- Email: [email protected]
Gastro-oesophageal reflux
ARTICLE IN PRESS Current Paediatrics (2004) 14, 586–592
www.elsevier.com/locate/cupe
Gastro-oesophageal reflux A. Willmotta, M.S. Murphya,b, a
Birmingham Children’s Hospital NHS Trust, UK University of Birmingham, Birmingham, UK
b
KEYWORDS Gastro-oesophageal reflux; Pulmonary aspiration; pH monitoring; Oesophagitis; Barrett’s oesophagus
Summary Gastro-oesophageal reflux is a common phenomenon in infancy, and medical intervention is usually unnecessary. If reflux causes illness, it is referred to as ‘gastro-oesophageal reflux disease’. Such patients require investigation and treatment. This review considers the epidemiology, aetiology, pathophysiology and clinical effects of gastro-oesophageal reflux disease. The role of various investigations and the choice of therapeutic strategy are discussed. r 2004 Elsevier Ltd. All rights reserved.
Introduction Practice points
Most infants with regurgitation do not require investigation. The choice of investigation in GORD is determined by the specific question to be addressed The availability of highly effective acidsuppressing agents such as PPIs has significantly altered the indication for surgery
Research directions
Long-term PPI treatment vs. surgery The natural history of GOR and GORD in infants, children and adolescents
Corresponding author. Institute of Child Health, Clinical Research Block, Whittall Street, Birmingham B4 6NH, UK. Tel.: +44-121-333-8705; fax: +44-121-333-8701. E-mail address: [email protected] (M.S. Murphy).
This review considers various aspects of gastrooesophageal reflux (GOR) in infancy and childhood, including aetiology and pathophysiology, clinical features, investigation and management. In this context, certain definitions are useful.1 ‘Physiological reflux’ refers to the involuntary passage of gastric contents into the oesophagus. This is a universal phenomenon throughout life, from infancy to old age. Such episodes are normally brief and the refluxate usually remains in the distal oesophagus. In infancy, overt GOR (regurgitation) is so common as to be considered a normal phenomenon. ‘Pathological reflux’ refers to reflux resulting in adverse consequences—‘gastro-oesophageal reflux disease’ (GORD).
Epidemiology Infant reflux often begins during the first 3 months of life, with half of babies at this age having at least
0957-5839/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2004.08.006
ARTICLE IN PRESS Gastro-oesophageal reflux one episode of regurgitation per day.2 The peak prevalence is at 4 months of age, when up to 70% of babies experience regurgitation, but by 1 year, 95% have recovered. GORD may occur without obvious explanation, but it is very common in association with neurodevelopmental disorders and in certain congenital abnormalities such as diaphragmatic hernia and oesophageal atresia (post-repair).
Aetiology and pathogenesis Various mechanisms limit reflux and protect the oesophageal mucosa.1,3 The lower oesophageal sphincter (LOS) and the angle of His (the acute angulation between the oesophagus and stomach) provide a mechanical barrier, aided by positive pressure on the segment of oesophagus lying within the abdomen. Oesophageal acid exposure is limited by the clearance that follows swallowing and peristalsis. Simultaneous measurement of intra-oesophageal pH and intraluminal pressure shows a stepwise increase in pH with successive swallows.4 The acid is also neutralized by swallowed saliva and oesophageal secretions. The time required for the pH to become44 is reduced if salivation is stimulated.4 In addition to acid, other potentially noxious reflux components include bile salts and digestive enzymes such as pepsin and trypsin. The mucosa possesses inherent defence mechanisms. The mucosal tight junctions resist intercellular ionic movement, and the presence of acid in the lumen results in an increase in potential difference that defends cellular integrity. Various factors contributing to the development of GORD are outlined in Fig. 1. The LOS is normally in a state of tonic contraction. With swallowing and peristalsis, relaxation occurs. ‘Transient LOS relaxation’ (TLOSR) refers to a vagally mediated phenomenon in
Figure 1 Factors that contribute to gastro-oesophageal reflux disease.
587 which the LOS tone is briefly but inappropriately lost, resulting in an episode of reflux. TLOSR is not induced by swallowing, but often occurs in the postprandial period in association with gastric distension, acid secretion and hyperosmolality. TLOSR is an important cause of GOR in infants and children, but in severe reflux oesophagitis, this mechanism seems to be relatively unimportant. Delayed gastric emptying is important in some cases, especially in children with neurological disorders. Gastric emptying time has been shown to be significantly delayed in children with GORD compared with controls.5 Different combinations of factors may operate in individual cases to lead to the development of GORD.
Infant reflux In the first year of life, the intra-abdominal segment of the oesophagus is very short and the location of the LOS moves gradually from above to below the diaphragm. This, together with frequent TLOSR, may be important factors in the frequency with which infant reflux occurs.
Secondary reflux Severe GOR and GORD often occur as a secondary phenomenon.6 Neurodevelopmental disorders, including cerebral palsy, may predispose to severe GORD. A number of factors may contribute, including oesophageal dysmotility with impaired acid clearance, gastroduodenal dysmotility with impaired gastric emptying, LOS dysfunction, spasticity or seizures with raised intra-abdominal pressure, reduced consistency of feeds, and postural factors such as a recumbent position or kyphoscoliosis. Anatomical abnormalities may also be important. Hiatus hernia is often associated with GORD, although most children with GOR do not have a hiatus hernia. GORD may be an important complication following surgical repair of oesophageal atresia. In these cases, there may be both congenital and surgery-related defects in oesophageal motility, and surgical repair may also result in upward displacement of the LOS. GORD is also very common following surgical repair of congenital diaphragmatic hernia. Chronic lung disease, for example in children with cystic fibrosis, may predispose to GORD. Possible mechanisms include raised intra-abdominal pressure secondary to coughing. Certain primary gastrointestinal disorders such as pseudo-obstruction or severe small
ARTICLE IN PRESS 588 bowel Crohn’s disease may also be associated with troublesome GOR.
