Pathophysiology and investigation of gastro-oesophageal reflux disease

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Pathophysiology and investigation of gastro-oesophageal reflux disease

John M. Findlay and Nicholas D. Maynard

Introduction

Gastro-oesophageal reflux disease (GORD) describes symptoms or mucosal damage caused by reflux of gastric contents into the oesophagus.¹ Symptoms are variable and along with damage are associated with many permutations of motility, endoscopic and physiological abnormalities. GORD is the major factor leading to the increasing incidence of oesophageal adenocarcinoma,² and is one of the commonest health problems in the developed world.

Epidemiology

Gastro-oesophageal reflux is universal, and as such can be viewed as a normal physiological process. Such physiological episodes are asymptomatic and rapidly cleared. They occur mainly after meals, in the upright position and when awake.^3,⁴ By contrast, pathological reflux results in chronic symptoms or mucosal damage. However, the subjectivity of symptoms is such that the boundary between the two is blurred, with many people viewing occasional reflux symptoms as normal, without seeking medical attention. For example, the reflux of air (belching) due to gastric distension is a universal experience, yet depending upon frequency and patient perception may be either normal or or a symptom of GORD. Unsurprisingly, the epidemiology of GORD is difficult to determine. A 2011 population-based cohort study of 45 000 people from Norway⁵ found the prevalence of any symptoms to be 41%, weekly symptoms to be 17% and severe symptoms to be 6.7% The figures had increased by 30%, 24% and 47%, respectively, over the previous decade. Incidence of any symptoms was 3%, with that of severe symptoms 0.2%, with spontaneous resolution of these symptoms occurring in 2% and 1%, respectively. A systematic review of 15 studies estimated a similar prevalence of weekly symptoms in 10–20% in the Western world (5% in Asia).⁶

One large population-based study and one systematic review estimated the Western prevalence of symptomatic GORD (at least weekly heartburn/acid regurgitation) to be 10–20%.^5,⁶

These findings were similar to a smaller Finnish study of 1562 consecutive patients referred for endoscopy. With the caveat of this selection bias, the overall incidence was estimated as 3%, of which 2% had endoscopic mucosal damage.⁷ Two additional studies have reached similar conclusions, with 32–38% of those with symptoms having normal endoscopies.^8,⁹ Importantly, the converse may be true, with up to 20% of those with oesophagitis or Barrett’s being asymptomatic.¹⁰

Two studies of patients with reflux symptoms found a normal oesophagus on endoscopy in 32% and 38% of subjects.^8,⁹ Up to 20% of those with oesophagitis or Barrett’s oesophagus are asymptomatic.¹⁰

Traditionally, GORD has been viewed as a spectrum of a single disease, with endoscopy-negative symptoms at the mild end, increasing grades of oesophagitis representing progressively severe disease, culminating in Barrett’s metaplasia.¹ However, this approach is undermined by a number of clinical, endoscopic and physiological findings, suggesting that the three may in fact be distinct groups and disease processes in themselves (Box 12.1).^11,¹² Most importantly, endoscopic progression from one end of the spectrum to the other is rare.¹²

Box 12.1 Distinct subgroups of GORD

• Symptomatic endoscopy-negative (non-erosive) GORD

• Oesophagitis and erosive reflux

• Barrett’s oesophagus

Symptoms

Symptoms tend to occur in combination rather than isolation, and are classed as typical and atypical. Typical symptoms comprise heartburn, acid brash and regurgitation (‘volume reflux’). Heartburn is defined as discomfort or burning behind the sternum; regurgitation as the perception of flow of gastric contents into the oro/hypopharynx. Intermittent dysphagia may also occur. Atypical symptoms include non-heartburn chest pain, epigastric pain and bloating, and can blur with other functional symptoms of the gastrointestinal tract so that even if excessive reflux is demonstrated physiologically, attributing causality may be difficult. Extra-oesophageal manifestations occur in the upper aerodigestive tract and lungs. GORD may be associated with a changing/hoarse voice, pharyngitis, tonsillitis and sinusitis, ‘globus’ symptoms (resulting from cricopharyngeal dysfunction) as well as throat clearing, chronic cough, dental decay and poor oral hygiene. GORD has also been implicated in exacerbations of asthma, possibly due to micro-aspiration.

Symptoms typically vary between the three GORD groups discussed above. Those with symptomatic endoscopy-negative disease (or non-erosive reflux) tend to have severe, often atypical symptoms with variable response to acid suppression (presumably representing oesophageal hypersensitivity to acid and non-acid reflux).¹² By contrast, those with erosive reflux and oesophagitis tend towards more typical symptoms responding well to acid suppression.¹² Finally, those with Barrett’s often have minimal symptoms, possibly due to the relative insensitivity of metaplastic epithelium to acid.¹³

These discrepancies emphasise the challenging multifactorial nature of GORD; central to its understanding is normal oesophageal anatomy and physiology.

Normal oesophageal anatomy

The oesophagus is a muscular tube, approximately 25 cm in length. It extends from the pharynx to the stomach, and is subdivided into three (arbitrary) anatomical segments: cervical, thoracic and abdominal. The cervical oesophagus (approximately 5 cm long) is a direct continuation of the hypopharynx, between cricopharyngeus and the thoracic inlet (T1). The thoracic segment (approximately 18 cm) ends at T10 at the oeophageal hiatus. The abdominal oesophagus (approximately 1–2 cm) ends at the gastro-oesophageal junction.

The muscle configuration of the body of the oesophagus is unique, with both smooth and striated muscle comprising a single functional unit. The muscularis propria consists of outer longitudinal and inner circular layers (the former spiralling slightly). These are exclusively striated muscle at the proximal end (including cricopharyngeus), mixing progressively with smooth muscle over the proximal and middle thirds. The lower third is entirely composed of smooth muscle. The epithelial lining is non-keratinising stratified squamous, abruptly becoming glandular columnar (evident endoscopically as the z-line) at the level of, or at a variable distance above, the gastro-oesophageal junction.

Between the mucosa and muscularis mucosa, and the circular muscle layer, lies the submucosa, which contains neurovascular and support tissue. Blood supply is predominantly from the inferior thyroid arteries, direct aortic branches and left gastric artery for the cervical, thoracic and abdominal segments, respectively. Parasympathetic innervation is predominantly from the vagus nerves, with some indirect contribution proximally from the recurrent laryngeal nerves. Sympathetic innervation is from the middle cervical ganglion proximally, and upper four thoracic ganglia distally. The oesophagus has two sphincters: upper and lower. The former comprises the inferior constrictor muscle, cricopharyngeus and proximal oesophageal muscle. The latter is less discrete and is discussed in greater depth later.

