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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e318186d35a
Original Articles: Gastroenterology

Lymphocytic Leiomyositis and Myenteric Ganglionitis Are Intrinsic Features of Cystic Fibrosis: Studies in Distal Intestinal Obstruction Syndrome and Meconium Ileus

Smith, Virpi V*; Schäppi, Michela G; Bisset, W Michael; Kiparissi, Fevronia*; Jaffe, Adam§; Milla, Peter J*; Lindley, Keith J*

Free Access
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Author Information

*Departments of Gastroenterology and Histopathology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK

Department of Pediatrics, University Hospital of Geneva, Geneva, Switzerland

Department of Paediatrics, Royal Aberdeen Children's Hospital, Aberdeen, UK

§Department of Respiratory Medicine, Sydney Children's Hospital, Sydney, NSW, Australia

Received 2 January, 2008

Accepted 10 July, 2008

Address correspondence and reprint requests to Dr Keith J. Lindley, Gastroenterology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK (e-mail: k.lindley@ich.ucl.ac.uk).

The views expressed on this publication are those of the authors and not necessary those of the NHS Executive.

The authors report no conflicts of interest.

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Background: Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS).

Methods and Patients: Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied.

Results: Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF.

Conclusions: Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

Cystic fibrosis (CF) is a multisystem disorder that arises as a consequence of a qualitative or quantitative defect in the gene product of ABCC7—the cystic fibrosis transmembrane regulator (CFTR) protein (1,2). More than 1500 disease-associated mutations have been described to date (3). Cystic fibrosis transmembrane regulator protein is a chloride and bicarbonate channel, which also regulates or influences other facets of cell function in epithelial and nonepithelial tissues (4). Recent evidence suggests that CF-associated mutations are inherently proinflammatory (5–8) and that gastrointestinal inflammation may be an intrinsic feature of CF (9).

Meconium ileus (MI) and distal ileal obstruction syndrome (DIOS) are forms of subacute intestinal obstruction encountered either at birth (MI) or in later childhood (DIOS) in individuals with CF (10,11). Meconium ileus affects approximately 15% of infants with CF. Forty percent of affected infants have complicated MI in which the disease is accompanied by neonatal volvolus, perforation, or atresia (12,13), and overall 78% require neonatal surgical intervention. The cause of MI/DIOS has often been attributed to suboptimal intralumenal digestion/hydration leading to inspissation of luminal contents. Meconium ileus occurs in the absence of pancreatic insufficiency (14), although such individuals will have impaired bicarbonate secretion (15). Fibrosis and inflammation of the small and large intestine is described in CF (16,17). Leiomyositis and myenteric ganglionitis are the established causes of intestinal dysmotility (18–20), which, if present in CF, may exacerbate any tendency to subacute intestinal obstruction. We demonstrate here an association between transmural ileal inflammation and severe DIOS, which is histopathologically distinct from fibrosing colonopathy. We further document the presence of mild forms of such changes at birth in neonates with MI. These findings support the notion that transmural gastrointestinal inflammation is an intrinsic feature of CF, which is independent of pancreatic enzyme replacement therapy (PERT). The findings provide a rationale for anti-inflammatory treatment in children with refractory DIOS.

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We conducted a retrospective review of children with CF treated at Great Ormond Street Hospital between November 1995 and December 2001 who had either presented with MI requiring laparotomy and stoma formation or who had experienced severe or recurrent DIOS responding poorly to standard medical treatments (21). Six patients with DIOS were identified in whom full-thickness terminal ileal tissue had been obtained surgically and was available for further study. Seven patients with complicated MI who had undergone laparotomy at birth were identified, of which histological material was available in 6. Six infants with non-CF intestinal atresia were identified as controls.

Four micrometer-thick histological sections were re-cut and stained with haematoxylin and eosin (H&E). The inflammatory process was assessed and graded 0 (normal) to 4 (severe) in the mucosa, submucosa, muscularis propria, myenteric plexus, and serosa. The prominent inflammatory cell types were noted, and the presence of submucosal and subserosal fibrosis were recorded. Inflammatory infiltrates were characterized by immunohistochemistry using monoclonal antibodies against CD45ro (UCHL1, 1:200; Dako, Glostrup, Denmark) that react with primed or memory T cells, the anti-pan T cell marker CD3 (1:50; Novocastra, Newcastle, UK), the anti-helper/inducer T cell marker CD4 (1:50; Novocastra), and CD8, a marker for suppressor/cytotoxic T cells (1:100; Dako). The integrity of the muscularis and characterization of mesenchymal cell phenotype were assessed by immunostaining using monoclonal antibodies against α-smooth muscle actin (1:2000; Dako) (SMA), desmin (1:100; Dako) (D), and vimentin (1:40; Dako) (V). Fibroblasts were considered to be SMA− D− V+ and myofibroblasts SMA+ D+ V−. Immunostaining using a monoclonal anti-neurofilament antibody (1:120; Eurodiagnostics, Apeldoorn, the Netherlands) was used to assess the integrity of neural elements. In addition, a monoclonal HLA-DR antibody (1:2000; Dako) was used to look for upregulation of antigen presentation. Antigen retrieval was achieved by pressure cooking for 4 minutes in citrate buffer for all antigens except smooth muscle actin and vimentin. Visualization was achieved using extravidin-biotin peroxidase detection system. Negative controls were performed for each specimen by omitting the primary antibody and positive controls using tonsillar tissue and, wherever appropriate, normal gut tissues.

