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Gastroesophageal Reflux Disease n patients who have typical symptoms of gastro- Iesophageal reflux disease, such as and Presenting with Intractable Nausea acid regurgilation. the diagnosis is usually obvious Ronald J. Brzana. MD, and Kenneth L, Koch. MD (1). A subsel of patients, however, can present with atypical symptoms, including -like chest , Background: Typical symptoms of gastroesophageal re- cough, wheezing, shortness of breath, and hoarse- flux disease are heartburn and régurgitation. A subset of ness, that hinder immediate diagnosis of gastro- patients present witb atypical symptoms, such as chest esophageal reflux disease. In addition to being a pain, cougb, wheezing, and hoarseness. symptom of gastroesophageal rellux disease, chronic Objective: To review the clinical presentation and treat- nausea ean be a symptom of chronic peptic ulcer ment of patients who presented with nausea as the pri- disease, . occult gastrointestinal cancer, mary symptom of gastroesophageal reflux disease. intestinal pseudo-obstruetion. and increased intra- Design: Case series. craniai pressure secondary to a tumor. Setting: Outpatient department of a university hospital. Patients: 10 outpatients who had chronic, intractable nausea and had not responded to empirical therapies. Measurements: Patients were evaluated by esophago- Methods gastroduodenoscopy, 24-hour esophageal pH studies, gas- tric-emptying tests, electrogastrography, or a Bernstein Patients test. We reviewed the charts of patients who had been Results: Abnormal acid reflux was found to be the cause referred to the gaslroenterology division of the Mii- of intractable nausea in all 10 patients. In 5 of the 10 ton S. Hei'shey Medical Center from September patients, was documented by esophagogas- 1991 to August 1995 ior evaluation of ehronie Idio- troduodenoscopy. Six patients had abnormal results on pathie nausea. Three men and seven women (ago the 24-hour esophageal pH study. In these 6 patients, 32 of range. 27 to 67 years) who had received a diagnosis 33 episodes of nausea were accompanied by an episode of of gastroesophageal reflux disease presented with acid reflux. One patient had positive results on the Bern- chronic nausea. The average duration of nausea was stein test. Nausea resolved after treatment with omepra- zole in 7 patients, after treatment with cisapride or raniti- 2.1 years (range, 3 months lo f) years). dine in 2 patients, and after Nissen fundoplication in 1 None of the 10 patients had responded to em- patient. pirical medical therapies for chronic nausea. In Conclusions: Intractable nausea is an atypical symptom some instances, the patients had not responded to that can occur in a subset of patients with gastroesopha- more than one treatment reghnen: Nine did not gea! reflux disease, A 24-hour esophagea! pH study should respond to standard -2 (H.) bloekers (4(10 be considered ¡n patients who have unexplained nausea mg of cimclidine. 150 mg of ranilidine. 20 mg of but normal findings on esophagogastroduodenoscopy, a famotidine. or 150 mg of nizatidhic twice daily); 6 gastric-emptying test, and electrogastrography. Nausea did not respond to inetoclopramide; (^ did not re- related to gastroesophageal reflux disease resolves or is spond to anticmefic agents: 3 did not respond to markedly reduced with proton-pump inhibitors or promo- eisapride; 2 did not respond to omeprazole (20 mg tility drugs. once daily): ! did not respond to high-dose H;, bloekers (300 mg of i'aniiidinc twice dailyj; 1 did not respond fo bethaneclioi: and i did not respond to sucralfate. Six of 10 patients had intermittent in addition to nausea, ln most patients, the vomiting did noE occur after nicals. Each patient had epi- sodes of nocturnal vomiting. Patients reported two .Inn Intern Med. l'I'H; 120:704-707, to eight episodes of vomiting per week. One patient had -dependent diabetes mellitus, a comorbid hiom Milton S. Herslicy Mediciil Ccnlcr. KcnnsylviiiiiL cuiTfiii auihnr addrcsso, six- end ol (i:xi. condition that can contribute to nausea: however.

