Gastroesophageal Reflux




Introduction


Gastroesophageal reflux (GER), the involuntary passage of gastric contents into the esophagus, occurs several times per day in every human, particularly after meals, and is a completely normal physiologic process. Most reflux episodes are asymptomatic, of short duration, and limited to the distal esophagus. Regurgitation—also called spitting-up, posseting, or spilling—is the passage of GER into the pharynx, mouth, or the perioral external area. Regurgitation is frequent in healthy infants, especially in the first months of life, with a peak incidence around 3 to 4 months, and after intake of large volumes as happens in young infants. Vomiting is a forceful expulsion of gastric contents from the mouth. Vomiting is a more complex phenomenon caused by a coordinated autonomic and voluntary motor response as a consequence of the activation of receptors, which are often located external to the gastrointestinal (GI) tract. GER disease (GERD) occurs when GER causes troublesome symptoms and/or complications. The spectrum of GER symptoms is atypical and nonspecific (such as behavioral, respiratory, feeding, or sleeping problems with or without esophageal signs and symptoms such as regurgitation or vomiting). GERD frequently causes an impaired quality of life, which is determined mainly by parental perception and coping during infancy and early childhood.


Mucosal complications of GERD such as Barrett’s esophagus are probably less frequent in children than in adults. The natural history, evolution, and progression of GERD are unclear for an individual patient and may depend on genetic, environmental, and mucosal factors.


In 2009, combined European and North American guidelines on the diagnosis and management of GER in children were published. In 2013 the American Academy of Pediatrics (AAP) confirmed and approved this document. However, it is difficult to inform general or family pediatricians about these guidelines. A consequence of the latter is that overdiagnosis of GERD and thus overtreatment with medication (mainly acid inhibitors) is common. Children are frequently prescribed proton pump inhibitors (PPIs) based on a previous (mis)diagnosis of GERD.




Prevalence


Determination of the exact prevalence of GER and GERD at any age is nearly impossible, mainly because symptoms are not specific, not all patients seek medical help, and many patients are not (fully) investigated. Many epidemiologic studies have evaluated the frequency of regurgitation. It is often postulated erroneously that GER and GERD are more frequent in infants than in children and adults; these data are not available. Regurgitation is more frequent in infants between 1 and 6 months of age than in any other age group. Symptoms of acid regurgitation, heartburn, or both, at least once a week occur in 10% to 20% of adults in the Western world, whereas in Asia the prevalence is roughly less than 5%.


In normal 3- to 4-month old infants, three to four episodes of GER are detectable during 5 minutes of intermittent fluoroscopic evaluation. According to esophageal pH monitoring, up to 31 ± 21 acid reflux episodes are recorded within a 24-hour period in infants. More recently, studies using esophageal impedance have reported up to 100 episodes and 70 episodes of reflux in 24 hours in infants and children, respectively. How­ever, for ethical reasons, these investigations were performed in symptomatic children. Less than 10% of infants and children have (acid and troublesome) GERD.


The rapidly increasing prevalence of obesity is causing a rising prevalence of GERD. The risk of GERD symptoms is associated with the increase in body mass index and waist circumference, even in normal-weight children. Total and abdominal obesity are risk factors for GERD symptoms in children.




Pathophysiology


Inappropriate transient lower esophageal sphincter relaxation (TLESR) is the most important pathophysiologic mechanism causing GER at any age. A TLESR is normal following a swallow; it is a neural reflex, triggered mainly by the distension of the proximal stomach and organized in the brainstem, with efferent and afferent pathways traveling in the vagus nerve, activating an intramural inhibitory neuron that releases nitric oxide to relax the lower esophageal sphincter (LES). TLESR is the main mechanism underlying GER events in patients with esophageal atresia (EA). Most infants and adults have impaired motility, delayed bolus clearance, and delayed gastric emptying. Increased abdominal or decreased LES basal pressure is less commonly involved.


GER is influenced by genetic, environmental (e.g., diet and smoking), anatomic, hormonal, and neurogenic factors ( Figure 21-1 ). Three major lines of defense limit the degree of GER and GERD: the anatomic “antireflux barrier,” consisting of the LES and the diaphragmatic pinchcock and angle of His, the esophageal peristalsis and clearance, and the esophageal mucosal resistance. Esophageal mucosa defense can be divided in preepithelial (protective factors in saliva and esophageal secretions containing bicarbonate, mucin, prostaglandin E2, epidermal growth factor, and transforming growth factor), epithelial (tight junctions and intercellular glycoprotein material), and postepithelial factors. Interindividual variation of reflux perception suggests different esophageal sensitive thresholds, which is in part determined by capsaicin levels and vanilloid receptor-1 activity There are acid-, temperature-, and volume-sensitive receptors in the esophageal mucosa. Widened intercellular spaces are found in patients with esophagitis and endoscopy-negative disease. Esophageal sensitivity to acid decreases when the esophagitis has healed. Duodenal fat increases the sensitivity to reflux.




Figure 21-1


Pathophysiologic mechanisms for GER.


Gastric distension and impaired accommodation of the gastric fundus may exacerbate TLESRs. Delayed gastric emptying may increase postprandial reflux, possibly by increasing the rate of TLESRs. Delayed gastric emptying has been documented in (a proportion of) infants and children with symptomatic GER, in particular in those with neurologic disorders. Esophageal acid exposure in patients with GERD is directly correlated with the emptying time of the proximal stomach. Acidity of the refluxate may also relate to a localized proximal gastric area called “the gastric acid pocket,” which may persist even in the postprandial period when (the rest of the) stomach content is neutralized by the meal. Position and sleeping influence GER and gastric emptying. In the recumbent position, noxious gastric materials, rather than air, are positioned at the cardia and may move more easily into the esophagus, especially when the LES tone is decreased during sleep. Both salivation and swallowing are markedly reduced during sleep, further impairing clearance.


