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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Background  Considerable information has been gathered on the functional organization of enteric neuronal circuitries regulating gastrointestinal motility. However, little is known about the neuropathophysiological mechanisms underlying gastrointestinal motor disorders.

Aim  To analyse the most important pathological findings, clinical implications and therapeutic management of idiopathic enteric neuropathies.

Methods  PubMed searches were used to retrieve the literature inherent to molecular determinants, pathophysiological bases and therapeutics of gastrointestinal dysmotility, such as achalasia, gastroparesis, chronic intestinal pseudo-obstruction, Hirschsprung’s disease and slow transit constipation, to unravel advances on digestive disorders resulting from enteric neuropathies.

Results  Current data on molecular and pathological features of enteric neuropathies indicate that degenerative and inflammatory abnormalities can compromise the morpho-functional integrity of the enteric nervous system. These alterations lead to a massive impairment in gut transit and result in severe abdominal symptoms with associated high morbidity, poor quality of life for patients and established mortality. Many pathophysiological aspects of these severe conditions remain obscure, and therefore treatment options are quite limited and often unsatisfactory.

Conclusions  This review of enteric nervous system abnormalities provides a framework to better understand the pathological processes underlying gut dysmotility, to translate this knowledge into clinical management and to foster the development of targeted therapeutic strategies.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Digestive functions are regulated by a complex neural network, known as enteric nervous system (ENS), endowed in the gut wall and extending throughout its length from the oesophagus to the internal anal sphincter (for reviews, see Ref. 1). The ENS comprises a myriad of neurons (as many as those contained in the spinal cord, i.e. up to 1010 in humans) organized into two major ganglionic structures, namely the myenteric (Auerbach’s) and submucosal (Meissner’s) plexuses. Each ganglion contains functionally distinct subclasses of neurons, which include primary intrinsic afferent neural cells, ascending and descending interneurons, excitatory and inhibitory motorneurons, vasomotorneurons and secretomotorneurons, arranged in circuitries to subserve coordinated motor functions, the best known of which is peristalsis.1 This highly integrated neural system is also referred to as the ‘brain-in-the-gut’, an expression coined by Wood in 1981,2 because of its capability to function in the absence of nerve inputs from the central nervous system.1, 3 Extrinsic nerve pathways contribute to the regulatory mechanisms underlying gut functions.1 In addition to exocrine and endocrine secretions, microcirculation and motility, there is evidence that the ENS is involved in the control of immune and inflammatory processes throughout the gut.4 Thus, it is not surprising that any damage to ENS circuitries results in a wide array of gut disorders, including motor impairments, which are characterized by high morbidity, with a markedly compromised patient’s quality of life and occasional fatal outcomes.

Besides a few exceptions, the mechanisms through which neural diseases cause gastrointestinal dysfunction, including motor abnormalities, remain poorly understood. Current evidence indicates that alterations in ENS, including loss, degeneration and functional impairment of enteric neurons, are associated with uncoordinated motor activities, which result in altered transit of intestinal contents.5, 6 In particular, several studies have provided insights into the intramural neural alterations, which underlie gastrointestinal motor disorders, as summarized in Table 1.

Table 1.   Neuropathological features and proposed aetiological factors of idiopathic enteric neuropathies
DiseaseNeuropathological featuresProposed aetiological factors
AchalasiaDefective inhibitory innervation with or without inflammatory neuropathy (myenteric ganglionitis) Complete loss of myenteric gangliaImmune-mediated (including antineuronal antibodies) Neurotropic viruses (e.g. Varicella zoster; Herpes simplex type 1) Genetic factors
GastroparesisDegenerative neuropathy Inflammatory neuropathy (myenteric ganglionitis)Immune-mediated (including antineuronal antibodies) Neurotropic viruses (undetermined) Genetic factors
Congenital hypertrophic pyloric stenosisDefective inhibitory innervationSelective alteration of nitrergic neurons
Chronic idiopathic intestinal pseudo-obstructionDegenerative neuropathy Inflammatory neuropathy (myenteric ganglionitis)Immune-mediated (including antineuronal antibodies) Neurotropic viruses (undetermined) Genetic factors
Slow transit constipationImpairment of neurotransmission without evidence of neuronal damage Degenerative neuropathy Inflammatory neuropathy (myenteric ganglionitis)Immune-mediated Neurotropic viruses (undetermined) Genetic factors
Hirschsprung’s disease Congenital defect in enteric neuron migration and maturation (aganglionosis)Genetic factors

A wide spectrum of diseases are known to affect the morpho-functional integrity of ENS, thereby resulting in digestive neuropathic disorders. In particular, some pathological conditions, e.g. diabetes or amyloidosis, may be responsible for patterns of gastrointestinal dysmotility, which are usually well recognized by the systemic or local features of the underlying disease. In contrast, idiopathic neuropathies represent a clinical challenge, as there is lack of information on their causal correlates.7, 8 Growing evidence, accumulated over recent years, has indicated that alterations of smooth muscle and interstitial cells of Cajal (ICC) may also contribute to the pathogenesis of gut dysmotility, as reported in previous articles (for review, see Refs 9, 10). Likewise, alterations in enteric glia, formerly defined as ‘supporting’ cells within the ENS, are gaining attention with regard to enteric neuropathies (for review, see Refs 11, 12). However, a detailed analysis of the roles played by both ICC and enteric glial cells in enteric neuropathies is beyond the purposes of this article. The aim of this review was to provide an accurate account of the molecular and pathological features, putative pathogenetic mechanisms and current indications for therapeutic management of enteric idiopathic neuropathies associated with major gastrointestinal motor dysfunctions.

