Gastroesophageal Reflux Diseaseand Complications

Adharsh Ravindran and Prasad G. Iyer

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Etiopathogenesis of GERD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Acid Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Acid Clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Mucosal Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Increased Intra-Abdominal Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Esophageal Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Extraesophageal Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Lifestyle Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Histamine-2-Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Proton Pump Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10PPI-Clopidogrel Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Potential Adverse Effects of Chronic PPI Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11PPI Use and Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11PPI Therapy and Enteric Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11PPIs, Osteoporosis, and Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12PPI, AKI, and CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12PPI and Gastric Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

A. RavindranDepartment of Internal Medicine, University at Buffalo,Buffalo, NY, USAe-mail: Ravindran.adharsh@gmail.com

P. G. Iyer (*)Division of Gastroenterology and Hepatology, MayoClinic, Rochester, MN, USAe-mail: iyer.prasad@mayo.edu

© Springer Nature Switzerland AG 2020C. S. Pitchumoni, T. S. Dharmarajan (eds.), Geriatric Gastroenterology,https://doi.org/10.1007/978-3-319-90761-1_42-1

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Endoscopic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Antireflux Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

AbstractGastroesophageal reflux disease (GERD) andits complications such as esophagitis, Barrett’sesophagus, and esophageal adenocarcinomaare more prevalent in the elderly compared tothe young. This is likely due to the higherprevalence of risk factors and hyposensitivityto symptoms in this age group, which makesdiagnosis and treatment more challenging. Inthis chapter we focus on the epidemiology,etiopathogenesis, diagnosis, and management(medical and surgical) of GERD and its com-plications in the elderly. Diagnosis of GERD ismade by a combination of clinical features(identification of risk factors and esophagealand extraesophageal symptoms) and investiga-tions (such as ambulatory pH monitoring andendoscopy). The mainstay of treatment is acombination of lifestyle modifications andmedications (predominantly proton pumpinhibitors and histamine receptor antagonists).Surgery is usually reserved for those withrefractory symptoms and complications notresponding to medications. We also addresssome of the current misconceptions on theadverse effects attributed to proton pump inhib-itors in the literature and provide recommenda-tions on their appropriate and judicious use.

KeywordsReflux · Heartburn · Regurgitation · Protonpump inhibitors · Barrett’s esophagus ·Esophageal adenocarcinoma · Ambulatory pHmonitoring · Complications

Introduction

Gastroesophageal reflux disease (GERD) isdefined as a condition that develops when thereflux of stomach contents causes troublesome

symptoms and/or complications (Vakil et al.2006). It is a condition that is fairly commonamong people of all ages, races, and genders.Older adults appear to be at a higher risk of mor-bidity from GERD due to the additionalcomorbidities and risk factors that play a role inthe development and progression of the disease.GERD is a multifactorial disorder that can havediverse clinical presentations and complicationsof varying severity. The recognition of this condi-tion in older adults warrants early diagnosis andtreatment to prevent progression of the diseaseinto precancerous and cancerous conditions likeesophagitis, Barrett’s esophagus, and esophagealadenocarcinoma (EAC). Elderly patients are alsoat risk of developing extraesophageal complica-tions with chronic GERD. Additionally, medicaltreatment of GERD with proton pump inhibitors(PPI) and histamine-2-receptor antagonists (H2RAs)is more cost-effective compared to nonmedical man-agement options for manifestations of GERD. How-ever, it is also important to recognize that over orinappropriate use of these medications in the old isprevalent.Hence, understanding the nature and sever-ity of GERD and personalizing the management ofthis condition in each individual are critical.

Epidemiology

GERD symptoms are highly prevalent in the gen-eral population worldwide (Table 1). Populationstudies have shown that one out of five individualsexperience heartburn or acid regurgitation on aweekly basis and two out of five experience heart-burn or acid regurgitation at least once a month(Locke et al. 1997). The prevalence of GERDworldwide appears to be increasing with higherrates in the Americas and Europe. A population-based study reported an overall increase in preva-lence of reflux symptoms from 10–20% in 2005 to

2 A. Ravindran and P. G. Iyer

18–27% in 2014 in North America (El-Serag et al.2014). Factors such as obesity, eradication ofH. pylori infection, and other lifestyle and geneticfactors could be related to this rise in prevalence.Several large population studies have demonstratedthat there is no significant increase in GERD symp-toms with age; despite that, the prevalence ofesophagitis is significantly higher in older com-pared to younger subjects (Pilotto et al. 2006).However, the actual prevalence of GERD in theelderly is probably higher given the low perceptionof symptoms and manifestations in this population.Epidemiologic data consistently support the viewthat as people age, the severity of reflux esophagitisincreases, whereas symptoms are attenuated andbecome less typical (Becher and Dent 2011).Indeed, a large epidemiological study from theUSA reported that age was an important risk factorfor the development of severe forms of GERD, inaddition to male gender, white ethnicity, and hiatushernia (Johnson and Fennerty 2004).

Etiopathogenesis of GERD

Reflux in the general population is not alwayspathologic (Crookes 2006). Physiologic refluxcan occur immediately after consumption offood or can occur at night. This is usually asymp-tomatic and brief and resolves on its own withoutneed for medical management. Pathologic refluxis usually symptomatic, commonly presentingwith acid reflux or heartburn symptoms with orwithout endoscopic evidence of esophagealmucosal inflammation. The factors that influenceprogression from physiologic reflex GERDinclude imbalances between acid production,

acid clearance, and mucosal defense in the esoph-agus (Boeckxstaens et al. 2014).

