Pathophysiology.doc

GI Motility online (2006) doi:10.1038/gimo22Published 16 May 2006Pathophysiology of achalasia and diffuse esophageal spasmIkuo Hirano, M.D.Key Points Achalasia is the best understood example of an esophageal motility disorder and characterized by esophageal aperistalsis and impaired relaxation of the lower esophageal sphincter. The histopathology of achalasia involves inflammation of the myenteric plexus of the esophagus with diminution of ganglion cells. Significant reduction in nitric oxide synthase containing neurons has been demonstrated using immunohistochemical staining. Autoimmune, neurodegenerative, and viral etiologies have been implicated in the pathogenesis of achalasia. However, the exact cause has yet to be elucidated. Pharmacologic studies in achalasia patients support the selective loss of inhibitory, nitrergic neurons with preservation of cholinergic innervation. Animal models that include genetically engineered mice with targeted disruption of the gene encoding for the neuronal form of nitric oxide synthase and pharmacologic administration of inhibitors of nitric oxide substantiate the role of nitrergic denervation in achalasia. Achalasia may be secondary to a wide range of secondary disorders including genetic syndromes, infectious diseases, neoplasm, and chronic inflammatory conditions.IntroductionSir Thomas Willis is credited with the first report of a patient with achalasia in 1674. Von Mikulicz in 1882 and Einhorn in 1888 hypothesized that the disease was due to the absence of opening of the cardia or cardiospasm. Over the past three centuries, achalasia has emerged as an important model by which to understand the pathophysiology and therapy of motility disorders emanating from a defect in the enteric nervous system. It is the most extensively studied and readily treatable gastrointestinal motor disorder. This review discusses current concepts in achalasia with an emphasis on the pathophysiology and etiology of the disease. Specific secondary etiologies of achalasia are discussed that provide insight into mechanisms responsible for the neurodegeneration that characterizes the disorder. Diffuse esophageal spasm is also discussed, although there is a paucity of data regarding this condition.Clinical Features of AchalasiaAchalasia occurs with an incidence of approximately 1:100,000 with an equal gender distribution.1 It occurs at all ages with an increase in incidence observed after the seventh decade. Dysphagia is the predominant symptom and it is typically accompanied by regurgitation. Upper endoscopy is often the first test used to evaluate patients with suspected achalasia and may detect esophageal dilatation with retained saliva or food. A barium esophagram can be highly suggestive of the diagnosis of achalasia, particularly when there is the combination of esophageal dilatation with retained food and barium and a smooth, tapered constriction of the gastroesophageal junction. Quantitative assessment of the degree of esophageal emptying of barium over time may increase the diagnostic sensitivity of the esophagram for achalasia and serves as a valuable means by which to follow patients response to therapy (Figure 1).2, 3 The test with the highest sensitivity in the diagnosis of achalasia is esophageal manometry. The defining manometric features of achalasia are aperistalsis of the distal esophagus and incomplete or absent lower esophageal sphincter (LES) relaxation (Figure 2). Additional supportive features include a hypertensive lower esophageal sphincter and low-amplitude esophageal body contractions. Preservation of proximal esophageal peristalsis can be seen in some cases without esophageal dilation (Figure 3a) but a pattern of complete esophageal aperistalsis is more common (Figure 3b).Figure 1:Timed barium swallow.Following the ingestion of a fixed volume of barium, sequential radiographs are taken at 1, 2, and 5 minutes. The three panels demonstrate a lack of emptying with a fixed column of barium persisting at 5 minutes. Full size image (47 KB) Download Power Point slide (1,463 KB) Figure 2:Esophageal manometric findings in achalasia.The tracing illustrates the findings in classic achalasia with esophageal body aperistalsis with low-amplitude simultaneous esophageal body contractions and failed relaxation of the lower esophageal sphincter. Full size image (69 KB) Download Power Point slide (494 KB) Figure 3:Contour plot topographic analysis of esophageal motility in achalasia.Topographic analysis is a method of axial data interpolation derived from computerized plotting of data from multiple, closely spaced, solid-state recording transducers. The interpolated pressure information is plotted as a two-dimensional contour plot in which pressure amplitude is coded by color. a: A normal esophageal study with propagation of the peristaltic wave and relaxation of the lower esophageal sphincter (LES). The upper esophageal sphincter is also depicted at the top of the panel, demonstrating a higher basal pressure and shorter relaxation phase. b: Study for a patient with achalasia demonstrating integrity of proximal esophageal peristalsis with mid and distal esophageal body aperistalsis (simultaneous contractions). Incomplete relaxation of the LES and elevated esophagastric pressure gradient are also demonstrated. c: A study from a patient with achalasia with complete esophageal aperistalsis and incomplete relaxation of the hypertensive LES. Although there is partial inhibition of the LES, the relaxation pressures exceed 40 mmHg. An esophagogastric pressure gradient is evident in the distal esophagus. Full size image (82 KB) Download Power Point slide (1,546 KB) High-resolution manometry combined with topographic analysis is an emerging technique that offers potential advantages over conventional esophageal manometry.4 Using this technique, a threshold value of 8 to 10 mmHg for the mean residual