Differential diagnoses and diagnostic approaches for infants with cholestasis
| DISEASE | DIAGNOSTIC APPROACH |
|---|---|
| Obstructive cholestasis | |
| Structural | |
| • Biliary atresia | Ultrasound (presence, size, and appearance of gallbladder; evidence of cirrhosis and portal hypertension, polysplenia, or asplenia) Hepatobiliary s cintigraphy (delayed or absent excretion) Liver biopsy Intraoperative cholangiogram |
| • Choledochal cyst, or other congenital bile duct anomaly | Ultrasound Cholangiogram (percutaneous and scintigraphic, to show communication with biliary tree and to rule out associated atresia) |
| • Caroli disease and congenital hepatic fibrosis | Ultrasound (liver and kidneys) Liver biopsy (rarely required) |
| • Gallstones or biliary sludge | Ultrasound |
| • Neonatal sclerosing cholangitis | Cholangiogram (endoscopic retrograde, percutaneous or intraoperative) |
| Duct paucity syndrome | |
| • Alagille syndrome | Physical examination for typical facial features, which might not be obvious during newborn period (broad forehead, pointed chin, elongated nose with bulbous tip) Chest x-ray scan (butterfly vertebrae) Ophthalmologic examination (posterior embryotoxon) Echocardiogram (peripheral pulmonic stenosis) Liver biopsy (paucity of small ducts) Genetic analysis (mutations in JAG1 gene) |
| Hepatocellular cholestasis | |
| • Idiopathic neonatal hepatitis | Diagnosed by exclusion of other causes of neonatal liver disease Liver biopsy (often not required) |
| Genetic and metabolic disorders | |
| • α 1-Antitrypsin deficiency | ∝1-Antitrypsin levels (reduced) Protein or genetic analysis (homozygous Pi type ZZ, SZ, or other rare deficiency variant) |
| • Galactosemia | Results of newborn screening Non–glucose reducing substances (positive) Galactose-1-phosphate uridyl transferase in red blood cells (low activity) Blood cultures (association with Escherichia coli sepsis) |
| • Tyrosinemia | Results of newborn screening Serum tyrosine and methionine levels (high) Serum α-fetoprotein levels (high) Succinylacetone detection in urine |
| • Hereditary fructosemia | Fructose-1-phosphate aldolase B activity low or absent in liver tissue Liver biopsy with EM Genetic analysis |
| • Neonatal hemochromatosis | Ferritin (high, usually > 1000 μg/L) Total iron binding capacity (low) Liver biopsy with iron stain, or buccal mucosal biopsy MRI (abdomen, for typical pattern of iron deposition) |
| • Cystic fibrosis | Results of newborn screening Sweat chloride test Genetic analysis |
| • Inborn errors of bile acid synthesis | Urinary bile acid analysis |
| • Progressive familial intrahepatic cholestasis | GGT (low to normal in types 1 and 2, high in type 3) Liver biopsy Genetic analysis |
| Endocrine disorders | |
| • Hypothyroidism | Results of newborn screening TSH (high), free T4 (usually low) |
| • Panhypopituitarism | Glucose (hypoglycemia common) Cortisol (low) TSH (low), T4 (low) |
| Toxic or secondary disorders | |
| • Parenteral nutrition–associated cholestasis | Correlation with clinical history Exclusion of other causes of cholestasis |
| • Drugs (acetaminophen, anticonvulsants, etc) | Correlation with clinical history Urine and serum toxicology screen |
| Infectious disorders | |
| • Toxoplasmosis | IgM-specific antibodies (detectable 2 weeks after infection, peak approximately 4 weeks after infection) Isolation of organism from blood, CSF, or liver Ophthalmologic examination (chorioretinitis) CT (head, intracranial calcifications) |
| • Rubella | IgM-specific antibodies (detectable 2 weeks after infection) Viral isolation (CSF, liver, urine, pharyngeal secretions) Ophthalmologic examination (cataracts) |
| • Cytomegalovirus | IgM-specific antibodies Viral isolation from blood, urine, CSF Ophthalmologic examination (for chorioretinitis) CT (head, intracranial calcifications) |
| • Herpes simplex virus | EM or viral culture of vesicle scrapings PCR of blood and CSF |
| • Human immunodeficiency virus | HIV DNA PCR Immunoglobulin levels CD4 count |
| • Syphilis | VDRL test Syphilis indirect hemagglutination test (TPHA) Fluorescent treponemal antibody levels Long-bone x-ray scans (osteochondritis, periostitis) |
| • Urinary tract infection | Urine culture, full septic workup where indicated |
| • Sepsis | Blood culture, full septic workup where indicated |
Adapted from Walsh et al.5
CSF—cerebrospinal fluid, CT—computed tomography, DNA—deoxyribonucleic acid, EM—electron microscopy, GGT—γ-glutamyltransferase, HIV—human immunodeficiency virus, IgM—immunoglobulin M, MRI—magnetic resonance imaging, PCR—polymerase chain reaction, T4—thyroxine, TPHA—treponema pallidum hemagglutination, TSH—thyroid stimulating hormone, VDRL—venereal disease research laboratory.