Normal oesophageal physiology

On swallowing the upper and lower oesophageal sphincters relax, and the food or liquid bolus is propelled distally by peristalsis to the stomach. The responsible mechanisms involve complicated coordination between central and local neuromuscular mechanisms. Peristalsis is the sequential contraction of the oesophageal body. Animal models demonstrate progression aborally in both longitudinal and circular layers, without torque.¹⁴ Primary peristalsis is instigated centrally in the swallowing centre by swallowing, with the wave arising in the pharynx. A persistent bolus distends the oesophagus, triggering local neural mechanisms and a secondary peristaltic wave.¹⁵ Tertiary contractions are aberrant, synchronous contractions of oesophageal segments, which play no role in peristalsis. During peristalsis, the oesophageal body contracts segmentally, with the greatest pressure at the mid-point of the contracted segment, a few centimetres behind the bolus¹⁶ (Fig. 12.1).

Figure 12.1 A standard six-sensor manometry trace of normal oesophageal peristalsis. Adapted from Anggiansah A, Marshal R. Use of the oesophageal laboratory, 1st edn. Oxford: Isis Medical Media, 2000. With permission from Isis Medical Media.

Whether the longitudinal and circular layers contract synchronously or not is disputed. A number of studies have suggested that the circular layer initially hyperpolarises, to contract two seconds after the longitudinal layer.17–19 However, this has been disputed, and it has been suggested that any delay is a function of the manometric techniques used.²⁰ In any case, the involvement of both layers confers mechanical advantages, with longitudinal contractions shortening the circular layer, allowing greater contractile force. In addition, contraction of both reduces wall tension at the site of contraction.²¹

Primary peristalsis is initiated centrally (via the vagus) and modified peripherally (via local myogenic and neuronal mechanisms). Vagal efferents from the nucleus ambiguous initiate skeletal muscle contraction, and those from the dorsomotor nucleus innervate smooth muscle. These do so via intrinsic neurons of the myenteric plexus (between the muscle layers). Modification within the oesophageal body occurs in response to volume, temperature and acid receptors, with central feedback via vagal afferents. Warm boluses initiate an exaggerated peristaltic wave, whereas cold boluses (e.g. ice cream) may not provoke distal peristalsis.²² This is true for wet and dry swallows, respectively. In addition, oesophageal acid receptors are believed to allow protective clearance of refluxate. Crucial to successful peristalsis is the oesophageal latency period. Following initial stimulation of the circular muscle layers, a variable period of membrane hyperpolarisation occurs, primarily mediated by intrinsic nitric oxide inhibition.²³ This period increases progressively, moving distally along the oesophageal body, with greater inhibitory inhibition.²⁴ Initial (or deglutitive) inhibition describes a refractory period of the oesophageal body due to myogenic and inhibitory properties. Swallowing for a second time within seconds causes the first peristaltic wave to be aborted.²⁵ This allows rapid sequences of swallows (used primarily for drinking).

Antireflux mechanisms

A positive pressure gradient of approximately 10 mmHg exists between the stomach and oesophagus. The stomach and abdominal oesophagus lie within 5 mmHg of positive intra-abdominal pressure, with the thoracic oesophagus exposed to 5 mmHg of negative pressure. That gastro-oesophageal reflux is the exception rather than the rule is due to several factors: the lower oesophageal sphincter (LOS), the diaphragmatic sphincter or ‘pinch-cock’, distal oesophageal compression, and other mechanical barriers such as the cardio-oesophageal angle (of His) and the mucosal rosette (Box 12.2).

Lower oesophageal sphincter

The LOS is the primary antireflux mechanism. Although not an anatomically discrete sphincter, it is a resting high-pressure zone in the distal oesophagus, which relaxes appropriately to allow swallowing, belching and vomiting.²⁶ It is composed of specialised smooth muscle, arranged in either clasp or sling formation, running in the distal 1–4 cm of the oesophagus and blending with the cardia.²⁷ The basal tone of the LOS is both intrinisic (inherent muscular properties) and extrinsic (excitatory cholinergic vagal input). Clasp and sling fibres vary in resting tone and responsiveness to stimulation; sling fibres have lower tone but greater responsiveness, probably due to differing proportions of contractile proteins. These fibres are also asymmetrically arranged, potentially accounting for the longitudinal and radial asymmetry of basal pressure (being greatest posteriorly and on the right).²⁸ LOS muscle cells are tonic, and as such distinct from the phasic cells of the oesophageal body (which have no intrinsic tone).

Neurological control of the LOS is complicated. Central control is mediated by vagal efferents originating in the dorsal motor nucleus (with excitatory cell bodies cephalad and inhibitory cells caudally).²⁹ Sensory feedback from the LOS is relayed via the tractus solitarius. Central neurotransmitters include glutamate, adrenaline, dopamine, acetylcholine and nitric oxide. Peripherally, vagal fibres synapse in the myenteric plexus via acetylcholine.³⁰ Both atropine and vagotomy reduce resting LOS pressure significantly.³¹ Nitric oxide is the primary inhibitory neurotransmitter of the LOS: in murine models nitric oxide knockout increases resting LOS pressure and prevents the transient LOS relaxations (TLOSRs) required for swallowing³² (Fig. 12.2). This inhibition may be further modified by the interstitial cells of Cajal.³³

Figure 12.2 High-resolution manometry demonstrating transient lower oesophageal sphincter relaxation (TLOSR). The upper oesophageal sphincter is demonstrated by the upper red and yellow zone, and the LOS by the lower red and yellow zone. On relaxation of the lower oesophageal sphincter a common cavity is created between the stomach and oesophagus – demonstrated by the light blue zone on the spatiotemporal plot (centre). These events are also observed on the axial pressure plot (right). The event is terminated and oesophagus cleared by primary peristalsis with intra-oesophageal pressure returning to baseline levels. Images acquired by 36-channel SSI Manoscan 360. Reproduced from Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008; 57(3):405–23. With permission from BMJ Publishing Group Ltd.

