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The adult cystic fibrosis patient with abdominal pain: what the radiologist needs to know
Clinical Radiology 66 (2011) 132e139
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad
Review
The adult cystic fibrosis patient with abdominal pain: what the radiologist needs to know S.Y. Liong a, D. Awad a, A.M. Jones b, c, S.A. Sukumar a, * a
Department of Radiology, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK Department of Respiratory Medicine, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK c Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK b
article in formation Article history: Received 17 March 2010 Received in revised form 6 September 2010 Accepted 13 September 2010
As the life expectancy of cystic fibrosis (CF) patients continues to increase, abdominal manifestations of CF are increasingly being encountered by clinicians and radiologists. Imaging plays an important role in the evaluation of adult CF patients with abdominal pain as a cause is often not discernable clinically. Accurate diagnosis is crucial in these patients as some causes may be managed conservatively, whilst others may require surgical intervention. In this review, we describe clinical presentation, imaging findings, and management of adult CF patients presenting with abdominal pain. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Cystic fibrosis (CF) is a common autosomal recessive disease affecting approximately 1 in 2400 live births in the UK.1 The disease is characterised by abnormal epithelial cell ion transport resulting in viscous secretions that may cause plugging. In the abdomen, CF can affect multiple organs including the liver, pancreas, and bowel.2 Over the past two decades, the pronounced improvement in the life expectancy of CF patients has largely been attributed to the centralisation of care at CF centres and aggressive treatment of symptoms.3 In 2008, the median predicted age of survival of patients on the US CF Patient Registry rose to 37.4 years, up from 32 in 2000.4 In the UK, it has been projected that a child born with CF in the past decade would typically be expected to live to be 50 years of age.1 In 2008, adults aged 16 and over accounted for 56.2% of 8513 patients with CF in the UK.5
* Guarantor and correspondent: S.A. Sukumar. Present address: Department of Clinical Radiology, University Hospital of South Manchester, Manchester, UK. E-mail address: [email protected] (S.A. Sukumar).
In keeping with improved survival rates, abdominal manifestations of CF are increasingly being encountered by clinicians. There is a wide spectrum of possible CF and nonCF-related causes for pain. The management of adult CF patients presenting with abdominal pain can be challenging for clinicians as a cause for pain is not often discernable clinically. In addition, the underlying diagnosis may be further masked by atypical clinical presentations in this group of patients. Our hospital is a major regional centre for CF with 333 adult CF patients on our database. In this pictorial essay, we will discuss the prevalence, presentation, and management of abdominal disease entities unique to CF; discuss the clinical presentation of general abdominal disease entities which are seen with increased or decreased incidence in patients with CF; and discuss the pattern and significance of bowel wall thickening seen on ultrasound and computed tomography (CT) in CF patients presenting with abdominal pain.
Imaging the adult CF patient with abdominal pain Plain radiography is often employed in the initial assessment of patients with acute abdominal pain. However, plain
0009-9260/$ e see front matter Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.09.002
S.Y. Liong et al. / Clinical Radiology 66 (2011) 132e139
radiography findings (e.g., dilated bowel loops) can be nonspecific and most patients will require further imaging assessment for detection and characterization of intraabdominal pathology. Ultrasound imaging has the advantage of being cheap, portable, and free from ionizing radiation. Its dynamic quality also enables assessment of bowel peristalsis and mobility in patients with suspected bowel pathology such as distal intestinal obstruction (DIOS), as discussed below. However, ultrasound imaging is heavily operator-dependent and satisfactory views can be subject to patient factors. Fluoroscopy has conventionally been employed in the assessment of bowel in non-CF patients. However, barium may precipitate obstruction in a cohort of patients with thickened intraluminal secretions and should be used with caution. Some CF patients may have empirically been given hypertonic oral contrast media to treat DIOS. It is important to take this into consideration when the patient is being considered for subsequent follow-through studies. However, fluoroscopy does have both diagnostic and therapeutic roles in patients with suspected intussusception as discussed below. Cross-sectional imaging techniques with CT or magnetic resonance imaging (MRI) can also be used in the assessment of these patients. CT, whilst being more readily available out of hours; entails a high dose of radiation in a group of relatively young patients and MRI has limited availability out of hours. At our institution, the CF patient presenting with acute abdominal pain is initially assessed with ultrasound, followed by CT if necessary. MRI is primarily used for hepatobiliary assessment (e.g., magnetic resonance cholangiopancreatography, MRCP) and for problem-solving.
Intussusception Intussusception is more common in CF patients than in the general population and is reportedly seen in 1% of children with CF.6 The incidence in the adult CF population
Figure 1 Axial CT image of a 22-year-old male CF patient who presented with severe abdominal pain depicted bowel-within-bowel configuration and eccentrically placed fat (white arrows) consistent with an ileocolic intussusception.
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has not been previously documented, but intestinal obstruction attributed to either intussusception or DIOS has been reported in 21% of adult CF patients in one series.7 Intraluminal inspissated mucus, undigested food, or enlarged lymphoid follicles can serve as lead points for intussusception. The triad of abdominal pain, vomiting, and bleeding per rectum may not be seen in adult patients.8,9 Sonographic and CT (Fig. 1) appearances of intussusception in CF patients are identical to that seen in the general population. An intussusceptum is seen to enter an intussuscipiens, trapping its mesentery between the layers of bowel wall. This bowel-within-bowel configuration, with or without eccentrically placed fat and mesenteric vessels is pathognomonic of intussusception.8,9 If diagnosis is delayed, there may be mesenteric vascular compromise resulting in further mural oedema of the involved segment.10 Traditionally, surgery has been the mainstay of treatment for intussusception. Air and contrast enemas are used for reduction in paediatric CF patients with intussusception.11,12 At our centre, in an effort to avoid surgery, radiological reduction with air enemas is attempted in selected cases of adult patients.
