Pulmonary disease is the primary cause of morbidity and mortality in people with cystic fibrosis (CF), but significant involvement within gastrointestinal, pancreatic, and hepatobiliary systems occurs as well. As in the airways, defects in CFTR alter epithelial surface fluid, mucus viscosity, and pH, increasing risk of stasis through the various hollow epithelial-lined structures of the gastrointestinal tract. This exerts secondary influences that are responsible for most gastrointestinal, pancreatic, and hepatobiliary manifestations of CF. Understanding these gastrointestinal morbidities of CF is essential in understanding and treating CF as a multisystem disease process and improving overall patient care.
Key points
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Gastrointestinal (GI) and hepatic manifestations of cystic fibrosis (CF) deserve special attention, as essentially all patients with CF will experience at least one such complaint during their lifetime.
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GI, pancreatic, and hepatic manifestations of CF are known to have significant effects on growth and nutrition, pulmonary function, and patient-perceived wellness.
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Defects in the CF transmembrane receptor protein affect fluid viscosity, flow, and pH, resulting in the clinical GI, pancreatic, and hepatobiliary manifestations of CF.
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Recognizing and managing GI manifestations is part of a comprehensive, multisystem approach to care.
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Clinicians should be aware of conditions in which diagnostic tests need to be interpreted differently in patients with CF than in the general population.
Pulmonary disease is the primary cause of morbidity and mortality in people with cystic fibrosis (CF), but significant involvement within gastrointestinal (GI), pancreatic, and hepatobiliary systems occurs as well. GI, pancreatic, and hepatic manifestations of CF deserve special attention, as essentially all patients with CF will experience at least 1 such complaint during their lifetime. Additionally, many GI, pancreatic, and hepatic manifestations of CF are known to have significant effects on disease outcomes, including but not limited to (1) growth and nutrition, (2) pulmonary function, and (3) patient-perceived wellness.
The CF transmembrane regulator protein (CFTR) is expressed on the apical epithelium of the intestines and pancreatic and biliary duct systems where it regulates chloride and bicarbonate secretion. Homozygosity of the mutant CFTR gene results in viscous and acidic secretions secondary to deficient surface fluid and bicarbonate efflux. This leads to partial or complete obstruction in the various hollow epithelial-lined structures of the GI tract and is responsible for most GI, pancreatic, and hepatobiliary manifestations of CF. The associated increase in local and systemic inflammation is also detrimental to nutrition and growth ( Fig. 1 ).
Pancreas
Severe CFTR mutations (class I–III) are associated with dramatically decreased pancreatic ductal flow and absent digestive enzymes (pancreatic insufficiency [PI]), whereas milder mutations (class IV and V) tend to be associated with decreased flow but to an extent that allows digestive enzymes to flow into the duodenum (pancreatic sufficiency [PS]). The bicarbonate milieu created by pancreatic fluid is essential to neutralize gastric acid so as to optimize the function of pancreatic enzymes, promote micelle formation, and dissolve the enteric coating on exogenous pancreatic enzyme replacement therapy (PERT). The result of alterations in fluid volume, viscosity, and flow is that proenzymes get trapped within the pancreatic ducts, leading to early activation of pancreatic enzymes that inflame and damage the pancreas. Damage begins in utero as early as 17 weeks gestation. Destruction of the pancreas leads to PI in most patients.
Diagnosis of Pancreatic Insufficiency
PI can be diagnosed by calculating the coefficient of fat absorption from a collection of feces produced during a 3-day diet containing 100 g of fat per day. PI is presumed if less than 93% of fat is absorbed or greater than 7 g of fat is excreted during this time period. In practice, this test has been replaced by the more efficient fecal elastase test, which measures the absence of endogenous elastase. Fecal elastase has a sensitivity of 72% and specificity of 90% for severe PI, but may not be as effective in diagnosis of mild to moderate PI. False positives are seen in the setting of watery diarrhea and diabetes (levels are noted to decrease with increased duration of diabetes). More invasive testing with secretin stimulation of the pancreas and direct collection and analysis of pancreatic juice is available but not often used. Patients do not have maldigestion until less than 10% of exocrine pancreatic function remains.
