Cystic fibrosis: Assessment and management of pancreatic insufficiency

INTRODUCTION — 

Pancreatic insufficiency is the most common gastrointestinal complication of cystic fibrosis (CF), affecting approximately 85 percent of patients at some time in their lives [1,2]. The major consequences of pancreatic insufficiency are due to nutrient malabsorption, which is caused by decreased production of pancreatic enzymes. As a result, people with CF are at risk for malnutrition, steatorrhea, hypoproteinemia, and fat-soluble vitamin deficiencies.

The pathogenesis, clinical manifestations, diagnosis, and management of pancreatic insufficiency in children with CF will be discussed here. The nutritional consequences of this disorder and other gastrointestinal complications of CF are discussed separately:

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Hepatobiliary disease".)

Other aspects of CF care are discussed in these topic reviews:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(See "Cystic fibrosis-related diabetes mellitus".)

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Management of pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

EPIDEMIOLOGY

Pancreatic phenotypes — Traditionally, people with CF have been categorized as having pancreatic sufficiency (10 to 15 percent) or pancreatic insufficiency (the remainder) [3]. It is now clear that pancreatic function in CF varies along a spectrum from normal to severely deficient. People with normal or near-normal pancreatic function tend to have less severe lung disease, and their nutritional status is better than their counterparts who have more severe pancreatic dysfunction. Pancreatic function also varies with the age of the patient; it tends to worsen over time. Approximately 60 percent of infants with CF have pancreatic insufficiency at birth, and 75 to 90 percent have developed pancreatic insufficiency by one year of age [4,5]. This represents the natural history of CF, which may change with the widespread use of CF transmembrane conductance regulator (CFTR) modulators. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Nonpulmonary outcomes'.)

Genotype associations — Pancreatic function correlates strongly with genotype. Pancreatic insufficiency generally develops within the first few months of life in infants who have two "severe" mutations of the CFTR gene, including F508del, N1303K, G542X, and G551D (table 1) [6-8]. These severe mutations usually are in the functional mutation groupings known as class I (defective CFTR protein synthesis), class II (defective CFTR protein processing), or class III (defective regulation/gating of the CFTR channel). By contrast, the presence of at least one "mild" mutation such as R117H or A445E usually is associated with pancreatic sufficiency [7,9]. These mild mutations tend to be from functional class IV (decreased CFTR channel conductance) or class V (reduced synthesis or trafficking). Of note, this genotype association is stronger for the pancreatic insufficiency phenotype and much weaker for the pulmonary disease phenotype. (See "Cystic fibrosis: Genetics and pathogenesis".)

PATHOGENESIS — 

Defective functioning of the CFTR gene leads to impaired transport of chloride, sodium, and bicarbonate. As a result, water does not diffuse out of the cell into the mucus layer, leading to viscous epithelial secretions. The resultant protein-rich, viscous exocrine fluid becomes inspissated in the proximal pancreatic ducts, leading to their obstruction.

Pancreatic duct obstruction begins during fetal life, as early as the second trimester of gestation. The functioning acinar cells are gradually replaced with adipose tissue and, later, with fibrotic tissue. Individuals with pancreatic insufficiency have decreased or absent levels of pancreatic amylase, lipase, colipase, and phospholipases. However, they have increased or normal production of salivary and brush border amylases, lingual lipases, and possibly brush border peptidases, which account for increased monosaccharide absorption and some residual lipolysis, respectively [10]. Because of the CF transmembrane conductance regulator (CFTR) protein dysfunction, people with CF also have decreased amounts of bicarbonate in their pancreatic secretions, which may further contribute to the deficiency of enzymatic activity since the remaining enzymes may not function optimally in an acidic environment.

In addition, people with CF may have primary abnormalities in fatty acid metabolism, as have been noted in biopsies of CFTR-expressing tissues [11]. These changes, which result in increased tissue levels of arachidonic acid, are also present in the mouse model of CF.

