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CF Diagnosis Clinical Care Guidelines 2016: Pancreatic Enzyme Therapy in Cystic Fibrosis

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Pancreatic insufficiency (PI) is a common and serious complication for most individuals living with cystic fibrosis (CF). If left unmanaged, PI can severely impact health, leading to malnutrition, failure to thrive in children, significant weight loss, uncomfortable abdominal distension, and troublesome gastrointestinal symptoms like foul-smelling stools and diarrhea. Pancreatic enzyme replacement therapy (PERT) has revolutionized CF care, offering a way to effectively manage these debilitating symptoms and improve quality of life.

In the early 1990s, concerns arose within the CF community regarding a potential link between high doses of PERT and fibrosing colonopathy, a condition characterized by colonic strictures. Between 1990 and 1994, the Cystic Fibrosis Foundation (CFF) received reports of 35 cases of colonic stricture, prompting a critical review of PERT dosing practices. In 1995, the CF Foundation, in collaboration with the U.S. Food and Drug Administration (FDA), convened a consensus conference to establish clear guidelines for PERT dosing and strategies to minimize the risk of fibrosing colonopathy. These landmark guidelines, published in 1995, provided essential recommendations for target PERT doses across different age groups and issued a cautionary note regarding exceeding 2,500 lipase units/kg/meal.

Since the initial 1995 publication, significant advancements have been made in our understanding of CF and PERT. New research and clinical experiences have emerged, necessitating a continued evaluation and refinement of these guidelines. This article serves as an executive summary of the key recommendations from the original guidelines, contextualized with relevant updates and ongoing considerations in CF care, particularly concerning pancreatic enzyme therapy. While the original guidelines were a crucial step, this discussion reflects the evolving landscape of CF management and emphasizes the importance of staying informed about current best practices in CF diagnosis clinical care guidelines.

Key Recommendations for Pancreatic Enzyme Replacement Therapy

For the majority of individuals with CF who experience pancreatic insufficiency, consistent and effective pancreatic enzyme replacement therapy is not just beneficial, but absolutely vital. It stands as a cornerstone of CF treatment, directly impacting nutritional status and overall well-being.

