Acute Liver Failure in a Patient with Cystic Fibrosis Taking Triple Combination Modulator

Macroenzymes as a reason for aminotransferases flare in cystic fibrosis patients on CFTR modulators therapy – Report of three cases

“…There were case reports on DILI during CFTR therapy [ 3 , 12 , 13 ]. However, in the long term observation, CFTR modulators may have beneficial effect on liver function [ 14 ] and it may improve markers of liver fibrosis [ 15 ].…”

“…After normalization of aminotransferases activity, the CFTR modulators therapy may be re-challenged in the reduced dose and under careful laboratory control of the liver function. There is one report describing liver failure requiring liver transplantation in patient who underwent ivacaftor + tezacaftor + elexacaftor (IVA + TEZ + ELX) combined with ivacaftor (IVA) therapy [ 3 ]. The patient had pretreatment liver cirrhosis and possibly autoimmune hepatitis, thus CFTR treatment should be used with care in patients with advanced CFLD (Cystic Fibrosis related Liver Disease) presenting as liver cirrhosis or portal hypertension.…”

Triple combination cystic fibrosis transmembrane conductance regulator modulator therapy in the real world – opportunities and challenges

“…Physicians described 7 cases of adults who developed biliary colic after treatment with ETI, including 6 who required cholecystectomy, an outcome also observed in one pregnant woman who used ETI during pregnancy [48 && ,49]. Although ETI has been successfully used in pwCF with known baseline CFrelated liver disease (based on ultrasound and/or biopsy), a case report of an adult with previously undetected preexisting liver disease developed acute liver failure requiring liver transplant following the reintroduction of ETI after initial discontinuation for elevated liver function tests [50,51]. Anecdotally, increased anxiety has also been reported with ETI use.…”

Drug-induced liver injury associated with elexacaftor/tezacaftor/ivacaftor from the FDA Adverse Event Reporting System (FAERS)

“…Results from one of the pivotal phase 3 trials showed that the incidence of maximum transaminase elevations above 8X, 5X, or 3X the upper limit of normal (ULN) occurred in 1%, 2%, and 8% of ETI-treated patients compared to 1%, 1%, and 5% for placebo, while the incidence of maximum total bilirubin above 2X ULN occurred in 4% of ETI-treated patients compared to <1% for placebo (1). In real-world use, DILI occurring after ETI administration has resulted in several cases of severe outcomes for patients, including acute liver failure requiring transplantation and a case of hepatic necrosis (12)(13)(14). A limitation of Phase III trials is their relatively small sample size and short term follow up which cannot capture rare safety concerns that may be revealed in a longer-term, larger pool of real-world patients.…”