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Can peptic ulcer disease be prevented?

Despite the improvements in our understanding of peptic ulceration

and the emergence of effective

anti-secretory drugs, gastrointestinal ulcer disease continues to be a significant problem in primary and secondary care.

Annually, around 40 per cent of the adult population suffer with dyspepsia, of which about 10 per cent will consult their GP, and 1 per cent will be endoscoped.

At endoscopy, 40 per cent have functional, or non-ulcer, dyspepsia,

40 per cent have gastro-oesophageal reflux disease, 13 per cent have some

form of ulcer and 3 per cent have cancer.1 In 2004 alone, drugs prescribed for dyspepsia cost the NHS £625 million,

7 per cent of the primary care prescribing budget.2

What is an ulcer?

Ulceration of the upper GI tract, in contrast to an erosion, refers to the situation where the lesion extends through the mucosa and the muscularis mucosae; an erosion is a focal loss of superficial epithelial cells and glands without extension through the muscularis mucosae.

At the other extreme, an ulcer may extend through the wall of the GI tract. This may result in the GI lumen becoming connected to the peritoneal cavity

(a perforated ulcer), a solid organ such

as the pancreas (a penetrating ulcer),

or another hollow organ such as the intestine or bile duct (a fistulising ulcer).

The majority of ulcers affecting the upper GI tract can be categorised into peptic ulcers and NSAID-related ulcers, reflecting their different aetiologies.

What causes upper GI ulceration?

The traditional view that upper GI ulceration was solely attributable to exposure of the gastric or duodenal mucosa to gastric acid and pepsin is not supported by recent research. The discovery of Helicobacter pylori has revealed the link between this organism and peptic ulceration.3 More than

95 per cent of patients with a peptic duodenal ulcer are infected with H. pylori, and H. pylori can be isolated from 70 per cent of patients with peptic gastric ulcers.

However, many upper GI ulcers are caused by NSAID use. A number of studies have shown that H. pylori was implicated in about half the patients with an acute upper GI bleed and most of the other bleeds were caused by NSAID use, with only 2 to 4 per cent of patients with non-H. pylori or non-NSAID related bleeds.4,5

In apparent non-H. pylori, non-NSAID related ulcers the following should be considered as possibilities:

• Failure to detect H. pylori infection because of recent PPI or antibiotic ingestion, or inadequate testing.

• Surreptitious or inadvertent NSAID or aspirin use.

• Ulcers related to ingestion of other drugs. Potassium chloride, bisphosphonates and immunosuppressive agents are recognised causes of ulcers, and more recently SSRIs have been implicated in GI bleeding.

• Zollinger-Ellison syndrome, especially in association with multiple ulcers, diarrhoea, weight loss and hypercalcaemia.

• Crohn's disease.

• Cancer (which requires immediate investigation and exclusion).

The differing aetiologies of ulceration point to the pathophysiology of ulcer formation. Ulceration associated with

H. pylori is poorly understood; its cause is likely to be multifactorial, including the virulence of the sub-species, raised gastrin levels, raised parietal cell mass and disruption of mucosal integrity.

NSAID-related ulceration is believed

to be secondary to a decrease in prostaglandin production resulting from the inhibition of cyclooxygenase.

There is evidence indicating that

H. pylori presence and NSAID use doubles the risk of developing a bleeding ulcer.6

What is the incidence of upper GI ulceration?

The annual incidence varies from 47 to

116 per 100,000 of the population. This equates to more than 2,500 hospital admissions each year in the United Kingdom.7 In addition, it is worthwhile considering the actual risk of ulceration. Not all patients who have H. pylori infection or who are taking NSAIDs will develop ulcers.

Duodenal ulcers are more common than gastric ulcers, and infection with

H. pylori increases the risk of peptic ulcer disease by five to seven times. Smoking doubles the risk of peptic ulcer disease, and daily NSAID use increases the risk of ulceration by a factor of 10 to 20.8 Patients who have first-degree relatives with peptic ulcer disease have three times the risk of developing the disease. The higher degree of risk seen here probably relates to the known propensity of H. pylori infection to spread within families, the acquisition of similar and possibly more virulent strains, and to a similar environment and diet.8

In one clinical study,9 blood group antigens were not correlated with either the risk of peptic ulcer disease or the likelihood of H. pylori infection. Similarly, ulcers are not caused by emotional stress or spicy (or any other) foods. However, emotional stress may aggravate ulcer disease in some patients.8

The changing pattern of upper GI ulceration

Throughout the past 200 years, the history of upper GI ulceration has been one of profound changes in frequency and clinical presentation; in the

19th century, gastric ulcers were a disease of young women, and duodenal ulceration was rare.

Recently, studies have reported changes in the trends of the natural history of this condition, as well as changes in the prognosis through advances in medical and surgical treatment.

A study in the Trent region10,11 showed that emergency admission rates for duodenal and gastric ulcer for complications or severe pain had fluctuated over the past three decades with little overall change, but elective surgery had declined dramatically.