Management of Pancreatic Insufficiency
PI is managed with exogenous PERT before every meal and snack and with fat-soluble vitamin supplementation. Presently, all PERT is formulated from porcine extracts that contain amylase (digests carbohydrates), protease (digests proteins), and lipase (digests fat). Dosing is based on lipase units/kg per meal or grams of fat ingested ( Table 1 ).
| Lipase units/kg/meal | Lipase units/kg/g of Fat Eaten |
|---|---|
| <4 y of age: 1000–2500 lipase units/kg/meal a 1/2 for snack | Infant formula or breast milk: 2000–4000 lipase units/120 mL |
| >4 y of age: 500–2500 lipase units/kg/meal a 1/2 for snack | Beyond infancy: 500–4000 lipase units/g of fat eaten |
a Adapted from CF Foundation Consensus Guidelines 1995; with permission.
For infants and those unable to swallow, PERT capsules can be opened and the enteric-coated beads can be mixed in applesauce or another acidic medium. The enteric-coated beads cannot be crushed. Acid-suppressing medications are often used to increase the pH of gastric fluid delivered to the proximal duodenum to allow the enteric coating to dissolve.
The efficacy of PERT is determined by monitoring weight, height, weight-for-length, and body mass index. Dose may be increased if there are symptoms of malabsorption. If PERT is at the recommended upper limit and growth is still lacking or malabsorption is still present, assessment for comorbid conditions should be initiated ( Fig. 2 ).
Pancreas
Severe CFTR mutations (class I–III) are associated with dramatically decreased pancreatic ductal flow and absent digestive enzymes (pancreatic insufficiency [PI]), whereas milder mutations (class IV and V) tend to be associated with decreased flow but to an extent that allows digestive enzymes to flow into the duodenum (pancreatic sufficiency [PS]). The bicarbonate milieu created by pancreatic fluid is essential to neutralize gastric acid so as to optimize the function of pancreatic enzymes, promote micelle formation, and dissolve the enteric coating on exogenous pancreatic enzyme replacement therapy (PERT). The result of alterations in fluid volume, viscosity, and flow is that proenzymes get trapped within the pancreatic ducts, leading to early activation of pancreatic enzymes that inflame and damage the pancreas. Damage begins in utero as early as 17 weeks gestation. Destruction of the pancreas leads to PI in most patients.
Diagnosis of Pancreatic Insufficiency
PI can be diagnosed by calculating the coefficient of fat absorption from a collection of feces produced during a 3-day diet containing 100 g of fat per day. PI is presumed if less than 93% of fat is absorbed or greater than 7 g of fat is excreted during this time period. In practice, this test has been replaced by the more efficient fecal elastase test, which measures the absence of endogenous elastase. Fecal elastase has a sensitivity of 72% and specificity of 90% for severe PI, but may not be as effective in diagnosis of mild to moderate PI. False positives are seen in the setting of watery diarrhea and diabetes (levels are noted to decrease with increased duration of diabetes). More invasive testing with secretin stimulation of the pancreas and direct collection and analysis of pancreatic juice is available but not often used. Patients do not have maldigestion until less than 10% of exocrine pancreatic function remains.
Management of Pancreatic Insufficiency
PI is managed with exogenous PERT before every meal and snack and with fat-soluble vitamin supplementation. Presently, all PERT is formulated from porcine extracts that contain amylase (digests carbohydrates), protease (digests proteins), and lipase (digests fat). Dosing is based on lipase units/kg per meal or grams of fat ingested ( Table 1 ).
| Lipase units/kg/meal | Lipase units/kg/g of Fat Eaten |
|---|---|
| <4 y of age: 1000–2500 lipase units/kg/meal a 1/2 for snack | Infant formula or breast milk: 2000–4000 lipase units/120 mL |
| >4 y of age: 500–2500 lipase units/kg/meal a 1/2 for snack | Beyond infancy: 500–4000 lipase units/g of fat eaten |
a Adapted from CF Foundation Consensus Guidelines 1995; with permission.
For infants and those unable to swallow, PERT capsules can be opened and the enteric-coated beads can be mixed in applesauce or another acidic medium. The enteric-coated beads cannot be crushed. Acid-suppressing medications are often used to increase the pH of gastric fluid delivered to the proximal duodenum to allow the enteric coating to dissolve.
The efficacy of PERT is determined by monitoring weight, height, weight-for-length, and body mass index. Dose may be increased if there are symptoms of malabsorption. If PERT is at the recommended upper limit and growth is still lacking or malabsorption is still present, assessment for comorbid conditions should be initiated ( Fig. 2 ).
