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 (1), 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 (2) 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 (3). Furthermore, a recent cross-sectional study showed no correlation between enzyme dose and growth or self-reported symptoms (4). 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. PATHOGENESIS OF PANCREATIC, HEPATIC AND INTESTINAL DISEASE IN CF Classic CF reflects two loss-of-function CFTR mutations whereas patients with nonclassic CF carry at least one copy of a mutant gene that confers partial function of the CFTR protein (5). Patients with “classic” and “nonclassic” CF exhibit wide heterogeneity in the severity of lung disease. However, in statistical terms, the overall rate of progression of lung disease among the nonclassic CF patients is slower and median survival is almost twice that of patients with “classic” CF. Among the various gastrointestinal organs affected by CF disease, the exocrine pancreas shows the strongest association between genotype and phenotype. Loss-of-function mutations on both alleles almost always confer pancreatic insufficiency (PI). In most cases, considerable obstructive destruction of the pancreas arises in utero and functional loss of the exocrine pancreas develops at birth or in early infancy. These patients need PERT with meals and snacks. In patients with the pancreatic sufficient phenotype the presence of at least one mutation with some residual CFTR function protects the pancreas from complete destruction. However, the functional capacity of the exocrine pancreas in the patients who are pancreatic sufficient varies widely, from values just above the threshold for developing PI to values that are within the reference range for healthy controls (6). Approximately 20% of pancreatic sufficient patients are at risk of developing symptoms of recurrent, acute pancreatitis or chronic pancreatitis. In contrast to the exocrine pancreas, expression of disease in other gastrointestinal organs is less clearly associated with CFTR genotype. However, patients with classic CF are more vulnerable than their nonclassic counterparts to meconium ileus (MI), distal intestinal obstruction syndrome (DIOS) and clinically significant liver disease (CFLD). As disease penetrance is incomplete, disease expression seems to depend on two loss-of-function CFTR mutations as well as the of and/or factors. 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However, in CF mice that loss of pancreatic function not with bowel the of mouse the and severity of in the presence of severe CFTR mutations on both alleles are likely to a in in to the symptoms of by the dose of PERT may not be of food products from showed on bowel obstruction in CF as nutritional factors may contribute to the of in is common in patients with CF and is associated with of (4). the of in CF is it is common in the and is to be less in CF. of may to treatment of than an in PERT. bowel are in 20% to of the population. We not have methods to distinguish between abdominal related to bowel and the various CF causes of abdominal bowel syndrome be considered in the of a patient with abdominal and or if other members have The CFA is the method for fat absorption. is not as it distinguish between pancreatic maldigestion and other causes of malabsorption, has and is to the stool stool the of a high fat or the patient be on the correct for before the stool when testing PERT at the and of the of high fat the stool to be to fat as and can be to in is and may improve of stool of fat to the CFA a or an incomplete to of fat to the CFA to of fat malabsorption. subjects for of malabsorption, subjects have of PI by CFA enzymes or of PERT efficacy in CF have included pancreatic sufficient this the CFA to CFA are for clinical care and to fat absorption and to distinguish maldigestion from malabsorption absorption of or their products in the of absorption in or fat using a in a stool The method is a from stool to the from using by a of products of absorption in after a is not a new it has been in a The two a and a study of with and a and dose of the two of and of is The and of fat with of from is a it is of pancreatic whereas is a and by pancreatic before absorption. have been used to the in of the two which in the of fat malabsorption to PI in patients with CF in other with pancreatic or nonpancreatic causes of malabsorption and/or and with among other has the to distinguish pancreatic from nonpancreatic causes of fat malabsorption. The and of using or a to a variety of and of to the and the of and of a and pancreatic enzyme can be using a The of on the of activity and fat absorption can be using a or However, after of correlation with fat absorption in a of subjects with CF study in with of the that the fat for fat absorption between However, the of fat malabsorption may use for diagnostic in individuals with less severe for fat absorption is on of an the gastrointestinal and a stool with a intestinal of the three is the the amount of and can be from two within the stool by the The of and of the to CFA a of be from have gastrointestinal absorption in CF intestinal of and the stool be and for the wide range of fat that is in CF and be to in fat absorption between patients with pancreatic and with pancreatic method appears to most The of the method over a wide range of on the of the of the and the of the has the to use to study a wide range of malabsorption in patients with CF and excellent correlation with CFA stool method has been developed which is a of and the that is used in a variety of is with other is in the because it is not by pancreatic from the the of is present in in the using as a of fat absorption in absorption of fat from in fat absorption with of to and fat absorption with of have on the dose and of of a stool the dose of to in of to and in stool and of the method to the method in healthy clinical the method with showed absorption of fat when healthy were receiving a is it may absorption of the used in the this this method is not as well as it shows The method a amount of stool and commonly in clinical and for As we have CF affects a variety of that on maldigestion and malabsorption CFTR function a in the gastrointestinal not just in the pancreas and the there is a need to the of loss of intestinal CFTR as a the of intestinal disease in CF be by further of the or of CFTR on the or of other as and as and The of mutant CFTR on the and on intestinal These and other factors may all contribute to and function in patients with CF. models of CF to the intestinal of loss of CFTR function or and the of and are intestinal factors and absorption in cystic this workshop on maldigestion and malabsorption of other and and and considerable it is likely that a understanding of the of and absorption will to with other The and of clinical to the of PERT risk and to subjects by methods of the of maldigestion and/or malabsorption, by using statistical to subjects to be and by the use of We need to and the and factors that may contribute to a or to PERT in a of patients with CF. ways of these factors will the of of PERT efficacy. We of the of PERT, not the of and PERT, the site of of PERT, the of intestinal and other confounding factors as and There is a need to and are in patients with CF, what can be used to study and to malabsorption. understanding of the pulmonary manifestations of CF has as we have the and these advances are treatments and patients less of our understanding and treatment of gastrointestinal manifestations of CF disease. AND