that encodes glypican 1, which is a heparan sulfate proteoglycan that regulates hedgehog signaling of inflammation
- Immunologic etiology
  - Immune dysregulation has been implicated in various studies
  - Livers of some infants with BA show activation of genes involved in lymphocyte differentiation, with overexpression of osteopontin and interferon-γ and subsequent dysregulated T-helper 1 immunity³⁷
  - Single-nucleotide polymorphisms at CD14 gene, which plays a role in the recognition of bacterial endotoxin, are associated with BA and idiopathic neonatal cholestasis³⁸

Risk Factors

Maternal pregestational diabetes
- Associated with increased risk (adjusted PR, 4.94; 95% CI, 2.32-10.54)⁷³⁹
Premature birth
- An infant born between 32 and 37 weeks of gestation (adjusted PR, 1.64; 95% confidence interval)
- An infant born before 32 weeks of gestation (adjusted PR, 3.85; 95% CI, 2.38-6.22) and before 37 weeks of gestation⁷⁴⁰⁴¹⁴²
Small for gestational age increases risk for cholestasis by 2 to 3 times⁴³⁴⁴
Female sex
- Reported in some but not all studies (adjusted PR, 1.68; 95% CI, 1.33-2.12)⁷
Maternal race
- Non-Hispanic Black patients have a higher risk when compared with non-Hispanic White patients (adjusted PR, 1.66; 95% CI, 1.11-2.49)⁷¹⁴

Diagnosis

Approach to Diagnosis

Figure 2. Diagnostic evaluation of neonatal cholestasis.BA, biliary atresia; AR, autosomal recessive; DB, direct bilirubin; CBD, common bile duct ; CSF, cerebrospinal fluid; NBS, newborn screening; MMP7, matrix metalloproteinase 7; PT, prothrombin time; PTT, partial thromboplastin time; SOD, septo-optic dysplasia; UA, urinalysis; US, ultrasonography; UTI, urinary tract infection.

Jaundice in the neonatal period and early infancy may be benign or serious, requiring emergent management
- Presentation for potentially serious causes of neonatal jaundice may include:
  - Jaundice that develops in the first 24 hours after birth or persists for more than 14 to 21 days
  - Ill appearance or concerns for infection (eg, fever, hypothermia)
  - Cholestatic jaundice is always pathologic; dark urine and acholic stools are characteristic findings associated with cholestatic jaundice
Fractionated bilirubin is the key initial laboratory test to determine the type (direct or indirect) and the degree of hyperbilirubinemia
With initial diagnostic evaluation, rule out more common diagnoses that may present with neonatal cholestasis, for example, sepsis or α₁-antitrypsin deficiency
When cholestatic jaundice is a clinical concern (or direct hyperbilirubinemia is found on fractionated bilirubin measurement), obtain the following laboratory tests: CBC, PT (prothrombin time) and PTT (partial thromboplastin time), liver profile, and α₁-antitrypsin. If concerns for infection (eg, ill appearance, fever, hypothermia), obtain blood, urine, and cerebrospinal fluid cultures
Tailor further laboratory evaluation to differential diagnosis guided by clinical presentation and based on results of initial screening blood tests
First imaging test to obtain during workup of direct hyperbilirubinemia is fasting abdominal ultrasonography with a focus on liver and biliary system to differentiate causes of obstructive jaundice
If after ultrasonography, clinical concern for BA remains, then obtain serum MMP7 (matrix metalloproteinase 7) level
Gold standard imaging test to confirm BA is intraoperative cholangiogram⁴⁵
With improvements in genetic testing and newer studies such as the MMP7, liver biopsy is not always necessary. It can be helpful in instances of diagnostic uncertainty
Secondary evaluation for commonly associated comorbid conditions may be warranted with studies, including chest radiograph and echocardiogram
Figure 2 outlines diagnostic approach of neonatal cholestasis