704 May 1997 • Annals of Inienial Medicine • Vokime 126 • Number Table 1. Results of Gastrointestinal and Studies m Patients with Nausea and Gastroesophageal Reflux Disease*

Patient Gastric Electrogastrography Abdominal upper Computed Tomography or Emptyingt Ultrasonography Gastrointestinal Series Magnetic Resonance Imaging

1 ND ND ND ND ND

IV J Normal (70%) Normal (3 cpm) ND Normal Normal 3 Normal (82%) Normal (3 cpm) Normal Normal Normal 4 Normal (92%) ND Normal ND ND 5 Norma i (76%) Normal (3 cpm) Normal Normal ND 6 ND ND Normal Normal ND 7 Normal (50%) ND Normal ND Normal 8 Normal (77%) Normal (3 cpm) Normal Normal Normal 9 Normal (72%) Normal (3 cpm) Normal Normal Normal 10 Normal (84%) Normal (3 cpm) Normal Normal Normal

' rpm - c/c!ei per minute; ND = no! cipierminpd. t Values yiwn in parentheses are ihe percentages enißtfed at 120 this patient was subsequently found to have normal minute were considered normal (5). Frequencies of gastric emptying. 0 to 2.4 cycles per minute were eonsidered to be After carefully reviewing the medieations of all bradygastrie; frequencies of 3.6 to 9.9 eyeles per patients, we did not believe that any medication was minute were eonsidered to be taehygastrie. causing the nausea. Dietary modifieations had not All patients had normal function test re- been prescribed for any patient before our discovery sults; complete blood eell eounts; and levels of amy- of gastroesophageal reflux disease. lase, lipase, , blood urea nitrogen, and One patient smoked eigarettes, and three infre- ereatinine. Normal results on other studies are quently drank aleoholic beverages. The referring listed in Table 1. physicians and investigators did not believe that any of the patients had neuropsychiatrie conditions. Results Evaluation All patients had esophageal and gastrie evalua- Either endoseopie studies or 24-hour esophageal tions: Ten had esophagogastroduodenoscopy, 6 had pH studies showed gastroesophageal acid reflux in 24-hour esophageal pH studies, and 1 had a Bern- all 10 patients (Table 2). Esophagitis was doeu- stein test for determination of acid perfusion. An mented in 5 of the 10 patients by esophagogas- ambulatory pH monitoring system (Synecties, Inc. troduodenoscopy and was graded according to a Houston, Texas) with dual monocrystalline anti- published endoseopie grading system (6). Three pa- mony pH catheters was used for the esophageai pH tients had grade 4 esophagitis (ulcération, diffuse studies as deseribed elsewhere (2). erythema, mueosal friability), 1 patient had grade 3 Solid-phase gastric-emptying scans were done in esophagitis (erosions, diffuse erythema, mucosa! fri- eight patients, and electrogastrography was done in ability), and 1 patient had grade I esophagitis (lo- six patients as part of the evaluation. The solid- calized erythema of the gastroesophageal junction). phase gastric-emptying scans were done by the nu- Six patients had 24-hour esophageal pH studies, and clear medicine division as described elsewhere (3). eaeh study showed abnormally increased acid reflux. Eleetrogastrography measures gastric myoelectrieal aetivity. Gastric dysrhythmias that alter upper gas- trointestinal motility may elude diagnosis if tests Table 2. Confirmation of Gastroesophageal Refiux Disease in Patients with Intractable Nausea* other than eleetrogastrography are used. Eleetroga- strography has shown altered gastrie myoeleetrieal Patient Esophogastroduodenoscopy 24-Hour Bernstein activity in patients who have unexplained nausea and Esophagitii pH Studyt Test and vomiting (4). 1 Yes ND ND Eleetrogastrograms were recorded by using four 2 Yes ND ND 3 No Yes (19%) ND standard silver-chloride electrodes positioned on the 4 No Yes (41%) ND epigastrium as described elsewhere (5) The elec- 5 No ND Yes 6 No Yes (9%) ND trodes were eonnected to a rectilinear recorder 7 Yes ND ND through a direct nystagmus coupler (Model 9859, 8 Yes Yes (NA) ND 9 Yes Yes (75%) ND Sensormedies, Inc., Anaheim, California), and a 10 No Yes (20%) ND hard copy of the electrogastrographie signa! was obtained. The signal was also analyzed by computer ' NA --- iioi available; ND = pot de'.ermined. t Values given ii parenthcws ¿ire !ne per(;£?niage5 of tirns^ tna1 esopnageal pH was less (5), and frequencies from 2.4 to 3.6 cycles per !han 4.0. 