Best Practices in the Management of the Gastrointestinal Aspects of CF

A panel of pediatric and adult gastroenterologists created this document to summarize and disseminate the existing medical literature regarding cystic fibrosis-specific gastrointestinal disease.

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Best Practices in the Management of the Gastrointestinal Aspects of Cystic Fibrosis

Freedman SD, Wilschanski M (eds.) Best Practices in the Management of the Gastrointestinal Aspects of Cystic Fibrosis. J Cyst Fibros. 2017 Nov;16 Suppl

Purpose and Background

A 3-year clinical training program for pediatric and adult gastroenterologists named DIGEST (Developing Innovative Gastrointestinal Specialty Training) was created to address gastrointestinal (GI) care for people with cystic fibrosis. The group developed an initiative to compile and review existing medical literature related to specific GI disease in CF, summarize the information, and disseminate this knowledge through the publication of a GI-related supplement to the Journal of Cystic Fibrosis. The work was carried out by pairing pediatric and adult gastroenterologists (DIGEST trainees and mentors/senior authors) in an international, collaborative writing effort.

Methodology

The journal supplement was developed to address 10 key CF-specific GI topic areas, providing reviews aiming to educate non-gastroenterologist CF care providers. Each article included:

  • Background.
  • Physiology.
  • Pathophysiology.
  • Clinical presentation.
  • Diagnostic work up.
  • Routine management.
  • A summary of potential clinical endpoints.
  • Future directions.

Where there was sufficient evidence and agreement across the literature, the authors proposed algorithms on how to approach the evaluation and management of these disorders and diseases.

Most of these articles reviewed current understanding of genotype-phenotype relationships.

Areas Discussed

Manuscript Topics included
Gastroesophageal reflux disease:

Physiology and pathophysiology specific to CF

Unique aspects of reflux and CF: complications, emerging concepts, and controversies

Bacterial overgrowth, dysbiosis, inflammation, and dysmotility: 

Pathophysiology specific to CF, including:

  • the CF intestine, inflammation, motility, and the microbiota
  • antibiotic use as a constant remodeling agent for the microbiome

Routine evaluation methodologies, emerging modalities for assessment and management

Chronic abdominal pain:   Pathophysiology specific to CF: differentiation of types of pain, red flags for pain
  • CF related appendicitis, fibrosing colonopathy, and medication-related pain
  • Risk factors for, and the unique presentation of, Clostridium difficile-related colitis that every patient and physician should be aware of
Meconium Ileus: Associated conditions and observations
Distal intestinal obstruction syndrome (DIOS), constipation, and colorectal cancer:

Differentiation of constipation in CF from that in non-affected individuals and from DIOS

Pathophysiology and risk factors in CF, including:

  • The relationship between steatorrhea and DIOS risk
  • Fluid management
  • Controversies regarding fiber in CF
  • The importance of adequate pancreatic enzyme replacement therapy
  • Use of N-acteylcysteine, contrast enemas as therapy
  • A review of medications and efficacy in CF

Colorectal cancer in patients with CF, and the importance of adequate screening and surveillance in this at increased risk population

Cystic fibrosis-related cirrhosis:  

Pathophysiology and emerging concepts with respect to mechanisms of risk and description of the spectrum of hepatobiliary involvement in CF and patterns observed

Evaluation (including the examination) and management specific to CF

Use of ursodeoxycholic acid including concepts and controversies and dosing recommendations

Gallbladder and bile duct disease:  

Specific risk factors including: environmental factors, luminal factors, and effect of transplantation

Concepts and controversies regarding use of ursodeoxycholic acid

Pancreatic insufficiency:

Current status of indirect and direct testing for exocrine pancreatic insufficiency

Pancreatic enzyme replacement therapy and novel emerging therapies

Pancreatitis and pancreatic cystosis:  

Intrinsic and extrinsic factors, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, and a model for risk for pancreatitis related to CFTR function and acinar reserve

Mechanisms and risk factors for development of cystosis and management algorithm

Prevention and management of nutritional failure:  

Nutritional status and interventions on current and future outcomes with respect to growth, pulmonary function, and other outcomes of clinical interest

Timing and targets/goals of nutritional therapy and multidisciplinary approach to evaluation and management

Themes

Several themes that run across disorders reviewed in this publication include:

  • Throughout the GI tract, CFTR mutations have significant impact on epithelial surfaces resulting in alterations in salt, water, and pH balance. These alterations result in pathophysiologic cascades unique to people with CF and necessitating management approaches different than those for the general population.
  • Because of this altered pathophysiology, many disease presentations in people with CF are different and distinct from those observed in the general population. Early recognition of these atypical presentations may be critically important to management and long-term outcomes.
  • People with CF are living longer as a result of clinical advances in care. Furthermore, long-term consequences of impaired CFTR function, intrinsic, extrinsic, environmental, and medication effects, and chronic inflammation may be part of the pathophysiology leading to an increased incidence of GI cancers. Clinicians must be cognizant of these factors as people with CF live longer and the early detection of GI malignancies becomes increasingly important.
  • Finally, the risk of esophageal, colorectal, biliary, and gallbladder cancers is significantly increased post lung transplant.

Unanswered Questions

  • Published literature is several years to decades old. Significant limitations in the interpretation of this literature exist because of changes in diagnostic technologies and management strategies. There is a critical need to update clinical practice guidelines to reflect current practice.
  • By identifying these gaps and potential clinical end points, the published review articles have highlighted specific questions and areas for future collaboration.
  • The emergence of the widespread use of CFTR modulators holds promise for improving CF-specific GI management. Close observation will be needed to determine the long-term effects of these therapies on GI function in CF and how that translates to disease management.

Further Reading

  • Carrion A, Borowitz DS, Freedman SD, et al. Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis with Ivacaftor: Case Series. J Pediatr Gastroenterol Nutr. 2018 Mar; 66 (3):451-454. doi: 10.1097/MPG.0000000000001788.
  • Knotts RM, Solfisburg QS, Keating C, et al. Cystic fibrosis is associated with an increased risk of Barrett's esophagus. J Cyst Fibros. 2018 Nov S1569-1993(18)30933-0. doi: 10.1016/j.jcf.2018.11.005. Epub 2018 Nov 23.
  • Liu K, Wang X, Zou C, et al. Defective CFTR promotes intestinal proliferation via inhibition of the hedgehog pathway during cystic fibrosis. Cancer Lett. 2019 Jan 10. S0304-3835(19)30008-4. doi: 10.1016/j.canlet.2018.12.018. Epub 2019 Jan 11
  • Zhu X, Gao L, Yan C, He Y. A novel role and mechanism of cystic fibrosis transmembrane conductance regulator in bisphenol A-induced prostate cancer. J Cell Biochem. 2018 Nov 28. doi: 10.1002/jcb.28156. [Epub ahead of print]
  • Platt KD, Sondhi AR, DiMagno MJ. Pancreatic Cancer: A Rare Cause of Abdominal Pain in Severe Cystic Fibrosis. Pancreas. 2019 Jan; 48(1):e3-e4. doi: 10.1097/MPA.0000000000001162
  • Gelfond D, Heltshe S, Ma C, et al. Impact of CFTR Modulation on Intestinal pH, Motility, and Clinical Outcomes in Patients With Cystic Fibrosis and the G551D Mutation. Clin Transl Gastroenterol. 2017 Mar 16; 8(3):e81. doi: 10.1038/ctg.2017.10.

This executive summary was prepared by:

Steven D. Freedman, MD (Beth Israel Deaconess Medical Center), Asim Maqbool, MD (The University of Pennsylvania Perelman School of Medicine)

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