Introduction

The survival of cystic fibrosis (CF) patients has dramatically improved because of centralized management of patients in specialized CF centers, more aggressive use of antibiotics, and intensive nutritional support [1]. Cystic fibrosis is mainly characterized by exocrine pancreatic insufficiency and progressive pulmonary disease, but with the improved life expectancy, less frequent and less severe manifestations of CF, such as the intestinal obstruction syndromes, are becoming clinically more relevant.

Meconium ileus (MI) at birth, distal intestinal obstruction syndrome (DIOS, formerly designated “meconium ileus equivalent”), and constipation are all consequences of the increased viscosity of intestinal mucus and the prolonged intestinal transit time in CF [2–5]. Meconium ileus is unique to CF and is characterized by complete intestinal obstruction in the neonatal period caused by accumulation of inspissated meconium. After the neonatal period, DIOS emerges, characterized by complete or incomplete intestinal obstruction of viscid fecal accumulation in the terminal ileum and proximal colon. Characteristically, DIOS patients have abdominal pain, distension, and vomiting in combination with a right lower quadrant mass, which is palpable and usually seen on plain abdominal radiography. An important differential diagnosis of DIOS is constipation. However, in contrast to DIOS, symptoms are usually milder and of longer standing. Each condition is frequently seen in CF patients, with constipation in particular being greatly underdiagnosed in CF [6•]. This review describes the incidence, genetics, risk factors, diagnosis, and treatment of MI, DIOS, and constipation in CF.

Incidence and Prevalence

Meconium Ileus Occurs at Birth in 13% to 17% of All CF Patients [7–10]

Studies on the incidence and prevalence of DIOS and constipation are difficult to compare because of the different definitions used. The recent consensus guidelines issued by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) CF Working Group define DIOS as an acute, complete or incomplete, fecal obstruction in the ileocecum, whereas constipation is defined as gradual fecal impaction of the total colon (Tables 1 and 2) [10]. Using these definitions, both the incidence (2.2–6.2 episodes per 1000 patient-years) and lifetime prevalence (7–8%) of DIOS in childhood is low [9, 11•, 12, 13]. Two studies report that DIOS incidence and lifetime prevalence increase as patients become older [12, 13]; indeed, incidence (23.3 episodes per 1000 patient-years) and lifetime prevalence (14–16%) are higher in adult patients [12–14]. Additionally, DIOS is recurrent medical issue, because 20% of all pediatric patients experienced more than one episode during a 5-year observation period [11•].

Table 1 European society for pediatric gastroenterology, hepatology, and nutrition CF working group definition for distal intestinal obstruction syndrome (DIOS) in cystic fibrosis
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Table 2 European society for pediatric gastroenterology, hepatology, and nutrition CF working group definition for constipation in cystic fibrosis
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Reports on lifetime prevalence of constipation are scarce; only two studies for pediatric patients (published in 1986 and 2010) [9, 13] and one for adult patients (published in 1986) [13] are available. They show that constipation is very common in both pediatric (lifetime prevalence 26–47%) and adult (lifetime prevalence 42%) CF patients [9, 13]. In the pediatric population, the prevalence of constipation seems to have increased over time [9, 13]. However, this might be a false image, because the use of laxatives was a key component in establishing constipation in both reports, and laxatives probably are prescribed more readily now in CF patients suspected of constipation, especially because current laxatives are almost devoid of side effects [15].

Genetics

Meconium Ileus

Meconium ileus occurs in 13–17% of all CF patients at birth [7–10], and is clearly influenced by genetic factors, because a large twin study reports that monozygous twins show a greater concordance for MI than dizygous twins [10]. This variation can be partially explained by the cystic fibrosis transmembrane regulator (CFTR) genotype. For example, homozygosity for the delta F508 deletion, the most common CFTR mutation in CF patients, is strongly associated with the presence of MI [10]. However non-CFTR genes (ie, modifier genes) also influence the risk for developing MI [10, 16, 17]. Several genes and regions have been reported to be associated with MI [9, 10, 16–18], but a solid association between a causal modifier gene and MI has yet to be discovered. Rozmahel et al. [18] were the first to report a modifier locus for MI (Cfm1) on chromosome 7 in a murine CF model. Subsequently, several markers on human chromosome 19, the region syntenic to the mouse locus, showed significant linkage with the presence of MI in 185 CF sibling pairs [16]. However, in a genome-wide analysis in more than 1000 patients, this reported linkage between CFM1 and MI could not be replicated [10]. Thus, a role of CFM1 in the development of MI seems to be unlikely. The genome-wide analysis by Dorfman et al. [17] provided two new candidate modifier genes (ADIPOR2 and SLC4A4), although the function of these genes and their relation to MI are unknown. In addition, we recently reported an association between a variant in the CLCA1 gene and MI in European CF patients [9]. The CLCA1 gene and its ortholog in mice, Clca3, encode a calcium-activated chloride channel. Recent studies show an important role for CLCA1/Clca3 in intestinal obstruction in CF; the expression of Clca3 in the intestine of CF mice, which all die of intestinal obstruction, is decreased [19, 20], and up-regulation of Clca3 in CF mice results in ameliorated intestinal disease and improved survival [20].