1 May 1997 • Annals of Internal Medicine • Volume 126 • Number 9 705 During the 24-hour period, the esophageal pH was patients, retrospective analysis, and short-term foi- less than 4.0 between 9% to 759r of the time (av- low-up. However,, gastroesophageal reflux disease erage, 33%). The normal range in our laboratory is should be considered in the differential diagnosis of less than 6%. Diaries of symptoms indicated that 32 chronic nausea, especially in troublesome cases in oí 33 reported episodes of nausea correlated with which gallbladder, pancreatic, neurologic, or peptic episodes of aeid reflux. One patient was believed to ulcer disease has been excluded. have gastroesophageal reflux disease on the basis of Because chronic nausea is not typically attributed positive results on the Bernstein test. to gastroesophageal reflux disease, abnormal acid Gastric emptying and gastric myoelcctrical activ- reflux was not eonsidered in our patients before ity were found to be normal according to a solid- referral. Even when esophagitis was seen on endos- phase gastric-emptying test and eiectrogastrography copy, the association with nausea was not appreci- (Table 1). ated and standard-dose Hj-biocker therapy was fre- After gastroesophageal reflux disease was shown quently unhelpful. Gastroesophagea! reflux disease to cause chronic nausea, treatment was directed cannot be exckided on the basis of normal endo- toward reducing acid reflux. In 7 of the 1Ü patients, scopie findings because lacks sufficient nausea was effectively treated with the following sensitivity (11-13). Endoscopie evidence of esoph- dosages of omeprazole: 20 mg twice daily (5 pa- agitis is present in only 50% to 60% of symptomatic tients), 20 mg once daily (1 patient), and 40 mg patients (14, 15). twice daily {! patient). Nausea was markedly re- If esophagitis is found on esophagogastroduode- duced in 1 patient who received 300 mg of raniti- noseopy, a course of high-dosage H:.-blocker ther- dine twice daily and in ! patient who received 10 mg of cisapride four times daily. Finally, 1 patient apy (for example. 300 mg of ranitidine twice daily did not respond to 300 mg of ranitidine twice daily or 40 mg of famotidine twice daily) or a proton- or to 60 mg of omeprazole once daily and thus had pump inhibitor can be started. In patients who have open Nissen fundoplication. Nausea resolved after chronic unexplained nausea and normal ñndings on the antireflux surgery. Time to resolution of nausea esophagogastroduodenoscopy. a 24-hour esophageal ranged from 1 to 16 weeks (mean. 7.3 weeks). All pH study is recommended because it is the most 10 patients were considered to have responded to sensitive test for diagnosing gastroesophagea! reflux these therapies for gastroesophageal reflux disease. disease (16). Because about 40% of patients with Acid suppression was objectively measured in gastroesophageal reflux disease have gastroparesis, an several patients. During treatment, three patients had assessment of gastric emptying may be helpñil. E!ec- follow-up studies to conflrm effective acid suppres- trogastrography can have a role in evaluating a pa- sion. Patients 2 and 7 (Table 2) initially had macro- tient with ehronic unexplained nausea beeause gastrie scopic esophagitis on esophagogastroduodenoscopy; dysrhythmias have been associated with nausea (4). repeated esophagogastroduodenoscopy confirmed We found it unusual for a patient with gastro- that the esophagitis had healed. Patient 4, who ini- esophageal reflux disease to respond to standard- tially had an esophageal pH less than 4.0 during dose H, blockers. The one patient whose nausea 41% of the 24-hour esophageal pH study, had nor- was relieved by an H2 blocker needed high-dosage mal results on follow-up while receiving therapy ranitidine (300 mg twice daily). We and other re- (esophageat pH < 4.0 for 1.3% of the time). The searehers (Í7, 18) have observed that a high level of total follow-up period ranged from 2 to 14 months acid suppression may be required to hea! esophagi- (mean, 6.4 months), and all patients reported con- tis in some patients. In our study, the most common tinued relief of nausea. dosage of omeprazole needed to relieve nausea was 20 mg twice daily. in eonelusion, chronic nausea can be caused by Discussion gastroesophageal reflux disease. In patients with un- explained nausea, gastroesophageal reflux disease Patients who present with atypieal symptoms of should therefore be considered if results on stan- gastroesophagea! reflux disease can present a diag- nostic challenge (7-10). After we extensively evalu- dard tests are normal. A 24-hour esophagea! pH ated a group of patients with ehronic intractable study may eonfirm ihat gastroesophageal reflux is nausea, gastroesophageal reflux disease was the only associated with nausea in patients who have normal abnormality we could find. Gastroesophageal reflux findings on esophagogastroduodenoscopy and gas- disease was diagnosed by esophagogastroduodenos- tric-emptying tests. In our experience, nausea re- copy. a 24-hour esophageal pH study, and a Bern- !ated to gastroesophagea! reflux disease was eff'ec- stein test. tive!y treated with proton-pump inhibitors and Our study is limited by the small number of promotihty agents.

