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Full-thickness biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility
  1. G Lindberg1,
  2. H Törnblom1,
  3. M Iwarzon1,
  4. B Nyberg2,
  5. J E Martin3,
  6. B Veress4
  1. 1
    Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  2. 2
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
  3. 3
    Institute of Cellular & Molecular Sciene, Barts and the London, Queen Mary’s School of Medicine & Dentistry, Whitechapel, London, UK
  4. 4
    University of Lund, Department of Pathology at University Hospital MAS, Malmö, Sweden
  1. Dr G Lindberg, Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden; greger.lindberg{at}ki.se

Abstract

Background and Aims: Small bowel manometry is increasingly used in the clinical investigation of patients with symptoms of intestinal motor dysfunction. Enteric dysmotility (ED) has been suggested as a new diagnostic term for patients with abnormal intestinal motor activity but no radiological signs of chronic intestinal pseudo-obstruction (CIP). Histopathological features of adult patients with ED and CIP have been compared in a large case series to study differences and similarities between the two diagnostic groups.

Methods: Routine staining and an extensive panel of immunohistochemical stains on transversal and tangential cuts from full-thickness biopsies of the small bowel were used.

Results: 39 females and 11 males with CIP and 58 females and 7 males with ED were investigated. The underlying lesion was more often a visceral myopathy (22% vs 5%) or neuromyopathy (30% vs 12%) in patients with CIP than in those with ED, whereas the predominant lesion in ED was neuropathy with inflammation.

Conclusion: CIP in adults is associated with very different underlying pathology, whereas ED is more homogeneously associated with neuropathy in the enteric nervous system. Neuropathy of enteric ganglia with inflammation seems to be the most common cause for measurable disturbances of intestinal motor function.

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Chronic intestinal pseudo-obstruction (CIP) is a descriptive term for disorders that affect gastrointestinal motor activity and produce symptoms and signs resembling those of a mechanical obstruction.1 Normally, coordinated peristaltic contractions of the stomach and the intestines transport ingested food along the gut. In CIP the coordination of such muscular contractions or their force has been partially or completely lost. Previously, the diagnosis of CIP rested upon symptoms, radiological findings of dilated bowel, and exploratory laparotomy to rule out a mechanical obstruction.2 With the advent of intestinal manometry it became possible to study the contractile activity of the gut over long periods of time. Several studies showed that patients with CIP had abnormal contractile activity in the gut.37 However, the increased use of antroduodenal and small bowel manometry in clinical investigations has led to more patients with intestinal motor abnormalities being detected, possibly also at an earlier stage of disease. A new diagnostic group “enteric dysmotility” (ED) was recently put forward to encompass patients with abnormal intestinal motor activity but no signs of obstruction.8 It is conceivable that such a group should exist between on one hand the functional bowel disorders, which do not exhibit any specific intestinal motor abnormalities,912 and on the other the end-stage motility disorder CIP. So far, ED has been a theoretical construct. Little is known about its clinical features and the underlying pathology has not been described. We have therefore analysed our case series of patients with severe motility disorders with the specific aim of defining the underlying pathology in patients with CIP and ED.

METHODS

We studied 115 consecutive adult patients who were diagnosed with CIP (n = 50) or ED (n = 65) and in whom full-thickness bowel biopsy material was available. Patients were collected during a 16 year period from 1987 to 2002 at Karolinska University Hospital, Huddinge. Patients with systemic diseases (neurological, endocrine and systemic inflammatory diseases) were seldom subjected to full-thickness biopsy. However, 7 patients had or were later shown to have systemic disorders with a probable relationship to CIP or ED. One patient had a previous diagnosis of morphea, one had mixed connective tissue disorder, one had Sjögren’s syndrome and hypothyroidism, two patients were later diagnosed with mitochondrial dysfunction, and one patient was later diagnosed with lung cancer. In order to receive a diagnosis of CIP, patients had to fulfil three criteria: a medical history compatible with pseudo-obstruction; documented events or chronic signs mimicking mechanical obstruction (bowel dilation and/or air/fluid levels); and absence of mechanical obstruction or other organic cause for symptoms and findings. All patients underwent radiological and/or endoscopic investigations of the entire gastrointestinal tract to rule out mechanical obstruction. The criteria for ED were gastrointestinal symptoms (nausea, vomiting, pain, distension, diarrhoea or constipation) that were severe enough to warrant referral for small bowel manometry, presence of abnormal motor patterns on small bowel manometry, absence of mechanical obstruction and absence of any medication that could lead to observed motor abnormalities. The study was approved by the Ethics Committee of Karolinska University Hospital, Huddinge.