Hiatal hernia increases the number of reflux episodes, and delays esophageal clearance by promoting retrograde flow across the esophagogastric junction when the LES relaxes after a swallow. This mechanism underlies the so-called re-reflux phenomenon (acid reflux when the pH is still below 4).


Carre described autosomal dominant inheritance of hiatal hernia by discovering familial hiatal hernia in five generations of a large family, but without demonstrating the link to GERD. Moreover, the concordance for GER is higher in monozygotic than dizygotic twins. Genes in question have been localized to chromosomes 9 and 13. A locus on chromosome 13q, between microsatellite D13S171 and D13S263, has been linked with severe GERD in five multiply affected families. This could not be confirmed in another five families, probably because of the genetic heterogeneity of GERD and different clinical presentations of patients. The relevance of these findings for the general population remains unclear.


Most pathophysiologic mechanisms of GERD have been studied in adults, and acid reflux has long been considered as the critical factor. However, in the last decade, an increasing body of evidence (based on esophageal impedance combined with pH monitoring) has shown that weakly acid reflux (that is GER with a pH between 4 and 7) is equally associated with symptoms, particularly in infants, during the postprandial period and in patients who are resistant to acid inhibitors. Components con­tributing to the noxiousness of refluxed material are pepsin, bile acids and salts, and trypsin. The latter two depend on duodenogastric reflux preceding GER and are implicated in the genesis of strictures and Barrett’s esophagus.


In respiratory symptoms related to GER, both (micro)aspiration and neurally (vagally) mediated mechanisms have been considered.


The role of Helicobacter pylori infection and the benefit of eradication of H. pylori in patients with GERD have long been debated without a clear conclusion.




Symptoms and Signs


Although reflux does occur physiologically at all ages, there is at all ages also a continuum between physiologic GER and GERD leading to significant symptoms, signs, and complications ( Boxes 21-1 and 21-2 and Table 21-1 ). GER symptoms are more frequent in children with functional constipation. The presenting symptoms of GERD differ according to age.



Box 21-1

Adapted from Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, et al. Pediatric gastroesophageal reflux clinical practice guidelines; Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009; 49 :498–547.

Symptoms and Signs That May Be Associated With Gastroesophageal Reflux





  • Symptoms




    • Recurrent regurgitation with/without vomiting



    • Weight loss or poor weight gain



    • Irritability in infants



    • Ruminative behavior



    • Heartburn or chest pain



    • Hematemesis



    • Dysphagia, odynophagia



    • Wheezing



    • Stridor



    • Cough



    • Hoarseness




  • Signs




    • Esophagitis



    • Esophageal stricture



    • Barrett’s esophagus



    • Laryngeal/pharyngeal inflammation



    • Recurrent pneumonia



    • Anemia



    • Dental erosion



    • Feeding refusal



    • Dystonic neck posturing (Sandifer’s syndrome)



    • Apnea spells



    • Apparent life-threatening events (ALTEs)





Box 21-2

Adapted from Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, et al. Pediatric gastroesophageal reflux clinical practice guidelines; Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009; 49 :498–547.

Warning Signals Requiring Investigation in Infants With Regurgitation or Vomiting





  • Bilious vomiting



  • GI bleeding




    • Hematemesis



    • Hematochezia




  • Consistently forceful vomiting



  • Onset of vomiting after 6 months of life



  • Failure to thrive



  • Diarrhea



  • Constipation



  • Fever



  • Lethargy



  • Hepatosplenomegaly



  • Bulging fontanel



  • Macro/microcephaly



  • Seizures



  • Abdominal tenderness or distension



  • Documented or suspected genetic/metabolic syndrome




TABLE 21-1

DIFFERENTIAL DIAGNOSIS OF VOMITING IN INFANTS AND CHILDREN

Adapted from Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, et al. Pediatric gastroesophageal reflux clinical practice guidelines; Joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009; 49 :498–547.






























GI obstruction


  • Pyloric stenosis



  • Malrotation with intermittent volvulus



  • Intestinal duplication



  • Hirschsprung’s disease



  • Antral/duodenal web



  • Foreign body



  • Incarcerated hernia

Other GI disorders


  • Achalasia



  • Gastroparesis



  • Peptic ulcer



  • Eosinophilic esophagitis/gastroenteritis



  • Food allergy



  • Inflammatory bowel disease



  • Pancreatitis



  • Appendicitis

Neurologic


  • Hydrocephaly



  • Subdural hematoma



  • Intracranial hemorrhage



  • Intracranial mass



  • Infant migraine



  • Chiari malformation

Infectious


  • Gastroenteritis



  • Sepsis



  • Meningitis



  • Urinary tract infection



  • Pneumonia



  • Otitis media



  • Hepatitis

Metabolic/endocrine


  • Galactosemia



  • Hereditary fructose intolerance



  • Urea cycle defects



  • Amino and organic acidemias



  • Congenital adrenal hyperplasia

Renal


  • Obstructive uropathy



  • Renal insufficiency

Toxic


  • Lead



  • Iron



  • Vitamins A and D



  • Medications—ipecac, digoxin, theophylline, etc.

Cardiac


  • Congestive heart failure



  • Vascular ring

Others


  • Pediatric falsification disorder (Munchausen syndrome by proxy)



  • Child neglect or abuse



  • Self-induced vomiting (rumination syndrome)



  • Cyclic vomiting syndrome



  • Autonomic dysfunction



Belching or eructation occurs during TLESR, and is an important method of venting air from the stomach. Hiccups are involuntary reflex contractions of the diaphragm followed by laryngeal closure. In some cases, hiccups cause GER.


Atypical symptoms such as epigastric pain, nausea, flatulence, hiccups, chronic cough, asthma, chest pain, and hoarseness account for 30% to 60% of presentations of GERD. Possible associations exist between GERD and asthma, pneumonia, bronchiectasis, ALTE (acute life-threatening event), laryngotracheitis, sinusitis, and dental erosion, but causality or temporal association have not been established. The paucity of studies, small sample sizes, and varying disease definitions do not allow for firm conclusions.