Staging or Classification

Isolated BA
- Without major malformations
- Most common, accounting for approximately 84% of infants with BA⁴⁶
- Cytomegalovirus variant
  - Variable incidence based on geography and methodologic detection
    - 10% to 20% in European series
    - Up to 50% in some series from China¹⁵⁴⁷⁴⁸
BA with laterality defects
- Also known as BASM 10%¹²⁴⁶
- Incidence of BASM is much lower in Asian countries compared with that in North America and Europe⁴⁹
- Malformations may include:
  - Splenic malformations
    - Most common anomaly (70%)
    - Asplenia, polysplenia, right-sided spleen, or double spleen
  - Cardiovascular anomalies
    - Dextrocardia, mesocardia, total or partial anomalous pulmonary venous return, absent or interrupted inferior vena cava, anomalous or bilateral superior vena cava, and/or preduodenal portal vein
  - Gastrointestinal anomalies
    - Abdominal heterotaxy, midline or transverse liver, right-sided stomach, intestinal malrotation, and anomalous or annular pancreas
  - History of gestational diabetes may be more prevalent in this group of infants⁷
BA without laterality but with at least 1 major malformation⁴⁶
- Accounts for 6%⁴⁶
- Malformations can include:
  - Cardiovascular anomalies (71%)
    - Aortic arch abnormalities, aortic coarctation, atrial septal defects, patent ductus arteriosus, patent foramen ovale, pulmonary artery stenosis, pulmonary valvular stenosis, tetralogy of Fallot, transposition of the great vessels, and ventricular septal defect
  - Gastrointestinal anomalies (24%)
    - Duodenal or jejunal atresia, esophageal atresia, and imperforate anus
  - Genitourinary anomalies (47%)
    - Most commonly cystic kidney and hydronephrosis
Cystic BA⁵⁰
- Onset prenatal
- Accounts for 5% to 10% of some large series
- Can be seen antenatally on maternal ultrasonography
- Has better prognosis, likely due to earlier presentation and intervention⁴⁸

Workup

History

Jaundice in newborns is a common symptom. Most often the etiology is benign—either physiologic jaundice or breastmilk jaundice. History consistent with physiologic or breastmilk jaundice includes:
- Breastfed infants
- Onset a few days after birth
ABO or Rh (Rhesus) incompatibility can suggest hemolytic etiology to jaundice
Jaundice beyond 14 to 21 days increases concern for a pathologic etiology and warrants further evaluation⁵¹
Jaundice within the first 24 hours of birth suggests a pathologic etiology
Dark urine and acholic stools are distinctive of cholestasis
- Pale stool color may be noted when using SCC (stool color card) screening tool
Perinatal factors may contribute to increased risk of neonatal cholestasis
- Premature birth
- Small for gestational age increases risk of cholestasis by 2- to 3-fold⁴³⁴⁴
- Neonatal hypoxia⁴⁴
- History of neonatal infection
  - Sepsis
  - Urinary tract infection
  - TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex)
Symptoms and historical elements that may suggest a specific etiology for neonatal cholestasis
- Abnormal newborn screening test result may be reported
  - May aid in the identification of an etiology for cholestasis (eg, cystic fibrosis, galactosemia, hypothyroidism)
- Parenteral nutrition can suggest cholestasis secondary to parenteral nutrition–associated cholestasis parenteral nutrition–associated cholestasis
- History of septo-optic dysplasia can suggest hypopituitarism⁵²
- Hearing loss may suggest TORCH infection or PFIC (progressive familial intrahepatic cholestasis)
- Vomiting suggests the following:
  - Metabolic disease, such as galactosemia
  - Bowel obstruction
- Delayed passage of meconium suggests cystic fibrosis
- History of abdominal surgery or necrotizing enterocolitis
Elements of prenatal history that increase risk of neonatal cholestasis are as follows:
- Cholestasis of pregnancy (suggests maternal heterozygosity for PFIC gene mutations)
- Acute fatty liver of pregnancy (suggests long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency)
- Maternal infections (TORCH)
Prenatal abnormal imaging results can often identify the etiology of cholestasis
- Growth restriction
- Choledochal cyst
- Bowel anomalies
- Cystic BA
- BASM
Family history that may increase risk for neonatal cholestasis
- Previous miscarriages or fetal loss suggests GALD (gestational alloimmune liver disease)
- Neonatal cholestasis in parent or siblings can suggest a hereditary etiology
  - PFIC
  - Cystic fibrosis
  - α₁-Antitrypsin deficiency
  - Alagille syndrome (OMIM #118450)