CLINICAL MANIFESTATIONS — 

Approximately two-thirds of infants with CF have pancreatic insufficiency at birth due to progressive pancreatic injury in utero [4]. If CF is not diagnosed through newborn screening, it will usually be diagnosed because of growth faltering or protein-calorie malnutrition, typically presenting before the age of one year in patients with pancreatic insufficiency [12]. Among individuals with relatively normal pancreatic function at birth, most will ultimately develop pancreatic dysfunction and insufficiency, but clinically apparent protein and fat deficiencies do not occur until over 90 percent of pancreatic function is lost.

Symptoms of pancreatic insufficiency may include frequent, bulky, foul-smelling stools that may be oily. Older children may also report that their stools float or stick to the toilet bowl (reflecting their high fat content). These features may not be as evident in infants, since they have wide variation in stool patterns at baseline [4]. Abdominal distention may also be present [13,14]. These characteristics, all suggestive of fat malabsorption, are not specific to pancreatic insufficiency due to CF; they can also be seen in people with small bowel mucosal disease or in other non-CF causes of pancreatic insufficiency. Moreover, these symptoms are subjective and nonspecific, so laboratory testing should be performed to determine if fat malabsorption is present. Because malabsorption can develop at variable time points in the course of CF, people with CF may require repeat testing and modification of their therapy as the disease progresses. (See 'Diagnosis' below.)

Other pancreatic complications of CF are:

●CF-related diabetes – People with CF involving the pancreas are at risk for developing CF-related diabetes due to progressive destruction of the pancreatic tissue and loss of its endocrine function; this is most common in those with underlying pancreatic insufficiency. Approximately 19 percent of the CF population have diabetes overall, and approximately 35 percent of adults are affected [15]. (See "Cystic fibrosis-related diabetes mellitus".)

●Pancreatitis – Other people with CF may develop pancreatitis, which is most common among those with pancreatic sufficiency at diagnosis. Chronic or recurrent pancreatitis may contribute to the development of pancreatic insufficiency as the disease progresses. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)

DIAGNOSIS

Approach to testing — Because a variety of factors can contribute to growth failure and abdominal symptoms, we suggest an objective assessment of pancreatic insufficiency (eg, fecal elastase testing or fecal fat collection) to document the need for pancreatic enzyme replacement therapy (PERT).

This approach is particularly appropriate when CF is diagnosed by newborn screening because at least three-quarters of these infants will develop pancreatic insufficiency within the first year of life [4,5,16]. Those who are pancreatic-sufficient initially should be retested annually and more frequently if there is diminished growth, poor weight gain, or abnormal stooling.

●Strong suspicion of pancreatic insufficiency – For these individuals, it is reasonable to make a presumptive diagnosis and begin PERT empirically prior to testing for pancreatic insufficiency [16]. This includes children with typical symptoms of pancreatic insufficiency (growth failure and symptoms of steatorrhea), or those with two CFTR gene mutations known to be associated with pancreatic insufficiency (table 1) (see 'Epidemiology' above). In this case, pancreatic insufficiency should be confirmed by measuring fecal elastase after starting PERT (see 'Fecal elastase' below). If the abdominal symptoms do not improve with PERT, alternate causes of the symptoms, including the possibility of constipation or small intestine bacterial overgrowth, should be sought and treated.

●Lower suspicion of pancreatic insufficiency – For children with normal growth and genotype associated with pancreatic sufficiency, pancreatic function should be evaluated periodically, usually by measuring fecal elastase, as described below. For these children, we typically check fecal elastase every 12 months, or more frequently if there is poor weight gain, evidence of malabsorption (steatorrhea, fat-soluble vitamin deficiencies), or recurrent pancreatitis. For these individuals, PERT should not be started empirically. (See 'Fecal elastase' below and 'Monitoring response and dose adjustment' below.)

