Rohan Williams

Esophagopharyngeal acid regurgitation: Dual pH monitoring criteria for its detection and insights into mechanisms☆☆☆

BACKGROUND & AIMS A valid technique for the detection of esophagopharyngeal acid regurgitation would be valuable to evaluate suspected reflux-related otolaryngologic and respiratory disorders. The aim of this study was to derive pH criteria that optimally define esophagopharyngeal acid regurgitation and to examine patterns of regurgitation. METHODS In 19 healthy controls and 15 patients with suspected regurgitation, dual or quadruple pH sensors were used to monitor pharyngeal and esophageal pH. For each combination of the 2 variables, DeltapH and nadir pH, proportions of pH decreases that occurred during or independent of esophageal acidification were calculated to determine the likelihood that an individual pharyngeal pH decrease was a candidate regurgitation event or a definite artifact. RESULTS Overall, 92% of pharyngeal pH decreases of 1-2 pH units and 66% of pH decreases of this magnitude reaching a nadir pH of <4 were artifactual. Optimal criteria defining a pharyngeal acid regurgitation event were a pH decrease that occurred during esophageal acidification, had a DeltapH of >2 units, and reached a nadir of <4 units in less than 30 seconds. Regurgitation occurred more frequently in subjects in an upright (32 of 35) than in a supine (3 of 35 events; P </= 0.0001) position and was more frequently abrupt (synchronous with esophageal acidification) than delayed (P </= 0.05). CONCLUSIONS Accepted criteria for gastroesophageal reflux are not applicable to the detection of esophagopharyngeal acid regurgitation, and most regurgitation occurs abruptly and in upright position.

Predictors of Outcome in an Open Label, Therapeutic Trial of High-Dose Omeprazole in Laryngitis

BACKGROUND:Gastroesophageal reflux is implicated in some cases of laryngitis. There are no established predictors of response to acid suppression therapy in suspected reflux laryngitis.AIM:In a population with laryngitis, the aim is to determine whether (a) omeprazole 20 mg tds (3 months) improves symptoms and laryngitis, and (b) the outcome in response to potent acid suppression can be predicted by esophageal and/or pharyngeal parameters during ambulatory pH monitoring or by other pretreatment variables.METHODS:From the 70 consecutive patients with laryngitis screened, 20 patients met the inclusion criteria (dysphonia >3 months; laryngoscopically demonstrated laryngitis); and 50 patients were excluded because of one or more criteria indicating alternative causes for laryngeal injury. The primary outcome measure was improvement of at least one level in a 4-point laryngitis grading at 3 months. Twenty-four-hour dual, pharyngo-esophageal pH monitoring was performed at baseline. Secondary outcomes (symptom questionnaire; computerized voice analysis) were measured at baseline, and at 6 and 12 wk.RESULTS:Response rates at 6 and 12 wk were 47% and 63%, respectively. GERD symptoms (heartburn (p= 0.03) and regurgitation (p= 0.0001)) improved. However, neither baseline GERD symptoms nor endoscopic findings predicted laryngoscopic or symptomatic response. Neither baseline laryngitis grade (p= 0.46) nor esophageal acid exposure on pH testing (p= 0.3) predicted outcome. Four of 20 patients demonstrated pharyngeal regurgitation on pH testing, all four of whom responded to potent acid suppression (p= 0.2). Computerized voice measures were not predictive of outcome, although fundamental frequency (Fo) was inversely related to baseline laryngoscopic grade.CONCLUSION:In a carefully defined population of patients with laryngitis (a) 63% have a laryngoscopic response to 3 months of potent acid suppression without significant improvement in laryngeal symptoms; (b) neither voice measures, esophageal acid exposure time, symptoms nor severity of laryngitis predict outcome; and (c) although numbers were small, all patients with a positive pharyngeal pH study responded to therapy and pharyngeal pH-metry may prove useful; (4) available evidence supports an empiric trial of high-dose proton pump inhibitors (PPI), for at least 12 wk, as the initial diagnostic step for suspected reflux laryngitis.

Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver

The molecular pathogenesis of alcoholic liver disease (ALD) is not well understood. Gene expression profiling has the potential to identify new pathways and altered molecules in ALD. Gene expression profiles of ALD in a baboon model and humans were compared using DNA arrays. Reverse transcriptase-polymerase chain reaction and immunohistochemistry were used for downstream analysis of array results. cDNA array analysis revealed differential expression of several novel genes and pathways in addition to genes known to be involved in ALD pathogenesis. Overall gene expression profiles were similar in both species, with a majority of genes involved with fibrogenesis and xenobiotic metabolism, as well as inflammation, oxidant stress, and cell signaling. Genes associated with stellate cell activation (collagens, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinase) were up-regulated in humans. Decreased expression of several metallothioneins was unexpected. Fourteen molecules related to the annexin family were up-regulated, including annexin A1 and A2. Immunofluorescence revealed a marked overexpression of annexin A2 in proliferating bile duct cells, hepatocyte cell surface, and selective co-localization with CD14-positive cells in human ALD. The gene expression profile of ALD is dominated by alcohol metabolism and inflammation and differs from other liver diseases. Annexins may play a role in the progression of fibrosis in ALD.

