Recognizing atypical manifestations of GERD. Asthma, chest pain, and otolaryngologic disorders may be due to reflux

The presence of common symptoms, such as heartburn and regurgitation, usually make the diagnosis of gastroesophageal reflux disease (GERD) fairly straightforward. However, extraesophageal symptoms of GERD, such as asthma, noncardiac chest pain, and hoarseness, are often not recognized and therefore are poorly managed. This article sheds light on the atypical manifestations of GERD as well as current approaches to diagnosis and treatment.     

Modern diagnosis of gastroesophageal reflux disease (GERD)

Typical dominant symptoms such as heartburn and regurgitation are very specific for the diagnosis of GERD. Unfortunately they are relatively insensitive. The diagnosis can be made reliably if mucosal breaks are present at endoscopy. In endoscopy-negative patients with atypical symtoms, the most accurate investigation is 24-hour pH-monitoring with symptom analysis. Another alternative which may prove more cost-effective is to start with a PPI-test (e.g. omeprazole 20 or 40 mg bid for one or two weeks) and to use the symptomatic response as a diagnostic test.     

Respiratory complications of gastrointestinal diseases

Further advances in the ability to diagnose GER disease by use of ambulatory pH monitoring have unveiled a host of extraesophageal manifestations of GERD. These include pulmonary symptoms of asthma, recurrent pneumonia, cough or bronchitis, and infant apnea. Many of these symptoms may be the sole presentations of GER in these patients. It is important that the clinician is aware of these atypical presentations of GERD. The expanding use of ambulatory pH monitoring is helping to clarify the underlying pathophysiology of these disorders as well as to improve the ability to diagnose the atypical manifestations of GERD.     

Evaluation of laparoscopic Toupet fundoplication as a primary repair for all patients with medically resistant gastroesophageal reflux

BACKGROUND: This prospective study assesses the outcome results in 100 consecutive patients with gastroesophageal reflux disease (GERD) treated with a laparoscopic Toupet fundoplication. METHODS: GERD was confirmed by 24-h pH study and/or esophagogastroduodenoscopy (EGD). Pre- and postoperative symptoms, operative times, and perioperative complications were recorded on standardized data forms. Early follow-up was at 3 months and late follow-up, including 24-h pH, manometry, and EGD was at 22 months. RESULTS: Preoperative symptoms included heartburn (92%), regurgitation (58%), water brash (39%), and dysphagia (39%). Mean operative time was 3.2 hours. There were no conversions to celiotomy and there were no mortalities. The perioperative complication rate was 14%; 6% (5/83) of patients reported heartburn at 3 months and 20% (15/74) at 22 months. Early and late dysphagia was 20% (17/83) and 9% (7/74), respectively; 24-h pH testing was abnormal in 90% of symptomatic patients (9/10), 39% of asymptomatic patients (12/31), and 51% overall. CONCLUSIONS: Despite early improvement in reflux symptoms following laparoscopic Toupet fundoplications, there is a high incidence of recurrent GERD. Symptomatic follow-up underestimates the true incidence of 24-h pH-documented reflux. Based on these results we cannot recommend the laparoscopic Toupet repair for GERD patients with normal esophageal motility.     

Dormancy-associated gene expression in pea axillary buds. Cloning and expression of PsDRM1 and PsDRM2