Achalasia

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Achalasia is an oesophageal disorder characterized by a marked reduction or absence of peristalsis and lack of lower oesophageal sphincter (LOS) relaxation.13 Patients with achalasia may report a variety of symptoms, although their complaints include mostly transfer dysphagia and regurgitation.13 Tissue analysis shows a prominent defect of intrinsic inhibitory neurones, releasing nitric oxide (NO), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide and adenosine-5′-triphosphate, both in the oesophageal body and LOS.5, 14 The imbalance between defective inhibitory innervation and apparently spared excitatory (cholinergic/tachykinergic) neuronal components is thought to play a major role in the pathogenesis of oesophageal motor abnormalities and LOS dysfunction.15, 16

Achalasia can be primary (or idiopathic) in nature, including familial and sporadic forms, or secondary to a large variety of diseases (for review, see Ref. 17). The aetiology of neuronal alterations detected in primary achalasia remains unknown. However, several lines of evidence indicate that infectious, immune and genetic factors may play important roles in the aetiopathogenesis of this neuropathy.18 These determinants are likely to act independently, and they are involved at different extents in distinct subgroups of patients with achalasia.19 In a study assessing the degree of inflammation in myenteric plexus of patients with end-stage achalasia, Goldblum et al.20 found a marked reduction in myenteric ganglion cells with associated lymphocytic and eosinophilic infiltrates in tissue specimens taken at oesophagomyotomy. In a follow-up study, designed to examine the histopathological features of myotomy specimens from patients with early-stage achalasia, the same authors found inflammation in both early- and end-stage achalasia, but only in the latter form there was evidence of fibrosis, suggesting a spectrum of histopathological changes at different stages of the disease.21 These two studies are consistent with other reports, which have shown myenteric inflammatory infiltrates (hence the term of ‘myenteric ganglionitis’), represented by CD3+ and CD8+ T cells in both early- and end-stage achalasia,22 as well as a normal number of myenteric ganglion cells in the early stage of the disease.23 Thus, the available evidence supports the hypothesis that infectious agents (e.g. viruses) might elicit immune responses targeting the oesophageal myenteric neurons. In this respect, previous work demonstrated Herpes zoster virus DNA in tissue specimens obtained from patients with sporadic forms of primary achalasia,24 even if other authors failed to identify viral products in oesophageal tissue specimens from achalasic patients.25 Although a causal link between neurotropic virus infections and neuropathological changes has not been demonstrated, recently Castagliuolo et al.26 showed an increased lymphocyte proliferation in cells isolated from oesophageal tissues of achalasic patients upon exposure to Herpes simplex virus 1. This finding suggests that achalasia may result from an abnormal immune reaction against neurotropic viruses in susceptible patients.

In addition to the local cellular response detectable in the oesophageal myenteric ganglia, several studies have investigated the presence of circulating antineuronal antibodies as potential factors involved in immune-mediated neuronal damage. Initial studies, demonstrating the existence of circulating antineuronal antibodies in patients with achalasia, were carried out by Eaker et al.27, 28 Subsequently, two studies19, 29 have demonstrated that the serum of patients with achalasia contains antineuronal antibodies that label neurons of rodent ENS. Serum samples from both cohorts of achalasic patients yielded identical results, as the immunohistochemical patterns were characterized by nuclear and cytoplasmic immunoreactivity visualized in myenteric and submucosal neurons. The molecular targets of these antineuronal antibodies remain unknown. Nonetheless, it is noteworthy that the immunolabelling was detected only in enteric, and not in other neurons, including those of sensory and superior cervical ganglia or spinal cord.29 More recently, Bruley des Varannes et al.30 examined sera from 18 achalasic patients and demonstrated that their application to gastric fundus muscle strips of healthy subjects elicited two main changes: (i) an alteration in the neurochemical coding (i.e. a reduced number of nitrergic/VIPergic neurons as opposed to increased cholinergic neuronal components) and (ii) an impairment in relaxing responses upon application of electrical stimuli. These data suggest that other factors, in addition to antineuronal antibodies, present in the sera of achalasic patients, may contribute to ENS dysfunction in the oesophagus as well as in other segments of the gastrointestinal tract.15

Genetic abnormalities have been found in rare cases of childhood and familial achalasia. To date, less than 10 cases with an apparent genetic background have been reported and only one case report described monozygotic twins with achalasia.31 Using linkage analysis, Tullio-Pelet et al.32 investigated 16 North African families (each one with an average of one to two affected family members) with Allgrove’s syndrome, an autosomal recessive disorder characterized by alacrima, achalasia and adrenocorticotropin-resistant adrenal insufficiency (hence the acronym of ‘triple-A’ syndrome, AAAS), along with signs of autonomic/peripheral neuropathies and mental retardation. In this condition, Tullio-Pelet et al. identified a locus on chromosome 12q13 containing a novel gene encoding a 547 amino acid protein named ALADIN (i.e. alacrima–achalasia–adrenal insufficiency neurological disorder). Under normal conditions, this protein, which belongs to the WD repeat family of regulatory proteins, exerts an important role in the nucleo-cytoplasmic signalling, thereby controlling the development and maintenance of several cells including central, peripheral and enteric neurons. In patients with Allgrove’s syndrome, AAAS gene mutations (one of the most common being 14+1G>A) generate an abnormal ALADIN protein, which is believed to contribute to the abnormalities of oesophageal myenteric neurons.32 In a recent study, we have screened the 16 exons of AAAS gene by means of denaturing high-performance liquid chromatography to identify possible mutations in patients with sporadic achalasia. All variants identified in these patients consisted of polymorphisms resulting in a functionally normal ALADIN protein. Thus, our data do not support a pathogenetic role of common AAAS gene mutations in patients with idiopathic achalasia unrelated to Allgrove’s syndrome.33

Overall, several lines of evidence lead to conclude that idiopathic achalasia can be regarded as an inflammatory disease of unknown aetiology characterized by a loss of inhibitory neurons in the oesophageal myenteric plexus. The initiating event might be an environmental insult, such as a viral infection, resulting in inflammation of the oesophageal myenteric plexus. Because of a genetic predisposition, susceptible subjects may develop an autoimmune response leading to chronic inflammation. In the early stage, ganglionitis without significant neuronal cell loss may be the predominant finding. At later stages, the autoimmune reaction damages the inhibitory neurons and progresses up to extensive neuronal loss accompanied by ganglionic fibrosis, which is the hallmark of established achalasia.

Gastroparesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Gastroparesis literally means ‘paralyzed stomach’ and it is used to indicate a significant delay in the emptying of solids and liquids from the stomach. Major complaints referred by patients with symptomatic gastroparesis include nausea, vomiting, bloating, early satiety and upper abdominal pain. In clinical practice, the two most common forms of gastroparesis include the idiopathic one (accounting for 50% of cases) and that secondary to diabetes mellitus.34, 35 Alterations in the extrinsic (autonomic) neural supply to the stomach are known to contribute to the pathophysiology of gastroparesis. Likewise, nearly any pathological process capable of disrupting the neuromuscular functions of the stomach can cause gastroparesis. The pathogenesis of idiopathic gastroparesis is multifactorial and still largely unsettled, mainly because of the lack of comprehensive studies on the neuromuscular alterations related to this condition. Specifically, the neuropathology of idiopathic gastroparesis remains virtually undefined and its current knowledge relies upon anecdotal reports. Although previous works have not shown apparent abnormalities of the intrinsic gastric innervation,36, 37 recently, Zarate et al.38 described a 32-year-old woman with severe idiopathic gastroparesis who, after failure of different pharmacological treatments and pyloroplasty, underwent subtotal gastrectomy. Tissue analysis demonstrated hypoganglionosis accompanied by findings suggestive of neuronal dysplasia. Along with neuronal alterations, the authors found a marked decrease in both myenteric and intramuscular ICC, suggesting that in this patient the degenerative changes affected other cell populations in addition to enteric neurons.

In addition to degenerative neuropathies, inflammatory forms, i.e. myenteric ganglionitis, can be responsible for gastroparesis. Several conditions, such as paraneoplastic syndromes, can be associated with inflammatory neuropathic abnormalities underlying gastroparesis.39 Nonetheless, cases of idiopathic inflammatory neuropathy with gastroparesis have been reported too. We previously described a young adult patient with intractable vomiting in which tissue analysis unravelled a dense lympho-plasmacellular infiltrate within the gastric myenteric plexus.40 Notably, this patient improved soon after the onset of a course of steroid therapy, thus providing further support to the role played by immune/inflammatory-dependent changes of gastric motor function, and suggesting that patients with histologically proven myenteric ganglionitis may be treated successfully when diagnosed in the early phase of their disease.40

A rare form of gastroparesis is represented by congenital hypertrophic pyloric stenosis, a disease typically found in paediatric patients. Usually, the disease remains asymptomatic for long periods because the antral contractions generate a propulsive force sufficient to ensure emptying of gastric contents. Morphological analysis of the pyloric innervation shows a qualitative alteration in the myenteric neurons that lack neuronal NO synthase (nNOS).41 This functional inhibitory denervation results in the absence of relaxations and promotes a sustained tonic contraction of the pylorus followed by muscle hypertrophy. A pathogenetic role of a defective nitrergic innervation is also supported by the Nos1−/− (i.e. nNOS) mouse model characterized by a functional gastric obstruction similar to that occurring in hypertrophic pyloric stenosis.42

Chronic intestinal pseudo-obstruction

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Chronic intestinal pseudo-obstruction represents a rare and highly morbid syndrome characterized by impaired gastrointestinal propulsion, together with symptoms and signs of bowel obstruction, in the absence of any lesion occluding the gut lumen.7, 8, 43 Chronic intestinal pseudo-obstruction can be classified as either secondary to a wide array of recognized pathological conditions or idiopathic in nature (chronic idiopathic intestinal pseudo-obstruction, CIIP).7, 8, 43 Although familial forms with autosomal dominant or recessive modes of inheritance have been reported, most cases of CIIP appear to be unrelated to familial clusters and therefore they are referred to as sporadic forms.7, 8, 17, 43 Based on histologic examination, CIIP can be classified into three major entities: neuropathies, ‘mesenchymopathies’ and myopathies, depending on the predominant involvement of enteric neurons, ICCs or smooth muscle cells, respectively.44 Although each of these entities can be responsible for dysmotility, combined forms (for instance, neuromyopathies) may also coexist in tissue specimens from the same patient.

Pioneering work, leading to the pathological characterization of enteric neuropathies, was performed by Schuffler et al.45, 46 At present, neuropathic CIIP can be distinguished into two major forms: (i) degenerative neuropathies, characterized by a picture of enteric neuronal degeneration in the absence of an evident inflammatory response; and (ii) inflammatory neuropathies in which a significant inflammatory/immune response can be identified within enteric ganglia and/or nerve processes.

Degenerative neuropathies may occur as a result of several putative pathogenetic mechanisms, such as altered calcium signalling, mitochondrial dysfunction and production of free radicals, leading to degeneration and loss of gut intrinsic neurons.47 Degenerative neuropathies can be familial (related to a genetic background – see below) or sporadic and classified into primary (idiopathic) or secondary to a variety of causes. Typical neuropathological findings reported in neurodegenerative CIIP include various qualitative (neuronal swelling, intranuclear inclusions, axonal degeneration and other lesions) and quantitative (especially hypoganglionosis) abnormalities of the ENS. Familial forms of CIIP can be inherited via autosomal dominant, recessive and X-linked transmission.6, 43, 44 Some genes and loci have been associated with syndromic forms of CIIP, including the transcription factor SOX10 on chromosome 22 (22p12), the DNA polymerase gamma gene (POLG) on chromosome 21 (21q17) and a locus on chromosome 8.17, 48, 49 With regard to X-linked inheritance, a two-base pair deletion in exon 2 of the filamin A gene (encoding a cytoskeletal protein) has been reported as a heterozygous condition in females of a family with syndromic CIIP.50 Familial cases can be associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), which is characterized by sub-occlusive episodes occurring along with lactic acidosis, skeletal muscle abnormalities and ultrastructural mitochondrial alterations.47, 51 Mutations of the thymidine phosphorylase gene (TP or endothelial cell growth factor-1, ECGF1), mapped to locus 22q13.32qter have been shown to determine MNGIE.51–55 As a result, the decreased TP activity leads to toxic levels of thymidine and deoxyuridine in both blood and tissues, which account for mitochondrial DNA abnormalities, including point mutations, multiple deletions and depletion.56–58 Sporadic cases of visceral neuropathies are associated with two major patterns of alterations: (i) marked reduction of intramural (especially myenteric) neural cells, mainly associated with swollen cell bodies and processes, fragmentation and loss of axons and proliferation of glial cells; and (ii) loss of normal staining in subsets of enteric neurons, in the absence of dendritic swelling or glial proliferation.6, 17, 46 As no reliable experimental models of degenerative neuropathies are currently available, the mechanisms through which exogenous noxae or other triggering factors initiate degenerative processes in enteric neurons remain obscure. Enteric neurons of patients with severe forms of idiopathic intrinsic neuropathy display a decreased expression of the protein encoded by BCL-2, a gene related to one of the intracellular pathways leading to programmed cell death.59, 60 Accordingly, this finding has been associated with an increased number of neurons positive for TUNEL, a marker of apoptosis.61