Clinicians need to be aware that not all regurgitation and vomiting in infants and young children is related to GER/GERD. Bilious vomiting, gastrointestinal bleeding, consistently forceful vomiting, weight loss or failure to thrive, diarrhea, constipation, fever, lethargy, hepatosplenomegaly, abdominal tenderness, and/or distension should raise the possibility of an alternate diagnosis.


GER and Regurgitation


Regurgitation is the most common presentation of infantile GER, with occasional projectile vomiting. The majority of infants have almost daily regurgitation in the first 6 months of life, with a peak at the age of 3 to 4 months, resolving without intervention in 95% of individuals by 12 to 14 months of age.


About 20% to 25% of parents seek medical advice because of frequent infantile regurgitation, which often corresponds to at least four episodes of regurgitation a day. A prospective follow-up reported disappearance of regurgitation in all subjects before 12 months, although the prevalence of feeding refusal, duration of meals, parental feeding-related distress, and impaired quality of life was observed, and was higher in those who presented with regurgitation (even after disappearance of symptoms) compared to those who never regurgitated. Regurgitation is frequent in infants because of the large liquid volume intake, the limited capacity of the esophagus (10 mL in newborn infants), the horizontal position of infants, and so on. “Excessive regurgitation” is one of the symptoms of GERD, but the terms regurgitation and GERD should not be used as synonyms. Regurgitation is a characteristic symptom of reflux in infants, but is neither necessary nor sufficient for a diagnosis of GERD, because regurgitation is not sensitive or specific. Irritability may accompany regurgitation and vomiting; however, in the absence of other warning symptoms, it is not an indication for extensive testing. The duration of crying is not related to acid reflux, as measured with pH metry. Irritability and crying are common in infants, are not specific symptoms of GERD, and should not be a reason for empirical treatment with acid inhibitors.


Poor weight gain is a crucial warning sign that necessitates clinical management. These infants need a complete diagnostic workup, starting with a dietary history to evaluate caloric intake. Hospitalization of these infants may be needed. Although usually regurgitation causes little more than a nuisance, important regurgitation also produces caloric insufficiency and malnutrition in a minority of patients. GERD is only one of the many etiologies of “feeding problems” in infancy.


GER(D) and Cow’s Milk Protein Allergy


The symptoms of cow’s milk protein allergy (CMPA) overlap with many symptoms of GER disease, and may coexist or complicate GERD ( Table 21-2 ). The recommended treatment for CMPA implies the use of extensive hydrolysates (or amino acid formula in the case of anaphylaxis). The positive response to CMP elimination from the diet and relapse of the symptoms, called a “challenge test,” is considered as the gold standard test for diagnosis of CMPA. An association between GERD and cow’s milk “hypersensitivity” was observed in both infants and children with severe GERD. Simultaneous cow’s milk challenge and pH monitoring had limited value as a method for identifying this subgroup. Impedance has shown that the incidence of nonacid postprandial reflux is decreased after a feeding with an amino acid–based formula compared to standard cow’s milk–based infant formula. An extensive hydrolysate reduces esophageal acid exposure in preterm infants with feeding intolerance and symptoms of GER. However, because amino acids (and extensive hydrolysates) have more rapid gastric emptying than standard infant formula, it is not possible to know if the decrease in GER is caused by the enhanced gastric emptying or an autoimmune mechanism. In other words: infants who regurgitate and vomit may have CMPA, GERD, both conditions, or none. A positive challenge test is an indication of involvement of CMP in GER, but not a proof of involvement of the immune system.



TABLE 21-2

SIGNS AND SYMPTOMS OF GASTROESOPHAGEAL REFLUX (DISEASE) AND COW’S MILK PROTEIN ALLERGY

From Salvatore S, Vandenplas Y. Gastroesophageal reflux and cow milk allergy: is there a link? Pediatrics 2002; 110 :972–84.












GER(D) GER(D)+/− CMPA CMPA



  • Aspiration



  • Back-arching



  • Bradycardia



  • Dysphagia



  • Hematemesis



  • Hiccups



  • Hoarseness



  • Laryngitis/stridor



  • Melena



  • Nausea/belching



  • Respiratory infections



  • Rumination



  • Sandifer’s syndrome




  • Apnea/ALTE/SIDS



  • Colic



  • Constipation



  • Failure to thrive



  • Feeding refusal



  • Irritability



  • Parenteral anxiety



  • Regurgitation



  • Sleep disturbances



  • Vomiting



  • Wheezing




  • Anaphylaxis



  • Angioedema



  • Bloody stools



  • Diarrhea



  • Eczema/dermatitis



  • Itching



  • Lip swelling



  • Nasal congestion



  • Rhinitis



  • Urticaria



GERD and Esophagitis


Esophagitis is defined as visible breaks of the esophageal mucosa. Histopathologic evaluation is recommended to rule out complications (Barrett’s esophagus) or other causes of esophagitis (eosinophilic esophagitis). In adults, reflux esophagitis is reported to occur in 2% to 5% of the population. Children with GER symptoms present with esophagitis in 15% up to 62%, Barrett’s esophagus in 0.1% to 3%, and refractory GERD requiring surgery in 6% to 13%. The huge variation in incidence is determined by patient recruitment, differences of definition of esophagitis, and availability of self-treatment.


More recently, erosive esophagitis has been reported in 12.4% of 0 to 17-year-old children with GERD symptoms, increasing with age and limited to 5.5% in children younger than one year, and more frequent in patients with hiatal hernia. This finding is in sharp contrast with the extremely high prescription rate of acid inhibitors, even in extremely low-birth-weight infants at the moment of discharge. GERD patients with a pathologic number of large breaks, assessed by high-resolution manometry, are characterized by a significantly prolonged reflux clearance in the supine position and higher acid exposure time. Patients with erosive reflux disease display a larger number of esophageal breaks that might explain the development of erosions.