Genetic factors The genetics of GORD have been well reviewed in a recent publication.7 Historically, there have been case reports of familial clustering of hiatus hernia and of Barrett’s oesophagus (see later). More recently, an increased prevalence of GOR symptoms was found in the relatives of patients with proven GORD. In monozygotic and dizygotic twins, concordance for GORD was 19% and 4%, respectively. A locus on chromosome 13 (13q14) has been linked to severe GORD but not to familial infant GORD. GOR is a complex condition with considerable phenotypic diversity. It seems unlikely that one genetic factor is important in all cases.
Clinical presentation The symptoms of GORD are diverse and vary from trivial regurgitation to potentially life-threatening episodes.4,8 Infant GOR usually presents as frequent regurgitation of feeds. Such episodes may be provoked by movement or by lying flat. Regurgitation often appears effortless although this is not always so. Some infants seem little affected by the episodes, while others appear to be distressed. When regurgitation is frequent, it is a nuisance and causes parental worry. Later in infancy, as GOR resolves, minor intercurrent infections may be associated with a temporary relapse. GORD may first present with symptoms of oesophagitis. Overt regurgitation may not be present. Oesophagitis is uncommon in very young infants. It is often suggested that infant colic might be due to pain associated with oesophagitis, but this is not common. It is also suggested that oesophagitis might be a cause of feeding difficulties and hence failure to thrive. In the absence of other suggestive symptoms, this is not a likely explanation. Young children with severe reflux oesophagitis may show a striking behavioural pattern of back arching known as Sandifer’s syndrome. It appears that they learn to control reflux by adopting such postures. Occasionally, the first evidence of oesophagitis is the occurrence of symptoms such as haematemesis or dysphagia. Erosive (ulcerative) oesophagitis is most common with secondary reflux, and oesophageal strictures may occur in such cases. Other complications include acute or chronic aspiration, recurrent pneumonia, recurrent apnoea
A. Willmott, M.S. Murphy and acute life-threatening events, in addition to relatively minor symptoms such as cough and wheeze. Aspiration is a particular risk to those with severe neurodevelopmental disorders, in whom the airway protective reflexes may be impaired. Although most acute life-threatening events are not usually due to reflux, there are cases in which this may be the precipitant. It has been reported that recurrent wheeze may improve with successful treatment of occult reflux.9 Wheezing may be due to vagally mediated reflex bronchospasm due to chemical irritation of the oesophageal mucosa. The general significance of reflux as a cause of bronchospasm is uncertain, however, as it is difficult to determine cause and effect. There are reports of occult reflux as the apparent cause of upper respiratory symptoms such as hoarseness and stridor; some of these children apparently improve with reflux treatment.
Barrett’s oesophagus The term ‘Barrett’s oesophagus’ refers to the presence of intestinal metaplasia in the oesophagus.6 Endoscopically, the salmon-pink abnormal epithelium extends up from the gastro-oesophageal junction (z-line), typically appearing as tongues and sometimes isolated ‘islands’ of abnormal mucosa. There may be signs of erosive oesophagitis in the adjacent mucosa. Mucosal biopsy shows the typical intestinal-type epithelium with goblet cells. It is uncommon but not rare in childhood. In adults (in whom it is a relatively common disorder), there is an estimated 0.4% yearly risk of adenocarcinoma, increasing with age and with the degree of epithelial dysplasia.10 In children, the natural history is poorly understood, and it has not been associated with significant dysplasia. However, prudence suggests that these children should undergo intermittent endoscopic and biopsy surveillance. A proposed regime, similar to adult practice, consists of a repeat examination after 12 months and then at 3-yearly intervals (assuming no dysplasia is seen).
Investigation and diagnosis Other causes of vomiting, such as gastrointestinal obstruction, urinary tract infection, raised intracranial pressure or metabolic disorders, should be considered, and relevant investigations should be performed if appropriate. Most infants presenting
ARTICLE IN PRESS Gastro-oesophageal reflux with simple regurgitation do not require any investigation. Some infants and children may require specific tests to demonstrate the presence of reflux, to rule out alternative causes of vomiting, or to look for evidence of complications.8,11 Late onset of regurgitation has been reported as a presenting sign in infants with brain tumours. Each case must be considered on its own merits, and the choice of investigation depends on the specific question. In most cases, a careful history and examination are all that is necessary. If regurgitation is frequent and troublesome, simple measures (see below) may be helpful. Some clinicians suggest that if the condition is severe enough to require drug therapy other than antacids, this is an indication for investigation. Of course, if clinicians have a low threshold for using drug therapy, this may not apply. Upper gastrointestinal barium contrast radiology can rule out an obstructive disorder such as a gastric web or malrotation. It may also demonstrate a hiatus hernia. If there is severe erosive oesophagitis, this may be seen, but it is an insensitive test for oesophagitis. Lastly, although a barium study may demonstrate an episode of severe reflux, it is a very insensitive test for GOR. This is therefore an appropriate investigation if there is uncertainty in the clinician’s mind as to whether vomiting/regurgitation is in fact due to GOR. A 24-h oesophageal pH study is often regarded as the gold-standard test for GOR. The pH of the distal oesophagus is recorded using an intraluminal antimony electrode and reflux episodes are identified as drops in pH o4. The reflux index is the percentage of time that this reading is o4, and normal values have been established for infancy and childhood. Very few patients with GOR need to undergo a pH study. Its primary role is in the demonstration of occult reflux. If an extragastrointestinal symptom such as apnoea is suspected as arising from episodic reflux, a time-based symptom record should be maintained during the course of the study. Usually a single pH probe is used, but dual probes (with distal and proximal pH detectors) have been used recently to monitor the pH at two sites simultaneously—for example, proximal and distal oesophagus, or stomach and oesophagus. The former allows the height of acid reflux to be documented. The latter may help in the interpretation of oesophageal acid reflux because gastric pH is not continuously acid. Intraluminal electrical impedance measurement provides a relatively new technique, not yet widely available, for detecting both acid and non-acid
