SymptomS and SignS

Symptoms and signs of upper gastrointestinal diseasederek gillen

Kenneth E L mcColl

Abstracta century ago, Lord moynihan suggested that the underlying cause of dys-­

pepsia could be discerned by symptoms alone. Subsequent studies have

suggested that, unfortunately, this is not the case, since the symptoms as-­

sociated with upper gastrointestinal (gi) disease lack both sensitivity and

specificity. ‘Classic’ symptoms of reflux disease (such as heartburn and re-­

gurgitation), peptic ulcer disease (such as post-­prandial epigastric pain) or

of functional dyspepsia (such as bloating) have been shown in a number

of studies to be poor guides to the underlying diagnosis. However, there is

an evidence base to support the use of ‘alarm’ symptoms, such as weight

loss and dysphagia, in an effort to target limited investigative resources

to upper gi cancer. Finally, careful consideration must always be given to

possible extraluminal causes of apparently upper gi symptoms, of which

unrecognized ischaemic heart disease is perhaps the most important.

Keywords alarm symptoms; dyspepsia; gastro-­oesophageal reflux disease;

non-­ulcer dyspepsia; peptic ulcer

In 1905, Moynihan suggested that patients presenting with dys-pepsia could be diagnosed solely on the basis of their symptoms.1 In the modern era, it is accepted that things are somewhat more complicated. As we shall see, the majority of upper gastrointes-tinal (GI) symptoms lack specificity and sensitivity and therefore correlate poorly with any particular underlying pathology.

‘Dyspepsia’ is a word that is often used to describe a range of upper GI symptoms. However, there are two different definitions in clinical use for this term. The first is as a general umbrella term which can essentially encompass the full constellation of upper GI symptoms. The second is much more specific, with dyspepsia correlating solely with pain or discomfort centred in the epigas-trium. This much more restrictive definition is often referred to as ‘Rome II’ dyspepsia, since it was agreed by a working group in functional GI disorders meeting in that city for a second time.2 This more focused definition was required for clinical research-ers. Clearly, the broader umbrella definition would make clinical

Derek Gillen MD FRCP(UK) is a Consultant Gastroenterologist in the

University Department of Medicine and Therapeutics of West Glasgow

Hospitals, Glasgow, UK. He is a graduate of the University of Glasgow

and his main research interest is the pathophysiology of upper GI

disease. Competing interests: none declared.

Kenneth McColl MD FMedSci is the Professor of Gastroenterology at

the University of Glasgow, Glasgow, UK. Competing interests:

none declared.

mEdiCinE 35:3 13

trials almost impossible to interpret, since otherwise one might be comparing the effects of a treatment on one patient’s bloat-ing with another patient’s heartburn. However, this evidently means that one must be careful in extrapolating the results of clinical trials which use this restricted definition to an individual patient’s symptoms.

In the following article, we shall review the ‘classic’ symp-toms often associated with the main upper GI disease processes. We shall also address the value of these symptoms/symptom clusters in elucidating underlying disease processes.

Gastro-oesophageal reflux disease (GORD)

DefinitionGastro-oesophageal reflux disease (GORD) is defined as symp-toms or complications arising from the reflux of gastric or duodenal contents into the oesophagus.3 It comprises a wide spec-trum of disorders. These range from symptoms associated with physiological amounts of reflux due to oesophageal hypersens-itivity, through to Barrett’s oesophagus, in which there is usually severe reflux, but sometimes few or no associated symptoms.

Symptoms of GORDA number of symptoms have been reported more frequently in patients with GORD versus healthy controls (Table 1). Further evidence that these symptoms are due to underlying acid reflux is their resolution in studies in which gastric acid is suppressed with effective acid inhibitory therapy.

The symptoms which have been classically associated with GORD include those detailed below.

Heartburn: this is a common symptom, with perhaps 4–9% of adults experiencing it on a daily basis and around 20% on a weekly basis.4 Patients usually describe it as a retrosternal sensa-tion of burning discomfort or pain. It is commonly post-prandial and exacerbated by lying flat or bending over.

Regurgitation: patients who suffer from this reflux-related symptom complain of the effortless return of gastric contents into

Upper GI symptoms

‘GORD-like’ symptoms

• heartburn

• regurgitation

• dysphagia

• odynophagia

• waterbrash

‘Ulcer-like’ symptoms

• Epigastric pain/discomfort

‘Dysmotility-like’ symptoms

• Bloating

• nausea and vomiting

• Early satiety

• Excessive flatus

Table 1

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SymptomS and SignS

the mouth and pharynx. This occurs in the absence of retching, which distinguishes it from vomiting.