Physical Examination

General appearance
- Ill appearance suggests pathologic etiology of jaundice, such as infection, or genetic or metabolic liver disease, such as galactosemia
- Poor growth can be consistent with cystic fibrosis or metabolic or genetic liver disease
- Low tone suggests genetic or metabolic liver disease
- Dysmorphic features suggest Alagille syndrome
Eyes
- Scleral icterus is consistent with elevated levels of bilirubin
- Cataracts suggest TORCH infections, or genetic or metabolic liver disease
- Inability to fix and follow beyond 3 months of age suggests septo-optic dysplasia
Cardiac examination
- Heart murmurs in the context of neonatal cholestasis can be consistent with Alagille syndrome, BASM, or congenital heart disease
Abdominal examination
- Ascites suggests liver failure as seen with GALD
- Hepatomegaly consistent with BA
- Splenomegaly is a later finding in BA
- Umbilical hernia can be seen with hypothyroidism
Stool inspection
- Integral part of the physical examination in any infant who has jaundice
- Acholic stools are consistent with obstruction of biliary tree
- Acholic stools are present in two-thirds of infants with BA at day of life 30⁵³
Petechiae and bleeding
- Petechiae suggests possible TORCH infection
- Bleeding can be consistent with vitamin K deficiency which can also be seen in severe liver failure such as GALD and tyrosinemia

Laboratory Tests

Liver profile
- Total bilirubin
  - If level is elevated in the context of a normal direct bilirubin level, it indicates an elevated indirect bilirubin level
  - Elevated indirect bilirubin level consistent with ABO or RH incompatibility
- Direct bilirubin
  - Surrogate marker of cholestasis in most cases⁵⁴⁵⁵
  - Indicated in any patient with jaundice beyond 14 days of age
  - Levels greater than 1 mg/dL 2 weeks after birth is diagnostic of neonatal cholestasis
  - Values exceeding 95% the reference range in the first few days of life is also diagnostic of neonatal cholestasis
  - Level uniformly elevated in patients with BA in the first 24 to 48 hours after birth⁵⁵
- GGT (γ-glutamyltransferase)
  - Higher in the neonatal period compared with older children⁵⁶
  - GGT value is usually high in cholestasis
    - Generally higher in BA, Alagille syndrome, and α₁-antitrypsin deficiency than in other etiologies of neonatal cholestasis⁵⁷
    - Normal GGT level at presentation predicts poor outcome in BA⁵⁸
  - Low or normal GGT level in the context of cholestasis
    - Suggests metabolic or inherited disorders, such as PFIC or bile acid synthesis defects⁵⁹
  - AST/ALT levels⁶⁰
    - Elevations suggest liver injury
- Isolated AST elevation
  - In instances when AST level is elevated, but total bilirubin, direct bilirubin, and ALT levels are not significantly elevated, hematologic or muscular sources are most likely
CBC
- Elevated WBC count suggests infection
- Low hemoglobin and RBC count suggest hemolysis
- Thrombocytopenia suggests infection or splenic sequestration
PT or INR
- May be prolonged with impaired liver synthetic function
PTT
- Prolongation is usually seen in hematologic disorders but may be prolonged with severe advanced liver disease
Newborn screening test results
- May help identify genetic causes of liver disease (eg, cystic fibrosis, galactosemia, hypothyroidism)
TSH and free T₄ (thyroxine)
- Both hypothyroidism and hyperthyroidism can cause neonatal cholestasis
- Elevated TSH level with low levels of free T₄, consistent with hypothyroidism
- Low TSH level with elevated levels of free T₄, consistent with hyperthyroidism
α₁-Antitrypsin phenotype⁶⁰
- α₁-Antitrypsin deficiency can present similarly to BA
- Normal allelic variant PiMM
- PiZZ and PiSZ associated with liver disease
- Patients with BA with non-M allele are listed for transplant earlier; these patients have lower survival with native liver at 24 months⁶¹
MMP7
- Indicated in neonates with cholestasis and elevated GGT level
- A protease expressed in normal cholangiocytes
  - Responsible for tissue remodeling
  - Associated with liver fibrosis
- Second-tier testing in neonates with high GGT cholestasis
- Levels vary with age, fibrotic disorders, and with congenital heart disease⁶²
- Levels also vary significantly among different enzyme-linked immunosorbent assay kits⁶³ but uniformly elevated in BA
  - In a prospective study of 135 infants with cholestasis compared with healthy infants, serum MMP7 values were higher in infants with BA
    - Diagnostic sensitivity and specificity were 98.67% and 95.00%, respectively, with a negative predictive value of 98.28% for BA (ROC AUC [area under the receiver operating characteristic curve] 0.99 using a cutoff of 52.85 ng/mL)⁶³
  - In another prospective study of 288 patients with neonatal obstructive jaundice, MMP7 demonstrated good accuracy in diagnosing BA (ROC AOC of 0.9829 at a cutoff value of 10.37 ng/mL), with sensitivity, specificity, positive predictive value, and negative predictive values of 95.19%, 93.07%, 97.27%, and 91.43%, respectively⁶⁴
- With increasing evidence of its accuracy and specificity, experts note its increasing use in clinical practice
  - Turnaround times can take several days