LOS resting pressure varies physiologically, in particular reducing with meals.³⁴ It also reduces in response to pharyngeal tactile stimulation (in the absence of swallowing or peristalsis).³⁵ In control subjects, transient increases in intra-abdominal pressure (e.g. induced by straight leg raising, coughing and straining) are met with reflex increase in LOS pressure that is both greater and faster than the increase in gastric pressure.³⁶ This response is due in part to neuromuscular reflexes (vagally mediated) and transmitted pressure from the crus of the diaphragm. Similarly, protective increases in pressure occur in response to drops in intrathoracic pressure.³⁷

TLOSRs are appropriate short-lived (usually less than 10 seconds) relaxations instigated by primary or secondary peristalsis, gastric distension and vomiting.^38,³⁹ In asymptomatic controls, TLOSRs account for 94% of reflux episodes,⁴⁰ primarily occurring after meals and when upright rather than supine^34,⁴¹ (correlating with the distribution of asymptomatic physiological reflux episodes discussed above). Fifty per cent of TLOSRs result in reflux episodes.^40,⁴² Their genesis is incompletely understood, but seems to be a vagally mediated response to proximal gastric distension sensed by mechanoreceptors.^41,⁴³ Fundoplication reduces the frequency of TLOSRs, potentially via reducing cardiac distensibility.^44,⁴⁵ Manometrically, TLOSRs are similar to the belch reflex, and many reflux episodes follow belching,^46,⁴⁷ suggesting that the former are aberrations of the latter. Pathological and physiological (swallow-induced) TLOSRs appear to be distinct, with pathological lasting longer (up to 45 seconds).⁴⁸

In a small controlled study of patients with oesophagitis, pathological reflux was found to be due to three primary mechanisms: TLOSRs (65%), spontaneous reflux due to low resting LOS pressure (18%) and transient increased intra-abdominal pressure (17%).⁴⁰ However, the commonest mechanisms vary between individuals.

Overall, pathological reflux is due to three primary mechanisms: TLOSRs (65%), a hypotensive LOS (18%) and transient increases in intra-abdominal pressure (17%).⁴⁰ However, these proportions vary widely within individuals.

Diaphragmatic sphincter

The slings of the right crus constitute a ‘pinch-cock’ mechanism. In the absence of a hiatus hernia, it is difficult to separate the relative contributions of the diaphragmatic sphincter and LOS. In those with a surgically resected LOS, however, a basal high-pressure zone is detectable (oscillating in line with ventilation), suggesting that the diaphragmatic sphincter has a tonic component.⁵⁰ Such increases in high-pressure zone pressure with inspiration are abolished with curare in feline models, so as with the LOS the diaphragmatic sphincter seems to have both basal and reactive tonicity.⁵¹ These increases in pressure are related to depth of inspiration⁴⁹ and are maximal during sleep (when the gastro-oesophageal pressure gradient is greatest).⁵² Functionally, in the absence of a hiatus hernia, both LOS and diaphragmatic sphincter contribute to the high-pressure zone.⁵³ However, the mechanism of diaphragmatic sphincter relaxation differs neurochemically and functionally. Oesophageal distension (due to swallowing) triggers incomplete diaphragmatic sphincter relaxation, whereas TLOSRs cause complete relaxation.⁵⁴ As with the LOS, this relaxation is both central and local. Central control is mediated via vagal afferents modifying control of the diaphragm,⁵⁵ although this may be distal to the medulla in site.⁵⁶ Local control may be due to stretching of diaphragmatic sphincter fibres by contraction of longitudinal oesophageal fibres.⁵⁷ Variation in the distensibility of the diaphragmatic sphincter affects reflux; greater distensibility predisposes to more reflux episodes.⁵⁸

Distal oesophageal compression

The abdominal oesophagus is exposed to positive pressure within the abdomen. This has a compressive effect on the distal oesophagus/LOS, with a shorter length correlating with more frequent reflux.⁵⁹ This is particularly important with increasing age and a recumbent position. The phreno-oesophageal ligament is a prolongation of abdominal fascia originating from the abdominal surface of the diaphragm, which anchors the oesophagus. As it approaches the oesophagus, it decussates into upper and lower leaves. The former inserts just above the squamocolumnar junction, with the latter inserting a few centimetres below, but is less well defined and often absent. The upper leaf inserts into the submucosa and intramuscular septae. This fibromuscular anchor is not absolute, allowing the oesophagus to slide 2 cm cranially when swallowing and, crucially, up to 4 cm during TLOSRs.^60,⁶¹ Whether the oesophagus herniates into the thorax under physiological conditions is unlikely, however, as the diaphragmatic hiatus moves almost as far cranially. This arrangement serves to keep the distal oesophagus within this positive pressure environment, ensuring that any increases in intra-abdominal pressure are transmitted to the LOS.⁶² Anatomical variations in strength and height of insertion of the phreno-oesophageal ligament presumably influence the length of oesophagus to which this applies. Disruption of the ligament predisposes to sliding hiatus hernias, although the hernia sac will still envelop the LOS within the physiological (but not anatomical) abdomen.

Other mechanical barriers

The acute angle of the gastro-oesophageal junction may represent a partial barrier to reflux, functioning as a ‘flap valve’ (the cardio-oesophageal angle of His). This angle disappears after death, suggesting that the angle is maintained by tonic contraction of the oblique sling fibres of the cardia.⁶³ This ‘valve’ lies below the physiological high-pressure zone determined with radiological contrast, and so its contribution is therefore limited. The mucosal rosette of the gastro-oesophageal junction is also reported to act as a partial barrier.

Oesophageal mucosal acid defence mechanisms

The main defence mechanisms comprise oesophageal clearance and tissue resistance. Reflex peristalsis is induced by oesophageal acid receptors and aided by gravity, both of which are impaired, particularly during sleep.⁶⁴

The oesophagus has a number of further protective mechanisms, both intrinsic and extrinsic, termed tissue resistance. These are such that continuous in vivo exposure of oesophageal epithelium to hydrochloric acid and pepsin does not cause damage for 1 hour.⁶⁵ Mechanisms are classed as pre-epithelial, epithelial and post-epithelial. Pre-epithelial resistance is conferred by the oesophageal buffer layer, augmented by saliva. In contrast to the gastroduodenal buffer layer, the (non-Barrett’s) oesophageal epithelium lacks a mucous gel barrier and the ability to secrete bicarbonate. However, the buffer needs only to raise pH above 3 to prevent pepsin-induced damage.⁶⁶

This buffer is augmented by the neutralising properties of saliva. Swallowing saliva contributes to approximately 5% of acid clearance by neutralising acid remaining after peristaltic clearance.⁶⁷ It has a pH of 7.02,⁶⁸ but the solubility of its mucins means that it cannot contribute permanently to the oesophageal buffer.⁶⁹ Consequently, when salivary production and primary oesophageal peristalsis cease at night, the oesophagus is particularly vulnerable.⁷⁰