Dysphagia: this often manifests itself to the patient as a sen-sation of food sticking in the retrosternal area. Difficulties with swallowing related to reflux disease are often intermittent, when they are probably related to reflux-related oesophageal spasm/disordered peristalsis. When less intermittent or progressive, they may be related to more structural reflux-related damage, such as peptic strictures or cancer.

Odynophagia: this is a sensation of painful swallowing. The patient will often describe being uncomfortably aware of the passage of food boluses or hot liquids from the upper sternum down to the epigastrium.

Waterbrash: this is the excessive accumulation of saliva in the mouth in response to acid reflux. Acid regurgitation is sometimes mistakenly confused with waterbrash, although true waterbrash lacks the bitter taste of acid and accumulates in the mouth, rather than coming from below up to the mouth/pharynx.

Extra-oesophageal manifestations of GORD: Table 2 outlines a number of extra-oesophageal disorders in which reflux may have either a direct or indirect causative role.5,6 There are clearly a wide spectrum of symptoms associated with these disorders, such as chronic cough, hoarseness, excessive phlegm and wheeze.

The sensitivity and specificity of symptoms in GORD: Table 3 dem-onstrates the frequency of various dyspeptic symptoms in a study

Suspected extra-oesophageal manifestations of GORD

Middle ear/eustachian tube

glue ear

otalgia

Nasal/sinusal

Chronic sinusitis

Oral

dental erosions

aphthous ulcers

Halitosis

Pharynx/larynx

pharyngitis

Chronic laryngitis

Laryngospasm

Cancer

globus

Airways

Chronic cough

aspiration pneumonia

asthma

Table 2

mEdiCinE 35:3 13

involving 304 patients referred for evaluation of possible oesopha-geal symptoms by means of 24-hour oesophageal pH monitoring.7 There are three possible main conclusions from these results. • The first is that symptoms such as heartburn and acid regur-gitation appear to be far from specific for GORD, since many patients with normal 24-hour oesophageal acid exposure also ex-perience them. • Secondly, clearly none of these symptoms are highly sensi-tive, since their occurrence is significantly less than 100% in the patients with abnormal 24-hour acid exposure. • Alternatively, 24-hour pH monitoring, which has hitherto been regarded as the ‘gold standard’ for the diagnosis of GORD, may be a relatively poor method to definitively diagnose this condition.The truth, in fact, probably contains elements of all three of these.

This study,7 therefore, suggests that individual reflux symp-toms are relatively insensitive. Further support for this possibil-ity comes from a number of studies which have demonstrated that a significant proportion of patients with severe reflux-related pathology, such as the higher grades of oesophagitis or Barrett’s oesophagus, may have few (or indeed no) symptoms. In practi-cal clinical terms, when these studies are considered together, this relative insensitivity means that a lack of ‘reflux’ symptoms does not exclude significant reflux disease.

Another difficulty which is clear from these studies is that these ‘reflux symptoms’ lack specificity. Non-erosive reflux dis-ease (NERD; heartburn in association with a normal endoscopy) is probably the commonest cause of heartburn. However, in NERD patients, studies suggest that active treatment with power-ful acid suppression for reflux symptoms has relatively little benefit when compared to placebo. Indeed in this situation, the therapeutic benefit is only about 25% for active treatment over placebo. Again in practical terms, reflux symptoms are therefore consistent with GORD, but far from diagnostic.

Signs of GORDThere are few, if any, signs of GORD. A small proportion of patients with severe GORD will have dental erosions from the effects of acid regurgitation on dental enamel.6 Similarly, some patients with proximal reflux have pharyngitis/laryngitis which is attributed to GORD. However, the majority of patients will have no signs.

Symptom frequency in patients with abnormal v normal 24 hour pH studies

Symptom Abnormal 24-hour

pH (%)

Normal 24-hour

pH (%)

Heartburn 68 48

acid regurgitation 60 48

odynophagia 10 8

Belching 49 40

nausea 38 32

Epigastric pain 54 53

Table 3

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SymptomS and SignS

Peptic ulcer disease (duodenal and gastric ulceration)

Symptoms of peptic ulcerationCertain ‘classic’ symptoms were ascribed to peptic ulcer dis-ease, as described in clinical practice by Lord Moynihan1 or in literature by the famous ulcer sufferer, John Buchan, the novel-ist and former Governor-General of Canada.8 The classic pattern of symptoms ascribed to duodenal ulcer were epigastric pain either several hours post-prandially and/or which awakened the patient from sleep. The patients were said to ‘feed’ their ulcers, since food often seemed to help. On the other hand, patients with gastric ulcers were said to have pain coming on soon after meals and for which food was unhelpful.