Biomechanics, diagnosis, and treatment outcome in inflammatory myopathy presenting as oropharyngeal dysphagia

Aims: In patients with inflammatory myopathy and dysphagia, our aims were to determine: (1) the diagnostic utility of clinical and laboratory indicators; (2) the biomechanical properties of the pharyngo-oesophageal segment; (3) the usefulness of pharyngeal videomanometry in distinguishing neuropathic from myopathic dysphagia; and (4) clinical outcome. Methods: Clinical, laboratory, and videomanometric assessment was performed in 13 patients with myositis and dysphagia, in 17 disease controls with dysphagia (due to proven CNS disease), and in 22 healthy age matched controls. The diagnostic accuracy of creatine kinase (CPK), erythrocyte sedimentation rate, antinuclear antibody, and electromyography (EMG) were compared with the gold standard muscle biopsy. The biomechanical properties of the pharyngo-oesophageal segment were assessed by videomanometry. Results: Mean time from dysphagia onset to the diagnosis of myositis was 55 months (range 1–180). One third had no extrapharyngeal muscle weakness; 25% had normal CPK, and EMG was unhelpful in 28%. Compared with neurogenic controls, myositis patients had more prevalent cricopharyngeal restrictive disorders (69% v 14%; p=0.0003), reduced upper oesophageal sphincter (UOS) opening (p=0.01), and elevated hypopharyngeal intrabolus pressures (p=0.001). Videomanometric features favouring a myopathic over a neuropathic aetiology were: preserved pharyngeal swallow response, complete UOS relaxation, and normal swallow coordination. The 12 month mortality was 31%. Conclusions: The notable lack of supportive clinical signs and significant false negative rates for laboratory tests contribute to the marked delay in diagnosis. The myopathic process is strongly associated with restricted sphincter opening suggesting that cricopharyngeal disruption is a useful adjunct to immunosuppressive therapy. The condition has a poor prognosis.

Oropharyngeal Scintigraphy: A Reliable Technique for the Quantitative Evaluation of Oral–Pharyngeal Swallowing

A valid and reliable technique to quantify the efficiency of the oral–pharyngeal phase of swallowing is needed to measure objectively the severity of dysphagia and longitudinal changes in swallowing in response to intervention. The objective of this study was to develop and validate a scintigraphic technique to quantify the efficiency of bolus clearance during the oral–pharyngeal swallow and assess its diagnostic accuracy. To accomplish this, postswallow oral and pharyngeal counts of residual for technetium-labeled 5- and 10-ml water boluses and regional transit times were measured in 3 separate healthy control groups and in a group of patients with proven oral–pharyngeal dysphagia. Repeat measures were obtained in one group of aged (> 55yr) controls to establish test–retest reliability. Scintigraphic transit measures were validated by comparison with radiographic temporal measures. Scintigraphic measures in those with proven dysphagia were compared with radiographic classification of oral vs. pharyngeal dysfunction to establish their diagnostic accuracy. We found that oral (p = 0.04), but not pharyngeal, isotope clearance is swallowed bolus-dependently. Scintigraphic transit times do not differ from times derived radiographically. All scintigraphic measures have extremely good test–retest reliability. The mean difference between test and retest for oral residual was −1% (95% CI −3%–1%) and for pharyngeal residual it was −2% (95% CI −5%–1%). Scintigraphic transit times have very poor diagnostic accuracy for regional dysfunction. Abnormal oral and pharyngeal residuals have positive predictive values of 100% and 92%, respectively, for regional dysfunction. We conclude that oral–pharyngeal scintigraphic clearance is highly reliable, bolus volume-dependent, and has a high predictive value for regional dysfunction. It may prove useful in assessment of dysphagia severity and longitudinal change.

The relationship between observations and measures of oral and pharyngeal residue from videofluorography and scintigraphy.

We examined measures of oral and pharyngeal residues from scintigraphic studies and estimates/observations from videofluorographic (modified barium swallow) studies taken on the same day but not concurrently in 16 dysphagic patients of varying etiologies presenting with oral and/or pharyngeal dysphagia. Oral and pharyngeal residuals following the swallow were quantified scintigraphically and were then compared with measures of residuals obtained from the modified barium swallow. Estimates of oral and pharyngeal residues from the modified barium swallows were generated by a trained observer who was blinded to the scintigraphic data. Positive and significant Spearman correlations between oral and pharyngeal residue measures from scintigraphy and observations of oral and pharyngeal residues from modified barium swallows were found. This supports the validity of observations of oral and pharyngeal residues in clinical studies. Limitations of these observations are discussed.