Acid Production

Although reducing the gastric acidity is the main-stay of management in GERD, it is rarely associ-ated with increased acid production. More oftenthan not, development of GERD is multifactorialexcept in conditions like Zollinger-Ellison syn-drome (Moore et al. 2013), atrophic gastritiswith hypergastrinemia (Phan et al. 2015; Dachaet al. 2015), and H. pylori infection (Phan et al.2015; Dacha et al. 2015) where the pathogenesisis primarily from acid hypersecretion. In additionto increased acid levels, the acidity of the secre-tions is also associated with gastric and esopha-geal mucosal injury (Goldberg et al. 1970).Gastric secretions with pH less than 4 have beenassociated with mucosal damage that can causeGERD and peptic ulcer disease (PUD) (Hunt1999). Presence of enzymes like pepsin and tryp-sin and bile acids in the refluxate can also poten-tiate symptomatic GERD and esophagitis even atnormal acid levels (Powell 1981).

Acid Clearance

Acid in the esophagus as a result of normal phys-iologic reflux is normally cleared by a combina-tion of peristalsis and alkaline saliva. Peristalsispushes acid into the stomach, while ingestedsaliva mixes and neutralizes the remaining acid.Hence, impaired peristalsis or reduced salivationcan lead to an increase in the duration of acidexposure in the esophagus, increasing the risk ofmucosal injury.

Impaired PeristalsisImpaired peristalsis could be related to ineffectiveemptying of acid into the stomach or reflux ofgastric contents back into the esophagus. This iscommonly seen in patients with low lower esoph-ageal sphincter (LES) pressure. LES pressure islower in older adults, which in turn can lead to

Table 1 GERD prevalence estimates in global population(El-Serag et al. 2014)

Geographical area Prevalence rates

North America 18–28%

South America 23%

Europe 9–26%

Middle East 9–33%

Australia 12%

East Asia 3–8%

Gastroesophageal Reflux Disease and Complications 3

increased esophageal acid exposure and incompleteacid clearance (Kahrilas et al. 1988; Lee et al. 2007).

Impaired esophageal body peristalsis as seen inachalasia can also present with symptoms ofheartburn and GERD. Achalasia is more commonin the older age group with a mean age at diagno-sis of 50 years; further, incidence increases withage (Wadhwa et al. 2017). Hiatal hernias, morecommon in the elderly over the age of 65, areassociated with increased retrograde acid flowdue to anatomic shortening of esophagus withswallowing. This further leads to increase in fre-quency and duration of esophageal acid exposure,thereby causing GERD (Kishikawa et al. 2017).Interestingly, a recent study from Japan revealedthat increased gastric acid secretion, with or with-out symptomatic GERD, independently induceddevelopment of hiatal hernias. The exactly patho-physiology is poorly understood, but it is likelyrelated to recurrent inflammation and healingoccurring with acid exposure causing acid-induced esophageal shortening which promotesproximal herniation of the stomach into the thorax(Kishikawa et al. 2017).

Salivary Hyposecretion or DysfunctionSaliva, with a normal alkaline pH between 6.3 and7.6 (Baliga et al. 2013), is a natural buffer forrefluxed gastric acid when it is swallowed.Patients with chronic xerostomia have beenshown to experience increased acid exposure tothe esophageal mucosa due to ineffective buffer-ing of refluxed gastric acid, compared to thosewith intact saliva production (Korsten et al. 1991).

The rate and composition of salivary secretionhave been studied to show an age-related decline.This age-related salivary dysfunction places olderpeople at risk for xerostomia-related adverseeffects (Dodds et al. 2005). In smokers, one ofthe mechanisms is related to salivary hypo-secretion and dysfunction that lead to xerostomiaand, hence, a delayed clearance of refluxed gastricacid. In addition, saliva in smokers has lowerlevels of titratable base than non-smokers, whichleads to ineffective neutralization of acid (Petrusicet al. 2015).

Mucosal Defense

The esophageal mucous layer acts as an epithelialbarrier against the harmful effects of acid. Integ-rity of this layer is important in the developmentof GERD. Several factors can influence integrityof the mucosal barrier such as age, lifestyle, nutri-tional status, medications, and pre-existing inju-ries from instrumentation. Any break in thecontinuity of this barrier exposes the esophagusto corrosive effects of acid which in turn can resultin GERD, esophagitis, ulceration, or rarelyperforation.

Increased Intra-Abdominal Pressure

An increase in the intra-abdominal pressure cancause elevated intragastric pressure. This furtherleads to increase in gastroesophageal reflux toincorporate the pressure gradient. Obesity hasbeen studied to have a strong association withGERD due to a mechanical rise in intra-abdominal pressure. The prevalence of obesityamong the elderly has been steadily rising. Datafrom CDC showed that more than one-third ofadults over 65 years of age were obese between2007 and 2010 with the prevalence being higherbetween 65 and 74 years (Fakhouri et al. 2012).Obesity is also associated with an increased risk ofdeveloping hiatal hernia which in turn can resultin acid reflux and heartburn. Drugs and lifestyleare important risk factors for development ofGERD. Alcohol, smoking, and certain foods(fatty food, citrus fruits, spicy food, caffeine, car-bonated drinks, and chocolate) have strong asso-ciation with GERD (Table 3).

