Updates on pancreas exocrine function in cystic fibrosis for the era of highly effective modulator therapy

The pancreas is one of the earliest affected organs in cystic fibrosis (CF). Most newborn screening programs are based on pancreatic inflammation causing elevated trypsinogen at birth, and most individuals with CF are born with exocrine pancreatic insufficiency (PI) which requires lifelong treatment with pancreas enzyme replacement therapy (PERT). However, as CFTR modulating therapies (CFTRm) are administered earlier and earlier, these paradigms may be changing. In this article, we summarize updates on the diagnosis and treatment of exocrine pancreatic disease in CF in the era of CFTRm. We provide a concise review on the natural history of the exocrine pancreas in CF as a context to discuss new observations of CFTRm use at different time points in utero, in childhood, and in adulthood. Clinicians are encouraged to obtain objective exocrine function testing (i.e., fecal elastase) among individuals receiving CFTRm therapy, and to counsel patients and/or parents on the unknowns regarding natural history during CFTRm use. Few patients will regain pancreatic sufficiency (PS) and we encourage clinicians to de-escalate PERT stepwise, rather than discontinue abruptly. Lastly, it is important to note that most reports of improved exocrine function are described in children, and individuals who started CFTRm in adulthood are unlikely to experience reduction in PERT dose and should continue close monitoring for late complications of severe PI, like fat soluble vitamin deficiency and metabolic bone disease.