Neonatal Cholestasis: Causes, Diagnosis, and Treatment in Infants

What is Neonatal Cholestasis?

• Neonatal cholestasis is a prolonged elevation of serum-conjugated bilirubin beyond the first 14 days of life.
• Conjugated hyperbilirubinemia elevates the conjugated or direct fraction by over 20% of the total serum bilirubin.
• Conjugated is always pathological at any time in neonates.
• Unconjugated bilirubinemia is physiological jaundice and is not pathological.

Causes of Neonatal Cholestasis

• Neonatal cholestasis is of two forms: intrahepatic and extrahepatic.
• The extra-hepatic disease is caused by extra-hepatic biliary atresia that causes obstruction or injury of the bile duct. 

Intrahepatic Disease

• Phenomena within the liver cause it: hepatocytic injury or bile duct injury.
• Bile duct injuries are categorised as intrahepatic bile duct injury or paucity.
• Hepatocytic injuries are due to three causes:
  • Metabolic abnormalities
  • Viral infections
  • Idiopathic neonatal hepatitis.

Extrahepatic Disease

• The most common cause of overall neonatal cholestasis is extra-hepatic biliary atresia, contributing to 35–41% of cases.
• Idiopathic neonatal hepatitis is the second most common cause of neonatal cholestasis.
• The other causes include
  • Alpha1-AT deficiency
  • Alagille syndrome
  • Neonatal hemochromatosis/GALD
  • Galactosemia
  • Tyrosinemia
  • Choledochal cyst
  • Mitochondrial disorders
  • Progressive familial intrahepatic cholestasis
  • Sepsis
  • TORCH infection
• Giant cell transformation of hepatocytes is frequently seen in the biopsy of infants with cholestasis, more commonly in patients with intrahepatic causes. It is not seen in older patients with cholestasis.
• Patients who develop ascites are at high risk of spontaneous bacterial peritonitis.
• Sepsis causes cholestasis mediated by endotoxin commonly produced by Escherichia coli.
• Prognosis in neonatal hepatitis
  • In sporadic cases, 60–70% recover with no evidence of hepatic structural or functional impairment.
  • In familial cases, only 20–30% recover.

Also read: Gastrointestinal Foreign Bodies in Children: Bezoars & Ingestion

Individual Disorders

Aagenaes Syndrome

• It is a form of idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities.
• Lymphedema is attributable to decreased hepatic lymph flow or hepatic lymphatic hypoplasia.
• The causative mutation occurs in the long arm of chromosome 15q.
• Patients with Aagenaes syndrome present episodic cholestasis with elevated serum aminotransferase, alkaline phosphatase, and bile acid levels.
• Between episodes, patients are usually asymptomatic and have improved biochemical indices.
• With age, the frequency of episodes decreases. Good prognosis.

PFIC

• It stands for Progressive Familial Intrahepatic Cholestasis.
• It is a group of disorders characterized by the deficiency or abnormality of biliary epithelial transporters.
• It occurs in three forms: PFIC 1 (earlier called Byler's disease), 2, and 3.
• They all show autosomal recessive inheritance, and the patients require an orthotropic liver transplant.

Familial Hypercholanemia

• It is characterized by elevated serum bile acid concentration, pruritis, failure to thrive, and coagulopathy.
• It can occur due to mutations in the following genes.
  • Bile acid CoA gene
  • BAAT gene
  • TJP2 gene
• Treatment for hypercholanemia is ursodeoxycholic acid.

Also read: Abdominal Tuberculosis in Children: Symptoms, Diagnosis &

Biliary Atresia

• It is also called non-cystic obliterative cholangiopathy.
• Its prevalence is 1 in 10000 to 15000 live births.
• It is more common in East Asian countries.

Anatomical Classification of Biliary Atrea

Anatomically, the cystic and hepatic ducts fuse to form a common bile duct.

Type 1

• Type 1 biliary atresia is characterized by obliteration of the proximal portion of the common bile duct, while the cystic duct and common hepatic duct are normal. Thus, atresia affects the part of the bile duct opening into the intestine.
• It is a rare form that occurs in about 7% of patients.

Type 2

• It contributes to about 15% of biliary atresia cases.
• It is of two subtypes: type 2A and type 2B.
• In type 2A, obliteration occurs in the common hepatic duct.
• In type 2B, the entire extra-hepatic biliary duct is obliterated with the normal intrahepatic duct.

Type 3

• In type 3, the entire bile duct tree, including intra- and extra-hepatic biliary ducts, is obliterated.
• It is the most severe and common form of biliary atresia. (60% cases)
• Types 1 and 2 are correctable forms, while type 3 is uncorrectable.