The epithelium itself possesses a combination of properties: a protective transmural electrochemical gradient, tight cell junctions, pH-dependent cation channels and intracellular buffers. Post-epithelial characteristics include adaptive perfusion and epithelial repair. For refluxed acid to cause epithelial cell death, hydrogen ions must enter the epithelial cytosol in sufficient quantities and for long enough to disrupt cytosol homeostasis and induce apoptosis/necrosis. One mechanism is transit of acid into the intercellular space, disrupting cell junctions and increasing permeability into the space, resulting in greater levels of acid. However, acid levels below that required to cause cellular damage may still be symptomatic. Nociceptors underlying heartburn can be found within the intercellular space within three cell layers of the oesophageal lumen,⁷¹ thus helping to explain the existence of heartburn without frank oesophagitis. Quite why pain and oesophagitis may be independent is not clear. Potentially this represents visceral hypersensitivity,⁷² or a reduction in acid sensitivity due to chronic reflux acid.⁷³

Risk factors for reflux

The complexity of the body’s control of swallowing and reflux means that there are numerous opportunities for disruption (and therefore pharmacological and surgical intervention). Pathological reflux is caused by excessive frequency of TLOSRs, inadequate high-pressure zone resting pressure, and inability of the LOS and diaphragmatic sphincter to compensate for increases in abdominal pressure. A number of factors have been implicated in these mechanisms (Table 12.1).

Table 12.1

Risk factors for GORD

Inherited factors

A small number of studies have demonstrated the role of a positive family history. A parental history of GORD conferred an odds ratio (OR) of 1.5 in one study,⁷⁴ with an OR of 2.6 when symptoms are extended to that of an immediate relative.⁷⁵ In the latter study, no association was found with GORD prevalence between spouses, implying genetic effects to be greater than shared environmental effects (although this has been disputed).⁷⁶ Greater concordance has also been demonstrated between monozygotic than dizygotic twins.⁷⁴

Demographic factors

No association between sex and GORD has been demonstrated. Findings assessing age have been equivocal; both European and US studies assessing symptomatology have found contradictory results. Overall, a marginally increased risk with increasing age seems likely (OR 1.1)⁷⁷ up to the age of 55, and possibly beyond.⁷⁸

Lifestyle factors

Longitudinal studies show that smoking increases the risk of GORD (OR 1.1–2.6)^77,⁷⁸ due to a chronic reduction in LOS pressure, combined with acute provocation of reflux (via coughing/deep inspiration). Particular foods and drinks are often felt to predispose to reflux episodes, although a Swedish case–control study of over 1000 subjects found no association between an extensive range of foodstuffs (including chocolate, coffee, onions and acidic fruits) and chronic symptoms of reflux (although the authors admit this may be due to avoidance in sufferers).⁷⁹ The study also found no correlation between portion size and eating late in the evening (albeit with the same caveat). Coffee is consistently cited as a factor, although one not demonstrated by additional studies.⁷⁴ Any underlying mechanism is believed to be due to caffeine-mediated inhibition of phosphodiesterase, inducing LOS relaxation.⁸⁰ Alcohol is generally agreed to lead to reflux – the US study above⁷⁸ found an OR of 1.8 between alcohol consumption and GORD. Again, this is thought to be via a reduction in LOS pressure, combined with direct irritation.⁸⁰

Obesity has been repeatedy shown to correlate with GORD, with ORs between 1.3 ⁷⁸ and 2.8.⁷⁷ A meta-analysis of nine studies found an OR of 1.4 for a body mass index (BMI) of 25–30, and 1.9 for a BMI greater than 30.⁸¹ Multiple mechanisms have been proposed: impaired LOS pressure, increased intra-abdominal pressure and delayed gastric emptying.⁸¹ A combination of GORD and obesity is a potent risk factor for oesophageal adenocarcinoma.⁸² The effect of weight loss on symptoms varies between studies, having been shown to improve symptoms⁸³ or have no effect.⁸⁴ Pregnancy induces progesterone-mediated LOS relaxation, in addition to increasing abdominal pressure.

Medical factors

GORD has been associated with a number of gastrointestinal and extragastrointestinal conditions, including irritable bowel syndrome, peptic ulceration, angina,⁷⁸ psychosomatic symptoms, anxiety and depression.^75,⁸⁵ Anticholinergic medications increase risk (OR 1.5),⁷⁴ but non-steroidal anti- inflammatory drugs do not.

Gastric function can influence GORD via a number of mechanisms. Overall, Helicobacter pylori seems to protect against GORD and its complications, via atrophic gastritis.⁸⁶ A Japanese study found H. pylori to be present in 71% of controls, 30% of those with oesophagitis and almost 0% of those with Barrett’s.⁸⁷ However, this relationship is not simple, and is dependent upon site of infection, extent and strain type. Indeed, antral infection induces acid hypersecretion and therefore may increase GORD. Helicobacter pylori eradication might therefore worsen GORD rates – however, associations with gastric carcinoma and ulceration are strong, and in practice eradication does not hamper treatment of oesophagitis with proton-pump inhibitors.⁸⁸ The hypersecretion of acid seen in Zollinger–Ellison syndrome is unsurprisingly associated with higher rates of GORD and oesophagitis;⁸⁹ however, supraphysiological levels of acid secretion in those with ‘normal’ GORD has not been demonstrated.⁹⁰ Delayed gastric emptying seems a plausible factor in GORD, and a recent study reported a prevalence of 26% in those with GORD.⁹¹ The consequent distension hypothetically may induce more TLOSRs and acid secretion, although this is unproven.

Hiatus hernia

For the reasons outlined above, sliding hiatus hernia is a strong risk factor for GORD. A multicentric study found the endoscopic prevalence of hiatus hernia overall to be 5.8%, rising to 32% in those with oesophagitis. One radiological study of those with oesophagitis found a much higher rate of 90%.⁹² Two-thirds of those with a hiatus hernia have GORD, and oesophagitis is more common.⁹³ The underlying mechanisms involve both an increase in duration and frequency of reflux episodes⁹⁴ (Fig. 12.3).

Figure 12.3 High-resolution manometry showing a single high-pressure zone in the lower oesophagus crossing the diaphragm on the left (LOS). In this spatiotemporal plot higher pressures are presented in the yellow–red spectrum and lower pressures in the green–blue spectrum. On the right there is separation of the lower oesophageal high-pressure zone (iLOS) and the high-pressure zone created by the diaphragmatic crura (cLOS) suggestive of a transient hiatus hernia. The longitudinal red and yellow zone on the right demonstrates the propagation of a peristaltic wave down the oesophagus. LOS, lower oesophageal sphincter; cLOS, crural LOS; iLOS, intrinsic LOS; UOS, upper oesophageal sphincter. Reproduced from Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008; 57(3):405–23. With permission from BMJ Publishing Group Ltd.

Hiatus hernia is a strong risk factor for GORD, present in 32% of those with oesophagitis;⁹² two-thirds of those with a hernia have GORD.⁹³

Oesophageal dysmotility and GORD: cause or effect?

