Review article 129

Abdominal pain in adults with cystic fibrosis Edward F. Nasha, Chandra M. Ohrib, Anne L. Stephensonc and Peter R. Duried Abdominal pain is a common symptom in individuals with cystic fibrosis (CF). As prognosis has improved, CF has changed from a pediatric disease to the current situation wherein most people with CF are adults. With improved survival, the spectrum of pathologies causing abdominal pain in CF has shifted. Despite this, there have been relatively few previous publications focusing on gastrointestinal disease in CF adults. The aim of this review was to examine the characteristics, differential diagnosis, investigation, and optimal management of adults with CF presenting with abdominal pain. Eur J Gastroenterol c 2014 Wolters Kluwer Health | Hepatol 26:129–136 Lippincott Williams & Wilkins.

Introduction Abdominal pain is a common symptom in individuals with cystic fibrosis (CF), as described by Dr Jim M. Littlewood in 1995 [1]. This excellent review article described the wide variety of etiologies for abdominal pain in CF, largely focusing on children. However, as prognosis has improved, CF has changed from a pediatric disease to the current situation wherein most people with CF are adults. Current median predicted survival in the UK is 41 years [2] and the birth cohort from the year 2000 is predicted to live into the sixth decade [3]. With improved survival, the spectrum of pathologies causing abdominal pain in CF has shifted. Conditions that are commonly seen in pediatric care, such as intussusception, are less common in adult patients [4]. Pathologies more common in adulthood, including gastrointestinal malignancy, are increasingly being reported in CF individuals [5]. In addition to improved survival, other factors have influenced the changes in prevalence of different abdominal pathologies. For example, fibrosing colonopathy, thought to be due to excessive high dosage of pancreatic enzymes, has become less commonly reported as the effectiveness of pancreatic enzyme replacement therapy (PERT) has improved [6]. Also, increasing use of solid organ transplantation has resulted in an increasing prevalence of a range of conditions such as postliver transplant portal vein thrombosis [7] and lymphoproliferative disorders [8]. Despite this, there have been relatively few previous publications focusing on gastrointestinal disease in CF adults. The aim of this review was to examine the characteristics, differential diagnosis, investigation, and optimal manageAll supplementary digital content is available directly from the corresponding author. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X

European Journal of Gastroenterology & Hepatology 2014, 26:129–136 Keywords: abdominal pain, cystic fibrosis, etiology, imaging, management a West Midlands Adult Cystic Fibrosis Centre, Heart of England NHS Foundation Trust, Birmingham, bLeicester Adult Cystic Fibrosis Centre, Glenfield Hospital, Leicester, UK, cToronto Adult CF Clinic, St Michael’s Hospital and dDepartment of Pediatrics, The Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Correspondence to Edward F. Nash, MRCP(UK), West Midlands Adult Cystic Fibrosis Centre, Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham, B9 5SS, UK Tel: + 44 121 424 1669; fax: + 44 121 424 1661; e-mail: [email protected] Received 9 June 2013 Accepted 17 September 2013

ment of adults with CF presenting with abdominal pain. The more common conditions resulting in abdominal pain in CF adults are included in the print version of the journal. Additional causes are included in the online supplement, including celiac disease, inflammatory bowel disease, Clostridium difficile colitis, pancreatic carcinoma, cholangiocarcinoma, hepatocellular carcinoma, portal vein thrombosis, splenic infarction, splenic capsular stretch, fibrosing colonopathy, and pancreatic cystosis.

Etiologies of abdominal pain in cystic fibrosis adults Intestinal pathology Distal intestinal obstruction syndrome

Distal intestinal obstruction syndrome (DIOS) (formerly known as ‘meconium ileus equivalent’) occurs frequently in people with CF and is commonly confused with other causes of abdominal pain. It is unique to CF and is characterized by recurrent episodes of partial (rarely complete) intestinal obstruction due to the accumulation of thickened, adherent fecal material, and mucus in the distal ileum and proximal colon. Since the original description in 1962 [9], the study of the characteristics of DIOS has been made difficult by the lack of a clear definition of the condition. However, in 2005 the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) CF Working Group proposed standardized definitions of incomplete and complete DIOS [10]. Incomplete or impending DIOS was defined as ‘a short history (days) of abdominal pain and/or distension and a fecal mass in ileocecum, but without signs of complete obstruction’. Complete DIOS was defined as ‘a fecal mass in the ileocecum’ associated with clinical and radiological evidence of complete intestinal obstruction. Using these definitions, the estimated prevalence of DIOS was 6.2 (95% confidence DOI: 10.1097/MEG.0000000000000011