Inflammatory neuropathies are characterized by a dense infiltrate of lymphocytes and plasma cells involving the two major ganglionic plexuses, although the myenteric ganglia and related nerve axons are more frequently affected (hence, the term myenteric ganglionitis).62 Usually, cases of myenteric ganglionitis are secondary to a variety of diseases, including paraneoplastic (for example, small cell lung carcinoma, carcinoid, neuroblastoma and thymoma), infectious (for example, Chagas’ disease), neurological (for example, encephalomyeloneuropathy), connective tissue (for example, scleroderma) and inflammatory bowel disorders (for review, see Ref. 62). Nevertheless, some cases can be idiopathic in nature.40, 63, 64 Immunohistopathological analysis shows that the immune infiltrate consists mainly of CD4+ and CD8+ lymphocytes, which can be identified both in idiopathic and secondary forms of myenteric ganglionitis (Figure 1). Lymphocytic myenteric ganglionitis is often associated with neuronal degeneration and loss, up to complete ganglion cell depletion, which occurs in the most severe forms (a feature referred to as ‘acquired aganglionosis’).63, 64 Besides lymphocytes, other inflammatory cells may affect the ENS of patients with CIIP. Schäppi et al.65 have reported a variety of ganglionitis characterized by eosinophils infiltrating the myenteric plexus of paediatric patients with CIIP. In contrast to the lymphocytic form, the eosinophilic ganglionitis does not appear to promote neuronal degeneration and loss, and therefore gut dysmotility may be interpreted as a functional impairment of the ENS because of either the infiltrate or humoural factors released by eosinophils. Recently, a ganglionitis characterized by a predominance of mast cell infiltration along with smooth muscle involvement has been described in patients with severe gut dysmotility, including CIIP.66 The mast cells detected within myenteric ganglia in these patients were associated with markedly reduced nNOS expression identified at molecular and immunohistochemical levels. These findings suggest an impaired enteric inhibitory innervation in this peculiar subgroup of patients with CIIP.

image

Figure 1.  Representative photomicrographs of myenteric ganglionitis in a patient with chronic intestinal pseudo-obstruction. A dense accumulation of CD3+ T lymphocytes (brown colour) is visible around and throughout a myenteric plexus of the ileum as exemplified in (a). Note the rosette-like pattern of CD8+ T lymphocytes around myenteric neurons in (b), which suggest an autoimmune origin of ganglionitis. Streptavidin–biotin complex peroxidase immunohistochemical technique. Original magnification: ×80 in (a) and (b).

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In addition to cell-mediated immune response, a significant humoural immune activation, leading to the production of a wide array of circulating antineuronal antibodies, has been identified in patients with severe intestinal dysmotility. Antineuronal antibodies can be associated with an underlying disease (mainly paraneoplastic syndromes), but they may also be detected in patients with idiopathic forms of myenteric ganglionitis. Of note, the identification of antineuronal antibodies is recommended as a useful tool to diagnose gut motility disorders related to an inflammatory neuropathy.67, 68 Indeed, antineuronal antibodies can be detected using a variety of approaches, including classic immunofluorescence techniques (commonly applied in autoantibody screening tests) (Figure 2) as well as enzyme-linked immunosorbent assay and immunoblotting.68, 69 With regard to diagnosis, it has been suggested that the motility phenotype of enteric neuropathies (i.e. hyperactive gut motility with suppression of the migrating motor complexes) reflects the loss of inhibitory nerve pathways involved in circular muscle innervation. Therefore, this motor pattern, in conjunction with assays for circulating antineuronal antibodies, can be regarded as a useful basis for a proper characterization of CIIP in the clinical setting.70

image

Figure 2.  Representative photomicrographs showing antineuronal antibody immunoreactivity (i.e. anti-Hu with a titre >1:10.000) in the rat cerebellum (a) and enteric nervous system (b) of a patient with chronic intestinal pseudo-obstruction. Panel (a) shows intense immunostaining in the nucleus and cytoplasm of Purkinje cells (arrows) along with positivity of granular layer neurons (arrowheads). Panel (b) illustrates a bright staining in the myenteric neurons (arrows) of the rat ileum. Original magnification: ×40 in (a) and (b).

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Currently identified molecular targets of antineuronal antibodies include RNA-binding protein, Hu proteins (anti-Hu, known also as type 1 antineuronal nuclear antibodies; ANNA-1), Purkinje cell Yo protein (anti-Yo, anti-Purkinje cell cytoplasmic antibodies), P/Q- and N-type Ca2+ channels, and ganglionic nicotinic cholinergic receptors. Among these, anti-Hu antibodies represent the most common type of antineuronal antibody that can be found both in primary62 (Figure 2) and in secondary (paraneoplastic)69–72 inflammatory neuropathies. Hu proteins (i.e. HuC, HuD, HuR and Hel-N1) are constitutively expressed in a variety of cell populations and share sequence homology with the embryonic-lethal abnormal vision RNA-binding proteins of Drosophila.73, 74 With the exception of HuR, Hu proteins can be detected in central, peripheral and enteric neurons, where they are involved in mechanisms of cell development and survival.73–75 HuR is ubiquitously expressed in proliferating cells. The binding of antibodies to Hu proteins on enteric neurons may promote the neurodegenerative processes underlying gut dysmotility. We have recently shown that exposure to serum with anti-Hu antibodies, obtained from patients with paraneoplastic gut dysmotility, was capable of inducing apoptosis both in a neuroblastoma cell line and in cultured enteric neurons.76 This phenomenon, which was associated with an intense activation of the pro-apoptotic messengers caspase-3 and Apaf-1 in both neuroblastoma cells and enteric neurons, suggests that anti-Hu antibodies may contribute to ENS impairment and related gut motor disorders. In addition, anti-Hu antibodies may exert a direct functional effect and impair enteric neuronal circuitries. For example, early results showed that anti-Hu antibodies alter ascending reflex pathway of peristalsis in in vitro preparations.77 In a more recent study, anti-Hu antibodies evoked a prominent response characterized by marked hyperexcitability in primary culture of myenteric neurons as revealed by Ca2+-imaging and neuroimaging techniques.78 In addition to the examples described above, in which circulating antineuronal antibodies with identified molecular targets appear to contribute to neuronal dysfunction, it is likely that antisera directed against neuronal proteins may be the result of neuronal degeneration in myenteric ganglionitis, as discussed above for achalasia.