Manometry

The motor activity of the small bowel was studied in 47/50 patients with CIP and all 65 patients with ED. Three patients with CIP could not tolerate intubation. Ambulatory long-term (12–24 h) manometry using 2–6 electronic sensors was done in 55 patients (28 with CIP) and stationary 5 h manometry using 6–8 water-perfused channels was done in 57 patients (19 with CIP).

Manometry recordings were evaluated visually with respect to the presence or absence of normal and abnormal features by two observers (GL and HT). A normal recording had to show fasting motor activity with at least one propagated activity front (phase III of the migrating motor complex) during 24 h and a fed pattern after each meal. We classified recordings as abnormal if no migrating motor complex was present during 24 h or during 12 h following a single meal, if two or more of the four criteria described by Stanghellini et al4 were present, or if the manometry showed pronounced hypomotility—that is, no contractions at all or only low-amplitude (<20 mm Hg) contractions. None of the criteria for abnormal small bowel motility was observed in previous studies from our centre on normal individuals.1315

Full-thickness biopsy of the small bowel

Previously resected small bowel (duodenum = 3, jejunum = 3, ileum = 7) was available for histopathological re-investigation in 13 patients (9 with CIP). Open operative bowel biopsies (jejunum = 16, ileum = 8, colon = 1) were taken in 25 patients (15 with CIP) in connection with a negative exploratory laparotomy (n = 7), adhesiolysis (n = 4), small bowel resection (n = 6), colectomy (n = 5), gastric resection (n = 1), sigmoid resection (n = 1) or ileostomy revision (n = 1). We used a previously described laparoscopy-assisted technique for taking full-thickness biopsies of the jejunum in the remaining 77 patients.16

Histological techniques

The full-thickness intestinal biopsy was pinned on a cork plate and fixed in 4% buffered formalin for 24 h. Following fixation, the specimen was divided into three parts: one part was conventionally sliced and embedded in paraffin for evaluation of all layers of the intestinal wall (transverse sections). From the tissue blocks, 4 μm thick sections were cut at three different levels containing three serial sections at each level. A small part of the biopsy was embedded for electron microscopy. The largest possible quadrangular piece was cut out from the remaining part of the biopsy and embedded with the serosal surface facing downwards in the embedding chamber for tangential sections. This paraffin block was serially sectioned in order to obtain for study large confluent areas of the nerve tissue of the myenteric plexus. Staining techniques are detailed in table 1. All biopsies were investigated by the same pathologist (BV), who was blinded for the underlying clinical diagnosis. The majority of biopsies (70/115) were reviewed by a second pathologist (JM). The agreement between pathologists regarding the histopathological diagnosis was 96%.

Table 1 Staining techniques and their use in the analysis of full-thickness bowel biopsies

Criteria for abnormal histopathology

Degenerative neuropathy can be seen either as swollen degeneration or as shrunken degeneration, accompanied by chromatolysis and sometimes karyolysis. Both types can occur with or without vacuolisation of the cytoplasm. Intranuclear inclusions may appear as large, rounded, deeply eosinophilic bodies surrounded by a halo. An increase of glial cells often occurs around the degenerating neurons. Apoptotic bodies are rarely present. Axons may show thickening and vacuolisation. In swollen degeneration, immunohistology shows diminished or absent staining for neuron-specific enolase (NSE)/protein gene product 9.5 (PGP 9.5)/bcl-2 whereas staining for neurofilament and substance P can be strongly increased. In shrunken neurons, NSE, PGP 9.5 and neurofilament usually show increased staining. The synaptophysin-positive layer around the plasma membrane is disorganised or absent in the degenerating neurons.