OBJECTIVE: We evaluated the efficacy and safety of a twice-daily dosage regimen of cisapride 20 mg in relieving the symptoms of mild-moderate gastroesophageal reflux disease (GERD) in patients with moderate intensity heartburn and no history of erosive esophagitis. METHODS: After a 2-wk, single-blind, placebo run-in period, 398 patients who continued to experience moderate intensity heartburn were randomized to either placebo (n = 196) or cisapride 20 mg (n = 202) twice daily for 4 wk. RESULTS: Compared with placebo, cisapride significantly reduced scores for daytime and nighttime heartburn (p < 0.001), total regurgitation (p < 0.001), eructation (p = 0.04), and early satiety (p = 0.04). Cisapride 20 mg b.i.d. was also superior to placebo in reducing total use of rescue antacid medication (p < 0.001); reducing, in concordance analyses, daytime and nighttime heartburn with antacid usage (p < 0.001); increasing the percentage of heartburn-free days and antacid-free nights (p < 0.5); and increasing the percentage of patients self-rated as having minimal or better symptomatic improvement (p = 0.01). Cisapride 20 mg b.i.d. was well tolerated. The most common adverse event in the cisapride group was diarrhea, reported by 10% of patients, compared with an incidence of 4% in the placebo group. CONCLUSION: Cisapride 20 mg b.i.d. was shown to be effective and safe for the short-term treatment of daytime and nighttime heartburn and for other symptoms associated with mild-moderate GERD.     

Abnormal gastro-oesophageal reflux in Chinese with atypical chest pain

Although atypical chest pain has been well described in the Western population, its frequency in Chinese is unknown. Over a period of 42 months, we studied 521 Chinese patients with chest pain and identified 108 patients (20.7%) whose pain was not related to cardiac causes, as determined by exercise ECG or cardiac catheterization. Using 24 h ambulatory pH monitoring and baseline oesophageal manometry, 28.7, 19.4 and 5.6% of these patients were found to have abnormal reflux parameters, abnormal manometric findings or both, respectively. There were significantly more patients complaining of chest pain during the study in the gastro-oesophageal reflux disease (GERD) group than in the non-GERD group (16/31 vs 20/77; P < 0.001). The lower oesophageal sphincter pressure was lower in those with abnormal reflex parameters than in those with normal reflux parameters (12.7 +/- 5.4 vs 17.8 +/- 5.8 mmHg; P < 0.05). There was no significant difference in symptoms, such as heartburn (54.8 vs 42.9%), regurgitation (38.7 vs 35.1%) and dysphagia (19.4 vs 24.7%), among the two groups. Non-specific changes were the most frequent baseline motility pattern. In conclusion, atypical chest pain and gastro-oesophageal reflux disease are not uncommon in Chinese and this deserves special emphasis as the continuation of anti-anginal drugs may aggravate their condition.     

Gastroesophageal reflux disease: pathophysiology, diagnosis and drug therapy

The principal mechanism leading to gastro-oesophageal reflux is an increased frequency of transient lower oesophageal sphincter relaxations; other factors are oesophageal hypersensitivity to gastric juice, hiatus hernia, and possible duodenal reflux. Patients with classical symptoms such as heartburn and regurgitation may be treated pharmaceutically combined with life style counselling. If the symptoms have not improved after 6 to 12 weeks, endoscopical examination is performed and, if necessary, 24-hour pH monitoring, barium radiographing and manometry. In the case of atypical symptoms such as dysphagia, laryngitis, asthma and chest pain, there is more reason to pursue diagnostic testing. In patients with dysphagia endoscopy is indicated to exclude malignancy. Drug treatment can be subdivided into antacids, H2 receptor antagonists, cytoprotective agents, prokinetics and proton pump inhibitors. In general practice a step-up approach to treatment is preferable, while for specialist treatment a stepdown approach is more (cost-)effective. Drawbacks of medical treatment are considerable frequency of recurrence of oesophagitis, persistence of regurgitation in 'volume refluxers' and controversial data on the possible development of (pre)malignant lesions of oesophagus and stomach. Surgical treatment is a good alternative for patients with persistent severe regurgitation during medical therapy and for young patients who prefer surgery to lifelong medication. Patients with Barrett's oesophagus should undergo regular endoscopic biopsy surveillance.     