Table 3 contains a list of commonly used med-ications that are associated with GERD.

Clinical Features

Reflux or regurgitation and heartburn are the mostcommon presentations of GERD. But patients withGERD need not necessarily have one of thesesymptoms. Some may not have any symptoms of

4 A. Ravindran and P. G. Iyer

GERD but can have endoscopic evidence of ero-sive esophagitis. This is more common in theelderly due to their relative hyposensitivity to per-ceiving acid reflux.

Heartburn is defined as a burning sensation inthe anterior chest (substernal or retrosternal). Itusually begins behind the sternum and radiatesupward to the throat and neck. This is one of themost common presentations of GERD in all agegroups especially in the elderly with comorbiditiesand polypharmacy (Vallot et al. 2011; Moshkowitzet al. 2011; Furuta et al. 2012). Heartburn is com-monly experienced in the postprandial period butcan be experienced during sleep or rest also in oldersubjects.

Regurgitation is the reflux of gastric contentsincluding acid and undigested or partially digestedfood through the esophagus into the mouth andcharacterized as a bitter or sour tasting fluid. Thisis more common in people with low LES tone andobesity due to the mechanical effects of intra-abdominal pressure that can increase the tendencyfor upward flow from the stomach.

In patients with chronic GERD, the acidic con-tent can eventually damage the esophageal barrierand lead to erosive esophagitis. Recurrent esoph-agitis can cause strictures, presenting as dyspha-gia to solid foods with food getting stuck in thelower esophagus. The evidence is unclear withregard to the presence of typical and atypicalGERD symptoms between the elderly andnon-elderly population as many other factors areinvolved in the pathogenesis and progression ofGERD, such as presence of mucosal breaks anddegree of esophagitis (Furuta et al. 2012).

Not all patients with symptomatic GERD willpresent with acid reflux and heartburn. Some ofthe atypical presentations of GERD in the old arenon-cardiac or atypical chest pain that may mimicangina, asthma, dysphagia, globus sensation inthe throat, chronic cough, laryngitis (hoarseness),dental erosions, and recurrent pulmonary aspira-tion (Vakil et al. 2006; Raiha et al. 1992).

Complications

Although GERD is a common condition in allages, diagnosis and timely management areimperative in preventing its progression to com-plications. The complications could be due to thelocal progression of mucosal injury (esophageal)or due to systemic effects from worsening reflux(extraesophageal).

Esophageal Complications

Esophageal complications occur as a series ofevents that unfold from untreated and worseningreflux.

– Erosive esophagitis: The esophageal mucosa isinjured with repeated or long-term exposure tothe acidic refluxate. The mucosa eventuallydevelops inflammation as cytokines and otherinflammatory factors are released, resulting inerosive esophagitis. Some of these patientsmay not have symptoms of GERD (Lee et al.2015). Erosive esophagitis is an endoscopicdiagnosis, and the severity is proportional tothe extent of mucosal injury, compliance tomedical treatment, and pre-existing mucosaldefects (Table 5). Figure 1 shows mucosalerosions in erosive esophagitis. A subset ofpatients may present with chronic regurgitationor heartburn symptoms without endoscopicevidence of esophagitis but may have histo-logic evidence of esophageal injury character-ized by basal cell hyperplasia. This condition istermed non-erosive reflux disease (NERD)(Dellon et al. 2014).

– Esophageal strictures: As a consequence oferosive esophagitis-related damage andhealing in the setting of chronic GERD, theesophageal mucosa can undergo morphologicand histologic changes leading to the forma-tion of strictures in the distal esophagus. Repet-itive damage and healing initiates fibrin andcollagen deposition that further leads to fibro-sis and scar formation. This distal scarringresults in shortening of the length of the esoph-agus and narrowing of the lumen. Strictures

Gastroesophageal Reflux Disease and Complications 5

may be seen in the elderly from chronic inflam-mation over the years. Management of stric-tures requires mechanical dilation of the lumenalong with acid suppressive therapy to preventrecurrence (Ravich 2017; Adler and Siddiqui2017). Esophageal strictures can also occur inpatients undergoing endoscopic managementfor esophageal varices, Barrett’s esophagus,or early-stage esophageal adenocarcinoma(EAC) which usually involves tissue coagula-tion using bipolar cautery, sclerotherapy, bandligation, or radiofrequency ablation (Reillyet al. 1984; Stier et al. 2016).

– Barrett’s esophagus: The esophagus is nor-mally lined by stratified squamous epitheliumthat provides adequate protection from acidinjury. The gastric mucosa is lined by columnarepithelium that helps with the secretory activ-ities of the stomach. The site of transition fromesophageal squamous to gastric columnar cellsis termed the squamocolumnar junction (SCJ).In patients with chronic GERD, the repetitiveirritation of esophageal squamous epitheliumat the GEJ can lead to metaplastic change at thelower esophagus to columnar epithelium. Thiscolumnar epithelial metaplasia in the distal

Fig. 1 Endoscopic images of erosive esophagitis

6 A. Ravindran and P. G. Iyer

esophagus with intestinal metaplasia on histol-ogy is called Barrett’s esophagus, a disorderassociated with an increased risk of progres-sion to EAC. Barrett’s esophagus progresses toEAC via the development of dysplasia (lowgrade and high grade). Hence screening forthe detection of BE and endoscopic surveil-lance for the detection of dysplasia arerecommended. If dysplasia is detected on his-tology, endoscopic ablation is recommended toreduce the risk of progression to EAC(Shaheen et al. 2016).