Slow transit constipation

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

This condition occurs predominantly in young women who are often unresponsive to high doses of laxatives.5, 59, 79 In recent years, clinical and manometric evidence has suggested that gut motor alterations in slow transit constipation (STC) might be considered as the consequence of a neuropathic disorder. Moreover, it has been observed that subtle alterations in the ENS, not evident to conventional histological examination, can be detected in these patients.80

Most studies, based on routine light microscopy, have failed to identify significant abnormalities of the ENS in patients with STC,81–83 apart from the presence of melanosis coli. However, a recent study has demonstrated that melanosis coli per se does not have any relationship with colonic ENS alterations in these patients.84 Morphological abnormalities of colonic innervation were initially described in STC patients by means of the silver staining technique.85 In general, these studies reported a reduction in the total number of argyrophilic neurons accompanied by structural alterations in both neuronal perikarya and axons.86, 87 Subsequently, other authors have shown that a decrease in enteric neural elements (i.e. cell bodies and/or processes) appears to be a constant feature in studies evaluating patients with STC who require surgery.88–90 In addition, there is evidence that neuronal alterations are often associated with reduced ICC and enteroglial cells.91–93 Bassotti et al.94 have recently examined a group of patients with severe and intractable STC, and they found that: (i) ICCs were significantly decreased; (ii) there was an enteric neuronal loss, which was partly ascribable to apoptotic cell death; and (iii) a significant decrease in the number of enteric glial cells was evident both in the submucosal and in myenteric plexus. However, upon examination of the terminal ileum in patients with intractable STC, the same authors observed only a reduction of enteric glial cells, while neuronal and ICC alterations were no longer evident.95

It has been proposed that colonic dysmotility related to STC might result from an imbalance of enteric neurotransmitters or neuropeptides. However, studies addressing this issue have often yielded inconsistent data. Indeed, looking at findings concerning the most frequently investigated mediators (VIP, substance P, neuropeptide Y and serotonin), decreased, increased or unchanged levels of immunoreactivity have been detected in patients with STC.96–99 On the basis of the above reports, it remains unclear whether alterations in enteric neurotransmitters play a role in the pathophysiology of STC. Nevertheless, more recent observations suggest that an excessive production of NO in the colonic myenteric plexus of patients with STC could be a significant pathophysiological determinant, contributing to the persistent inhibition of propulsive contractile activity.100

Hirschsprung’s disease

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Hirschsprung’s (HSCR) disease is characterized by the complete absence of ganglion cells in the submucosal and myenteric plexuses. HSCR is one of the best known forms of enteric neuropathy and its prevalence is about one case out of 5000 live births. The lack of enteric neurons leads to tonic contraction of the aganglionic gut segment, mainly the proximal rectum,101 with a concomitant functional obstruction, which is responsible for a massive dilatation of the proximal bowel (hence the term ‘congenital megacolon’ often applied to this condition). HSCR occurs as either familial or sporadic forms and, based on the extent of aganglionic tract, short- or long-segment types of HSCR can be distinguished. Most of sporadic HSCR forms are characterized by short-segment aganglionosis, whereas familial HSCR, affecting mainly male individuals (male to female ratio is 4:1), is associated with aganglionic tracts of variable length. Moreover, HSCR can exist as a single alteration or be a component of composite clinical pictures including different congenital abnormalities.102 Of note, HSCR can occur as a consequence of Down’s syndrome in about 10% of cases.

Suction rectal biopsies, which allow obtaining small amounts of rectal submucosa, can show the absence of submucosal ganglia and the presence of hypertrophic submucosal nerves, which represent projections of extrinsic nerve fibres into the muscularis mucosae and lamina propria.103 The immunohistochemical analysis of acetylcholinesterase or other neuronal markers may facilitate the diagnosis. However, a physiological zone of aganglionosis may exist in the terminal 1–3 cm of rectum and may lead to a false-positive diagnosis of HSCR.104 Conversely, biopsies from areas proximal to this physiological aganglionated zone may miss very short segments of clinically significant aganglionosis.105

Current evidence indicates that in familial HSCR, the inheritance conforms to a non-Mendelian transmission, thus implying the contribution of multiple genes. Consistent with this view, morphological and molecular investigations have shown that HSCR is a polygenic disorder, characterized by mutations affecting a wide array of genes involved in the control of neurotrophin and tyrosine kinase functions, which play crucial roles in neuronal differentiation and maturation. In particular, mutations implicated in HSCR affect the following genes: (i) rearranged during Transfection (RET) proto-oncogene and genes coding for its ligands (i.e. glial cell-derived neurotrophic factor and neurturin); (ii) endothelin-3, endothelin-B receptor and type 1 endothelin-converting enzyme; and (iii) transcription factors Sox10 and SMADIP1.106–114 RET mutations have been found in about 50% of familial and 17–20% of sporadic forms of HSCR.106–108 In addition, other genes, presently undetermined, are likely to play significant pathogenetic roles in HSCR.102Table 2 summarizes the genes and related syndromic and nonsyndromic forms of HSCR.