Oesophageal dysmotility (as distinct from inappropriate TLOSR and low resting LOS) is a common finding in GORD. This exists in many guises, but predominantly that of hypomotility and ineffective peristalsis. It remains unclear whether dysmotility predisposes to GORD, whether GORD predisposes to dysmotility, or indeed to what extent dysmotility is responsible for symptoms.

As discussed above, peristaltic acid clearance is an integral component of the body’s antireflux mechanism. Surrogate radiological and manometric simulation using barium fluoroscopy in one study demonstrated complete clearance with a single effective peristaltic wave greater than 20 mmHg.⁹⁴ In 1968, Booth et al.⁹⁵ described their standard acid clearance test, having demonstrated that those with GORD required more swallows to clear acid than controls. However, whilst subsequent studies have confirmed this, the utility of this test is very limited by both poor sensitivity and specificity⁹⁶ for assessing GORD. The potential role of reduced or delayed acid clearance in GORD as a function of dysmotility is plausible and supported by a number of studies. Pathological reflux episodes last longer than physiological episodes, and this has been suggested to be due to impaired acid clearance. Corroborating evidence by DeMeester et al.⁹⁷ expanded upon the different patterns of reflux seen between cases and controls. The former experienced longer nocturnal supine episodes, compared with the more physiological transient upright episodes in the latter. These nocturnal episodes are due to reduced peristaltic acid clearance,⁹⁷ both in terms of reduced frequency and probably quality of peristaltic waves,^98,⁹⁹ compounded by a lack of gravitational clearance.¹⁰⁰ Elevating the head of the bed compensates partially, and improves both acid clearance and microscopic oesophagitis.¹⁰¹

Pathological reflux differs from physiological reflux. In the former, episodes are primarily supine or nocturnal and last longer. This is probably due in part to impaired acid clearance (both quality and quantity of protective peristalsis).98–100

In one of the first such studies, Olsen and Schlegel ¹⁰² assessed motility in 50 subjects with oesophagitis, finding normal activity in 28%, incoordinated peristalsis in 32%, hypotensive peristalsis in 37% and complete motor failure in 8%. Progressively worse motility was seen with worsening degrees of oesophagitis. In a separate study, 48% of those with severe oesophagitis displayed peristaltic dysfunction.¹⁰³ A later study supported this, finding non-specific dysmotility or aperistalsis in 64% of those with benign peptic stricutres, compared to 32% of those with non-stricturing GORD.¹⁰⁴

It is highly relevant, of course, that oesophageal sensitivity to acid is often reduced,¹ and this combination of motor and sensory dysfunction may lead to particularly severe acid exposure, with resultant significant mucosal damage.¹⁰⁵ Abnormal motility has been found in 46% of those with Barrett’s oesophagus, with a longer segment correlating with worse motility.¹⁰⁶ These findings have recently been corroborated in a 1000-patient (with proven GORD) study by Diener et al.¹⁰⁷ Peristalsis was normal in 56%, ineffective (hypotensive or incoordinated) in 21% and non-specifically abnormal in 23%. Those with ineffective peristalsis had worse symptoms, slower acid clearance and greater mucosal injury.

Whether this dysmotility with consequent delayed acid clearance is a primary phenomenon or occurs secondary to reflux-induced damage is unclear. Eriksen et al.,¹⁰⁸ using the solid bolus oesophageal egg transit test, compared the transit times of those with GORD and controls. Whilst delayed transit times correlated with the frequency of prolonged reflux episodes, no correlation was demonstrated between symptoms and oesophagitis and motility. The study authors argued that this dysmotility may be a primary phenomenon. Contradictory evidence exists in the form of improvements in oesophageal motility seen after antireflux surgery.¹⁰⁹ Other studies have found no such improvements, despite objective improvements in reflux, suggesting that either reflux-induced dysmotility may be permanent or it is a primary phenomenon.^110,¹¹¹ Perhaps both may be true, with reflux-induced dysmotility perpetuating a vicious cycle of impaired peristalsis and LOS function.

Certainly, molecular mechanisms exist for this. Inflammation has been shown to impair both oesophageal motility and LOS function. Proinflammatory cytokines such as interleukin (IL)-1B, IL-6 and IL-8 have been shown to inhibit in vitro motility.¹¹² IL-1B induces prostaglandin E2 (PGE2)-mediated relaxation of the LOS,¹¹³ and IL-6 induces PGE2- and platelet activating factor-mediated relaxation of the LOS.¹¹⁴ Inflammation also increases nitric oxide and consequent inhibition of motility.¹¹⁵

Dysmotility is common in GORD, present in 44%. Those with ineffective peristalsis have worse symptoms, acid clearance and mucosal damage.¹⁰⁷ As motility worsens, so does severity of oesophagitis and Barrett’s.^103,¹⁰⁵ What is not clear is whether dysmotility causes, results from or is synergistic with GORD.

Role of duodenogastric reflux

Whilst gastric acid (potentiated by pepsin) is the predominant source of inflammation and symptoms, the role of non-acidic duodenogastric reflux is not as clear cut. Observationally, oesophagitis is more common in those with both acid and duodenal reflux, compared with acid alone,¹¹⁶ and duodenal reflux is more frequently seen in those with peptic strictures and Barrett’s.¹¹⁷ Bile acids contribute to the sequence of oesophagitis, metaplasia and dysplasia, and with progressively severe disease (from endoscopy-negative reflux, to simple oesophagitis, to peptic stricturing, and on to Barrett’s metaplasia and finally dysplasia) so the relative proportion of bile acids in the refluxate increases.¹¹⁸ Despite this, abolition of acid seems adequate to prevent progression.¹¹⁹ Bile acids cause pain independently of acid,¹²⁰ but the two are probably synergistic, with biliary reflux the lesser culprit.^121,¹²² Duodenogastric reflux is difficult to assess, but can be detected using bilirubin as a surrogate (via spectrophotometry).¹²³ This topic is being further assessed by the use of impedance techniques.

Duodenogastric reflux is synergistic with acid reflux, with increasing levels of bilious reflux correlating with worsening oesophagitis.¹¹⁸ However, abolition of acid alone is usually adequate. With advances in impedance techniques, the role of duodenogastric reflux should be better delineated.

Investigation and diagnosis

The oesophagus is readily accessible, and so a large array of investigations have been developed. Flexible endoscopy and simple contrast radiology are widely available, with more specialist investigations such as physiology and manometry confined largely to tertiary centres, and yet more specialist techniques (such as aspiration studies) restricted to research.