Imaging Studies

Fasting abdominal ultrasonography
- Initial imaging study to evaluate cholestasis in neonates
- Fasting should be carried out with caution in infants with a higher suspicion for metabolic liver disease
- Identify cystic lesions
  - Choledochal cyst
  - Cyst in liver hilum as seen with cystic BA
  - Visible obstructing lesions of the biliary tree
- Signs with a high specificity for BA⁶⁵
  - Triangular cord sign (obliterated fibrous ductal remnant)
  - Gallbladder abnormalities
  - Variable sensitivity depending on the operator or institution
- Can identify vascular or splenic abnormalities as seen with BASM
- Evaluate for signs of advanced liver disease, such as splenomegaly, nodular liver, and varices
- Many, but not all, infants with BA have a small or undetectable gallbladder⁶⁰⁶⁶
- A normal study does not exclude BA⁶⁵
HBS (hepatobiliary scintigraphy)
- HBS uses technetium-99m–labeled iminodiacetic acid derivatives as a radiotracer
- HBS can exclude BA by demonstrating transit of the radiotracer into the bowel
- No need for NPO status for infants to exclude BA
- Administration of phenobarbital for 5 days before the study may enhance biliary excretion of the isotope; its use is center dependent
- Acquire images dynamically up until 1 hour; if no excretion, delayed static imaging should be acquired at 4 hours and at 24 hours postinjection
- Nonsecretion is not specific to BA and can also be seen with other etiologies of cholestatis⁶⁷
- An appropriately performed study is sensitive with rare false-negative results;⁶⁸ for example, excretion of radiotracer into the intestine is very helpful to exclude BA; absence of excretion does not in aid in diagnosis
Magnetic resonance cholecystopancreatography
- Findings consistent with BA⁶⁷
  - Nonvisualization of extrahepatic biliary tree
  - Nonvisualization of gallbladder
  - Periportal thickening at porta hepatis on T2-weighted images
- Use is center dependent
- Gentle swaddling or sedation is a possible option to avoid movement artifact
- Meta-analysis of 7 studies demonstrated sensitivity of 89% and specificity of 64.7%⁶⁹
PTCC (percutaneous transhepatic cholecysto-cholangiography)
- Limited role, at present, because few centers in the United States are using this study⁷⁰
  - Limited expertise
  - Invasive
- Alternative to intraoperative cholangiogram
- PTCC is an ultrasonography-guided technique performed under general anesthesia
  - Nonionic contrast medium is injected into the gallbladder via liver parenchyma
  - Can only be performed when gallbladder lumen is present⁶⁷
- Might miss an atretic common hepatic duct⁷¹
- Is usually done instead of intraoperative cholangiogram, which is considered the gold standard
ERCP (endoscopic retrograde cholangiopancreatography)
- Limited use due to the need of an experienced endoscopist and infant-specific endoscope
- Requires general anesthesia
- ERCP sensitivity ranges between 86% and 100%, with the specificity 79% to 94% (age range: 19-175 days); range of sensitivity and specificity due to interoperator variability⁷²⁷³

Diagnostic Procedures

Figure 3. Histology of BA. Hematoxylin and eosin stain of a liver biopsy of a 3-month-old girl show a proliferation of bile ductules. Bile plugs are present. – BA, biliary atresia.From Lane ER et al. Disorders of the liver. In: Gleason CA et al, eds. Avery’s Diseases of the Newborn. 10th ed. Elsevier; 2018:1098-1112.e2, Figure 77.3.

