Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The gene product, CFTR protein, has important manifestations in the intestine, pancreas and hepatobiliary system. Increased survival has caused CF to be primarily an adult disease today. Physicians must be knowledgeable as to the varied phenotype in the gastrointestinal tract. This review will outline the main gastrointestinal manifestations including a section on gastrointestinal malignancy in CF. Novel treatments treating the basic effect in CF are now being introduced and their effects on the gastrointestinal tract are discussed.
- cystic fibrosis
- pancreatic disease
- cancer syndromes
- chronic liver disease
Statistics from Altmetric.com
Cystic fibrosis is an autosomal recessive disease whose gene product, cystic fibrosis transmembrane regulator protein functions as a chloride or bicarbonate channel at the apical surface of epithelial cells in the pancreas, hepatobiliary system and intestine.
Increased survival has created a situation that most cystic fibrosis patients are now adults and therefore gastroenterologists will be taking care of these patients.
Cystic fibrosis affects many organs in the gastrointestinal tract and this review discusses the main manifestations.
Gastrointestinal malignancies are more common and this is discussed.
Exciting novel treatments have been introduced and the effect on the gastrointestinal tract is critical.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The genetic defect was discovered 31 years ago and tremendous progress has been made since then in our understanding of how CFTR mutations cause disease and how this can be addressed therapeutically. CF used to be considered a childhood disorder but now the majority of children will survive into adulthood. Manifestations in the gastrointestinal tract like distal intestinal obstruction syndrome (DIOS) and colorectal cancer (CRC) are more common the adult population . Physicians should be knowledgeable of the phenotype in adults.
CF is a multisystem disorder affecting the lungs, pancreas, intestine and hepatobiliary tract (figure 1). The CFTR protein, whose function is the regulation of chloride and sodium transport in epithelial cells, is highly expressed on the apical surface of intestinal epithelial cells, pancreatic ductal cells and cholangiocytes which in health transport ions, bicarbonate and fluid to the lumen.1 Thus, CFTR dysfunction results in viscous luminal secretions obstructing the bile and pancreatic ducts as well as the intestine. Gastroenterological symptoms feature prominently as over 15% of patients are diagnosed after birth with meconium ileus (MI) and 85% of patients have exocrine pancreatic insufficiency (PI), and around 10% of these suffer from significant liver disease.
This review will discuss the main gastrointestinal manifestations of CF including the adult specific complications and the promise of treatment of gastrointestinal complications with modifier medications.
Exocrine pancreatic disease
The exocrine pancreatic pathophysiology may be used as a model for all secretory organs. Digestive enzymes are secreted into the pancreatic acinar lumen. Normally, chloride and bicarbonate ions are secreted into the ductal lumen via the CF transmembrane regulator (CFTR) and bicarbonate exchangers (figure 2). The transport of water follows, maintaining the solubility of secreted proteins in a dilute, alkaline solution. In CF, anion transport is impaired, resulting in decreased secretion of a more concentrated, acidic fluid, leading to protein precipitation. Intraluminal obstruction of the microscopic ducts occurs in utero, followed by the larger ducts, causing progressive pancreatic damage and gross pancreatic atrophy.
For several months after birth, there is a release of proteins into the bloodstream, of pancreatic origin. This can measured as immune reactive trypsinogen (IRT), the neonatal screening test for CF. Interestingly this process is asymptomatic. This process eventually results in severe inflammation, duct obstruction, acini destruction, and pancreatic fibrosis. The high IRT in the first few months of life does show that some exocrine pancreatic tissue is still present and may have a bearing on possible small molecule therapy targeted at the remainder of the pancreas which may rescue enough tissue to cause viability of the remaining pancreas. This of course contradicts the popular belief that the pancreas is entirely nonfunctioning at birth.