DIOS DIOS (meconium ileus equivalent in adults) has been reported to occur in 11e15% of adult CF patients and is thought to be caused by thickened intraluminal secretions in concert with undigested food secondary to impaired motility.13,14 Patients develop progressive symptoms of recurrent colicky abdominal pain, bloating, nausea and anorexia, and signs of small intestinal obstruction. As both intussusception and DIOS can cause acute abdominal pain with obstructive symptoms, accurate diagnosis is important as the former may require operative intervention; whilst DIOS
Figure 2 Sonographic image of a 30-year-old female CF patient with abdominal pain revealed dilated loops of small bowel. There were “swirling” echogenic contents, but no forward propulsion was seen. These features are in keeping with DIOS.
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Figure 3 Axial CT images in a 19-year-old female CF patient with leftsided abdominal and vomiting depicted dilated small bowel loops, oedema of the ileal walls with intraluminal small bowel faeces (white arrow). There was also ascites. This patient was managed conservatively.
is often managed non-surgically with laxatives, hydration, and hypertonic oral solutions.13,14 The dynamic nature of ultrasound makes it a useful imaging technique in the diagnosis of DIOS. Dilated loops of small bowel containing “swirling” echogenic intraluminal material, without propulsive peristalsis are seen; in keeping with obstruction (Fig. 2). In the absence of a soft-tissue mass (representing an intussusceptum) or previous surgery to account for adhesions; these features are diagnostic of DIOS. On CT, DIOS manifests as dilated small bowel loops containing intraluminal bubbly material (“small bowel faeces”, Fig. 3).
Clostridium difficile colitis Studies of adult and paediatric CF patients have reported C. difficile carriage rates of between 32e47%.15,16 Despite frequent use of antibiotics in CF patients, C. difficile colitis is an
uncommon complication.16,17 CF patients with C. difficile colitis can present as a diagnostic challenge because patients may present with constipation, absence of diarrhoea, and symptoms mimicking DIOS or instussusception.12 Patients are often managed conservatively with antibiotics. Computed tomography is used to determine the extent and severity of C. difficile colitis. CT findings include marked thickening of the mucosal and submucosal layers with a prominent haustral pattern that may result in an accordion appearance (“accordion sign”, Fig. 4a).18 Associated pericolonic stranding and ascites may also be present. Sonographically, C. difficile colitis manifests as bowel wall thickening with the oedematous mucosal and sub-mucosal layers seen together as a layer of intermediate echogenicity (Fig. 4b). The muscularis propria appears as an outer hypoechoic layer. Echogenic contents of the large bowel and the trapped intervening pseudo-membrane between the thickened haustra may result in an appearance equivalent to the “accordion sign” seen on CT.19 These appearances are not seen in DIOS, which may mimic C. difficile colitis clinically.
Bowel wall thickening and redundancy Bowel wall thickening on CT can be non-specific and secondary to local and systemic causes. The CF transmembrane regulator (CFTR), which is mutated in CF, is thought to modulate epithelial permeability, mucus production, and epithelial interactions with bacteria.20 This underlying physiological alteration may predispose patients with CF to bowel wall thickening. Fibrosing colonopathy is a disorder characterized histologically by submucosal fibrosis and clinically by abdominal pain. It has mainly been reported in children with CF on highstrength pancreatic-enzyme supplements.21,22 However, two cases in adult CF patients have been reported.23,24 Imaging plays a limited role, depicting non-specific colonic thickening24 and diagnosis is usually through histology.
Figure 4 Axial contrast-enhanced CT (a) image of a 38-year-old CF patient on prolonged antibiotics revealed marked mural oedema, and a prominent haustral pattern (“accordion sign”). A longitudinal sonographic image in the same patient showed the echogenic trapped intervening pseudomembrane and bowel contents (white arrow). This patient was managed conservatively with antibiotics.
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Figure 5 Axial CT (a) and sonographic (b) images of a 20-year-old female CF patient with abdominal pain showed thickened right colonic wall with overlapping inner folds (redundancy) giving a wrinkled morphological appearance. Colonic and ileal biopsies obtained at colonoscopy seven weeks later were normal. The symptoms settled with conservative management.
Figure 6 Axial CT images of the abdomen and pelvis of a 21-year-old patient with right iliac fossa pain depicted thickening and redundancy of the right colon (a, white arrow). The patient presented 1 year later with abdominal pain. Second CT (b,c) showed thickening of the right colon and pericolonic lymph nodes. Histology (d) obtained 1 month after the second CT demonstrated crypt abscesses (black arrows).