Liver biopsy
- Continues to play an important role in the diagnostic workup of infants with BA; however, timing of liver biopsy might evolve with the addition of new diagnostic tests, such as MMP7, and improvements in genetic testing
- Ultrasonography-guided percutaneous core liver biopsy is a safe option in children with a low complication rate of 1.7%⁷⁴
- Liver biopsy interpretation by an experienced pathologist can provide the correct diagnosis in 90% to 95% of cases in patients with cholestasis⁷⁵⁷⁶
- Pathologists are able to diagnose obstruction in 79% to 98% of the cases, with a positive predictive value of 90.7%
- Classic histologic features of biliary obstruction (Figure 3)
  - Bile duct proliferation
  - Bile plugs
  - Portal or perilobular fibrosis
  - Edema
  - Preservation of the basic hepatic lobular architecture
- Parenteral nutrition–associated liver disease and α₁-antitrypsin deficiency have findings similar to those of BA
  - α₁-Antitrypsin phenotype and history of total parenteral nutrition infusion to differentiate
- Early liver biopsies may not have the classic obstructive signs⁷⁷
- In many centers, liver biopsy (needle core or surgical wedge biopsy) is obtained at the time of PTCC or intraoperative cholangiogram to exclude BA
- Degree of liver fibrosis can correlate with outcomes
IOC (intraoperative cholangiogram)
- IOC and histologic examination of the duct remnant are considered the gold standard to diagnose BA⁶⁰
- A catheter is placed into the cystic duct and dye is injected to visualize patency of the bile ducts proximally into the liver and distally into the duodenum
- If IOC is consistent with an atretic bile duct, then the surgeon proceeds to KPE at the same time

Differential Diagnosis

Table 1. Differential Diagnosis: Neonatal cholestasis.

Condition	Description	Differentiated by
Bile duct obstruction
BA	• Neonatal progressive obliterative fibroinflammatory disease of the intra- and extrahepatic biliary tree	• Intraoperative cholangiogram that shows obstruction of biliary tree
Alagille syndrome	• Autosomal dominant genetic disorder with abnormal bile duct development often associated with cardiac anomalies, triangular facies, or butterfly-shaped vertebra	• Liver biopsy demonstrating few bile ducts and associated cardiac, bony, or facial abnormalities • Genetic testing
Choledochal cyst	• Congenital cyst in the bile duct	• Isolated abnormality and remainder of biliary tree is normal
Neonatal sclerosing cholangitis	• Fibrosis of biliary ducts	• Patent biliary tree • Gene sequencing: CLDN1 and DCDC2 can help in diagnosis
Genetic disorders
Cystic fibrosis	• Genetic disorder of chloride channel that causes thickened secretions affecting the lungs and digestive tracts	• Abnormal newborn screening test result • Abnormal sweat chloride test result
α₁-Antitrypsin deficiency	• Inadequate production of α₁-antitrypsin protein	• Low levels of α₁-antitrypsin • Confirmed with α₁-antitrypsin phenotype or genotype
Metabolic disorders
Galactosemia	• Inability to break down galactose, which can lead to seizures, vomiting, increased risk of infection, or developmental delay	• Generally identified on newborn screening test results with consistent laboratory findings
Fatty acid oxidation defects	• Inability to break down fats and can present with weakness, hypotonia, poor growth, or vomiting	• Patients often present with hypoglycemia and identified on newborn screening test results
Glycogen storage disease	• Inability to use or produce glycogen that can result in hypoglycemia and hepatomegaly	• Tissue biopsy and genetic testing
Mitochondrial disorders⁷⁸	• Abnormalities of the mitochondria with a wide array of symptoms but often with hypotonia, seizures, or developmental delay	• Consistent laboratory studies, including abnormalities in serum or urine organic acid, amino acid, pyruvate, acylcarnitine, and lactate levels, with muscle biopsy for confirmation⁷⁸
Endocrine disorders
Hypothyroidism	• Often presents with lethargy, constipation, feeding difficulty	• Can be identified by newborn screening tests and confirmed with low levels of free T₄
Panhypopituitarism	• Deficiency of all hormones produced by pituitary gland	• Confirmed by newborn screening tests, blood tests, and brain imaging
Toxins
Parenteral nutrition–associated cholestasis	• Neonates requiring prolonged parenteral nutrition can develop cholestasis with increasing bilirubin level	• Normal hepatobiliary scintigraphy, cholangiogram, and abdominal ultrasonography
Infection or immune mediated
TORCH	• Ill-appearing infants	• Serologies
GALD	• Ill-appearing infants, fetal growth retardation, jaundice, or acute liver failure soon after birth	• MRI of the abdomen • Tissue biopsy demonstrating iron deposits