706 1 May I'->J7 • Annals of Internal Medicine • Volume 126 • NunUicr 9 Acknowledgments: The authors thank Pamela Petito for her as- sistance in preparing this manuscript. Risk Factors for Deep Venous Thrombosis of the Upper Requests for Reprints: Kenneth L. Koch, MD, Division of Gastro- enterology, Milton S. Hershey Medical Center, Pennsylvania Extremities State University, PO Box 850, Hershey, PA 17033. Ida Marîinelli, MD; Marco Caííaneo, MD; Current Author Addresses: Drs. Brzana and Koch; Division of Daniela Panzeri, MD; Emanuela Taioli, MD, MS; , Milton S. Hershey Medical Center, Pennsylva- and Pier Mannuccio Mannucci, MD nia State University, PO Box 850, Hershey, PA 17033. Background: Hypercoagulable states and triggering fac- tors (surgery, trauma, immobilization, , and use References of oral contraceptives) are associated with an increased risk for deep venous thrombosis of the lov^/er extremities.

1. Klau5er AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastro- In contrast, risk factors for deep venous thrombosis of the oe5ophageai reflu;< disease. Lancet, 1990;33S:205-a. upper extremities have not been identified. 2. Johnsson F, Joelsson B, isberg PE. Ambulatory 24 hour intraesophageal pH-monitoring Gut, 1987;28:1145-50, Objective: To evaluate the prevalence of hypercoagu- 3. Koch KL, Stern RM, Stewart WR. Vasey MW, Sullivan ML. Gastric lable states and triggering factors in patients with primary emptying and gastric myoelectrical activity in patients witii diabetic gastropa- resis: effecl of long-term treatment. Am J Gastroenterol, 1989; deep venous thrombosis of the upper extremities. 84:1059-75 4. You CH, Lee KY, Chey WY, Menguy R. Electrogastrographic study of Design: Frequency-matched case-control study. patients with unexplained nausea, , and vomiting. G astro ente roi ogy. 1980,79:311-4, Setting: Hemophilia and thrombosis center at a univer- 5. Koch KL, Stem RM. Electrogastrography. ¡n: Kumar D, Wingate D, eds. sity hospital. Illustrated Guide to Gastrointestinal Moüiity. London: Churchill Ln/ingstone; 1993:290-307, Patients: 36 patients who had primary deep venous 6. Cloud ML^ Offen WW, Robinson M. Nizatidine versus placebo in gaslro- thrombosisof the upper extremities, 121 patients who had esophageal reflux disease: a 12-week, muiticenter, randomized, doubie-biind study, AmJ Gast roen te roj. 199l;86:1735-42, primary deep venous thrombosis of the lower extremities, 7. Fitzgerald JM, Allen CJ, Craven MA, Newhouse MT. Chronic cough and and 108 healthy controls. Patients who had deep venous gastroesophageal refiux. Can Med Assoc J 1989,140:520-4, 8. Davies HA, Jones DB, Rhodes J, Newcombe RG, Angina-like esophageal thrombosis of the lower extremities and study controls pain: differentiation from cardiac pain by history. J Clin Gastroenterol. 1985; were frequency-matched by age, sex, geographic origin, 7:477-81. and social status with patients who had deep venous 9. Schofield PM, Whorvi/ell PJ, Brooks NH, Befinett DH, Jones PE. Oesoph- ageal function in patients with angina peaoris: a comparison of pat(enl5 with thrombosis of the upper extremities. normal coronary angiograms and patients with coronary arteiy disease. Digestion. 