DIOS and Constipation

Some studies report an increased frequency of severe CFTR genotypes in DIOS [14, 11•], whereas others report no differences [10], and a large twin study shows equally low concordance rates for DIOS in monozygous and dizygous twins [10]. Constipation in CF is not associated with a severe CFTR genotype [6•]. Therefore, genetic factors, both CFTR and non-CFTR, seem not to play an important role in DIOS or constipation in CF.

Risk Factors

Relationship with Diet

The relationship between pancreatic insufficiency, or poorly controlled steatorrhea, and constipation or DIOS is unclear; conflicting results have been published. In general, it is thought that constipation correlates with high doses of pancreatic supplements [21, 22]. However, this is not supported by Baker et al. [23], who report no correlation between constipation and the dosage of pancreatic supplements. We recently found that constipated patients had a lower total fat absorption than control patients, although both patient groups (with and without constipation) had adequate control of steatorrhea, with a mean total fat absorption of 86% and 90%, respectively [6•]. Koletzko et al. [24] also describe a higher fat excretion in DIOS patients compared to controls. Slow intestinal transit, as is frequently seen in CF [2, 3], could be aggravated by a high percentage of undigested food and may promote the accumulation of fecal material.

Furthermore, fiber and fluid intake are not correlated with constipation in CF [6•, 25], despite the general opinion that inadequate fluid and fiber intake is an etiological factor of constipation in CF [13].

Relationship with Other Gastrointestinal CF Manifestations

The relationship between MI and CF-related liver disease is unclear; some report a higher frequency of MI in patients with CF-related liver disease [26–28], but others report no differences [29–32, 33•]. One study even reports a significantly lower frequency of MI in patients with CF-related liver disease [34].

A relatively new research topic in CF is intestinal inflammation. In the majority of the general CF population, intestinal inflammation is present, as evidenced directly by capsule endoscopy or indirectly by elevated fecal calprotectin levels [35, 36]. More specifically, ileal biopsies from both MI and DIOS patients also show signs of intestinal inflammation, especially in the myenteric ganglion cells and myocytes [37•]. This intestinal inflammation may play a role in the development of intestinal obstruction in CF, either directly or indirectly, through delaying intestinal transit time.

We found a surprisingly high frequency of MI in patients with gastroesophageal reflux disease (42%) compared to controls (10%) [38]. Our findings are supported by a study reporting a higher number of reflux episodes in MI patients [39]. Furthermore, gastrointestinal motility disorders are frequently reported in CF. For example, CF patients with symptoms suggesting gastroesophageal reflux may have esophageal motility defects [40], and in the general CF population, prolonged intestinal transit time is described [2, 3]. Although the intestinal transit time in MI patients is unknown, the association between gastroesophageal reflux disease and MI suggests common defects in gastrointestinal motility.

After lung transplantation, DIOS is frequently seen; about 10% to 20% of CF lung transplant patients develop at least one DIOS episode early in the post-transplant period [41]. The transplantation period is characterized by dehydration, immobility, and opiate use, and in combination with predisposing factors (eg, MI or abdominal surgery), could promote fecal impaction in the ileocecum, eventually leading to complete intestinal obstruction in selected patients. As in the general CF population [10], DIOS occurs mainly in patients with a history of MI or laparotomy [41]. Therefore, starting preventive laxative treatment in these high-risk patients after lung transplantation could be considered.

