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Definition & epidemiology Causes of dyspepsia Diagnosis Management & referral Prognosis

The author

Dyspepsia
Background
DYSPEPSIA, from the Greek dys (bad) and peptein (digest) is a common presentation in general practice and a source of considerable morbidity and cost to the community. When William Brinton wrote in 1865 that dyspepsia is not so much a single and substantive disease as a variety of ailments ... characterised not so much by the presence of certain symptoms as by the absence of structural lesions he was not to know that in 2009 his statement would have particular relevance. In Western societies today, structural lesions previously associated with dyspepsia, such as upper gastrointestinal cancer and peptic ulcer disease, are far less prevalent than in the late 19th and 20th centuries. Today, dyspepsia is more commonly dis-ease than a disease. discomfort, heartburn, nausea, vomiting or other symptoms considered to be referable to the proximal alimentary tract. mate that about 10% of patient attendances in Australia are due to GORD, the single most common cause of upper GI symptoms. Estimates from these data suggest there are more than two million Australians with GORD. We know that only a proportion of those with dyspepsia will ever consult a GP, and estimates from community studies in a number of Western countries are that up to 40% of the population have upper GI symptoms. Despite under-presentation to general practice, the cost to the PBS of prescribed acid-suppression therapy was more than $400 million, or about 10% of our national drug budget in 2007/08. A US survey of 117,497 endoscopic reports involving 99,558 patients found that 43% of endoscopies were for dyspepsia and onethird of patients were under 50 and had no alarm symptoms.1
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DR ANNE DUGGAN, gastroenterologist and associate director, clinical governance, Hunter New England Area Health, and conjoint professor, school of medical practice and population health, The University of Newcastle, NSW.

Epidemiology
The overall incidence and prevalence of dyspepsia is difficult to establish because of the different definitions used but appears to be unchanged over recent years. This is probably due to the ageing population and the increasing prevalence of NSAID use counteracting the effects of falling prevalence of Helicobacter pylorirelated ulcers. Other risk factors that influence dyspepsia prevalence include: Smoking. Use of NSAIDs. Alcohol intake. Socioeconomic status. Obesity, particularly in relation to gastro-oesophageal reflux disease (GORD).1 General practice activity data estiwww.australiandoctor.com.au

Definition
For the purposes of this review, dyspepsia is defined pragmatically as upper abdominal or retrosternal pain,

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HOW TO TREAT Dyspepsia

Causes of dyspepsia
SINCE the publication of the first Helicobacter pylori eradication trial in 1988 there has been great enthusiasm for attributing dyspepsia to H. pylori infection, an enthusiasm that was misplaced and is now waning. It is now clear that in most Western countries H. pylori is responsible for only a minority of the cases of dyspepsia. Infected individuals have an estimated 1:4-1:10 lifetime risk of developing ulcer disease and an increased risk of gastric cancer. As fewer people in the population acquire H. pylori in their childhood, H. pyloriassociated ulcer disease is becoming increasingly uncommon and gastric cancer is becoming rare. In most Western countries young people are more likely to stay uninfected than infected with H. pylori. In contrast, the elderly continue to carry much of the risk of ulcer disease and the small increased risk of gastric cancer because a higher proportion of them have acquired H. pylori as a result of the poorer domestic hygiene in their childhood. The second reason for attributing only a minority oof dyspepsia cases to H. pylori is that there is little evidence to implicate this bacterium as a cause for dyspepsia in the absence of an ulcer. This is clearly demonstrated by the disappointing outcomes of H. pylori eradication therapy for GORD, gastritis and non-ulcer dyspepsia. As the prevalence of H. pylori has fallen, so too has the proportion of patients with a lesion as a cause for their dyspepsia. Recent endoscopic studies demonstrate this and, in particular, the marked decline in the prevalence of peptic ulcer disease and gastric cancer. A recent study from 17 mainly Western countries reviewed the endoscopic findings of patients aged 18-70 presenting to primary care with dyspepsia without alarm symptoms. Only 23% were reported to have endoscopic abnormalities. The most common pathology found was reflux oesophagitis (table 1).2

Table 1: Endoscopic findings for patients with dyspepsia investigated in the primary care setting
Findings Normal findings Reflux oesophagitis Gastric ulcer Gastric erosions Duodenal ulcer Duodenal erosions Gastro-oesophageal malignancy
*Some patients had dual pathology

Table 2: Causes of H. pylori-negative peptic ulcers

False-negative H. pylori diagnostic test NSAID use (recognised or unrecognised) Other ulcerogenic drugs Smoking Gastric hypersecretion (ZollingerEllison syndrome) (very rarely) Mucosal diseases (Crohns disease, lymphoma, neoplasm) Infection (CMV, herpes simplex virus) Concomitant diseases (chronic renal failure, cirrhosis, malignancy)

%* 77% 15.5% 2.3% 6.2% 2.7% 3.5% 0.2%

Figure 1: Age standardised incidence of oesophageal adenocarcinoma in NSW by gender, 1972-2005. Reproduced from Stavrou E, et al. Medical Journal of Australia 2009; 191:310-14, using NSW Central
Cancer Registry data.