1989;42:70-8, Measurements: Resistance to activated protein C was 10. Schroeder PL, Filler SJ, Ramirex B, Lazarchik DA, Vaezi MF, Richter JE. evaluated by a clotting method based on the activated Dentai erosion artd acid reflux disease. Ann Intern Med, 1995;122'809-15. 11. DeMeester TR, Wang Cl, Wernly JA, Pellegrini CA, Little AG, Klements- partial thromboplastin time. If test results were abnormal chttsch P, et ai. Technique, indications, and clinical use of 24-hour esophageal or borderline, DNA analysis for substitution in coagulation pH monitonng, J Thorac Cardiovasc Surg, 1980,79:655-70, 12. Johnson F, Joelsson B, Gudmundsson K, Greiff L. Symptoms and endo- factor V gene was done. Antithrombin, protein C, protein scopie findings in the diagnosis of gastroesophageai reflux disease. Scand J S, antiphospholipid antibodies, and total plasma homocys- Gastroenieroi. t987;22:714-8, 13. Klauser AG, Heinrich C Schmdibeck NE, Müller-üssner SA. Is long-term teine levels were also measured. esophageal pH monitoring of ciinica! value? Am J Gastroenteroi, 1989;84;362-5, 14. Rokkas T, Sladen GE. Ambulatory esophageai pH recording in gastroesoph- Results: Prevalences of abnormalities of the natural anti- ageal reflux: reievance to the devetopment of esophagilis. Am J Gastroen- coagulant system (9%) and hyperhomocysteinemia (6%) in terol, 1988;83-629-32. patients who had deep venous thrombosis of the upper 15. Shay SS, Abrev SH, Tsuchida A. Scintigraphy in gastroesophageai reflux disease: comparison to endoscopy, LESp, and 24-hour pH score, as weii as to extremities were similar to prevalences of both factors in simultaneous pH monitoring. Am J Gastroenteroi, 1992:87.1094-101. controls (6% and 7%, respectively) but lower than in pa- 16. Horrocks JC, De Dombal FT. Clinical presentation of patients with "dys- pepsia " Detailed symptomatic study of 360 patients Gut, 1978; 19:19-26, tients who had deep venous thrombosis of the lower 17. Colten MJ, Ciarlegro CA, Stanczak VJ, Lewis JH, Cattail EL, Fleischer extremities (31% and 14%, respectively). Antiphospho- DE. Basal acid output in patients with gastroescphagea! reflux disease [Ab- stract!, Gastroenteroiogy. 1987;92:A1350 lipid antibodies were found only in patients who had 1S. Robertson DA, Aldersley MA, Shepherd H, Lloyd RS, Smith CL H2 venous thrombosis of the lower extremities (7%). The antagonists in the treatment of reflux esophagitis: can physiological studies predict the response? Gut. 1987,28:946-9, overall prevalence of hypercoagulable states in patients who had thrombosis of the upper extremities (15%) was © 1997 American College of Physicians similar to that in controls (12%) but was significantly lower than that in patients who had thrombosis of the lower extremities (56%). A recent history of strenuous exercise of muscles in the affected extremity was the most frequent triggering factor for patients who had deep venous throm- bosis in the upper extremities (33%). Conclusions: This preliminary study indicates that the prevalence of hypercoagulable states is low in patients who have primary deep venous thrombosis of the upper extremities.

Ann Intem Med iy97;126:7a7-711,

From IRCCS Maggiore Hospital, University of Milan, Milan, haSy, For eurrenl auihor addresses, see end of text. 1 May ¡997 • Annals of Internal Medicine • Volume 126 • Number y 707