Neonatal cholestasis

doi:10.1053/j.semperi.2004.09.008

Seminars in Perinatology

Volume 28, Issue 5, October 2004, Pages 348-355

https://doi.org/10.1053/j.semperi.2004.09.008 Get rights and content

Any infant who is jaundiced beyond two to three weeks of life should be evaluated for neonatal cholestasis. Neonatal cholestasis is defined as accumulation of bile substances in blood due to impaired excretion. These infants should always have fractionated serum bilirubin levels checked to differentiate the conjugated hyperbilirubinemia of cholestasis from unconjugated hyperbilirubinemia that is usually benign and spontaneously resolves. Conjugated hyperbilirubinemia, pale stools and dark urine are the cardinal features of neonatal cholestasis. The differential diagnosis of cholestasis is extensive and a systematic approach is helpful to quickly establish the diagnosis. Biliary atresia is a common cause of neonatal cholestasis and affected infants need surgery before 60 days of life for better prognosis. Premature infants have multifactorial cholestasis and need a modified approach to the evaluation of cholestasis. Management of cholestasis is mostly supportive, consisting of medical management of complications of chronic cholestasis like pruritus and nutritional support for malabsorption and vitamin deficiency.

Section snippets

Pathophysiology

The normal process of bile production involves two main processes: uptake of bile acids by hepatocytes from the blood and excretion of bile acids into the biliary canaliculus. Uptake of bile acids from sinusoidal blood is an active process at the sinusoidal membrane of the hepatocytes. Na taurocholate cotransporting polypeptide (NTCP) and organic anion transporting proteins (OATP) are the two main receptors involved in the uptake of conjugated bile acids by the liver cells. These receptors are

Classification of neonatal cholestasis

The differential diagnosis of neonatal cholestasis is extensive and can be classified based on the anatomic location of the pathology into extrahepatic and intrahepatic causes. Biliary atresia and choledochal cyst are examples of extrahepatic causes while common intrahepatic causes include idiopathic neonatal hepatitis, infections, α₁-antitrypsin deficiency and other metabolic disorders.2, 3, 4, 5, 6 The different causes of cholestasis can also divided into broad etiological categories like

Clinical presentation

An infant with cholestasis usually presents with prolonged jaundice, pale stools and dark urine. Acholic stools are a cardinal feature of cholestasis and should be promptly evaluated. Some infants may present with signs of coagulopathy due to deficiency of clotting factors or vitamin K deficiency. Neurological abnormalities like irritability, lethargy, seizures and poor feeding may indicate either sepsis or metabolic disorders.

Physical examination is remarkable for jaundice. Hepatomegaly is

Evaluation of cholestasis

Any infant presenting with jaundice beyond 2 weeks after birth should be immediately evaluated for cholestasis.7 A detailed history (including family history, pregnancy and delivery history and postnatal course) and physical examination could provide clues to a specific diagnosis. Breastfed infants who can be reliably monitored and have an otherwise normal history and physical examination should be reevaluated at 3 weeks of age and if still jaundiced, have fractionated serum bilirubin levels

Management of cholestasis

Medical management of cholestasis is mostly supportive and does not alter the natural course of the disease. It is aimed mostly at treating the complications of chronic cholestasis like pruritus, malabsorption and nutritional deficiencies and portal hypertension.

Biliary atresia

Biliary atresia is an idiopathic inflammatory process involving the bile ducts resulting in obstruction of the biliary tract, chronic cholestasis and progressive fibrosis and eventually to biliary cirrhosis. It accounts for approximately one-third of the cases of neonatal cholestasis and is the most common cause of liver transplantation in children.