Dysphagia may be present in (reflux and eosinophilic) esophagitis but is also caused by neuromuscular disorders and extrinsic compression. Barrett’s esophagus is not rare in adolescents with chronic GERD. Esophagitis, identified by histology, occurs in 61% to 83% of infants with reflux symptoms sufficiently severe for endoscopy. Although esophagitis may present with pain, it can also be asymptomatic. The group with asymptomatic esophagitis is in some ways the most problematic. Even severe esophagitis may remain asymptomatic, as demonstrated by children who present with peptic strictures without having experienced any discomfort attributable to esophagitis. Typical substernal burning pain (“heartburn,” pyrosis) occurs in many children with esophagitis. Odynophagia, which is pain on swallowing, usually represents esophageal inflammation. In nonverbal infants, symptoms of crying, irritability, sleep disturbance, or “colic,” have long been considered as heartburn equivalent and a possible clue of esophagitis at early ages. Although it is important to consider that the following is not evidence based, a genetic or environmental factor may be of importance. North African children living in North Africa present by far more often with esophageal stricture or stenosis than children in other populations or regions. And this despite that the North African doctors are trained in Western Europe (similar training), and that many North Africans live in Western Europe (similar genetic background). Thus, although difficult to explain the reasons, the difference in incidence of esophageal stenosis as first presentation of GERD exists.


GER(D) and Eosinophilic Esophagitis


Eosinophilic esophagitis (EoE) is a chronic immune/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction that results from severe eosinophil-predominant inflammation. The reasons for the impressive increase in the prevalence of EoE is still poorly understood. Atopic features (allergic symptoms or positive allergic tests) are reported in more than 90% and peripheral eosinophilia in 50% of patients, although this depends also on patient selection. Seven percent of patients presenting only with cough were diagnosed with EoE.


At endoscopy, a pale, granular, furrowed, and occasionally ringed esophageal mucosa is evident, and, in more severe cases, esophageal stenosis may appear. How­ever, the esophageal mucosa may also appear visually normal, which highlights the importance of histologic evaluation. The hallmark of EoE is an eosinophilic infiltrate of more than 15 eosinophils per high power field (HPF), whereas in reflux esophagitis, the eosinophils are limited to fewer than 5 per HPF. As in reflux esophagitis, there is no specific symptom of EoE, but dysphagia for solids is often reported in older children, whereas symptoms in infants are more reflux-like (including vomiting, regurgitation, feeding refusal, and failure to thrive). A recent study demonstrated six factors significantly associated with EoE: male gender (odds ratio [OR] 1.82), dysphagia (OR 2.02), (the absence of) pyrosis (OR 0.4), food impaction (OR 5.39), linear furrowing (OR 8.16), and white papules (OR 9.61) at endoscopy.


Candidate gene studies have identified genetic variants in CCL26, TGFB1, TSLP, and FLG (involving eotaxin-3, transforming growth factor β (TGF-β), thymic stromal lymphopoietin, and filaggrin) associated with EoE risk. A genome-wide association study on 351 patients with EoE identified the 5q22 locus encoding TSLP and WDR36 as an EoE susceptibility locus. Response to PPIs has classically been considered specific for reflux esophagitis. More recently, pathologic esophageal acid exposure at pH monitoring and high-dose (initial) response to PPI have also been reported in EoE, highlighting a partial overlapping condition or a PPI-responsive EoE. Today, repeated endoscopy with esophageal histology in combination with response to treatment may in some cases be the only way to separate reflux esophagitis from EoE. EoE necessitates properly tailored treatment such as hypoallergenic diet, topical swallowed (rarely systemic) corticoids, leukotriene receptor antagonists, anti–immunoglobulin E (IgE) and anti–interleukin (IL)-5 monoclonal antibodies, and esophageal dilation, depending on both the presenting symptoms and response to treatment. Allergens (mainly food but also inhalant) that trigger the disease vary from patient to patient. Also in EoE, the results of allergy tests do not always support the clinical findings. Therefore, the optimal dietary intervention needs to be individualized. As with all elimination diets, there may be poor (long-term) compliance, requiring regular dietetic support to ensure nutritional adequacy. The most upregulated micro RNAs (miRNAs) (miR-21 and miR-223) and the most downregulated miRNA (miR-375) strongly correlated with EoE levels. The differentially expressed miRNAs are largely reversible in patients who respond to glucocorticoid treatment.


EoE is a chronic or relapsing disease. The origin and natural history of EoE are still poorly understood. An in-depth discussion of eosinophilic esophagitis is beyond the scope of this chapter.


GER(D) and Heartburn


GERD in adolescents is more adult-like (2B). Heartburn is a symptom of GERD with or without esophagitis, but in most cases is responsive to PPIs. According to parents, heartburn is present in 1.8% of 3- to 9-year-old healthy children and 3.5% of 10- to 17-year-old adolescents; regurgitation is reported to occur in 2.3% and 1.4%, respectively, and 0.5% and 1.9% need antacid medication. According to self-reports published in 2000, adolescents complain of heartburn in 5.2% and regurgitation in up to 8.2%, whereas antacids are taken by 2.3% and histamine-2 receptor antagonists (H2RAs) by 1.3%, suggesting that symptoms of GER are not rare during childhood and are underreported by parents or over­estimated by adolescents. In adults, PPI response and typical symptoms are not always reliable predictors of the diagnosis of GERD.


The natural history of persistence of symptoms and progression to complications is unpredictable both for a group of patients and for the individual patient. Overall, the correlation between the severity of heartburn and the results of investigations is poor.


GER(D) and Distressed Behavior in Infants


The assumption that distressed behavior is a manifestation of GER is largely derived from adult data based on the assumption that crying is the result of heartburn. Adults with GERD are known to have an impaired quality of life, regardless of the presence of esophagitis. In infants and young children, verbal expression of symptoms is often vague or impossible. Persistent crying, irritability, back-arching, and feeding and sleeping difficulties have long been proposed as possible equivalents of adult heartburn. Heine and co-workers showed the absence of any relation between crying duration and result of pH monitoring.