Inflammatory neuropathy shows the above features of degeneration together with infiltration of lymphocytes in and around ganglia or along small nerves. We counted the number of CD3-positive lymphocytes that were present within 50 μm of the border of at least 20 myenteric ganglions. Periganglional lymphocytes in vascular channels were not counted. Control values were determined from 15 deceased patients with no known history of bowel symptoms. The mean (SD) number of lymphocytes per ganglion in the control material was 0.17(0.63) and the upper normal limit was set at mean+3SD as 2.0 lymphocytes per ganglion. No lymphocytes were observed within the ganglia in the control material. The presence of an increased number of intraepithelial lymphocytes was assessed as described previously.16

The criteria for neuronal intestinal dysplasia were: presence of large submucosal ganglia containing >11 neurons/ganglion; presence of “displaced” neurons within the lamina propria and within the musculoaris mucosae; and increased numbers of mucosal nerve fibres as shown by immunohistochemistry.17 18

Degenerative myopathy is characterised by swelling of myocytes with vacuolisation of the cytoplasm or by the presence of homogeneous, eosinophilic inclusions, or by very faintly stained, pale cytoplasm of the muscle cell, in the absence of fixation or cautery artefact. The nucleus of a degenerating myocyte may appear pyknotic. Sometimes groups of myocytes are atrophic, often with fibrosis. The distribution of the contractile filaments is disturbed or there is no immunoreactivity in the degenerated myocytes.

α-Actin deficiency is characterised by the absence of staining with antibodies against smooth muscle-specific α-actin in the jejunum.19 20 Deficient staining for α-actin occurs only in the outer part of the circular muscle layer, whereas the thin inner part of the circular muscle layer and the whole longitudinal muscle layer are spared. Other intermediate filaments stain normally.

Abnormal architecture is seen either as a patchy absence of one of the muscle layers without signs of degeneration or by the presence of a third muscle layer which can be either circular or longitudinal.

Inflammatory myopathy is characterised by signs of muscle degeneration together with infiltration of inflammatory cells in the muscle layers.

Interstitial cells of Cajal (ICC) were assessed using morphometry on CD117-stained sections from both transversal and tangential cuts by comparison with sections from control small bowel (10 cases of small bowel resection due to tumour). Only the numbers of ICC nuclei were recorded either within the intermyenteric/periganglional plexus (ICC-AP) or within the whole circular muscle (ICC-CM). Control values were 11–22 ICC nuclei per 1 mm length of myenteric plexus and 5–16 ICC nuclei per mm2 of circular muscle.

Statistical methods

Normally distributed data were expressed as the mean (SD). Non-normal data were expressed as median and full range. Nominal data were compared using Fisher’s exact test or the χ2 test, whereas parametric data were compared using Student t test or the Mann–Whitney U test whenever appropriate. p Values <0.05 were considered statistically significant.

RESULTS

CIP was diagnosed in 39 females and 11 males with a median age of 39 (range 23–69) years whereas 58 females and 7 males with a median age of 39 (17–71) years fulfilled our criteria for ED. The total number of patients that underwent small bowel manometry as part of their examination for the suspicion of an intestinal motility disorder at our unit during the study period was 507. We excluded from this report 29 patients (19 with systemic diseases) who had abnormal manometry but no biopsy.