Caption: CMV, cytomegalovirus; GALD, gestational alloimmune liver disease; T4, thyroxine; TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex.

Treatment

Approach to Treatment

Treatment of BA is primarily surgical and aimed at reestablishing bile flow by HPE (hepatoportoenterostomy)
Infants who present late can have evidence of cirrhosis at the time of referral and may require primary liver transplant rather than HPE
In addition to surgery, treatment modalities include:
- Nutritional optimization to meet caloric demands and attain appropriate growth parameters
- Medications aimed at improving bile flow and decrease risk of infection

Initial Treatment Procedures

Kasai Portoenterostomy

Figure 4. Anatomy of KPE. – KPE, Kasai portoenterostomy.From Rogers JL. McCance and Huether’s Pathophysiology: The Biologic Basis for Disease in Adults and Children. 9th ed. Elsevier;2024:chap 42, Figure 42.9.

HPE procedure that allows for drainage of bile into the small intestine, thereby decreasing liver injury⁷⁹ (Figure 4)
- Developed by Dr Morio Kasai in the 1950s
- Excision of entire remnant of extrahepatic biliary tree
- A limb of the jejunum is anastomosed to the exposed remaining ductules or the hilum of the liver surface
- Distal duodenum is anastomosed to the jejunal limb, creating the Roux-en-Y configuration
Most infants with BA undergo KPE
KPE is not a curative procedure due to the intrahepatic biliary duct involvement of BA
Previous studies have indicated longer operating times with worse outcomes when the procedure was done laparoscopically
With technological improvements, procedures done laparoscopically can have equivalent outcomes compared with those done open, often with decreased operative bleeding and shortened duration of time when infants are able to tolerate feeds⁸⁰⁸¹
Early KPE, ideally before 30 days of life, is associated with improved native liver survival¹¹

Nondrug and Supportive Care

Nutritional supplementation
- Essential in infants with BA, especially in those with nondraining KPE
- Malnutrition can be due to multifactorial causes⁸²
  - Poor caloric intake
  - Intolerance to enteral feeding
  - Fat malabsorption secondary to insufficient intraluminal bile salts
  - Increased caloric demand
- Caloric needs in infants with BA are approximately 130% to 150% of the recommended energy intake for healthy infants and children
  - Protein needs are also increased 3 to 4 g/kg/day in infants and 2 to 3 g/kg/day in children⁸³
- Expressed breast milk can be fortified with medium-chain triglyceride oil, which is beneficial because it does not require bile acids for absorption
- Use high medium-chain triglyceride content formulas, which can be concentrated to provide 24 to 27 kcal/oz or more to achieve growth⁸³
- Supplemental feeding by a nasogastric tube is frequently needed in infants with cholestasis and in children with nondraining KPE due to inability to meet their caloric needs
- Gastrostomy tubes are usually avoided, because many patients with BA develop portal hypertension early in their disease course
- Parenteral nutrition can be considered in patients with malnutrition or with complications of chronic liver disease and awaiting liver transplant⁸⁴