Multiple studies have demonstrated that in irritable and crying infants, the effect of different PPIs on crying time was similar to placebo, despite a significant reduction in esophageal acid exposure, documented by pH-monitoring. In infants and toddlers, there is no symptom or group of symptoms that can reliably diagnose GERD or predict treatment response. Many factors, such as colic, constipation, smoke exposure, CMPA, and neurologic disorders may cause infant irritability. There is substantial individual variability; some healthy infants may cry up to 6 hours a day. In preterm infants the left-side position decreases GER. A pilot study suggested that a 40° supine position in a specially developed “Multicare-AR Bed” decreased significantly regurgitation and infant irritability.


GERD and Sandifer’s Syndrome


Sandifer’s syndrome (spasmodic torsional dystonia with arching of the back and opisthotonic posturing mainly involving the neck and back) is an uncommon but specific manifestation of GERD.


GER(D) and Respiratory Disorders


GER can be related to respiratory signs and symptoms through different mechanisms such as direct (micro)aspiration, vagal-mediated bronchial and laryngeal spasm, and neural-mediated inflammation. Old literature in asthmatic adults suggests that esophageal acidification can produce airway hyperresponsiveness and airflow obstruction. Few studies have tempted to evaluate the opposite: the impact of asthma on the severity of GERD. Chronic hyperinflation as occurs in asthma favors many GER mechanisms. An association between asthma and reflux measured by pH or impedance probe has been reported in some studies, but contradicted in others. In a series of 46 children with persistent moderate asthma despite bronchodilators, inhaled corticosteroids, and leukotriene antagonists, 59% (27 of 46) had an abnormal pH metry. Very few prospective, randomized and blinded intervention studies have been performed in children. Omeprazole is ineffective in improving asthma symptoms and parameters in children with asthma. There is no association between asthma control status and laryngopharyngeal reflux (LPR) and GER. Current evidence does not support routine use of anti-GERD medication in the treatment of poorly controlled asthma. A recent pediatric multicenter study randomized 306 children with poorly controlled asthma, without heartburn, to lansoprazole or placebo. The PPI improved neither respiratory symptoms nor lung function but was associated with increased adverse events (such as infections).


No test can determine whether GER is causing recurrent pneumonia. Upper esophageal and pharyngeal pH and impedance recordings have provided contradictory information. It is still debated if reflux recording in the upper esophagus or pharynx will help in making therapeutic decisions. A new technique to record pharyngeal reflux has been developed (Restech). How­ever, recent results suggest that the results of this technique do not correlate with the results of esophageal impedance.


The sensitivity and specificity of lipid-laden macrophages for GER are too low to be clinically useful. Nuclear scintigraphy with late imaging showed, according to one study, pulmonary activity in 50% of patients. However, other studies failed to reproduce these findings. Microaspiration also occurs during swallowing and, in healthy subjects, especially during sleep. Both acid and nonacid or weakly acid GER may precede cough in children with unexplained cough, but cough does not induce GER. In a group of 112 children with different resistant respiratory symptoms (chronic cough, wheezing, lower respiratory infections, laryngospasm, apnea/ALTE), weakly acid reflux was at least as common as acid reflux and often associated with infections. Combined impedance pH manometry recording improves symptom association analysis.


GER(D) and Apnea, ALTE, and SIDS


In most cases, there is no temporal and thus no causal relation between apnea or ALTE and GER. However, there may be coexistence in some patients, particularly in preterms but also in young infants, mainly because apnea and GER are frequent physiologic occurring events in the first months of life. Outcomes of studies are difficult to compare because of heterogeneity in the population studied and diagnostic criteria of apnea and GER(D). In very preterm infants, simultaneous polysomnography and combined impedance and pH monitoring showed an increased frequency of apnea after nonacid GER. However, physiologic apnea following GER is a well-known physiologic protective mechanism to prevent aspiration. GER is a frequent cause of interrupted sleep in infants, and nonacid GER is equally as important as acid GER for causing arousals and awakenings in infants. Discomfort is significantly associated with reflux events and does not differ between weakly acid and acid reflux episodes. Overall, GER is not related to pathologic apnea, significant bradycardia, ALTE, or sudden infant death syndrome (SIDS). The vigilance state influenced the distribution of GER events ( p < 0.001), with 53.4% observed during wakefulness, 37.6% observed during active sleep, and only 9% observed during quiet sleep. A significant increase in the sympathovagal ratio (32%, p = 0.013) was observed in the period immediately prior to reflux, due to a 15% reduction in parasympathetic activity ( p = 0.017)), relative to the control period. This phenomenon was observed during both wakefulness and active sleep. This suggests that a pre-reflux change in autonomic nervous system activity is one of the factors contributing to the mechanism of reflux in neonates. GER was a frequent cause of interrupting sleep among our infant patients, and non-acid GER proved to be equally important as acid GER for causing arousals and awakenings in infants. Physiologic data suggest that when there is a temporal relationship, apnea may be more likely to predispose to GER via esophageal sphincter relaxation than vice versa. In general, multichannel intraluminal impedance and pH monitoring (MII-pH) recording did not demonstrate a causal relationship between apnea and GER.


GER(D) and Cystic Fibrosis (CF)


Young patients with cystic fibrosis (CF) have a high prevalence of acid GER, even before respiratory symptoms develop. Patients with CF also have duodenal-gastroesophageal reflux of bile acids. It is likely that both acid and bile reflux aggravate the respiratory symptoms, and that the respiratory symptoms aggravate the reflux. Aggressive medical and surgical reflux treatment in this patient group seems reasonable. In children with CF, a better weight gain was reported during PPI treatment (whether this is due to a reduction of acid reflux or better buffering of acid gastric content in the intestine is not clear). Compared to symptomatic non-CF children, CF children do not have more frequent reflux. Actually, they have better bolus clearance efficiency following reflux and may even have better control over the number of GER episodes that reach the proximal esophagus. Chemical clearance of acid GER, however, is significantly prolonged in the CF cohort, likely due to hyperacidity of refluxed gastric contents.


