Unmasking hereditary hemochromatosis with CFTR modulator therapy

Abstract

Cystic Fibrosis (CF) is a genetic condition affecting the ability to excrete chloride, resulting in multi-system organ damage. Liver disease is one co-morbidity that affects 20-40% of people with CF. This case describes a 16-year-old male with CF (F508Del and Q493X mutations) who was started one lexacaftor/tezacaftor/ifacaftortriple CF Transmembrane Regulator (CFTR) modulator therapy. Prior to starting treatment, it was noted that he had transaminitis (AST 69, ALT 120, Total bilirubin 0.4). His liver enzymes continued to increase with therapy and at week 8 of treatment he complained of abdominal pain, body aches, and fatigue warranting further evaluation. At that time, AST and ALT were elevated at 5- and 13-times the Upper Limits of Normal (ULN) and creatinine kinase was elevated at 12-times ULN. A dose reduction led to a decrease in AST and ALT to 2 and 4-times ULN, but total and direct bilirubin increased to 2.2 mg/dl and 0.5 mg/dl, warranting a liver ultrasound and biopsy. Pathology showed fatty liver and hepatocyte iron deposition, but no indications of cirrhosis. Iron studies and genetic testing confirmed a diagnosis of HH (Homozygous HIS63ASP gene mutation). After stopping triple CFTR modulator therapy, AST and ALT continued to rise, prompting further evaluation by hepatology and hematology. Upon discontinuation of drug therapy, his lung function dropped significantly back to baseline values and respiratory symptoms returned. Discussion: Hereditary hemochromatosis gene mutations have been shown to have a gene modulating impact on CFTR gene mutations that can affect CF disease phenotype, which negatively affects pulmonary function and gastrointestinal disease. In this case, the introduction of a new medication instigated further work-up leading to the discovery of a potential alternative cause of hepatic dysfunction while attempting to optimize medications to sustain improvements in pulmonary function. Although elevated hepatic transaminases can be expected from CF and CFTR modulator therapy, further investigation may be indicated in patients with persistent elevations despite medication adjustments. This workup may lead to important considerations in balancing liver function with lung function. Keywords: cystic fibrosis; elexacaftor; tezacaftor; ivacaftor; liver transaminases; hereditary hemochromatosis.