Esophageal pneumatic dilation for postfundoplication dysphagia: safety, efficacy, and predictors of outcome

OBJECTIVE:Persistent dysphagia occurs in 5–10% of patients after fundoplication. The cause is obscure in most cases, and the management has not been well established. The aim of this study is to evaluate the clinical outcomes and the predictors of success for esophageal pneumatic dilations in patients with dysphagia after fundoplication.METHODS:We retrospectively reviewed 14 patients who underwent pneumatic dilation for persistent postfundoplication dysphagia. All patients had esophageal manometry before dilations.RESULTS:There were nine responders to pneumatic dilations (30–40-mm balloons). The nadir lower esophageal sphincter (LES) relaxation pressure was the only significant predictor for successful dilation and was higher among the responders than nonresponders (median 10 mm Hg vs 5 mm Hg). All six of 14 patients with nadir LES pressure ≥10 mm Hg had a good response. There was no significant difference in the LES basal pressure between the responders and nonresponders (median 20 mm Hg vs 12 mm Hg). The median distal peristaltic amplitude (74 mm Hg vs 69 mm Hg), percent of failed peristalsis (8% vs 45%), and ramp pressure (19 mm Hg vs 17 mm Hg) did not differ significantly between the responders and nonresponders. No perforations occurred.CONCLUSIONS:Pneumatic dilation is a reasonably safe and effective treatment for patients with postfundoplication dysphagia. Raised nadir LES relaxation pressure seems to be a useful predictor of successful outcome.

Cricopharyngeal myotomy does not increase the risk of esophagopharyngeal acid regurgitation

OBJECTIVE:It is not known whether cricopharyngeal myotomy predisposes to esophagopharyngeal regurgitation. Using ambulatory, dual pharyngeal, and esophageal pH monitoring before and after cricopharyngeal myotomy, our aim was to determine the effect, if any, of myotomy on the frequency of esophagopharyngeal acid regurgitation.METHODS:We studied prospectively 18 patients who underwent cricopharyngeal myotomy for pharyngeal dysphagia (10 Zenkers, eight neurogenic dysphagia), of whom 17 agreed to undergo dual pH monitoring preoperatively, and 10 who agreed to both pre- and postoperative monitoring.RESULTS:Symptoms of gastroesophageal reflux disease were present in 30%. Cricopharyngeal myotomy significantly reduced basal upper esophageal sphincter pressure by 49%, from 37 ± 5 mm Hg to 19 ± 3 mm Hg (p= 0.007). Esophagopharyngeal regurgitation was a rare event and the frequency of it did not differ between patients and healthy controls. Preoperatively, three regurgitation events in two patients did not differ from the postoperative frequency of a total of two events in the same two patients.CONCLUSIONS:Increased esophageal acid exposure is common and esophagopharyngeal regurgitation is rare in unselected patients undergoing cricopharyngeal myotomy for pharyngeal dysphagia. Myotomy does not increase the frequency of esophagopharyngeal acid regurgitation in such patients.

Gene expression in HIV-1/Mycobacterium tuberculosis co-infected macrophages is dominated by M. tuberculosis.

The resurgence of tuberculosis worldwide has closely mirrored the HIV pandemic. In regions like sub-Saharan Africa, a large proportion of individuals are co-infected with Mycobacterium tuberculosis and HIV. Macrophages are the reservoir host cells for both pathogens, however the interactions between both pathogens in co-infected cells remain poorly understood. Thus, the global gene responses of primary human macrophages following productive co-infection with highly purified HIV and M. tuberculosis were analyzed using cDNA microarrays. A broad range of genes was up-regulated in response to co-infection or M. tuberculosis infection of primary macrophages, including those encoding pro-inflammatory chemokines and cytokines, their receptors, signalling associated genes, type I IFN signalling genes and genes of the tryptophan degradation pathway. Real-time RT-PCR analysis confirmed up-regulation of a wide variety of genes including indoleamine 2,3 dioxygenase and Sp110 in M. tuberculosis and co-infected samples. Downstream analysis confirmed significant elevation of the chemokines CCL3, CCL4 and CCL8 in M. tuberculosis and co-infected culture supernatants. In contrast, the changes seen in gene expression following HIV infection alone were fewer in number and significantly less in magnitude. Thus, the effects of M. tuberculosis infection on global gene expression dominated the effects of HIV-1 in co-infected primary human macrophages.

Upregulation of the esophago‐UES relaxation response: a possible pathophysiological mechanism in suspected reflux laryngitis

Background  Inappropriate or excessive, non‐swallow related, reflexive relaxation of the upper esophageal sphincter (UES) in response to esophageal distension may be the principal mechanism permitting retrograde trans‐sphincteric flow during acid regurgitation. The neural pathways mediating reflexive UES relaxation in the human have received little attention. Patients with laryngitis demonstrate an increased acid reflux in the proximal esophagus. Such events, combined with an increased tendency for UES relaxation, might precipitate regurgitation into the pharynx.