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during the 4e7 weeks interval between CT and colonoscopy. The symptoms of all five patients settled with conservative management. Based on experience at our centre and that of published literature, we now favour a conservative approach in our patients with non-specific bowel thickening; with colonoscopy reserved for patients with persisting or worsening abdominal symptoms. Colonic redundancy is an emerging term used to describe “wrinkled” morphological appearances of the proximal colon, attributed to overlapping thickened inner wall folds (Figs. 5 and 6).27,28 This finding has been observed in 39% of CF patients with or without abdominal pain and may mimic intussusception.28 The mean colonic wall thickness of the ascending colon in patients with colonic wall redundancy (4 mm) was greater than that in patients without redundancy (1.8 mm) or that in the control population (1.2 mm).28 The basis of the presumed association between Crohn’s disease and CF remains speculative with conflicting views on whether there is an increased incidence of Crohn’s in patients with CF.20,29 At our centre, we have not observed an increased prevalence of Crohn’s disease in our CF population. CT in one of our patients who had undergone previous appendicectomy and terminal ileum resection for complications following appendicitis showed thickening of the neo-caecum and pelvic small bowel loops with associated peri-enteric fibro-fatty proliferation and lymphadenopathy (Fig. 7). Based on these radiological features, a diagnosis of Crohn’s disease was considered, but subsequent colonoscopy and biopsies were normal.
Appendiceal disease
Figure 7 Axial (a) and reformatted coronal (b) CT images of a 24year-old male patient with a 4 month history of right iliac fossa pain. The patient had previously undergone resection of caecum and terminal ileum for complicated appendicitis. The images depicted thickening of the peri-anastomotic bowel segments (neo-caecum and neo-terminal ileum, black arrows) at the right iliac fossa. There was associated perienteric fibrofatty proliferation and clustering of reactive mesenteric lymph nodes measuring up to 1 cm (white arrow). Subsequent colonoscopy and biopsies were normal.
Although not a well-known abdominal manifestation of CF, colonic thickening with mesenteric fat proliferation has been reported in the literature.25,26 These changes predominantly affect the right colon (Figs. 5 and 6) with variable extension into the transverse or descending colon and have been attributed to chronic inflammation. Specimens obtained at subsequent colonoscopy have revealed normal mucosa, microcolitis, or non-specific inflammatory changes.25,26 Non-specific small and large bowel wall thickening was observed on CT in five patients who presented to our centre with abdominal pain. Subsequent colonoscopy performed in three of five patients revealed normal findings (two patients) and non-specific colonic inflammatory changes (one patient) (Fig. 6d). However, we acknowledge that colonic changes could have resolved
Appendiceal disease in CF patients represents a spectrum ranging from mucous distension to acute appendicitis with perforation and abscess formation.30 Appendicitis is relatively uncommon in CF patients, with reported incidence of 1e2% compared with an overall incidence of 7% in healthy subjects.30,31 The cause for this is uncertain, but it has been
Figure 8 Axial CT in a CF patient presenting with abdominal pain and vomiting. The appendix was thickened (white arrow) and contains echogenic intraluminal material. In addition, there was dilatation of a pelvic ileal loop containing faecalized small bowel contents (black arrow).
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Figure 11 Axial CT in a CF patient with upper abdominal pain and elevated amylase reveal subtle peripancreatic stranding. Note preserved pancreatic parenchyma in this patient. Figure 9 Magnetic resonance cholangiography in a CF patient with abdominal pain depicting a distal common bile duct stone with proximal ductal dilatation.
suggested that inspissated secretions render some protection against appendicitis.31 Acute appendicitis can be misdiagnosed as other intraabdominal conditions more commonly associated with CF, leading to delayed diagnosis and subsequent abscess formation. Therefore, although relatively uncommon in CF patients, acute appendicitis should always be considered as a cause for pain. Ultrasound or CT (Fig. 8) features of appendicitis are similar to those seen in the general population. However, it is important to look for other abdominal features of CF as a small percentage of CF patients remain undiagnosed until adulthood,4 and abdominal manifestations may present as the first clue to the diagnosis.
Figure 10 Axial CT through the upper abdomen in a CF patient depicting complete fatty replacement of the pancreas (white arrow).
Hepatobiliary manifestations Hepatobiliary manifestations of CF are common and include hepatic fatty infiltration, cirrhosis, microgallbladder, intra- and extrahepatic biliary duct dilatation.32,33 Patients with these hepatobiliary conditions are largely asymptomatic, but 20% of CF patients aged 16 years or over develop cholelithiasis, which can result in pain.34 Biliary calculi (Fig. 9) are most commonly composed of cholesterol and are thought to result from pancreatic insufficiency leading to production of thick lithogenic bile.32 In addition, splenic infarcts can be considered in the differential diagnosis of abdominal pain in CF patients with splenomegaly secondary to portal hypertension.
Figure 12 Axial CT image of CF patient with abdominal pain showing chronic calcific pancreatitis (white arrow) and a pseudocyst within the lesser sac (black arrow). Note the well-preserved pancreatic parenchyma in this CF patient.
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Although the overall incidence of malignancy among CF patients is not statistically significantly greater than expected in the general population, a greater than expected number of digestive tract cancers have been observed in CF cohorts compared with background age- and sex-specific cancer incidence rates.38,39 The increased risk of digestive tract cancer was primarily associated with the larger numbers of cancers detected in the small intestine, colon, liver, and pancreas. Increased numbers of cancers were not observed in the stomach or rectum. Finally, in CF patients following lung transplant, it is also important to consider lymphomas and post-transplant lymphoproliferative disorder (PTLD) as causes of abdominal pain.