Pancreatic Enzyme Replacement Therapy Recommendations
Recommendations
1. Dietary Fat Intake: Patients with pancreatic insufficiency should adhere to a high-calorie diet that includes unrestricted fat intake, appropriate for their age and clinical condition. Research consistently demonstrates that such diets are more effective than low-fat diets in promoting healthy growth and optimal lung function in CF patients.
2. Regular Nutritional Assessment: Nutritional status should be routinely evaluated as part of standard CF care. Furthermore, a thorough nutritional assessment is crucial whenever PERT dosages are adjusted to ensure appropriate management and efficacy.
3. Enzyme Dosing Strategies: PERT dosing can be calculated based on either the grams of fat consumed or the patient’s weight. While fat-based dosing more closely mimics the body’s natural pancreatic response to meals, weight-based dosing can be more practical, particularly for older children and adults, simplifying the administration process.
4. Infant Dosing: Infants typically require a PERT dosage of 450-900 lipase units per gram of fat ingested. Alternatively, for formula-fed infants or those breastfeeding, a dosage of 2,000–4,000 lipase units per 120 ml of formula or breastfeeding session is generally recommended. It’s important to note that infants typically consume a higher proportion of fat per kilogram of body weight compared to adults.
5. Dosing for Older Children and Adults: Older children and adults generally require a PERT range of 500–4,000 lipase units per gram of fat consumed, with an average dose around 1,800 lipase units/g of fat. Another dosing strategy is 500-2,500 lipase units/kg/meal, and 250-1,250 lipase units/kg/snack, assuming a regimen of three meals and two to three snacks daily. It is advisable to start with a lower dose within this range and gradually increase (titrate up) as needed to effectively manage malabsorption symptoms.
6. High-Dose Enzyme Caution: PERT doses exceeding 2,500 lipase units/kg/meal, or 4,000 lipase units/g of fat, warrant careful investigation and reconsideration. Doses surpassing 6,000 lipase units/kg/meal have been linked to the development of fibrosing colonopathy. The safety of doses above 2,500 lipase units/kg/meal or 4,000 lipase units/g of fat remains uncertain. Furthermore, it’s unlikely that escalating enzyme doses beyond these thresholds will provide additional clinical benefit for CF patients experiencing poor growth or persistent gastrointestinal symptoms. Therefore, it is recommended to avoid exceeding these doses and to actively reduce enzyme dosages for patients currently on higher amounts.
7. Product Brand Consistency: Patients should consistently use only the specific PERT product brands prescribed by their CF care center. Enteric-coated, microencapsulated enzyme formulations are recognized as the most effective treatment approach for pancreatic insufficiency in CF. Patients should not substitute with over-the-counter enzymes from health food stores or non-enteric-coated enzymes unless explicitly directed by their CF physician.
8. Enzyme Administration: PERT capsules can be opened, and the contents mixed with a small amount of applesauce or another non-alkaline food to ease administration, particularly for children. However, the enzyme contents should not be crushed or allowed to sit in food for extended periods. Enzymes are susceptible to inactivation in alkaline environments or with prolonged exposure to moisture.
9. Enzyme Storage: Enzymes should be stored in a cool, dry place and regularly checked for expiration dates to ensure potency and effectiveness.
10. Recognizing Inadequate Enzyme Response: Signs and symptoms indicating a poor response to enzyme therapy can include abdominal discomfort such as bloating, excessive gas (flatus), abdominal pain, and loose, frequent stools or overt diarrhea. Symptomatic steatorrhea, characterized by bulky, oily, foul-smelling stools, and poor growth are also key indicators. It’s important to remember that these symptoms can also be associated with other conditions. Before simply increasing enzyme dosages in response to these symptoms, it’s crucial to consider other contributing factors, including dietary issues, adherence to PERT regimen, intestinal hyperacidity, abnormal intestinal motility, and liver disease with low intestinal bile salt content, as well as non-CF gastrointestinal disorders.
11. Fibrosing Colonopathy Considerations: Fibrosing colonopathy should be suspected in CF patients presenting with evidence of bowel obstruction, bloody diarrhea, or chylous ascites, or a combination of persistent abdominal pain, ongoing diarrhea, and/or poor weight gain. This condition is characterized by colonic strictures. While the exact cause remains unclear, it has been linked to high doses of pancreatic enzyme supplements. Patients at higher risk include children under 12 years of age, those taking more than 6,000 lipase units/kg/meal for over 6 months, individuals with a history of meconium ileus in infancy or distal intestinal obstruction syndrome (DIOS), and those with a history of prior intestinal surgery. Diagnosis is typically confirmed through imaging studies or histopathology. In early stages, fibrosing colonopathy may respond to a reduction in enzyme dose. However, in more advanced cases, colectomy (surgical removal of the colon) may be necessary.

Emerging Issues in CF PERT Management

Several important issues have emerged since the initial guidelines were published, shaping current approaches to PERT in CF.

  1. Fecal Pancreatic Elastase-1 Testing: The fecal pancreatic elastase-1 test has become the most widely used non-invasive tool for screening and diagnosing pancreatic insufficiency in individuals with CF. A fecal elastase-1 value below 200 μg/g is generally indicative of pancreatic insufficiency. This test provides a convenient and reliable way to assess pancreatic function and guide PERT initiation.

  2. FDA Approval of PERT Products: In 2004, the FDA mandated that PERT products, previously available without prescription, must undergo a New Drug Application process to ensure efficacy and safety. This landmark decision led to all manufacturers conducting clinical trials and seeking FDA approval for their PERT products. Since 2009, the FDA has granted approval to five oral pancreatic enzyme products specifically for PERT in CF and other conditions: Creon®, Pancreaze®, Pertzye®, UltresaTM, and Zenpep®. This regulatory change has standardized the quality and oversight of PERT medications available to patients.

