“Dark and bright sides” of Gilbert’s syndrome

Abstract

Gilbert’s syndrome, also known as benign hyperbilirubinemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterized by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt RBC hemolysis. The molecular basis of Gilbert’s syndrome lies in the impairment of the conjugation of bilirubin with glucuronic acid in the hepatocytes, which is mediated by a specific hepatic enzyme named bilirubin-UDP-glucuronosyl transferase 1A1 that forms bilirubin diglucuronoside. Clearance of various xenobiotics, which are not substrates for glucuronosylation, is impaired in patients with Gilbert’s syndrome; their detailed list is provided in the article. Fatigue, asthenia, and various vaguely defined dyspeptic complaints attributed to Gilbert’s syndrome in the past are no longer considered a part of this condition, and proper evaluation of possible causes is required in these cases. Since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as the multiple intracellular signalling pathways affected by bilirubin, an ever-increasing body of evidence suggests that individuals with Gilbert’s syndrome may benefit from the mild hyperbilirubinemia and are actually protected from the development of a wide range of “diseases of civilization”, such as cardiovascular diseases, certain cancers, and autoimmune or neurodegenerative diseases. Gilbert’s syndrome is defined phenotypically, and therefore not according to predisposing genetic markers, as the elevation of serum unconjugated bilirubin concentration above the upper limit of normal, with no laboratory signs of hemolysis or liver damage. This review analyses the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and provides a new perspective on this condition.