Table 2.   Genes involved in the pathogenesis of Hirschsprung’s disease
GeneClinical featuresInheritence
  1. ECE1, endothelin-converting enzyme 1; EDN3, endothelin 3; EDNRB, endothelin receptor B; GDNF, glial cell-line-derived neurotrophic factor; HSCR, Hirschsprung’s disease; MEN2A, multiple endocrine neoplasia, type IIA; NRTN, neurturin; PHOX2b, paired-like homeobox 2b; RET, rearranged during transfection; SOX10, SRY-box 10; ZFHX1B, zinc finger homeobox 1b.

  2. Note: Waardenburg–Shah syndrome is characterized by the combination of HSCR with pigmentation defects, while patients with Mowat–Wilson syndrome have HSCR in concomitance with distinct facial phenotypes (including high forehead, frontal bossing, large eyebrows and hypertelorism), moderate-to-severe intellectual deficiency, epilepsy, genitourinary anomalies, congenital heart defects and eye anomalies. Patients affected by Ondine’s curse syndrome (also known as congenital central hypoventilation syndrome) show impaired autonomic control of ventilation, which may be associated with HSCR in approximately 16% of cases. The clinical features of Goldberg–Shprintzen syndrome are microcephaly and mental retardation as well as HSCR (for review, see Ref. 102).

RETNonsyndromic HSCR/MEN2AAutosomal dominant with incomplete penetrance (50% familial; 15–35% sporadic cases)
GDNFNonsyndromic HSCRNon-Mendelian (sporadic cases)
NRTNNonsyndromic HSCRNon-Mendelian (sporadic cases)
EDNRBWaardenburg–Shah syndromeAutosomal recessive
Nonsyndromic HSCRAutosomal dominant (3–7% of cases)
EDN3Waardenburg–Shah syndromeAutosomal recessive
Nonsyndromic HSCRAutosomal dominant with incomplete penetrance (∼5% of cases)
ECE1HSCR with cardiac and autonomic nervous system abnormalitiesDe novo autosomal dominant (sporadic cases)
SOX10Waardenburg–Shah syndromeDe novo autosomal dominant
PHOX2bOndine’s curse syndromeDe novo autosomal dominant
ZFHX1BMowat–Wilson syndromeDe novo autosomal dominant
KIAA1279Goldberg–Shprintzen syndromeAutosomal recessive

Clinical management and current therapeutic indications

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

The diagnosis of gastrointestinal motility disorders can be considered when undigested solid food and/or large volumes of liquids are found during a digestive endoscopy performed to investigate upper abdominal symptoms. The goals of subsequent exams are to find out what regions of the digestive tract are affected and whether the complained symptoms are ascribable to underlying abnormalities of the neuromuscular layer. Specifically, diagnostic procedures (e.g. upper esophago-gastro-duodenoscopy, small bowel follow-through) should rule out the presence of mechanical obstruction, assess gut motor function (using a multilumen recording catheter equipped with sensors placed in the distal stomach and proximal small bowel), identify complications of motor disorders (i.e. nutritional abnormalities and bacterial overgrowth) and gain pathogenetic insights into the underlying enteric neuropathy. In this respect, full thickness gut biopsy sampling may be part of the diagnostic work-up (for review, see Ref. 6).

The current treatment of enteric neuropathies and related dysmotilities is rather unsatisfactory because of uncertainties and limited knowledge about the pathogenetic basis of these conditions. Indeed, solid rationales, supporting appropriate therapeutic managements of patients with neuropathic dysmotility, are still lacking. A summary of options for pharmacological treatments of enteric neuropathies and related motor disorders is reported in Table 3.

Table 3.   Summary of available options for pharmacological treatment of patients with enteric neuropathy and related motor disorders
DiseaseDrugsComments
AchalasiaNitrates Phosphodiesterase-5 inhibitors Ca2+ channel blockers Botulinum toxinLimited efficacy; common occurrence of side effects and tolerance; current evidence indicates these drugs as temporary measures
GastroparesisSerotonergic/dopaminergic prokinetics and antiemetics Erythromycin and motilides Botulinum toxinLimited evidence of clinical efficacy; short duration; risk of major adverse effects
Chronic idiopathic intestinal pseudo-obstructionSerotonergic/dopaminergic prokinetics and antiemetics Anticholinesterases Erythromycin and motilides Somatostatin analogues Antibiotics Analgesics Immunosuppressant agentsLimited evidence of clinical efficacy; short duration; risk of major adverse effects Anticholinesterases are indicated in acute pseudo-obstruction Somatostatin analogues are indicated for bacterial overgrowth and symptom control Immunosuppressants may be of help in patients with established myenteric ganglionitis
Slow transit constipationSerotonergic prokinetics Neurotrophins Bicyclic fatty acidsLimited evidence of clinical efficacy; risk of major adverse effects for serotonergic prokinetics Neutrophin need further clinical investigation Promising data for bicyclic fatty acids (lubiprostone)

Achalasia

There are three objectives in the treatment of patients with achalasia: to achieve symptom control by improvement or relief of the main complaints (dysphagia and regurgitation), to reduce LOS pressure and to prevent the progression of the disease towards megaoesophagus.115 A number of drawbacks hamper the pharmacological approach to this disease. Particularly, most studies have been uncontrolled and usually included only a small number of patients. Very few single or double-blind, placebo-controlled trials are currently available. Thus, the pharmacological approach should be indicated only in patients unsuitable for any other procedure, those scheduled for a more definitive therapy or as supportive treatment for refractory chest pain.115, 116 Nitrates (nitroglycerin and isosorbide dinitrate), acting as NO donors and known to have powerful smooth muscle relaxing properties, have been proposed for achalasia. However, the relatively high frequency of side effects, the rapid development of tolerance and the lack of controlled, randomized studies supporting their actual efficacy limit their clinical use.117, 118 Still undefined is the role of long-acting nitrates as well as the more recently developed phosphodiesterase-5 inhibitors (i.e. sildenafil), which have been proposed for treatment of achalasia.119 Calcium channel blockers, another drug class endowed with well known smooth muscle relaxing activity, have been also used. In particular, nifedipine has the widest published clinical and experimental evidence supporting its efficacy. The suggested therapeutic schedule consists of a sublingual administration of 10–20 mg, 15–30 min before meals. Its effectiveness varies largely from 50% to 90% in clinical trials, with side effects complained by up to 30% of patients. Adverse effects include peripheral oedema, headache and hypotension, even if tolerance to these side effects may develop over time.120