Systemic clotting activation by low-grade endotoxaemia in liver cirrhosis: a potential role for endothelial procoagulant activation

Laparoscopic fundoplication is technically feasible in treating gastroesophageal reflux disease (GERD). Although medication is the primary treatment for GERD, not all patients respond completely or are able to adhere to a medical regimen. In the present series, 59 patients were laparoscopically treated for GERD at three centers using a standardized technique. All patients had been medically treated prior to referral, although 84 per cent had heartburn and 2 per cent had laryngitis despite 20 to 40 mg/day of omeprazole. Fifteen per cent of patients were intolerant of or would no longer take omeprazole. Patients were evaluated by esophageal manometry (in 100%) and 24-hour pH studies (in 66%). Seventy-six per cent of patients had lower-esophageal sphincter pressure <15 mm Hg. Five patients had low esophageal body peristaltic pressures (<35 mm Hg). These patients underwent Toupet partial fundoplication, whereas 54 patients underwent Nissen fundoplication. Mean operative time was 158 +/- 7 minutes, and three patients (5%) were converted to an open procedure. Operative complications were minor and occurred in 13 per cent. In 45 patients evaluated 1 year after surgery, heartburn had resolved in 98 per cent. Thirty-nine of 56 patients (70%) had mild early (<1 month postoperatively) dysphagia, and 9 (19%) had severe early dysphagia, which improved in 7 after nonoperative dilatation. Two of these had continued mild dysphagia. Two patients had severe dysphagia and were laparoscopically converted from Nissen to Toupet fundoplications, which resulted in marked improvement. Early gas bloat symptoms occurred in 45 per cent and dropped to 5 per cent at 1 year. Laparoscopic treatment of GERD is safe and effective in preventing reflux symptoms. Although mild dysphagia occurs after the procedure, this is transient in most patients. Patients with severe dysphagia can be treated with nonoperative dilatation or laparoscopic partial fundoplication and maintain the antireflux characteristics of the wrap.     

Follistatin-like immunoreactivity in the cytoplasm and nucleus of spermatogenic cells in the rat

Incidence of Kawasaki disease in Japan is 10 times higher than in the United States. Approximately 10% of patients have atypical clinical presentations. Because echocardiographic or angiographic evidence of coronary artery complications is needed for diagnosis, such atypical cases often result in either delay or omission of intravenous gamma globulin therapy and higher incidence of coronary artery aneurysms than those patients with classical presentations. Despite ongoing research, no universally accepted etiologic theory exists today. Intravenous gamma globulin remains the mainstay of the acute phase treatment of Kawasaki disease. However, reported transmission of hepatitis C virus via a brand of intravenous gamm globulin leaves us with a lingering concern about the safety of this treatment. In terms of long-term follow-up, emergencence of a number of newer diagnostic modalities is promising and warrants careful evaluation. Surgical therapy for coronary artery disease needs to be approached cautiously.     

Has laparoscopy changed the surgical approach in gastroesophageal reflux? Apropos of an experience with 63 cases of gastroesophageal reflux treated by laparoscopy

INTRODUCTION: Indications for surgery in gastrooesophageal reflux disease (GERD) have decreased significantly since the introduction of proton pump inhibitors. At the same time there has been renewed surgical interest in this disease triggered by the development of laparoscopy. We present our results with laparoscopic treatment of GERD and the change in our surgical approach to the condition during the past few years. METHODS: All patients admitted to the surgical department underwent prior evaluation by a gastroenterologist. Indications for surgery were resistance to medical therapy in 30 cases, recurrence of GERD after cessation of treatment in 25 cases and personal preference of the patient when maintenance therapy was necessary in 6 cases. The data were reviewed and the patients contacted during the first trimester of 1998 to evaluate long-term results. RESULTS: 63 patients were operated on between 1991 and July 1997. Rossetti-Nissen fundoplication was performed routinely until March 1995. Thereafter, the type of antireflux surgery has been chosen according to the preoperative evaluation of the patients, including endoscopy, oesophageal manometry and gastric emptying studies. There was no mortality and, except for one case, only minor morbidity. Four patients required reoperation, two for severe gas bloat syndrome and two for recurrence of GERD. Overall, the long-term follow-up shows that 93 patients are satisfied or very satisfied with their outcome (Visick 1 or 2). 5% of the patients need daily medication for heartburn, 5% complain of occasionally disturbing dysphagia, and 12% of sometimes distressing gas bloat. More patients have gas bloat after the Rossetti-Nissen procedure than after the Nissen or Toupet fundoplications. CONCLUSIONS: The enthusiasm of surgeons for the laparoscopic approach to GERD has prompted renewed interest in the pathophysiology of the disease. Consequently, indications for surgery are better defined, surgical technique is chosen according to the individual patient based on objective preoperative studies and follow-up has improved. In this setting, laparoscopic fundoplication represents an effective treatment for GERD. It is associated with lower postoperative morbidity than open surgery and represents the first choice when surgery is indicated.     

Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells

Patients admitted acutely to hospital may be at risk of increased morbidity and mortality as a result of gastroesophageal reflux and its complications. The recognized association of gastroesophageal reflux with cardiac and respiratory disease, the use of drugs that reduce lower esophageal sphincter pressure, and the supine position in which many patients are nursed may increase the risk of gastroesophageal reflux. This study aimed to determine the prevalence and severity of refluxlike symptoms in a series of consecutive unselected patients admitted acutely through the accident and emergency department of a district general hospital and to study the effect of hospitalization on these symptoms. Patients were interviewed by questionnaire on two occasions: immediately following admission and again 7-10 days later. The frequency of symptoms of heartburn, acid regurgitation, dysphagia, nausea, and belching were recorded on a 6-point scale, in addition to whether these symptoms occurred at night. Medication history, the number of days spent on bed rest, nasogastric intubation, and operation history were also recorded. In all, 275 patients were interviewed, of whom 229 had a second interview; 27% (62) had symptoms at least once a week (49% reported symptoms at least once a month) prior to admission, of whom 4% (9) had daily heartburn and/or acid regurgitation. Following admission to hospital there was a significant (P < 0.001) fall in the prevalence and frequency of refluxlike symptoms. There was a significant association of refluxlike symptoms with number of days spent in bed (P < 0.05) and with the use of nonsteroidal antiinflammatory drugs in hospital (P < 0.0001). Logistic regression analysis confirmed the association of NSAIDs with refluxlike symptoms. Nasogastric intubation and surgery were not associated with heartburn. In conclusion, symptoms of heartburn and acid regurgitation become less frequent following admission to hospital. This probably relates to a reduction in physical exertion following hospital admission but may reflect a reduction in anxiety levels or treatment of underlying disease. Patients on prolonged bed rest and those given non-steroidal anti-inflammatory drugs are at increased risk of refluxlike symptoms and may require antireflux measures.     

Health-related quality of life outcomes of omeprazole versus ranitidine in poorly responsive symptomatic gastroesophageal reflux disease

OBJECTIVE: This study evaluated changes in health-related quality of life (HRQL) outcomes of once-daily omeprazole compared with ranitidine for the short-term treatment of patients with poorly responsive symptomatic gastroesophageal reflux disease (GERD). METHODS: A double-blind, randomized clinical trial, compared omeprazole versus ranitidine for the treatment of poorly responsive GERD. Eligible patients had a history of predominant heartburn symptoms with symptomatic heartburn after 6 weeks of ranitidine treatment. Patients were randomized to omeprazole 20 mg once daily (n = 156) or ranitidine 150 mg twice daily (n = 161) and followed for 8 weeks. Assessments were completed at baseline and after 8 weeks with physician-rated symptoms: Gastrointestinal Symptom Rating Scale (GSRS); Psychological General Well-Being (PGWB) Index; Sleep Scale; Impact on Daily Activities Scale, and Overall Treatment Effect. Primary HRQL endpoints were the GSRS reflux scale and PGWB total score. RESULTS: No differences between the 2 treatment groups were observed in baseline demographic, clinical or HRQL measures. After 8 weeks, omeprazole-treated patients had greater improvement in GSRS reflux scale scores (p<0.0001) and PGWB total scores (p = 0. 019) compared with ranitidine-treated patients. Significant between group differences favoring omeprazole were also observed in GSRS total scores (p<0.0001), abdominal pain scale scores (p = 0.003), and indigestion scale scores (p = 0.003), Impact on Daily Activities (p = 0.001), PGWB positive well-being (p = 0.015), anxiety (p = 0. 030), and general health scale scores (p = 0.010). Patient ratings of overall treatment effect demonstrated the significantly (p<0. 0001) greater benefits of omeprazole (mean = 5.26) compared with ranitidine treatment (mean = 3.83). CONCLUSIONS: Omeprazole treatment significantly reduced persistent reflux-related symptoms and normalized psychological well-being compared with ranitidine in poorly responsive symptomatic patients with GERD.     

