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Amin Madani, HBSc; Leigh Sowerby, MD; James C. Gregor, MD, Detecting the other refl ux FRCPC; Eric Wong, MD, MClSc(FM), CCFP; Kevin Fung, MD, disease FRCSC, FACS Schulich School of Laryngopharyngeal refl ux is a disorder, unlike GERD, Medicine & Dentistry (Mr. Madani and that few patients (and too few physicians) are familiar Dr. Wong); Department of Otolaryngology–Head and with. Misdiagnosis is common—unless you know what Surgery (Dr. Sowerby); Department of Otolaryngology, to look for. Division of Head and Neck Oncology and Reconstructive Surgery (Dr. Fung); and Department of Medicine (Dr. Gregor), aryngopharyngeal refl ux (LPR), the retrograde move- University of Western Ontario, PRACTICE ment of gastric content into the upper aerodigestive London, ON, Canada RECOMMENDATIONS tract, is a common—and commonly underdiagnosed— kevin.fung@ L lhsc.on.ca › Suspect laryngopharyngeal condition. Characterized by infl ammation of the laryngophar- refl ux (LPR) in a patient ynx, LPR can coexist with gastroesophageal refl ux disease The authors reported no potential with chronic ; confl ict of interest relevant to this (GERD), but it is a distinct disorder.1 In GERD, the lower article. 50% to 60% of such cases esophageal sphincter malfunctions, whereas LPR involves a are related to LPR. B dysfunctional upper esophageal sphincter. › Refer patients with risk fac- Because both conditions involve acid refl ux, LPR is some- tors for head and neck cancer times mistaken for GERD. Often, too, patients and physicians or whose symptoms persist alike attribute LPR’s , which are largely despite lifestyle modification and medical management nonspecifi c, to other causes. Th e hoarseness and laryngitis to an otolaryngologist. A that are characteristic of LPR may be blamed on vocal cord abuse or smoking, for instance; the chronic and throat › While symptoms of LPR clearing associated with LPR thought to be caused by allergies; should show improvement and the and postnasal drip that often accompany after 6 to 8 weeks of proton pump inhibitor therapy, LPR attributed to infection. Another reason LPR is underdiag- advise patients to continue nosed: Primary care physicians, who are often the fi rst clini- treatment for 4 to 6 months cians from whom symptomatic patients seek treatment, are to ensure that laryngeal often unfamiliar with this lesser-known refl ux disease.2 lesions and resolve. B Th e failure to recognize and provide timely treatment for LPR may increase patients’ risk for a number of conditions, Strength of recommendation (SOR) including laryngeal ulcers, , , A Good-quality patient- oriented evidence chronic , , , and asth- 1 B Inconsistent or limited-quality ma. Evidence suggests that LPR increases the risk for esopha- patient-oriented evidence geal and laryngeal carcinomas,3,4 and for laryngeal injury from C Consensus, usual practice, opinion, disease-oriented intubation, as well.1 To minimize these risks, it is important evidence, case series for primary care physicians to promptly identify this disorder, treat it appropriately, and recognize red fl ags that warrant re- ferral to a specialist.

How LPR develops, what to look for Th ere is no gold standard for the diagnosis of LPR. Nonethe-

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102_JFP0210 102 1/21/10 1:54:44 PM Patients with LPR are particularly prone to developing hoarseness, globus pharyngeus— a sensation of a foreign body in the — and sore throat.

