| Finding | Implications |
| Initial tests for all infants | |
| |
| To evaluate for conjugated hyperbilirubinemia (cholestasis) versus unconjugated hyperbilirubinemia. |
| To assess for hepatocyte injury. |
| To assess for biliary injury. Furthermore, several genetic/metabolic disorders can be divided into high- and low-GGTP categories¶. |
| To assess hepatocyte function. Low albumin suggests poor nutrition, renal losses, or poor hepatic synthetic function. |
| To assess for metabolic disease. Abnormalities in these results are often seen in infants with metabolic disease. |
| To assess for infection and/or splenic sequestration. Elevated WBC is suggestive of infection. Low WBC and platelet count could indicate portal hypertension (with splenic sequestration). |
| To assess hepatocyte function and/or vitamin K deficiency. Abnormal results indicate impaired liver synthetic function and/or vitamin K deficiency. |
| Additional tests to evaluate for systemic illness of specific liver diseasesΔ | |
| Appropriate for most infants with cholestasis to exclude urinary tract infection and to evaluate possible renal involvement. |
| If clinical presentation suggests sepsis. |
| Screen for galactosemia (in infants ingesting lactose)◊. |
| Screen for tyrosinemia. |
| Elevations are diagnostic of cholestasis. Serum bile acids will be low in infants with bile acid synthetic disorders. |
| Low levels suggest alpha-1 antitrypsin deficiency. Normal levels do not exclude alpha-1 antitrypsin deficiency, because this is an acute phase reactant. |
| The primary alleles associated with liver disease are PI*ZZ homozygosity or PI*SZ heterozygosity. |
| Screen for congenital hypothyroidism (primary or central). |
| Screen for adrenal insufficiency and hypopituitarism. |
| Elevations suggestive of GALD and HLH. |
| Screen for bile acid synthetic defects (BASD), which may present with low-GGT cholestasis§. |
| If a metabolic disorder is suspected, initial screening includes creatine kinase, plasma amino acids, urine organic acids, acylcarnitine profile, ammonia, lactate:pyruvate ratio. |
| Genetic testing is rapidly evolving with the availability of new technologies¥. It may include karyotype, targeted gene panels, and/or whole-exome sequencing. |
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGTP: gamma-glutamyl transpeptidase; CBC: complete blood count; WBC: white blood cell count; PT: prothrombin time; INR: international normalized ratio; PTT: partial thromboplastin time; TSH: thyroid-stimulating hormone (thyrotropin); T4: thyroxine; ACTH: adrenocorticotropic hormone; GALD: gestational alloimmune liver disease; HLH: hemophagocytic lymphohistiocytosis; FAB-MS: fast atom bombardment mass spectrometry; BASD: bile acid synthetic defects; GGT: gamma-glutamyl transferase.
¶ GGTP is disproportionately elevated (compared with AST and ALT) in the most common types of neonatal cholestasis, including biliary atresia and Alagille syndrome, while a normal or low GGTP is seen in most forms of progressive familial intrahepatic cholestasis, BASD, and arthrogryposis-renal dysfunction-cholestasis syndrome.
Δ These tests are selected based upon the clinical presentation and results of initial tests.
◊ Urine-reducing substances is only valid as a screen for galactosemia if the infant is fed breast milk or a cow's milk-based formula (which contains lactose, then hydrolyzed to galactose).
§ Infants must be off of ursodeoxycholic acid for at least 5 days prior to urine collection for bile acid analysis because the FAB-MS signature of the drug overlaps with some of the abnormal bile acid metabolites seen in BASD.
¥ Individual gene sequencing can be done if the clinical presentation suggests a specific diagnosis, such as Alagille syndrome. For screening of multiple genes associated with inherited cholestasis, next-generation sequencing panels are available. Each panel interrogates approximately 20 to 70 genes. Current information is available at GeneTests.org.