Sections were examined by light microscopy independently and blinded by an experienced paediatric histopathologist and a paediatric gastroenterologist. The morphological change and the degree of inflammation were assessed systematically as described above.

Histological scoring of CF and control tissues were compared using Fisher exact test.

Archival antroduodenal manometry data were available from an infant who had experienced neonatal MI studied using water-perfused catheters and a previously validated data acquisition and analysis system (18).

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Six patients, 3 males and 3 females, ages 2 months to 15 years, were included in the study. Patients were either homozygotes (patients 1 and 6) or compound heterozygotes for the ΔF508 mutation (patients 2, 3, 4, and 5) (Table 1). Pancreatic exocrine insufficiency was present in all and PERT was prescribed for all (lipase dose equivalent to 1000–20,000 IU · kg−1 · day). All had presented with symptoms/signs compatible with intestinal obstruction including abdominal pain and bilious vomiting. Plain abdominal radiograph demonstrated dilated proximal intestinal loops in 6 of 6. None had improved with conservative medical management (22).

Table 1
Table 1
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Three patients had an ill-defined ileal mass with a degree of ileal stricturing and underwent hemicolectomy (patients 1, 4, and 6); 3 had an ileostomy fashioned without intestinal resection. Full-thickness terminal ileal tissue was taken at the time of surgery in all cases. None had radiological or pathological evidence of colonic stricture.

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H&E Staining

Mucosal inflammation of differing intensity was present in all 6 cases (grades 1–3). Lymphocytes were the most prominent component, although neutrophils and eosinophils were also seen. Ulceration of the surface epithelium was present in 4 of 6 patients. An increase in intraepithelial lymphocytes (3/6) and intraepithelial neutrophils/eosinophils (5/6) was apparent. Cryptitis of varying degrees was present in all patients, and crypt abscesses were seen in 2 of 6. Cellularity of the submucosa, muscularis propria, myenteric plexus, and serosa was increased (Fig. 1A–D, Table 2).

Fig. 1
Fig. 1
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Table 2
Table 2
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The scores “0 or 1” in Table 2 reflect the patchy nature of these increases. Overt lymphocytic ganglionitis was present in 4 of 6 specimens (Fig. 2A and B). Mild submucosal fibrosis was present in 5 of 6.

Fig. 2
Fig. 2
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No data are available on patient 3 because of insufficient tissue within the tissue archive. Lymphocytes were seen in the myenteric plexus in 3 of 5. Numbers of myenteric neurons were not decreased in any of the samples and neurofilament staining was unremarkable in all sections. Chronic myositis of the muscularis propria, which was particularly obvious on immunostaining with UCLH1 was present in 5 of 5 (Fig. 2C).

HLA-DR staining was possible in 4 of 5 patients for whom adequate tissue was available. HLA-DR positivity was exhibited by surface epithelial cells and immunocytes in 4 of 4, by blood vessels within the submucosa and serosa in 3 of 4 and the muscularis propria in 4 of 4 (Fig. 2D). HLA-DR positive immunocytes were detected in the myenteric plexus in 3 of 4.

No abnormality was detected in smooth muscle actin and desmin immunostaining of the myocytes of the muscularis propria. Four out of five patients had evidence of myofibroblastic transformation of fibroblasts (positivity for both smooth muscle actin and desmin and negativity for vimentin) in the submucosa and serosa (Fig. 3A and B). In the submucosa, these cells appeared to be located luminal to the circular muscle. In patient 2, these were particularly prominent in the vicinity of the submucosal blood vessels. Data are summarized in Table 2.

Fig. 3
Fig. 3
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Antroduodenal Manometry

Antroduodenal manomerty was not performed routinely in any member of the cohort of children described in the present study. However, such data were available to us from our archive of motility studies performed in children investigated at Great Ormond Street Hospital (performed by W.M.B.). One such tracing (Fig. 4) of a 13-month-old child who had experienced MI and had recurrent episodes of subacute intestinal obstruction has been shown. The tracing demonstrates contractile activity of normal frequency but reduced amplitude phase III activity of shortened duration and abnormal patterns of propagation/failure of propagation consistent with a neuropathic disturbance (18). Specific abnormalities included bursts of propagated 12 cycles per minute activity with amplitude approximately 20 cmH2O but duration of typically approximately 30 seconds. At times the frequency of contractile activity during phase III suddenly halved raising the possibility of a deficiency in myoelectrical coupling in this individual as has been described in adults with myenteric ganglionitis.