less, a review of the pathophysiology and clin- ical presentation of this refl ux disorder and the ways in which it diff ers from GERD will help you identify cases of LPR. Th e prevalence of LPR in the general population is uncertain. But reports suggest that as many as 10% of otolaryngology referrals are for patients with a classic presentation of LPR, and that 50% to refl exes through irritation of the , 60% of cases of chronic laryngitis are related leading to vagally mediated changes such as to LPR.1,5,6 and bronchoconstriction. ❚ Enzyme production declines. Under The laryngopharynx becomes normal circumstances, carbonic anhydrase irritated and infl amed isoenzyme III (CAIII) is produced in the When the physiological barriers protecting posterior aspect of the larynx, catalyzing the the laryngopharynx from the retrograde fl ow production of bicarbonate and neutralizing of gastric content break down, gastric con- stomach acid.9-11 In LPR, however, the produc- tents can directly irritate the ciliated colum- tion of CAIII decreases signifi cantly, thereby nar epithelial cells of the upper respiratory exposing the larynx to stomach acid without tract, leading to ciliary dysfunction. A lack of the enzyme’s protective eff ect.9,10 At the same mucous clearance leads to mucous stasis time, a marked increase in levels inten- and, subsequently, to excessive throat clear- sifi es laryngeal injury.10,12,13 ing and the sensation of postnasal drip.7 In ❚ The larynx is highly vulnerable. Th e la- addition, the laryngopharyngeal ryngopharynx is much more susceptible to pa- becomes infl amed, and this aff ects the sensi- thology from gastric refl ux than the esophagus, tivity of laryngeal sensory endings and leads for a number of reasons. Damage can occur to laryngospasm and coughing.8 Th e infl am- with much less exposure to acid,1 not only be-

IMAGE © KIMBERLY MARTENS matory reaction in turn leads to vocal fold cause of the decrease in CAIII, but also because edema, contact ulcers, and granulomas. Th ese of the absence of peristalsis in the larynx. changes make patients with LPR particularly What’s more, the esophagus has the prone to developing hoarseness, globus pha- ability to clear gastric refl ux and minimize ryngeus—a sensation of a foreign body in the damage to the epithelial layer.9,10,14,15 In most larynx—and sore throat.5,7 Th e gastric content patients who develop signs and symptoms of can also act indirectly by initiating laryngeal LPR, there has been enough gastric refl ux to

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103_JFP0210 103 1/20/10 12:53:05 PM FIGURE Fiberoptic : Before and after treatment

Fiberoptic laryngoscopy reveals evidence of Two months after the initiation of twice-daily proton laryngopharyngeal refl ux (LPR), including post-cricoid pump inhibitor therapy, the physical manifestations edema (black arrow), ventricular edema (gray arrow), of LPR had resolved. , and vocal fold edema (white arrow). , and night- damage the laryngopharynx but not enough further assess the probability and sever- time refl ux, to overcome the protective mechanisms of the ity of LPR, use the Refl ux Symptom Index18 characteristics esophagus. Th at’s why most LPR patients have (TABLE 1). A recent cohort study validated the of GERD, are little or none of the heartburn and esophagitis index, with an average score of 21.2 for those not common in that are classic symptoms of GERD. with LPR, vs an average of 11.6 for controls patients with (P<.001). A score >13 is suggestive of LPR LPR. Common signs and symptoms (odds ratio=9.19), the researchers found.18 that signal LPR If the diagnosis remains uncertain and LPR is primarily a clinical diagnosis based on the patient continues to be troubled by signs signs and symptoms—which are also used and symptoms suggestive of LPR, refer him or to rule out GERD. Notably, less than 50% of her to an otolaryngologist for further inves- patients with LPR suff er from heartburn and tigation. A referral is needed, too, to rule out regurgitation.16 Th ose who do have heartburn malignancy in any patient with 3 or more of and regurgitation typically suff er with refl ux the following red fl ags: older than 50 years, during the day, when they’re in an upright po- otalgia, weight loss, progressive hoarseness, sition, whereas refl ux associated with GERD neck mass, a signifi cant history of alcohol use, develops primarily at night.16 Th e results of and a history of smoking.7 a recent survey of members of the American Bronchoesophagological Association high- light the most common signs and symptoms Diagnostic tools the of LPR, listed below from the most to the least specialists will use frequent:17 ❚ Fiberoptic laryngoscopy is the most com- • throat clearing mon test used by otolaryngologists to con- • persistent cough fi rm LPR and rule out other pathology. Th e • globus sensation test reveals infl ammatory fi ndings (FIGURE), • hoarseness such as erythema, edema, granulomas, and • choking episodes. contact ulcers, in several anatomical loca- Additional signs and symptoms include tions of the larynx—especially the posterior excessive and chronic throat clearing, sore aspect and the true vocal folds. It is important throat, postnasal drip, and . to note, however, that as many as 70% of the

