Diagnostic criteria and contributors to Gilbert’s syndrome

Figures & data

Figure 1. Bile pigment metabolism – from heme to bilirubin (modified according to Wagner et al. [33]). Hemoglobin is cleaved to yield globin and heme. Heme is enzymatically converted to biliverdin by liberating iron, via oxidation of its α-methene bridge, with loss of a carbon atom (CO). This opens the porphyrin ring, forms the open-chain, linear tetrapyrrole biliverdin, which yields bilirubin after enzymatic reduction of biliverdin’s central methine bond. In the liver, bilirubin is conjugated to enable excretion into the bile, requiring the enzymes UGT1A1 (conjugation) and MRP2 (excretion into the bile). HO: heme oxygenase; BLAVR: biliverdin reductase; UGT1A1: uridine glucuronosyl transferase 1A1; MRP2: multi-drug resistance protein-2.

Figure 2. Geographical prevalence of benign hyperbilirubinemia (GS) in articles reporting TB concentrations (i.e. data are not derived from genetic analysis) in the general population [19–27].

Table 1. Diagnostic and clinical features of hyperbilirubinemia syndromes (modified according to Strassburg [67]).

	Gilbert´s syndrome (GS)/ Crigler-Najjar (CN) syndrome	Dubin Johnson syndrome	Rotor syndrome
Molecular mechanism	Impaired UGT1A1 activity (conjugation); GS: up to 70% reduction; CN: up to 100%	ABCC2 transporter affected; biliary transport deficiency of non-bile acid organic anions	Hepatic storage deficiency of conjugated bilirubin
Expected plasma concentration of unconjugated bilirubin	GS: 17–85–100 µmol/L CN: 100 - >800 µmol/L	50–100 µmol/L, up to 400 µmol/L possible	50–100 µmol/L
Histology	Normal	Gross pathology: black liver, histology: lysosomal pigment	Normal
Urine	Normal urine coproporphyrin	Normal urine coproporphyrin	2–5-fold increased excretion of coproporphyrin
Aminotransferases	Normal	Normal	Normal
Hepatobiliary transport	Alterations in hepatic indocyanine green and bromosulphthalein excretion possible, impairment of hepatic uptake possible	Biphasic bromosulphthalein clearance: normal at 45 min; secondary peak at 90 min	Increased retention of bromosulphthalein at 45 min; no 90 min peak
Pruritus	Absent	Absent	Absent
Prognosis	Benign (GS)/potentially fatal (CN)	Benign	Benign
Precipitating factors	Fasting/reduced gastrointestinal motility, onset of pubescence.	Oral contraceptives, pregnancy, intercurrent illness	Oral contraceptives
Hematology	Limited evidence of increased RBC count/total hemoglobin.	Not documented	Not documented

Figure 3. Summary of the different hyperbilirubinemia syndromes (GS, Crigler-Najjar syndromes type 1 and 2 OR CN-1 and CN-2) based on different UGT1A1 activities.

Figure 4. Factors affecting circulating unconjugated bilirubin concentrations.

Wagner KH, Wallner M, Molzer C, et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci. 2015;129:1–25.

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Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010;24:555–571.

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