Conclusion Figure 13 Axial CT in a CF patient depicting a stone in the left renal pelvis (black arrow), urothelial thickening and mild perinephric stranding (white arrows).
Pancreatitis Pancreatitis is an important differential diagnosis to consider in a CF patient presenting with abdominal pain. The reported incidence of pancreatitis in a series of 10071 patients with CF was 1.24%, with the first episode of pancreatitis occurring at the mean age of 19.9 years.35 In CF patients, inspissated secretions causing pancreatic duct obstruction may lead to acinar destruction and ultimately exocrine insufficiency. In up to 90% of CF patients, the pancreas is atrophic and undergoes fatty replacement (Fig. 10), rendering the patient “pancreatic insufficient”.32 Patients with preserved parenchyma (“pancreatic sufficient”) are believed to be more susceptible to pancreatitis (Figs. 11 and 12).34 Pancreatic cysts are relatively common in adult CF patients. These cysts vary in size (a few millimetres to several centimetres) and number. At the extreme end of the spectrum, clusters of true-epithelial lined cysts completely replace the pancreas (“pancreatic cystosis”) and may cause pain through mass effect.32,36
Nephrolithiasis There is an increased incidence of nephrolithiasis among CF patients, and it is, therefore, an important diagnostic consideration in CF patients presenting with abdominal pain. Nephrolithiasis (Fig. 13) has been reported to occur in 3e6.3% of CF patients in comparison to 1e2% of agematched control subjects.37
Other considerations In CF patients who have had previous abdominal surgery, it is important to consider adhesions as a cause for the abdominal pain.
There is a wide spectrum of CF-related abdominal manifestations that may cause abdominal pain. As clinical diagnosis is not often straightforward, imaging plays an important role in the management of adult CF patients presenting with abdominal pain. It is important for radiologists to be familiar with the imaging appearances of abdominal manifestations of CF as correct diagnosis is crucial for guiding appropriate management.
Acknowledgements The authors acknowledge Dr J. Crampton, Consultant Gastroenterologist, and Dr S. Pritchard, Consultant Pathologist, both at the University of South Manchester, for their input into this manuscript.
References 1. Dodge JA, Lewis PA, Stanton M, et al. Cystic fibrosis mortality and survival in the UK: 1947e2003. Eur Respir J 2007;29:552e6. 2. Turcios N. Cystic fibrosis: an overview. J Clin Gastroenterol 2005;39:307e17. 3. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet 2009;373:1891e904. 4. Cystic Fibrosis Foundation patient registry: annual data report 2008. Bethesda, USA: Cystic Fibrosis Foundation, http://www.cff.org/ UploadedFiles/research/ClinicalResearch/2008-Patient-Registry-Report. pdf; 2009 [accessed 04.07.10]. 5. Cystic Fibrosis database: annual data report 2004. London, UK: Cystic Fibrosis Trust, http://www.cystic-fibrosis.org.uk/pdfs/annualreport/ AuditReport2004.pdf; 2006 [accessed 04.07.10]. 6. Holsclaw DS, Rocmans C, Shwachman H. Intussusception in patients with cystic fibrosis. Pediatrics 1971;48:51e8. 7. di Sant’Agnese PA, Davis PB. Cystic fibrosis in adults. 75 cases and a review of 232 cases in the literature. Am J Med 1979;66:121e32. 8. Gayer G, Hertz M, Zissin R. CT findings of intussusception in adutls. Semin Ultrasound CT MR 2003;24:377e86. 9. Warshauer DM, Lee JKT. Adult intussusception detected at CT or MR imaging: clinicaleimaging correlation. Radiology 1999;212:853e60. 10. Park SB, Ha HK, Kim AY, et al. The diagnostic role of abdominal CT imaging findings in adults intussusception: focus on the vascular compromise. Eur J Radiol 2007;62:406e15. 11. Pomerantz B, Anupindi S, Wales P, et al. Radiographic reduction of intussusception in patients with cystic fibrosis. Pediatr Surg Int 2007;23:763e5. 12. Navarro O, Daneman A, Chae A. Intussusception: the use of delayed, repeated reduction attempts and the management of intussusceptions
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due to pathologic lead points in pediatric patients. AJR Am J Roentgenol 2004;182:1169e75. Morton JR, Ansari N, Glanville AR, et al. Distal intestinal obstruction syndrome (DIOS) in patients with cystic fibrosis after lung transplantation. J Gastrointest Surg 2009;13:1448e53. Speck K, Charles A. Distal intestinal obstructive syndrome in adults with cystic fibrosis: a surgical perspective. Arch Surg 2008;143:601e3. Peach SL, Borriello SP, Gaya H, et al. Asymptomatic carriage of Clostridium difficile in patients with cystic fibrosis. J Clin Pathol 1986;39:1013e8. Yahav J, Samra Z, Blau H, et al. Helicobacter pylori and Clostridium difficile in cystic fibrosis patients. Dig Dis Sci 2006;51:2274e9. Binkovitz LA, Allen E, Bloom D, et al. Atypical presentation of Clostridium difficile colitis in patients with cystic fibrosis. AJR Am J Roentgenol 1999;172:517e21. Ramachandran I, Sinha R, Rodgers P. Pseudomembranous colitis revisited: spectrum of imaging findings. Clin Radiol 2006;61:535e44. Razzaq R, Sukumar SA. Ultrasound diagnosis of clinically undetected Clostridium difficile toxin colitis. Clin Radiol 2006;61:446e52. Bresso F, Askling J, Astegiano M, et al. Potential role for the common cystic fibrosis ΔF508 mutation in Crohn’s disease. Inflamm Bowel Dis 2007;13:531e6. FitzSimmons SC, Burkhart GA, Borowitz D, et al. High-dose pancreaticenzyme supplements and fibrosing colonopathy in children with cystic fibrosis. N Engl J Med 1997;336:1283e9. Smyth RL. Fibrosing colonopathy in cystic fibrosis. Arch Dis Child 1996;74:464e8. €usler M, Meilicke R, Biesterfeld S, et al. First adult patient with Ha fibrosing colonopathy. Am J Gastroenterol 1998;93:1171e2. Mack EH, Brett AS, Brown D. Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. South Med J 2004;97:901e4. Chaun H. Colonic disorders in adult cystic fibrosis. Can J Gastroenterol 2001;15:586e90. Pickhardt PJ, Yagan N, Siegel MJ, et al. Cystic fibrosis: CT findings of colonic disease. Radiology 1998;725e730.