❚ Use a validated symptom index. To general population will have some laryngeal OF AMIN MADANI, HBSC, UNIVERSITY WESTERN ONTARIO IMAGES COURTESY

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TABLE 1 Th e Refl ux Symptom Index for laryngopharyngeal refl ux

Within the last month, how did the 0 = NO PROBLEM 5 = SEVERE PROBLEM following problems affect you? (CIRCLE THE APPROPRIATE RESPONSE)

1. Hoarseness or a problem with your voice 0 1 2 3 4 5

2. Clearing your throat 0 1 2 3 4 5

3. Excess throat mucus or postnasal drip 0 1 2 3 4 5

4. Diffi culty swallowing food, liquids, or pills 0 1 2 3 4 5

5. Coughing after you ate or after lying down 0 1 2 3 4 5

6. Breathing diffi culties or choking episodes 0 1 2 3 4 5

7. Troublesome or annoying cough 0 1 2 3 4 5

8. Sensations of something sticking in your throat or a lump 012345 in your throat

9. Heartburn, chest pain, , or stomach acid 012345 coming up Advise patients TOTAL SCORE= to avoid eating

*A score >13 is considered suggestive of laryngopharyngeal refl ux. too rapidly or Source: Belafsky PC et al. J Voice. 2002.18 Reprinted with permission. drinking large quantities of fl uid. infl ammation, so these fi ndings alone are not EGD should be considered only when heart- defi nitive evidence of LPR.7 burn is a primary complaint in a patient with ❚ Ambulatory 24-hour dual sensor pH signs and symptoms of LPR—or when a pa- probe monitoring is sometimes used as an tient believed to have LPR fails to respond to adjunctive test to confi rm LPR. In 2005, 2 meta- medical management.24 analyses found that the pH probe is reliable and sensitive and specifi c enough to identify signifi cantly more acid refl ux in patients with Treating LPR: Lifestyle changes, LPR than in controls.19,20 However, not every- drug therapy one agrees: Some clinicians question its use For all patients with LPR, dietary and life- as a diagnostic tool for LPR, citing problems style modifi cations have been shown to be with observer reliability, among other things. both clinically eff ective and cost eff ective.25 Because it increases costs to the patient and In addition to dietary restrictions (TABLE 2), is impractical, pH monitoring is not widely advise patients to avoid eating too rapidly or used by specialists, but primarily as a research drinking large quantities of fl uid. Late night tool.21,22 meals—indeed, eating within 3 hours of bed- ❚ Barium swallow and esophagogastro- time—should also be avoided, as should heavy duodenoscopy (EGD) are relatively common lunches and dinners. Tell patients to eat small, diagnostic tools used to identify anatomical frequent meals instead.7,25,26 abnormalities in the , ❚ Recommend other behavioral changes, such as a Schatzki’s ring or hiatal , that as well. Tell patients to avoid tight clothing, ly- can lead to symptoms of GERD and/or LPR. ing down immediately after a meal, and apply- Some studies suggest that all patients with ing pressure to the abdomen, whether through symptoms of LPR should undergo EGD to exercise, heavy lifting, singing, or bending over. screen for esophageal adenocarcinoma.23,24 Smoking and overuse (or misuse) of the voice— Because LPR symptoms are relatively com- screaming at a concert or singing for hours, for mon, however, many clinicians believe that instance—are contraindicated, as well.7,25,26 CONTINUED