At the time of diagnosis, dilated small bowel was present in 15 patients with CIP, 1 had dilatation of the colon and 3 had dilatation of both the colon and the small bowel. The remaining 31 patients with CIP presented with subocclusive events with air/fluid levels on plain abdominal x ray and no evidence of obstruction at barium meal follow-through or exploratory laparotomy. Seven patients who had normal calibre bowel between subocclusive events had dilated bowel during such events. All patients with ED had normal calibre bowel and no documented event with air/fluid levels or dilatation. The median duration of symptoms before diagnosis was 11.1 (0.3–39.3) years in patients with CIP and 4.7 (0.3–65.6) years in patients with ED (p = 0.15).

Histopathological findings

Muscle pathology was diagnosed in 11/50 patients (22%) with CIP and 3/65 patients (5%) with ED, visceral neuropathy in 24 patients (48%) with CIP and 54 patients (83%) with ED, and 15 patients (30%) with CIP and 8 patients (12%) with ED had a combined visceral neuropathy and myopathy (table 2). The difference between CIP and ED in the distribution of histopathological diagnoses was statistically significant (p<0.001).

Table 2 Histopathological findings in full-thickness biopsies from the small bowel in 50 patients with chronic intestinal pseudo-obstruction (CIP) and 65 patients with enteric dysmotility (ED)

Abnormal architecture of the muscle layers with an additional muscle layer (fig 1A) was found in 2 patients with CIP. Vacuolar degeneration and fibrosis mainly in the longitudinal layer, as described for hollow visceral myopathy,21 was found in 11 patients, 3 had inclusion bodies (fig 1B), and 10/11 patients with longitudinal muscle degeneration had CIP. Fifteen patients had other types of muscle degeneration mainly in the inner circular muscle layer or in both layers.

Figure 1

(A) Abnormal architecture of tunica muscularis. Three distinct layers of tunica muscularis of the small intestine. The innermost and outer layers are composed of longitudinally oriented myocytes. The thickest middle layer is circular. Muscularis mucosa is also hypertrophic, thickened. M = mucosa. Actin immunoperoxidase, ×100. (B) Hollow visceral myopathy with inclusions. Inner part of the circular muscle layer. There are red, homogeneous inclusions in some of the myocytes (arrows). The cytoplasm of the smooth muscle cells in the centre of the muscle bundle is pale, in contrast to the normally stained myocytes at the periphery. Masson trichrome, ×480. (C) Degenerative neuropathy, myenteric plexus. Extensive vacuolisation of most of the neurons. H&E, ×480 (tangential section). (D) Lymphocytic ganglionitis, myenteric plexus. Dense lymphocytic infiltrate around and within the myenteric ganglion (arrowheads). Lymphocytes can also be observed along the small peripheral nerve fibres within the longitudinal muscle layer (arrows). H&E, ×180. (E) Low-grade lymphocyte infiltration of the myenteric plexus. Black arrows indicate neurons and white arrows indicate T lymphocytes. CD3 immunoperoxidase, ×320. (F) Large number of interstitial cells of Cajal in the intermyenteric/periganglionar plexus. All the Cajal cells are enlarged and instead of cellular projections the plasma membrane is flattened. CD117-immunohistochemistry, ×180.

One patient with CIP had severe loss of muscle cells in muscularis propria due to leiomyositis in combination with inflammatory neuropathy. He was a 37-year-old male who 5 years earlier had been diagnosed with morphea, a localised form of scleroderma and eosinophilic fasciitits, and who presented with gross dilatation of the entire small bowel. One patient with ED, a 55-year-old female who also suffered from Sjögren’s syndrome and hypothyroidism, had intestinal leiomyositis with patchy lymphocytic infiltration of the circular muscle layer in combination with lymphocytic infiltration of the myenteric plexus.

Visceral neuropathy was found in 78% of patients with CIP and 95% of those with ED (p<0.01). Degenerative neuropathy (fig 1C) was found in 21 patients with CIP and 13 patients with ED. Degenerative changes were confined to the myenteric plexus in 19 patients (11 with CIP) whereas 15 patients (12 with CIP) had degeneration of neurons in both the submucous and the myenteric plexus. One patient with CIP had pronounced degeneration of axons together with degeneration of neurons in the two plexuses.