589 reflux episodes. This detects fluid bolus movement in the oesophagus, using the increased conductivity of liquid to detect the presence of refluxate in the oesophageal lumen. A flexible catheter with up to seven impedance electrodes at various levels is placed in the oesophagus. This technique has shown that 75% of reflux occurs during or within 2 h of a feed, and this is not usually detectable on pH monitoring as the postprandial pH is often44 (the conventional cut-off for recording acid reflux).4 As few as 15% of impedance-detected reflux episodes are in fact acid, and hence pH studies underestimate reflux.12 For example, in one study, 30% of infant apnoeas were associated with GOR, but only 22% of these were detected by pH monitoring.13 Upper gastrointestinal endoscopy with oesophageal biopsy is the technique for the diagnosis of reflux oesophagitis. Mucosal redness, pallor, erosions or ulceration may be seen. Histology characteristically shows hyperplasia of the epithelial basal zone, increased papillary length and the presence of intra-epithelial eosinophils. Children should not receive prolonged treatment for oesophagitis with acid-blocking agents (see below) without establishing a firm histological diagnosis. In a few children, a more severe eosinophilic infiltrate than is usually associated with reflux oeosophagitis may be noted, and some of these patients do not appear to respond to medical reflux therapy, including effective acid suppression. These cases appear to belong to a newly recognized clinical entity known as eosinophilic oesophagitis. They commonly present with unexplained dysphagia. The infiltrate may form superficial mucosal eosinophilic abscesses, and these may be seen as tiny pale spots coating the oesophageal surface. The endoscopist may also recognize other unusual features including mucosal furrowing or ridges, and luminal narrowing. Some have postulated that it may be due to food sensitivity, but the aetiology of this condition is not uncertain.14
Significance of Helicobacter pylori colonization In the course of investigating a child for GORD, gastric colonization with Helicobacter pylori (H. pylori) is sometimes identified as a coincidental finding.15,16 About 5–15% of children are colonized with H. pylori by 10 years of age, and although all have histological evidence of gastritis, this is not usually thought to be associated with clinical symptoms. Eradication reduces the
ARTICLE IN PRESS 590 risk of future peptic ulcer disease and probably of gastric carcinoma. There have been some concerns, however, that it might increase the risk of GORD. Children are mainly found to have antral colonization and antral gastritis, and this may be associated with increased acid production. In that case, eradication might improve GORD. Adults more often have diffuse gastritis with involvement of the corpus, and this is associated with reduced acid secretion. Eradication in such cases may increase acid production and worsen GORD or even the risk of oesophageal cancer. There is, therefore, controversy about the possible risks and benefits of H. pylori eradication in those with GORD. The data from paediatric studies are limited, so no firm guidance can currently be provided.
Treatment The management of GORD depends on the nature and severity of associated symptoms or complications.8,17 For many infants with simple regurgitation, explanation and reassurance are all that is required.
Simple measures If the regurgitation is very frequent and troublesome, some simple measures may help. Elevating the head end of the cot is commonly advised, although there is no evidence that this is effective. It is crucial that feeds are not restricted to control regurgitation, as this is the most common cause of failure to thrive in these infants. However, small frequent feeds may reduce regurgitation. Thickeners, such as those based on carob seed flour, can be added to each feed. This may reduce regurgitation, although studies have indicated that it does not affect the severity of acid reflux on oesophageal pH monitoring. Although most reflux is not related to milk intolerance, symptoms of cow’s milk protein (CMP) intolerance can be hard to distinguish from those of GOR in infants, hence some may consider a 2- to 4-week trial on a CMPfree formula.
Antacids As with adults, magnesium-, aluminium- or calcium-based antacids are quite often used for symptomatic relief in children with mild intermittent symptoms such as heartburn. Aluminium-based antacids are often avoided in children because of
A. Willmott, M.S. Murphy concerns regarding possible toxicity. Elevated plasma levels have been documented in those with normal renal function, as well as those at higher risk because of renal impairment. Magnesium compounds can cause diarrhoea. In infants, sodium alginate preparations such as Gaviscon (R&C) are widely used. Alginate precipitates in the presence of acid, CO2 from bicarbonate is incorporated, and a ‘raft’ is formed that floats on the gastric contents while neutralizing acid. Compared with placebo, these alginate preparations have been shown to reduce vomiting and also acid reflux as measured by pH monitoring.
Prokinetic agents The so-called prokinetic agents have been very widely used to control reflux in infants and children. All have the potential to cause sideeffects, and there is some uncertainty regarding their efficacy. It may be that they are prescribed too frequently. Metoclopramide (a dopamine antagonist) increases LOS pressure and alters peristalsis, as well as improving gastric emptying. It is widely used but does have the potential for side-effects (including Parkinsonian reactions and acute dystonia). Randomized clinical trials in adults and children have produced conflicting results; there may be a reduction in the reflux index, but no improvement in symptoms compared with placebo. Most trials in children have been small and some were very short term. Domperidone (a dopamine antagonist that does not cross the blood–brain barrier) is often used, but whilst it has been shown to increase basal LOS pressure and improve gastric emptying in adults, evidence, including a small shortterm randomized trial, does not show significant symptom reduction in children. Cisapride (a serotonin receptor agonist that facilitates acetyl choline release at the synapses of the myenteric plexus) was widely used until recently. Whilst there is some evidence that it may reduce the reflux index on pH monitoring, a recent Cochrane review found no definitive evidence that it reduced symptoms. Although widely withdrawn because of cardiac dysrhythmia as a rare but potentially dangerous side-effect, it is still available on a limited basis.
