How useful are the biochemical tests in guiding the diagnostic workup of infantile cholestasis?

Background: The objective of our study was to determine whether biochemical tests, frequently requested at first presentation of infants with cholestasis, have a role in focusing investigations toward certain disease entities. Methods: All infants with cholestasis (2008 to 2020) were identified and reviewed for final diagnosis and serum levels of alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), lactate, cholesterol, ferritin, alpha-fetoprotein (AFP), total bile acids (TBAs), and hypoglycemia at first presentation. Results: ALT levels were normal in all infants with Dubin–Johnson syndrome. A normal TBA (0–10 μmol/L) in an infant with normal-GGT cholestasis was consistent with bile acids synthesis disorders (BASDs). There was a dichotomy pattern of “high-GGT cholestasis” [associated with biliary obstruction, Alagille syndrome, ciliopathies, mitochondrial hepatopathies] and “low GGT cholestasis”, [associated with mutations in ATP8B1, ABCB11, TJP2, USP53, LSR, MYO5B, VIP AS39, NR1H4, BASD, galactosemia, gestational alloimmune liver disease (GALD), and endocrine causes]. Plasma lactate level was significantly elevated in infants with mitochondrial hepatopathies and hemophagocytic lymphohistiocytosis (HLH) [median 5.8 mmol/L and 7.7 mmo/L, respectively; P < 0.001]. The highest ferritin concentrations were in infants with HLH and GALD [medians 4883 μg/L and 2098 μg/L, respectively; P < 0.001]. The most marked elevation of AFP was consistent in all infants with mitochondrial hepatopathies, tyrosinemia, and GALD (median: 99637 ng/mL, 40000 ng/mL; 22566 ng/mL) as compared to causes of biliary obstruction (median: 3662 ng/mL). Hypoglycemia with preserved liver synthetic function was associated with metabolic or endocrine disorders. Conclusion: Although none of these biochemical tests is diagnostic in itself, they can be actionable red flags to triage infants with cholestasis toward the most appropriate specific investigations.