Could a less sedative drug than phenobarbital be used in the treatment of Gilbert´s disease?

Fråga: Could a less sedative drug than phenobarbital be used in the treatment of Gilbert´s disease?

Sammanfattning: Gilbert´s syndrome is a benigh disorder involving different pathways of bilirubin metabolism including increased pigment production, reduced hepatic uptake of bilirubin and impaired hepatic conjugation. Various therapeutic agents can decrease plasma bilirubin levels but the decision to treat must be weighed against the predictable side effects of enzyme-inducers. Among them, phenobarbital at doses of 60 mg twice daily or 100 mg at bed time can DECREASE PLASMA BILIRUBIN LEVELS, although its mechanisms of action are still unclear and the dose cited in reference appears to be arbitrary and high. Lower doses and larger dosage intervals are to be suggested if phenobarbital therapy is judged necessary. Other microsomal enzyme inducers are likely to have the same effect on bilirubin plasma levels but the advantages of the therapy must be compared with the inconvenience of long term use. Corticosteroid use does not appear reasonable, nor does use of the other therapeutic agents mentioned above.

Svar: GILBERT´S SYNDROME. This benign but chronic disorder is characterized by a mild, fluctuating, unconjugated hyperbilirubinemia. The total serum bilirubin level usually ranges from 1.2 to 3 mg per 100 ml and is increased following prolonged fasting or after intravenous nicotinic acid administration. Less than 20 per cent of the total serum bilirubin is conjugated and patients show a modest increase in monoconjugate of bilirubin in bile (1,2). Liver function tests are not perturbed and the liver histology is normal on light microscopy. Electron microscopy suggests hypertrophy of the smooth endoplasmic reticulum.

This hereditary defect is a remarkable illustration of genetic polymorphism. It seems to be inherited as an autosomal dominant character with incomplete penetrance, but shows male preponderance (3). In this constitutional hepatic dysfunction, bilirubin clearance is decreased due to a partial deficiency of bilirubin-UDP-glucuronyltransferase activity. The ratio of monoglucuronide to diglucuronide of bilirubin in gall-bladder bile is increased, suggesting a second enzyme defect (4). It is associated, in some cases, with defective bilirubin uptake, a deficiency of one of the intrahepatocytic anion-carrying proteins, and with increased hemolysis in 50 per cent of patients with Gilbert´s syndrome (5).

The glucuronidation of foreign compounds such as menthol (6), paracetamol (7), clofibrate (8) and oestradiol benzoate (9) is also impaired. One study showed (10) that most patients with Gilbert´s syndrome have an isolated deficiency of bilirubin-glucuronyltransferase activity. Only 25 per cent of the patients also had impaired liver glucuronyltransferase activity for paranitrophenol. Other metabolic defects may be associated, with Gilbert´s syndrome as suggested by the higher prevalence of slow acetylators of sulphadimidine, (11) and the reduced clearance of tolbutamide (12) and bromosulfophthalein (13), probably related to diminished hepatic uptake. The molecular mechanism of the decreased glucuronidation of bilirubin may be a functional or quantitative defect of a particular uridine diphosphate glucuronyltransferase (UDPGT) form, or a structural abnormality in the microsomal membrane (14).

Phenobarbital (60 mg twice daily) or gluthetimide (500 mg at night) can reduce bilirubin plasma levels (14b) by enhancing bilirubin-UDPGT activity and the hepatic uptake of bilirubin perhaps by induction of ligandins as shown by an in vitro study (15). The mechanism of action of phenobarbital remains unclear, as it can diminish plasma bilirubin levels even in the complete absence of bilirubin-glucuronyltransferase (16).

Corticosteroid administration may decrease serum bilirubin concentration in Gilbert´s syndrome, largely due to enhanced hepatic uptake or storage of bilirubin (17). In contrast to the effects of phenobarbital, the antihyperlipemic drug clofibrate increases the yglucuronidation of bilirubin without changing the ratio of bilirubin mono-to di-conjugates in bile (18). Phototherapy has a favorable effect by degrading bilirubin in the skin but is not a practical long term treatment (19).

In two subjects with Gilbert´s syndrome, Sn-protoporphyrin, a potent inhibitor of heme oxygenase has been effective in decreasing bilirubin plasma concentrations when administered intravenously (20).