Gastroesophageal reflux in children

BACKGROUND: Gastroesophageal reflux is common in small children. It is important to recognise that its natural history and management differ from reflux in adults. OBJECTIVE: This article will summarise the clinical presentation, pathophysiology, appropriate investigations and therapy of reflux in small children. DISCUSSION: A small amount of regurgitation is common in infancy, and is only pathological if it results in harm. In children, reflux-induced injury can result from either acid exposure, nutrient loss or respiratory complications. Recognised presentations include heartburn, oesophagitis, infant irritability, dysphagia, haematemesis, stricture, growth failure, aspiration, apnoea and pneumonia. Excessive crying and irritable behaviour in infancy can be due to a variety of causes, but there is a fashionable tendency to assume that gastroesophageal reflux is a major factor. Regurgitation can be a symptom of other conditions such as infection or metabolic disturbance. It is important to carefully evaluate any infant with distressed behaviour to exclude a significant medical cause. Prolonged oesophageal pH monitoring is a very useful means of linking episodes of reflux with putative symptoms. The severity of gastroesophageal reflux tends to improve with age in infants and this should be considered when advising appropriate therapy, especially fundoplication.     

Nonspecific and atypical presentation of disease in the older patient

Symptoms, physical findings, and laboratory values exhibited by some older patients with acute illnesses may differ from those normally expected in a younger population. This variation in presentation can make it difficult to diagnose pneumonia or myocardial infarction and exacerbations of chronic disease, such as depression. The physician who is aware of why and how diseases can present atypically in older patients can improve outcomes by minimizing diagnostic mistakes and delays in treatment. Five common disease states in which atypical presentations may be seen include infections, cardiovascular disease, the acute abdomen, hyperthyroidism, and depression.     

Clinical applications of esophageal manometry and pH monitoring

In summary, GERD patients are usually well managed using a careful medical history, endoscopy, and empirical trials of antireflux medications. Extended esophageal pH monitoring is unnecessary in most patients but can be of considerable value in managing patients with typical or atypical symptoms who are refractory to standard therapy for GERD. Furthermore, the test can be useful in documenting abnormal reflux in an individual without esophagitis being evaluated for antireflux surgery. The test is done with compact, portable data loggers, miniature pH electrodes, and computerized data analysis. The pH electrode should be positioned 5 cm above the manometrically defined upper limit of the LES, and patients should undergo the test on an unrestricted diet. In terms of data analysis, the total percentage time of pH < 4 provides as much information as any other scheme of quantifying esophageal acid exposure, but symptom association is essential when evaluating atypical or sporadic symptoms. Enthusiasm for 24-h pH monitoring must, however, be tempered with an analysis of its proven clinical utility in patient management with its utility rightfully compared with that of an empirical trial of anti-reflux therapy. Ambulatory pH monitoring is probably most useful in examining patients without typical reflux symptoms or patients who have either partially or completely failed a trial of anti-reflux therapy. To date, there have not been any prospective, controlled clinical trials evaluating these uses. Suggested clinical indications for ambulatory pH monitoring are listed in Table 5 (53).     

