We report on a previously unknown heterozygous
ABCB11 variant and provide for the first time the histological proof of BSEP decompensation in TNC after severe neonatal asphyxia. Ischemic liver injury occurs as part of so-called “multi-organ damage” following perinatal asphyxia and becomes manifest biochemically in peaks of LDH and liver enzymes within the first 24–72 h. These elevated parameters usually decrease in the following days and return to normal between 6 and 12 days after the hypoxic event [
8]. However, prolonged cholestasis in our patient was inconsistent with a course of asphyxia-related liver injury (Table
1). Moreover, evolution of serum liver tests suggested that in contrast to asphyxia-mediated massive hepatocellular damage immediately after birth, impairment of bile elimination mechanisms were responsible for chronic liver injury (ALT/AP ratio of 1.4 at the age of 3 months vs. ALT/AP ratio of 8 on day 1
post-partum). Genetic analysis determined a new heterozygous variant of
ABCB11, a unique BS-specific transporter, which loss cannot be compensated by an alternative export mechanism in humans. Due to limited size of the liver specimen and based on data obtained from the genetic analysis, examination of potential molecular mechanisms causing cholestasis was restricted to studying BSEP as the most likely candidate. Although the identified mutation was found in a heterozygous state and GGT levels did not match with classical BSEP deficiency, histologically BSEP was almost abolished from hepatocyte canalicular membrane in our patient. Since clinical severity of different
ABCB11 mutations directly correlates with the amount of mature protein on hepatocellular membrane [
2,
3], impaired canalicular BSEP expression is likely to play at least a partial role in the pathogenesis of prolonged cholestasis in our patient. Of note, the mother of our patient carries the same mutation with no cholestatic events in her history, indicating that the heterozygous state of the identified mutation is likely to be sufficient to maintain BS excretion under normal conditions. In addition, occasionally elevated GGT levels in our patient were inconsistent with classical presentation of BSEP deficiency in PFIC2. It can, therefore, be speculated that the complicated neonatal period and multifactorial liver injury played a critical role in transient decompensation of
ABCB11 originating from non-mutated gene copy. It still remains unclear which mechanisms are responsible for long-term BSEP inhibition in our patient. BSEP is believed to recycle between the plasma membrane and subapical vesicles and its half-life in the apical membrane ranges from 4 to 6 days [
3]. This may explain short-term BSEP decompensation and its rapid recovery after triggering factor has resolved, as reported in cases of hypoxia-, sepsis-, PN-induced cholestasis or DILI. In contrast, mechanisms responsible for persisting BSEP dysfunction long after termination of damaging factors, as observed in our patient, remain so far elusive. Interestingly, prolonged cholestasis has been observed in rare cases of DILI [
9]. However, the pathogenesis of DILI is complex and involves -in addition to BSEP inhibition- additional mechanisms [
10,
11]. This is supported by the fact that only a very low percent of newborns with drug intake during the complicated neonatal course develop TNC. In this context, indirect inhibition of
BSEP by other hepatobiliary transporters through the farnesoid X receptor (FXR)-mediated signaling has to be considered. Despite two heterozygous mutations found in
ATP8B1 were of unknown significance, BSEP inhibition through
ATP8B1-FXR-mediated mechanism cannot be excluded [
12] and ATP8B1 dysfunction should be considered as additional potentially pathogenic mechanism in course of transient cholestasis in our patient. We believe that prolonged BSEP deficiency and resulting intracellular cholestasis were of multifactorial origin in our patient. In this context, persisting hepatocyte inflammatory response triggered by initial massive liver and multiorgan damage and maintained by ongoing interplay of drugs/toxins, mitochondrial inflammatory reaction by accumulating bile acids [
13,
14] as well as immaturity of regulatory mechanisms are likely to contribute to BSEP inhibition. However, BSEP inhibition itself, even if secondary to inflammation or toxicity by endogenous intermediates, played important role for the maintenance of prolonged cholestasis in our patient.