GER(D) and Upper Airway Disease: ENT-Manifestations


Data suggesting a causal relation between reflux and upper airway disease are limited. Otolaryngologists and gastroenterologists commonly disagree on the underlying cause for complaints in patients with one of the suspected extraesophageal reflux syndromes; most of the time otolaryngologists are “pro” and gastroenterologists are “con.” The accuracy of diagnostic tests (laryngoscopy, endoscopy, and pH- or pH-impedance monitoring) for patients with suspected extraesophageal manifestations of GERD is suboptimal. Although a temporal relationship between cough and reflux events has been suggested by studies utilizing impedance-pH monitoring of reflux events and objective cough recording, consensus is lacking in terms of whether this temporal relationship proves a causal link between reflux and cough.


Data from several placebo-controlled studies and meta-analyses uniformly have shown no effect of antireflux therapy on upper airway symptoms or signs. However, well-designed, prospective, placebo-controlled, blinded studies are needed. The selection of patients may also be a bias, since these studies are frequently set up in tertiary care centers in highly selected patient populations.


Several studies revealed the presence of pepsin in middle-ear fluid, but with a huge variation in incidence (14% to 73%). In addition, bile acids have been detected in middle-ear liquid, in higher concentrations than in serum. The presence of pepsin and bile in middle ear fluid might well be the consequence of reflux (and vomiting) at the moment of the acute middle ear infection than an argument to hypothesize that chronic GER may be at the origin of the chronic middle ear problem. Conversely, there are several epidemiologic studies suggesting a low incidence of reflux symptoms in patients with recurrent middle ear infections. This may have to do with the selection of patients: one can imagine that patients who vomit frequently are more likely to have pepsin and bile salts in their middle ear fluid than those who do not vomit.


Carr et al. have suggested that specific laryngeal signs (such as severe erythema and edema of posterior commissure and arytenoid cartilages) could be pathognomonic of GER in children. However, other authors did not find any correlation between laryngeal findings and esophagitis, abnormal pH monitoring, or response to acid inhibitors (in adults). Laryngeal findings are often nonspecific and the laryngoscopic diagnosis of LPR tends to be subjective. There is still little or no evidence on which to base the diagnosis or the treatment of LPR, particularly in children.


GER(D) and Dental Erosions


Young children and children with neurologic impairment are at greatest risk for dental erosions. Whether these erosions are caused by decreased hygiene or by GER is debated. Juice drinking, bulimia, and racial and genetic factors that affect dental enamel and saliva might be confounding variables that have been insufficiently considered. Recently, a positive correlation between GERD and dental erosion has been confirmed as well as refuted. There are no long-term (intervention) follow-up studies in high-risk populations.


GER(D) and Neurologic Impairment


Neurologically impaired children accumulate many risk factors for severe GERD: for example, spasticity or hypotonicity, supine position, and constipation. Diagnosis of reflux disease in these children is often difficult because of their underlying conditions. Whether this group of patients has more severe reflux disease, or has less effective defense mechanisms, or presents with more severe symptoms because of the inability to express and/or recognize symptoms remains open for debate. Response to treatment, both medical and surgical, is poor in the neurologically impaired child compared to the neurologically normal child.


GER(D) and Other Risk Groups


There are no data in the literature to suggest that preterm infants have reflux disease more often than term infants, although preterms are treated by far more often with anti-acid medication than term babies.


Children with congenital abnormalities such as esophageal atresia, hiatal hernia, and malrotation, or after major thoracic or abdominal surgery are at risk for developing severe GERD. Symptomatic GER and GERD are frequent in patients treated for esophageal atresia and/or tracheoesophageal fistula because of serious structural and functional deficiencies. GERD in these children is often refractory to medical treatment and requires antireflux surgery. However, the high rates of wrap failure invite close follow-up in all cases and reoperation or other measures whenever necessary. Many of these children are continuously on antireflux (antacid) medication. However, given the increasing knowledge of the side-effects of PPIs, the pros and cons of this approach should be evaluated.


GERD and Complications


Children with congenital malformations, neurologic impairment, and chronic lung disease (especially cystic fibrosis) have the most severe GERD and are at high risk for the development of complications of GERD. Barrett’s esophagus, strictures, and esophageal adenocarcinoma are complications of chronic severe GERD.


Barrett’s esophagus is a premalignant condition in which metaplastic specialized columnar epithelium with goblet cells is present in the tubular esophagus. Differences in esophageal mucosal resistance and genetic factors may partially explain the diversity of lesions and symptoms. Barrett’s esophagus has a male predominance and increases with age. There is a genetic predisposition in families of patients with Barrett’s esophagus and esophageal carcinoma. Reflux symptoms during childhood did not differ in adults without and adults with Barrett’s esophagus. Patients with short segments of columnar-lined esophagus and intestinal metaplasia have similar esophageal acid exposure but significantly higher frequency of abnormal bilirubin exposure and longer median duration of reflux symptoms than patients without intestinal metaplasia. In a series including 402 children with GERD without neurologic or congenital anomalies, no case of Barrett’s esophagus was detected. In another series including 103 children with long-lasting GERD, and not previously treated with H2RAs or PPIs, Barrett’s esophagus was detected in 13%. An esophageal stricture was present in 5 of the 13 patients with Barrett’s (38%). More than 40 years ago, in the absence of reflux treatment, esophageal strictures were reported in about 5% of children with reflux symptoms. Currently, esophageal stenosis and ulceration in children have become rare (although for unclear reasons, esophageal stricture is still reported in North Africa with a higher incidence than everywhere else in the world).