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105_JFP0210 105 1/21/10 1:54:48 PM TABLE 2 tients should continue the twice-daily regi- Dietary management of LPR: men for 4 to 6 months, although the optimal What to tell patients7,14,24 duration is unknown.26 One study found 4 months of therapy to be Avoid* Enjoy† eff ective;28 others suggest that while symptom Caffeine Meat relief should begin after 6 to 8 weeks of treat- ment, 6 months of PPI therapy is needed for la- Alcohol Poultry ryngeal lesions and edema to resolve.1,8 Despite Spicy foods Seafood the time frame, patients should be weaned Tomatoes Milk gradually to prevent the delayed rebound eff ect Chocolate Fresh vegetables‡ associated with abrupt cessation of PPIs. ❚ The PPI controversy. Not only the length Fats of treatment is controversial, however, but the Citrus fruits effi cacy of PPIs for LPR. Many studies, includ- Carbonated beverages ing several prospective cohort studies and Jams/jellies 9 RCTs, have reported signifi cant improve- ment in laryngeal symptoms, but evidence Barbecue sauces that PPIs are signifi cantly better than placebo Salad dressings is weak.25,29,30 In fact, a systematic review and For maximum Hot mustard 2 meta-analyses concluded that not only is there benefi t, patients Curry a lack of suffi cient evidence to draw reliable con- with LPR should clusions about the effi cacy of PPIs vs placebo for continue Hot peppers the treatment of LPR, but there seems to be a taking PPIs *Other acidic foods. signifi cant response to placebo among patients †Other foods and beverages that are neither spicy nor 25,29,30 twice daily for acidic. with this condition, as well. 4 to 6 months. ‡ Except tomatoes. ❚ The role of adjunctive therapy. Hista- mine type 2 (H2) blockers have been shown Tell patients that weight loss, as needed, to be helpful in the treatment of GERD. But is likely to bring some symptom relief. Using data showing their effi cacy for LPR, either as a wooden blocks to elevate the head of the bed single agent or in combination with a PPI, are about 4 to 6 inches may also be helpful, par- limited. Indeed, 3 clinical trials have found ticularly for patients who suff er from both LPR that H2 blockers do not provide any added and GERD.7,25,26 benefi t to PPI therapy for LPR. All 3 were co- hort studies that compared the treatment Drug therapy: Straightforward, outcomes of PPI alone vs PPI and H2 block- but not without controversy ers, and found no statistically signifi cant dif- ❚ Acid suppression with proton pump inhibi- ference (P>.05).28,31,32 Despite these fi ndings, tors (PPIs) is the primary treatment for LPR, recent studies suggest that 300 mg ranitidine as it is for GERD. But because the larynx is ex- twice a day provides added benefi t P( <.01).33,34 tremely susceptible to injury from acid refl ux, Given these mixed fi ndings, H2 blockers may LPR typically requires more aggressive and be considered as adjuvant therapy to the PPI prolonged treatment, compared with GERD.1,5 regimen to further reduce acid production Clinical trials have shown that PPIs do not in patients with more severe symptoms. Ant- inhibit acid production to an intragastric pH acids and prokinetic agents are sometimes of >4 for more than 16.8 hours.1,27 Th us, most used for this purpose, as well. patients need twice-daily dosing (although once-a-day dosing or conservative manage- When medical management fails ment may be suffi cient for those with mild Surgery has a limited, but useful, role in the and intermittent symptoms).27,28 Regardless treatment of LPR. of dosing, PPIs should be taken on an empty ❚ —a procedure stomach, 30 minutes before a meal to increase in which the fundus of the stomach is passed bioavailability. For maximum benefi ts, pa- posteriorly behind the esophagus to encircle

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it and provide mechanical obstruction to the gery can be used to treat vocal fold sequelae retrograde movement of acid—may be con- of LPR, such as granulomas—with a higher sidered for patients with a confi rmed diag- likelihood of success.35 nosis, severe symptoms, and little response CORRESPONDENCE to treatment. However, there is little evidence Kevin Fung, MD, FRCSC, FACS, University of Western Ontario, that this procedure will result in long-term im- London Health Sciences Center - Victoria Hospital, 800 Commissioners Road East, Room B3-427, London, Ontario, provement in LPR symptoms. Laryngeal sur- Canada, N6A 4G5; [email protected]

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Belafsky PC, Postma GN, Koufman JA. Validity and reliability of laser surgery: a review of 443 cases using three wavelengths. the Refl ux Symptom Index (RSI).J Voice. 2002;16:274-277. Otolaryngol Head Neck Surg. 2007;137:146-151.

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