Testing methods — For the initial diagnosis of pancreatic insufficiency in CF, our preferred approach is to measure fecal elastase because it is practical and easy for routine screening. Quantitative measurement of fat in the stool is more sensitive but more difficult to perform accurately. Pancreatic function also can be measured directly by performing a secretin stimulation test at endoscopy. However, this test is invasive, expensive, and not routinely used.

Fecal elastase — To determine the need for PERT, our preferred initial approach is to measure fecal elastase, which serves as an index of pancreatic exocrine function [17]. It is not useful as a measure to monitor the effectiveness of PERT or for dose adjustments, because it is a measure of intrinsic pancreatic function and not a measure of fat malabsorption [3]. Fecal elastase values less than 200 mcg/g indicate pancreatic insufficiency [4,16].

This assay does not detect enzyme activity in porcine-derived PERT [18], so testing does not require discontinuation of PERT. The test can be performed on a single stool sample that requires no special storage. The stool sample must be formed or semiformed; a watery stool may give a falsely low fecal elastase level. In patients with diarrhea, it may be necessary to initiate PERT and repeat the fecal elastase on a more formed stool or to perform an alternative test.

Fecal elastase testing has high sensitivity and specificity in detecting severe pancreatic insufficiency in children with CF [3,17,19,20]. However, the test performs less well for detecting mild or moderate pancreatic insufficiency and also displays variability with repeat testing in this type of patient [21,22]. Thus, results of fecal elastase testing should be combined with clinical observations, including nutritional status and symptoms of steatorrhea, to determine the need for PERT.

The results of fecal elastase testing correlate well with the secretin stimulation test [23]. The sensitivity and specificity of fecal elastase in detecting severe pancreatic insufficiency in children with CF range from 89 to 100 percent and 86 to 100 percent, respectively, depending upon the cutoff values (<100 versus <200 mcg/g stool) and the gold standard for diagnosis (eg, secretin stimulation, fecal fat collection, clinical evaluation) [20,23-26]. (See 'Other tests' below.)

Other tests

●Other fecal enzymes – Measurements of fecal chymotrypsin or lipase also can be used for the diagnosis of pancreatic insufficiency but appear to be less sensitive than fecal elastase [27,28]. For these tests, PERT must be withheld for several days prior to testing because of cross-reactivity with porcine enzymes, whereas this is not necessary for fecal elastase testing. The diagnostic accuracy of these tests is discussed in greater detail separately. (See "Exocrine pancreatic insufficiency".)

●Fecal fat – Measurement of fecal fat can be used but is challenging to perform. Therefore, we do not usually use this test for initial diagnosis of pancreatic insufficiency. However, fecal fat testing is occasionally used to monitor the response to PERT therapy, when needed. Fecal fat testing and its limitations are discussed below. (See 'Monitoring response and dose adjustment' below.)

●Direct tests – Direct tests of pancreatic function are more accurate than indirect tests across the range of pancreatic function but require endoscopy, so they are invasive and expensive [19,29,30]. Thus, they are rarely appropriate for the initial diagnosis or monitoring of pancreatic insufficiency in a person with CF, except in unusual cases in which indirect tests or empiric trials of PERT are inconclusive.

These tests involve the collection of duodenal aspirates before and after stimulation of the pancreas with a secretagogue, such as secretin [31]. The basis for this test is that secretin causes the secretion of bicarbonate- and enzyme-rich fluid from the pancreas. A peak bicarbonate concentration of less than 80 mEq/L is consistent with pancreatic exocrine insufficiency. (See "Exocrine pancreatic insufficiency", section on 'Direct pancreatic function tests'.)

MANAGEMENT — 

Historically, pancreatic insufficiency in CF is irreversible and requires lifetime treatment with pancreatic enzymes. Preliminary evidence suggests that CF transmembrane conductance regulator (CFTR) modulators may be effective at preventing, delaying, or possibly reversing pancreatic insufficiency when begun in early childhood; this evidence is discussed in a separate topic review. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Nonpulmonary outcomes'.)