Pancreatitis
Patients with milder mutations (class IV and V) are likely to be PS and are much more likely to develop pancreatitis than those with PI (10.3% vs 0.5%). There is good correlation between genotype and pancreatic functional status but not between genotype and which patients with PS will develop pancreatitis. Pancreatitis is most frequently seen in patients with recurrent pulmonary exacerbations, viral infections, or after surgery. Patients with PS who have chronic recurrent pancreatitis are at high risk for developing PI as well as cystic fibrosis related diabetes (CFRD) due to ongoing damage within the pancreas. Pancreatitis can be the initial presentation of CF and therefore patients with recurrent pancreatitis should be investigated for CF.
Monitoring of pancreatic sufficiency to pancreatic insufficiency
Infants may be PS at diagnosis but convert to PI during the first year of life due to ongoing pancreatic damage. Even in the absence of pancreatitis, some older patients will progress from PS to PI. For this reason, in patients with CF and PS, fecal elastase should be considered as part of the annual evaluation.
Gastroesophageal reflux disease
Patients with CF experience an increased number of transient lower esophageal sphincter relaxations and may have delayed gastric emptying. In patients with CF, the combination of these physiologic processes as well as a number of secondary pathophysiologic mechanisms ( Fig. 3 ) increases the risk to develop gastroesophageal reflux disease (GERD). Therefore, it is not surprising that reflux is one of the most common GI manifestations of CF, with its prevalence reported as high as 25% in infants and up to 85% in children and adults.
Recent pH-impedance data suggest that reflux is present in more than half of children with CF, with nearly two-thirds of those patients reporting no clinical signs or symptoms of GERD. More than 75% of reflux episodes were acidic and more than 40% of episodes were “full-column,” reaching the proximal esophagus. GERD may be asymptomatic or may present as abdominal or chest pain, dysphasia, odynophagia, food impaction, and/or cough. Although the impact of asymptomatic GERD is unclear in patients with CF, symptomatic GERD has been associated with worse pulmonary outcomes in CF but its severity is poorly correlated with objective measures of pulmonary function.
The therapeutic approach for uncomplicated GERD in patients with CF is no different than for the general population; proton-pump inhibitors (PPIs) are preferentially used for acid suppression. Improved lung function parameters are seen in patients on PPI therapy but long-term adverse effects have been described in people without CF. Both benefits and risks have been seen in people with CF treated with PPIs, yet no adequately powered randomization trials have been conducted. For patients with more complicated GERD, fundoplication has been reported to decrease the reflux-cough sequence, decrease the number of pulmonary exacerbations, slow pulmonary function decline, and aid in weight gain. However, the rate of complications postoperatively may be higher than in non-CF patient populations and should be reserved for high-risk patients in consultation with a gastroenterologist familiar with CF.
Intestinal motility
A number of CF-associated variables, such as frequent antibiotic use, intestinal inflammation, and small bowel bacterial overgrowth (SBBO), have all been shown to impact gut motility in CF animal models. Additionally, poor glycemic control, fat-rich and/or carbohydrate-rich meals, previous surgery, and hydration may affect gut motility. Clinical studies have shown inconsistent results (normal, delayed, and rapid transit times all reported) and are hampered by small study sizes and a lack of standard outcome measures.
Gastric Emptying
Delayed gastric emptying has been reported in as many as one-third of adults with CF. Others have reported both normal and increased gastric emptying in children and adults. Gastric emptying may be influenced by glycemic control and whether patients with PI are adherent to PERT. Thus, the potential benefits of prokinetics on gastric emptying must be evaluated on a patient-by-patient basis.
Small Bowel Transit
Delayed small bowel transit has consistently been observed in patients with CF and may be up to twice as long as that seen in healthy controls. The impact of delayed transit time on PERT effectiveness and common CF-associated GI conditions, including abdominal pain, bloating, and SBBO, is unclear.
Total Gastrointestinal Transit
Despite slow small bowel transit time, total GI and colonic transit time are not significantly different in patients with CF compared with healthy controls. These findings are surprising, as constipation is common and some patients develop distal intestinal obstruction syndrome (DIOS). Retained mucofeculent material adherent to the bowel wall with a liquid central channel could explain this discrepancy.