  3. PERT Adherence Factors: Understanding and addressing factors that influence patient adherence to PERT regimens is critical for optimal treatment outcomes. Research highlights various challenges affecting adherence, including the burden of taking medication with every meal and snack, palatability issues, and psychosocial factors, particularly in adolescents and young adults (Barker 2016). Healthcare providers must be aware of these barriers and implement strategies to support and improve PERT adherence in their patients.

Unresolved Questions and Future Directions

Despite significant progress, several key questions regarding PERT in CF remain unanswered, highlighting areas for future research and clinical investigation.

  1. Acid Suppression and Enzyme Absorption: The question of whether adding an acid-suppressing medication, such as a histamine-2-blocker or a proton pump inhibitor, to a PERT regimen enhances enzyme absorption remains unclear. While the CF Foundation preschool guidelines suggest considering acid suppression if malabsorption persists despite optimized PERT dosing (Lahiri 2016, Sander-Struckmeier 2013), definitive evidence supporting this practice is still needed. Further research is warranted to clarify the potential benefits of acid suppression in conjunction with PERT.

  2. Non-Porcine Enzyme Products: Currently, there are no FDA-approved non-porcine PERT products available in the US. Sollpura (LiprotamaseTM), a non-porcine enzyme replacement therapy derived from biotechnology, has completed Phase 3 clinical trials and holds promise as a potential alternative to porcine-based PERT if FDA approval is granted. Sollpura contains highly purified enzymes (lipase, protease, and amylase) (Borowitz D 2012) and could address concerns for patients with dietary restrictions or cultural preferences.

  3. PERT Administration with Continuous G-tube Feedings: Optimal strategies for administering PERT with continuous overnight gastrostomy tube (g-tube) feedings are not well-established (Borowitz 2012, Erskine 2007). RELiZORB®, an FDA-approved cartridge containing immobilized lipase, is available for use with tube feedings in adults. However, RELiZORB only digests fats and does not address protein or carbohydrate digestion. Further research is needed to determine the most effective methods for PERT administration in patients receiving continuous enteral nutrition.

  4. Impact of CFTR Modulators on PERT Needs: Ivacaftor, a CFTR potentiator medication, has shown to improve fecal elastase-1 concentrations in some CF patients, suggesting a potential impact on pancreatic function. Studies indicate that Ivacaftor may reduce or eliminate the need for PERT in a subset of individuals with CF, particularly when initiated early in the disease course (Davies 2016). Further research is needed to fully understand the long-term effects of CFTR modulators on pancreatic function and PERT requirements in different CF genotypes and age groups.

  5. Non-invasive Monitoring of Fat Absorption: Healthcare providers would greatly benefit from a non-invasive test to effectively monitor fat absorption in patients on PERT. Currently, assessing PERT adequacy relies heavily on symptom evaluation, which can be unreliable. PERT adjustments are often made empirically due to the lack of objective monitoring tools (Mascarenhas 2015). The development of a reliable non-invasive test for fat absorption would significantly improve PERT management and allow for more personalized and effective treatment strategies.

  6. Head-to-Head Comparisons of PERT Products: Comparative studies directly comparing different FDA-approved PERT products are needed to determine if they are clinically equivalent. A single study conducted in the U.K. (Taylor CF 2016) provides some initial data, but more research is necessary to guide product selection and ensure optimal patient outcomes. Head-to-head trials would help clinicians make evidence-based decisions when choosing among the available PERT formulations.

Further Resources and Guidelines

For more in-depth information and expanded discussions on PERT and CF nutritional management, refer to these resources:

  1. Preschool Guidelines (Lahiri 2016): Provides detailed guidance on PERT use and nutritional management in preschool-aged children with CF.
  2. Nutritional Guidelines (Borowitz 2002, Stallings 2008): Offers comprehensive recommendations on nutritional care for pediatric CF patients, including PERT considerations.
  3. Infant Guidelines (Borowitz 2009): Contains specific information on PERT dosing and administration in infants with CF.
  4. Adult Guidelines (Yankaskas 2004): Reviews PERT dosing in adults with CF, although some details may be outdated due to recent FDA approvals and advancements in PERT products.
  5. ESPEN-ESPGHAN-ECFS Guidelines (Turck 2016): European guidelines on nutrition care for infants, children, and adults with cystic fibrosis, offering a broader international perspective.