Genetic factors exquisitely influence the degree of pancreatic disease and its rate of progression.2 Eighty-five per cent of patients with CF are classified as PI which means that they have steatorrhea (faecal fat greater than 7% of fat intake in infants over 6 months of age and over 15% under 6 months of age), requiring these patients to have pancreatic enzyme replacement therapy (PERT) with meals. The other 15% are pancreatic sufficient (PS). These patients have evidence of exocrine pancreatic pathology, but retain sufficient endogenous exocrine pancreatic function to sustain normal digestion Analysis of particular CFTR mutations in patients with pancreatic phenotypes (PI vs PS) revealed two categories of alleles: ‘severe’ and ‘mild’.3 Six different classes of mutations have been described (figure 3). Classes I–III mutations are termed ‘severe’. Classes IV and V are ‘mild’. Class I mutations include nonsense, missense or frameshift, mutations that result in defective protein biosynthesis and the protein does not leave the nucleus. Class II mutations, which include the most common mutation F508del, produce a misfolded functional CFTR protein, which is degraded intracellularly preventing trafficking to the apical surface of the cell. In Class III mutations the protein reaches the apical membrane but channel activation is affected by prevention of binding and hydrolysis of ATP at one of the two nucleotide-binding domains (NBD1, NBD2). Class IV mutations produce a protein with impaired function due to abnormal anion conduction. Class V mutations result in a reduced number of normally functioning CFTR molecules on the apical surface. Class VI mutations result from truncation of the C-terminus of CFTR and produce an unstable protein. Mutations belonging to classes I–III and VI confer no functional CFTR at the apical membrane. As a consequence, inheritance of homozygous or compound heterozygous mutations belonging to these classes are predicted to have severe consequences. Mutations belonging to Classes IV and V on the other hand which confer residual CFTR-mediated channel function will have milder consequences. In fact, it is patients with at least one mutation belonging to classes IV or V who generally present with symptoms in late childhood or adulthood including recurrent acute pancreatitis.
Patients who carry two severe mutations develop PI. Those patients who carry at least one mild mutation usually remain PS. Patients homozygous or compound heterozygous for severe alleles belonging to classes I–III or VI confer PI as opposed to patients with a mild class IV or V allele even when the second mutation is severe are PS. Although these mutations confer sufficient CFTR function to prevent the pancreas from being completely destroyed, many PS patients have reduced exocrine pancreatic capacity and are associated with an increased risk of pancreatitis, as discussed below. A very small number (2%–3%) of patients carrying severe mutations on both alleles are PS at diagnosis; however, many patients will experience a gradual transition from PS to PI. A few missense mutations (eg, G85E) confer a variable pancreatic phenotype.
Many PS patients have reduced exocrine pancreatic capacity and are associated with an increased risk of pancreatitis, even though mild mutations confer sufficient CFTR function to prevent the pancreas from being completely destroyed. In a large cohort of over 1000 patients followed over a period of 30 years, the incidence of pancreatitis was 1.7%.4 The incidence of acute pancreatitis childhood is in the range of 3–13 cases per 100 000 persons per year, which overlaps with the lower end of the range in adults (5–60 cases per 100 000 persons per year. All patients with pancreatitis were PS but only one in five had pancreatitis. Ooi et al determined the association between severity of CFTR genotype and the risk of pancreatitis.5 They examined 277 PS patients from 2 CF centres; 62 with pancreatitis. The milder the mutation, the risk of pancreatitis increased.
Diagnosis of pancreatic phenotype
In order to enable a rational use of oral PERT, a determination must be made if the patient is PI or PS.6 The diagnosis of PI is straightforward when patients have steatorrhea (oil droplets on stool microscopy), hypoalbuminemia, and low fat-soluble vitamin levels Due to the technical difficulties surrounding the 3-day faecal fat test most laboratories are using the spot faecal elastase-1 test (normal (>500 µg/g stool).
Patients with CF have a wide range of hepatobiliary pathology (table 1). However, for the vast majority of patients there are no clinical consequences.
Similar to the pathology in the pancreas, the lack of functional CFTR causes acidification, dehydration and concentration of the biliary ductule contents. Precipitation of biliary secretions and ductular obstruction ensues. The pathological changes in most patients are focal and are clinically inconsequential (circled area figure 4). However, in up to 10% of patients with CF, evidence of multilobular cirrhosis and portal hypertension develop. CF-related liver disease (CFLD) is responsible for 2.5% of overall mortality in CF and is the single most important non-pulmonary cause of death. The average age of diagnosis of CFLD is 10–11 years of age, and 90% are diagnosed before the age of 20.7 Following routine examination or by laboratory evidence of hypersplenism, most patients are asymptomatic and are often identified by the evidence of hepatosplenomegaly. Hepatocellular function may remain well preserved for years, even decades. Other genetic and/or environmental factors may modulate susceptibility to more severe liver disease.