Adenocarcinoma 5 Number of cases per 100,000 4

Female

Male

JP female

JP male

APC3 = 4.2%

2 APC1 = -6.6% 1 APC2 = 21.6% APC4 = 4.3%

Transient lower-oesophageal sphincter relaxation. Anatomical disruption of the diaphragmatic sphincter. Free reflux across a hypotensive lower-oesophageal sphincter. Smoking, fats, caffeine, alcohol and a variety of drugs such as theophylline and calciumchannel blockers decrease lower-oesophageal sphincter pressure and may precipitate symptomatic reflux. H. pylori infection is not a cause of GORD and may even be protective, by raising gastric pH.

divided into two groups: postprandial distress syndrome, consisting of postprandial fullness and early satiety; and epigastric pain syndrome, with more consistent and less mealrelated symptoms. While this new classification may help our future understanding of the pathophysiology and ultimately lead to better treatment, its value for current management is unclear. A substantial proportion of patients with functional dyspepsia also have irritable bowel syndrome. The mechanism of both disorders may be similar and be a clue to the pathophysiology.

0 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004
APC = annual percentage point change JP = joinpoint analysis

Oesophageal adenocarcinoma
GORD is a risk factor for adenocarcinoma of the oesophagus and its pre-cursor Barretts oesophagus. A large study from Sweden found patients with oesophageal adenocarcinoma were more than seven times more likely to have symptomatic heartburn than the background population. The recent rise in the prevalence of adenocarcinoma in Australia and elsewhere is thought to be due to an increase in the prevalence of GORD (figure 1). However, oesophageal adenocarcinoma remains a rare cause of dyspepsia and may be an incidental finding at endoscopy. Figure 2 shows age-specific rates of oesophageal cancer.

Dual pathology
It is important to recognise that patients may have a combination of causes for dyspepsia, such as ulcer disease as well as GORD. A patient with peptic ulcer not improving after H. pylori eradication may have GORD requiring acidsuppression therapy.

Figure 2: Age-specific rates of oesophageal cancer, Australia 2001.

Source: Australian Institute of Health and Welfare. 200

160

Number per 100,000

120

Other
Drug therapy is often an unrecognised cause of dyspepsia. Examples include NSAIDs, digoxin, antibiotics (including erythromycin), and iron therapy. Ten to 20 per cent of patients taking NSAIDs have associated dyspepsia, with or without an ulcer being present, and within six months of starting NSAID therapy 515% of patients will discontinue it because of dyspepsia. Patients taking COX-2 inhibitors such as celecoxib, rofecoxib (withdrawn worldwide) and meloxicam have a similar frequency of dyspepsia to non-selective NSAIDS but a lower risk of peptic ulcer complications. The contribution of biliary pain and dysmotility to dyspepsia (including sphincter of Oddi dysfunction) is unclear but probably small. Systemic disorders such as diabetes and hypercalcaemia may rarely cause dyspepsia. There is debate as to whether dyspepsia is more common among patients with undiagnosed coeliac disease. The background prevalence of coeliac disease is about one in 100 and so is not infrequently found, including in patients with GI symptoms.
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80

40

0 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Age

Figure 3: Age-specific rates of gastric cancer Australia 2001.

Source: Australian Institute of Health and Welfare. 350

Number per 100,000

300 250 200 150 100 50 0 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Adenocarcinoma of the stomach

In the past, one of the main arguments for investigating dyspepsia was to avoid missing gastric cancer. Gastric cancer is now known to have a rare association with dyspepsia. In Australia the age-standardised rate of gastric cancer is 9.7/100,000 in males, and lower in females, with a median age of diagnosis over 70 in both groups. As figure 3 shows, gastric cancer is rare under the age of 50 years.

Peptic ulcer disease

About 5% of patients with dyspepsia have peptic ulcer disease. The association between H. pylori and peptic ulcer disease is well documented. More than 90% of duodenal ulcers are associated with the infection, as are a similar proportion of nonNSAID-induced gastric ulcers. As expected, with the fall in prevalence of H. pylori infection there has been a marked fall in peptic ulcer disease prevalence. Over the 10 years from 1970 some countries reported an almost 10-fold decline in hospitalisation rates for peptic ulcer disease.

Age

The second leading cause of peptic ulcer disease in our community is the use of NSAIDs, including aspirin. A recent meta-analysis showed that the risk of GI complications from NSAIDs is 1.5-2% per year in the average patient and 10% per year in the highrisk patient. The risk of ulcer complications from COX-2selective inhibitors is about half that for naproxen. It is worth noting that most NSAID-induced erosions and

ulcers are asymptomatic, with GI haemorrhage often being the first indication of an NSAID-induced ulcer. NSAIDS and H. pylori are thought to induce ulcer disease by different mechanisms but with synergism between the two risk factors. H. pylori infection increases the risk of bleeding from peptic ulceration twofold, NSAIDS fivefold and together there is a sixfold increase. H. pylori-negative NSAID-

negative peptic ulcers do occur, but true H. pylori-negative NSAID-negative ulcers are very uncommon and are a diagnosis by exclusion (table 2). Smoking increases the risk of peptic ulcer disease in a dose-dependent manner.

Functional dyspepsia
Functional dyspepsia is defined as chronic dyspepsia in the absence of a structural lesion that may account for the symptoms. The pathophysiology of this condition has been poorly characterised. Recently, Rome III, a meeting of GI experts, proposed that functional dyspepsia be

Gastro-oesophageal reflux disease

The aetiology of GORD is unknown but thought to occur by three mechanisms:

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HOW TO TREAT Dyspepsia

Diagnosis
History
IT is important to assess the timing of symptom onset in relation to starting of new medications and to ask about alcohol and cigarette consumption. Specific questioning about weight loss, dysphagia, symptoms resistant to acid-suppression therapy, early satiety, melaena and haematemesis are essential to evaluate the likelihood of upper GI malignancy. A dietary history of known precipitants of GORD may be very important for future management, as stopping excessive consumption of caffeine, chocolate, alcohol or fatty and spicy food may be sufficient to prevent further symptoms. A history of predominant heartburn or reflux is useful for the diagnosis of GORD. However, up to one in five patients are unable to decide on their most bothersome symptom. A variety of respiratory and laryngeal symptoms has been attributed to GORD. These include cough, wheeze, and hoarse voice or sore throat, and may occur in the presence or absence of dyspepsia. Water brash (stimulation of salivation by the presence of gastric acid in the lower oesophagus) also rarely occurs. Dysphagia and odynophagia may result from altered oesophageal peristalsis, stricture or increased sensitivity. These symptoms should be treated with potent acid-suppression therapy, but the response is often slow and may be poor. Despite traditional teaching, the clinical diagnosis of peptic ulcer disease is difficult. Fewer than 25% of ulcers are diagnosable on history. The accuracy of clinical diagnosis can be increased by considering risk factors (table 3). Family history is a risk factor for peptic ulcer disease, with twin studies showing this to be due to both genetic and environmental factors. Smoking and a history of pain on an empty stomach have been shown to increase the likelihood of ulcer disease as the cause of dyspepsia. In the elderly, a history of aspirin and NSAID consumption is particularly important. The risk for NSAID complications increases with advanced age, H. pylori infection, smoking, previous ulcer history, concurrent anticoagulant and prednisone use. SSRIs also slightly increase the risk of peptic ulcer disease. Comorbidities such as cardiac failure and diabetes increase the risk of peptic ulcer bleeding. The importance of a past history of peptic ulcer disease cannot be sufficiently emphasised. A recent survey in a NSW hospital found that 85% of patients admitted

Table 3: Clues to peptic ulcer disease as a cause for dyspepsia

Past history of peptic ulcer disease Family history of peptic ulcer disease Smoking Periodicity of symptoms History of pain on an empty stomach Use of NSAIDs, SSRIs, COX-2 inhibitors, prednisone

Table 4: Investigation of dyspepsia

Strategy Empirical therapy Gastroscopy Advantages Diagnostic of acid-related disorder; does not require specialist referral Diagnosis of curable disease; diagnosis of H. pylori infection; patient reassurance Cures H. pylori-associated disease; does not require specialist referral Selective treatment of H. pyloriassociated disease Disadvantages Does not cure peptic ulcer disease; adequate patient/GP reassurance?; misses the rare early malignancy Expensive; poorly predictive of response to acidsuppression therapy; inconvenient; results often normal Requires access to good H. pylori diagnostic methods; unnecessary exposure to antibiotics; promotes antibiotic resistance; adequate patient/GP reassurance? Misses H. pylori-negative peptic-ulcer disease; requires access to good H. pylori diagnostic methods; adequate patient/GP reassurance?

H. pylori test and treat H. pylori test and refer

Table 5: Advantages and disadvantages of different tests for H. pylori diagnosis

ENDOSCOPIC TESTS All Advantages Microbial culture Histology Urease test

Useful pre- and post-treatment

High specificity Allows determination of

antibiotic resistance

High specificity Permanent record Observer dependent Does not allow determination
of antibiotic resistance

High specificity Rapid Inexpensive

Does not allow determination of antibiotic resistance

Disadvantages Expense of endoscopy Sampling-error-dependent sensitivity

Time consuming Preparation dependent

NON-INVASIVE TESTS

All Advantages Non invasive

Urea breath test

Serology

Rapid serology (near-patient tests)

High sensitivity and specificity Can confirm efficacy of

eradication using 13C testing Can be performed at a distance from the centre performing the analysis

Inexpensive Quick Easy to perform Requires no specialised equipment

Inexpensive Quick Easy to perform Requires no specialised equipment

Disadvantages No diagnostic information on H. pylori-induced disease Do not allow determination of antibiotic resistance

13C urea and isotope ratio mass spectrometry are expensive

Need local validation accuracy depends on purification of strains and suitability of strain types for group being tested

Need local validation Operator dependent

with a past history of peptic ulcer disease denied previous treatment with H. pylori eradication therapy and had positive H. pylori serology indicative of ongoing infection.3 These patients should be offered H. pylori eradication therapy without further investigation. The benefits are threefold: A substantially reduced ulcer risk with or without NSAIDS. Improved quality of life for those who become asymptomatic. Savings from avoided treatment.

Endoscopic diagnosis is unnecessary for most patients with dyspepsia.

weeks of acid-suppression therapy. Gastroscopy in the latter instance should be performed after PPIs have been ceased.

Early investigation why not initial endoscopy?

Endoscopic diagnosis is unnecessary for most patients with dyspepsia because of its low yield, particularly in those under 50 (table 4). The most frequent abnormal finding at endoscopy is erosive oesophagitis, which responds to empirical therapy, making endoscopy unnecessary. Fewer than 50% of patients with GORD have endoscopic evidence of oesophagitis. Multiple studies have shown that few treatable cancers are detected by early endoscopy. A recent large study in primary care in 17 mostly Western countries provides a useful summary of the role of endoscopy in diagnosing cancer in countries like Australia.2 In this study 2741 patients aged 18-70 with dyspepsia and without alarm symptoms had endoscopy. Upper GI cancer was found in two per 1000 patients (0.22%). The authors concluded that if endoscopy were limited to only dyspeptic patients 50 years and over, one oesophageal cancer and no gastric cancer would have been missed. If endoscopy cost $500 it would cost about

Trial of acid-suppression therapy

For most patients a trial of acid-suppression therapy is usually diagnostic of an acidrelated disorder and is safe. Rapid symptom recurrence on stopping acid-suppression therapy is virtually diagnostic of GORD. Patients should be advised to present again if symptoms do not resolve following 2-4 weeks of acid-suppression therapy