– Esophageal adenocarcinoma: Incidence ofEAC has been rising steadily in Western coun-tries with strong predominance in Caucasianmales. Risk factors like smoking, older age,central obesity, and Barrett’s esophagus thatare commonly associated with chronic GERDhave been associated with a higher risk ofprogression to EAC (Rubenstein et al. 2011).Early-stage EAC can be successfully treatedendoscopically.

Extraesophageal Complications

GERD has been associated with many extra-esophageal complications in the elderly. This iscommon due to the synergism between GERDand coexisting comorbidities that pose higherrisk in the geriatric population. In patients withasthma, untreated GERD may trigger asthmaexacerbations. The mechanism for these triggerscould be related to bronchoconstriction fromincreased vagal tone with acid exposure, airwayhyper-reactivity, and micro-aspiration of gastricrefluxate. Treatment of GERD symptoms in asth-matic patients may lower exacerbation rates (Fieldand Sutherland 1998).

One of the very common atypical presentationsof GERD in older adults is non-cardiac chest painor pseudoangina. It can appear as a retrosternal,midsternal, or epigastric pain or tightness whichmimics angina. In geriatric patients withcomorbidities and risk factors for cardiac disease,it is important to rule out acute coronary syndrome(ACS) with EKG and serial troponins before the

symptoms can safely be attributed to GERD(Barboi et al. 2016).

Other less common extraesophageal complica-tions are chronic laryngitis, laryngeal stenosis,chronic cough, bronchitis, and aspiration pneu-monia. Furthermore, in bedridden patients andpatients under palliative care, the risk of develop-ing pulmonary complications such as recurrentaspiration is higher due to underlying swallowingimpairment, esophageal dysphagia, loss of esoph-ageal peristalsis, and impaired LES contraction(Palmer et al. 2000) (Table 2).

GERD has been shown to have a strong asso-ciation with sleep disorders. A high prevalence ofsymptomatic GERD was noticed in patients withsevere obstructive sleep apnea (OSA). Althoughobesity is a confounding factor and could be amajor contributor to both GERD and OSA, treat-ment of OSAwith CPAP has shown to be benefi-cial for OSA and GERD symptoms in somepatient populations (Green et al. 2003; Shakerand Magdy 2016). Symptomatic GERD is alsoknown to cause conscious and unconsciousarousals at night that leads to poor quality ofsleep and disruptive sleep patterns. This nocturnalincrease in GERD intensity is likely due to theincreased acid exposure time at night. However,

Table 2 Complications of gastroesophageal reflux dis-ease (Chait 2010)

Esophageal Erosive esophagitis

Esophageal stricture

Barrett’s esophagus

Esophageal adenocarcinoma

Extraesophageal Atypical non-cardiac chest pain

Globus sensation

Pharyngitis

Sinusitis

Dental erosions

Hoarseness

Laryngitis

Vocal cord granulomas

Subglottic stenosis

Laryngeal cancer

Chronic cough

Asthma

Pulmonary fibrosis

Aspiration pneumonia

Gastroesophageal Reflux Disease and Complications 7

good sleep quality with minimal disruptions hasalso been studied to relieve GERD symptoms. In astudy involving patients with erosive esophagitis,patients had a significant decrease in lag time toonset of symptoms and an overall increase inintensity rating during sleep-deprived nights ascompared to the nights with good sleep (Junget al. 2010; Schey et al. 2007).

Diagnosis

GERD is usually diagnosed based on clinical pre-sentation with typical symptoms of acid reflux orheartburn. Sometimes patients can present withatypical symptoms like chronic cough, atypicalnon-cardiac chest pain, globus sensation, or noc-turnal wheezing. In such cases, it is imperative torule out other conditions that could be causingthese symptoms before a diagnosis of GERD canbe established. In some patients, GERD can pre-sent as chest pain indistinguishable from the painof angina. In such cases, complete cardiac workupshould be performed, particularly in those withcardiovascular risk factors. An upper gastrointes-tinal endoscopy is not always needed to diagnoseGERD (particularly in the presence of typicalsymptoms); however, it may be needed in patientswith suspected complications of GERD likeesophagitis, Barrett’s esophagus, and EAC. Inpatients with chronic GERD refractory to PPI

therapy, upper GI endoscopy with biopsy can beconsidered to rule out alternate diagnoses such aseosinophilic esophagitis and achalasia. Eosino-philic esophagitis (EE), an inflammatory condi-tion of the esophagus caused by eosinophilicinfiltration of the esophageal mucosa, can alsopresent with GERD-like symptoms. EE has abimodal incidence with high incidence in adultsand elderly (Trifan et al. 2016). Gastroenterolo-gists and geriatricians should have high suspicionof EE in adults and elderly presenting with chronicpersistent heartburn and dysphagia refractory toPPI use. Endoscopic examination and biopsies areessential in these patients to diagnose EE.