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interval, 4.4–7.9) episodes per 1000 patient-years in a pediatric multicenter prospective cohort study [10]. The prevalence in adults using these definitions has not as yet been reported. DIOS almost exclusively affects pancreatic exocrine insufficient (PI) individuals with severe cystic fibrosis transmembrane conductance regulator (CFTR) mutations, with 44% of those affected also having a prior history of neonatal meconium ileus [10]. Patients undergoing lung transplantation [11,12] or other major gastrointestinal surgery are at particular risk of developing DIOS in the immediate postoperative period. The role of PERT in the pathogenesis of DIOS is unclear. Some investigators report that inadequate dosing of PERT leads to an increased risk of DIOS [13]. It has also been suggested that as PERT results in less undigested food in the intestine this may promote DIOS [6]. In addition, a recent genome-wide analysis study identified certain solute carrier genes (SLC9A3, SLC6A14, SLC26A9) associated with meconium ileus in CF [14]. As the incidence of DIOS is greatly increased in individuals with a history of childhood meconium ileus (more than double the frequency) and occurs in the same intestinal region, the authors speculate that DIOS may also be related to the same or similar intestinal transporters. DIOS presents with intermittent abdominal pain that is often severe and is typically either central or localized to the right lower quadrant. Importantly, in incomplete DIOS, which is much more common than complete DIOS, bowel motions are usually of normal consistency and frequency. This is in distinction to constipation, where less frequent bowel motions and hardened stool are characteristic. Nausea, vomiting, and abdominal distension may occur in patients with complete DIOS, but persistent vomiting, especially combined with reduced frequency of bowel motions, should prompt investigations to exclude an alternative cause for intestinal obstruction. The possibility of intussusception should always be considered, especially in patients with rapid onset acute symptoms that fail to resolve following an intervention for DIOS. A palpable right lower quadrant fecal mass is common in DIOS but this is often nontender or only mildly tender. A more tender right lower quadrant mass should prompt consideration of appendicitis. Additional differential diagnoses include constipation, acute pancreatitis [consider only in individuals who are pancreatic sufficient (PS)], small bowel bacterial overgrowth, gynecological pathology, and gastrointestinal malignancy. Diagnosis of DIOS may be straightforward, based on previous similar episodes, but investigations to exclude alternative diagnoses should be performed, particularly in patients presenting for the first time with abdominal pain or in those with an atypical clinical presentation or with nonresolving symptoms. Plain abdominal radiograph features of DIOS include ileal and proximal colonic loading

with or without mild small intestinal dilatation (Fig. 1). Erect chest radiograph is useful to exclude free abdominal air due to perforated peptic ulcer. With atypical features, gastrointestinal contrast studies, abdominal ultrasound, computed tomography (CT) (Supplementary Fig. 2) and magnetic resonance enterography should be considered to exclude alternative pathologies. Treatment of partial intestinal obstruction due to DIOS differs from center to center, but typically consists of intravenous fluid resuscitation combined with one or more of oral polyethylene glycol lavage solution, oral N-acetylcysteine, and oral gastrografin. These medical treatments are effective in the majority of cases [10]. In our experience, radiologically-guided gastrografin (or polyethylene glycol lavage solution) enema has proven useful in patients with resistant DIOS and should always be used in those with complete obstruction (Supplementary Fig. 3). This technique allows the contrast material to be visualized thereby ensuring that it reaches the site of obstruction. In nonresolving cases the differential diagnoses mentioned previously should be reconsidered. Opiates should be avoided as this will slow bowel transit and potentially worsen the condition. Surgery is rarely required and should be reserved for severe cases that fail to resolve despite intensive medical treatment. Fig. 1

Plain film appearances of distal intestinal obstruction syndrome in a cystic fibrosis adult, demonstrating fecal mass in the cecum (arrow).

