Diseases of bile duct in children

Table 1 Screening methods for biliary atresia

	Methods	Country (yr)	Sensitivity (%)	Specificity (%)	Prevalence of BA (per 10000 live births)	Outcomes/advantages
Yellow Alert campaign	Testing conjugated bilirubin in all babies with persistent jaundice after 2 wk	United Kingdom (1993)	N/A	N/A	N/A	N/A
SCC	Distribution of a picture of abnormal stool color to raise BA awareness	Japan[38] (1994)	76.5	99.9	1.1	The mean age of Kasai was 59.7 and 68.2 d, and NLS at 12.5 years was 48.5% vs 36.6% (SCC users vs non-users)
		Taiwan (2004)	84	99.9	1.7	67% of patients with BA underwent Kasai within 60 d
		China[57] (2013)	100	99.9	1.3	N/A
		British Columbia (2014)	83	99.9	0.7	The median age at Kasai was 49 vs 116 d (success vs failed program screening)
Mobile application	PoopMD[44]	United State (2015)	100	89	N/A	Easy to use; improve the ability to analyze near-normal stool color; automated reminder every 1-2 wk until 8 wk of life; current contact with a pediatrician if abnormal
	BabyPoop[45]	Japan (2017)	100	100	N/A
	Popòapp[46]	Italy (2020)	100	99	N/A
Fractionated bilirubin screening	Measuring conjugated bilirubin levels in all infants aged 4-28 d infants with conjugated bilirubin > 18 μmol or % conjugated bilirubin > 20% were followed up and further evaluated immediately	United Kingdom[49] (1995)	100	95.5	N/A	Can also identify other causes of cholestasis jaundice earlier
	N/A	United States[48] (1998)	100	99.9	1.7
Laboratory markers	Matrix metalloproteinase-7	United States[51] (2017)	97	91	N/A	N/A
		China[52] (2018)	98.6	95	N/A	52.85 ng/mL (AUC 0.99)
		Taiwan[58] (2019)	97	83	N/A	1.43 ng/mL (AUC 0.96)
		Iran[53] (2022)	95.5	94.5	N/A	7.8 ng/mL (AUC 0.98)

SCC: Stool color card; BA: Biliary atresia; NLS: Native liver survival; N/A: Not applicable; AUC: Area under the curve.

Table 2 Summary of the accuracy of abdominal sonography in the preoperative diagnosis of biliary atresia[62-65]

Finding	Sensitivity (%)	Specificity (%)	Positive predive value (%)	Negative predictive value (%)
Triangular cord sign	23.3-93	97.1-100	77.8	74.4
Abnormal gallbladder	83.3-85	82.6-94.4	67.6	91.9
Absent gallbladder	28-53	94-100	96-100	46-75
Nonvisualized common bile duct	83-93.3	47.8-71	43.8-90	56-94.3
Negative triangular cord sign with a normal gallbladder	-	-	-	91.9

Table 3 Disorders associated with nonsyndromic bile duct paucity in children[109,110]

Disease type	Cause
Metabolic and genetic disorders	Alpha-1 antitrypsin deficiency
	Cystic fibrosis
	Peroxisomal disorders
	Niemann pick type C
	Kabuki syndrome (rare)
	Chromosomal abnormality (trisomy 17, 18, or 21) (rare)
Infections	Congenital cytomegalovirus, syphilis, and rubella infection
Inflammatory and immune disorders	Hemophagocytic lymphohistiocytosis
	Graft-versus-host disease
	Chronic hepatic allograft rejection
	Sclerosing cholangitis (primary or secondary)
	Biliary atresia (late)
Others	Drug- or antibiotic-associated vanishing bile duct syndrome
	Panhypopituitarism
	Idiopathic

Table 4 Revised diagnostic criteria for diagnosis of Alagille syndrome[113-115]

Major criteria: Organ involvement (%)	Findings	Frequency in mutation-positive patients
		JAG1	NOTCH2
Hepatic (75%-100%)	Bile duct paucity and/or cholestasis	100%	100%
Cardiac (85%-98%)	Peripheral pulmonary artery stenosis, pulmonary atresia, atrial or ventricular septal defect, and Tetralogy of Fallot	100%	60%
Skeletal (33%-87%)	Butterfly vertebrae, hemivertebrae, fusion of adjacent vertebrae, and spina bifida occulta	64%	10%
Renal (19%-73%)	Uteropelvic junction anomaly or renal tubular acidosis	40%	44%
Ocular (56%-88%)	Posterior embryotoxon, optic drusen, pigmentary retinopathy, and angulated retinal vessels	75%	63%
Facial characteristics (70%-98%)	Broad forehead, deep-set eyes, up-slanting palpebral fissure, prominent ears, straight nose with bulbous tip, and pointed chin (triangular facies)	97%	20%
Vascular (4%-38%)	Aneurysm of intracranial vessels, Moya Moya disease, aneurysm of intra-abdominal vessels, renovascular anomalies, and middle aortic syndrome[116]	N/A	N/A

JAG1: Jagged canonical notch ligand 1; NOTCH2: Neurogenic locus notch homolog protein 1; N/A: Not applicable.