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27. Caruso S, Crino F, Maruzzelli L, et al. Imaging findings of colonic wall redundancy in cystic fibrosis patients: two case reports. Abdom Imaging published online ahead of print 21 Feb 2010; doi:10.1007/s00261-0109605-9. 28. Webb EM, Kleinhenz ME, Coakley FV, et al. Colonic wall redundancy at CT in patients with cystic fibrosis. Radiology 2008;248:869e75. 29. Lloyd-Still JD. Crohn’s disease and cystic fibrosis. Dig Dis Sci 1994;39:880e5. 30. Coughlin JP, Gauderer MW, Stern RC, et al. The spectrum of appendiceal disease in cystic fibrosis. J Pediatr Surg 1990;25:835e9. 31. McCarthy VP, Mischler EH, Hubbard VS, et al. Appendiceal abscess in cystic fibrosis. A diagnostic challenge. Gastroenterology 1984;86:564e8. 32. Agrons GA, Corse WR, Markowitz RI, et al. Gastrointestinal manifestations of cystic fibrosis: radiologicepathologic correlation. RadioGraphics 1996;16:871e93. 33. Robertson MB, Choe KA, Joseph PM. Review of the abdominal manifestations of cystic fibrosis in the adult patient. RadioGraphics 2006;26:679e90. 34. L’Heureux PR, Isenberg JN, Sharp HL, et al. Gallbladder disease in cystic fibrosis. AJR Am J Roentgenol 1977;128:953e6. 35. De Boeck K, Weren M, Proesmans M, et al. Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype. Pediatrics 2005;115:463e9. 36. Dewar AL, Connett GJ. Diffuse microcystic pancreatic enlargement in a cystic fibrosis patient causing severe gastrointestinal symptoms and successfully treated by total pancreatectomy. J Pediatr Gastroenterol Nutr 1998;26:454e7. 37. Gibney EM, Goldfard DS. The association of nephrolithiasis with cystic fibrosis. Am J Kidney Dis 2003;42:1e11. 38. Maisonneuve P, FitzSimmons SC, Neglia JP, et al. Cancer risk in nontransplanted and transplanted cystic fibrosis patients: a 10-year study. J Natl Cancer Inst 2003;95:381e7. 39. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med 1995;494e499.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad
Review
The adult cystic fibrosis patient with abdominal pain: what the radiologist needs to know S.Y. Liong a, D. Awad a, A.M. Jones b, c, S.A. Sukumar a, * a
Department of Radiology, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK Department of Respiratory Medicine, University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK c Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK b
article in formation Article history: Received 17 March 2010 Received in revised form 6 September 2010 Accepted 13 September 2010
As the life expectancy of cystic fibrosis (CF) patients continues to increase, abdominal manifestations of CF are increasingly being encountered by clinicians and radiologists. Imaging plays an important role in the evaluation of adult CF patients with abdominal pain as a cause is often not discernable clinically. Accurate diagnosis is crucial in these patients as some causes may be managed conservatively, whilst others may require surgical intervention. In this review, we describe clinical presentation, imaging findings, and management of adult CF patients presenting with abdominal pain. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Cystic fibrosis (CF) is a common autosomal recessive disease affecting approximately 1 in 2400 live births in the UK.1 The disease is characterised by abnormal epithelial cell ion transport resulting in viscous secretions that may cause plugging. In the abdomen, CF can affect multiple organs including the liver, pancreas, and bowel.2 Over the past two decades, the pronounced improvement in the life expectancy of CF patients has largely been attributed to the centralisation of care at CF centres and aggressive treatment of symptoms.3 In 2008, the median predicted age of survival of patients on the US CF Patient Registry rose to 37.4 years, up from 32 in 2000.4 In the UK, it has been projected that a child born with CF in the past decade would typically be expected to live to be 50 years of age.1 In 2008, adults aged 16 and over accounted for 56.2% of 8513 patients with CF in the UK.5
* Guarantor and correspondent: S.A. Sukumar. Present address: Department of Clinical Radiology, University Hospital of South Manchester, Manchester, UK. E-mail address: [email protected] (S.A. Sukumar).