An endoscopic examination is also mandatoryin patients with chronic GERD who developalarm symptoms such as gastrointestinal bleeding,anemia dysphagia, odynophagia, and weight loss.It is also essential to first exclude cardiac causes ofchest discomfort before considering GERD as thediagnosis.

Ambulatory pHmonitoring which involves theplacement of a pH sensor in the distal esophagusto measure the intra-esophageal pH over 24–48 hmay be needed to confirm the diagnosis of GERDin those with a negative endoscopic exam or thosenot responding to a therapeutic trial with PPIs.Ambulatory pH monitoring also allows the corre-lation of symptoms experienced by the patientwith intra-esophageal pH. This can be done intwo ways: first, placing the sensor transnasallywith a thin tube containing a sensor 5 cm proximal

Table 3 List of commonly used medications that may be associated with GERD

Decrease LES pressure Directly injure esophageal mucosa Delay gastric emptying

Anticholinergics Antiretroviral agents Anticholinergics

Barbiturates Ascorbic acid Calcium channel blocker

Benzodiazepines Aspirin Clonidine

Beta-agonists Bisphosphonates Dopamine agonists

Caffeine Doxycycline Lithium

Calcium channel blockers Ferrous sulfate Narcotics

Dopamine Phenytoin Nicotine

Ethanol Potassium chloride Progesterone

Estrogen Propranolol

Nitrates NSAIDs

Progesterone Tetracycline

Theophylline Trimethoprim–sulfamethoxazole

Quinidine

8 A. Ravindran and P. G. Iyer

to the lower esophageal sphincter, which isretained for 24 h, or, second, deploying the sensorendoscopically and retaining for 48–96 h (BravopH monitoring) (Ang et al. 2010). The test can beperformed on or off medications to answer appro-priate questions: off medications, does the patienthave GERD, and on medications, do the patient’ssymptoms on medications correlate with persis-tent uncontrolled reflux?

Management

Lifestyle Management

The goals of treatment of GERD are essentiallythe same in all adults and include symptom relief,healing of erosive esophagitis, and prevention andmanagement of complications. Lifestyle modifi-cation is an important first step in the managementof GERD. Food-induced reflux and heartburn areone of the most important and reversible causes ofGERD. Spicy foods have been known to increaserisk of symptomatic GERD from direct irritationof esophageal mucosa. Capsaicin, a neurotoxinfound in red pepper, has been shown to delaygastric emptying, thereby increasing the risk ofreflux (Milke et al. 2006; Choe et al. 2017). Foodsrich in fat may also increase esophageal acidexposure by delaying gastric emptying andincreasing frequency of transient lower esopha-geal sphincter relaxation (tLESRs). Similarly,peppermint and chocolate may induce refluxsymptoms by reducing the LES pressure. Bever-ages such as coffee, tea, soda, tomato, and citrusjuice, which are either acidic or can stimulategastric acid production, contribute to heartburn(Dore et al. 2008). Table 4 contains a list ofcommonly consumed beverages and their pH.

Smoking has been shown to increase distalesophageal exposure time through the effect onthe LES, while alcohol may precipitate GERD byincreasing acid secretion, reducing LES pressure,increasing spontaneous LES relaxations, andimpairing esophageal motility and gastric empty-ing (Festi et al. 2009).

However, a systemic review that evaluated theliterature from 1975 to 2004 revealed no evidence

supporting an improvement in GERD symptomsafter cessation of smoking, alcohol, and other die-tary interventions (Kaltenbach et al. 2006). In thesame study, only reduction of excess weight andelevation of the head of the bed were shown tobenefit patient symptoms, but neither preventedcomplications. Additionally ensuring a 3- to 4-hinterval between the last meal of the day and bed-time is also helpful in helping with nocturnal symp-toms, particularly regurgitation. A careful reviewof the patient’s current medications, and wherepossible, avoidance of drugs known to worsenGERD, is also prudent (Table 3). Weight loss hasalso been shown to improve GERD symptoms andshould be recommended. Body posture and posi-tioning during sleep are one of the simple, yetimportant ways to reduce nocturnal GERD symp-toms. Studies have shown improvement in noctur-nal heartburn and reflux with keeping the head endelevated during sleep (Khan et al. 2012). A morerecent study that tested body posture during sleeprevealed that people who slept with their left sidedown had significantly lesser GERD symptomsthan right. This difference is likely due to collectionof gastric contents close to GE junction with rightlateral position, thereby promoting reflux andGERD, whereas the gastric contents are collectedin the dependent part of the stomach while lying onleft lateral position (Person et al. 2015).

Antacids

Antacids are available over the counter andpromptly act by neutralizing gastric acid.Simethicone is added to many formulations andprovides an additional physical barrier to acid.These measures help self-treat mild, infrequentheartburn symptoms and provide rapid relief;however, they do not heal erosive esophagitis,nor prevent complications (Behar et al. 1975).Furthermore, antacids require frequent dosingand should be used with caution in older adultsdue to the potential risk of salt overload, calcinosisand calcium nephrolithiasis, constipation, diar-rhea, and drug interactions. Alginate-antacid com-binations have been widely used in management

Gastroesophageal Reflux Disease and Complications 9

of reflux symptoms. They have also been provento reduce the incidence of acid reflux episodes(Yuan et al. 2016). This can be used in combina-tion with acid suppressive therapy in patients withGERD refractory to PPI monotherapy. Sucralfate,a commonly used agent in management of gastricand duodenal ulcers, has also shown to have ben-efit in GERD and reflux esophagitis by promotingtissue healing as a result of providing mucosalprotection (Laitinen et al. 1985).

