Neonatal Cholestasis
Neonatal Cholestasis: Excerpt from The 5-Minute Pediatric Consult
Binita M. Kamath, MBBChir
Neonatal Cholestasis - BASICS
Neonatal Cholestasis - description
Neonatal cholestasis presents at or shortly after birth with the accumulation of bilirubin, bile acids, and cholesterol in blood and extrahepatic tissues. Neonatal cholestasis most often manifests with conjugated hyperbilirubinemia and jaundice. Any infant who is jaundiced beyond 2 weeks of life warrants further evaluation for neonatal cholestasis.
Biochemical definition: Serum conjugated bilirubin >2 mg/dL or >15% of the total bilirubin concentration
Neonatal Cholestasis - epidemiology
Estimated frequency of causes of neonatal cholestasis:
- Biliary atresia 25–30%
- Idiopathic neonatal hepatitis 15%
- Alpha-1-antitrypsin deficiency 7–10%
- Intrahepatic cholestasis syndromes (e.g., Alagille syndrome) 20%
- Infection 3–8%
- Metabolic/Endocrine 2–7%
Neonatal Cholestasis - incidence
Overall incidence of neonatal liver disease is 1 in 2,500 live births.
Neonatal Cholestasis - risk factors
Neonatal Cholestasis - genetics
Genetics of biliary atresia, neonatal hepatitis, and most causes of neonatal cholestasis are unknown.
- Alpha-1-antitrypsin deficiency:
- Autosomal recessive
- 10–15% of individuals with at risk genotypes (e.g., PIZZ) develop liver disease
- Alagille syndrome:
- Autosomal dominant, variable expressivity
- Caused by mutations in Jagged1 and Notch2
- Progressive familial intrahepatic cholestasis:
- Autosomal recessive
- Caused by mutations in FIC1, BSEP and MDR3
Neonatal Cholestasis - pathophysiology
Cholestasis is defined physiologically as a reduction in bile flow. In infancy, bile flow is primarily dependent on the secretion of bile acids by hepatocytes. The hepatobiliary excretory system is functionally and structurally immature at birth, leaving the neonate vulnerable to cholestasis. In neonates, bile acid synthesis and secretion are impaired; in addition, there is inefficient enterohepatic bile acid cycling due to reduced expression of bile acid transport proteins.
Neonatal Cholestasis - etiology
- Idiopathic neonatal hepatitis
- Cholestasis associated with infection:
- Sepsis (especially urinary tract infection)
- Congenital viral infections (cytomegalovirus, adenovirus, herpesvirus, coxsackievirus, echovirus, rubella, hepatitis B, HIV, parvovirus B19)
- Toxoplasmosis
- Listeriosis
- Syphilis
- Tuberculosis
- Biliary obstruction:
- Biliary atresia
- Choledochal cyst
- Inspissated bile
- Other biliary disorders:
- Neonatal sclerosing cholangitis
- Alagille syndrome
- Caroli disease
- Congenital hepatic fibrosis
- Metabolic and genetic disorders:
- Alpha-1-antitrypsin deficiency
- Cystic fibrosis
- Tyrosinemia
- Galactosemia
- Urea cycle disorders
- Neonatal hemochromatosis
- Nieman-Pick disease
- Gaucher disease
- Bile acid synthetic defects
- Progressive familial intrahepatic cholestasis
- Endocrine disorders:
- Hypothyroidism
- Panhypopituitarism
- Toxic:
- Drugs
- Total parenteral nutrition
- Vascular disorders:
- Budd-Chiari syndrome
- Perinatal asphyxia (shock)
Neonatal Cholestasis - associated conditions
- Biliary atresia (syndromic form):
- Heterotaxy
- Polysplenia
- Malrotation
- Congenital heart disease
- Alagille syndrome:
- Cardiac lesions, typically peripheral pulmonary stenosis
- Butterfly vertebrae
- Posterior embryotoxon in the eye
- Characteristic facies
Neonatal Cholestasis - DIAGNOSIS
Neonatal Cholestasis - signs & symptoms
- Jaundice
- Hepatomegaly
- Splenomegaly
- Rickets
- For specific diagnoses:
- Acholic stools in biliary obstruction (usually biliary atresia)
- Characteristic facies, heart murmur in Alagille syndrome
- Low birth weight, microcephaly, purpura, chorioretinitis in congenital infections
- Irritability, poor feeding, lethargy in metabolic disorders
Neonatal Cholestasis - history
- Pregnancy and birth history
- Family history
- Presence of extrahepatic anomalies
- Stool color
Neonatal Cholestasis - physical exam
- Dysmorphic facial features
- Cardiac examination
- Hepatomegaly
- Splenomegaly
- Purpura
Neonatal Cholestasis - tests
- Opthalmologic evaluation (for chorioretinitis, posterior embryotoxon)
- Sweat chloride/cystic fibrosis mutation analysis
Neonatal Cholestasis - lab
- Fractionated serum bilirubin (total and conjugated)
- Serum transaminases (alanine transferase, aspartate transferase)
- Alkaline phosphatase, gamma glutamyl transpeptidase
- Serum albumin
- Prothrombin time, partial thromboplastin time, international normalized ratio
- Serum cholesterol
- CBC
- Bacterial blood culture
- Urine culture
- Serologies for infectious serologies (hepatitis B surface antigen [HepBsAg], TORCH [toxoplasmosis rubella cytomegalo inclusion herpes], Venereal Disease Research Laboratory [VDRL], HIV, other)
- Serum alpha-1-antitrypsin level and phenotype
- Metabolic screen (plasma and urine amino acids, urine organic acids, lactate)
- Red cell galactose-1-phosphate uridyl transferase (galactosemia)
- Urine succinylacetone (tyrosinemia)
- Thyroid function tests
- Serum iron and ferritin
- Serum and urine bile acids
- Genetic testing for Alagille syndrome
- Genetic testing for progressive familial intrahepatic cholestasis
Neonatal Cholestasis - imaging
- Abdominal ultrasonography
- Hepatobiliary scintigraphy
- X-rays of spine (for butterfly vertebrae)
- X-rays of skull and long bones (for congenital infections)
Neonatal Cholestasis - diag proced-surgery
- Liver biopsy
- Percutaneous transhepatic cholangiogram
- Intraoperative cholangiogram
- Consider bone marrow examination (for storage disorders)
Neonatal Cholestasis - pathological findings
Dependent on etiology
Neonatal Cholestasis - differencial diagnosis
See “Etiology.”
