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Neuropathy should be considered as a possible etiological factor in patients with severe gastrointestinal symptoms, without signs of disease on routine investigations. Examinations of the autonomic and peripheral nervous systems may be helpful to select the patients who should be investigated with full‐thickness intestinal biopsy, and to give appropriate care.

A full-thickness biopsy of the bowel wall is required to evaluate the enteric nervous system. A patient with aggravating gastrointestinal symptoms underwent a laparoscopic full-thickness biopsy of the ileum and, 1 year later, an endoscopic full-thickness biopsy of the sigmoid colon. Both samples showed enteric neuropathy characterized by vacuolated and enlarged neurons. The length of the myenteric plexus was greater in the endoscopic (23 mm) compared to the laparoscopic (11 mm) biopsy, with fewer tissue artefacts in the laparoscopic approach. Clinical deterioration was paralleled by enteric neuropathy with an increase in the percentage of vacuolated and enlarged enteric neurons from 24 to 35%.

The cover image is based on the Case Report Autonomic and peripheral neuropathy with reduced intraepidermal nerve fiber density can be observed in patients with gastrointestinal dysmotility by Bodil Ohlsson, Béla Veress, LARS B DAHLIN et al., https://doi.org/10.1002/ccr3.2575. [Image: see text]

Objectives: Light microscopical analysis in two dimensions, combined with immunohistochemistry, is presently the gold standard to describe the enteric nervous system (ENS). Our aim was to assess the usefulness of three-dimensional (3D) imaging by X-ray phase-contrast tomography in evaluating the ENS of the human bowel. Material and methods: Myenteric ganglia were identified in full-thickness biopsies of the ileum and colon by hematoxylin & eosin staining. A1-mm biopsy punch was taken from the paraffin blocks and placed into a Kapton® tube for subsequent tomographic investigation. The samples were scanned, without further preparation, using phase-contrast tomography at two different scales: overview scans (performed with laboratory setups), which allowed localization of the nervous tissue (∼1µm effective voxel size); and high-resolution scans (performed with a synchrotron endstation), which imaged localized regions of 320x320x320 µm3 (176 nm effective voxel size). Results: The contrast allowed us to follow the shape and the size changes of the ganglia, as well as to study their cellular components together with the cells and cellular projections of the periganglional space. Furthermore, it was possible to show the 3D network of the myenteric plexus and to quantify its volume within the samples. Conclusions: Phase-contrast X-ray tomography can be applied for volume analyses of the human ENS and to study tissue components in unstained paraffin-embedded tissue biopsies. This technique could potentially be used to study disease mechanisms, and to compare healthy and diseased tissues in clinical research.

Gastrointestinal complaints without obvious organic causes confirmed by clinical laboratory analyses, endoscopy or radiology are often referred to functional entities. Irritable bowel syndrome (IBS) is the most common functional disorder in the gut. Careful examination of these patients may reveal other diagnoses of defined etiologies, e.g., enteric neuropathy, microscopic colitis, and primary Sjögre’s syndrome. The present case describes a young patient with incapacitating gastrointestinal symptoms presumed to be IBS, who underwent endoscopic full-thickness biopsy in sigmoid colon. Histopathological examination revealed degenerative enteric neuropathy, possibly secondary to chronic ischemia.

Little is known about the enteric ganglionic system in subjects with gastrointestinal dysmotility syndrome (GIDS). Furthermore, dysfunction of gastrointestinal motility is an early complaint of subjects with Parkinson’s disease. Here, we assessed p62/sequestosome-1(p62) and α-synuclein (αS) immunoreactivity (IR) in full-thickness bowel specimens of the gut obtained from six subjects with GIDS and from 17 controls. In the myenteric neurons, fine punctuate p62-IR were seen in all of the controls, whereas diffuse cytoplasmic and nuclear p62-IR were seen in the GIDS cases. Physiological αS-IR (clone 42/αS) was seen in all of the controls and the GIDS cases in the lamina propria, the submucosal and in the myenteric plexuses. The disease associated αS (clone 5G4) labeled the cytoplasm of the ganglion cells only in the myenteric plexus in three out of the four subjects with the GIDS/inflammatory neuropathy. In summary, ganglion cells were readily visualized in all of the layers of the bowel with clone 42/αS, and p62 displayed altered patterns of labeling in subjects with the GIDS. Labeling seen with the disease associated clone 5G4/αS in the GIDS/inflammatory neuropathy is intriguing and might indicate that the alteration of αS is triggered by a chronic inflammation.

Background Patients with gastrointestinal neuromuscular diseases may undergo operative procedures that yield tissue appropriate to diagnosis of underlying neuromuscular pathology. Critical to accurate diagnosis is the determination of limits of normality based on the study of control human tissues. Although robust diagnostic criteria exist for many qualitative alterations in the neuromuscular apparatus, these do not include quantitative values due to lack of adequate control data. Purpose The aim of this report was to summarize all relevant available published quantitative data for elements of the human enteric nervous system (neuronal cell bodies, glial cells, and nerve fibers) from the perspective of the practicing pathologist. Forty studies meeting inclusion criteria were systematically reviewed with data tabulated in detail and discussed in the context of methodological variations and limitations. The results reveal a lack of concordance between observations of different investigators resulting in data insufficient to produce robust normal ranges. This diversity highlights the need to standardize the way pathologists collect, process, and quantitate neuronal and glial elements in enteric neuropathologic samples, as suggested by recent international guidelines on gastrointestinal neuromuscular pathology. (Less)

Objective Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material. Design Consensual processes undertaken by the IWG and following established guideline decision group methodologies. Results and conclusion This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named ‘The London Classification’. The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available.

The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented.