Symptomatic diagnosis

Symptoms alone have limited utility. Whilst heartburn and regurgitation are typical symptoms and highly suggestive of GORD, their utility is limited by subjectivity and lack of evidence comparing them with investigations. One systematic review concluded that reflux symptoms had limited sensitivity (30–76%) and specificity (62–96%) in diagnosing oesophagitis.¹¹⁹ One meta-analysis reported response of chest pain to proton-pump inhibitors to be suggestive of GORD, but significantly less specific (74%) and sensitive (80%) than 24-hour pH studies.¹²⁰ A number of standardised symptom questionnaires have been developed to aid diagnosis, but these are limited in terms of their diagnostic validity.¹²¹ They may have a greater role to play in assessing and standardising functional end-points of treatment (particularly in clinical trials), such as the Reflux Questionnaire (ReQuest).¹²²

Symptoms have limited diagnostic utility, with or without oesophagitis.¹¹⁹ Symptomatic response to proton-pump inhibitors is more useful, but still significantly less specific (74%) and sensitive (80%) than 24-hour pH studies.¹²⁰

Endoscopy

Flexible endoscopy is typically first line for investigation of oesophageal symptoms. The current UK National Institute for Health and Clinical Excellence (NICE) guidelines endorsed by the British Society of Gastroenterology suggest urgent endoscopy for patients of any age with dyspeptic symptoms plus any of: chronic gastrointestinal bleeding, progressive unintentional weight loss, progressive dysphagia, persistent vomiting, iron deficiency anaemia, epigastric mass or suspicious contrast swallow radiology. In those aged 55 years or more, unexplained and persistent dyspepsia alone mandates endoscopy.¹²¹ In reality, endoscopy is used much more liberally. It allows diagnosis via inspection of the mucosa, and biopsy for histology, as well as various therapeutic interventions. Clues towards underlying dysmotility may be apparent, such as a dilated oesophagus, the presence of food residue and diverticula. Oesophagitis and Barrett’s mucosa indicate reflux, but a subset of those with GORD will have normal endoscopies. Consequently, whilst the sensitivity and specificity of diagnosing mucosal lesions is high (and assessment of oesophagitis is reliable between observers),¹²² those for diagnosing GORD are low relative to 24-hour pH monitoring. The roles of newer techniques (such as high-resolution, narrow-band and chromendoscopy) have yet to be determined.

Contrast radiology

Contrast radiology, whilst lacking the ability to biopsy and perform therapuetic procedures, has an important complementary role to endoscopy. A double-contrast barium swallow is highly sensitive at diagnosing significant complications of GORD (mucosal abnormalities such as strictures or malignancy).¹²³ It will also demonstrate associated anatomical abnormalities such as hiatus hernias and diverticula, and may give useful information as to motility via the presence and quality of peristalsis. In particular it may demonstrate the classical appearances of achalasia or diffuse oesophageal spasm (‘corkscrew oesophagus’). However, the diagnostic ability of contrast radiology for GORD is limited; radiological features of finely nodular or granular mucosa may be visualised, or frank reflux may occur during the study. One review found radiological evidence of reflux in just 35% of symptomatic patients.¹²⁴ One study (n = 112) compared barium swallow to 24-hour pH monitoring, concluding that just 30% of those with pH monitoring-diagnosed GORD had radiological abnormalities.¹²⁵ This poor sensitivity may be somewhat improved by provocative manoeuvres (such as the water siphon test).

Contrast radiology has a limited role in diagnosing GORD, with abnormal studies in just 35% of those with symptoms ¹²⁴ and 30% of those with pH.¹²⁵ However, it is much more sensitive for structural complications of GORD and may demonstrate alternate diagnoses such as achalasia.¹²³

pH studies

Since the original description in 1969 by Spencer, advances in nasogastric pH catheters, portable digital recorders and computer software have allowed 24-hour ambulatory pH studies to become widely available. Of great importance is the ability of the patient to mark symptoms by pressing a button, allowing correlation of symptoms with reflux episodes (Fig. 12.4). Computer analysis of the resultant data generates multiple variables, which are then compared to those of controls (Table 12.1). Indications for 24-hour pH monitoring include refractory typical symptoms, assessment of atypical symptoms and suspected motility disorders (as pH studies are usually combined with manometry), and as such are a prerequesite when considering anti-reflux surgery.¹²⁴

Figure 12.4 A 24-hour pH study showing excessive acid reflux in a patient with Barrett’s oesophagus. Note the correlation of the patient’s pain with acid in the oesophagus.

Positioning of the pH probe 5 cm above the top of the LOS is crucial. Too low and the probe will dip into the stomach on swallowing, too high and reflux will be underestimated. As distance from nose to LOS is variable, manometry is required to determine location. When the probe registers a pH less than 4, it records a reflux episode lasting usually until the pH rises above 5 (or 4 in some laboratories). One limitation is that a prolonged reflux episode may be a single episode (implying poor clearance) or multiple overlapping transient episodes. In the case of doubt (e.g. whether the probe is too low and generating a falsely positive reading), a second probe can be positioned cranially to the first. Multiple probes may also be placed higher to assess more proximal symptoms (such as chronic cough).

Twenty-four-hour studies are considered the gold standard, although there is some evidence that shorter studies may be representative and better tolerated.¹²⁶ Antireflux medications are usually stopped to increase diagnostic yield,¹²⁷ although performing the test whilst on treatment may be useful in assessing refractory symptoms. Patients should take a normal diet, but complete a food and drink diary to allow elimination of acidic foodstuffs from the analysis.

Parameters generated include the number of reflux episodes, those that are prolonged beyond 5 minutes and the total reflux time (expressed as a percentage of the study time). This should be less than 5% of a 24-hour period.¹²⁸ These parameters can be subdivided into periods, such as when supine or upright. These may then be used to generate composite scores with reference to controls. The most commonly used is the DeMeester score. This combines the parameters in Tables 12.2 and 12.3 (number of episodes, number over 5 minutes and longest episode, with total reflux, upright and supine times (weighted towards supine)).¹²⁹ A normal value is < 14.72.

Table 12.2

Findings of pH study conducted on patient illustrated in Fig. 12.4

Table 12.3

Scores according to Johnson and DeMeester for pH < 4 for findings in Table 12.1 (study of patient illustrated in Fig. 12.4)

However, the presence of increased reflux and symptoms does not prove causality as the mere presence of acid in the oesophagus often correlates poorly with symptoms and inflammation. Correlation of episodes with symptoms is therefore central to diagnosis. A patient with both an abnormal study and symptoms does not necessarily have GORD if these symptoms occur in the absence of a reflux episode. In contrast, the patient with a normal study but typical symptoms coinciding with proven reflux episodes may well have GORD. This is further complicated by the controversy regarding performing studies on or off medical treatment. An abnormal pH study off treatment implies reflux, yet if treatment does not improve symptoms, the relevance of this reflux is questionable. To this end, three symptom-reflux values are usually generated (with a reflux episode generally considered to cause symptoms if occurring in the preceding 2 minutes).