Histamine-2-Receptor Antagonists

Acid secretion by gastric parietal cells is stimulatedby acetylcholine, histamine, and gastrin. Histamine-

2-receptor antagonists (H2RAs) reduce acid secre-tion by competing for histamine receptors on parie-tal cells. They are more effective in controllingnocturnal as compared with meal-related acid secre-tion because the parietal cell is stimulated postpran-dially by gastrin and by acetylcholine (Lipsy et al.1990). Compared to placebo, H2RAs significantlydecreased heartburn, although symptoms are rarelyabolished. The overall esophagitis healing rates withH2RAs rarely exceed 60% following 12 weeks oftreatment, evenwhen higher doseswere used (Wanget al. 2005). H2RAs are relatively safe with a sideeffect rate of about 4%, most being minor andreversible. However, cimetidine and to a lesserdegree ranitidine can inhibit the P450 cytochromesystem causing drug interactions, which requiresmonitoring of other medications taken simulta-neously. When used intermittently, H2RAs can beeffective in blocking nocturnal acid reflux. Whenused daily, tolerance develops and the benefit dimin-ishes. Hence an intermittent drug holiday may be ofbenefit in those patients who use the medicationregularly.

Proton Pump Inhibitors

PPIs provide meal-stimulated and nocturnal gas-tric acid inhibition of the parietal cell regardless ofany stimuli and to a significantly greater degreethan H2Ras and are currently the cornerstone oftreatment of GERD. Compared to H2RAs, PPIspromote a greater degree and more sustainedduration of acid suppression. In a recent Cochranereview involving 4032 patients in 26 RCT trials,PPIs were superior to H2RAs in healing esopha-gitis at 4–8 weeks with a number to treat of3 (Khan et al. 2007). Currently, there are sevenPPIs available in the market with similar thera-peutic efficacies; however, large studies compar-ing PPIs found a greater therapeutic advantage tousing esomeprazole in severe LA grade C/Desophagitis (Metz et al. 2000). A recommendedregimen in patients with confirmed esophagitis isa 2-month course of daily PPI with expected curerates over 90%. However, GERD is a chronicdisease, and most elderly will require long-termmaintenance therapy. The relapse rate can be as

Table 4 Commonly consumed beverages and their pH(Reddy et al. 2016)

Drink pH

Tap water 7.20

Milk 6.90

Dasani Regular 5.03

Vitamin Water Zero 3.10

Perrier Carbonated Mineral Water 5.25

Arizona Diet Green Tea 3.29

Starbucks Medium Roast 5.11

Lemon Juice 2.25

Canada Dry Club Soda 5.24

Canada Dry Ginger Ale 2.82

Rockstar Energy Drink 2.84

A&W Root Beer 4.27

Monster Energy 3.48

Coca-Cola 2.37

Pepsi 2.39

Red Bull 3.43

Gatorade Orange 2.99

Powerade Orange 2.73

Diet Coca-Cola 3.10

Coca-Cola Zero 2.96

Dr. Pepper 2.88

Ocean Spray Cranberry 2.56

Minute Maid Orange Juice 2.85

Minute Maid Lemonade 2.57

Tropicana 100% Apple Juice 3.50

Tropicana 100% Orange Juice 3.80

Tropicana Lemonade 2.70

Welch’s 100% Grape Juice 3.38

V8 Vegetable Juice 4.23

10 A. Ravindran and P. G. Iyer

high as 90% annually after discontinuation ofPPIs (Pilotto et al. 2003). Relapse rates increasefollowing the abrupt discontinuation of a PPI dueto oxyntic cell hyperplasia (Niklasson et al. 2010).Tapering off the PPI over 3–4 weeks may reducerelapse. PPIs are widely used with high effective-ness and safety in the old. Common side effectsinclude diarrhea including predisposition to Clos-tridium difficile infection, abdominal pain, consti-pation, osteoporosis, hypomagnesemia, andheadache which are rarely limiting and typicallyrespond to dose reduction or discontinuation ofthe medication. When PPIs are ineffective, analternate diagnosis should be sought for (Table 4).

PPI-Clopidogrel Interaction

Following widespread use of antiplatelet therapy,upper gastrointestinal bleeding (UGI) hasemerged as a common and often life-threateningcomplication. Prophylactic co-administration ofPPIs significantly reduces bleeding risk; however,some studies have questioned the safety of thisapproach. Clopidogrel, a prodrug, undergoesCYP2C19- dependent activation in the liver. Exvivo studies suggest that PPIs, such as omeprazole,competitively inhibit the CYP2C19 enzyme, therebyinterfering with activation of clopidogrel anddecrease its antiplatelet effect (Gilard et al. 2008).The FDA issued a warning regarding the concomi-tant use of clopidogrel and PPIs. However subse-quent studies have not revealed any substantialincrease in cardiac events in patients taking PPIswith clopidogrel, and hence this potential interactionis not thought to be clinically relevant. Other drug-drug interactions are mentioned in Table 5.

