Purpose and Goal: CEARP #1096

  • Describe the etiology of neonatal cholestasis.
  • Identify at least two options for the treatment of neonatal cholestasis.

None of the planners, faculty or content specialists has any conflict of interest or will be presenting any off-label product use. This presentation has no commercial support or sponsorship, nor is it co-sponsored.

Requirements for Successful Completion

  • Successfully complete the post-test.
  • Complete the evaluation form.

Date

  • February 2014 - February 2016

Learning Objectives

  • Describe the etiology of neonatal cholestasis.
  • Describe the clinical presentation of neonatal cholestasis.
  • Identify at least two treatment options for neonatal cholestasis.

Introduction

  • Neonatal cholestasis is prolonged direct hyperbilirubinemia.
  • Direct hyperbilirubinemia is also known as conjugated hyperbilirubinemia.
  • It results from diminished bile flow and/or bile excretion.
  • The most common cause is long-term use of TPN.
  • Non-TPN-associated cholestasis affects 1 in 2,500 births.

Definition of Cholestasis

  • Cholestasis is an impairment in the excretion of bile.
  • It may be transient or may be related to serious pathology.
  • Causes of cholestasis:
    • Defects in intrahepatic production
    • Defects in transmembrane transport of bile
    • Mechanical obstruction of bile flow
     
  • Severity of cholestasis varies with underlying disorder.
    • Elevated direct bilirubin is the most common sign.
    • Direct hyperbilirubinemia is a direct bilirubin >1.0 mg/dl.
    • An elevated direct bilirubin is an abnormal finding.
    • Additional evaluation is always needed.
     

Definition of Neonatal Cholestasis

  • Direct hyperbilirubinemia in the first 90 days
  • Direct bilirubin >1.5-2.0 mg/dl
  • Direct bilirubin generally >20% of total bilirubin

Etiology of Neonatal Cholestasis

  • Extrahepatic obstruction
    • Biliary atresia
    • Choledochal cyst
    • Bile duct stenosis
    • Perforation of bile duct
    • Cholelithiasis (biliary sludge)
    • Inspissated bile/mucus plug
    • Tumors/masses
     
  • Intrahepatic etiologies
    • Idiopathic
    • Toxic
    • Genetic
    • Chromosomal
    • Infectious
    • Metabolic
    • Miscellaneous 
     

Intrahepatic Etiologies of Neonatal Cholestasis

  • Idiopathic
    • Alagille syndrome
    • Byler disease
    • Caroli's disease
     
  • Toxic
    • TPN-associated cholestasis
    • Drug-induced cholestasis
     
  • Genetic/chromosomal
    • Trisomy 18
    • Trisomy 21
     
  • Infectious
    • Viral sepsis
      • Rubella
      • Herpes virus
      • Cytomegalovirus
      • Parvovirus
      • Echovirus
      • Adenovirus
      • Coxsackievirus
      • Hepatitis A, B, C
       
     
  • Bacterial sepsis
    • Urinary tract infection
    • Sepsis
      • E. coli
      • Listeriosis
      • Staph aureus
       
     
  • Protozoal sepsis
    • Toxoplasmosis
     
  • Metabolic
    • Disorders of carbohydrate metabolism
      • Galactosemia
      • Fructosemia
      • Type IV glycogenosis
       
    • Disorders of amino acid metabolism
      • Tyrosemia
       
    • Disorders of lipid metabolism
      • Niemann-Pick disease
      • Wolman disease
      • Gaucher disease
       
    • Disorders of bile acid metabolism
      • 3B-hydroxysteroid dehydrogenase deficiency
      • Zellweger syndrome
       
    • Endocrine disorders
      • Hypothyroidism
      • Hypopituitarism
       
    • Miscellaneous metabolic disorders
      • Alpha-1-antitrypsin deficiency
      • Cystic fibrosis
       
     
  • Miscellaneous
    • Congenital hepatic fibrosis
    • Familial intrahepatic cholestasis
    • Shock/hypoperfusion
    • Neonatal lupus
    • Intestinal obstruction
     

Most Common Causes of Neonatal Cholestasis

  • TPN-associated cholestasis
    • Most common cause (40%-60%)
     
  • Non-TPN-associated cholestasis
    • Biliary atresia (25%-35%)
    • Genetic disorders (25%)
    • Metabolic diseases (20%)
    • Alpha-1-antitrypsin deficiency (10%)
     

TPN-Associated Cholestasis

  • Long-term TPN use results in liver injury and cholestasis.
    • 40%-60% of infants treated with TPN >14 days
    • 50% of infants <1 kg treated with TPN >14 days
     
  • TPN components act as toxins.
    • Thought to be related to amino acids
    • Increasing evidence that IL play a role
     
  • Significant contributors:
    • Immature liver
    • Bacterial endotoxins
    • Lack of enteral feeding
     
  • Risk factors:
    • Prematurity
    • Congenital/neonatal sepsis
    • Bacterial overgrowth of small intestine
    • Intestinal failure
      • Necrotizing enterocolitis
      • Gastroschisis
      • Intestinal atresia
       
     

Clinical Presentation

  • Jaundice
  • Bronze-colored skin
  • Scleral icterus
  • Acholic (clay-colored) stools
  • Dark yellow urine
  • Chronic pruritus (itching)
  • Hepatomegaly