Symptom Index (SI) is the proportion of symptoms relating to reflux:

An SI of 50% or more is usually considered to be positive, although with the caveats that it does not take account of the frequency or severity of symptoms. Consequently, in those with frequent reflux episodes or infrequent symptoms these may coincide with symptoms purely by chance.¹³⁰ Despite this, a positive SI has been demonstrated to correlate with greatest improvement with proton-pump inhibitor acid suppression.¹³¹

The Symptom Sensitivity Index (SSI) takes into account the number of reflux episodes:

An SSI ≥ 10% is considered positive, and strengthening evidence of GORD.

The Symptom Association Probability (SAP) was introduced by Weuston and colleagues, and represents a more complex probability calculation. This aims to calculate the probability that the association of reflux and symptoms is not due to chance. This is performed by generating a 2 × 2 contingency table analysing each 2-minute segment of the study period. An SAP > 95% represents a P value < 0.05 and so is considered positive. Whilst the caveat of probability should not be forgotten, it has been shown to have (limited) success in predicting successful response to both proton-pump inhibitors ¹³² and antireflux surgery.¹³³

The Ghillebert Probability Estimate (GPE) was similarly developed to assess the probability of symptoms occurring by chance. It uses a binomial formula, inputting the number of symptom episodes, the number occurring within 2 minutes of demonstrated reflux, and the individual probability of an episode of pain coinciding with reflux.¹³⁴

The concordance of SI, SAP and GPE was assessed in a recent study of 772 subjects. SAP and GPE were extremely concordant, with major discordance in 2.8%. GPE underestimated symptom association, whereas SAP overestimated. This discordance increased with greater frequency of symptoms and total reflux time. Similarly, SI became discordant with SAP when symptoms were less frequent than two or greater than 18. The authors concluded that SAP and GPE were interchangable.¹³⁰ Taghavi et al.,¹³² using 50% reduction in heartburn with proton-pump inhibitor treatment as an end-point, calculated positive predictive vaules of SI (73%), SSI (81%) and SAP (79%). The imperfect diagnostic and predictive characteristics of these indices reinforce the need to interpret pH studies within the context of symptoms, endoscopic and radiological findings, manometry and any response to acid suppression. This is especially so when considering surgical intervention.

Twenty-four-hour pH studies are the traditional gold standard of diagnosis,¹³⁵ although their sensitivity and specificity are imperfect, as are derivative symptom-reflux values. Consequently, it remains crucial to interpret them within their clinical, endoscopic and manometric contexts; this is particularly so when considering antireflux surgery.

Wireless pH monitoring

A major drawback to catheter-based pH studies is the catheter; this may preclude testing in the 5–10% who are intolerant,⁷³ or inhibit the ability to eat or function normally in the remainder (due to discomfort or social embarrassment), possibly causing a false-negative test. Wireless capsule-based systems have been designed to avoid this. The second major drawback is reproducibility; significant day-to-day variation occurs (up to the order of 3.2),¹³⁶ with overall reproducibility of 70–80%.¹³⁷

The Bravo® pH system (Medtronic, Minneapolis, MN, USA) is a wireless capsule system that may avoid both disadvantages (Fig. 12.5). It consists of a 26 mm × 6 mm capsule with an antimony electrode and radiofrequency transmitter, which is placed endoscopically 6 cm above the z-line (the high pressure zone being 1–1.5 cm above the squamocolumnar junction). Data are transmitted to a recorder attached to the patient’s belt. It is better tolerated than conventional catheter-based studies¹³⁸ and allows prolonged measurement (up to 96 hours), which may be particularly useful in those with intermittent symptoms.¹³⁹ One study found the Bravo® system to under-record acid exposure, although it concluded that this did not affect sensitivity provided it was allowed for.¹⁴⁰ It has a particularly useful role in those intolerant of a catheter (and as such is recommended by NICE for this subgroup;¹⁴¹ the largest study to date successfully used the Bravo® system in 129 of 134 (96%) patients who failed a catheter system.¹⁴² The authors also reported less oropharyngeal discomfort, dysphagia and chest pain.

Figure 12.5 Bravo® delivery system and capsule. The delivery system is inserted in the same way as a nasogastric tube, although it is usually delivered orally. Markings on the side depict the distance from the incisors. The capsule is deployed 6 cm above the anatomical z-line (or 5 cm above the proximal LOS high-pressure zone). The delivery system is then retracted and the receiver is synchronised. It remains attached to the patient (via belt clip or shoulder pouch) for 48 hours at least. Capsules all fall off inevitably within 10 days (usually 5–7). Complications requiring early removal are almost unheard of. Reprinted by permission from Macmillan Publishers Ltd: Pandolfino JE, Richter JE, Ours T et al. Ambulatory oesophageal pH monitoring using a wireless system. Am J Gastroenterol 2003; 98 (4):740–9, copyright 2003.

There are a number of disadvantages, however. Foremost is that of cost. A very small minority develop pain on implantation of the capsule, requiring removal. Furthermore, one small study reported that 25% of patients experienced significant hypercontractillity on placement of the capsule, leading to chest pain in six of 40.¹⁴³

Oesophageal impedance monitoring

Multichannel intraluminal impedance (MII) was described by Silny in 1991 ¹⁴⁴ and represents a novel direction in monitoring of refluxate. Impedance is the opposite of current flow, measured by detecting resistance to alternating current. This allows detection and differentiation of gas and liquid reflux (irrespective of pH). Paired electrodes are placed in the oesophageal lumen, separated by a non-conducting catheter (Fig. 12.6). The circuit is completed by ions within the oesophageal mucosa and lumen, the availability of which varies with luminal content. When empty, ionic conduction is relatively stable. The presence of liquid (either swallowed or refluxing), with its greater ionic concentration, improves conduction and therefore impedance drops. Conversely, the presence of air reduces conduction and increases impedance. Impedance for both returns to baseline when the refluxate has been cleared. Multiple electrodes along the catheter determine the direction of flow. Sensitivity is high, and boluses of just 1 mL can be detected.¹⁴⁵

Figure 12.6 Example of impedance catheter. This one has six impedance sensors and two pH sensors. Reprinted by permission from Macmillan Publishers Ltd: Sifrim D, Blondeau K. Technology insight: the role of impedance testing for esophageal disorders. Nat Clin Pract Gastroenterol Hepatol 2006; 3(4):210–9, copyright 2006.