In keeping with improved survival rates, abdominal manifestations of CF are increasingly being encountered by clinicians. There is a wide spectrum of possible CF and nonCF-related causes for pain. The management of adult CF patients presenting with abdominal pain can be challenging for clinicians as a cause for pain is not often discernable clinically. In addition, the underlying diagnosis may be further masked by atypical clinical presentations in this group of patients. Our hospital is a major regional centre for CF with 333 adult CF patients on our database. In this pictorial essay, we will discuss the prevalence, presentation, and management of abdominal disease entities unique to CF; discuss the clinical presentation of general abdominal disease entities which are seen with increased or decreased incidence in patients with CF; and discuss the pattern and significance of bowel wall thickening seen on ultrasound and computed tomography (CT) in CF patients presenting with abdominal pain.
Imaging the adult CF patient with abdominal pain Plain radiography is often employed in the initial assessment of patients with acute abdominal pain. However, plain
0009-9260/$ e see front matter Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.09.002
S.Y. Liong et al. / Clinical Radiology 66 (2011) 132e139
radiography findings (e.g., dilated bowel loops) can be nonspecific and most patients will require further imaging assessment for detection and characterization of intraabdominal pathology. Ultrasound imaging has the advantage of being cheap, portable, and free from ionizing radiation. Its dynamic quality also enables assessment of bowel peristalsis and mobility in patients with suspected bowel pathology such as distal intestinal obstruction (DIOS), as discussed below. However, ultrasound imaging is heavily operator-dependent and satisfactory views can be subject to patient factors. Fluoroscopy has conventionally been employed in the assessment of bowel in non-CF patients. However, barium may precipitate obstruction in a cohort of patients with thickened intraluminal secretions and should be used with caution. Some CF patients may have empirically been given hypertonic oral contrast media to treat DIOS. It is important to take this into consideration when the patient is being considered for subsequent follow-through studies. However, fluoroscopy does have both diagnostic and therapeutic roles in patients with suspected intussusception as discussed below. Cross-sectional imaging techniques with CT or magnetic resonance imaging (MRI) can also be used in the assessment of these patients. CT, whilst being more readily available out of hours; entails a high dose of radiation in a group of relatively young patients and MRI has limited availability out of hours. At our institution, the CF patient presenting with acute abdominal pain is initially assessed with ultrasound, followed by CT if necessary. MRI is primarily used for hepatobiliary assessment (e.g., magnetic resonance cholangiopancreatography, MRCP) and for problem-solving.
Intussusception Intussusception is more common in CF patients than in the general population and is reportedly seen in 1% of children with CF.6 The incidence in the adult CF population
Figure 1 Axial CT image of a 22-year-old male CF patient who presented with severe abdominal pain depicted bowel-within-bowel configuration and eccentrically placed fat (white arrows) consistent with an ileocolic intussusception.
133
has not been previously documented, but intestinal obstruction attributed to either intussusception or DIOS has been reported in 21% of adult CF patients in one series.7 Intraluminal inspissated mucus, undigested food, or enlarged lymphoid follicles can serve as lead points for intussusception. The triad of abdominal pain, vomiting, and bleeding per rectum may not be seen in adult patients.8,9 Sonographic and CT (Fig. 1) appearances of intussusception in CF patients are identical to that seen in the general population. An intussusceptum is seen to enter an intussuscipiens, trapping its mesentery between the layers of bowel wall. This bowel-within-bowel configuration, with or without eccentrically placed fat and mesenteric vessels is pathognomonic of intussusception.8,9 If diagnosis is delayed, there may be mesenteric vascular compromise resulting in further mural oedema of the involved segment.10 Traditionally, surgery has been the mainstay of treatment for intussusception. Air and contrast enemas are used for reduction in paediatric CF patients with intussusception.11,12 At our centre, in an effort to avoid surgery, radiological reduction with air enemas is attempted in selected cases of adult patients.
DIOS DIOS (meconium ileus equivalent in adults) has been reported to occur in 11e15% of adult CF patients and is thought to be caused by thickened intraluminal secretions in concert with undigested food secondary to impaired motility.13,14 Patients develop progressive symptoms of recurrent colicky abdominal pain, bloating, nausea and anorexia, and signs of small intestinal obstruction. As both intussusception and DIOS can cause acute abdominal pain with obstructive symptoms, accurate diagnosis is important as the former may require operative intervention; whilst DIOS
Figure 2 Sonographic image of a 30-year-old female CF patient with abdominal pain revealed dilated loops of small bowel. There were “swirling” echogenic contents, but no forward propulsion was seen. These features are in keeping with DIOS.
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Figure 3 Axial CT images in a 19-year-old female CF patient with leftsided abdominal and vomiting depicted dilated small bowel loops, oedema of the ileal walls with intraluminal small bowel faeces (white arrow). There was also ascites. This patient was managed conservatively.
is often managed non-surgically with laxatives, hydration, and hypertonic oral solutions.13,14 The dynamic nature of ultrasound makes it a useful imaging technique in the diagnosis of DIOS. Dilated loops of small bowel containing “swirling” echogenic intraluminal material, without propulsive peristalsis are seen; in keeping with obstruction (Fig. 2). In the absence of a soft-tissue mass (representing an intussusceptum) or previous surgery to account for adhesions; these features are diagnostic of DIOS. On CT, DIOS manifests as dilated small bowel loops containing intraluminal bubbly material (“small bowel faeces”, Fig. 3).