Table 5 Nutritional management in children with cholestasis[118]

Nutrition	Daily requirement
Energy	130% of the requirement for age
Fat	30%-50% of total calories (MCT/LCT = 30%/70% of total fat calories)
Protein	130%-150% of requirement for age
Carbohydrate	40%-60% of total calories
Vitamins and minerals
Vitamin A	< 10 kg: 5000 IU/d
	> 10 kg: 10000 IU/d
Vitamin D	Cholecalciferol: 2000-5000 IU/d
Vitamin E	TPGS: 15-25 IU/kg/d
Vitamin K	2-5 mg/d

MCT: Medium-chain triglyceride; LCT: Long-chain triglyceride; TPGS: Tocophersolan.

Table 6 Medications for cholestasis and pruritus in Alagille syndrome[109,114,123]

Medications	Actions	Dose (kg/d)	Adverse effects
Ursodeoxycholic acid	Choleretic, stimulates bile flow	10-20 mg	Vomiting, diarrhea, and abdominal pain
Cholestyramine	Bile acid-binding resins	0.25-0.5 g	Vomiting, diarrhea, and poor palatability
Rifampicin	Pregnane X receptor agonist increases the metabolism of pruritogenic substances	5-10 mg	Hepatitis, thrombocytopenia, hemolytic anemia, and red discoloration of bodily fluid (sweat, tears)
Phenobarbital	Choleretic enhancement of glucuronyl transferase activity	5-10 mg	Central nervous system depression and vomiting
Naltrexone	Opioid receptor antagonist	0.25-0.5 mg	Opioid withdrawal-like reactions, abdominal pain, and irritability
Maralixibat	Ileal bile salt transporter	380 μg	Diarrhea, abdominal pain, and rash
Ondansetron	Serotonin (5-HT3) receptor antagonist	0.1-0.2 mg	Dizziness, constipation
Hydroxyzine	Antihistamine	2 mg	Rash, drowsiness, and dry mouth
Diphenhydramine	Antihistamine	5 mg/kg/d	Drowsiness, constipation, and nausea

Table 7 Characteristics of cholesterol and pigmented gallstones in children[150,152]

	Cholesterol stones	Pigmented stones
		Brown	Black
Mechanism	Hypersecretion of cholesterol. Increased mucin production. Decreased gallbladder motility	Biliary tract infected with bacteria producing β-glucuronidase. Excess bilirubin glucuronides in bile to unconjugated bilirubin or phospholipase A1 hydrolysis of biliary phosphatidylcholines that creates calcium salts	Increased bilirubin production. Decreased enterohepatic circulation (ileal disease) of the endogenous bile salt pool
Content	Cholesterol (50%), glycoprotein and minimal calcium salts	Calcium bilirubinate (60%), calcium palmitate and stearate (15%), cholesterol (15%), and mucin glycoprotein (10%)	Bile-pigmented polymer (40%), calcium carbonate or phosphate salts (15%), and cholesterol (5%)
Risk factor	Obesity, adolescence, Hispanic ethnicity, female, and family history	Bacterial (E.coli) or parasitic infection, bile duct anomaly, and birth control pills	Hemolytic anemia, cirrhosis, TPN, ceftriaxone, and ileal resection
Age	Puberty increases with age	Any	Any
Size, number	Solitary 2-4 cm. Multiple < 5 mm	Vary	Multiple 1-3 cm
Radiopaque	No	No	Yes (50%)
Recurrent	Yes	Yes	No

E.coli: Escherichia coli; TPN: Total parenteral nutrition.

Table 8 Todani classification of choledochal cyst by types and features[161]

Type	Features
I	Cystic dilatation of the common bile ducts
Ia	Large saccular cystic dilatation
Ib	Small localized segmental dilatation
Ic	Diffuse (cyclindric) fusiform dilatation
II	Diverticulum of the common bile duct and/or gallbladder
III	Choledochocele
IV	Multiple cysts
IVa	Intrahepatic and extrahepatic
IVb	Extrahepatic only
V	Fusiform intrahepatic dilatation (may be related to Caroli’s disease)