MII can therefore determine the following:

• whether the bolus is swallowed or refluxed;

• how long it takes to be swallowed or cleared;

• the velocity of transit;

• whether the bolus is liquid or gas;

• how proximally reflux extends;

• whether superimposed episodes of reflux occur (re-reflux).

Importantly, MII cannot determine the volume of refluxate.

The combination of MII and pH monitoring is easily achieved with a nasogastric catheter. MII–pH can be used to characterise the following for reflux episodes:

• nature (i.e. gas, liquid or mixed);

• acidity (acidic, weakly acidic or weakly alkaline);

• height (of reflux episode);

• the presence of a bolus;

• acid clearance;

• superimposed reflux.

This more comprehensive assessment allows a more sensitive approach to reflux, correlating symptoms beyond the somewhat arbitrary threshold of a pH of 4 for reflux.¹⁴⁶ This is important for both gastroduodenal reflux and postprandial reflux (which may be non-acidic yet still symptomatic). It also allows consideration of the role of disturbances of bolus transport in oesophageal symptoms. It is reproducible¹⁴⁷ and, consequently, MII–pH represents the most sensitive investigation for GORD, potentially increasing the detection of pathological reflux by a factor of four^148,¹⁴⁹ and improving symptom correlation by 10–20%.¹⁵⁰ It has a particularly useful role in investigating the troublesome subgroup increasingly referred to surgeons: those with symptoms despite acid suppression. This group are often considered not to have GORD as determined by conventional pH studies, yet may be shown to have symptoms correlating with non-acidic or weakly acidic reflux.¹⁵¹ Consequently, a negative MII–pH study is a more discriminatory tool in the selection of patients who will benefit from antireflux surgery.¹⁴⁸

The combination of multichannel intraluminal impedance and pH monitoring is the most powerful diagnostic test for GORD, although it is not readily available. It is up to 400% more sensitive than pH studies alone,^148,¹⁴⁹ with 10–20% greater symptom correlation.¹⁵⁰

Manometry

Oesophageal manometry is the gold standard of assessment tools for motor function. Whilst there are no diagnostic criteria for GORD, manometry has a number of important functions. The role of dysmotility in GORD has been discussed, but it is important to exclude those with reflux-type symptoms due to a formal dysmotility disorder (in whom treatment will be entirely different). The typical example is achalasia; oesophageal stasis, with bacterial fermentation and production of lactic acid, may cause heartburn, odynophagia and volume reflux indistinguishable from GORD. However, fundoplication will be disastrous. Manometry allows the position of the high-pressure zone to be determined, and therefore accurate placement of pH catheters. It also allows detection of those with GORD and major defects in peristalsis, which may impair surgical outcomes.

Standard static manometry

This measures a number of parameters. Multiple pressure sensors can be used to map and characterise peristalsis, and determine the resting and functional pressures of the oesophageal sphincters. Consequently, circumferential contraction, peristaltic wave duration and velocity can be determined. Normal peristaltic sequences (as previously discussed) consist of upper and lower oesophageal sphincter relaxation, followed by segmental contraction of adjacent oesophageal body segments, coordinated to give a smooth peristaltic wave. Contractions typically last for up to 6 seconds (in individual segments) and can reach pressures of 180 mmHg distally, with an overall velocity of 5 cm/s.¹⁵¹

There are two major options available: intraluminal solid-state transducers versus water-perfused assemblies connected to external transducers. Ultimately both are roughly equivalent, with the exceptions of pharyngeal pressures (best assessed with solid-state transducers), the ability to use larger numbers of recording points (perfused systems) and better assessment of the LOS (sleeve-perfused systems). Perhaps most significantly, perfused systems are cheaper.

Measurements are taken using a manometry catheter, with multiple measurement ports. This is passed nasogastrically, then withdrawn from the stomach via the LOS, with the multiple ports used to estimate resting sphincter pressure and length. The ports are then positioned within the oesophageal body (with at least three placed 5 cm apart, although typically five to eight are used). Motility is then assessed using the standard 10 wet swallow test, with amplitudes, coordination and velocity compared to control values. Abnormal contractions (either simultaneous or non-peristaltic) can also be characterised. Water-perfused systems can be combined with a sleeve device that straddles the LOS, to allow for axial movement of the sphincter.

Clearly, this limited assessment has a number of caveats. Firstly, measuring just 10 of the approximately 1000–2000 peristaltic swallows occurring per day means that intermittent or subtle dysmotility may be missed. Secondly, the experimental conditions are different to those of normal swallows; small-volume water swallows may not trigger symptoms occurring during normal activity. This is particularly true of GORD (with often postprandial symptoms triggered by physical activity or position). Thirdly, anatomical resolution is limited: focal anatomical or physiological abnormalities may lie between measurement ports and be missed. In addition, the presence of a hiatus hernia may distort the position of the LOS and affect its measurement. However, the availability and cost-effectiveness of standard manometry is such that it is the commonest investigation used in assessing motility.¹⁵² Although diagnosis may be limited to characteristic disorders such as achalasia and diffuse oesophageal spasm (with the rest characterised as inneffective or non-specific dysmotility), this may be adequate for the purposes of GORD assessment.

High-resolution manometry (HRM)

To circumvent some of these limitations, Clouse and Staiano developed HRM.^153,¹⁵⁴ A larger number of more closely spaced ports has become possible with the development of both micromanometric solid-state and perfused transducers. Up to 36 pressure sensors can be used to generate a three-dimensional representation, combining time, position and amplitude with greatly increased spatial resolution. This can be represented as a two-dimensional plot, with pressure represented with a colour spectrum (Fig. 12.7 and 12.8), and allows better characterisation of peristalsis.¹⁵² This has three specific advantages within the assessment of GORD: firstly, associated or causative dysmotility can be better defined; secondly, acid clearance can be better predicted; and thirdly the LOS can be better assessed (in both function and anatomy; Table 12.4).¹⁵² A sophisticated development is that of the ‘e-sleeve’. This is a software emulation of the sleeve device of standard pull-through manometry. This allows better characterisation of the LOS and also more rapid positioning of the catheter array. Furthermore, HRM can be used more easily to assess the dynamics of more frequent liquid swallows, and also solids, which may improve the sensitivity of GORD assessment (by being more physiologically representative and challenging).^153–155 Manometry can be combined with MII to provide a valuable functional perspective.¹⁵⁶

Table 12.4

Comparison between standard and high-resolution manometry

LOS, lower oesophageal sphincter; UOS, upper oesophageal sphincter.

Reproduced from Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008; 57(3):405–23. With permission from BMJ Publishing Group Ltd.