The incidence of biliary atresia has been estimated to be about 1:15,000. It is worldwide in distribution and occurs in all races, though more

Idiopathic neonatal hepatitis

Idiopathic neonatal hepatitis, also known as giant cell hepatitis, accounts for approximately one-third of the cases of neonatal cholestasis. It is diagnosed by the presence of the classic pathological findings and the absence of any identifiable cause of cholestasis. There are two different categories: sporadic cases and familial cases that could likely suggest an undiagnosed genetic or metabolic disease. These infants usually have low birth weight. Jaundice is present within the first week of

Cholestasis in premature infants

Cholestasis is a common finding in very low birth weight infants and is multifactorial in etiology. The biliary tract is structurally and functionally immature in these infants leading to an exaggerated physiologic cholestasis of infancy. In addition, other risk factors like perinatal hypoxia,15 parenteral nutrition, sepsis, and poor enteral feedings can contribute to cholestasis. In premature infants biliary atresia is uncommon, so a modified schematic for evaluation may be followed (Fig. 1).

α₁-antitrypsin (α₁AT) deficiency

This is the most common inherited cause of neonatal cholestasis. α₁AT is a protease inhibitor produced in the liver. The deficiency is caused by mutations in the gene found on chromosome 14. More than 75 different phenotypes of α₁AT are named according to migration characteristics on polyacrylamide gels, based on differences in isoelectric point (Pi), with M normal and Z most deficient.17 The incidence of homozygous PiZZ that is associated with neonatal liver disease and adult emphysema is 1 in

Progressive familial intrahepatic cholestasis (PFIC)

PFIC is a group of genetic disorders that show progressive intrahepatic cholestasis. All these disorders have an autosomal recessive inheritance.

PFIC-1 is caused by mutation in the FIC 1 gene and is the original Byler disease described in the descendants of an Amish American family. The FIC1 gene is expressed in the canalicular membranes. Patients present with episodic cholestasis in the first month of life. Diarrhea, pancreatitis and deficiency of fat-soluble vitamins are seen. Serum GGT

Alagille syndrome

Alagille syndrome is an autosomal dominant disorder characterized by paucity of the interlobular bile ducts. The incidence is reported to be 1 in 100,000 births. It is also known as Watson-Alagille syndrome, arteriohepatic dysplasia, syndromic bile duct paucity (SBDP), syndromic intrahepatic biliary hypoplasia, intrahepatic biliary atresia and intrahepatic biliary dysgenesis. Alagille syndrome is caused by mutations in the human Jagged 1 gene that has been mapped to chromosome 20p12. This gene

References (22)

Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation
Pediatrics
(2004)
F.J. Suchy
Approach to the infant with cholestasis
P.J. McKiernan
Neonatal cholestasis
Semin Neonatol
(2002)
W.A. Walker et al.
Pediatric Gastrointestinal DiseasePathophysiology, Diagnosis, Management
(2004)
E.A. Roberts
Neonatal hepatitis syndrome
Semin Neonatol
(2003)
S.J. Karpen
Update on the etiologies and management of neonatal cholestasis
Clin Perinatol
(2002)
V. Moyer et al.
Guideline for the evaluation of cholestatic jaundice in infantsRecommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
J Pediatr Gastroenterol Nutr
(2004)
W.H. Park et al.
A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord signComparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis
J Pediatr Surg
(1997)
M.A. Kotb et al.
Evaluation of the triangular cord sign in the diagnosis of biliary atresia
Pediatrics
(2001)
E.C. Lin et al.
Radionuclide imaging of hepatic and biliary disease
Semin Liver Dis
(2001)

K.I. Norton et al.

