IBAT inhibitor case studies point to adult intrahepatic cholestasis benefits

The first study reports the outcome of a woman who was treated with odevixibat for severe drug-induced PFIC, while the second details the management of a pregnant woman with a history of benign recurrent intrahepatic cholestasis (BRIC) and intrahepatic cholestasis of pregnancy (ICP) with maralixibat.

Adult-onset PFIC and odevixibat

In a letter to JHEP Reports, Mario Masarone (University of Salerno, Italy) and co-authors of the first study say the 27-year-old patient developed severe jaundice, intractable pruritus and severe mixed hyperbilirubinemia 5 months after beginning levonorgestrel/ethinylestradiol for dysmenorrhea.

The patient was diagnosed with biliary cholelithiasis complicated by drug-induced liver injury and underwent laparoscopic cholecystectomy. She did not respond to cholestyramine and ursodeoxycholic acid, with worsening hyperbilirubinemia and renal failure. There were no hepatic or biliary tract lesions on imaging but liver biopsy revealed mild inflammation, fibrosis, focal steatosis, cholestasis and focal bile duct degeneration.

She was treated with plasmapheresis four times for suspected bile cast nephropathy, but subclavian artery rupture on the last occasion led to liver and renal function worsening, and listing for liver transplantation.

The patient’s clinicians suspected PFIC on the basis of hyperbilirubinemia (≤40.03 mg/dL) elevated total serum bile acids (TSBAs, 262 µmol/L) and mildly elevated gamma-glutamyltransferase (1.2 x upper limited normal), and the patient was therefore treated with odevixibat 2400 µg/day.

“Within weeks, odevixibat markedly improved her hyperbilirubinemia, pruritus, and liver and renal function, allowing her to be removed from the transplantation list”, Masarone et al say.

The patient’s severe PFIC phenotype and incomplete liver function recovery led to odevixibat treatment being continued beyond the acute episode, which is a “topic of debate,” the researchers admit.

Genetic testing at the time of odevixibat initiation confirmed that the woman carried two different rare heterozygous ABCB11 variants, one previously linked to cholestasis, and one known to cause an in-frame deletion-insertion, as well as a SERPINA1 mutation.

“This case underscores the pivotal role of early odevixibat in treating severe hyperbilirubinemia complicated by [cholemic nephropathy],” particularly for patients with a phenotype indicative of PFIC, the authors say.

“Furthermore, it highlights the importance of initiating treatment on clinical suspicion, even before confirming genetic testing results, to halt progression towards end-stage liver disease,” they emphasize.

Masarone et al add: “This case also expands the understanding of PFIC as a condition that can manifest in adulthood, often triggered by factors such as estrogen-progestin-induced liver injury.”

ICP and maralixibat

Tatyana Kushner (Weill Cornell Medicine, New York, USA) and co-authors of the second case study say their 36-year-old patient was initially diagnosed with BRIC at 21 years old following the onset of persistent pruritus that required 1 year of therapy with ursodiol and rifampin.

The patient subsequently experienced mild recurrence of pruritus annually and showed liver enzyme elevations during asymptomatic periods, but genetic testing did not identify BRIC-related alterations.

During the second trimester of her first pregnancy at age 33 years the patient developed ICP. After experiencing minimal benefit from increased doses of ursodiol and rifampin treatment, the patient was hospitalized at 34+5 weeks’ gestation for severely elevated TSBAs and induced at 35+1 weeks, with a complicated vaginal delivery resulting in interventions for postpartum hemorrhage. The infant was admitted to the neonatal intensive care unit for prematurity and respiratory care.

The woman was discharged with ursodiol therapy, and Kushner et al say that 1 month after delivery, her TSBAs and liver enzymes were only mildly elevated and she had been able to breastfeed without pruritus.

The woman began ursodiol therapy when planning a second pregnancy at age 36 years and required a dose increase at 8.5 weeks’ gestation for severe pruritus, resulting in symptoms being limited to her palms and soles and normal liver enzyme test results.

However, the patient’s persistent TSBAs elevation and history of ICP prompted her clinicians to obtain access to maralixibat 190 µg/kg, which was given daily from week 24, increased to twice daily after 1 week for persistent pruritus, and again to 380 µg/kg twice daily at week 28.

The researchers report that the woman had “clay-colored stools and steatorrhea” following the final dose increase. She was given subcutaneous vitamin K supplementation to treat a persistently low level, as well as oral vitamin A, E, and D supplements.  

Kushner and co-authors say the patient’s TSBAs peaked around week 35 and she was induced at week 37. She had an uncomplicated vaginal delivery and healthy infant. The patient was discharged with ursodiol therapy and remained asymptomatic thereafter.

They believe that maralixibat offered a “novel therapeutic approach” to managing ICP that reduced pruritus and achieved TSBA levels “below the highest-risk threshold (>100 µmol/L), demonstrating the potential benefit of IBAT inhibitors in ICP.”

Treatment was described as “well tolerated” and the team says it was “reassuring” that the patient maintained a healthy international normalized ratio throughout her pregnancy. However, Kushner et al recognize the possibility for fat-soluble vitamin deficiency with maralixibat and advise “proactive screening.”

In a letter to the Journal of Hepatology, the clinicians recommend further research “to develop safety and clinical guidelines, including the establishment of a pregnancy registry to gather real-world data.”

Kusher and co-authors state that “expedited access is crucial given ICP’s rapid progression,” and that “[p]reconception planning and personalized approaches to ICP management are also warranted, as distinct phenotypes may respond differently to targeted therapies.”

They therefore conclude: “Future studies should refine patient selection criteria, optimize treatment timing and dosing, assess long-term neonatal outcomes, and determine the place of IBAT inhibitors in clinical guidelines.”