Biochemical markers of liver disease do not reliably identify patients with multilobular cirrhosis nor do they predict the development of end-stage liver disease. About 40%–50% of patients with CF exhibit intermittent elevations of aspartate aminotransferase, alanine aminotransferase or gamma glutamyltransferase, which are generally 1–2.5 times above the upper reference limits. Furthermore, patients with advanced multilobular cirrhosis may have normal liver biochemistry test results. CFLD occurs predominantly in PI patients with a male preponderance.
In a multinational gene modifier study of the different candidate genes, the SERPINA 1 Z allele of alpha-1 antitrysin deficiency was found to be strongly associated with CFLD. This result is intriguing as the patient with CF may require a double hit to develop CFLD. Biliary pathology is not uncommon in CF (Table). Debray et al have proposed using the knockout mouse model that the gallbladder itself, rather than the bile duct epithelia may be the major site for a bile acid shunt, the cholecystohepatic shunt, from the gall bladder back to the liver.8
An alternative hypothesis of the aetiology of CFLD, derived from the histopathological study of liver biopsies suggest vascular changes, namely obliteration of portal vein branches with fibrosis leading to portal hypertension.9
A combined European and North American initiative from the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition) is underway has convened to reach a uniform definition and classification of CFLD. At present, the diagnosis of CFLD frequently is based on the Debray et al 10 criteria which includes palpation of liver and spleen, persistent elevation of liver tests and abnormal ultrasonographic findings. A liver biopsy is not included due to the patchiness of the histopathology in the liver. It is unclear if these criteria differentiate between clinically relevant CFLD or not. Further development of diagnostic criteria including longitudinal rather than single measurements may be important as well as combinations of tests rather than single ones.
Diagnosis and management
The evidence of liver disease is often subclinical until CFLD develops as previously stated. Raised serum liver enzymes in a patient with CF may be due to the normal of waxing and waning of liver tests in CF. Persistent increases in liver tests point to the possibility of alternative pathology unrelated to CF. It is imperative to rule out infectious or autoimmune hepatitis, wilson disease and other cause of steatosis (malnutrition, diabetes mellitus). Neonatal cholestasis may be a rare presentation of CF, which usually resolves with no long-term affect.
Ultrasound scan is commonly used but sensitivity is low. Elastography, which is a test of liver stiffness (a marker of fibrosis), is used in other chronic liver diseases such as hepatitis C and may be useful.11
A number of investigational avenues targeting different aspects of liver disease are being explored. New investigational bile acid analogues include NorUDCA (a side chain–shortened homologue of ursodeoxycholic acid with one less methylene group) has shown promise in preliminary studies.13
The follow-up and management of CFLD are similar to other chronic liver diseases. However, the use of beta blockade prophylaxis for variceal bleeding requires consultation with pulmonologists. for Liver transplantation selection criteria have not been fully established. There is new data that CFLD may begin in adulthood. Koh et al followed a cohort of adult patients diagnosed with CFLD at a median age of 34.8 years. These adults presented with persistently raised liver enzymes and signs of chronic liver disease. This paper has suggested adult-based criteria for diagnosis of CFLD including fibrosis biomarker assessment and liver biopsy.14
The presentation of MI is usually within the first day or 2 of life with failure to pass meconium, abdominal distension and bilious vomiting. MI occurs in 15%–20% of patients with CF.15
A family history of CF may help in the diagnosis. An abdominal X-ray may show distension of bowel loops and a ground-glass appearance due to ileocecal inspissated meconium.
A hypertonic enema (with Gastrografin or Telebrix) may be diagnostic and therapeutic as it will flush the meconium plug. This procedure may be repeated several times in order to avoid surgery.
A rare complication is in utero perforation causing meconium peritonitis. During the third trimester intra-abdominal calcification may be observed incidentally. Postnatally, nearly half of babies with MI may have additional pathology including intestinal atresias and malrotation with volvulus. This is termed ‘complicated MI’. There is increasing evidence that other apical transporter genes may modify MI.