Inflammatory neuropathy—that is, neuron degeneration associated with infiltration of lymphocytes in the ganglia of the myenteric plexus—was found in 17 patients with CIP and 48 patients with ED. In 10 patients with CIP and 43 patients with ED, neuropathy and inflammation were confined to the myenteric plexus, but in 7 patients with CIP and 5 patients with ED inflammation and neuropathy also involved the submucous plexus. Two patients with CIP and 15 patients with ED also exhibited inflammation along axons with axonopathy. Dense infiltration of lymphocytes in ganglia of the myenteric plexus (fig 1D) was found in 6 patients with CIP and 1 patient with ED, whereas 12 patients with CIP and 47 patients with ED had less pronounced infiltration of lymphocytes in the myenteric plexus (fig 1E). The mean number of lymphocytes per ganglion was 5.1 (3.3) in the 59 patients with low-grade ganglionitis. Microfoci with >10 lymphocytes were seen in 2 patients with CIP and in 12 patients with ED who had low-grade inflammatory neuropathy. The distribution of lymphocyte counts among our patients with inflammatory neuropathy and those with neuropathy without inflammation is shown in fig 2. A concomitant increase of intraepithelial lymphocytes was noted in 4/17 (24%) patients with CIP and 14/48 (29%) patients with ED.

Figure 2

Distribution of lymphocyte counts among 36 patients with visceral neuropathy without inflammation (white bars) and 65 patients with lymphocytic ganglionitis (grey bars).

Seven patients with inflammatory neuropathy and one patient with degenerative neuropathy also showed an increase of mast cells in the submucosa and muscularis propria (n = 5), around ganglia (n = 1) or along nerve fibres (n = 4).

The ICC were studied in 60 patients (CIP = 16; ED = 44). Decreased numbers of ICC were noted in 11/39 patients (28%) with inflammatory neuropathy (2/5 with CIP), 3/15 patients (20%) with degenerative neuropathy (2/7 with CIP) and in 2/6 patients (33%) with myopathy. Increased numbers of ICC or hypertrophy of ICC was found in 22/39 patients (56%) with inflammatory neuropathy (3/5 of those with CIP), 7/15 patients (47%) with degenerative neuropathy (2/7 with CIP) and in 4/6 patients (67%) with myopathy (4/4 with CIP). One patient with CIP and degenerative neuropathy had vacuolisation of ICC and one patient with ED and combined degenerative neuropathy and α-actin deficiency exhibited ICC with a flat surface (fig 1F). Normal ICCs were found in 6 patients with inflammatory neuropathy and ED and in 3 patients with degenerative neuropathy (CIP = 2; ED = 1).

We compared histological findings with findings from small bowel manometry in 112 patients (table 3). Manometry findings were very similar in inflammatory and non-inflammatory neuropathy (not shown). Only one finding showed a significant relationship to the underlying pathology and that was severe hypomotility, which was seen only in patients with myopathy or combined neuromypathy (p<0.001).

Table 3 Prevalence of abnormal small bowel manometry patterns among patients with different types of gastrointestinal neuromuscular pathology

DISCUSSION

We report histological findings in a large case series of patients with CIP and ED that were collected during a 16 year period in a tertiary referral centre in Sweden. Our study is the first to describe histological findings in a new pathophysiologically defined group, enteric dysmotility. Symptoms do not distinguish between CIP and ED. Both groups may present with attacks of abdominal pain and distension. The distinction between the two is whether or not there are subocclusive events with radiological signs mimicking mechanical obstruction. We defined this as at least one documented episode with air/fluid levels with or without dilatation of small bowel or chronic dilatation of bowel. The sensitivity of air/fluid levels on plain abdominal x ray for pseudo-obstruction is not known, but such findings are by no means specific for pseudo-obstruction since not only mechanical obstruction but also several acute intra-abdominal inflammatory conditions including appendicitis, diverticulitis and mesenteric ischaemia may cause a similar picture.22 The presence of abnormal small bowel motor activity was recently suggested as an additional criterion for CIP.8 We included in our series 3 patients with pseudo-obstruction who could not be investigated by small bowel manometry, but all other patients with CIP had abnormal small bowel motor activity.