Evaluation of Direct Hyperbilirubinemia

  • Basic evaluation
    • History and physical
      • Congenital infection
      • Neonatal infection
      • Examination of stool color
       
    • CBC and reticulocyte count
    • Serum glucose
    • Electrolytes
    • Calcium and phosphorous
    • BUN and creatinine
    • Serum albumin
    • Liver Function Tests
      • SGOT
      • SGPT
      • GGT
      • Alkaline phosphatase
       
     
  • Infectious disease evaluation
    • Blood culture
    • Urine culture
    • CSF culture
    • TORCH titers
    • RPR/VDRL screen
    • Urine for CMV
    • Hepatitis B serology
    • Hepatitis C serology
     
  • Ophthalmologic evaluation
  • Metabolic evaluation
    • Alpha-1-antitrypsin level
    • Thyroid function tests
    • Sweat chloride test
    • Serum amino acids
    • Newborn metabolic screen
    • Urine organic acids
    • Urine reducing substances
    • Urine bile salts
     
  • Radiological evaluation
    • Abdominal ultrasound
      • Evaluate gallbladder function
       
    • CT scan
      • Evaluate liver structure
       
    • Hepatobiliary scintigraphy
     
  • Invasive studies
    • Liver biopsy
    • Exploratory laparotomy
     

Goals of Evaluation and Treatment

  • Initial goal is to rapidly diagnose and treat:
    • Sepsis
    • Hypothyroidism
    • Inborn errors of metabolism
     
  • Second goal is to distinguish biliary atresia from other causes.
    • Key steps are ultrasound and liver biopsy.
    • Early surgical intervention results in improved outcomes.
     
  • Additional goals aimed at diagnosing specific conditions
  • Untreated or prolonged cholestasis
    • Growth failure
    • Hepatic fibrosis
    • Cirrhosis
    • Portal hypertension
    • Ascites
    • GI bleeding
     

Treatment of Neonatal Cholestasis

  • Treatment is specific to the cause of cholestasis:
    • Infection → antibiotics or antivirals
    • Galactosemia → galactose-free diet
    • Tyrosinemia → low-tyrosine/phenylalanine diet
    • Fructose intolerance → fructose- and sucrose-free diet
    • Hypothyroidism → thyroid hormone replacement
    • Cystic fibrosis → pancreatic enzymes
    • Hypopituitarism → thyroid, growth hormone and cortisol replacement
    • Biliary atresia → Kasai surgical procedure
    • Choledochal cyst → choledochoenterostomy
    • Spontaneous perforation → surgical drainage
    • Inspissated bile/mucus plug → biliary tract irrigation
    • TPN-associated → wean from TPN, increase feeds 
     

Pharmacologic Treatment of Neonatal Cholestasis

  • Ursodeoxycholic acid (ursodial)
    • Naturally occurring bile acid
    • Increases bile formation
    • Stimulates bile flow
      • Increases excretion of bilirubin
      • Increases excretion of bile salts
       
     
  • Phenobarbital
    • Stimulates bile flow
      • Increases excretion of bilirubin
      • Increases excretion of bile salts
       
    • Treats chronic pruritus
     

Nutritional Support of Neonatal Cholestasis

  • Nutritional therapy is critical.
    • Feedings increase bile flow.
    • Feedings improve gastric motility.
     
  • Growth failure is common.
    • Impaired absorption of nutrients
    • Increased metabolic demand
     
  • Optimal nutritional support:
    • Caloric intake 125% of daily requirement
    • Protein intake of 2-3 grams/kg
    • Medium-chain triglycerides (MCT)
      • Absorbed without bile salts
      • Pregestimil formula
      • Alimentum formula
       
    • Fat-soluble vitamins
      • Vitamins A, D, E, K
      • Continued for 3 months
      • Levels should be followed
       
    • Calcium and phosphate supplements
    • Zinc supplements
     

TPN-Associated Cholestasis

  • Wean from TPN if possible.
    • Adjust amino acid profile.
      • Increase taurine.
      • Increase L-cysteine.
      • Decrease methionine.
       
    • Remove copper and manganese.
    • Eliminate sources of aluminum.
     
  • Wean from IL if possible.
    • IL have been implicated as a causative factor.
      • Soybean lipid emulsions most common
      • Soybeans are rich in omega-6 fatty acids.
       
    • Fish oil lipid emulsions can reverse cholestasis.
      • Fish oil is rich in omega-3 fatty acids.
      • OMEGAVEN has been used successfully.
      • Currently available for compassionate use only
       
     
  • Promote and increase oral feedings:
    • Improve GI adaptation to nutrients
    • Improve intestinal epithelial cell growth
    • Improve brush-border enzyme activity
    • Improve GI motility
     

References

  1. Beachy, J.M. Investigating Jaundice in the Newborn. 2007. Neonatal Network, 26(5), p. 327-333.
  2. Hengst, J.M. Direct Hyperbilirubinemia: A Case Study of Parenteral Nutrition-Induce Cholestatic Jaundice. 2002. Neonatal Network, 21(4), p. 57-69.
  3. NeoReviews: Neonatal Cholestasis  
  4. UpToDate: Causes of Neonatal Cholestasis  
  5. UpToDate: Approach to Neonatal Cholestasis  
  6. UpToDate: Parenteral Nutrition-Associated Liver Disease in Infants  

Test and Evaluation