Acid-blocking agents H2 receptor antagonists such as cimetidine and ranitidine reduce gastric acid production by block-
ARTICLE IN PRESS Gastro-oesophageal reflux ing histamine H2 receptors. They control symptoms of oesophagitis and in adequate dosage they can heal oesophagitis.18 The proton pump inhibitors (PPIs) such as omeprazole and lansoprazole, and more recently esomeprazole and rabeprazole, form an even more potent class of acid-suppressing agents. There is no clear advantage to the various preparations, with some of the reported differences in potency perhaps reflecting dose effects.19 PPIs covalently bind to the gastric H+ /K+ ATPase pump, permanently inhibiting it. They are also effective at healing oesophagitis.20 Omeprazole has been shown to be effective in reducing symptoms and endoscopic signs of oesophagitis in some children who did not respond to H2 blockers. PPIs should be considered for these children and those in whom potent inhibition of acid is appropriate, such as those with erosive oesophagitis, neurological dysfunction, respiratory complications or Barrett’s oesophagus.
Surgery A very small proportion of patients require surgery to control GOR. A procedure such as a Nissen’s fundoplication (full wrap) or Thal fundoplication (partial wrap) may be performed. The procedure may be performed laparoscopically. Surgery is normally reserved for those with severe GORD unresponsive to optimal medical therapy. Its place in those who require long-term PPI treatment is still debated. Fundoplication is irreversible and is not always successful. Although good short-term success is often reported, the wrap may break down, especially in those with impaired gastric emptying and persistent post-fundoplication retching. Particular difficulties have been encountered in children with neurodevelopmental disorders, a group often in need of effective therapy but in whom gastrointestinal dysmotility may militate against a successful outcome from surgery. Other complications include gas bloat syndrome, retching, chronic diarrhoea, dumping syndrome and small bowel obstruction.
Prognosis The natural history of GORD in its various forms has not been studied adequately. Although infant GOR settles by 1 year of age in most cases, the outcome in older children is unclear. It has been reported that adults with GORD were more likely than controls to have experienced symptoms of reflux
591 or to have received treatment for reflux during childhood.21
References 1. Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002;35:119–36. 2. Nelson S, Chen E, Syniar G, Kaufer-Christofel K. Arch Pediatr Adolesc Med 1997;151:569–72. 3. Thompson M. Disorders of the oesophagus and stomach. Balliere’s Clin Gastroenterol 1997; 547–71. 4. Helm J, Dodds W, Riedel D, Teeter B, Hogan W, Arndorfer R. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 1983;85:607–12. 5. Cucchiara S, Salvia G, Borrelli O, et al. Gastric electrical dysrhythmias and gastric emptying in gastroesophageal reflux disease. Am J Gastroenterol 1997;92: 1103–8. 6. Hassall E. Co-morbidities in childhood Barrett’s oesophagus. J Pediatr Gastroenterol Nutr 1997;25:255–60. 7. Orenstein S, Shalaby T, Barada M, Whitcomb D. Genetics of gastroesophageal reflux disease: a review. J Pediatr Gastroenterol Nutr 2002;34:506–10. 8. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatrics. J Pediatr Gastroenterol Nutr 2001;32(Suppl. 2):S1–31. 9. Khoshoo V, Le T, Haydel R, Landry, Nelson C. Role of gastroesophageal reflux in older children with persistent asthma. Chest 2003;123:1008–13. 10. Murray L, Watson P, Johnston B, Sloan J, Mohan Lal Mainie I, Gavin A. Risk of adenocarcinoma in Barrett’s oesophagus: population based study. Br Med J 2003; 534–5. 11. Orenstein S. Tests to assess symptoms of gastroesophageal reflux in infants and children. J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S29–32. 12. Wenzl TG, Moroder C, Trachterna M, et al. Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2002;34:519–23. 13. Wenzl TG, Schenke S, Peschgens T, Silny J, Heimann G, Skopnik H. Association of apnoea and non-acid gastroesophageal reflux in infants: investigations with intraluminal impedance technique. Pediatr Pulmonol 2001;31: 144–9. 14. Liacouras C. Eosinophilic oesophagitis in children and adults. J Pediatr Gastroenterol Nutr 2003;37:S23–8. 15. Falk GW. GERD and H. pylori, is there a link? Semin Gastrointest Dis 2001;12:16–25. 16. Schwiser W, Fox M. Helicobacter pylori and gastroesphageal reflux disease: a complex organism in a complex host. J Pediatr Gastroenterol Nutr 2004;38:12–5. 17. Colletti R, Di Lorenzo C. Overview of pediatric gastroesophageal reflux disease and proton pump inhibitor therapy. J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S7–11. 18. Cucchiara S, Gobio-Casali L, Balli F, et al. Cimetidine treatment of reflux esophagitis in children: an Italian multicentre study. J Pediatr Gastroenterol Nutr 1989;8: 150–6.
ARTICLE IN PRESS 592 19. Franco M, Salvia G, Terrin G, et al. Lansoprazole in the treatment of gastroesophageal reflux disease in children. Dig Liver Dis 2000;32:660–6. 20. Cucchiara S, Minella R, Iervolino MR, et al. Omeprazole and high dose ranitidine in the treatment of refractory reflux oesophagitis. Arch Dis Child 1993;69:655–9. 21. Gold B. Outcomes of pediatric gastroesophageal reflux disease: in the first year of life, in adulthood, and in adults. J Pediatr Gastroenterol Nutr 2003;37:S33–9.