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Constipation

Constipation is extremely common in CF adults, particularly in PI individuals and is frequently confused with DIOS [15]. The two conditions may of course present simultaneously in the same patient and require concurrent treatment. Constipation is due to colonic fecal loading and, in contrast to DIOS, stooling frequency and consistency are abnormal. ESPGHAN define constipation as ‘abdominal pain or distension or both’, ‘with a decline in the frequency of bowel movements in the last few weeks to months or increased consistency of stools in the last few weeks or months or both’, and the symptoms being relieved by the use of laxatives [10]. Central abdominal pain is typical in constipation; nonresolving nausea and vomiting should suggest an alternative (or additional) diagnosis. Abdominal examination may reveal palpable left sided or generalized colonic fecal loading. Plain abdominal radiographs typically demonstrate fecal loading beginning in the rectum and extending proximally, sometimes filling the entire colon. Mild small bowel dilatation may be seen, but more severe dilatation suggests alternative conditions such as DIOS or intussusception. As in the general population a variety of oral laxatives are used, such as docusate sodium, senna, gastrografin, or polyethylene glycol lavage solution, with or without rectal suppositories or enemas. Dehydration should be treated and dietetic assessment is important to ensure adequate PERT. As with DIOS, opiates should be avoided if possible to avoid further slowing of colonic transit. Appendiceal disease

Appendicitis is reported to be less common in CF compared with the general population. In the Toronto clinic, 1.1% of patients in a large CF cohort underwent appendectomy compared with 7% prevalence in the general population [16]. Potential explanations for this apparently lower prevalence include frequent use of antibiotics, obstruction of the appendiceal lumen by thickened mucus, and misdiagnosis for another condition resulting in gradual resolution without appendectomy. CF patients that are correctly diagnosed with appendicitis are often diagnosed late and as a result the majority of reported cases have already developed complications such as localized perforation or abscess formation [16]. This may be due to a number of factors, including partial resolution of appendiceal inflammation by intravenous antibiotics intended to treat pulmonary exacerbations and presumption of an alternative diagnoses such as DIOS. Supplementary Fig. 4 demonstrates the CT appearances of a psoas abscess complicating appendicitis in a 23-yearold CF male. Supplementary Fig. 5 demonstrates the CT appearances of a tubo-ovarian abscess complicating appendicitis in a 25-year-old CF female. In both cases, surgical resection, antibiotics, and supportive care resulted in successful outcomes.

As with non-CF individuals, patients typically present with central abdominal pain that migrates to the right iliac fossa. An exquisitely tender palpable right lower quadrant mass, fever, and elevated inflammatory markers should prompt consideration of this diagnosis rather than DIOS (unless the patient has already had their appendix removed). Some patients may present with a positive psoas sign due to inflammation of the psoas muscle. Typically bowel habit is initially normal but may become less frequent as ileus ensues. Nausea and vomiting may occur, and this combined with a tender right lower quadrant mass should lead to reconsideration of a diagnosis of DIOS. Diagnosis by abdominal ultrasound and CT is feasible, although due to the frequently abnormal appearance of the CF appendix even in the absence of appendicitis, the correct diagnosis may only be confirmed at laparotomy.

Intussusception

Symptomatic intussusception is relatively common in children with CF, but the frequency is unknown in adults. A recent retrospective study of data from two large CF centers identified six CF adults with symptomatic intussusception and a literature review identified three additional cases reported from other centers [4]. Patients presented with sudden onset colicky abdominal pain in all cases, with nausea, vomiting, and less frequent bowel motions also being reported. In five of the nine patients, there was a palpable right lower quadrant mass. Patients were often initially misdiagnosed with DIOS and there was a significant delay between initial presentation and definitive diagnosis (ranging between 3 and 14 days). All patients had ileocolic intussusception identified by imaging (either abdominal ultrasound or CT). Air or contrast enema (which may be therapeutic as well as diagnostic) was only attempted in one of the nine patients. This is in contrast to the management of intussusceptions in childhood, where this is a routine practice. Indeed, all patients underwent laparotomy and surgical resection where in the majority a benign focal underlying lesion was found at the lead point (inflamed appendix in three patients and benign ileal polyp in two). Differential diagnosis for symptomatic intussusception includes DIOS, appendicitis, and appendiceal abscess. As mentioned previously, bowel habit is usually normal in pure DIOS and vomiting is usually only seen in cases with severe obstruction. As in appendiceal disease the right lower quadrant is generally tender, but if doubt persists abdominal imaging is indicated. Abdominal ultrasound (Supplementary Fig. 6), CT (Fig. 2) [17], and contrast enema are all valuable in confirming the diagnosis of symptomatic intussusception. Ultrasound and CT may have more value in diagnosing alternative pathologies, but contrast studies have the benefit of being both diagnostic and potentially therapeutic.