Pancreatic enzyme replacement therapy — The mainstay of treatment for pancreatic insufficiency in CF is pancreatic enzyme replacement therapy (PERT). Pancreatic enzymes are extracts of porcine pancreas containing varying amounts of lipase, protease, and amylase. PERT clearly improves fecal fat absorption in most patients with pancreatic insufficiency. This was demonstrated by a double-blind, placebo-controlled trial in children and adults with CF and severe pancreatic insufficiency, in which PERT decreased fecal fat excretion (45.4 versus 4.1 g/day) and increased the coefficient of fat absorption, as well as decreased stool frequency [32]. The effectiveness of PERT may depend, in part, on the pH of the gastrointestinal tract, which varies between individuals and also varies over time in the same person [33]. Several studies suggest that suppression of gastric acid improves the efficiency of PERT in CF, but most of the evidence is of low quality [34,35].

Indications — PERT is indicated for people with CF with any of the following:

●Proven pancreatic insufficiency

●Strong clinical suspicion of pancreatic insufficiency (including CFTR gene mutations known to be associated with pancreatic insufficiency (table 1))

●Laboratory evidence of abnormal pancreatic function (eg, fecal elastase values less than 200 mcg/g or elevated fecal fat) (see 'Testing methods' above)

PERT is not indicated for people with pancreatic sufficiency, as determined by normal fecal elastase or fecal fat testing and no clinical evidence of malabsorption. In particular, those with one or two CFTR gene mutations known to be associated with pancreatic sufficiency (table 1) should not be given PERT unless there is clear evidence of fat malabsorption [16] (see 'Epidemiology' above). Because pancreatic insufficiency may develop over time, these individuals should be evaluated at every visit for clinical symptoms of fat malabsorption and also monitored with periodic measurements of fecal elastase and fat-soluble vitamins [4,36]. Vitamin supplementation and monitoring are recommended for all people with CF, as discussed separately. (See "Cystic fibrosis: Nutritional issues", section on 'Fat-soluble vitamins'.)

Available formulations — Multiple formulations of pancreatic enzymes exist, with different combinations of lipase, protease, and amylase. Preparations with equivalent doses of enzymes may still differ in their effects. Patients should be reevaluated after any changes in the enzyme preparation or dose. The guidelines endorsed by the CF Foundation do not recommend use of generic or nonproprietary preparations [16,37]. Individual product contents, preparation type, and units of activity vary by country, so product information should be consulted before using or changing products. Patients and families should review the manufacturer's guidance about storage of PERT because excessive heat or moisture can reduce its efficacy.

Most enzyme preparations are in the form of granules, microtablets, or microspheres that are coated with a pH-sensitive material that protects the enzyme from destruction by acid in the stomach. The coating dissolves in the alkaline milieu of the duodenum, releasing the enzyme [38].

Dosing considerations — Most pancreatic enzyme preparations consist of capsules containing microspheres or microtablets. Older children and adults generally swallow the capsule whole. For younger children and infants, enzymes are administered by opening the capsule and sprinkling the microspheres on food. The food should be soft so that it does not require chewing and should be relatively acidic to avoid dissolving the enteric coating (eg, applesauce, gelatins, pureed apricot, bananas, or sweet potatoes).

PERT should generally be administered at the beginning of meals; some clinicians advise giving part of the dose halfway through the meal, particularly a meal lasting 30 minutes or more. Administering PERT following a meal is clearly not as effective.

Dosing of pancreatic enzymes is based upon the units of lipase determined as a function of patient weight or dietary fat intake. In all cases, a dietitian with experience in CF is essential to assist with diet, PERT dosing, and patient education.