Gastroscopy
Gastroscopy is indicated if malignancy is suspected because of the presence of alarm symptoms such as weight loss, dysphagia, early satiety, haematemesis, melaena, anaemia and bloody stools, or if dyspeptic symptoms are unresponsive to 2-4

$82,900 (between $35,714 and $250,000) to detect that 2 cancer. Up to 40% of patients diagnosed with oesophageal adenocarcinoma have no prior history of dyspepsia. Endoscopy has had little impact on gastric cancer survival because most cancers are advanced when diagnosed and treatment options are limited. Current five-year survival for gastric cancer is 25% compared with 58% for cancer overall and 61% for colonic cancer. As 37% of oesophageal adenocarcinoma in Australia is attributable to poor physical activity and obesity, the logical management strategy for its prevention is promoting exercise and appropriate dietary intake.4 Advocates of endoscopy argue that initial empirical therapy may miss Barretts oesophagus. The risk of Barretts oesophagus increases with duration of reflux and is least likely to be found at the time of onset of symptoms. It is important to distinguish endoscopy before starting acid-suppression therapy from endoscopy after a trial of acidsuppression therapy. A study of the effect of time between withdrawing PPIs and gastroscopy showed a greater diagnostic yield the longer the time gap. A course of PPI therapy will heal more than 60% of peptic ulcers in two weeks

and 94% within a month. PPIs should be stopped for at least four weeks before endoscopy is performed.

H. pylori testing
H. pylori testing and eradication should be offered to patients with peptic ulcer disease or those starting NSAID therapy, as it is of proven benefit for these conditions. The yield from H. pylori testing has fallen as a result of its decreasing prevalence. The main methods for detecting H. pylori are shown in table 5. Serology remains the most readily available, inexpensive and accurate test for detection. To confirm eradication, the urea breath test is the best non-invasive option, as serology may remain positive for up to 12 months.

pH monitoring
pH monitoring involves inserting a pH probe into the distal oesophagus and recording of the proportion of time pH falls below 4 over a 24hour period. It has a limited role in the diagnosis and management of dyspepsia but can be useful to assess the adequacy of therapy if a patient is still symptomatic on maximal acid-suppression therapy, or, off therapy, to assess symptom correlation. Patients can have GORD symptoms despite a normal pH study.

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Management
UNDERSTANDING why people present may be the key to effective management. An Australian population-based survey found that only 56% of people with dyspepsia had ever consulted about their symptoms. Consultation seems not just related to age or the severity or duration of symptoms, but also to more complex issues such as anxiety, including fear of serious disease and stressful life events. Patients concerned about the possibility of cancer are unlikely to have symptom resolution without appropriate counselling. Figure 4: Algorithm for managing patients requiring NSAIDs.

Table 6: Modifiable dyspepsia-related risk factors

Drugs, eg, NSAIDs, COX-2 inhibitors Smoking Excess alcohol High fat intake Obesity Large meals Low fruit intake (may be a factor)
Source: Rostom, 2009.5

Patient requires NSAIDs

Hi GI risk

Low GI risk

Remove the cause

It is important to see the patients current symptoms in the context of their overall health. It is therefore logical to address lifestyle factors known to promote dyspepsia and to impact on health in general by taking a comprehensive dietary and drug history and providing appropriate counselling (table 6). Frequent dietary components associated with reflux include coffee, orange juice, alcohol and fatty and spicy foods. Patients with suspected reflux should also be advised to avoid eating large meals just before going to bed and to avoid tight-fitting clothes after meals. A wedge pillow or elevation of the head of the bed can help to reduce nocturnal symptoms. Up to 20% of patients will respond to lifestyle intervention alone. NSAID therapy should be reviewed and stopped if possible. Patients in the high-risk group for peptic ulcer complications should be offered concurrent proton-pump inhibitor therapy and be prescribed the least-toxic NSAID (either ibuprofen or diclofenac), unless they are also high risk for cardiovascular disease, in which case NSAIDs should be avoided, or, if an NSAID is needed, naproxen with a PPI is the preferred choice. Consensus guidelines for management with NSAIDs are now well established (figure 4).5 It is clear that patients who are H. pylori positive are at higher risk of NSAID-associated ulcer complications and that H. pylori eradication before starting NSAIDs reduces that risk. The data on eradication after an NSAID ulcer complication has occurred are less clear. Another group of patients of particular concern are those with coronary artery stents who are often receiving aggressive antithrombotic therapy with both aspirin and clopidogrel to prevent stent blockage. The GI bleeding risk increases with the number of antithrombotic agents used. Clopidogrel synergistically causes GI bleeding in patients using aspirin, non-selective NSAIDs or anticoagulants and increases the blood loss caused by NSAIDs. There has been recent concern over whether PPIs decrease effectiveness of clopidogrel if concomitantly prescribed. In November 2008 the American Heart Association, the American College of Cardiology and the American College of Gastroenterology issued a joint statement concluding that there was no definite evidence to justify changing clinical practice. A clinical trial is under way to provide more data.