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Fig. 2

Computed tomography image of intussusception in a cystic fibrosis adult, demonstrating intussuscipiens (solid arrow) and intussesceptum (dashed arrow).

If intussusception is reduced by a contrast enema or manually at laparotomy in an adult, we would suggest that follow-up imaging be performed to exclude an underlying bowel lesion. This is largely because of the concern of a potential underlying lesion that may require definitive treatment (e.g. adenomatous polyp or colonic malignancy). It should be mentioned that asymptomatic, transient intussusception is a well-recognized entity in CF [18] and even if imaging demonstrates intussusception, this may not necessarily explain the patient’s symptoms. If the clinical picture is not typical, an alternative diagnosis should be considered.

There are several theoretical reasons for an increased prevalence of SIBO in CF patients, including production of more acidic intestinal, biliary, and pancreatic secretions, prolonged intestinal transit, previous intestinal surgery, ingestion of pulmonary bacteria, adhesion of bacteria to sticky luminal mucus, and reduced mucosal host defense due to intestinal inflammation. In addition, the frequent use of proton pump inhibitors as well as azithromycin [21] has been linked with the presence of SIBO. In the non-CF population, SIBO typically presents with abdominal pain, bloating, diarrhea, and steatorrhea. However, similar symptoms are common in pancreatic insufficient CF adults without SIBO, making it difficult to make a confident diagnosis. Therefore, we suggest that a therapeutic trial be considered in patients with nonresolving or refractory abdominal symptoms. There are limited data on which to base treatment regimes for SIBO in CF adults. A combination of ciprofloxacin and metronidazole reduces small bowel mucus accumulation in the CF mouse model [23]. Intravenous amikacin and ceftazidime, as well as oral ciprofloxacin, administered to CF patients with SIBO (diagnosed by the hydrogen breath test) reduce exhaled breath hydrogen/methane [24], but we are not aware of other in-vivo studies of different treatment regimes in humans. In addition to antibiotic therapy, oral probiotics have been suggested to be beneficial for CF individuals in one small study [25]. Our local practice in patients suspected of SIBO is a therapeutic trial of several cycles of high-dose oral metronidazole. If this approach is used, we strongly suggest cycles of ‘2 weeks on’ and ‘2 weeks off’ treatment, or else cycles of different antibiotics every 2 weeks, to reduce the risk of establishing antibiotic resistant organisms. Treatment as well as diagnosis of this condition requires further study. Intra-abdominal malignancy

Small intestinal bacterial overgrowth

Small intestinal bacterial overgrowth (SIBO) has been reported in a high proportion of CF patients [19–21]. Using the hydrogen glucose breath test as the diagnostic test, between 32 and 68% of CF patients were tested positive [19,21,22]. Importantly, however, it should be noted that an abnormal hydrogen breath test in a CF patient with abdominal pain does not necessarily confirm that the symptoms are due to SIBO. The hydrogen glucose breath test may result in a falsely high prevalence of SIBO, due to the slow intestinal transit commonly seen in CF [22]. This is supported by the observation that patients with elevated hydrogen breath concentration had no evidence of increased gastrointestinal symptoms [21] or failure to thrive [22] compared with patients with negative hydrogen breath tests. Microbiological counts of jejunal aspirates are the best method of confirming SIBO, but this approach is relatively invasive. Further study is required to determine the true prevalence and comorbidity of SIBO in CF adults.