pressure in a 3-second postdeglutitive interval distinguished achalasia patients from controls.5 Greater accuracy was achieved utilizing the transsphincteric pressure gradient during the 2- to 6-second post-swallow interval. Pressure gradients exceeding 5 mmHg had a sensitivity of 94% and specificity of 98% for detecting achalasia. Although an emerging methodology for investigative purposes, the advantages of high-resolution manometry with topography over conventional manometry for clinical practice are still being established. Figure 3 illustrates a contour plot topographic analysis of two patients with achalasia.Although manometry is accepted as the gold standard for making the diagnosis of achalasia, heterogeneity does exist in the manometric presentation.6 The most commonly recognized variant of achalasia is known as vigorous achalasia, variably defined by the presence of normal to high-amplitude simultaneous esophageal body contractions in the presence of a nonrelaxing LES (Figure 4). The amplitudes of preserved esophageal body contractions used to define vigorous achalasia have ranged from 37 mmHg to 60 mmHg. High-amplitude and long-duration esophageal body contractions have also been reported. These manometric features of vigorous achalasia overlap with diffuse esophageal spasm. Although vigorous achalasia may represent an early stage of achalasia, studies have failed to demonstrate differences in terms of clinical presentation in such patients including duration of disease or the occurrence of chest pain. Additional manometric variants of achalasia include rare patients with intact peristalsis through the more than 50% of the distal esophageal body and others with preservation of either deglutitive or transient LES relaxation (Figure 5).6, 7 In these reports, the diagnosis of achalasia was substantiated by demonstrating degeneration of myenteric neurons as well as the clinical response to disruption of the LES. The clinical significance of defining these variants of achalasia lies in the recognition that these sometimes confusing manometric findings are still consistent with achalasia when combined with additional data supportive of the diagnosis. The variants also provide clues to the pathophysiology of the disease.Figure 4:Esophageal manometric findings in vigorous achalasia.The recording is from a patient with vigorous achalasia demonstrating robust, simultaneous esophageal body contractions and failed relaxation of a hypertensive lower esophageal sphincter. Full size image (71 KB) Download Power Point slide (531 KB) Figure 5:Esophageal manometric findings in achalasia variant with preserved LES relaxation.The panel illustrates the findings in classic achalasia with esophageal body aperistalsis with low-amplitude simultaneous esophageal body contractions and apparent relaxation of the lower esophageal sphincter. Full size image (69 KB) Download Power Point slide (538 KB) In addition to limitations in the sensitivity of the manometric features of achalasia, there also exist limitations in their specificity. Scleroderma shares many of the manometric features of achalasia with the exception of failed deglutitive relaxation of a hypertensive LES. This distinction becomes blurred in the setting of idiopathic achalasia with a low-normal LES basal pressure or treated achalasia. In addition, a prominent crural diaphragm contribution to LES basal pressure can be misinterpreted as the intrinsic basal LES pressure, and when combined with the presence of esophageal body aperistalsis of scleroderma esophagus, leads to a misdiagnosis of achalasia. Complicating matters, the esophageal manifestations of scleroderma may be the initial presentation in some patients with scleroderma. As mentioned, diffuse esophageal spasm has several manometric features that overlap with the vigorous form of achalasia. This overlap, combined with reports of progression of patients from esophageal spasm to achalasia, has led some authorities to question the existence of esophageal spasm as a distinct entity. Finally, a number of secondary causes of achalasia exist and are manometrically indistinguishable from idiopathic achalasia. The most clinically important secondary causes that need to be differentiated include pseudoachalasia as a consequence of neoplastic infiltration of the gastroesophageal junction and mechanical obstruction of the junction by a surgically created fundoplication. These and other secondary causes are discussed in a later section.Top of page Pathophysiology of AchalasiaEsophageal Motility AbnormalitiesHistopathologyOver the past 75 years, several pathologic studies have demonstrated the marked diminution of neurons from the myenteric plexus in achalasia.8, 9, 10, 11, 12 Illustrative of this is the large series by Goldblums group13 in which complete absence of myenteric ganglion cells was demonstrated in 64% and marked reduction in 36% of the esophagi of 42 patients with achalasia who underwent esophagectomy. The same investigators also demonstrated a marked, T-cell predominant inflammatory infiltration of the myenteric plexus with fibrosis that was inversely correlated with the number of preserved ganglia.11 Recent studies have examined muscle biopsies from achalasia patients treated at an earlier stage of disease. These studies have detected intact, though a reduced number of, ganglion cells in achalasia patients having a shorter duration of symptoms and a nondilated esophagus,10, 14, 15 or preservation of esophageal contractile activity.11 The supposition is that myenteric inflammation occurs early in the natural history of achalasia and leads to aganglionosis and fibrosis. Figure 6 depicts a panel of varying degrees of myenteric inflammation and aganglionosis.Figure 6:Histopathology of achalasia.a: Normal myenteric plexus demonstrating multiple ganglion cells and minimal lymphocytic infiltration. b: Mild myenteric inflammation. There is mild