Potential Adverse Effects of ChronicPPI Use

PPI Use and Pneumonia

Gastric acid is an important barrier to colonizationand infection by invading pathogens. Attenuationof this acidity results in increased bacterial

colonization of the upper aerodigestive tract, pro-viding a plausible mechanism as to why patientson PPIs or H2RAs might be at increased risk ofpneumonia. Studies designed to clarify this riskhave shown contradictory results. A recent largeUS-based population study did not observe anincreased risk of community-acquired pneumonia(CAP) in older adults on PPI and H2RAs (Dublinet al. 2010). On the other hand, several studiesdemonstrate a slight trend toward an associationbetween PPI use and pneumonia, with a higherrisk for PPIs over H2RAs (Fohl and Regal 2011;Laheij et al. 2004). However, the associationbetween CAP and PPI use is stronger with acutethan with chronic PPI use. Indeed, a meta-analysisof eight observational studies showed significantassociation of CAP with recent initiation of PPI(<7 days and <30 days) (Eom et al. 2011). Thisappears to be inconsistent with a biological effectand more suggestive of confounding. Therefore,the use of PPIs should be limited to situationswhere the indications are clear, and in suchcases, they must be used in the lowest effectivedose and for the shortest duration.

PPI Therapy and Enteric Infections

Potent inhibition of gastric acid can reduce theantiseptic benefit of gastric acid and lead to aproliferation and increased enteric exposure toingested pathogenic bacteria. Enteric infectionsincluding Salmonella, Campylobacter, and Shi-gella are more prevalent in those on PPIs (Leon-ard et al. 2007). More importantly, an increased

Table 5 The Los Angeles classification of erosive esoph-agitis (Lundell et al. 1999)

Grade A One (or more) mucosal break no longer than5 mm that does not extend between the topsof two mucosal folds

Grade B One (or more) mucosal break more than5 mm long that does not extend between thetops of two mucosal folds

Grade C One (or more) mucosal break that iscontinuous between the tops of two or moremucosal folds but which involves less than75% of the circumference

Grade D One (or more) mucosal break which involvesat least 75% of the esophageal circumference

Gastroesophageal Reflux Disease and Complications 11

incidence of Clostridium difficile infections hasbeen reported with PPI administration, with adoubling in the incidence of infections (Dialet al. 2004; Wright et al. 2008). The duration ofPPI treatment was found to be an independent riskfactor in one study, with the incidence of infectionincreasing from 5 to 23% in those on PPI therapyfor over 6 months (Dalton et al. 2009).

Therefore, a risk-benefit evaluation is neces-sary prior to initiating antisecretory therapy inthose at high risk of developing enteric infections(e.g., hospitalized patients on antibiotics, frail andelderly, immunosuppressed). In such patients,preventative measures may be utilized.

PPIs, Osteoporosis, and Fractures

PPIs may interfere with calcium absorption, aprocess dependent on gastric acidity. In turn, thisleads to a decline in bone loss and increased riskof fractures (Wright et al. 2008). Several retro-spective studies suggest that a higher dose andduration of PPI use conferred an increased risk,the largest odds ratio being 1.92 (1.16–3.18) after7 years of PPI use (Kaye and Jick 2008). Thestudies have shown that the drop in bone densityscores is comparable over time between those onand not on PPIs. Additionally, the use of chronichigh-dose PPIs was not shown to increase theincidence of fractures in a population-basedstudy (Kumar et al. 2017). Nevertheless, theFDA has recently issued a warning regarding thepossible link between PPI use and increased frac-ture risk. In those who require high-dose, long-term PPIs, osteoporosis and fall risk should beassessed, and the use of medications revised asappropriate. This includes the use of calcium sup-plements, vitamin D, and/or bisphosphonates. Inthe elderly, with osseointegrated dental implants,PPI use has shown to have higher risk of dentalimplant failures (Wu et al. 2017; Chrcanovic et al.2017). Impaired intestinal calcium absorptionlinked with PPI use leads to decreased serumcalcium levels. Proton pumps (H+/K+ ATPase)have also been found to be located in osteoclastcells (Costa-Rodrigues et al. 2013). PPI use canlead to inhibition of these proton pumps leading to

inhibition of osteoclastic activity and therebybone and dental remodeling.

PPI, AKI, and CKD

Both acute and chronic uses of PPI have beenassociated with renal injury. Acute use (3–4 weeks into starting PPI) has been associatedwith biopsy-proven acute interstitial nephritis(AIN) (Muriithi et al. 2014; Sampathkumar et al.2013). This effect is usually not dose-dependentand can result in serious kidney damage. Chronicuse of PPI in the elderly has been associated withdevelopment of CKD. In a large study involvingthe VA population in New York with a mean ageof 56 years, 24.4% of the population developedCKD with chronic PPI use (Arora et al. 2016).The mechanism for development of CKD is likelydue to the cumulative damage to kidneys causedby undiagnosed and untreated subclinical AINfrom chronic PPI use. It is important to understandmechanisms of renal injury in patients with acuteand chronic PPI use to prevent irreversible dam-age. Although there are no current guidelines tomonitor renal function with PPI use, it is reason-able to monitor GFR annually in patients whorequire chronic PPI.