Fig. 4
Fig. 4
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Meconium Ileus
Table 3
Table 3
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Of the neonates with complicated MI, 4 of 6 had a volvolus and 4 of 6 had antenatal intestinal perforation. Five of six carried the ΔF508 mutation on 1 or more alleles (Table 4). A 7-year-old patient (patient 5) had undergone a further intestinal resection following an intestinal volvolus. In this individual, ileum was studied from the second resection and the initial (MI) resection. Only “healthy” tissues most distant from the perforation/volvolus were scored histologically.

Table 4
Table 4
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H&E Staining

Mucosal inflammation extending into submucosal tissues was present universally in all CF resection specimens. Mucosal inflammation was present in 2 of 6 non-CF atresia specimens, extending mildly (grade 1/4) into the submucosa in 1 of 6. Transmural inflammation was present in 3 of 6, myenteric ganglionitis in 2 of 6 and submucosal fibrosis in 6 of 6 (Table 5). Submucosal inflammation and fibrosis, as seen in DIOS ilea, was a characteristic of MI tissues not seen in non-CF atresias.

Table 5
Table 5
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Myofibroblastic transformation of fibroblasts (positivity for both smooth muscle actin and desmin and negativity for vimentin) was again prominent in the submucosa of CF tissues (5/6 patients) and uncommon in non-CF tissues (1/6) (Fig. 3C and D). CD45ro positivity (UCHL1 antibody) within the submucosa was a feature of CF tissues (6/6 CF tissues vs weakly in 1/6 non-CF atresias) (Table 6). The combined finding of submucosal myofibroblast proliferation and submucosal DC45ro positivity was highly predictive of CF. These findings are similar to those seen in DIOS tissues.

Table 6
Table 6
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The features apparent in patient 5m at birth were still present at the age of 7 years when a second ileal resection was performed (Table 7). By this age, the transmural lymphocyte predominant imflammatory process apparent in individuals with DIOS and in 1 of 6 patients with MI at birth (patient 2m) was obviously apparent.

Table 7
Table 7
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DIOS is probably a multifactorial syndrome, which is the end result of a number of processes to which children with CF are predisposed. Although there has been a reduction in incidence since the introduction of more efficacious microsphere enzyme replacement therapies (23), it seems unlikely that it is simply due to inspissation of incompletely digested and hydrated intestinal luminal contents. In keeping with this is the observation that it occurs in both pancreatic-sufficient and pancreatic-insufficient individuals (14,24). MI is positively associated with the ΔF508 genotype and negatively associated with G551D (25). Both ΔF508 and G551D have similar net deleterious effects on CFTR-mediated chloride currents and in this respect are severe phenotypes. This discordance for MI suggests that factors other than chloride currents are important in the genesis of MI. Individuals with MI are at increased risk of developing DIOS in later life. The ΔF508 mutation activates NFκB, a proinflammatory nuclear transcription factor, to a greater extent than G551D, raising the possibility that DIOS is an inflammatory dysmotility syndrome (8).

Transmural ileal inflammation in individuals with CF has been recognized for a number of years (16,26). Myenteric ganglionitis and myositis are well-recognized causes of intestinal dysmotility and delayed intestinal transit in the absence of intestinal luminal stricture or distortion (18–20,27,28). We have demonstrated a lymphocyte predominant inflammatory process extending the full thickness of the bowel wall in 6 of 6 individuals with DIOS with evidence of lymphocytes myenteric ganglionitis in 4 of 6 patients. In contrast to lymphocytic ganglionitis with anti-neuronal antibodies (20), numbers of myenteric neurons are preserved in CF. Where ganglionitis is present in CF, it is part of a transmural CD45ro lymphocyte predominant inflammatory infiltrate. Similar, although less pronounced, findings are apparent at birth in infants with complicated MI, but not in non-CF atresias. GI motility is known to be altered adversely in individuals with CF (29), and it is not unreasonable to suppose that the transmural inflammatory process present from birth in individuals with CF may contribute to this and constitute an additional risk factor for the development of DIOS in later life.