Hi CV risk (on aspirin)

Low CV risk

High CV risk (on aspirin)

Low CV risk

Avoid NSAID if possible

Cant avoid NSAID

COX-2 alone or traditional NSAID + PPI

Naproxen + PPI

Traditional NSAID

Very high CV risk is primary concern Naproxen + PPI

Very high GI risk is primary concern Cox-2 + PPI

GI = gastrointestinal PPI = proton-pump inhibitor CV = cardiovascular

Acid-suppression therapy
A proportion of patients will respond to an initial 1-2-week trial of acid-suppression therapy without further need for medication, at least for a number of months. A single daily standard dose of a PPI results in a gastric pH >4 about 67% of the time and is sufficient for most patients requiring daily therapy, with a few requiring a twice-daily dose. Others can be well controlled with, and may prefer, on demand therapy with acid-suppression therapy or antacids. On-demand therapy has been shown to be effective for a large proportion of patients with GORD, with similar levels of patient satisfaction to those taking regular acid-suppression therapies. For patients with evidence of oesophagitis on endoscopy, severity of disease can determine treatment needs. Patients with severe oesophagitis are more likely to develop local complications such as stricturing and bleeding. They should be maintained on PPI therapy to avoid these complications. The expected success rates for medical treatment of GORD vary widely. Recognised approaches, from the most successful to the less successful, are as follows: Increased daily dose PPI (100% success). Single daily dose PPI (80%). Cisapride (50%). H2-receptor agonists (50%). Antacids (20%). Lifestyle modification (20%).6 There are few data showing a step-down approach to be more cost effective than a strategy of targeting therapy to symptoms. Prokinetic therapy may be useful for patients with dyspepsia unresponsive to acid-suppression therapy. Options include domperidone and metaclopramide. Treatment for functional dyspepsia is difficult. Initial therapy should comprise acid suppression, with sub-

sequent use of prokinetic agents, antispasmodics, antidepressants and behavioural therapy or psychotherapy considered for resistant symptoms.

Is long-term acid-suppression therapy safe?

Postmarketing surveillance data for use of H2-receptor antagonists compared with community controls show them to be relatively safe. Long-term postmarketing surveillance data for PPIs are not yet available despite the first PPI being released in 1988. The most common side effects of PPIs are headache and diarrhoea and they are uncommon. Other rarer but serious reported side effects are interstitial nephritis, which is not always reversible and, hypomagnesaemia. PPIs act by reducing gastric acid production. Reduced gastric acid promotes the growth of enteric and swallowed flora in the proximal gut and leads to a small increased risk of community-acquired pneumonia and of enteric infection. An acid environment is also needed for calcium absorption, and longterm PPI use may predispose to osteoporosis-associated hip fracture. The medications appear to be safe in pregnancy.

cation strategy is based on the principle that H. pylori eradication will cure non-NSAID ulcer disease, and acid-suppression therapy most of the remainder. Antibiotic intolerance, side effects and the impact of inappropriate use of antibiotics on community antibiotic resistance are some of the disadvantages of H. pylori-eradicationbased strategies. A meta-analysis of H. pylori-eradication studies in patients with nonulcer dyspepsia concluded that H. pylori eradication therapy has a small but statistically significant effect in H. pylori-positive non-ulcer dyspepsia. The number needed to treat to cure one case of dyspepsia was 14. The number needed to harm was not calculated.7 The benefits of secondary prevention of gastric cancer through H. pylori eradication are theoretical, although biologically plausible, but there are no data to indicate optimal time for treatment to be effective. It is reasonable to offer H. pylorieradication therapy to patients with dyspepsia and a family history of gastric cancer, as a history of a firstdegree relative with gastric cancer increases the risk threefold.

In the event of allergy or resistance to either of these antibiotics, a second prescription for metronidazole 400mg twice daily can be written and the offending antibiotic substituted. All regimens involve antibiotics to which H. pylori has been demonstrated to develop resistance. Australian studies show resistance for clarithromycin is about 6%. In vitro metronidazole resistance has been shown to be up to 40%. The need to confirm the success of eradication therapy has been questioned because of the high efficacy of eradication therapies and the cost involved detecting few failures. A pragmatic approach is to confirm eradication for patients who have had complicated ulcer disease, and who, because of comorbidity, would poorly tolerate ulcer complications. Options to detect failed eradication are limited to endoscopic methods (which are invasive), and urea breath testing. There is a prolonged antibody response to infection, making serology unhelpful. Patients failing H. pylori eradication can be referred to a gastroenterologist to determine the most appropriate antibiotic combination or for consideration of H. pylori culture and sensitivities, if the initial indication for H. pylori eradication was justified. After eradication, the risk of re-infection is small (of the order of 0.5-1% per annum). In the absence of aspirin or NSAID use, eradication therapy virtually cures H. pylori-associated peptic ulcer disease without any further treatment. After successful eradication, about 5% of ulcers recur over a 6-12-month period, compared with 25% of those given H2-receptor antagonists, and just under 75% of those untreated. It needs to be remembered that a proportion of patients will have concurrent GORD and may therefore need treatment for this.

Anti-reflux surgery
Effective acid-suppression therapy has meant that surgery is rarely indicated for ulcer disease except in the presence of complications. Indications for anti-reflux surgery (fundoplication) include: Refractory reflux disease or oesophagitis. Recurrent oesophageal strictures. Recurrent aspiration due to GORD. Recurrent bleeding from either oesophageal or associated gastric (Camerons) ulcers. Up to 80-90% of patients have good to excellent outcomes at 10 or more years. Laparoscopic fundoplication has less short-term morbidity than open surgery.
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Treatment of H. pylori
Two H pylori-post-testing treatment strategies have been recommended: H. pylori-negative patients: treatment with a PPI. H. pylori positive patients: either referral for endoscopy, or H. pylori eradication treatment, with subsequent referral only of those who have persistent symptoms after a trial of acid-suppression therapy (see table 4). The strategy of referral for endoscopy is based on the association between H. pylori infection and peptic ulcer and gastric cancer, and increases the diagnostic yield of selective endoscopy. The H. pylori eradiwww.australiandoctor.com.au

Which H. pylori treatment option?