Botulinum toxin can ensure an adequate LOS relaxation by inhibition of acetylcholine release from cholinergic nerve endings. Accordingly, endoscopic intrasphincteric injection of botulinum toxin has been shown to ameliorate significantly the symptoms of achalasia, and early cumulative data indicated that botulinum toxin relieved symptoms in about 85% of patients at the first treatment.121 Unfortunately, the favourable outcome of the intervention is relatively short-lived, and symptom recurs in more than 50% of patients within 6 months. More recent studies indicate that botulinum toxin injection is less efficacious than balloon dilatation in promoting symptom resolution.122, 123

At present, forceful dilatation of LOS is regarded as the most effective nonsurgical treatment for achalasia, although details of the procedure vary in different institutions.124 Overall, a literature analysis of more than 3000 patients showed that the efficacy of pneumatic dilatation in relieving symptoms is 85%, with a range of 65–90%. Perforation is probably the main adverse event associated with pneumatic dilatation, and it may often require a surgical repair. Another drawback of pneumatic dilatation is a possible relapse of symptoms, which requires additional dilatatory interventions.116

Given the relatively modest effects of medical therapy and the shortcomings of endoscopic dilatation, alternative surgical strategies have been considered for the management of achalasia. Based on current evidence, laparoscopic Heller myotomy is generally accepted as the operative procedure of choice.124

Gastroparesis

Current pharmacological therapies for gastroparesis are based on the assumption that the paralysed stomach lacks adequate contractile activity. In line with this concept, prokinetic drugs are the mainstay of pharmacological strategies to treat gastroparesis. The beneficial effects resulting from the use of some of these drugs (e.g. domperidone and metoclopramide) may depend on their antiemetic properties (Table 4). Few randomized controlled trials have assessed the efficacy of prokinetic drugs in gastroparesis.125 The risk of severe toxicity may represent a major drawback for the use of these drugs in routine clinical practice. For instance, cisapride has been retired from the market owing to cardiac arrhythmias.126–131 Erythromycin is a motilin agonist, which is known to induce migrating motor complex contractions thereby accelerating gastric emptying. This pharmacological property is shared by more recently developed erythromycin derivatives (motilides) devoid of antibiotic activity but endowed with prokinetic effects. Overall, macrolide derivatives have been proven to be effective in promoting gastric emptying, although their clinical benefits remain limited because of poor symptom control, rapid development of tolerance and adverse effects resulting from bacterial resistance in the case of erythromycin.125

Table 4.   Prokinetic drugs with therapeutic indications in the treatment of gastrointestinal dysmotility disorders
DrugReceptor pathwaysGenerationPredominant effects
D2 (antagonism)5-HT4 (agonism)5-HT3 (antagonism)
  1. D2, type 2 dopamine receptor; 5-HT3, type 3 serotonin receptor; 5-HT4, type 4 serotonin receptor.

  2. Receptor affinity: +++, very high; ++, high; +, moderate; ±, low; −, none; ?, undetermined.

  3. * Predominant action on upper gastrointestinal (GI) tract.

  4. † Antiemetic effect resulting from 5-HT3 receptor antagonism.

  5. ‡ Antagonism on 5-HT3 receptors by a metabolite of mosapride.

  6. § Partial agonism.

  7. ¶ Prokinetic effect resulting from agonism on motilin receptors.

Butyrophenones
 Domperidone++FirstAntiemetic, prokinetic (upper GI tract)
Benzamides
 Levosulpiride+++±FirstAntiemetic, prokinetic (upper GI tract)
 Metoclopramide++++FirstAntiemetic, prokinetic (upper GI tract)
 Clebopride++??FirstAntiemetic, prokinetic (upper GI tract)
 Bromopride++??FirstAntiemetic, prokinetic (upper GI tract)
 Cisapride+++SecondProkinetic*
 Renzapride++++SecondAntiemetic, prokinetic (upper GI tract)†
 Zacopride+++++SecondAntiemetic, prokinetic (upper GI tract)†
 Mosapride++++‡SecondProkinetic (upper GI tract)
Benzofuranes
 Prucalopride+++ThirdProkinetic (lower GI tract)
Aminoguanydilindoles
 Tegaserod++§ThirdProkinetic (lower GI tract)
Macrolides
 ErythromycinThirdProkinetic (upper GI tract)¶

There is some evidence to support the use of intrapyloric injection of botulinum toxin in gastroparesis. Most of the current experience with this agent refers to patients with diabetic gastroparesis, while data on idiopathic forms are limited and, in some instances, disappointing.125 A study on patients with severe idiopathic gastroparesis showed that botulinum toxin accelerated gastric emptying and reduced symptoms.132 The reported duration of improvements achieved with botulinum toxin was about 6 weeks for gastric emptying and 8 weeks for symptoms. In a retrospective analysis of patients with refractory gastroparesis subjected to open-label treatment with botulinum toxin, a response rate of 43% in symptom improvement for 2 months was observed.133

Some patients may fail to achieve symptom relief despite dietary and pharmacological treatments. In some instances, these patients may benefit from endoscopic or surgical interventions. In selected cases, a gastrostomy can be performed either endoscopically (percutaneous endoscopic gastrostomy) or surgically. The gastrostomy is then opened intermittently to alleviate postprandial nausea, bloating and abdominal pain. One study reported a dramatic improvement in symptoms, weight and overall well-being over a 3-year period in patients subjected to venting gastrostomy.134 Patients failing to respond to venting gastrostomy and medical therapy should be considered for endoscopic or surgical jejunostomy to maintain nutrition and adequate hydration.135 Total parenteral nutrition can be indicated if patients are unable to tolerate adequate oral or tube feeding. Total parenteral nutrition may also be used on short term during hospitalizations to manage an acute flare of symptoms. However, the use of chronic total parenteral nutrition should be discouraged because of its cost and the specific risks of sepsis, thrombosis and liver disease.