Prominent myofibroblastic transformation in the submucosa seen in individuals with both DIOS and MI supports an inflammatory origin of the fibrotic reaction that is seen more prominently in children with DIOS. Precise definition of an activated or fibrogenic phenotype of intestinal mesenchymal cell may be difficult. We have used dual positivity for desmin (D) and α-smooth muscle actin (SMA) together with negativity for vimentin (V) as a marker for myofibroblasts (MF) (30–32). In normal intestine MF and fibroblasts in submucosa, serosa, and intermuscular connective tissue are the primary sites of collagen synthesis (31,33). V+/SMA−/D+ fibroblasts and V−/SMA+/D+ myofibroblasts are the major sites of collagen type 1 synthesis in Crohn disease (31). The myofibroblastic transformation and proliferation of mesenchymal cells in the submucosa of patients with CF is in keeping with the contemporary view that some types of chronic intestinal inflammation are able to cause muscularis overgrowth and a change in enteric smooth muscle phenotype towards a collagen-producing myofibroblast phenotype (31,32). Procollagen genes can be induced by fibrogenic cytokines such as transforming growth factor-β (TGF-β) (32). Abnormalities in the innate immune response, which are a consistent characteristic of CF epithelia (34,35), may also provide an inherently profibrogenic influence (36,37). Interstitial cells of Cajal (ICC), a myofibroblast related intestinal cell subtype which is important in the regulation of gastrointestinal motor activity, are capable of dedifferentiation into a collagen-producing fibroblast or myofibroblast phenotype in chronic transmural intestinal inflammatory conditions (30,38). In addition to promoting fibrosis, the fibroblastic transformation of ICC would be expected to adversely affect gastrointestinal motility.

That fibrosis may be an intrinsic feature of CF rather than a secondary event is illustrated by the observation that ileal fibrosis can be present at birth in infants with severe CF genotypes (39). Colonic fibrosis is recognized in CF within the context of the so-called fibrosing colonopathy (40). Pathological descriptions of fibrosing colonopathy allude to the finding (in the colon) of severe fibrosis of the submucosa, muscularis propria, and lamina propria, which is out of proportion to the mild degree of mucosal inflammation (41). Ileal involvement was either inconspicuous or absent in earlier descriptions of fibrosing colonopathy (40,42–45), although a more contemporary publication alludes to ileal involvement with fibrosis of the mucosa, submucosa, and muscularis propria, and infiltration of the mucosa with eosinophils, although not with lymphocytes (41). Our ileal histopathological findings are different from those described in association with fibrosing colonopathy. Theories concerning the genesis of fibrosing colonopathy, in particular whether it is related to the formulation or dose of pancreatic exocrine supplement, have been the subject of substantial, sometimes acrimonious, debate (17,46–52). Although the numbers of case reports of fibrosing colonopathy (53) have fallen since the introduction of guidelines that total daily dose of lipase should equate to <10,000 IU lipase per kilogram of body weight per day (54), our data and that of others (55) support the notion that intestinal fibrosis in CF need not necessarily be iatrogenic. The thickened bowel visible on abdominal ultrasound in individuals with CF (56,57) is also independent of both dose and formulation of enzyme replacement administered (58) and seems likely to represent a further manifestation of a chronic transmural inflammatory process. The observation of echogenic bowel in infants with CF in utero (57,59) and our findings of myofibroblastic proliferation in infants with CF at birth support the notion that this is an inherent feature of CF.

These observations support the hypothesis that intestinal fibrosis in CF is unrelated to PERT. They also provide an as yet unproven rationale for anti-inflammatory treatment(s) in individuals with early-onset CF-associated motility disturbances and anti-fibrotic therapies to alter the natural history of DIOS. We believe that our observations make a strong case for routine and early ileal mucosal and laparoscopic seromuscular ileal biopsy (60) in individuals with severe and recurrent DIOS. Specific anti-inflammatory treatments and/or antifibrotic therapies may become justifiable when further data become available about both the prevalence of these changes and also the efficacy of early anti-inflammatory therapies. This approach seems more appropriate than what is essentially symptomatic treatment with bowel cleansing agents, mucolytics, and increased doses of pancreatic enzymes (21,24,61,62). It seems likely that the potential association of intestinal colonic fibrosis with dose, duration, and brand of pancreatic enzyme administered has detracted the physician's focus of attention from an underlying gastrointestinal inflammatory process that is inherent to CF (17).

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Transmural ileal inflammation, including lymphocytic myositis and ganglionitis, is a consistent finding in individuals with CF and symptomatic small intestinal obstruction and could lead to fibrosis through myofibroblastic transformation of connective tissue cells. These abnormalities appear to be intrinsic to CF because they are present before PERT, but progress with the passage of time. Further prospective studies of the prevalence of these changes and of the efficacy of early intervention appear warranted.

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Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from R&D funding received from the NHS Executive.

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Cystic fibrosis; Distal ileal obstruction syndrome; Ganglionitis; Inflammation; Meconium ileus

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