Distal intestinal obstruction syndrome
DIOS occurs in older children and adults with CF. DIOS is a chronic, recurrent form of intestinal obstruction. Unique to CF, DIOS results from thick, adherent, intestinal contents obstructing the terminal ileum and proximal colon. It occurs almost exclusively in those with PI with a prevalence of around 20%. It is frequently confused with other common causes of abdominal pain in patients with CF. Patients usually complain of intermittent episodes of pain which range from mild to intractable and which may or may not be localised to the right lower quadrant. A mass may be palpated in the right lower quadrant.Usually there is partial intestinal obstruction but, rarely, complete bowel obstruction occurs.
The ESPGHAN definition of complete DIOS is the combination of (1) complete intestinal obstruction, as evidenced by bilious vomiting and fluid levels on abdominal radiography with (2) a faecal mass in the ileocecum and (3) abdominal pain and or distension. Incomplete or impending DIOS is defined as (1) a short history of abdominal pain and/or distension (2) a faecal mass in ileocecum but without signs of complete obstruction.16
The factors which may cause DIOS include a prior history of MI, slow intestinal transit, intestinal mucus abnormalities, dehydration of intraluminal contents, and poor compliance with pancreatic enzyme therapy. DIOS is often confused with simple constipation which is common in patients with CF. This proves the importance of a rectal examination. In constipation, the rectum will characteristically be full of stool and stooling patterns and consistency are abnormal. Patients undergoing lung or liver transplantation, carry an increased risk of DIOS during the immediate postoperative period.
Abdominal ultrasound and CT scans may be necessary to exclude other CF-associated or non-CF gastrointestinal disease including appendiceal disease, intussusception, Crohn’s disease, fibrosing colonopathy or malignancy.
Patients with incomplete DIOS usually respond to oral rehydration combined with mineral oil or polyethylene glycol preparations. In complete DIOS, the patient requires hospitalisation and intravenous rehydration Enemas of sodium meglumine diatrizoate (Gastrografin or Telebrix) may be performed by experienced radiologists, but the enema must enter the ileocecal valve to get above the obstruction. Treatment of DIOS is still largely empirical due to few randomised controlled trials. In most cases early, aggressive medical management will avoid surgery. Laparoscopy and intraluminal milking and washout are recommended before resection. A single episode of DIOS is a risk factor for recurrence; maintenance therapy should be considered along with regular follow-up by experienced gastroenterologists.
In a multinational prospective study, 112 episodes were studied. Delayed arrival at hospital and weight loss prior to the attack of DIOS had a significant impact on the time needed for resolution.17 18
Gastro-oesophageal reflux disease
Gastro-oesophageal reflux disease (GERD) is common in patients with CF. It is a multifactorial problem with contributions from both the severity and treatment of lung disease, physiotherapy, transient inappropriate lower oesophageal sphincter relaxation, and delayed gastric emptying., There is some evidence that GERD may contribute to the progression of respiratory disease either by pulmonary aspiration of refluxed gastric contents or by neutrally mediated reflex bronchoconstriction secondary to irritation of the oesophageal mucosa.19 Other complications include reduced energy intake from dysphagia and oesophageal strictures and malnutrition due to increased losses through emesis or. Since silent GERD is common in patients with CF, a lack of reported symptoms does not exclude this diagnosis. Bile acids are found in the sputum of children with CF suggesting bile reflux. Oesophageal pH or impedance monitoring is useful, however, upper endoscopy and biopsy are recommended to define the extent of disease and to rule out other oesophageal pathology such as eosinophilic esophagitis especially when drug trials have failed. Woodley et al investigated 28 children and adults with pH-multichannel impedance. The adult cohort had significantly worse results suggesting that there is increased risk for acid exposure with advancing age.20
Early detection of CF especially neonatal screening, improvements in nutrition, bronchial clearance, antibiotics and organ transplantation have led to a tremendous increase in life expectancy . The majority of patients with CF are adults. One of the corollaries of CF becoming an adult disease is that patients suffer from adult problems including in particular gastrointestinal malignancies especially colon cancer.21
The effect of non functioning CFTR protein on the intestine is being recognised. The impaired electrolyte transport leads to mucosal barrier dysfunction leading to bacterial colonisation, and mucosal inflammation. This has been well documented in CFTR-knockout mice and in humans we coined the term “CF enteropathy” after studying the intestinal mucosa with video capsule endoscopy which has been repeated by other researchers.22 On the molecular level, absence of CFTR causes upregulation of oncogenic genes.23 The inflammatory state in the gastrointestinal tract in patients with CF promotes oncogenesis.