MR cholangiography in the evaluation of neonatal cholestasisinitial results

Radiology

(2002)

Cited by (79)

Neurotensin contributes to cholestatic liver disease potentially modulating matrix metalloprotease-7
2024, International Journal of Biochemistry and Cell Biology
The diagnosis and treatment of biliary atresia pose challenges due to the absence of reliable biomarkers and limited understanding of its etiology. The plasma and liver of patients with biliary atresia exhibit elevated levels of neurotensin. To investigate the specific role of neurotensin in the progression of biliary atresia, the patient's liver pathological section was employed. Biliary organoids, cultured biliary cells, and a mouse model were employed to elucidate both the potential diagnostic significance of neurotensin and its underlying mechanistic pathway. In patients’ blood, the levels of neurotensin were positively correlated with matrix metalloprotease-7, interleukin-8, and liver function enzymes. Neurotensin and neurotensin receptors were mainly expressed in the intrahepatic biliary cells and were stimulated by bile acids. Neurotensin suppressed the growth and increased expression of matrix metalloprotease-7 in biliary organoids. Neurotensin inhibited mitochondrial respiration, oxidative phosphorylation, and attenuated the activation of calmodulin-dependent kinase kinase 2-adenosine monophosphate-activated protein kinase (CaMKK2-AMPK) signaling in cultured biliary cells. The stimulation of neurotensin in mice and cultured cholangiocytes resulted in the upregulation of matrix metalloprotease-7 expression through binding to its receptors, namely neurotensin receptors 1/3, thereby attenuating the activation of the CaMKK2-AMPK pathway. In conclusion, these findings revealed the changes of neurotensin in patients with cholestatic liver disease and its mechanism in the progression of the disease, providing a new understanding of the complex mechanism of hepatobiliary injury in children with biliary atresia.
Endoscopic Retrograde Cholangiopancreatography
2020, Pediatric Gastrointestinal and Liver Disease, Sixth Edition
Endoscopic retrograde cholangiopancreatography (ERCP) is widely performed in adult patients, less commonly in pediatric patients. ERCP in children can have unique indications, procedural considerations, technical approaches, and follow-up plans when compared to adult ERCP. This chapter will review the indications, technique, interpretation, risks, adverse events, and outcomes of ERCP in a pediatric population.
Toll-like receptor 7 agonist induces hypoplasia of the biliary system in a neonatal mouse model
2018, Journal of Microbiology, Immunology and Infection
Citation Excerpt :
The liver of newborns is prone to cholestatic liver disease when prolonged direct type jaundice lasts beyond 2 weeks after birth.1,2
Viral infections and innate immunity signaling, especially Toll-like receptor 7 (TLR7) have been implicated in the pathogenesis of biliary atresia (BA). Administration of rhesus rotavirus-type A to newborn Balb/c mice produces inflammatory obstruction of bile ducts, which resembles human BA. However, whether activation of TLR7 signaling plays a role in neonatal hepatobiliary injury remains to be investigated.
TLR7 agonist, imiquimod (R837), was intraperitoneally administered to Balb/c mice within 24 hours of birth and then every other day. Morphological and histological injuries of liver and gallbladder were examined at 2 weeks. Hepatic messenger RNA expression of TLR7 signaling was studied. Terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeling staining was used to delineate hepatobiliary apoptosis upon TLR7 stimulation.
TLR7 agonist, imiquimod, induced hypoplasia of the biliary system of neonatal Balb/c mice both in atrophic gallbladder and in paucity of intrahepatic bile ducts. There was significantly higher hepatic expression of TLR7 and downstream innate immunity-mediated interferon regulatory factor 7, interferon-α, and tumor necrosis factor-α. In addition, terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick end labeling-positive cells in the liver were increased after injections of TLR7 agonist.
The results demonstrate that TLR7 activation may trigger innate immunity pathways and induce apoptosis and hypoplasia of neonatal biliary trees in Balb/c mice. The novel findings give an implication of pathogenesis of infantile cholestasis, such as BA.
The effects of gestational age on neonatal cholestasis: A retrospective cohort study
2024, Journal of Neonatal-Perinatal Medicine
Biliatresone induces cholangiopathy in C57BL/6J neonates
2023, Scientific Reports
Neonatal intestinal failure: Growth pattern and nutrition intakes in accordance with weaning from parenteral nutrition
2023, Journal of Parenteral and Enteral Nutrition

View all citing articles on Scopus

View full text