Peptic ulcer disease/ Helicobacter pylori
Despite reduced bicarbonate secretion in patients with CF, normal or even decreased prevalence rates of peptic ulcer disease (PUD) and Helicobacter pylori infections are seen. This “CF paradox” may be due to retained bicarbonate within the enterocyte cytoplasm, which prevents injury and ulcer formation. Alternatively, gastric metaplasia as a host defense mechanism in conjunction with frequent antibiotic use may prevent PUD and duodenal ulcerations in CF.
Use of fecal immunoassay to detect H pylori in the CF population may be compromised due to cross-reactivity with anti- Pseudomonas antibodies. Urea breath test (UBT) in the CF population is also problematic, as the test cannot differentiate SBBO or malabsorption from H pylori infection and there is discordance between stool antigen detection and UBT test results. Therefore, indirect H pylori testing in the pediatric CF population must be interpreted with caution. Endoscopic evaluation can provide definitive diagnosis, but risks of anesthesia must be considered in the context of the patient’s medical needs and underlying pulmonary status.
Small bowel bacterial overgrowth
SBBO is defined as greater than 10 5 colony-forming units per milliliter in the small intestine with a predominance of colonic/anaerobic species. SBBO defined by breath testing has a prevalence of 30% to 55% in the CF population. Delayed small bowel transit time, frequent antibiotics, prolonged use of acid suppression medications, PI, intestinal inflammation, and high rates of constipation increase the risk of developing SBBO.
The presentation of SBBO can vary widely from direct consequences of the excessive bacterial burden (eg, bloating and abdominal pain) to secondary effects of intestinal damage (eg, anemia, malabsorption, malnutrition). Failure to adequately treat SBBO can also result in a “positive feedback” that ultimately leads to worsening of the overgrowth and further consequences of intestinal inflammation/damage, as outlined in Fig. 4 .
Consensus about diagnostic modalities and treatment is lacking. A high index of suspicion should be maintained for SBBO among patients with CF with prolonged GI symptoms or persistent fat malabsorption, especially those with a history of intestinal surgery. Antibiotics covering gram-negative anaerobic bacteria should be used (ie, metronidazole, amoxicillin-clavulanate, fluoroquinolones, gentamicin, rifamycin). Due to high reoccurrence rates, rotating oral antibiotic treatment strategies may be required. However, these regimens, especially if required over long periods of time, carry a theoretic risk of bacterial resistance and increased Clostridium difficile infections. Probiotics have been shown to be safe and efficacious in CF patient populations and may be considered as supplemental therapy. Probiotics should be used with caution in any patient with indwelling port-a-caths, due to lactobacillus sepsis having been reported in patients with compromised gut motility and permeability.
Mucosal diseases
Celiac Disease
Scandinavian population studies have shown a 2 to 3 times higher risk of developing celiac disease in patients with CF compared with the general population. Diagnosis may be challenging given the varied and nonspecific presentations of celiac disease. Additionally, tissue transglutaminase immunoglobulin (Ig)A, which is used as a screening marker for celiac tissue, is often falsely elevated in patients with CF due to nonspecific intestinal inflammation. As in the general population, duodenal biopsy is required for diagnosis. Assistance from a skilled CF dietician is critical to ensure that appropriate nutritional status is maintained if a gluten-free diet is required.
Inflammatory Bowel Disease
Initial reports suggested a seven-fold increase in Crohn disease among the CF population, but subsequent studies have come to different conclusions. Bresso and colleagues determined in a European cohort that F508del mutant CFTR might exert a protective effect against the development of inflammatory bowel disease (IBD), whereas Bahmanyar and colleagues reported no association between CFTR gene mutations and IBD using the Swedish national registry. Calprotectin may be elevated in patients with CF due to nonspecific intestinal inflammation and is not useful in screening for IBD. Thus, endoscopic evaluation with biopsy is warranted for any patient with CF presenting with signs and/or symptoms of IBD.
Appendiceal findings
The appendix of children with CF is more distended than is seen in the general population. However, patients with CF are largely asymptomatic or have symptoms inconsistent with acute appendicitis. Despite the distention, the prevalence of appendicitis in the CF population is only 1% to 2% as compared with 7% in the general population. Distention of the appendix with mucin, which appears as a mucoid appendix or a mucocele on imaging and is difficult to distinguish from acute appendicitis, in addition to frequent antibiotic use, may serve to protect the patient with CF from appendicitis. When appendicitis does occur, it is often misdiagnosed due to its relatively low incidence and propensity to present with nonclassic symptoms (often mistaken for DIOS). This results in an increased risk for appendiceal perforation and abscess formation.
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