It has become clear that CF individuals are at increased risk of cancer in epithelial organs with high levels of CFTR expression (gastrointestinal tract, pancreas, and hepatobiliary organs). This is in contrast to organs with low levels of CFTR expression, such as lungs, wherein despite the presence of chronic inflammation, there is no evidence to date of increased risk of malignancy. Sheldon et al. [26] reported a single-centre retrospective study suggesting that adenocarcinoma of the terminal ileum was associated with CF. Neglia et al. [27] attempted to quantify the risk of cancer in CF patients by sending a case-finding questionnaire to all North American and European CF centers, requesting details of all patients diagnosed with histologically proven cancer. By comparing the North American data with expected incidence rates in the general population, the incidence of gastrointestinal tract cancer was found to be 6.5 times higher than expected (95% confidence interval, 3.5–11.1). Analysis of the European data yielded very similar findings, with an odds ratio of 6.4 (95% confidence

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interval, 2.9–14.0), with significantly increased rates for cancer of the esophagus, small bowel, and large bowel. The risk of gastrointestinal tract cancer increased with age, with patients aged 20–29 years having an odds ratio of 20.2 (95% confidence interval, 6.1–67) [27]. Subsequently, Maisonneuve et al. [28] analyzed prospectively collected North American registry data and confirmed that gastrointestinal tract cancers are more common than expected in CF individuals, particularly affecting the small and large bowel and biliary tract. The evidence for increased risk of pancreatic cancer in CF individuals is discussed separately in the online supplement. Hepatocellular carcinoma and cholangiocarcinoma are also discussed in the online supplement. As would be expected, the risk of intra-abdominal cancer appears to be even more pronounced after lung transplantation. Nonresolving symptoms in CF adults, particularly recurrent or constant abdominal pain, weight loss, jaundice, rectal bleeding, bowel obstruction, or unexplained anemia, should be fully investigated to rule out gastrointestinal tract malignancy. As in the non-CF population, investigations including CT scanning, gastroscopy, and colonoscopy may be required to reach a diagnosis.

Acute and chronic pancreatitis

The CFTR protein is highly expressed in the pancreatic ductal epithelia and is vital in controlling ion and fluid secretion into the ductal lumen. In the majority of individuals with CF, absent or reduced CFTR function results in the production of a reduced volume of abnormally thickened ductal fluid [29]. This proteinaceous fluid is thought to precipitate in utero and result in pancreatic ductal obstruction, acinar cell damage, and almost complete destruction of the pancreas in the first few years of life. Overall, B65% of CF adults are PI and need to consume exogenous pancreatic enzymes in an effort to improve absorption of bowel contents. The remaining 35% have evidence of pancreatic damage but retain sufficient pancreatic exocrine to sustain normal digestion (PS). It should be noted that a much higher percentage of children with CF are PI (B85%), because of better survival among PS individuals diagnosed in childhood and a greater likelihood of PS among individuals with a de-novo diagnosis of CF in adulthood. Interestingly, non-CF individuals with ‘idiopathic’ pancreatitis carry a much higher frequency of mutations in the CFTR gene than the normal population, confirming the vital importance of normal CFTR function in pancreatic homeostasis [30]. Pancreatitis can indeed be the presenting symptom leading to a subsequent diagnosis of CF [31] and sweat testing together with CFTR mutation analysis should therefore be included in the diagnostic work-up of any individual with recurrent episodes of ‘idiopathic’ recurrent acute or chronic pancreatitis.