lymphocytic inflammation, and ganglion cells can be identified. c: Moderate myenteric inflammation with lymphocytic infiltrate is present. Ganglion cells are absent. d: Severe myenteric inflammation with lymphocytes densely clustered within this myenteric plexus. Ganglion cells are absent. (Source: Hirano and Kahrilas112 with permission from Blackwell Publishing.) Full size image (67 KB) Download Power Point slide (1,462 KB) Histologic examination of the smooth muscle of the esophagus of patients with achalasia have demonstrated a distinct abnormalities.10, 11, 16 Goldblum16 described hypertrophy as well as muscle degeneration of the muscularis propria and muscularis mucosae in the majority of 42 cases that underwent resection. Using high-frequency ultrasonography, Mittal et al.17 demonstrated a marked increase in both muscle wall thickness as well as cross-sectional area in achalasia patients. The increase in muscle mass was present in patients with and without esophageal dilation. The mechanism responsible for the muscle hypertrophy is unclear. Obstruction of esophageal outflow has been shown to result in secondary muscle hypertrophy in animal models.18, 19 In addition, the deficiency in nitric oxide that characterizes achalasia could also be responsible. Nitric oxide has an inhibitory effect on smooth muscle proliferation, and visceral smooth muscle hypertrophy has been described in neuronal nitric oxide synthase knockout mice.20Interestingly, 52% of 42 specimens from esophageal resections for achalasia had eosinophilia of the muscularis propria. Tottrup et al.21 detected increased expression of eosinophilic cationic protein in achalasia, suggesting a possible pathogenic role for activated eosinophils in achalasia. Although eosinophils are not present in the esophagus of control specimens, no relationship between the increasingly recognized entity of eosinophilic esophagitis and achalasia has been established. Eosinophilic esophagitis is characterized by the finding of eosinophilic infiltration of the squamous mucosa, although cases of infiltration of the muscularis propria have been reported.22Integrity of Cholinergic InnervationA number of physiologic studies have uncovered an intact cholinergic innervation to the esophagus in achalasia. An in vitro study by Trounce et al.23 in 1957 demonstrated contractions of muscle strips from achalasia patients to the combination of the acetylcholinesterase inhibitor, eserine, and the ganglionic agonist, nicotine. Intact acetylcholinesterase activity of preserved ganglion cells in the lower segment of the esophagus of achalasia patients was described by Adams24 in 1961. The acetylcholinesterase inhibitor edrophonium chloride was later shown to significantly increase the LES pressures in patients with achalasia.25 These findings suggest that at least some postganglionic, cholinergic nerve endings remain intact. Further evidence in this regard came from a study looking at the effects of the anticholinergic agent atropine in patients with achalasia.26 This study demonstrated a 30% to 60% reduction in LES pressure with atropine in patients with achalasia. A similar reduction was found in a control group of healthy volunteers. Of note, however, is the fact that the residual pressure after atropine was significantly higher in the achalasia patients (17 mmHg) than in the normal subjects (5 mmHg).Recently, botulinum toxin has been introduced as a novel treatment for achalasia. Botulinum toxin acts to inhibit the exocytosis of acetylcholine from cholinergic nerve endings. Most studies using botulinum toxin have found a significant symptomatic response rate. However, objective measures of response including LES pressure and esophageal emptying were modest and in some studies not significantly different from baseline values.27, 28 Similar to the studies using atropine, a significant residual LES pressure was observed following botulinum toxin, 25 mmHg in a study by Pasricha et al.28 and 20 mmHg in a study by Cuilliere et al.29 Therefore, the studies using atropine and botulinum toxin both support the concept of preservation of cholinergic nerves in patients with achalasia. Furthermore, they have provided evidence for a significant, noncholinergic component to LES basal pressure. It is likely that this residual pressure represents the myogenic contribution to LES tone. Heterogeneity in the response to botulinum toxin suggests a variable degree of cholinergic preservation of individual achalasia patients.Loss of Inhibitory InnervationPreservation of the excitatory, cholinergic innervation to the esophagus implies that the neuronal loss that characterizes achalasia may be selective for inhibitory neurons. Dodds et al.30 provided indirect evidence for this through the use of cholecystokinin, which has direct excitatory effects on smooth muscle as well as indirect inhibitory effects via postganglionic inhibitory neurons. In patients with achalasia, cholecystokinin induced LES contraction as opposed to the relaxation of the LES seen in control subjects, thereby providing evidence for impaired postganglionic inhibitory nerves. More recent evidence comes from in vitro studies looking at the responses of preparations of LES specimens from patients with achalasia. Circular muscles strips of the LES from normal subjects characteristically relax in response to electrical field stimulation through the activation of nitric oxide containing inhibitory neurons.31, 32 Paradoxically, LES strips from achalasia patients were found to contract in response to electrical field stimulation (Figure 7).31 Such findings can be readily explained by the absence of inhibitory neurons and presence of excitatory neurons.Figure 7:In vitro study demonstrating the effects of electrical field stimulation (EFS) on circular muscle strips from the LES of control subjects (a) and patients with achalasia (b).Electrical field stimulation activat