Isotypic antibody responses of a population in an endemic area of schistosomiasis japonica and their epidemiologic significance

OBJECTIVE: Chordal transposition was advocated for correction of anterior mitral prolapse. We have evaluated the early and late results of this technique in different anatomical presentations. METHODS: From 1986 to 1995, 185 mitral valve repairs were carried out for pure mitral regurgitation due to a degenerative disease. Eighty-nine patients had either an anterior prolapse (39) or prolapse of both leaflets (50) at initial presentation and underwent chordal transposition from the mural leaflet to the anterior leaflet. The corrective procedure was completed by polytetrafluoroethylene or pericardial posterior annuloplasty. Twenty patients presented a complex pathology and 26 had chordal elongation of mural leaflet. Annular calcifications were found in 9 patients. Seven patients required shortening of transposed chordae and two patients the additional shortening of an anterior chorda. RESULTS: Operative mortality was 3.3% and follow-up was 95% complete (average 41 months). There were five postreconstruction valve replacements (two earlier and three later) for a probability of freedom from late reoperation or 3+ mitral regurgitation of 88.6 +/- 4.8% at 5 years. Of the patients 79% presented no or trivial residual MR, 17% moderate MR and 4% severe MR. The presence of a complex pathology or posterior chordal elongation did not influence the entity of postoperative residual regurgitation. On the contrary, the patients with annular calcifications had a residual regurgitation/left atrium area ratio greater than patients without annular calcification (15.8 +/- 11.5% vs. 6.1 + 9.9%; P = 0.009). CONCLUSIONS: Chordal transposition is an effective and easily carried out technique for the correction of anterior mitral prolapse. The presence of a complex pathology or posterior chordal elongation do not rule out the procedure. The absence of annular calcification is important in order to obtain a satisfactory correction.     

On the many faces of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.     

Incidental lung carcinoma detected at CT in patients selected for lung volume reduction surgery to treat severe pulmonary emphysema

OBJECTIVE: Ovarian vein thrombosis (OVT) is a pathologic entity classically considered a postpartum complication and only rarely associated with other disease processes. Before modern imaging methods, diagnosis was primarily made clinically or at exploratory surgery. Our objective was to show that with CT and sonographic imaging, OVT can be detected in atypical clinical situations and that the condition may also be occult. CONCLUSION: Only two of six cases at our institution fit the classic picture of postpartum infection complicated by OVT. The other four cases occurred in conjunction with other pathologic conditions, one of which has not to our knowledge been previously associated with OVT. The diagnosis was not clinically suspected in these four cases. On CT and sonography, OVT was detected incidentally, because clinical symptoms were atypical or absent. Such atypical presentations of OVT pose a clinical dilemma as to appropriate management.     

How familial is familial tremor? The genetic epidemiology of essential tremor

BACKGROUND & AIMS: Dilated intercellular spaces are a sign of epithelial damage in acid-perfused rabbit esophagus, a change best identified by transmission electron microscopy. The aim of this study was to determine if this change is also a feature of acid damage to human esophageal epithelium. METHODS: Endoscopic esophageal biopsy specimens from patients with (n = 11) and without (n = 13) recurrent heartburn were examined using transmission electron microscopy. Of 11 patients with heartburn, 6 had erosive esophagitis and 5 had normal-appearing mucosa on endoscopy; 13 controls had no symptoms or signs of esophageal disease. Using a computer, intercellular space diameter was measured from transmission electron microscopy photomicrographs of the specimen from each patient. RESULTS: Intercellular space diameter was significantly greater in specimens from patients with heartburn than those from controls; this was true irrespective of whether the patient had erosive or nonerosive disease. Space diameters of > or = 2.4 microns were present in 8 of 11 patients with heartburn and in no controls. CONCLUSIONS: Dilated intercellular spaces are a feature of reflux damage to human esophageal epithelium. As a morphological marker of increased paracellular permeability, its presence in patients without endoscopic abnormalities may help explain their development of heartburn.