In selected cases of gastroparesis refractory to medical treatments, gastric electrical stimulation has been shown to be effective in normalizing gastric dysrhythmia, accelerating gastric emptying and improving nausea and vomiting. An implantable device has been made available to deliver gastric electrical stimulation and treat gastroparesis. However, development of new devices and controlled clinical studies are required to prove conclusively the clinical efficacy of gastric electrical stimulation.136

Chronic idiopathic intestinal pseudo-obstruction

Treatment of CIIP is usually disappointing even if nutritional, pharmacological and surgical therapies have somehow improved the management of these patients in the last few decades. The main problem of patients with predominant involvement of the small bowel is malnutrition caused by both malabsorption and inadequate food intake, as a consequence of severe digestive symptoms. For these reasons, CIIP should be regarded as a relevant cause of intestinal failure. Small, low-fat and low-fibre meals with liquid or homogenized foods are generally better tolerated and may help patients with residual digestive functions. Supplementation with multivitamin products and salts is generally necessary. Hypercaloric liquid preparations are available and can be helpful if tolerated. In most severe cases of gut dysmotility with inability to receive oral feeding, nutrients can be provided by either enteral (using feeding jejunostomy with or without decompression gastrostomy) or parenteral nutrition. The main limitations of parenteral nutrition include severe complications such as liver failure, pancreatitis, glomerulonephritis and catheter-related complications (i.e. thrombosis and sepsis).137 In most cases, small bowel bacterial overgrowth is an important cause of diarrhoea and malnutrition, and it should be treated with antibiotic therapy. Although unabsorbable antibiotics (i.e. rifaximin) represent the treatment of choice,138 courses of other antibiotics, such as metronidazole, ciprofloxacin and doxycycline, may be introduced to counteract the possible occurrence of bacterial resistance. Furthermore, the long-acting somatostatin analogue octreotide has been successfully tested at low doses to treat small intestine bacterial overgrowth, owing to its ability to generate migrating motor complexes in patients with CIIP and sclerodermia-related chronic intestinal pseudo-obstruction.139 A variety of drugs have been used to improve gut motor functions (Table 4). In particular, erythromycin, metoclopramide, domperidone, cisapride and tegaserod may be considered as possible therapeutic choices. In addition, anticholinesterases (e.g. neostigmine, pyridostigmine) have been successfully employed in acute colonic pseudo-obstruction (Ogilvie’s syndrome), whereas there is little evidence about their efficacy in CIIP. As CIIP is a quite rare condition, only a few trials have been published140–144 and a vast majority of these studies are uncontrolled. In two controlled trials, Camilleri et al. described positive effects of cisapride in accelerating gastric emptying141 and improving symptoms.144 Various associations of prokinetic drugs are often empirically tested145 in the attempt to enhance their therapeutic effects, while decreasing the risk of drug tolerance and adverse effects. Analgesics, preferably those not directly affecting gut motility, should be added in the clinical management of abdominal pain in CIIP.

In very selected cases in which CIIP is related to an underlying inflammatory neuropathy (i.e. myenteric ganglionitis) established by tissue analysis or suspected by identification of circulating antineuronal (e.g. anti-Hu) antibodies, a treatment course with immunosuppressive agents may be advised.6

Slow transit constipation

Ideally, STC should be treated with a prokinetic agent capable of selectively stimulating colonic peristalsis. Despite research efforts, unmet need still exists for effective drugs to be used in the treatment of gastrointestinal motor disorders, including the most severe forms. At present, data emerged from serotonergic receptor pharmacology have not allowed the clinical development of effective and well tolerated enterokinetic drugs. Nonetheless, preliminary studies with the 5HT4 serotonin receptor full agonist prucalopride have shown promising results, with increased stool frequency and improved colonic transit time146 (Table 4). Likewise, recent studies on the partial agonist of 5HT4 serotonin receptor tegaserod have shown improvements in bowel symptoms and colonic transit in constipated patients.147

Laxatives are also commonly employed in the medical therapy of STC, but evidence from controlled clinical trials to support their use is quite modest. According to clinical experience, bulk forming or osmotic laxatives, such as psyllium seeds or polyethylene glycol solutions, are generally not effective. Stimulant laxatives, such as bisacodyl, are regarded as a first line therapy, although some studies show a reduced colonic motor response to such agents. Saline laxatives can be considered for the elderly, provided there are no cardiac or renal comorbid contraindications. There is no compelling evidence to suggest that the chronic use of these laxatives is harmful if they are used two to three times per week.148–150

A novel therapeutic approach has been the use of neurotrophins, in particular neurotrophin-3, to resolve constipation.151 A recent 4-week, double-blind, controlled trial showed that neurotrophin-3 improved symptoms, in particular stool frequency, consistency, straining effort and accelerated colonic transit time in patients with STC.152 Finally, lubiprostone, a bicyclic fatty acid targeting the gastrointestinal tract, has been shown to act as a selective chloride channel activator in the apical membrane of enterocytes where it stimulates intestinal water secretion.153 This effect causes an increment of gut intraluminal fluids, which facilitates intestinal transit thereby promoting stool passage.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

At present, the growing knowledge of the functional organization, neurotransmitters and pharmacological modulation of the enteric neuronal circuitries has had a modest impact on the understanding of enteric neuropathies. Many pathophysiological aspects of these severe conditions remain largely obscure and so treatment options are quite limited and often unsatisfactory. Nonetheless, advances in understanding basic mechanisms and molecular pathology of enteric neuropathies augur well for the development of more effective therapies for these severe conditions. To this end, it is critically important that translational medical research bridges the gap between findings in basic science and data in the clinical setting.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References

Declaration of personal interests: None. Declaration of funding interests: Some of the data presented in this review derived from original work partly funded by the Italian Ministry of University and Research (COFIN Projects No. 2004062155 and No. 2003064378 to VS, GB and RDeG), RFO and FAR funds from University of Bologna and Pavia, and a grant from ‘Fondazione Del Monte di Bologna e Ravenna’ to RDeG.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Achalasia
  5. Gastroparesis
  6. Chronic intestinal pseudo-obstruction
  7. Slow transit constipation
  8. Hirschsprung’s disease
  9. Clinical management and current therapeutic indications
  10. Conclusions
  11. Acknowledgements
  12. References