For H. pylori infection the main issues surrounding treatment are which regimen to use and whether eradication of infection needs to be confirmed. Controversy remains as to the preferred combination of antibiotics to use for eradication therapy. PPI-based therapies have been shown to have a higher efficacy and to be better tolerated than bismuth-based therapies. The main PPI-based combination packs are Nexium Hp7 and Klacid Hp7, seven-day regimens of twicedaily clarithromycin 500mg, amoxycillin 1g and esomeprazole 20mg or omeprazole 20mg.

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Psychological interventions
Despite reports of benefits for both psychotherapy and hypnotherapy for functional dyspepsia, this is not confirmed in formal studies.

Meeting patient expectations

Some patients are dissatisfied out of proportion to their residual symptoms after treatment. A major cause of dissatisfaction is unmet expectations. A US survey of patients visiting primary care physicians for various reasons found 98% had at least one pre-visit expectation.8 The most frequent expectations were: A diagnosis (81%). An estimate of how long the symptom would last (63%).

A prescription (60%). A diagnostic test (54%). A subspecialty referral (45%). Resurvey immediately after their visit found the most common unmet expectations were prognostic information (51%) followed by diagnostic information (33%). Of note, patients with no unmet expectations had less worry about serious illness (54% vs 27%), significantly greater satisfaction (59% vs 19%) and were more likely to have symptom alleviation. A study of 91 patients starting PPI therapy for gastro-oesophageal reflux symptoms found that patients expected: Improvement (61%). Return to normal daily life (46%). Improved quality of life (44%).

No further treatment after the initial treatment (36%). For the PPI to have no side effects (34%). Elimination of symptoms (33%).9 Only four patients had no real expectations of the medication. There are clearly common themes in regard to what patients want to know and most patients want to be involved in their care.

Who and when to refer

All patients with alarm symptoms and those who, on clinical grounds, are suspected of having peptic ulcer disease should be referred for endoscopy before acid-suppression therapy. It is also not unreasonable to refer the elderly patient with new-onset dyspepsia

in the absence of a medication change. Whether to refer the patient with longstanding symptoms of GORD for screening for Barretts oesophagus remains controversial. The higher-risk group are male smokers with longstanding and severe symptoms. If referred for surgery, these patients should be fit enough for the procedure. The largest referral group will be those who have not responded to high-dose acid-suppression therapy, and these can be the most difficult group to treat. A major role for the gastroenterologist is to exclude other pathology and to document oesophageal acid exposure by pH testing. For some patients, concern about the significance of their symptoms may only be allayed by referral to a specialist.

References
Available on request from julian.mcallan@reedbusiness. com.au

Online resources
Gastroenterological Society of Australia: www.gesa.org.au/pdf/ Healthy_Gut_2nd_03.pdf, www.gesa.org.au/pdf/ Heartburn_3Ed_07.pdf, www.gesa.org.au/pdf/ H_Pylori_2nd_03.pdf

Prognosis
Does dyspepsia get worse over time?
GORD

The future
SEVERAL endoscopic anti-reflux techniques are under evaluation and may obviate the need for surgery in people with severe GORD. This is unlikely to have a major impact at a population level. In contrast, the rise in obesity a risk factor for reflux may result in a substantial rise in the number of consultations for GORD in the future and in turn the incidence of oesophageal adenocarcinoma. Whether the fall in H. pylori prevalence can be implicated in these events remains to be determined.

Summary
Dyspepsia is commonly due to GORD or functional symptoms and
rarely due to upper GI malignancy.

THE natural history of GORD is not well documented. Most data come from patients with symptoms severe enough to warrant referral to secondary care. Some community-based longitudinal studies report a steady prevalence, with the proportion of affected individuals having symptom resolution being matched by a similar proportion becoming symptomatic. These studies also report poorer quality of life. A systematic review of patient outcomes for GORD found 40% of those taking prescription medications reported residual symptoms.10
Peptic ulcer disease

Acid-suppression therapy is both a diagnostic and therapeutic

strategy for most patients with dyspepsia.

Patients should be questioned about alarm symptoms and referred

for endoscopy if any are present.

For patients with uncomplicated GORD, therapy should be tailored

to achieve symptom control.

Endoscopy should be considered for patients who fail to respond

to acid-suppression therapy.

H. pylori testing and eradication should be offered to patients with

peptic ulcer disease or those starting NSAID therapy, as it is of proven benefit for these conditions.

A guide to the management of dyspepsia

Dypepsia history: Alarm symptoms Peptic ulcer disease risk factors Yes No

H. pylori eradication virtually cures duodenal ulcer disease, with relapse rates at one year of about 5%. Without treatment, about 40% of duodenal ulcers and about 30% of gastric ulcers heal at four weeks, but 5080% recur in the subsequent 6-12 months. It is controversial whether recurrences continue indefinitely.
Functional dyspepsia

Endoscopy

Remove risk factors Lifestyle modification Acid-suppression therapy according to symptom severity Consider other diagnoses Response No cause found Yes No

Functional dyspepsia has a high placebo response of up to 50%, consistent with a generally good prognosis for this disorder. Longitudinal studies of functional dyspepsia that have followed patients for more than a decade show a large amount of overlap with IBS and a high rate (up to 40%) of change of predominant symptomatology from the upper to lower gut, and vice versa.

Carcinoma

Peptic ulcer H. pylori testing

Refer

Treat

Continue current management

Endoscopy

Authors case study

MR RL, 52, has been troubled by knee pain not responsive to intermittent paracetamol. He recently started a health kick because a friend of similar age suffered a fatal MI. He presented to a colleague 10 days ago because his knee pain was limiting his weight-loss program. He is 100kg and 165cm. He was prescribed indomethacin but found he developed nausea, upper abdominal pain, burning and intermittent belching. He comes to you requesting treatment for his abdominal symptoms. He reports he has previously been well although has not had a check-up for years. He has a family history of ischaemic heart disease and peptic ulcer disease. He smokes 20 cigarettes a day and, with his job involving the entertainment of clients, drinks 50-60g of alcohol daily. He is taking no regular medications.