Whereas subocclusive events constituted the upper limit for ED, the lower limit was set where abnormal motor activity of the small bowel could be documented. Current terminology would place patients without subocclusive events into a symptom-defined group such as irritable bowel syndrome (IBS), since the diagnosis of a functional bowel disorder only requires the absence of structural and biochemical explanations for the symptoms.23

It is perhaps a bit disappointing that manometry findings could not differentiate between myopathic and neuropathic conditions apart from the more advanced stages of myopathy with bowel dilation and severe hypomotility. Phase III abnormalities, bursts and sustained periods of uncoordinated phasic activity were originally described in a series of patients with presumed neuropathy.4 However, in that study, full-thickness bowel biopsies were available in only 15/42 patients and, using H&E staining, neuropathy was actually detected in only 3 patients. It is difficult to envisage the absence of neuropathic findings on biopsy as evidence against myopathy, in particular since no immunohistochemistry was done. A more recent study described 59 patients with CIP, and biopsy material was available in 11 patients, who all had neuropathy.7 Unfortunately, no information was given regarding underlying pathology in the remaining patients and manometry findings were not presented in relation to underlying pathology. To our knowledge, motility patterns in less severe forms of myopathy have never been described before. Our findings indicate that the motility patterns that previously were associated primarily with neuropathic conditions were equally common in myopathic disorders.

CIP is obviously a heterogeneous diagnosis and in adults the spectrum of diseases causing CIP seems to differ from that seen in paediatric CIP.24 While the majority of children with pseudo-obstruction present congenitally, have dilated bowel and frequent involvement of extraintestinal organs,25 26 adults usually present with presumably acquired forms of pseudo-obstruction, normal bowel width and less frequent involvement of extraintestinal organs such as the urinary bladder. All patients with severe dilatation and intestinal hypomotility were found to have visceral myopathy, and 13/19 patients with dilated bowel had myopathy or combined neuropathy and myopathy. Similarly, Mann et al reported a series of 20 adult patients with pseudo-obstruction and dilated bowel, and they also found visceral myopathy in 13/19 patients.27

Visceral neuropathy was the most common finding in our series of patients with CIP. An earlier series from the USA included 27 patients with CIP.28 That series comprised 14 patients with progressive systemic sclerosis and 11 patients with idiopathic CIP. Among the latter, 4 had myopathy, 2 had neuropathy and 5 had no defined pathology. The two patients with neuropathy were a brother and a sister with a familial form of visceral neuropathy. Familial forms of neuropathic CIP in adults have been reported to have autosomal dominant transmission29 30 as well as recessive transmission.31 Only 2 of our patients had a family history of severe motility disorders and those were two sisters aged 37 and 44 years who both had degenerative neuromyopathy. The older of the two also has a daughter with pseudo-obstruction (not included in this series).

The most striking finding in our series is the high prevalence of inflammatory neuropathy. Dense lymphocytic infiltration of enteric ganglia occurs in Chagas disease,32 33 and infection with cytomegalovirus (CMV)34 or Epstein–Barr virus (EBV),35 but has mainly been reported as a paraneoplastic phenomenon33 in particular with small cell lung carcinoma.36 37 One of our patients with inflammatory neuropathy, a 62-year-old male, was diagnosed with small cell lung carcinoma 2 months after the diagnosis of pseudo-obstruction. Lymphocytic infiltration is also a feature of Chagas disease, but none of our patients had trypanosomal infection. An idiopathic form of inflammatory visceral neuropathy has been described in a few cases.3840 We found dense lymphocytic infiltration of myenteric ganglions in 6 patients without concomitant malignancy, Chagas disease or serological markers for ongoing CMV or EBV infection.