Clinical Classification of Biliary Atresia

• Perinatal type.
  • It is the most common type that accounts for 70% of cases.
  • They have no associated malformation.
• BASM syndrome type
  • It accounts for about 15% of cases.
  • It is associated with polysplenia, situs inversus, malrotation, and CHD.
• BA-associated with the choledochal cyst and renal and cardiac anomalies.
  • It is seen in about 15% of cases.

Also read: Alagille Syndrome – Clinical Features And Diagnosis

Stool Color Cards

• In countries with high prevalence, parents are guided to screen their infants for biliary atresia based on stool color cards.
• The card contains a series of colors for normal and abnormal stool colors. Parents can identify the possibility of biliary atresia based on the reference on the card.

Investigations in Biliary Atresia 

• Markers for cholestasis are elevated GGT, 5-nucleotidase, and ALP. But they are nonspecific.
• Ultrasonography
  • High-frequency ultrasonography, called HUS, offers better resolution than conventional USG.
  • The findings include
    • Triangular cord sign
    • Non-visualization of gallbladder
    • Microscopic gall bladder
• Scintigraphy
  • It is also called a HIDA scan.
  • It offers high sensitivity but low specificity.
  • The test takes five days for the results.
  • It needs protobarbital preloading.
• ERCP and MRCP are not useful in newborns but suitable for older children.
• Liver biopsy
  • It is the most valuable procedure due to its high specificity.
  • The findings for biliary atresia include
    • Bile duct proliferation
    • Bile plugs
    • Portal edema and fibrosis
    • Intact hepatic architecture
• Intraoperative cholangiogram
  • It is the standard gold method of investigation.
  • It shows the location and extent of the atresia.
  • It is the most accurate in delineating the disease.

Variant of Biliary Atresia 

• It is a peculiar anatomical form of biliary atresia in 10–20% of cases.
• It is called cystic biliary atresia.
• It is often misdiagnosed as a choledochal cyst.
• ·It can be differentiated through intraoperative cholangiography by the following findings:.
  • Absence of epithelium in biliary atresia
  • Lack of communication with the intrahepatic bile duct.
  • The prognosis of the disease with early surgery is good.

Also read: Reye's Syndrome: Understanding A Rare But Serious Illness

Treatment of Biliary Atresia 

• The treatment modalities used depend on the type of lesions. Hence, every patient must undergo exploratory laparotomy and intraoperative cholangiography.
• For correctable lesions, the treatment includes repairing the lesions and establishing direct drainage.
• For uncorrectable lesions, Kasai's hepatoportoenterostomy is the choice of procedure. It involves connecting the portal duct to the intestine. The success rate is high in infants younger than eight weeks.
• If Kasai surgery fails / late presentation, the patient needs liver transplantation.

EHBA Versus Neonatal Hepatitis 

• Idiopathic neonatal hepatitis has a familial incidence of about 20%, while EBHA is not familial.
• Idiopathic neonatal hepatitis is not associated with syndromes and multiple organ systems, but biliary atresia has.
• Idiopathic neonatal hepatitis presents transient acholic stools while EHBA shows persistent acholic stools.
• Progressive portal hypertension is more common in untreated cases of biliary atresia than neonatal hepatitis.
• Abnormal consistency or hepatomegaly favors biliary atresia.
• USG findings are more consistent in EHBA than in neonatal hepatitis.
• Hepatocellular architecture is preserved in biliary atresia but disrupted in neonatal hepatitis.

Management of Pruritis 

• Pruritis is a multifactorial clinical manifestation in patients with cholestasis.
• It is prominent at night and affects sleep. In children, it causes difficulty in feeding and is resistant to therapy.

Ursodeoxycholic Acid

• It is the first-line treatment for pruritis.
• It increases the bile flow or interrupts the enterohepatic circulation of bile acids, decreasing the xanthomas and ameliorating the pruritis.
• It can also lower serum cholesterol levels. The recommended initial dose is 15 mg/Kg/day.
• The augmentation of UDCA therapy with serotonin, antihistamines, or SSRIs can help some patients.

Management of Refractory Pruritis

• Refractory pruritis needs surgical intervention, as follows:.
  • Partial external biliary diversion (PEBD) involves creating a stoma at the point of biliary drainage.
  • Open button cholecystostomy and laparoscopic PEBD
  • Legal exclusion is less effective compared to other procedures.
  • Orthotopic liver transplantation

Also read: Autoimmune Hepatitis: Types, Clinical Presentation, Diagnosis And

Hope you found this blog helpful for your NEET SS Pediatrics Gastroenterology Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.