●The weight-based method can generally be used at any age. The starting dose for children less than four years of age is 1000 lipase units/kg body weight per meal; for children older than four years of age, the starting dose is 500 lipase units/kg body weight per meal [37,39]. Smaller doses (eg, one-half to three-quarters of the mealtime dose) usually are given for between-meal snacks that contain fat. The PERT dose is increased as the child's body weight increases. To a lesser extent, it may be increased with symptoms of pancreatic insufficiency, to a maximum of 2500 lipase units/kg body weight per meal. The dose should be escalated with caution, and the total daily dose should not exceed 10,000 lipase units/kg/day, due to risks of fibrosing colonopathy [40] (see 'Adverse effects' below). In children with gastrointestinal symptoms or poor weight gain at near-maximal doses of PERT, alternate diagnoses should be considered to explain these problems before increasing the PERT dose.

●The fat-based method is useful for individuals willing to estimate grams of fat in feeds or those who are on liquid diets (ie, infants or patients who receive tube feedings).

•Infants – For infants, the dose starts at approximately 2000 lipase units/120 mL of formula or per breastfeeding session. The dose can be adjusted as high as 4000 units lipase/120 mL feeding. Dosing for infant pureed food is usually 2000 units lipase/g of dietary fat (maximum dose 10,000 lipase units/kg/day) [40].

•Children one to four years – For children between one and four years of age, dosing is 2000 to 4000 units lipase/gram dietary fat, increasing the dose upward as needed (maximum dose 10,000 units lipase/kg/day) [40].

•Children >4 years and adults – For this age group, it is usually easier to dose per kg (as outlined above). However, for those who want to continue dosing per gram of fat, the dose is 2000 to 4000 units lipase/gram dietary fat taken with all fat-containing meals, snacks, and drinks (maximum dose 10,000 units lipase/kg/day) [40].

For all age groups, PERT should be escalated with caution and the total daily dose should not exceed 10,000 units lipase/kg/day, due to risk of fibrosing colonopathy. (See 'Adverse effects' below.)

Enzyme replacement for patients receiving nutritional support via enteral feedings is discussed separately. (See "Cystic fibrosis: Nutritional issues", section on 'Enteral feedings'.)

●Overnight feeds – For children who receive overnight tube feedings via feeding pump, one option is to use a cartridge (brand name: Relizorb) that contains lipase immobilized onto polymeric carrier beads. The cartridge is placed in line with the feeding tube and hydrolyzes the lipid in the formula as it passes through. Relizorb is not a substitute for PERT therapy, because it does not provide protease or amylase. It must be used with a hydrolyzed protein formula. The manufacturers warn against using Relizorb with a formula that contains insoluble fiber because fiber could clog the Relizorb cartridge. Relizorb improves anthropometrics and fat absorption in people with CF [41]. It can help reduce early morning satiety and bloating for some individuals [42].

Monitoring response and dose adjustment

●Clinical response – Adjustment of PERT doses is typically guided by patient-reported symptoms of malabsorption, such as diarrhea (foul-smelling, greasy, bulky stools), bloating, gassiness, and abdominal pain. Unfortunately, symptoms do not correlate well with the efficacy of PERT in the individual patients [13,43]. Thus, if such symptoms persist despite doses of PERT approaching the daily maximum, alternate causes of abdominal symptoms, such as constipation or small intestine bacterial overgrowth, should be sought and treated, ideally in consultation with a gastroenterologist. There is no evidence that constipation is caused by supratherapeutic or inadequate enzyme doses.

If symptoms persist despite maximal doses of supplemental pancreatic enzymes, a trial of acid suppression therapy may be warranted, using a histamine 2 receptor antagonist (H2RA), such as famotidine, or proton pump inhibitor (PPI), such as omeprazole. The rationale is that the intestinal pH must be high to allow full release of the enzyme product and, in people with CF, gastric acid is not neutralized by pancreatic bicarbonate [44]. However, but the practice is based on limited evidence [35]. The use of H2RAs is limited by the development of tachyphylaxis, and the use of PPIs is limited by potential adverse effects, including possibly increased risks for vitamin B12 deficiency and detrimental effects on bone health. Any trial of acid suppression for this indication should have clear objectives and a limited trial timeline. (See "Gastroesophageal reflux disease in children and adolescents: Management", section on 'Safety'.)