The largest group of patients in our series comprised patients with neuropathy and low-grade infiltration of lymphocytes in ganglia and/or along axons. In many instances it was difficult to find low-grade inflammation on transverse sections. This is not surprising since transverse sections will inevitably have a large sampling error with respect to the number of ganglia that can be seen on any one section. Tangential sections with immunohistochemistry for lymphocytes greatly improve the sensitivity with which even patchy and numerically few lymphocytes can be detected. Previous studies27 28 reported apparently normal biopsies in 5/13 and 3/20 patients, respectively, with CIP, whereas Stanghellini et al7 found degenerative neuropathy in 10/11 patients and neuronal intestinal dysplasia in one patient with CIP. We found abnormalities in all our patients. It is possible that low-grade ganglionitis may have been overlooked in some previous studies, that a different threshold for the definition of ganglionitis was used or that the use of tangential sections increases the likelihood of this notoriously patchy process being detected.

A recent case–control study of oesophageal involvement in systemic sclerosis found lymphocytic “cellular infiltrates” in the myenteric plexus of 61/74 cases and 68/74 control patients.41 Most infiltrates “were trivial, involving few lymphocytes”. However, the study seems to have included for analysis lymphocytes located to lymphatic vessels. We do not think that the presence of perineural lymphocytes should be interpreted as inflammatory infiltrate. True intraneural lymphocytes were observed in 2 controls (3%) and 13 cases (18%) (p<0.01). Although no information was given about the disease spectrum among control patients, the observation that intraneural lymphocytes were present in only 2/74 controls lends support to our assumption that the presence of myenteric intraneural/intraganglional lymphocytes is abnormal.

Surgical manipulation of the bowel has been reported to cause infiltration of leucocytes (mainly neutrophil granulocytes) and macrophages into the muscularis propria,42 but there are no reports of lymphocyte migration to nerve plexuses. Two circumstances contradict the idea that surgical manipulation might underlie our finding of low-grade myenteric inflammation: one is the time frame for biopsy taking. The median operation time in our series was 50 (range 30–125) min.43 The time for manipulation of the bowel before biopsy taking was usually <20 min and this is probably too short for manipulation-induced changes to take place.44 Secondly, we did not observe lymphocytes in biopsies from patients with myopathy, nor in biopsies from those with degenerative neuropathy.

The lack of a good control group for full-thickness biopsy findings remains an issue. Such a control group would also have to exclude patients with functional bowel disorders, since we also found low-grade ganglionitis in 9/10 patients with IBS and no abnormalities on small bowel manometry.16 Controls from autopsy material are difficult to assess since information about functional bowel disorders is usually not available. It is also difficult to find a suitable patient group in whom it would be ethical to take a full-thickness biopsy of the jejunum. Most patient groups that undergo bowel resection have symptoms that make it impossible to exclude a functional bowel disorder. These difficulties may explain why there are no data in the literature on histopathological findings from full-thickness bowel biopsies of healthy controls.

In our study of IBS, neuropathic features were not consistently present.16 It is tempting to hypothesise that ED may represent a subgroup of functional bowel disorders with a more advanced stage of a disease that can be detected by small bowel manometry and that is characterised by enteric ganglionitis leading to neuron degeneration and progressively impaired function.

Acknowledgments

This study was supported by funds from the Swedish Medical Research Council (grant 2002-5489) and The Swedish Society of Medicine (Ihre’s fond).

REFERENCES

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Footnotes

  • Competing interests: None.

  • Patient consent: The study was approved by the Ethics Committee of Karolinska University Hospital, Huddinge.

  • See Commentary, p 1042

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