Diagnostic Investigations

Constipation is a clinical diagnosis based on a careful history and physical examination. The recent definition of constipation includes 1) abdominal pain and/or distension, or 2a) a reduced frequency of bowel movements in the past few weeks, and/or 2b) increased consistency of stools in the past few weeks, while 3) the symptoms are relieved by the use of laxatives [11•]. Additionally, complete DIOS is defined as the combination of 1) complete intestinal obstruction, as evidenced by vomiting of bilious material and/or fluid levels in the small intestine on an abdominal radiography, with 2) a fecal mass in the ileocecum, and 3) abdominal pain and/or distension. Incomplete or impending DIOS is defined as a short history (days) of abdominal pain and/or distension and a fecal mass in the ileocecum, but without signs of complete intestinal obstruction [11•]. Despite these strict definitions, diagnosing constipation or DIOS can be a real challenge. Abdominal radiography in CF patients, using the Barr and Leech scoring systems, has both a poor value for diagnosing constipation and poor inter- and intraobserver variability [6•]. Consequently, abdominal radiography is not recommended as a standard diagnostic tool in the regular gastrointestinal follow-up of CF patients. However, abdominal radiography is useful to differentiate between constipation and DIOS in CF patients with acute abdominal pain, because DIOS patients have a fecal mass in the ileocecum with or without fluid levels in the small intestine, whereas constipation patients have a distribution of fecal material throughout the colon [11•]. Therefore, plain abdominal radiography is recommended in CF patients with acute abdominal pain.

Treatment and Long-Term Effects

Meconium Ileus

Survival in patients with MI has improved dramatically; Kerem et al. [7] report that survival through the first year of life increased from 55% in CF patients born between 1958 and 1972 to 96% in those born between 1973 and 1987. More recent articles even report no differences in survival between MI and non-MI patients [33•, 42•]. Nutritional status follows the same trend as survival; an older study showed worse long-term nutritional outcomes in MI patients [7], but more recent reports show no differences between MI and non-MI patients [33•, 42•, 43–45]. In contrast, the long-term outcome of pulmonary function in MI patients is less uniform between the MI and non-MI groups. Although the majority of papers report no differences between patients with or without MI [8, 33•, 42•, 43], two other studies report a worse pulmonary function in MI patients. These ambiguities could be explained by the control groups used; the first studies used controls who were diagnosed based on suggestive symptoms of CF [8, 33•, 42•, 43], whereas the last two studies used matched controls diagnosed in infancy through a newborn screening program [45, 46]. Consequently, this suggests that MI patients have a worse pulmonary phenotype, when corrections for the advantage of early detection and treatment were made.

DIOS and Constipation

Most DIOS episodes can be treated conservatively with intensive laxative treatment (oral laxatives and/or enema or polyethylene glycol lavage), and most large studies report low numbers of surgical interventions [11•, 13, 14]. Nevertheless, the frequency of surgery varies widely among studies (0–11%) [11•, 12–14, 41].

For treatment of constipation, we prefer polyethylene glycol, because it is more effective and does not have the adverse events inherent to lactulose (flatulence and abdominal cramps) [15]. For DIOS patients, treatment is still largely empiric because there are no reported trials. It is generally recommended to start with an oral laxative (polyethylene glycol), with or without an enema, and restoration of adequate hydration, in patients with impending DIOS and in those with complete DIOS, at least in patients who do not vomit [47]. When this treatment is not effective, or in more severe DIOS episodes, intestinal polyethylene glycol lavage with a balanced electrolyte osmotic solution is started orally or via nasogastric tube. In rare cases, the retrograde use of meglumine diatrizoate (Gastrografin; Schering AG, Berlin, Germany) can be considered, although this intervention might have serious complications, such as fluid shift from the circulation to the bowel leading to shock, perforation, and necrotizing enterocolitis [47]. Surgery should be used if conservative treatment is not successful; however, with early aggressive medical management, surgery is seldom required.

Because most DIOS patients have more than one episode, continuation of the laxative treatment (polyethylene glycol) after the first DIOS episode can be considered and seems logical, although no published evidence for this approach is available. Furthermore, dehydration and fat malabsorption (coefficient of fat absorption < 85%) should be avoided to prevent recurrence. Finally, in transplantation patients, pre-transplant bowel preparation with polyethylene glycol and early postoperative start of enteral feeding seem appropriate, as does adequate use of pancreatic enzymes and polyethylene glycol [41].

Conclusions

Intestinal obstruction syndromes are significant issues for CF patients. Long-term outcomes for MI have improved dramatically, and today no differences are seen between MI and non-MI patients. Later in life, DIOS becomes an issue, with a lifetime prevalence of 8% in pediatric CF patients and 16% in adult CF patients. In DIOS, early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution is almost always effective, making surgical interventions rare. With adequate use of polyethylene glycol, constipation, which is frequently seen in CF, can generally be well controlled.