A. Willmott, M.S. Murphy
Further reading 1. J Paediatr Gastroenterol Nutr 2003; 37 (Suppl. 1). 2. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32(Suppl. 2):S1–31.
www.elsevier.com/locate/cupe
Gastro-oesophageal reflux A. Willmotta, M.S. Murphya,b, a
Birmingham Children’s Hospital NHS Trust, UK University of Birmingham, Birmingham, UK
b
KEYWORDS Gastro-oesophageal reflux; Pulmonary aspiration; pH monitoring; Oesophagitis; Barrett’s oesophagus
Summary Gastro-oesophageal reflux is a common phenomenon in infancy, and medical intervention is usually unnecessary. If reflux causes illness, it is referred to as ‘gastro-oesophageal reflux disease’. Such patients require investigation and treatment. This review considers the epidemiology, aetiology, pathophysiology and clinical effects of gastro-oesophageal reflux disease. The role of various investigations and the choice of therapeutic strategy are discussed. r 2004 Elsevier Ltd. All rights reserved.
Introduction Practice points
Most infants with regurgitation do not require investigation. The choice of investigation in GORD is determined by the specific question to be addressed The availability of highly effective acidsuppressing agents such as PPIs has significantly altered the indication for surgery
Research directions
Long-term PPI treatment vs. surgery The natural history of GOR and GORD in infants, children and adolescents
Corresponding author. Institute of Child Health, Clinical Research Block, Whittall Street, Birmingham B4 6NH, UK. Tel.: +44-121-333-8705; fax: +44-121-333-8701. E-mail address: [email protected] (M.S. Murphy).
This review considers various aspects of gastrooesophageal reflux (GOR) in infancy and childhood, including aetiology and pathophysiology, clinical features, investigation and management. In this context, certain definitions are useful.1 ‘Physiological reflux’ refers to the involuntary passage of gastric contents into the oesophagus. This is a universal phenomenon throughout life, from infancy to old age. Such episodes are normally brief and the refluxate usually remains in the distal oesophagus. In infancy, overt GOR (regurgitation) is so common as to be considered a normal phenomenon. ‘Pathological reflux’ refers to reflux resulting in adverse consequences—‘gastro-oesophageal reflux disease’ (GORD).
Epidemiology Infant reflux often begins during the first 3 months of life, with half of babies at this age having at least
0957-5839/$ - see front matter r 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2004.08.006
ARTICLE IN PRESS Gastro-oesophageal reflux one episode of regurgitation per day.2 The peak prevalence is at 4 months of age, when up to 70% of babies experience regurgitation, but by 1 year, 95% have recovered. GORD may occur without obvious explanation, but it is very common in association with neurodevelopmental disorders and in certain congenital abnormalities such as diaphragmatic hernia and oesophageal atresia (post-repair).
Aetiology and pathogenesis Various mechanisms limit reflux and protect the oesophageal mucosa.1,3 The lower oesophageal sphincter (LOS) and the angle of His (the acute angulation between the oesophagus and stomach) provide a mechanical barrier, aided by positive pressure on the segment of oesophagus lying within the abdomen. Oesophageal acid exposure is limited by the clearance that follows swallowing and peristalsis. Simultaneous measurement of intra-oesophageal pH and intraluminal pressure shows a stepwise increase in pH with successive swallows.4 The acid is also neutralized by swallowed saliva and oesophageal secretions. The time required for the pH to become44 is reduced if salivation is stimulated.4 In addition to acid, other potentially noxious reflux components include bile salts and digestive enzymes such as pepsin and trypsin. The mucosa possesses inherent defence mechanisms. The mucosal tight junctions resist intercellular ionic movement, and the presence of acid in the lumen results in an increase in potential difference that defends cellular integrity. Various factors contributing to the development of GORD are outlined in Fig. 1. The LOS is normally in a state of tonic contraction. With swallowing and peristalsis, relaxation occurs. ‘Transient LOS relaxation’ (TLOSR) refers to a vagally mediated phenomenon in
Figure 1 Factors that contribute to gastro-oesophageal reflux disease.
587 which the LOS tone is briefly but inappropriately lost, resulting in an episode of reflux. TLOSR is not induced by swallowing, but often occurs in the postprandial period in association with gastric distension, acid secretion and hyperosmolality. TLOSR is an important cause of GOR in infants and children, but in severe reflux oesophagitis, this mechanism seems to be relatively unimportant. Delayed gastric emptying is important in some cases, especially in children with neurological disorders. Gastric emptying time has been shown to be significantly delayed in children with GORD compared with controls.5 Different combinations of factors may operate in individual cases to lead to the development of GORD.
Infant reflux In the first year of life, the intra-abdominal segment of the oesophagus is very short and the location of the LOS moves gradually from above to below the diaphragm. This, together with frequent TLOSR, may be important factors in the frequency with which infant reflux occurs.
Secondary reflux Severe GOR and GORD often occur as a secondary phenomenon.6 Neurodevelopmental disorders, including cerebral palsy, may predispose to severe GORD. A number of factors may contribute, including oesophageal dysmotility with impaired acid clearance, gastroduodenal dysmotility with impaired gastric emptying, LOS dysfunction, spasticity or seizures with raised intra-abdominal pressure, reduced consistency of feeds, and postural factors such as a recumbent position or kyphoscoliosis. Anatomical abnormalities may also be important. Hiatus hernia is often associated with GORD, although most children with GOR do not have a hiatus hernia. GORD may be an important complication following surgical repair of oesophageal atresia. In these cases, there may be both congenital and surgery-related defects in oesophageal motility, and surgical repair may also result in upward displacement of the LOS. GORD is also very common following surgical repair of congenital diaphragmatic hernia. Chronic lung disease, for example in children with cystic fibrosis, may predispose to GORD. Possible mechanisms include raised intra-abdominal pressure secondary to coughing. Certain primary gastrointestinal disorders such as pseudo-obstruction or severe small
ARTICLE IN PRESS 588 bowel Crohn’s disease may also be associated with troublesome GOR.