PS CF patients are particularly prone to pancreatitis, with 22% developing this complication in a recent wellconducted study [32]. PS individuals developing pancreatitis are more likely to carry mild CFTR mutations than moderate–severe CFTR mutations, with a hazard ratio of 2.4 on multivariate analysis [32]. There are case reports of PI patients developing pancreatitis, but this is extremely unlikely as all functioning exocrine pancreatic tissue is usually destroyed in infancy or early childhood. We suspect that a proportion of these cases can be explained by misinterpretation of the imaging and histological changes of the pancreatic damage in PI patients with CF, as these changes can look exactly the same as those caused by chronic pancreatitis in non-CF individuals. We would suggest that pancreatitis should only generally be considered as a potential cause of abdominal pain in PS individuals. This is complicated by the observation that PS individuals with a history of pancreatitis have an increased risk of becoming PI, due to progressive pancreatic damage [32]. PS individuals with a previous history of pancreatitis usually experience recurrent episodes of acute pancreatitis and some develop chronic pancreatitis [32]. Patients may present with typical symptoms, including severe central abdominal pain sometimes penetrating to the back and with central abdominal tenderness. Serum amylase is usually elevated, but may not be as high as in non-CF individuals due to the relative scarcity of functional pancreatic exocrine function even in PS individuals. CT may demonstrate evidence of peripancreatic inflammation with or without pseudocyst formation. CT scanning may identify underlying gallstones, although endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography may be required to definitively exclude biliary sludge or small retained stones. Treatment is generally the same as for any individual with pancreatitis; intravenous fluid resuscitation and analgesia and making the patient nil by mouth. In nonresolving or recurrent cases, the authors sometimes advocate ‘putting the pancreas to sleep’ by giving highdose proton pump inhibitor and uncoated pancreatic enzymes. This theoretically reduces the release of endogenous pancreatic enzymes and dampens down the cycle of pancreatic inflammation. Anecdotally this has been successful in some patients, although evidence is lacking to support this practice. Surgical intervention is rarely indicated acutely in CF adults with pancreatitis, although patients with extensive pancreatic necrosis and infection may require debridement if not settling. Cholecystectomy may be required in the presence of gallstone disease once active pancreatitis has settled.

Cholelithiasis

The association of cholelithiasis with CF was first reported in 1973 [33] and since then there have been

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several epidemiological reports suggesting an increased prevalence of symptomatic gallbladder disease in people with CF. In a single-centre retrospective study, Modelell et al. [34] reported a 12.4% prevalence of cholelithiasis in 89 patients, although it was not stated whether these patients were symptomatic. Using a similar study design, Stern et al. [35] reported that 3.6% of 670 CF patients developed symptomatic cholelithiasis, with the majority being adults at diagnosis. Analysis of Swedish CF registry data demonstrated a 3.2% prevalence of cholelithiasis and a 1.2% prevalence of cholecystitis, with both conditions being significantly more prevalent in CF individuals than in nonCF controls [36]. The CF Trust registry report for 2009 found that of 4065 CF adults in the UK, 30 had gallbladder disease requiring surgery, an incidence of 0.7% [37]. Cholestasis due to intrahepatic sludge and stones is a frequent finding in CF individuals and should not be confused with primary sclerosing cholangitis, to which there is a clinical and histological resemblance. The discrimination between these conditions is made more complex by the observation that certain CFTR variants are associated with lower risk of primary sclerosing cholangitis [38]. Several potential causes for the increased prevalence of cholelithiasis in CF have been proposed, including cholesterol supersaturation of abnormally viscid bile, biliary stasis, and swallowed mucin acting as a ‘nucleating factor’. Interestingly, this increased prevalence is observed despite the majority of CF individuals having a contracted nonfunctional gallbladder, which would intuitively suggest a reduced tendency to gallstone disease. Gallstones are typically radiolucent in CF individuals making them invisible on plain abdominal radiography, and magnetic resonance cholangiopancreatography is the imaging investigation of choice. Symptomatic cholelithiasis most commonly presents with biliary colic, but less common complications include choledocolithiasis causing obstructive jaundice, cholecystitis, and cholangitis [36]. The administration of ursodeoxycholic acid has been proposed as a means of dissolving cholesterol gallstones [39], but this treatment was subsequently shown to be ineffective [40]. This is likely because gallstones are not composed of cholesterol and instead are more commonly composed of calcium salts (including calcium bilirubinate) and proteins [41]. Endoscopic retrograde cholangiopancreatography has a useful role in the management of common bile duct stones. If required, open cholecystectomy is reported to be a safe procedure [35], although the laparoscopic procedure is preferable in patients with severe obstructive lung disease [42,43]. However, due to the multiple causes of abdominal pain in CF, patients may continue to remain symptomatic following cholecystectomy if an alternative diagnosis was in fact responsible for the patient’s symptoms [43]. Biliary sludge is a common finding on routine ultrasonography, but is usually asymptomatic.