Epidemiological studies have suggested that CF is associated with an increased risk of gastrointestinal tract cancers. Colon cancer is the most common and represents the most significant risk. The risk was higher in male patients, those with PI and a history of DIOS. The increase in colonic neoplasms from the age of 40 is fivefold.24 Early detection of CRC and removal of adenomatous polyps results in significant reduction in mortality. The risk of CRC in patients with CF increases markedly after organ transplantation with the risk being over 25 times the age-adjusted baseline .
Yamada et al have performed the first meta-analysis of the risk of gastrointestinal cancers in patients with CF compared with the general population.21 The overall risk of gastrointestinal cancer was significantly elevated SIR (Standardised Incidence Ratio) was 9.37 with significant increase in transplanted patients. The SIR of site-specific cancers of small bowel, colon, biliary tract and pancreas were all elevated.
The marked increase in the incidence of CRC prompted the North American CF Foundation to set up a Task Force.25 Colonoscopic screening for CRC should begin at 40 years of age with rescreening every 5 years. In patients who have had adenomas detected this is increased to every 3 years. In transplanted patients screening should begin at 30 years of age within 2 years of transplantation.
The emergence of gastrointestinal cancer as a potentially significant clinical problem in adult patients with CF is a direct consequence of the greatly improved life expentancy. There is a possibility that chemopreventive drugs and the new CFTR modulator drugs (see below) which increase expression of CFTR protein at the apical surface may also decrease the incidence of gastrointestinal cancers.
However, the meta-analysis has shown that CF should be added to the list of gastrointestinal cancer syndromes deserving special considerations for screening and surveillance.26
With improved survival, the variety of aetiologies of abdominal pain, which is a commom complaint of subjects with CF, has shifted. The history must include the character, chronicity, intenstity and localisation of the pain. Exocrine pancreatic function must be noted together with weight loss, change in bowel habit and previous surgery. CF-specific causes of abdominal pain include oesophagitis and peptic ulcer due to the hyperacidity in CF. Constipation, DIOS, small intestinal overgrowth, cholecystisis and malignancy must be considered and in a PS patient acute and chronic pancreatitis. Fibrosing colonopathy is an obstructive disorder with colonic fibrosis causing abdominal pain often accompanied by hematochezia first reported in the 1990s. Evidence pointed to an iatrogenic condition due to overdosing of pancreatic enzyme supplements. Subsequent to an upper limit of enzyme dose being implemented this entity has all but disappeared.
CFTR correctors and potentiators
The emergence of novel targeted agents, that directly correct CFTR, has created new treatment opportunities for patients with CF. There are two main types of new treatments, correctors and potentiators.
The first drug approved was ivacaftor a CFTR potentiating drug which was successful in treating class III mutations (figure 3). Remarkably, this drug improved respiratory function and decreased sweat chloride concentration to near-normal levels and caused a substantial weight gain.27
The second drug approved was a combination of Ivacaftor and Lumicaftor for the more common class II mutations28 and recently a triple combination of ivacaftor, lumicaftor and tezecaftor has shown impressive improvement in the most common class II mutation F508.29 30
The increase in weight cannot be explained by the improvement in respiratory function alone leading to speculation that these drugs also improve the function of the gastrointestinal tract. There is increasing evidence that there are direct effects of the modulator drugs on the gastrointestinal tract.31 There is increasing evidence that exocrine pancreatic function improves in patients taking Ivacaftor with the intriguing notion that if treatment is started early enough exocrine pancreatic function may be preserved.32 33 The incidence of recurrent pancreatitis was reduced.34 Ooi et al have shown that treatment with Ivacaftor reduced stool calprotectin significantly and changes in the microbiome suggesting an improvement in intestinal inflammation.35 The increased availability of these novel drugs will enable research into specific disease processes affecting the liver, intestine and exocrine pancreas in CF.
In conclusion, children and adults with CF have a wide range of gastroenterological manifestations. Gastroenterologists must be involved to improve the quality of life and outcomes of these patients especially in the era of new treatments for the basic defect in CF.
Patient consent for publication
Contributors Following Professor Beatties kind invitation, my colleague MS and myself planned the main points of the article. MS researched new studies in pubmed. MS wrote the first draft after which we wrote the article together.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.