References

  1. Borowitz DS, Grant RJ Durie PR, the Consensus Committee. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr. 1995; 127:681-84.
  2. Food and Drug Administration. Updated questions and answers: healthcare professionals and public use of approved pancreatic enzyme products. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/updated-questions-and-answers-healthcare-professionals-and-public-use-approved-pancreatic-enzyme
  3. Barker DH, Quittner AL. Parental depression and pancreatic enzymes adherence in children with cystic fibrosis. Pediatrics. 2016;137(2):2015-2296. Epub 2016 Jan 5. PMID: 26738883
  4. Lahiri T, Hempstead SE, Brady C, Cannon CL, Clark K, Condren ME, Guill MF, Guillerman RP, Leone CG, Maguiness K, Monchil L, Powers SW, Rosenfeld M, Schwarzenberg SJ, Tompkins CL, Zemanick ET, Davis SD. Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis. Pediatrics. 2016 Apr;137(4). PMID: 27009033
  5. Sander-Struckmeier S, Beckmann K, Janssen-van Solingen G, Pollack P. Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin (CREON®) in patients with pancreatic exocrine insufficiency. Pancreas. 2013; 42(6);983-89. PMID: 27068495
  6. Borowitz D, Stevens C, Brettman LR, Campion M, Wilschanski M, Thompson H; Liprotamase 767 Study Group. Liprotamase long-term safety and support of nutritional status in pancreatic-insufficient cystic fibrosis. J Pediatr Gastroenterol Nutr. 2012 Feb;54(2):248-57. PMID: 22266487
  7. Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009 Dec;155(6 Suppl):S73-93. PMID: 19914445
  8. Erskine JM, Lingard C, Sontag M. Update on enteral nutrition support for cystic fibrosis. Nutr Clin Pract. 2007 Apr;22(2):223-32. PMID: 17374796
  9. Davies JC, Cunningham S, Harris WT, Lapey A, Regelmann WE, Sawicki GS, Southern KW, Robertson S, Green Y, Cooke J, Rosenfeld M; KIWI Study Group. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med. 2016;4:107-15. Epub 2016 Jan 21. PMID: 26803277
  10. Mascarenhas MR, Mondick J, Barrett JS, Wilson M, Stallings VA, Schall JI. Malabsorption blood test: Assessing fat absorption in patients with cystic fibrosis and pancreatic insufficiency. J Clin Pharmacol. 2015;55:854-65. Epub 2015 Mar 23. PMID: 25689042
  11. Taylor CJ, Thieroff-Ekerdt R, Shiff S, Magnus L, Fleming R, Gommoll C. Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis. J Cyst Fibros. 2016 Sep;15(5):675-80. Epub 2016 Mar 21. PMID: 27013382
  12. Turck D, Braegger CP, Colombo C, Declercq D, Morton A, Pancheva R, Robberecht E, Stern M, Strandvik B, Wolfe S, Schneider SM, Wilschanski M. ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis. Clin Nutr. 2016 Jun;35(3):557-77. Epub 2016 Mar 15. PMID: 27068495
  13. Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2002 Sep;35(3):246-59. PMID: 12352509
  14. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H; Clinical Practice Guidelines on Growth and Nutrition Subcommittee; Ad Hoc Working Group. Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review. J Am Diet Assoc. 2008;108(5):832-39. PMID: 18442507
  15. Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodman D. Cystic fibrosis adult care: Consensus conference report. Chest. 2004 Jan;125(1 Suppl):1S-39S. PMID: 14734689

Disclaimer: This executive summary is intended to provide a concise overview of clinical care guidelines and should not be considered a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment decisions related to cystic fibrosis.

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