Genetic factors The genetics of GORD have been well reviewed in a recent publication.7 Historically, there have been case reports of familial clustering of hiatus hernia and of Barrett’s oesophagus (see later). More recently, an increased prevalence of GOR symptoms was found in the relatives of patients with proven GORD. In monozygotic and dizygotic twins, concordance for GORD was 19% and 4%, respectively. A locus on chromosome 13 (13q14) has been linked to severe GORD but not to familial infant GORD. GOR is a complex condition with considerable phenotypic diversity. It seems unlikely that one genetic factor is important in all cases.
Clinical presentation The symptoms of GORD are diverse and vary from trivial regurgitation to potentially life-threatening episodes.4,8 Infant GOR usually presents as frequent regurgitation of feeds. Such episodes may be provoked by movement or by lying flat. Regurgitation often appears effortless although this is not always so. Some infants seem little affected by the episodes, while others appear to be distressed. When regurgitation is frequent, it is a nuisance and causes parental worry. Later in infancy, as GOR resolves, minor intercurrent infections may be associated with a temporary relapse. GORD may first present with symptoms of oesophagitis. Overt regurgitation may not be present. Oesophagitis is uncommon in very young infants. It is often suggested that infant colic might be due to pain associated with oesophagitis, but this is not common. It is also suggested that oesophagitis might be a cause of feeding difficulties and hence failure to thrive. In the absence of other suggestive symptoms, this is not a likely explanation. Young children with severe reflux oesophagitis may show a striking behavioural pattern of back arching known as Sandifer’s syndrome. It appears that they learn to control reflux by adopting such postures. Occasionally, the first evidence of oesophagitis is the occurrence of symptoms such as haematemesis or dysphagia. Erosive (ulcerative) oesophagitis is most common with secondary reflux, and oesophageal strictures may occur in such cases. Other complications include acute or chronic aspiration, recurrent pneumonia, recurrent apnoea
A. Willmott, M.S. Murphy and acute life-threatening events, in addition to relatively minor symptoms such as cough and wheeze. Aspiration is a particular risk to those with severe neurodevelopmental disorders, in whom the airway protective reflexes may be impaired. Although most acute life-threatening events are not usually due to reflux, there are cases in which this may be the precipitant. It has been reported that recurrent wheeze may improve with successful treatment of occult reflux.9 Wheezing may be due to vagally mediated reflex bronchospasm due to chemical irritation of the oesophageal mucosa. The general significance of reflux as a cause of bronchospasm is uncertain, however, as it is difficult to determine cause and effect. There are reports of occult reflux as the apparent cause of upper respiratory symptoms such as hoarseness and stridor; some of these children apparently improve with reflux treatment.
Barrett’s oesophagus The term ‘Barrett’s oesophagus’ refers to the presence of intestinal metaplasia in the oesophagus.6 Endoscopically, the salmon-pink abnormal epithelium extends up from the gastro-oesophageal junction (z-line), typically appearing as tongues and sometimes isolated ‘islands’ of abnormal mucosa. There may be signs of erosive oesophagitis in the adjacent mucosa. Mucosal biopsy shows the typical intestinal-type epithelium with goblet cells. It is uncommon but not rare in childhood. In adults (in whom it is a relatively common disorder), there is an estimated 0.4% yearly risk of adenocarcinoma, increasing with age and with the degree of epithelial dysplasia.10 In children, the natural history is poorly understood, and it has not been associated with significant dysplasia. However, prudence suggests that these children should undergo intermittent endoscopic and biopsy surveillance. A proposed regime, similar to adult practice, consists of a repeat examination after 12 months and then at 3-yearly intervals (assuming no dysplasia is seen).
Investigation and diagnosis Other causes of vomiting, such as gastrointestinal obstruction, urinary tract infection, raised intracranial pressure or metabolic disorders, should be considered, and relevant investigations should be performed if appropriate. Most infants presenting
ARTICLE IN PRESS Gastro-oesophageal reflux with simple regurgitation do not require any investigation. Some infants and children may require specific tests to demonstrate the presence of reflux, to rule out alternative causes of vomiting, or to look for evidence of complications.8,11 Late onset of regurgitation has been reported as a presenting sign in infants with brain tumours. Each case must be considered on its own merits, and the choice of investigation depends on the specific question. In most cases, a careful history and examination are all that is necessary. If regurgitation is frequent and troublesome, simple measures (see below) may be helpful. Some clinicians suggest that if the condition is severe enough to require drug therapy other than antacids, this is an indication for investigation. Of course, if clinicians have a low threshold for using drug therapy, this may not apply. Upper gastrointestinal barium contrast radiology can rule out an obstructive disorder such as a gastric web or malrotation. It may also demonstrate a hiatus hernia. If there is severe erosive oesophagitis, this may be seen, but it is an insensitive test for oesophagitis. Lastly, although a barium study may demonstrate an episode of severe reflux, it is a very insensitive test for GOR. This is therefore an appropriate investigation if there is uncertainty in the clinician’s mind as to whether vomiting/regurgitation is in fact due to GOR. A 24-h oesophageal pH study is often regarded as the gold-standard test for GOR. The pH of the distal oesophagus is recorded using an intraluminal antimony electrode and reflux episodes are identified as drops in pH o4. The reflux index is the percentage of time that this reading is o4, and normal values have been established for infancy and childhood. Very few patients with GOR need to undergo a pH study. Its primary role is in the demonstration of occult reflux. If an extragastrointestinal symptom such as apnoea is suspected as arising from episodic reflux, a time-based symptom record should be maintained during the course of the study. Usually a single pH probe is used, but dual probes (with distal and proximal pH detectors) have been used recently to monitor the pH at two sites simultaneously—for example, proximal and distal oesophagus, or stomach and oesophagus. The former allows the height of acid reflux to be documented. The latter may help in the interpretation of oesophageal acid reflux because gastric pH is not continuously acid. Intraluminal electrical impedance measurement provides a relatively new technique, not yet widely available, for detecting both acid and non-acid