Clostridium difficile colitis Studies of adult and paediatric CF patients have reported C. difficile carriage rates of between 32e47%.15,16 Despite frequent use of antibiotics in CF patients, C. difficile colitis is an
uncommon complication.16,17 CF patients with C. difficile colitis can present as a diagnostic challenge because patients may present with constipation, absence of diarrhoea, and symptoms mimicking DIOS or instussusception.12 Patients are often managed conservatively with antibiotics. Computed tomography is used to determine the extent and severity of C. difficile colitis. CT findings include marked thickening of the mucosal and submucosal layers with a prominent haustral pattern that may result in an accordion appearance (“accordion sign”, Fig. 4a).18 Associated pericolonic stranding and ascites may also be present. Sonographically, C. difficile colitis manifests as bowel wall thickening with the oedematous mucosal and sub-mucosal layers seen together as a layer of intermediate echogenicity (Fig. 4b). The muscularis propria appears as an outer hypoechoic layer. Echogenic contents of the large bowel and the trapped intervening pseudo-membrane between the thickened haustra may result in an appearance equivalent to the “accordion sign” seen on CT.19 These appearances are not seen in DIOS, which may mimic C. difficile colitis clinically.
Bowel wall thickening and redundancy Bowel wall thickening on CT can be non-specific and secondary to local and systemic causes. The CF transmembrane regulator (CFTR), which is mutated in CF, is thought to modulate epithelial permeability, mucus production, and epithelial interactions with bacteria.20 This underlying physiological alteration may predispose patients with CF to bowel wall thickening. Fibrosing colonopathy is a disorder characterized histologically by submucosal fibrosis and clinically by abdominal pain. It has mainly been reported in children with CF on highstrength pancreatic-enzyme supplements.21,22 However, two cases in adult CF patients have been reported.23,24 Imaging plays a limited role, depicting non-specific colonic thickening24 and diagnosis is usually through histology.
Figure 4 Axial contrast-enhanced CT (a) image of a 38-year-old CF patient on prolonged antibiotics revealed marked mural oedema, and a prominent haustral pattern (“accordion sign”). A longitudinal sonographic image in the same patient showed the echogenic trapped intervening pseudomembrane and bowel contents (white arrow). This patient was managed conservatively with antibiotics.
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Figure 5 Axial CT (a) and sonographic (b) images of a 20-year-old female CF patient with abdominal pain showed thickened right colonic wall with overlapping inner folds (redundancy) giving a wrinkled morphological appearance. Colonic and ileal biopsies obtained at colonoscopy seven weeks later were normal. The symptoms settled with conservative management.
Figure 6 Axial CT images of the abdomen and pelvis of a 21-year-old patient with right iliac fossa pain depicted thickening and redundancy of the right colon (a, white arrow). The patient presented 1 year later with abdominal pain. Second CT (b,c) showed thickening of the right colon and pericolonic lymph nodes. Histology (d) obtained 1 month after the second CT demonstrated crypt abscesses (black arrows).
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during the 4e7 weeks interval between CT and colonoscopy. The symptoms of all five patients settled with conservative management. Based on experience at our centre and that of published literature, we now favour a conservative approach in our patients with non-specific bowel thickening; with colonoscopy reserved for patients with persisting or worsening abdominal symptoms. Colonic redundancy is an emerging term used to describe “wrinkled” morphological appearances of the proximal colon, attributed to overlapping thickened inner wall folds (Figs. 5 and 6).27,28 This finding has been observed in 39% of CF patients with or without abdominal pain and may mimic intussusception.28 The mean colonic wall thickness of the ascending colon in patients with colonic wall redundancy (4 mm) was greater than that in patients without redundancy (1.8 mm) or that in the control population (1.2 mm).28 The basis of the presumed association between Crohn’s disease and CF remains speculative with conflicting views on whether there is an increased incidence of Crohn’s in patients with CF.20,29 At our centre, we have not observed an increased prevalence of Crohn’s disease in our CF population. CT in one of our patients who had undergone previous appendicectomy and terminal ileum resection for complications following appendicitis showed thickening of the neo-caecum and pelvic small bowel loops with associated peri-enteric fibro-fatty proliferation and lymphadenopathy (Fig. 7). Based on these radiological features, a diagnosis of Crohn’s disease was considered, but subsequent colonoscopy and biopsies were normal.
Appendiceal disease
Figure 7 Axial (a) and reformatted coronal (b) CT images of a 24year-old male patient with a 4 month history of right iliac fossa pain. The patient had previously undergone resection of caecum and terminal ileum for complicated appendicitis. The images depicted thickening of the peri-anastomotic bowel segments (neo-caecum and neo-terminal ileum, black arrows) at the right iliac fossa. There was associated perienteric fibrofatty proliferation and clustering of reactive mesenteric lymph nodes measuring up to 1 cm (white arrow). Subsequent colonoscopy and biopsies were normal.