Conjugated hyperbilirubinemia must be distinguished from physiologic or breast milk jaundice. Any infant who is jaundiced for >14 days should have a total and conjugated hyperbilirubinemia measured to identify neonatal cholestasis.
Certain causes of neonatal cholestasis require expedited management (potentially life threatening if not treated quickly):
- Sepsis
- Biliary atresia
- Galactosemia
- Tyrosinemia
- Hypothyroidism
Neonatal Cholestasis - TREATMENT
Neonatal Cholestasis - initial stabilization
- Identify and treat coagulopathy with parenteral vitamin K.
- Identify and treat sepsis.
Neonatal Cholestasis - general measures
Neonatal Cholestasis - diet
- Aggressive nutritional support is vital. A hydrolysate formula with a high content of medium chain triglycerides is better absorbed in cholestasis.
- Special diets:
- Galactose-free (galactosemia)
- Low tyrosine/phenylalanine (tyrosinemia)
Neonatal Cholestasis - special therapy
- Fat-soluble vitamin supplementation
- Water-soluble vitamin supplementation
Neonatal Cholestasis - iv fluids
Limit sodium intake in children with liver disease. Use D10 1/Neonatal Cholestasis - iv fluids_complementary-and-alternative-therapies
Milk thistle has been used in cholestasis, but its use is not validated.
Neonatal Cholestasis - medication
- Ursodeoxycholic acid (choleretic)
- Vitamin E (antioxidant)
- Antihistamines, rifampin, naltrexone (pruritus)
- Antibiotics or antivirals (congenital infections)
Neonatal Cholestasis - surgery
- Kasai procedure (hepatoportoenterostomy) for biliary atresia
- Surgical drainage (choledochoenterostomy) for choledochal cyst
- Biliary diversion for Alagille syndrome and PFIC
Neonatal Cholestasis - FOLLOW UP
Neonatal Cholestasis - disposition
Neonatal Cholestasis - issues for referral
All neonates with conjugated hyperbilirubinemia should be referred to a pediatric gastroenterologist. In cases of suspected biliary atresia, sepsis or metabolic disease; referral should be prompt.
Neonatal Cholestasis - prognosis
Dependent on etiology. Biliary atresia is the most common indication for pediatric liver transplantation.
Neonatal Cholestasis - complications
- Growth failure
- End-stage liver disease (ascites, coagulopathy) and portal hypertension
- Fractures
Neonatal Cholestasis - bibliography
- Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39(2):115–128.
Walker WA, Goulet O, Kleinman RE, et al. Pediatric gastrointestinal disease: Pathophysiology, diagnosis, management. Hamilton, Ontario, Canada: B.C. Decker Inc.; 2004.
Neonatal Cholestasis - ADDITIONAL READING
- Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann. 2006;35(4):280–286.
- Suchy FJ. Approach to the infant with cholestasis. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:187–194.
- Venigalla S, Gourley GR. Neonatal cholestasis. Semin Perinatol. 2004;28(5):348–355.
Neonatal Cholestasis - CODES
Neonatal Cholestasis - icd9
- 573.2 Hepatitis in other infectious diseases classified elsewhere
- 751.61 Biliary atresia
- 751.69 Other anomalies of gallbladder, bile ducts, and liver
- 774.4 Perinatal jaundice due to hepatocellular damage
Book Source Details
- Book Title: The 5-Minute Pediatric Consult
- Author(s): M. William Schwartz MD; et al.
- Year of Publication: 2008
- Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.
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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.
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More About This Book:
Title: The 5-Minute Pediatric Consult
Authors: M. William Schwartz MD; et al.
Publisher: Lippincott Williams & Wilkins
Copyright: 2008
ISBN: 0-7817-7577-9
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