589 reflux episodes. This detects fluid bolus movement in the oesophagus, using the increased conductivity of liquid to detect the presence of refluxate in the oesophageal lumen. A flexible catheter with up to seven impedance electrodes at various levels is placed in the oesophagus. This technique has shown that 75% of reflux occurs during or within 2 h of a feed, and this is not usually detectable on pH monitoring as the postprandial pH is often44 (the conventional cut-off for recording acid reflux).4 As few as 15% of impedance-detected reflux episodes are in fact acid, and hence pH studies underestimate reflux.12 For example, in one study, 30% of infant apnoeas were associated with GOR, but only 22% of these were detected by pH monitoring.13 Upper gastrointestinal endoscopy with oesophageal biopsy is the technique for the diagnosis of reflux oesophagitis. Mucosal redness, pallor, erosions or ulceration may be seen. Histology characteristically shows hyperplasia of the epithelial basal zone, increased papillary length and the presence of intra-epithelial eosinophils. Children should not receive prolonged treatment for oesophagitis with acid-blocking agents (see below) without establishing a firm histological diagnosis. In a few children, a more severe eosinophilic infiltrate than is usually associated with reflux oeosophagitis may be noted, and some of these patients do not appear to respond to medical reflux therapy, including effective acid suppression. These cases appear to belong to a newly recognized clinical entity known as eosinophilic oesophagitis. They commonly present with unexplained dysphagia. The infiltrate may form superficial mucosal eosinophilic abscesses, and these may be seen as tiny pale spots coating the oesophageal surface. The endoscopist may also recognize other unusual features including mucosal furrowing or ridges, and luminal narrowing. Some have postulated that it may be due to food sensitivity, but the aetiology of this condition is not uncertain.14
Significance of Helicobacter pylori colonization In the course of investigating a child for GORD, gastric colonization with Helicobacter pylori (H. pylori) is sometimes identified as a coincidental finding.15,16 About 5–15% of children are colonized with H. pylori by 10 years of age, and although all have histological evidence of gastritis, this is not usually thought to be associated with clinical symptoms. Eradication reduces the
ARTICLE IN PRESS 590 risk of future peptic ulcer disease and probably of gastric carcinoma. There have been some concerns, however, that it might increase the risk of GORD. Children are mainly found to have antral colonization and antral gastritis, and this may be associated with increased acid production. In that case, eradication might improve GORD. Adults more often have diffuse gastritis with involvement of the corpus, and this is associated with reduced acid secretion. Eradication in such cases may increase acid production and worsen GORD or even the risk of oesophageal cancer. There is, therefore, controversy about the possible risks and benefits of H. pylori eradication in those with GORD. The data from paediatric studies are limited, so no firm guidance can currently be provided.
Treatment The management of GORD depends on the nature and severity of associated symptoms or complications.8,17 For many infants with simple regurgitation, explanation and reassurance are all that is required.
Simple measures If the regurgitation is very frequent and troublesome, some simple measures may help. Elevating the head end of the cot is commonly advised, although there is no evidence that this is effective. It is crucial that feeds are not restricted to control regurgitation, as this is the most common cause of failure to thrive in these infants. However, small frequent feeds may reduce regurgitation. Thickeners, such as those based on carob seed flour, can be added to each feed. This may reduce regurgitation, although studies have indicated that it does not affect the severity of acid reflux on oesophageal pH monitoring. Although most reflux is not related to milk intolerance, symptoms of cow’s milk protein (CMP) intolerance can be hard to distinguish from those of GOR in infants, hence some may consider a 2- to 4-week trial on a CMPfree formula.
Antacids As with adults, magnesium-, aluminium- or calcium-based antacids are quite often used for symptomatic relief in children with mild intermittent symptoms such as heartburn. Aluminium-based antacids are often avoided in children because of
A. Willmott, M.S. Murphy concerns regarding possible toxicity. Elevated plasma levels have been documented in those with normal renal function, as well as those at higher risk because of renal impairment. Magnesium compounds can cause diarrhoea. In infants, sodium alginate preparations such as Gaviscon (R&C) are widely used. Alginate precipitates in the presence of acid, CO2 from bicarbonate is incorporated, and a ‘raft’ is formed that floats on the gastric contents while neutralizing acid. Compared with placebo, these alginate preparations have been shown to reduce vomiting and also acid reflux as measured by pH monitoring.
Prokinetic agents The so-called prokinetic agents have been very widely used to control reflux in infants and children. All have the potential to cause sideeffects, and there is some uncertainty regarding their efficacy. It may be that they are prescribed too frequently. Metoclopramide (a dopamine antagonist) increases LOS pressure and alters peristalsis, as well as improving gastric emptying. It is widely used but does have the potential for side-effects (including Parkinsonian reactions and acute dystonia). Randomized clinical trials in adults and children have produced conflicting results; there may be a reduction in the reflux index, but no improvement in symptoms compared with placebo. Most trials in children have been small and some were very short term. Domperidone (a dopamine antagonist that does not cross the blood–brain barrier) is often used, but whilst it has been shown to increase basal LOS pressure and improve gastric emptying in adults, evidence, including a small shortterm randomized trial, does not show significant symptom reduction in children. Cisapride (a serotonin receptor agonist that facilitates acetyl choline release at the synapses of the myenteric plexus) was widely used until recently. Whilst there is some evidence that it may reduce the reflux index on pH monitoring, a recent Cochrane review found no definitive evidence that it reduced symptoms. Although widely withdrawn because of cardiac dysrhythmia as a rare but potentially dangerous side-effect, it is still available on a limited basis.
