Infantile Cholestasis: Approach and Diagnostic Algorithm



Biliary atresia

Congenital TORCH infection:

Choledochal cyst


Syndromic and nonsyndromic paucity of interlobular bile ducts


Inspissated bile syndrome

 Herpes virus

Caroli’s disease/congenital hepatic fibrosis


Neonatal sclerosing cholangitis

Bacterial sepsis
Urinary tract infection

Idiopathic neonatal hepatitis

Bile acid synthesis defects
Gestational alloimmune liver disease/neonatal hemochromatosis
Hereditary tyrosinemia
Storage diseases



Alpha-1-antitrypsin deficiency

Parenteral nutrition

Alagille syndrome


Progressive familial intrahepatic cholestasis
Cystic fibrosis
Arthrogryposis–renal dysfunction–cholestasis syndrome (ARC)

HIV human immunodeficiency virus, TORCH Toxoplasmosis, Other Agents, Rubella, Cytomegalovirus, Herpes Simplex


BA is a destructive, inflammatory process that causes fibrosis of the intra- and extrahepatic biliary tree. It is the most common cause of chronic cholestasis in infants and children, and it is the most common indication for liver transplant in the pediatric population. It is estimated to affect 1 in 8000–12,000 live births worldwide with a slight female predominance. There are two types of BA: congenital/embryonic which accounts for 15–20 % of cases and perinatal or acquired which is the majority of cases. The etiology of BA remains deeply researched. Typically, the presentation of direct hyperbilirubinemia with acholic stools in infants a few weeks old should prompt the expedient evaluation forBA. There is a tremendous amount of evidence that suggests earlier diagnosis and surgical repair with a Kasai portoenterostomy will lead to a better outcome when performed before the age of 45–60 days [1214].

A choledochal cyst is a congenital condition involving cystic dilation of the bile ducts. There are five different types, classified based on site of the dilation. The most common are types 1 (saccular dilation of only the extrahepatic bile duct) and 4 (saccular dilations of the intra- and extrahepatic biliary tree). The majority of cases present within the first year of life.


INH is defined as a prolonged conjugated hyperbilirubinemia with no known etiology after a thorough evaluation has ruled out identifiable infectious and metabolic/genetic causes. Histologically, the typical findings would include widespread transformation of multinucleated giant cells. As discussed above, with the advancement of diagnostic techniques, the incidence of INH has sharply declined [7].

Bacterial, viral, and fungal infections can all cause cholestasis. Congenitally acquired pathogens capable of doing so include rubella, toxoplasmosis, cytomegalovirus, herpes, human immunodeficiency virus, and syphilis. Bacterial infections with either gram-negative or gram-positive organisms have also been implicated; in fact, jaundice may be one of the presenting symptoms of urinary tract infections in infants.


Alpha-1-antirypsin (α1-AT) deficiency is an autosomal recessive disorder caused by a misfolded protein that prohibits its secretion, leading to intracellular accumulation of the protein. This accumulation leads to liver injury, cirrhosis , and increased risk for hepatocellular carcinoma through the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation [15]. Its incidence is approximately 1 in 1600–2000 live births, and it is extremely rare in the non-Caucasian population. Diagnosis is made based on the serum levels of α1-AT and the phenotype. Individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema, while the heterozygous carrier state for the mutant Z gene may be a modifier gene for liver disease. In infancy, the typical presentation is one of neonatal cholestasis , but the presentation of patients can be highly varied. In fact, only 8–10 % of individuals born with the homozygous Z allele develop any clinically significant liver disease over the first 20 years of life. Liver biopsy may show globular, eosinophilic inclusions in hepatocytes, representing dilated endoplasmic reticulum membranes and the accumulated Z protein. It stains positive with periodic acid–Schiff and is diastase resistant [15]. Prospective studies indicate that 80 % of patients with the homozygous Z allele and presenting with neonatal cholestasis are healthy and free of chronic disease by the age of 18 years [16].

