Gastrointestinal outcomes and confounders in cystic fibrosis

Until the mid 20th century, children with cystic fibrosis (CF) died at a young age from a combination of malnutrition and suppurative lung disease. In the past three to four decades, coincident with new treatments for pulmonary complications and the use of high-calorie diets without restrictions on fat intake, there has been marked and progressive improvement in lung function, nutritional status and survival. However, treatment for pancreatic insufficiency, which affects most individuals with CF, remains largely unchanged, and there have been few advances in our understanding and management of gastrointestinal problems in this population. Pancreatic Enzyme Replacement Therapy (PERT), principally using enzyme extracts of porcine origin, has been the mainstay for treating maldigestion resulting from pancreatic insufficiency (PI) for over a century. Powdered PERT was instituted before the 1931 creation of the United States Food and Drug Administration (FDA) and the subsequent Federal Food, Drug and Cosmetic Act of 1938 that required proof of safety and efficacy before approval of drugs for marketing. Enteric-coated microcapsules, the most commonly used PERT, have never been FDA approved. After the epidemic of fibrosing colonopathy in the early 1990s, a condition that was clearly related to high doses of exogenous pancreatic enzymes, the FDA initiated a process of re-evaluating the safety and efficacy of PERT. In 2004, the FDA released a draft of a new Guidance Document for public comment that stated that within the next 4 years, all manufacturers of current enzyme products will need to submit a New Drug Application to the FDA with proof of safety in manufacturing, stability and efficacy. The coefficient of fat absorption (CFA) is the traditional method of testing the clinical efficacy of PERT. CF clinicians have long recognized that there is a very wide range of CFA in patients with CF. Less well known is that there is marked variability in the actual amount of enzyme in each capsule. Capsules are overfilled so that the stated dosage reflects the least amount of enzyme activity present after a six-month shelf life. There is little correlation between CFA and enzyme dose when subjects are receiving a dose of PERT considered optimal by the caregiver and/or patient. Furthermore, a recent cross-sectional study showed no correlation between enzyme dose and growth or self-reported symptoms. Consequently, the common belief that PERT dose can be titrated to correct malabsorption and/or maldigestion using patient-reported relief of abdominal symptoms or stool bulk and consistency appears to be questionable. PERT may not completely correct PI even if given in adequate doses because the release and onset of activity is not synchronous with the presence of food in the proximal intestine, the site for optimal absorption. Furthermore, as discussed below, it is becoming evident that poorly understood nonpancreatic intestinal and/or hepatobiliary factors likely contribute to incomplete and variable nutrient assimilation in patients with CF. However, we lack tools to distinguish PERT-related factors that might contribute to treatment failure from other confounding factors. Ironically, as mouse models of CF were developed in the late 20th century, these animals did not develop lung or severe pancreatic manifestations. However, the mice have characteristic CF-like bowel obstruction and are proving to be excellent models for study of nonpancreatic gastrointestinal manifestations of CF. The combination of new ways to study gastrointestinal disease in CF that further our understanding of the pathophysiology of CF and the need to evaluate novel methods to study pancreatic and nonpancreatic causes of maldigestion and malabsorption led the CF Foundation to sponsor a workshop, which was held in Baltimore in May 2005. The goals of this workshop were to evaluate what is known about gastrointestinal issues leading to malabsorption, to consider other factors that may contribute to malabsorption and to identify ways to improve care of patients with CF. We set an agenda for further clinical and laboratory-based investigations that would help to elucidate the spectrum of causes of maldigestion and malabsorption. The workshop participants included clinicians and investigators with a variety of interests, members of the US and European regulatory agencies and individuals from industry who were involved in producing traditional PERT or developing novel PERT or diagnostic tests. © 2005 Lippincott Williams & Wilkins, Inc.