Although not a well-known abdominal manifestation of CF, colonic thickening with mesenteric fat proliferation has been reported in the literature.25,26 These changes predominantly affect the right colon (Figs. 5 and 6) with variable extension into the transverse or descending colon and have been attributed to chronic inflammation. Specimens obtained at subsequent colonoscopy have revealed normal mucosa, microcolitis, or non-specific inflammatory changes.25,26 Non-specific small and large bowel wall thickening was observed on CT in five patients who presented to our centre with abdominal pain. Subsequent colonoscopy performed in three of five patients revealed normal findings (two patients) and non-specific colonic inflammatory changes (one patient) (Fig. 6d). However, we acknowledge that colonic changes could have resolved
Appendiceal disease in CF patients represents a spectrum ranging from mucous distension to acute appendicitis with perforation and abscess formation.30 Appendicitis is relatively uncommon in CF patients, with reported incidence of 1e2% compared with an overall incidence of 7% in healthy subjects.30,31 The cause for this is uncertain, but it has been
Figure 8 Axial CT in a CF patient presenting with abdominal pain and vomiting. The appendix was thickened (white arrow) and contains echogenic intraluminal material. In addition, there was dilatation of a pelvic ileal loop containing faecalized small bowel contents (black arrow).
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Figure 11 Axial CT in a CF patient with upper abdominal pain and elevated amylase reveal subtle peripancreatic stranding. Note preserved pancreatic parenchyma in this patient. Figure 9 Magnetic resonance cholangiography in a CF patient with abdominal pain depicting a distal common bile duct stone with proximal ductal dilatation.
suggested that inspissated secretions render some protection against appendicitis.31 Acute appendicitis can be misdiagnosed as other intraabdominal conditions more commonly associated with CF, leading to delayed diagnosis and subsequent abscess formation. Therefore, although relatively uncommon in CF patients, acute appendicitis should always be considered as a cause for pain. Ultrasound or CT (Fig. 8) features of appendicitis are similar to those seen in the general population. However, it is important to look for other abdominal features of CF as a small percentage of CF patients remain undiagnosed until adulthood,4 and abdominal manifestations may present as the first clue to the diagnosis.
Figure 10 Axial CT through the upper abdomen in a CF patient depicting complete fatty replacement of the pancreas (white arrow).
Hepatobiliary manifestations Hepatobiliary manifestations of CF are common and include hepatic fatty infiltration, cirrhosis, microgallbladder, intra- and extrahepatic biliary duct dilatation.32,33 Patients with these hepatobiliary conditions are largely asymptomatic, but 20% of CF patients aged 16 years or over develop cholelithiasis, which can result in pain.34 Biliary calculi (Fig. 9) are most commonly composed of cholesterol and are thought to result from pancreatic insufficiency leading to production of thick lithogenic bile.32 In addition, splenic infarcts can be considered in the differential diagnosis of abdominal pain in CF patients with splenomegaly secondary to portal hypertension.
Figure 12 Axial CT image of CF patient with abdominal pain showing chronic calcific pancreatitis (white arrow) and a pseudocyst within the lesser sac (black arrow). Note the well-preserved pancreatic parenchyma in this CF patient.
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Although the overall incidence of malignancy among CF patients is not statistically significantly greater than expected in the general population, a greater than expected number of digestive tract cancers have been observed in CF cohorts compared with background age- and sex-specific cancer incidence rates.38,39 The increased risk of digestive tract cancer was primarily associated with the larger numbers of cancers detected in the small intestine, colon, liver, and pancreas. Increased numbers of cancers were not observed in the stomach or rectum. Finally, in CF patients following lung transplant, it is also important to consider lymphomas and post-transplant lymphoproliferative disorder (PTLD) as causes of abdominal pain.
Conclusion Figure 13 Axial CT in a CF patient depicting a stone in the left renal pelvis (black arrow), urothelial thickening and mild perinephric stranding (white arrows).
Pancreatitis Pancreatitis is an important differential diagnosis to consider in a CF patient presenting with abdominal pain. The reported incidence of pancreatitis in a series of 10071 patients with CF was 1.24%, with the first episode of pancreatitis occurring at the mean age of 19.9 years.35 In CF patients, inspissated secretions causing pancreatic duct obstruction may lead to acinar destruction and ultimately exocrine insufficiency. In up to 90% of CF patients, the pancreas is atrophic and undergoes fatty replacement (Fig. 10), rendering the patient “pancreatic insufficient”.32 Patients with preserved parenchyma (“pancreatic sufficient”) are believed to be more susceptible to pancreatitis (Figs. 11 and 12).34 Pancreatic cysts are relatively common in adult CF patients. These cysts vary in size (a few millimetres to several centimetres) and number. At the extreme end of the spectrum, clusters of true-epithelial lined cysts completely replace the pancreas (“pancreatic cystosis”) and may cause pain through mass effect.32,36
Nephrolithiasis There is an increased incidence of nephrolithiasis among CF patients, and it is, therefore, an important diagnostic consideration in CF patients presenting with abdominal pain. Nephrolithiasis (Fig. 13) has been reported to occur in 3e6.3% of CF patients in comparison to 1e2% of agematched control subjects.37
Other considerations In CF patients who have had previous abdominal surgery, it is important to consider adhesions as a cause for the abdominal pain.
There is a wide spectrum of CF-related abdominal manifestations that may cause abdominal pain. As clinical diagnosis is not often straightforward, imaging plays an important role in the management of adult CF patients presenting with abdominal pain. It is important for radiologists to be familiar with the imaging appearances of abdominal manifestations of CF as correct diagnosis is crucial for guiding appropriate management.
Acknowledgements The authors acknowledge Dr J. Crampton, Consultant Gastroenterologist, and Dr S. Pritchard, Consultant Pathologist, both at the University of South Manchester, for their input into this manuscript.
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