Alagille syndrome is an autosomal dominant multisystemic disease that results from mutation usually involving the Jagged 1 or NOTCH2 gene. Jagged-1 is a member of the Jagged family of genes that encode cell surface proteins that interact with Notch receptors; this interaction regulates cell fate during embryogenesis. The syndrome is characterized by paucity of interlobular bile ducts. The variable penetrance of the mutation leads to different characteristics of the disease including: abnormal facies, chronic cholestasis, posterior embryotoxon, butterfly-like vertebral arch defects, and cardiovascular malformations. Associated vascular abnormalities have been noted in Alagille patients including decreased intrahepatic portal vein radicals and cerebrovascular abnormalities similar to Moyamoya disease. Infantile presentation follows a variable course with some developing gradual improvement as they get older, whereas others progress into cirrhosis . Medical management emphasizes on the supplementation of medium-chain triglycerides, essential fatty acids, and fat-soluble vitamins . Liver transplantation may be needed in cases of cirrhosis, portal hypertension , or severe pruritus [17].

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders that disrupt bile formation [18] . It is divided into three subtypes. Type I, also known as Byler disease or familial intrahepatic cholestasis (FIC)1 disease, is caused by a mutation in the P-type ATPase FIC gene. FIC1 is expressed in several epithelial tissues, including the small intestine, pancreas, and liver, and thus patients express extrahepatic manifestations as well like recurrent pancreatitis, diarrhea, wheezing and cough, sensorineural hearing loss, and posttransplant steatosis. A benign form of recurrent intrahepatic cholestasis (BRIC) with symptom-free intervals in between the attacks could be seen in patients with mutations in the same gene.

PFIC type II is caused by a defect in the bile sale export pump (BSEP/ABCB11) gene, which leads to impaired bile acid transport from the hepatocytes into the bile canaliculus. The gene is liver specific, and thus mutations result in no extrahepatic manifestations. Similar to FIC1 disease, genetic mutations in BSEP could manifest in a more benign recurrent disease called BRIC2. Both type I and II have normal serum γ-glutamyltranspeptidase (γ-GTP) levels, unlike type III.

PFIC type III is due to a defect in MDR3 which is a member of the adenosine triphosphate (ATP)-binding cassette family of transporters that serve as phospholipid flippases. Its impairment leads to defective biliary phospholipid secretion, impairing the balance in cholesterol saturation index and leading to crystallization of cholesterol, and lithogenicity of bile, and bile duct injury.

Galactosemia is an autosomal recessive disorder that can result from deficiencies of three different enzymes; the most common and severe form is caused by a complete deficiency of galactose-1-phosphate uridyltransferase (GALT). Most states in the USA include testing in the newborn screening, but infants may become symptomatic prior to the availability of these test results. The gold standard for diagnosis is the demonstration of nearly complete absence of GALT activity in red blood cells. It is important to remember that blood transfusions from a donor may interfere with the diagnosis. Physical exam and history will typically reveal a jaundiced infant that may be lethargic, hypotonic, with poor feeding, and displays hepatomegaly. Dietary restriction of galactose in the newborn period reverses the hepatic dysfunction. However, chronic and progressive neurologic impairments may occur even in patients with dietary compliance [19].

Tyrosinemia is an inborn error of metabolism that results from deficiencies in specific enzymes in the tyrosine catabolic pathway, leading to the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate. It is characterized by acute liver failure in the first weeks or months of life. It is detected by quantitative measurement of plasma amino acids and urine succinylacetone levels. The treatment is dietary restriction of tyrosine and phenylalanine as well as early initiation of the medication nitosine, a potent inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase. This decreases the concentration of succinylacetone.

There are numerous other inborn errors of metabolism that can be screened for with serum amino acid and urine organic acid concentrations. The remainder will not be discussed in detail at this time.
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Jul 12, 2016 | Posted by in HEPATOPANCREATOBILIARY | Comments Off on Infantile Cholestasis: Approach and Diagnostic Algorithm
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