Orlistat Treatment of Unconjugated Hyperbilirubinemia in Crigler-Najjar Disease: A Randomized Controlled Trial

Abstract

Unconjugated hyperbilirubinemia in Crigler-Najjar (CN) disease is conventionally treated with phototherapy and phenobarbital. Orlistat treatment increases fecal fat excretion and decreases plasma unconjugated bilirubin (UCB) concentrations in Gunn rats, the animal model for CN disease. We determined in CN patients the effects of orlistat treatment on plasma UCB concentrations, and on fecal excretion of fat and UCB. A randomized, placebocontrolled, double-blind, cross-over trial was conducted in 16 patients, simultaneous with their regular treatment (phototherapy, n ϭ 11, and/or phenobarbital, n ϭ 6). Patients received orlistat or placebo, each for 4 -6 wk. Compared with placebo, orlistat increased fecal fat excretion (ϩ333%) and fecal UCB excretion (ϩ43%). Orlistat treatment significantly decreased plasma UCB concentration (-9%). In 7 of 16 patients, the decrease in plasma UCB levels was clinically relevant (Ͼ10%, mean 21%). In patients with a clinically relevant response, plasma UCB concentrations during orlistat were strongly, negatively correlated with fecal fat excretion (r ϭ -0.93). Clinically relevant response to orlistat treatment was not correlated with age, sex, CN type, BMI, or co-treatment with phototherapy or phenobarbital, but appeared correlated with a relatively lower dietary fat intake. In conclusion, orlistat treatment decreases plasma UCB concentrations, particularly in a subgroup of CN patients. Dietary fat intake may determine the responsiveness to orlistat treatment.

Gallstone disease: From genes to evidence-based therapy

“…Recently the lipase inhibitor orlistat has been demonstrated to enhance faecal bilirubin excretion and to decrease serum bilirubin levels [85], but its stone protective effects have yet to be studied.…”

Combined Treatment Strategies for Unconjugated Hyperbilirubinemia in Gunn Rats

“…Although this was not observed in other groups, it should be emphasized that diarrhea and malabsorption of vitamins (A, D, E, K) have been reported during orlistat, UDCA, and CaP treatment (18,35,36,38). Regular assessments of the nutritional (vitamin) status and/or vitamin supplementation would be indicated if one would combine these treatments with a laxative such as PEG in patient studies.…”

“…Interestingly, previous findings have suggested that phototherapy and oral treatments that enhance transmucosal UCB diffusion [e.g. orlistat (17,18), bile salts (13), or amorphous calcium phosphate (CaP) (19)] might indeed influence transit time (20 -25). We presently show that neither phototherapy nor oral treatment with orlistat, ursodeoxycholic acid (UDCA), or CaP affects the gastrointestinal transit time in Gunn rats.…”

Bilirubin Metabolism and Jaundice

“…Efforts to reduce unconjugated hyperbilirubinemia in such situations by interrupting the enterohepatic circulation of unconjugated bilirubin with the use of agents such as oral agar, charcoal, or cholestyramine have had at best limited and inconsistent success [78,79,89]. Recent reports suggest that oral administration of calcium phosphate with or without the lipase inhibitor orlistat may be an efficient means to interrupt bilirubin enterohepatic cycling to reduce serum bilirubin levels [90][91][92].…”