●Fecal fat testing – Laboratory tests generally are not helpful for adjustment of PERT doses, because there are no methods that are accurate and clinically practical. However, if there is uncertainty about optimal dosing of PERT in a particular individual after adjustment based on clinical symptoms, then fecal fat measurements can be performed. Of note, fecal elastase is not useful for this purpose, because it is a measure of intrinsic pancreatic function rather than fat malabsorption [3].

The most accurate and commonly used fecal fat test is the collection of a 72-hour stool sample, in conjunction with a careful record of dietary intake (table 2). For an individual older than six months of age, fecal fat excretion is considered abnormal if it is more than 7 percent of the fat intake [12,29]. For infants under six months of age, fecal fat excretion of up to 15 percent of total fat intake can be normal [16]. This test has moderate sensitivity and specificity for fat malabsorption, but the collection procedure is onerous for most patients [3]. The test does not distinguish between hepatobiliary, mucosal, and pancreatic causes of fat malabsorption. The test can be used for initial diagnosis of pancreatic insufficiency, but in this case, PERT must be discontinued during the collection period.

Other approaches to evaluating fecal fat are easier to perform but have low accuracy. Qualitative measurement (Sudan stain) of a spot stool specimen is easier to perform but is not reliable, because fecal fat may not be evenly distributed in individuals consuming a mixed diet.

These tests for fecal fat are discussed in more detail in a separate topic review. (See "Approach to the adult patient with suspected malabsorption", section on 'Stool tests for fat malabsorption'.)

Despite optimized pancreatic enzyme replacement, residual fat malabsorption exists. This remaining fat malabsorption is thought to be due to decreased long-chain fatty acid uptake by the gut and not the result of reduced pancreatic enzyme-mediated lipolysis. A structured lipid matrix supplement (Encala) has been developed that is formulated with lysophosphatidyl monoglycerides and essential fatty acids and does not require lipase for digestion/absorption of fatty acids. In a randomized trial in people with severe residual fat malabsorption despite PERT and a CF diet, this supplement improved the coefficient of fat absorption, plasma fatty acid profile, and growth [45]. It represents the only non-enzymatic treatment for fat malabsorption in CF.

Adverse effects — Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers, especially with the powdered form. To prevent this complication, children should learn to swallow capsules as early as possible; some can master the technique as young as three to four years of age. When it is necessary to open the capsules for enzyme delivery to younger children, the microspheres should be administered with food (eg, applesauce), even in infants. The parent or caregiver should inspect the child's mouth after eating and rinse their mouth with water, milk, or formula if necessary to remove any beads clinging to the oral mucosa [44].

Other complications and considerations include:

●Areolar excoriation for breastfeeding mothers – In women who are breastfeeding, the areolae may become excoriated due to exposure to residual enzymes in the baby's mouth. This can be addressed by rinsing the infant's mouth after giving the enzymes and before breastfeeding.

●Perianal rash – Infants may develop a perianal rash due to exposure to residual enzymes in the stool. This is best addressed by using a barrier cream and changing the diaper promptly after each bowel movement.

●Wheezing – A few children develop wheezing from an allergic reaction if they breathe aerosolized enzyme (powder form). This can be addressed by using a microsphere form of enzyme (if possible) or by assiduous measures to avoid exposing the child to aerosolized residue.

Limited evidence suggests that excessive doses of PERT are associated with fibrosing colonopathy, characterized by inflammation and intestinal strictures. As a result, a maximum dose of 2500 lipase units/kg body weight per meal (or less than 10,000 lipase units/kg body weight per day) is recommended [39,43], although a causal relationship has not been demonstrated and is the subject of ongoing investigation. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Fibrosing colonopathy'.)