A number of studies in the century since Moynihan’s assertion have shown that the classic patterns of symptoms are insensitive for ulcer disease. They can present with any symptom from the dyspeptic constellation,9–12 including symptoms such as bloat-ing. Furthermore, some ulcer patients will present with no symp-toms,13 perhaps presenting either incidentally during endoscopy or following ulcer complications, such as bleeding or perforation. These ‘silent’ ulcers seem to be more common in the elderly14 and when the ulcer is NSAID-induced.13 Similarly, these ‘classic’ ulcer symptoms are not specific, being frequently reported by patients with no evidence of ulcers.9–12

Signs of peptic ulcer diseaseEpigastric tenderness was often suggested as a sign of possible peptic ulceration. However, studies have since shown that this sign has no discriminating value in indicating the possible under-lying pathology.15

Functional upper GI disease (‘non-ulcer dyspepsia’)

Dyspepsia for which organic causes, such as GORD, peptic ulcer or cancer have been excluded is often ascribed to functional causes. A wide range of symptoms may be related to functional upper GI disease and are sometimes grouped into three categories of ‘GORD-like’, ‘ulcer-like’ and ‘dysmotility-like’ (Table 1). How-ever, it has recently been recognized that this symptom grouping is artificial, since patients frequently change between groups.16–18 It should be recognized that upper GI symptoms without underly-ing disease (i.e. functional symptoms) are more common than similar symptoms associated with organic upper GI disease. For example, endoscopy for upper GI symptoms reveals evidence of underlying upper GI disease in only a small minority of patients.

Specificity and sensitivity of symptoms for functional dyspepsiaAs for GORD and peptic ulcer, the attempts to use ‘classical’ symp-tom clusters to diagnose functional dyspepsia has not withstood scientific scrutiny. These symptoms are neither sensitive nor spe-cific for any individual underlying diagnosis and are therefore not particularly helpful in arriving at a diagnosis in an individual patient.9–12 However, there are two caveats to this general rule. Firstly, the presence of ‘alarm’ symptoms, as described below, indicates the likelihood of organic, rather than functional disease. Secondly, the symptoms must always be considered in the full con-text of the entire clinical consultation. For instance, factors such as the patient’s general demeanour and external life stressors may

mEdiCinE 35:3

be as important (and perhaps more important) and as legitimate an influence on their overall clinical impression as any individual symptom or group of symptoms elicited in the consultation.

Upper GI malignancy

Symptoms of malignancyAlarm symptoms and signs: there has been understandable frustration that upper GI cancers often present in an advanced state. Initially, open-access endoscopy for simple dyspepsia was the main strategy developed to try to increase the yield of patients presenting with early, potentially more curable, cancers. However, studies suggested that such a strategy may increase the number of endoscopies performed up to tenfold, whilst not increasing the yield of early cancers.19 An alternative strategy was therefore sought, to allow the limited resource of endoscopy to be targeted to cancers. Alarm symptoms, such as those outlined in Table 4 have therefore been suggested as a possible alternative strategy to target scarce endoscopic resources to the most approp-riate patients.20–22 Initially, retrospective studies in South West England and the West of Scotland, which are both areas of high upper GI malignancy incidence, demonstrated that these cancers rarely present without alarm symptoms.20,21 Furthermore, when they do present without these, they are usually advanced.21 Sub-sequently, a prospective study which looked at all upper GI can-cers presenting in Scotland over a two-year period, confirmed that these cancers rarely present without alarm symptoms (and also that when they do, they are usually advanced).22 The frequent occurrence of these symptoms at the time of presentation of upper GI malignancy has supported their use as one of the main guides for the targeting of urgent endoscopy in modern investigative algorithms (Figure 1), such as the Scottish Intercollegiate Guidelines Network (SIGN)23 and the National Institute of Health and Clinical Excellence (NICE)24 dyspepsia guidelines.

As with other upper GI symptoms, alarm symptoms lack specificity. Although in one series about a quarter of patients with true obstructive dysphagia were found to have cancer,25 it is recognized that approximately 10% of patients presenting with dyspepsia in primary care have alarm symptoms.26 Fur-thermore, in one large study, the yield of upper GI malignancy from targeting by alarm symptoms was only 4%, i.e. 96% of the endoscopies performed did not show a cancer to be present.27 In addition, when found, the cancer is often advanced, so these symptoms are relatively insensitive for early, potentially curable cancer.21 Clinically, alarm symptoms are therefore an imperfect way to target upper GI cancer, but at present are probably the most effective method available.