Author comments
Mr RLs dyspepsia follows the prescription of an NSAID for his knee pain and, if caused by it, should resolve on stopping the medication. His dyspepsia may or may not be due to an acute ulcer. NSAID-induced ulcers can occur acutely and are often silent. RL has risk factors for ulcer disease, being a smoker of 20 a day and having a positive family history for ulcer disease. The diagnosis is relevant if he is to continue an NSAID, but the first question is whether he needs an NSAID. He requires a step-up approach to the management of his knee pain, including modification of lifestyle factors, and if medication is required, this should start with regular paracetamol.

NSAID-induced ulcers can occur acutely and are often silent.

Non-weight-bearing exercise such as swimming may help achieve his goal of weight loss without exacerbating his knee pain. If these measures fail, he will need an NSAID and this should be one with the least GI toxicity, such as ibuprofen or diclofenac, if he has a low risk for cardiovascular events. A COX-2 inhibitor has no advantages in terms of symptoms, as it is associated with a similar amount of dyspepsia. He can reduce his ulcer risk

and improve his cardiovascular risk profile by stopping smoking. It is important at this stage to assess his cardiovascular risk factors, in particular his blood pressure, lipid profile and blood sugar level, all of which may improve with successful weight loss. However, if he does fall into the classification of high risk of cardiovascular disease (>15% risk of a major cardiovascular event in the next five years), he will need to start aspirin. In that case he should have his H. pylori serology tested and, if positive, be offered treatment before starting aspirin. Your choice of NSAID, if required, would then be guided by his greater need for cardiovascular protection, and naproxen with a PPI would be the better choice of NSAID.

Practice points
Establish patient drivers
for presentation.

Address lifestyle factors

contributing to dyspepsia.

Check for alarm

symptoms.

Reassure patients about

the good prognosis for dyspepsia.

Use endoscopy
selectively.

Consider H. pylori testing

when there is a history of peptic ulcer disease or when starting an NSAID.

Assess both
cardiovascular and GI risk when considering NSAID therapy.
contd page 24

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HOW TO TREAT Dyspepsia

GPs contribution
an SSRI for depression and Panadeine Forte when the pain was very severe. She denied any other medications even with specific questioning about over-the-counter ones. On her second visit, for review of blood tests I had organised, she excused herself after belching and reached into her bag, popping an antacid into her mouth. After I asked her about this antacid use , its frequency and any other symptoms she had experienced, she stated that it was just the normal amount of heartburn she had on a daily basis and was nothing to worry about, as it had been this way for years. Endoscopy showed grade-4 reflux oesophagitis with Barretts oesophagus. PPIs were prescribed and Mary is now pain free. She cant believe she put up with the pain for so long! out a past history of peptic ulcer disease. As many people now turn to natural therapies, can you comment on the efficacy of the use of aloe, slippery elm, apple cider vinegar, orange peel extract and marshmallow root? There is no evidence for any of these treatments for dyspepsia. Feedback I received from our drug information service for interest is as follows. Oral aloe vera is a popular treatment for a variety of GI disorders (improves colonic bacterial activity, GI pH, stool specific gravity and GI motility) and may be effective for diarrhoea-predominant irritable bowel syndrome and ulcerative colitis. However, there is no evidence for use in dyspepsia Based on traditional evidence, slippery elm is taken internally to relieve the symptoms of gastritis, acid dyspepsia, gastric reflux, peptic ulcers, IBS, and Crohn's disease. Currently, clinical research is not available to determine the effectiveness of slippery elm in these conditions; anecdotally the treatment appears to be successful and patients report rapid improvement in upper GI symptoms. A search of available resources failed to located evidence for the use of apple cider vinegar in GI disorders. Oral orange peel extract is used for dyspepsia, GI disturbances, duodenal ulcers and constipation. However, there is insufficient reliable information about its effectiveness in these conditions. Traditionally, marshmallow root has been used internally for the treatment of inflammation of gastric mucosa, diarrhoea, peptic ulcers and constipation. Again, however, there is insufficient reliable information available to rate its effectiveness for these conditions. You mentioned the inhibition of calcium absorption and hence increased risk of osteoporotic hip fracture. Will regular blood tests help to determine who is at greater risk? Do you suggest calcium supplementation for most patients on PPIs? The data are that PPIs may predispose to osteoporosisassociated hip fracture. As osteoporosis and hip fracture is such a public health issue in our community, particularly among the elderly, I would recommend that all patients be given advice about appropriate preventive strategies to reduce the risk of these conditions, particularly adequate calcium intake, weight-bearing exercise and not smoking. In terms of blood tests I think there should be a high index of suspicion for coeliac disease, which affects about one in 100 of the population and, if untreated, can be associated with calcium malabsorption. If coeliac disease is a possibility, a transglutaminase antibody test (TGA IgA/IgG) should be ordered.