PPI and Gastric Cancer

Chronic PPI use was previously studied to have asignificant association with new onset gastric can-cers. The pathogenesis was assumed as a result ofhypergastrinemia from chronic PPI use. It wasalso seen in this study that more than 25% ofpeople over the age of 60 were on chronic PPI.However, the study was limited due to lack ofinformation on underlying H. pylori infectionthat is a major confounding factor (Poulsen et al.2009). In a recent study in China, chronic PPI useafter eradication of H. pylori infection was foundto result in higher incidence of gastric cancers.This study had limitation in generalizabilitybeyond the Chinese population, where incidencerates are already high (Cheung et al. 2018). Cur-rently, the evidence to provide a strong causal

12 A. Ravindran and P. G. Iyer

relationship between PPI use and gastric cancersis limited and needs additional study.

Endoscopic Therapy

Although PPIs have remained the mainstay man-agement of GERD, a proportion of patients witherosive and non-erosive reflux disease fail torespond to PPI therapy. Minimally invasive endo-scopic therapies have been used in PPI-resistantpatients who may not wish to proceed with anti-reflux surgery. Some of the antireflux endoscopictherapies used in the management of GERD in theUSA are radiofrequency ablation and transoralincisionless fundoplication (Nabi and Reddy2016; Rouphael et al. 2018). Long-term data onsymptom control and acid reflux control afterthese procedures are awaited.

Antireflux Surgery

Performed in expert hands, antireflux surgery canpotentially eliminate GERD by increasing basalLES pressure, decreasing episodes of tLESRs,and inhibiting complete LES relaxation. Long-term maintenance studies comparing medicaltherapy with antireflux surgery have demonstratedeither similar clinical efficacy or significantly bet-ter control of GERD symptoms postsurgery(Oelschlager et al. 2008; Galmiche et al. 2011).Therefore, patients with typical or atypical GERDsymptoms well controlled on PPIs desiring alterna-tive therapy or patientswith volume regurgitation andaspiration symptoms not controlled on PPIs maybenefit from surgery. Currently, the twomost popularprocedures, performed laparoscopically through theabdomen, are the Nissen 360� fundoplication and theToupet partial fundoplication. Postoperativemortalityis rare (<1%), but a variety of complications occurwith relative frequency after antireflux surgery,including dysphagia, gas-bloat syndrome, and post-vagotomy symptoms. Perhaps far more concerning isthe high recurrence rate of GERD symptoms afterantireflux surgery (Galmiche et al. 2011).

Several studies have observed that laparoscopicfundoplication-related mortality or morbidity does

not increase in older adults compared to youngercounterparts (Brunt et al. 1999; Wang et al. 2008).Therefore, the healthy older adult should not berefused antireflux surgery solely on the basis ofage. Best results are obtained by experienced sur-geons in high-volume centers who report recur-rence of symptoms in only 10–15% of patients;long-term studies suggest that 60% of patients areback on acid-suppressive medication 5–15 yearslater. Furthermore, fundoplication procedure is dif-ficult to perform in morbidly obese patients, andthe rate of failure is high in comparison tonon-obese patients. In this subset of patients, bar-iatric surgery may provide better results in control-ling and curing GERD symptoms. Certain bariatricsurgeries like gastric banding and Roux-en-Y gas-tric bypass have shown to alleviate GERD symp-toms, while sleeve gastrectomy has shown toworsen manifestations (El-Hadi et al. 2014). Priorto antireflux surgery, endoscopy must beperformed to identify Barrett’s esophagus andexclude stricture, dysplasia, or carcinoma. Motilitystudies in selected patients can identify ineffectiveesophageal peristalsis or diagnose a motility disor-der which may alter management. Although notroutinely indicated, barium esophagogram canhelp define a nonreducible hiatal hernia and ashortened esophagus which may entail additionalsurgical maneuvers. In the subset of patients witherosive esophagitis not responding to PPI therapyor those with non-erosive GERD, 24-h pH testingis necessary to confirm the diagnosis (Fass et al.1994).

Overall, PPIs seem to be a safe therapy in theelderly, while antireflux or bariatric surgery maybe safe and effective in a subset of older adultswith GERD (Poh et al. 2010).

Key Points

• GERD is a common condition caused by reflux ofgastric contents into the esophagus causing trou-blesome symptoms and related complications.

• It is a multifactorial disorder with diverse clin-ical presentations. Symptom severity may varyfrom person to person.

Gastroesophageal Reflux Disease and Complications 13

• Factors influencing GERD are imbalances inacid production, acid clearance, integrity of thegastroesophageal junction reflux barrier, andesophageal mucosal defense.

• Complications of GERDmay be esophageal orextraesophageal.

• Important esophageal complications includeesophagitis, strictures, Barrett’s esophagus,and esophageal adenocarcinoma.

• Some of the extraesophageal complicationsinclude asthma, non-cardiac chest pain, chroniccough, chronic laryngitis, and pneumonia.

• Diagnosis is usually based on clinical presen-tation. Endoscopic diagnosis may be requiredin chronic, refractory GERD and to rule outesophageal complications. Ambulatory pHmonitoring can help confirm excessive distalesophageal acid/non-acid exposure.

• Proton pump inhibitors are the mainstay inmanagement of symptomatic GERD.

• Management therapies include lifestyle changes,medical management, and endoscopic and surgi-cal management.

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