Alarm signs and symptoms

• Weight loss

• dysphagia

• Recurrent vomiting

• Haematemesis and melaena

• anaemia

• Epigastric mass

Table 4

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SymptomS and SignS

The SIGN algorithm for the evidence-based management of dyspepsia

‘Indigestion’

Dyspepsia*Predominant heartburn

Manage as gastro-oesophageal

reflux disease (GORD)

Consider:

• Heart

• Liver

• Gall bladder

• Pancreas

• Bowel

• NSAIDs, etc. Alarm features:

• Dysphagia

• Evidence of GI blood loss

• Persistent vomiting

• Unexplained weight loss

• Upper abdominal mass

Uncomplicated dyspepsia

Consider:

• Lifestyle

• Antacids/H2RA

Hp test −veHelicobacter pylori (Hp) test

No

Refer to hospital

specialist

Age

Hp test +ve

YesNo

Yes

Persistent/ recurrent symptomsEradicate Hp

Consider referral to

hospital specialist

Manage as functional

dyspepsia

<55 >55Asymptomatic

Persistent/ recurrent symptoms

*Rome II definition

Reproduced from the SIGN dyspepsia guideline.23

Figure 1

Signs of upper GI cancerNon-specific signs such as anaemia, weight loss, an epigastric mass, hepatomegaly and ascites are relatively common at the time of presentation and suggest advanced disease. Similarly, rarer associated signs such as a left supraclavicular lymph node (of Virchow) or infiltration of the umbilicus (Sister Joseph’s nodule) are suggestive of metastatic disease.

Extra-luminal diseases

For any patient with symptoms which appear to be referable to the upper GI- tract, it is sensible for clinicians to consider alternative possible sources of their symptoms in the differential diagnosis. Possible alternative diagnoses fall into two main categories: GI- and non-GI-related (Table 5).

Pancreatic pain is characteristically a constant epigastric pain. It is often said to lessen with leaning forward. In both acute and chronic forms, a history of excessive alcohol ingestion will raise the diagnostician’s index of suspicion. However, the absence of a history of significant alcohol ingestion does not exclude these diagnoses.

Although the pain and discomfort of cholecystitis are often felt to be classically located in the right upper quadrant, observational

mEdiCinE 35:3 1

series suggest that pain that is maximal in the epigastrium is probably more common than this ‘classic’ presentation. Other sites, such as the left upper quadrant, chest and lower abdomen are less frequent, but are still recognized sites of maximum pain in these case series. The differentiation of cholecystitis from other sources of upper abdominal pain is clearly often difficult and requires a high index of clinical suspicion.

Chronic mesenteric ischaemia characteristically presents as upper/mid abdominal pain which occurs within 30 minutes of

Alternative extraluminal sources of apparently upper GI symptoms

GI-related

• acute and chronic pancreatitis

• acute and chronic cholecystitis

• mesenteric ischaemia

Non-GI-related

• ischaemic heart disease

Table 5

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SymptomS and SignS

eating, gradually increasing to a plateau, then remits over several hours. Initially patients often notice it only with large meals, but gradually it tends to increase in frequency.

Ischaemic heart disease can be very difficult to distinguish from heartburn for both patients and clinicians. Furthermore, angina can present with epigastric pain, which may be indis-tinguishable from dyspepsia. Although angina may be exercise-related, there are reports suggesting the triggering of GORD by exercise, even during exercise testing.28 In addition, oesophageal acid stimulation in patients with co-existing coronary artery dis-ease can lead to ECG changes.29 Ultimately, although responsive-ness to antacids and acid suppression may help, since upper GI symptoms and ischaemic heart disease are both common and therefore may co-exist, if doubt remains symptoms may be an insufficient guide. In that situation, more formal investigation to exclude ischaemic heart disease may be required.

Summary

The upper GI tract is a common source of symptoms in humans, but an uncommon source of signs. Although ‘classical’ patterns of dyspeptic symptoms had been described, which were felt to correlate with specific underlying upper GI disease processes, modern studies suggest that many of these symptoms lack sensi-tivity and specificity. Alarm symptoms are an important element in a history related to the upper GI tract. Although also lacking in specificity, there is an evidence base for their use to attempt to target urgent investigation for possible sinister upper GI disease. Finally, some consideration must be given to alterna-tive possible differential diagnoses, with ischaemic heart disease perhaps being the most frequent and important non-GI diagnosis to consider. ◆

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