DR CAROLYN BLOCK
Rose Bay, NSW

Case study
IN many patients minds, a medication that is available over the counter is not truly a medication and hence not worth mentioning. James requested I see his mother as a patient, as he was not happy with the care she had been receiving. Mary came to see me, an obese 77-yearold with severe OA who had had bilateral knee replacements and postoperative complications requiring two further operations on the left knee. She had an antalgic gait, required a stick to walk, and her mobility was extremely limited. She was taking COX2s and Di-Gesic for pain relief,

Questions for the author

What effects both positive and negative do you feel

will occur because of these medications (ranitidine and diclofenac) being available OTC? Clearly both drugs are effective for some symptoms, otherwise they would quickly go off the shelf/market. Both have a role and are quite effective for patients with mild, rapidly responding symptoms. The risks are when people avoid appropriate treatment of symptoms that do not resolve with a trial of these drugs, or when NSAIDs are self-prescribed by patients with severe comorbidities such as heart disease with or with-

How to Treat Quiz

Dyspepsia 22 January 2010
1. Which THREE of the following statements are correct? a) Dyspepsia includes upper abdominal or retrosternal pain, discomfort, heartburn, nausea, and vomiting b) Gastro-oesophageal reflux disease (GORD) is an uncommon cause of upper gastrointestinal symptoms c) Risk factors for dyspepsia include smoking, use of NSAIDs, alcohol intake, socioeconomic status, and obesity d) GI alarm symptoms include anaemia, melaena, bloody stools, dysphagia, jaundice, early satiety, weight loss, and symptoms resistant to acid-suppression therapy 2. Which TWO of the following statements are correct? a) Patients infected with Helicobacter pylori have a 10-25% lifetime risk of developing peptic ulcer disease, and are at an increased risk of gastric carcinoma b) The rates of infection with H. pylori in children and adolescents are decreasing c) Eradication of H. pylori in the absence of an ulcer resolves dyspeptic symptoms d) In Western countries H. pylori infection is the most common cause of dyspepsia 3. Which TWO of the following statements are correct? a) Of patients with dyspepsia and no alarm symptoms who have an endoscopy, >70% will have normal endoscopic findings and about 15% will have reflux oesophagitis b) 90% of duodenal ulcers and non-NSAIDinduced gastric ulcers are associated with H. pylori infection c) Dyspepsia is a symptom associated with most NSAID-induced gastric erosions and peptic ulcers d) Smoking is no longer regarded as a risk factor for peptic ulcers 4. Which TWO of the following statements are correct? a) GORD is thought to result from acid reflux across a lax lower-oesophageal sphincter b) Calcium-channel blockers increase the tone of the lower oesophageal sphincter c) H. pylori may protect against GORD by raising gastric pH d) Smoking, fats, caffeine and alcohol are not associated with GORD 5. Which THREE of the following statements are correct? a) GORD is a risk factor for adenocarcinoma of the oesophagus and its precursor Barretts oesophagus b) Oesophageal cancer is a rare cause of dyspepsia c) Gastric cancer is commonly associated with dyspepsia d) Functional dyspepsia is defined as chronic dyspepsia in the absence of a structural lesion that may account for the symptoms 6. Which TWO of the following statements are correct? a) The urea breath test is a specific and sensitive non-invasive test for H. pylori that also provides

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information on the presence of ulcers b) Antibiotic resistance has been identified for combination therapies against H. pylori c) Persistent dyspepsia after H. pylori eradication in patients with a peptic ulcer may indicate dual pathology d) Patients taking COX-2-selective inhibitors have a lower frequency of dyspepsia and peptic ulcer complications compared with nonselective NSAIDs 7. Which TWO of the following statements are correct? a) Peptic ulcer disease may be associated with cough, wheeze, hoarse voice or sore throat b) Drugs associated with dyspepsia include NSAIDs, COX-2-selective inhibitors, prednisone, antibiotics and SSRIs c) Clues to peptic ulcer disease include past or family history of peptic ulcer disease, smoking, periodicity of symptoms, history of pain on an empty stomach, and use of NSAIDs, SSRIs or COX-2 inhibitors d) For patients with a high GI risk and a low cardiovascular risk who require an NSAID, naproxen is the recommended treatment 8. Which TWO of the following statements are correct? a) For patients with a high GI risk and a high CV risk who require an NSAID, naproxen with a PPI or COX-2 inhibitor with a PPI are the recommended treatments b) For those with a low GI risk and a low CV risk who require an NSAID, a COX-2-inhibitor is the recommended treatment c) Patients with coronary artery stents who are receiving aspirin and clopidogrel are not at increased risk of GI bleeding d) Rapid symptom recurrence on stopping acidsuppression therapy is virtually diagnostic of GORD 9. Which TWO of the following statements are correct? a) Gastroscopy is indicated if malignancy is suspected or dyspeptic symptoms are unresponsive to acid-suppression therapy b) On-demand therapy is ineffective compared with regular acid-suppression therapies for most patients with GORD c) Patients with severe oesophagitis should be maintained on PPI therapy to avoid complications d) Lifestyle modification or simple antacids are as effective as single daily dose PPIs in the management of GORD 10. Which TWO of the following statements are correct? a) Few treatable upper GI cancers are detected by early endoscopy in patients with dyspepsia b) Endoscopy after a trial of acid-suppression therapy has a greater diagnostic yield than endoscopy before or during acid-suppression therapy c) H. pylori-negative patients with dyspepsia should have an endoscopy before treatment with a PPI d) H. pylori-positive patients should always be referred for an endoscopy before being given pharmacotherapy

CPD QUIZ UPDATE

The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOW TO TREAT Editor: Dr Giovanna Zingarelli Co-ordinator: Julian McAllan Quiz: Dr Giovanna Zingarelli

NEXT WEEK Abdominal aortic aneurysms (AAAs) are silent time bombs, but the treatment of AAAs is not what it used to be in particular, recent advances in endovascular surgery have dramatically lowered the associated morbidity and mortality of elective aortic surgery. The next How to Treat focuses on detecting and managing AAAs. The authors are Dr Dom Simring and Dr Steven Dubenec, both of Royal Prince Alfred Hospital, and Vascular Associates Camperdown, NSW.

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| Australian Doctor | 22 January 2010

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