Drug Therapy

FSV (fat-soluble vitamin) supplementation
- Indicated in all infants with BA
- FSV deficiencies are very common in patients with BA with persistent cholestasis at all time points⁸⁵
- Supplementation with high-dose FSVs, such as DEKAs Plus, is typically preferred with extra supplementation of specific FSV deficiencies⁸⁶
- DEKAs Plus liquid dosing: 1 mL PO daily⁸⁷
Ursodeoxycholic acid⁸⁸
- A hydrophilic bile acid
- Although generally recognized as standard of care, it has not been rigorously studied⁸⁹⁹⁰
- Increases hydrophilic bile acid pool
- Stabilizes plasma membranes
- Prevents apoptosis
- Acts as an immunomodulator
- Dose: 10-20 mg/kg/day PO divided twice a day
Prophylactic antibiotics
- Most infants will have at least 1 episode of cholangitis before age 2 years,⁹¹⁹² with the incidence of cholangitis post-KPE between 40% and 90%⁹³⁹⁴
- Use of IV antibiotics immediately after KPE is standard of care
- Transition to oral prophylactic antibiotics for a minimum of 6 to 12 months after KPE⁹¹⁹² to prevent cholangitis, which may affect long- and short-term outcomes⁹¹⁹²
- Prophylactic antibiotic regimens can include:⁹⁵⁹⁶⁹⁷
  - Trimethoprim-sulfamethoxazole, which is most commonly prescribed
  - Neomycin
  - Oral penicillins, such as amoxicillin or amoxicillin-clavulanate
  - Oral cephalosporins
Glucocorticoids
- Not clinically indicated
- Use did not improve outcomes
  - In a randomized placebo-controlled trial of glucocorticoid treatment in 140 infants with BA given for 13 weeks did not improve bile drainage at 6 and 24 months post-HPE, nor did it improve survival with native liver at age 2 years⁹⁸
  - More adverse events related to impaired growth across all parameters (length, weight, and head circumference) for at least 6 months post-HPE⁹⁹
  - Despite evidence to the contrary, various centers continue to use high-dose glucocorticoid regimens, some demonstrating improved outcome
    - Larger cohorts are needed to validate these results
Immunoglobulin therapy
- Has not been demonstrated to improve outcomes
- In a multicenter, prospective, open-labeled, phase I or IIA trial of IVIg, with 1 g/kg/dose of IVIg infused at 3 to 5, 30, and 60 days post-HPE, there was no trend to lower bilirubin levels or improve 360-day survival in 29 infants with the native liver as compared with historical controls¹⁰⁰

Liver Transplant

Most patients with BA require liver transplant in childhood, with only 20% to 30% entering adulthood with their native liver⁵⁶
Indications⁸⁴
- Nondraining KPE
- Refractory growth failure
- Decompensated cirrhosis manifests as follows:
  - Ascites
  - Recurrent variceal bleeding
  - Hepatopulmonary syndrome: pulmonary vascular dilation and hypoxemia
- Recurrent cholangitis
- Metabolic bone disease
- Hepatocellular carcinoma
1- and 5-Year patient survival after liver transplant for patients with BA is excellent at 95% to 97%, respectively¹⁰¹
Long-term survival after liver transplant in general is excellent, with a projected survival of 80% at 30 years after liver transplant¹⁰²
Liver transplant is curative
After liver transplant, patients require lifelong immunosuppression

Admission Criteria

At initial presentation, extensive evaluation may necessitate admission
Other indications for admission include:
- Symptoms of cholangitis, for example, fever, abdominal pain, or vomiting
- Poor growth despite outpatient interventions
- Signs and symptoms of liver failure, for example, confusion or altered mental status, or coagulopathy
- Bleeding varices (because of portal hypertension)

Follow-Up

Monitoring

FSV (fat-soluble vitamin) levels
- Monitor FSV levels routinely starting at the first month after HPE or at the establishment of diagnosis of BA if late referral
- Low levels of specific vitamins may require individual vitamin supplementation in addition to DEKAs
- If FSV levels are in the target range, then frequency of monitoring can be decreased from every 3 months to 6 months⁸⁶
INR
- Indicator of vitamin K deficiency, in addition to liver function
- Every 2 to 4 weeks in infants with cholestasis
Posttransplant¹⁰³
- Immediately after transplant, follow-up visits are more frequent, for example, weekly
- Over time, follow-up visits may be less frequent, for example, every few months but at least annually
- Monitor growth. Measure height and weight at each follow-up visit
- Screen for hearing loss at 1 year after transplant
- Monitor immunosuppression levels at each visit
- Serial measurements of liver enzyme and bilirubin levels to assess graft health