Esophageal peptic ulcer caused by GERD and esophageal neoplastic changes is extremely rare in children. In adults, over the last 30 years, a decreased prevalence of gastric cancer and peptic ulcer with an opposite increase in esophageal adenocarcinoma and GERD has been noted. This has been attributed to independent factors, among which are changes in dietary habits such as a higher fat intake, an increased incidence of obesity, and a decreased incidence of H. pylori infection. Frequency, severity, and duration of reflux symptoms are related to the risk for developing esophageal cancer. Among adults with longstanding and severe reflux, the odds ratios are 43.5 for esophageal adenocarcinoma and 4.4 for adenocarcinoma at the cardia. In the 21st century, the incidence of esophageal adenocarcinoma continues to rise while the percentage of patients diagnosed with in situ cancer has declined. Whether better and/or earlier diagnosis and treatment of (pediatric) GERD plays a role in these findings is not known. Furthermore, it is unknown whether mild esophagitis or GER symptoms persisting from childhood are related to an increased risk of severe complications in adults.




Diagnosis


Detailed information regarding indications and pitfalls of radiologic contrast studies, nuclear reflux scintig­raphy, ultrasound, pH-metry and intraluminal impedance, endoscopy, manometry, gastric emptying tests, and electrogastrography can be found in review papers and guidelines.


In adults, diagnosis of GERD is based primarily on clinical history. However, even in adults, the sensitivity and specificity of history is questioned. History is useful for predicting acid GERD, but not for diagnosing nonacid GERD, and is inferior to MII-pH. However, in children younger than 8 years of age, or even younger than 12 years of age, history is considered poorly reliable. Questionnaires were developed to improve the reliability of history. Orenstein developed the Infant Gastroesophageal Reflux Questionnaire (I-GERQ), which results in an objective, validated, and repeatable quantification of symptoms suggestive for GERD. The I-GERQ was revised (the I-GERQ-R) in 185 patients and 93 controls, resulting in an internal consistency and test–retest reliability of greater than 0.85. However, Aggarwal and co-workers obtained with the same I-GERQ a sensitivity of only 43% and a specificity of 79%. Moreover, pH-metry results were not different according to a “positive” or “negative” score of the I-GERQ. Vandenplas and co-workers showed that not one question was found to be significantly predictive of the presence of esophagitis; I-GERQ cut-off score failed to identify 26% of infants with GERD (according to pH-metry results or presence of esophagitis) and was positive in 81% of infants with a normal esophageal histology and normal pH-metry results. Deal et al. developed two different questionnaires, one for infants and one for older children, and showed that the score was higher in symptomatic than in asymptomatic children. In other words: the correlation between the results of history obtained with the help of questionnaires on the one side and of reflux investigations on the other side, is poor. Because the existing questionnaires seem to be of limited value, more research is needed on this topic. In many countries, history is the only diagnostic tool available, and at any rate one should have a reliable history to select the appropriate children to investigate.


Barium contrast radiography, nuclear scintiscanning, and ultrasound are techniques that evaluate postprandial reflux and provide also some information on gastric emptying. Normal ranges are not established for any of these procedures. There is broad consensus that barium studies are not recommended as first-line investigation for diagnosis of GERD, but radiologic examination is of importance for diagnosis of anatomic abnormalities such as malrotation, duodenal web, and stenosis, and may suggest functional abnormalities such as achalasia. In addition, in many countries, barium contrast is still the only investigative technique available. Nuclear scintigraphy may show pulmonary aspiration. However, these data still need confirmation, since experience from many centers indicates that aspiration occurs only seldom. Aspiration of saliva and gastric contents occurs physiologically during sleep in healthy adults. Scintigraphy also evaluates gastric emptying. But, the 13C-octanoic acid (for solids) and 13C-acetate (for liquids) breath tests are more appropriate for measuring gastric emptying. The role of delayed gastric emptying in GER(D) remains controversial. The results of ultrasound are investigator dependent, and a relation between reflux seen on ultrasound and symptoms has not been established. There is no indication for electrogastrography in the diagnostic workup of a patient suspected of GERD.


Modern endoscopes are so miniaturized that scoping of preterm infants weighing less than 1,000 g has become technically easy. Operator experience is an important component of interobserver reliability. Endoscopy allows direct visual examination of the esophageal mucosa. Macroscopic lesions associated with GERD include esophagitis, erosions, exudate, ulcers, structures, and hiatal hernia. Redness of the distal esophagus in young infants is a normal observation because of the increased number of small blood vessels in the cardiac region. Endoscopy may also show a “sliding hernia,” the stomach that is protruding into the esophagus during burping. Recent consensus guidelines define reflux esophagitis as the presence of endoscopically visible breaks in the esophageal mucosa at or immediately above the gastroesophageal junction. Endoscopy-negative reflux disease is common. There is a poor correlation between the severity of symptoms and presence and absence of esophagitis. There is insufficient evidence to support histology to diagnose or exclude GERD. Dilated intercellular space diameter seems to be a useful and objective marker for esophageal damage in pediatric GERD, regardless of acid exposure. In childhood, different GERD phenotypes cannot be discriminated on the basis of reflux pattern. In children with reflux-related cough, dilated intercellular space diameter appears to be an objective and useful marker for esophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients in whom the diagnosis is uncertain. Biopsies of duodenal, gastric, and esophageal mucosa are mandatory to exclude other diseases. More detailed information on pros and cons of histology can be found in consensus papers.


Manometry does not demonstrate reflux, but it is of interest to analyze pathophysiologic mechanisms causing the reflux, mainly by visualizing and measuring TLESRs, and is indicated in the diagnosis of specific conditions such as achalasia. Ambulatory 24-hour esophageal manometry, in combination with pH-metry and/or impedance recording, is nowadays technically feasible. This technique is used mainly in (clinical) research, and allows the objective demonstration of reflux-symptom association (e.g., in patients presenting with chronic cough).


Experience in children with spectrophotometric esophageal probes to detect bilirubin remained limited. Using these probes, Orel and co-workers showed that some children with esophagitis have bile reflux. However, because of technical limitations, the technique is not applied routinely.