COMPLICATIONS

Poor growth — Pancreatic insufficiency in CF may cause malabsorption of fat and other macronutrients, which is particularly problematic because the disease may also cause increased energy requirements. Thus, it is imperative that growth parameters are followed closely. For all people with CF, weight and length (or height) should be measured at every contact (at least every three months), then weight/length or body mass index calculated (table 3). Head circumference should also be monitored for children younger than two years. Some centers measure mid-arm circumference and triceps skin-fold thickness for children over one year of age. (See "Cystic fibrosis: Nutritional issues", section on 'Assessing and monitoring nutrition'.)

Some people with CF require dietary supplements either by mouth or by tube feeds to maintain adequate nutrition [44]. This is becoming less common with the advent of CF transmembrane conductance regulator (CFTR) modulator therapy, which often improves nutritional status and lung function. (See "Cystic fibrosis: Nutritional issues", section on 'Nutrition support' and "Cystic fibrosis: Treatment with CFTR modulators".)

Children with growth failure should be evaluated for contributing factors other than pancreatic insufficiency, including worsening pulmonary disease, CF-related diabetes, CF-related liver disease, small bowel bacterial overgrowth, and zinc deficiency. (See "Cystic fibrosis: Nutritional issues", section on 'Evaluation for comorbidities' and "Cystic fibrosis-related diabetes mellitus".)

Fat-soluble vitamin deficiencies — Pancreatic insufficiency and CF-related liver disease lead to fat malabsorption that predisposes people with CF to deficiencies of the fat-soluble vitamins: vitamins A, D, E, and K. Requirements for these nutrients and monitoring recommendations are summarized in the table (table 4) and discussed in detail separately. (See "Cystic fibrosis: Nutritional issues", section on 'Fat-soluble vitamins'.)

Bone disease — Bone disease, characterized by decreased mineral density, increased fracture rates, and kyphosis, is common in people with CF, even among those with pancreatic sufficiency. Important contributors to the problem include malabsorption of calcium, magnesium, and fat-soluble vitamins (vitamin D and, possibly, vitamin K). Prevention, monitoring, and treatment of bone disease are summarized in the table (table 4) and discussed separately. (See "Cystic fibrosis: Nutritional issues", section on 'Bone disease'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis" and "Society guideline links: Chronic pancreatitis and pancreatic exocrine insufficiency".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Cystic fibrosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Prevalence – Most people with cystic fibrosis (CF) have some degree of pancreatic exocrine dysfunction. This problem tends to worsen over time, and, historically, at least 85 percent developed clinically important pancreatic insufficiency. This natural history may change with the widespread use of CF transmembrane conductance regulator (CFTR) modulators. There is a moderate association between the patient's genotype and the probability of developing pancreatic insufficiency (table 1). (See 'Epidemiology' above.)

●Surveillance – All people with CF should be screened for pancreatic insufficiency; this is generally done with fecal elastase testing. Those with normal results should be retested annually and more frequently if there is diminished growth, poor weight gain, or abnormal stools to monitor for development of pancreatic insufficiency. (See 'Diagnosis' above.)

●Pancreatic enzyme replacement – Individuals with pancreatic insufficiency (as determined by fecal elastase testing or other measure) should be treated with pancreatic enzyme replacement therapy (PERT).

•Dosing – Dosing is generally estimated by the person's weight and adjusted depending on the clinical response and symptoms. Suppression of gastric acid may improve the efficiency of PERT in some individuals, but this practice is based on limited evidence and must be balanced against potential adverse effects of the acid-suppressing medications. (See 'Dosing considerations' above.)

•Safety considerations – Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers and should be avoided. PERT doses should be limited to 2500 lipase units/kg body weight per meal to avoid fibrosing colonopathy. (See 'Adverse effects' above.)

●Complications and monitoring – Even with optimal management, people with CF-related pancreatic insufficiency are at risk for growth failure, deficiencies of fat-soluble vitamins and other micronutrients, and bone disease. Prevention and monitoring for these complications are summarized in the tables (table 3 and table 4) and discussed separately. (See 'Complications' above and "Cystic fibrosis: Nutritional issues".)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Julie P Katkin, MD, and Robert D Baker, MD, PhD, who contributed to earlier versions of this topic review.