Complications

Cholangitis

Ascending cholangitis is inflammation and infection of bile ducts and is the most common complication in patients after HPE, with incidence as high as 50% to 90% (more common in draining HPE)⁹³⁹⁴
Can recur with highest incidence in the first 2 years after HPE
Appropriate prophylactic antimicrobial treatment is used to decrease the incidence of ascending cholangitis after KPE
- Gram-negative pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, are the most frequently reported isolated bacteria
- Of the gram-positive pathogens, Enterococcus species and Staphylococcus aureus are more common
- Candidal fungal infection is less commonly reported⁹²
Cholangitis can present with the following:
- Fever without a clear source of infection, the most common symptom
- Abdominal pain
- Acholic stools
- Irritability
Treatment with broad-spectrum IV antibiotics
- Piperacillin-tazobactam
- Ceftriaxone plus metronidazole
- Ampicillin-sulbactam
- In patients with penicillin allergy, quinolones, such as ciprofloxacin, or aminoglycosides with metronidazole can be used
Recurrent cholangitis may increase risk for progressive liver disease¹⁰⁴
- Presence of bile lakes increases risk for cholangitis¹⁰⁵¹⁰⁶

Portal Hypertension, Variceal Bleeding, and Ascites

Most children with BA have chronic liver disease and portal hypertension¹⁰⁷
In children with BA, suspect portal hypertension if¹⁰⁸
- Thrombocytopenia (platelet count less than 150,000/mm³)
- Splenomegaly (2 cm below costal margin)
Most common complications of decompensated cirrhosis¹⁰⁷
- Ascites
- Variceal bleeding¹⁰⁸
  - Incidence in children with BA at 5 years is around 10%

Prognosis

Early identification of cholestatic jaundice improves outcome
Native liver survival and overall survival rates are inversely correlated with age at KPE and reestablishment of bile flow³¹⁰⁹¹¹⁰
Infants with poor biliary drainage after HPE develop end-stage liver disease and progress to liver transplant within the first 2 to 3 years of life
Some countries have adopted centralization of surgical procedures at designated centers where expertise and higher caseloads have yielded better long-term outcomes¹¹¹¹¹²
After KPE, bilirubin levels at 3 months of age in infants with BA correlate with transplant-free survival at 2 years¹¹³
- 86% in the patient group with total bilirubin level less than 2 mg/dL
- 20% in the patient group with total bilirubin level more than 2 mg/dL. These patients also are more likely to experience the following:¹¹³
  - Diminished weight gain
  - Ascites
  - Hypoalbuminemia
  - Coagulopathy
  - Death
Almost all patients (more than 98%) with BA living with their native liver for 5 or more years after KPE have chronic liver disease¹⁰⁷
20-Year transplant-free survival rate is around approximately 30%.¹¹⁴ All these patients have chronic liver disease and portal hypertension

Referral

Refer any infant with cholestasis to a pediatric gastroenterologist or hepatologist for appropriate workup
Refer any infant with BA to a liver transplant center for evaluation and transplant listing if they have persistent cholestasis, growth failure, and/or decompensated cirrhosis

Screening and Prevention

Screening

SCC programs
- SCC programs give caregivers after birth of their baby a card with color photographs of normal and pale stools in infants. Caregivers are instructed to call a central phone number if they notice pale stools. They are also instructed to return the stool card after 1 month by mail or during health visit
- National screening for BA using SCC program was first implemented in Taiwan, which has one of the highest incidences of BA
  - Sensitivity, specificity, and positive predictive value for detecting BA by 60 days of age were 89.7%, 99.9%, and 28.6%, respectively
  - Screening program led to more KPs before 60 days of life⁹
SCC has also been implemented successfully in other countries, such as Japan, Germany, Switzerland, and Brazil with some variations¹¹⁵¹¹⁶
Although not widely adopted, an app for stool color using a smartphone’s camera and internal color recognition software has been developed and may be a valuable tool in earlier identification of cholestasis¹¹⁷

References

1.Sundaram SS et al. Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care. Liver Transpl. 2017;23(1):96-109.