Background & Aims: A 30-year-old woman, treated with buserelin, an analogue of gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone-releasing hormone, LH-RH), developed chronic intestinal pseudo-obstruction (CIPO). The sudden onset of this disease in a previously healthy woman perplexed us. CIPO refers to a gastrointestinal disorder that can have a variety of causes, such as drugs, among others. Thus, we wanted to examine whether in this patient the development of CIPO is related to the treatment with buserelin. Methods: The patient was examined using esophagogastroduodenoscopy, esophageal, and antroduodenojejunal manometry, gastric emptying tests, and histologic analyses and immunohistochemistry on full-thickness biopsies including staining with anti-GnRH antibody. Plasma samples were examined by the standard serologic analyses and specifically for the occurrence of anti-GnRH antibodies by enzyme-linked immunosorbent assay methods. Results: CIPO was diagnosed based on symptoms (abdominal pain, vomiting, and constipation), and the results of the clinical examinations, such as signs of esophageal aperistalsis, delayed gastric emptying, and small intestinal bursts. Histologic examination revealed a decreased number of myenteric neurons as well as increased neuronal degeneration and an abnormal immune profile. There was a loss of GnRH-containing neurons. The patient had high plasma titers of anti-GnRH antibodies, which occurred on the occasions of the treatment with buserelin. Conclusions: Our findings suggest that the patient has developed CIPO due to buserelin-induced formation of anti-GnRH antibodies destroying GnRH-producing neurons of the myenteric plexus.

Chronic idiopathic intestinal pseudo obstruction (CIIP) is a severe condition presenting with abdominal pain and dysmotility. Inflammatory or degenerative changes of the autonomic nervous system or of the muscles of the bowel have been observed in CIIP.1,2 As patients with inflammatory bowel disease (IBD) may show clinical3,4 and histological5 signs of autonomic neuropathy and dysmotility,6,7 the aim of this study was to examine whether there is an association between CIIP and IBD. Six patients at our hospital presenting with signs and symptoms of intestinal dysmotility were diagnosed with CIIP based on clinical features, antroduodenojejunal manometry, and full thickness biopsies (table 1).8,9 Patient No 1 had an acute erosive colitis some years previously with bloody diarrhoea and an enhanced sedimentation rate, which was treated with steroids, …

Deposition of fibrin in the form of fibrinoid necrosis is a common feature of severe acute renal allograft rejection. The role of the coagulation system and its initiator tissue factor (TF) during this process is, however, still poorly understood. In this study, we analyzed the expression of TF in 88 renal transplants afflicted with different forms of rejection and calcineurin inhibitor-induced nephrotoxicity, to see whether there was differential expression of this protein. TF immunoreactivity was evaluated semiquantitatively in six different renal structures: the podocytes, Bowman epithelium, the endothelium of the glomeruli, the brush border of tubular cells, the thin ascending loop of Henle, and small arteries/arterioles. The TF expression of normal renal tissue (n = 6) was restricted to the glomerular podocytes and Bowman epithelium, and to some extent the ascending loop of Henle. Renal allografts undergoing acute rejection (AR) of grades I–III, (n = 13, n = 17 and n = 12, respectively) did not show any altered TF expression in the glomeruli or vascular endothelium. In the ascending loop of Henle, a reduced expression could be seen (ARI, p = 0.015; and ARII, p = 0.043). TF staining of the brush border of renal transplants undergoing acute cyclosporin A (CsA) nephrotoxicity (n = 18) was significantly higher than in normal kidneys (p = 0.0003), as well as in transplants undergoing various degrees of acute rejection (ARI, p = 0.027; ARII, p = 0.0012; and ARIII, p = 0.0001). Tubular brush border-expressed TF was also evident in 10 of 15 allografts suffering from chronic CsA nephrotoxicity, compared to 4 out of 13 cases with chronic allograft vasculopathy (CAV), but the increase was not statistically significant relative to normal kidneys. The majority of the grafts afflicted with either of the two chronic conditions displayed a TF-positive arterial endothelium (CAV, p = 0.0034; and chronic CsA nephrotoxicity, p = 0.0026) relative to controls. In conclusion, these results indicate that vascular TF expression is not altered during acute rejection, but may be of importance in chronic allograft nephropathy. Furthermore, TF immunoreactivity in the tubular brush border may be specific to acute CsA nephrotoxicity and might be used as a biomarker for this condition. Further studies are required to evaluate the possible role of brush border-expressed TF in the pathogenesis of CsA nephrotoxicity.

Background and aims: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a severe motility disorder associated with significant morbidity. Several histopathological (neuropathic and myopathic) phenotypes have been described but only a single adult with jejunal smooth (circular) muscle α-actin deficiency. We present a prospective multinational case series investigating smooth muscle α-actin deficiency as a biomarker of this disease. Methods: A total of 115 fully clinically and physiologically (including prolonged (24 hour) ambulatory jejunal manometry) characterised CIIP patients from three European centres were studied. Immunohistochemical localisation of actins and other cytoskeletal proteins were performed on laparoscopic full thickness jejunal biopsies and compared with adult controls. Distribution of α-actin was also characterised in other gut regions and in the developing human alimentary tract. Results: Twenty eight of 115 (24%) CIIP patient biopsies had absent (n = 22) or partial (n = 6) jejunal smooth muscle α-actin immunostaining in the circular muscle layer. In contrast, smooth muscle α-actin staining was preserved in the longitudinal muscle and in adult jejunal controls (n = 20). Comparative study of other adult alimentary tract regions and fetal small intestine, suggested significant spatial and temporal variations in smooth muscle α-actin expression. Conclusions: The ability to modulate α-smooth muscle actin expression, evident in development, is maintained in adult life and may be influenced by disease, rendering it a valuable biomarker even in the absence of other structural abnormalities.