Renal stones

There is an increased prevalence of nephrocalcinosis and urolithiasis in CF individuals compared with the general population. Symptomatic renal stones occur in 3.0–6.3% of patients with CF [44] compared with 1.0–2.1% of agematched non-CF controls [45]. However, the prevalence of asymptomatic nephrocalcinosis is likely to be much higher, as evidenced by a postmortem study demonstrating a 92.1% prevalence of microscopic nephrocalcinosis [46]. The prevalence of symptomatic renal stones increases with age, with the majority of cases being reported in adolescence and early adulthood. In addition, CF individuals who have diabetes may have an increased risk of symptomatic renal stones [47]. The exact mechanism of stone disease is unclear, although several potential explanations have been suggested. Stones are usually composed of calcium oxalate, and the finding of a high prevalence of hyperoxaluria in stone formers suggests that this is an important risk factor [48,49]. Hyperoxaluria in CF may be because of increased intestinal oxalate absorption due to fat malabsorption [50], as well as the absence of Oxalobacter formigenes, a normal enteric bacterium that assists in degrading oxalate [51]. Decreased levels of urinary citrate, relatively low urinary volumes, and more acidic urine may also promote stone formation [48,49]. Older reports suggest that the use of high-dose pancreatic enzymes increased the risk of uric acid stone formation [52], but this is unlikely to be relevant with the advent of modern enzyme formulations. Symptomatic renal stones present with the same symptoms as in non-CF individuals, with loin pain, back pain, and hematuria. The majority of renal stones in CF are radiopaque and therefore may be visible on plain radiograph, but CT or ultrasound may be required to identify small stones and assess for hydronephrosis. Stones may be passed without any intervention, but lithotripsy or ureteroscopy may be required [49].

Summary

Abdominal pain in CF adults often presents a diagnostic challenge due to the frequency of this symptom and the wide variety of potential underlying diagnoses. In this review we have discussed the presentation and management of the most common conditions presenting with abdominal pain. Table 1 divides the etiologies according to the anatomical location of the pain, although there are always exceptions to these general principles. Potential extra-abdominal pathologies causing abdominal pain in CF adults are included in Table 2, although this list is by no means exhaustive. In common with all good clinical practice, the assessment of abdominal pain in CF adults requires careful attention to the history and examination, judicious use of appropriate investigations and careful reassessment following a trial of therapy.

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Locations of different causes of abdominal pain in cystic fibrosis adults

Table 1

3 4

Locations Central/generalized

Right lower quadrant

Right upper quadrant

Left upper quadrant Lower quadrants Flank (loin)

Differential diagnosis DIOS Constipation Appendicitis/appendiceal abscess Intussusception Acute/chronic pancreatitis Gastrointestinal/pancreatic malignancy Inflammatory bowel disease Clostridium difficile colitis Gynecological Celiac disease Small intestinal bacterial overgrowth Fibrosing colonopathy DIOS Appendicitis/appendiceal abscess Intussusception Gynecological Cholelithiasis/cholecystitis/cholangitis Hepatocellular carcinoma Portal vein thrombosis Hepatic capsular stretch Splenic infarct/capsular stretch Constipation Gynecological Renal stones

DIOS, distal intestinal obstruction syndrome.

5

6 7

8

9 10

11

12

13

Potential extra-abdominal causes of abdominal pain in cystic fibrosis adults

Table 2

14 Gastrointestinal Irritable bowel syndrome Lactose intolerance Complications of previous surgery (e.g. adhesions) Pulmonary Pneumonia Pulmonary embolus Genitourinary tract Urinary tract infection Gynecological disorders Testicular torsion Miscellaneous Musculoskeletal pain Drug reactions (e.g. tigecycline) Henoch–Scho¨nlein purpura (HSP)

15

16 17 18

19

Acknowledgements

20

Edward F. Nash conceived of the review, cowrote, and performed the literature review; Chandra Ohri, Anne L. Stephenson, and Peter R. Durie cowrote the review.

21

22

Dr Nash was supported by the Scadding-Morriston Davies Joint Fellowship in Respiratory Medicine and the St John’s Ambulance Airwing Travelling Fellowship.

23

Conflicts of interest

24

There are no conflicts of interest. 25

References 1 2

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Abdominal pain in adults with cystic fibrosis.

Abdominal pain is a common symptom in individuals with cystic fibrosis (CF). As prognosis has improved, CF has changed from a pediatric disease to the...
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