Acid-blocking agents H2 receptor antagonists such as cimetidine and ranitidine reduce gastric acid production by block-
ARTICLE IN PRESS Gastro-oesophageal reflux ing histamine H2 receptors. They control symptoms of oesophagitis and in adequate dosage they can heal oesophagitis.18 The proton pump inhibitors (PPIs) such as omeprazole and lansoprazole, and more recently esomeprazole and rabeprazole, form an even more potent class of acid-suppressing agents. There is no clear advantage to the various preparations, with some of the reported differences in potency perhaps reflecting dose effects.19 PPIs covalently bind to the gastric H+ /K+ ATPase pump, permanently inhibiting it. They are also effective at healing oesophagitis.20 Omeprazole has been shown to be effective in reducing symptoms and endoscopic signs of oesophagitis in some children who did not respond to H2 blockers. PPIs should be considered for these children and those in whom potent inhibition of acid is appropriate, such as those with erosive oesophagitis, neurological dysfunction, respiratory complications or Barrett’s oesophagus.
Surgery A very small proportion of patients require surgery to control GOR. A procedure such as a Nissen’s fundoplication (full wrap) or Thal fundoplication (partial wrap) may be performed. The procedure may be performed laparoscopically. Surgery is normally reserved for those with severe GORD unresponsive to optimal medical therapy. Its place in those who require long-term PPI treatment is still debated. Fundoplication is irreversible and is not always successful. Although good short-term success is often reported, the wrap may break down, especially in those with impaired gastric emptying and persistent post-fundoplication retching. Particular difficulties have been encountered in children with neurodevelopmental disorders, a group often in need of effective therapy but in whom gastrointestinal dysmotility may militate against a successful outcome from surgery. Other complications include gas bloat syndrome, retching, chronic diarrhoea, dumping syndrome and small bowel obstruction.
Prognosis The natural history of GORD in its various forms has not been studied adequately. Although infant GOR settles by 1 year of age in most cases, the outcome in older children is unclear. It has been reported that adults with GORD were more likely than controls to have experienced symptoms of reflux
591 or to have received treatment for reflux during childhood.21
References 1. Vandenplas Y, Hassall E. Mechanisms of gastroesophageal reflux and gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2002;35:119–36. 2. Nelson S, Chen E, Syniar G, Kaufer-Christofel K. Arch Pediatr Adolesc Med 1997;151:569–72. 3. Thompson M. Disorders of the oesophagus and stomach. Balliere’s Clin Gastroenterol 1997; 547–71. 4. Helm J, Dodds W, Riedel D, Teeter B, Hogan W, Arndorfer R. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 1983;85:607–12. 5. Cucchiara S, Salvia G, Borrelli O, et al. Gastric electrical dysrhythmias and gastric emptying in gastroesophageal reflux disease. Am J Gastroenterol 1997;92: 1103–8. 6. Hassall E. Co-morbidities in childhood Barrett’s oesophagus. J Pediatr Gastroenterol Nutr 1997;25:255–60. 7. Orenstein S, Shalaby T, Barada M, Whitcomb D. Genetics of gastroesophageal reflux disease: a review. J Pediatr Gastroenterol Nutr 2002;34:506–10. 8. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatrics. J Pediatr Gastroenterol Nutr 2001;32(Suppl. 2):S1–31. 9. Khoshoo V, Le T, Haydel R, Landry, Nelson C. Role of gastroesophageal reflux in older children with persistent asthma. Chest 2003;123:1008–13. 10. Murray L, Watson P, Johnston B, Sloan J, Mohan Lal Mainie I, Gavin A. Risk of adenocarcinoma in Barrett’s oesophagus: population based study. Br Med J 2003; 534–5. 11. Orenstein S. Tests to assess symptoms of gastroesophageal reflux in infants and children. J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S29–32. 12. Wenzl TG, Moroder C, Trachterna M, et al. Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2002;34:519–23. 13. Wenzl TG, Schenke S, Peschgens T, Silny J, Heimann G, Skopnik H. Association of apnoea and non-acid gastroesophageal reflux in infants: investigations with intraluminal impedance technique. Pediatr Pulmonol 2001;31: 144–9. 14. Liacouras C. Eosinophilic oesophagitis in children and adults. J Pediatr Gastroenterol Nutr 2003;37:S23–8. 15. Falk GW. GERD and H. pylori, is there a link? Semin Gastrointest Dis 2001;12:16–25. 16. Schwiser W, Fox M. Helicobacter pylori and gastroesphageal reflux disease: a complex organism in a complex host. J Pediatr Gastroenterol Nutr 2004;38:12–5. 17. Colletti R, Di Lorenzo C. Overview of pediatric gastroesophageal reflux disease and proton pump inhibitor therapy. J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S7–11. 18. Cucchiara S, Gobio-Casali L, Balli F, et al. Cimetidine treatment of reflux esophagitis in children: an Italian multicentre study. J Pediatr Gastroenterol Nutr 1989;8: 150–6.
ARTICLE IN PRESS 592 19. Franco M, Salvia G, Terrin G, et al. Lansoprazole in the treatment of gastroesophageal reflux disease in children. Dig Liver Dis 2000;32:660–6. 20. Cucchiara S, Minella R, Iervolino MR, et al. Omeprazole and high dose ranitidine in the treatment of refractory reflux oesophagitis. Arch Dis Child 1993;69:655–9. 21. Gold B. Outcomes of pediatric gastroesophageal reflux disease: in the first year of life, in adulthood, and in adults. J Pediatr Gastroenterol Nutr 2003;37:S33–9.
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Further reading 1. J Paediatr Gastroenterol Nutr 2003; 37 (Suppl. 1). 2. Rudolph C, Mazur L, Liptak G, et al. Guidelines for the evaluation and treatment of gastroesophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32(Suppl. 2):S1–31.