Esophageal pH-metry is the best method for measuring acid in the esophagus, but not all reflux that causes symptoms is acidic and not all acid reflux causes symptoms. Esophageal pH-metry is useful for evaluating the effect of a therapeutic intervention on reducing esophageal acid exposure. Normal ranges have been established for pH-metry. However, results depend on the hardware and software used. Normal ranges have been established using glass electrodes, which have been shown (in several studies in children and in adults) to pick up more acid reflux episodes than antimony electrodes, which are nowadays the most popular. Esophageal pH monitoring is likely to be of limited value for reflux causing extraesophageal manifestations. The demonstration of a time association between GER episodes and symptoms is one of the major indications for this technique. The most common MII-pH abnormality was an abnormal symptom association between cough and reflux and the most common endoscopic abnormality was reflux esophagitis. However, the optimal time-frame to be considered as “time-association” and the optimal parameter to calculate significant association are still debated. Oropharyngeal pH-metry detected fewer reflux episodes than MII-pH; 35% of the oropharyngeal events were swallows according to MII-pH. Time correlation between cough and reflux could not be demonstrated with oropharyngeal pH-metry.


MII measures electrical potential differences. As a consequence, the detection of reflux with MII is not pH dependent, but in combination with pH-metry MII allows detection of acid (pH <4.0), nonacid, or weakly acidic (pH 4.0-7.0) and alkaline reflux (pH > 7.0). MII in combination with pH-metry definitively measures more reflux episodes than pH-metry alone. MII-pH in newborns has prognostic value regarding the duration of GERD symptoms and provides useful information that clinicians may share with parents about the prognosis of symptomatic infants. Impedance bolus exposure index and proximal reflux frequency seem to be the variables with the highest predictive value. Weakly acidic reflux events play an important role in determining the duration of GERD symptoms in newborns. MII is more sensitive than pH monitoring for establishing the diagnosis of GER in nonenterally fed critically ill children with mechanical ventilation in the first 48 hours after admission to the pediatric intensive care unit (PICU) because the refluxate is an alkaline or weak acid in the majority of episodes. Patients who received muscle relaxants had a lower frequency of GER. Of interest, pH-only episodes, that is, reflux episodes detected with pH-metry but not with impedance (drop in pH without bolus movement) occur in young children. pH-only events occur mainly during the night and in young infants. Whether this is the “infant presentation” of the “gastric acid pocket,” which was recently described in adults with symptomatic reflux that is resistant to antacid medications is not known. Impedance also measures gas reflux, since liquid causes a drop in impedance and an increase in gas. In adults, baseline impedance was shown to be lower in esophagitis, and treatment of esophagitis with PPIs does increase baseline impedance. The sensitivity and specificity of baseline impedance as a marker for esophageal injury is debated in the literature. In children with reflux-related cough, baseline impedance levels were shown to have no role in identifying reflux-induced esophageal mucosal ultrastructural changes. Pathologic MII-pH results are not predictive for an erosive esophagitis and vice versa. A lower baseline impedance is associated with esophagitis, LA-grade B or higher and may be caused by longer acid exposure, but also by longer bolus exposure, and thus may be another useful parameter in GERD monitoring. These differences in observation regarding the utility of determining the impedance baseline may be related to the baseline impedance, which is age-dependent. The presence of esophagitis may also determine a decreased impedance baseline regardless of the age of the patients. The role of nonacid reflux measured by impedance pH testing in adult patients presenting with symptoms that were refractory to PPI treatment is uncertain at best, and the results from this test alone should not be used to refer patients for surgical fundoplication.


In a substantial subgroup of (adult) patients with heartburn that responded to PPIs, diagnosis of GERD could not be confirmed with MII-pH monitoring. This could mean that PPI response and heartburn are not reliable predictors of GERD diagnosis, or that MII-pH recording is not (always) a reliable diagnostic technique. Acid-related parameters are significantly related to MII baselines. An excellent correlation between manual and automated analyses of MII baselines was found. Distal MII baselines were significantly lower in children with a positive overall MII-pH outcome compared with the proximal esophagus.


Interpretation of an impedance recording is laborious and necessitates experience, since the automatic analysis is not yet standardized and validated in (young) children and infants. One of the major clinical interests of MII seems to be demonstration of symptom association, but normal data and validation of symptom association parameters in children are missing. Recently, attention has focused on baseline impedance, which is age dependent, decreased in esophagitis, and increased with PPI treatment. Infants (especially in the first months of life) and young children present a significantly lower impedance baseline compared to older children, both in the proximal and distal esophagus. Given the high cost of equipment, electrodes, the time needed for analysis and interpretation of impedance, the pros and cons in comparison to pH-metry are still debated. As long as medical therapeutic options are limited primarily to antacid medication, the clinical impact of measuring nonacid reflux is poor. In the meantime, research should focus on determining whether nonacid or weakly acid reflux is causally associated with symptoms.


Indirect techniques have been developed, mainly to diagnose GER(D) in patients with extraesophageal manifestations. Accumulation of evidence regarding the determination of lipid laden macrophages (LLMs) in bronchoalveolar liquid (BAL) resulted in the conclusion that this method lacks sensitivity and specificity. More recent data show the presence of pepsin and bile in BAL and middle ear fluid. There is no prospective, double-blind, placebo-controlled study treating reflux and evaluating the ear, nose, and throat (ENT) outcome as primary endpoint. It has yet to be determined if this association, if any, is “causal” or “consequence.”


An empiric trial of PPIs in adult patients without alarm features can be helpful, but the response to therapy is variable. Empirical treatment in children may be an even bigger challenge, since children are less accurate in reporting symptoms.


In conclusion, all GER-investigation techniques measure different aspects of reflux. Therefore, it is not unexpected that the correlation between the results of the different techniques is poor. There is no “always-best” investigation technique for diagnosing GER(D) because the clinical situation of each individual patients differs. Endoscopy is the only diagnostic tool to identify esophagitis; 24-hour pH-metry measures acid GER, MII detects acidic and weakly acidic GER episodes and reflux-associated symptoms. Barium meal is the best technique to provide information about the anatomy, and is in many countries the only technique available, although it has been shown to be unreliable for diagnosing GERD.

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Jul 24, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on Gastroesophageal Reflux

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