However, the incidence of emergency surgery for ulcers increased significantly between 1987 and 2000, though the surgical mortality remained static between 5 and 14 per cent in the UK and North America between 1987 and 1999.12

An important factor in the unchanging mortality relates to the comorbidity often associated with the increasing age of the population.13 In the past 30 years, upper

GI ulceration has become a disease of elderly patients. Another study, in 2002, recognised that admission rates for gastric and duodenal ulcer haemorrhage and duodenal ulcer, but not gastric ulcer perforation, had increased among older patients.14

Although altered transmissibility brought about by improvements in hygiene and increased use of antibiotics and PPIs has resulted in a fall in the incidence of H. pylori-associated ulceration,15 the increase in NSAID and low-dose aspirin related ulceration has negated this effect, particularly among the older population.

Upper GI ulceration

and NSAIDS

NSAIDs and aspirin are prescribed in large quantities for a number of conditions;14 in 2004 the cost of prescribing NSAIDs in the UK was £259 million.16 A study in 200417 showed that among users of these drug classes the risk of upper GI ulceration was one case per 1,000 person-years. Compared with non-users, the relative risk was 2.9 for aspirin (for doses up to 300mg) and 4.0 for NSAIDs.

A strategy to reduce this risk is to prescribe a standard NSAID with gastroprotection. Misoprostol reduces serious upper GI complications in high-risk patients compared with placebo, and significantly reduces NSAID-related gastric and duodenal ulcers found on endoscopy.18 PPIs or double dose

H2-receptor antagonists also reduce the risk of gastric and duodenal ulcers. Currently there is no clear evidence as to which strategy is more cost effective. Eradicating H. pylori before commencing an NSAID is useful in patients with a previous history, or at high risk, of peptic ulcer disease.19

Diagnosis

Upper GI ulceration is difficult to differentiate clinically from functional dyspepsia. The main distinguishing feature is bleeding, and this is not a reliable indicator; it could be bleeding from oesophageal varices in a patient who also suffers from dyspepsia.

Therefore, a suspected diagnosis of upper GI ulceration needs to be confirmed by endoscopy or, in exceptional cases,

a barium meal.20 The advantage of endoscopy is that therapeutic measures to control the bleeding may be performed at the same time, and the patient may be screened for H. pylori by biopsy or the rapid urease test.

Initial management

Primary care management is determined by whether an ulcer is suspected or if there is an acute upper GI haemorrhage.

A suspected ulcer will be treated with acid suppression and a request for an endoscopy, whereas bleeding requires urgent referral to hospital.21 A minority of fit, young patients whose index symptom is a melaena stool may be managed as outpatients, but an urgent endoscopy is still required. The majority of patients will require urgent transfer. Even when a patient is haemodynamically stable at presentation they might, and often do, deteriorate very rapidly. Intravenous access should be obtained and oxygen administered as the patient is transferred to hospital.

primary care Follow-up

The GP has an important role in following up patients. Advice on lifestyle, including smoking cessation, weight reduction and healthy eating is appropriate,21 although clear evidence is lacking. Ensuring that the patient does not inadvertently take NSAIDs is also important.

If symptoms fail to settle, it might indicate failure of H. pylori eradication therapy. A study in the Netherlands demonstrated that mean eradication rates for bismuth-based triple therapy, PPI triple therapy, quadruple and ranitidine bismuth citrate combination therapies vary from 65 to 92 per cent.22 A more recent study from Italy confirmed that in clinical practice the recommended treatment regimens achieve only an 80 per cent

H. pylori eradication rate.23 Testing for

H. pylori using urea breath tests is the most accurate technique in primary care, with greater than 95 per cent sensitivity and specificity, but the patient needs to stop PPIs and antibiotics two weeks before testing.24

Conclusion

The GP is in an unenviable position when trying to prevent this condition, and the evidence for the best treatment strategy is lacking in many key areas. Questions that need to be considered include:

• Should all patients have H. pylori screening before embarking on long-term aspirin or NSAID treatment?

• Should patients over 60 years on

aspirin or NSAIDs receive routine gastroprotection, and what is the most effective agent for this?

•What are the best treatment strategies for patients at any age with chronic arthritic conditions?

Addressing these points will allow targeted treatments for the at-risk patient, and should help reduce the incidence of ulceration.

References

1 The Care of GI Disorders Outside Hospital, PCSG, March 2006 www.pcsg.org.uk

2 Mason J, Hungin APS. Review article: GORD – the health economic implications. Ailment Pharmacol Ther 2005;22 Suppl 1:20-31

3 Marshall BJ and Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1(8390):1311-5

4 Chan HL, Wu JC, Chan FK et al. Is non-Helicobacter pylori, non-NSAID peptic ulcer a common cause of upper GI bleeding? A prospective study of 977 patients. Gastrointest Endosc 2001;53(4):438-42

5 Arroyo MT, Forne M, de Argila?CM, et al. The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe. Helicobacter 2004;9:249-254

6Aalykke C, Lauritsen JM, Hallas?J, et al. Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case-control study. Gastroenterology 1999;116:1305-9

7 Dallal H and Palmer K. ABC of the upper gastrointestinal tract. BMJ 2001;323:1115-7

8 Graham DY. Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer:

a model. Gastroenterology 1997;113(6):1983-91

9 Umlauft F, Keeffe EB, Offner F, et al. Helicobacter pylori infection and blood group antigens: lack of clinical association. Am J Gastroenterol 1996;91(10):2135-8

10 Bardhan KD, Williamson M, Lyon?C et al. Gastric ulcer (GU) admissions in the Trent regional Authority (TRHA), UK 1972 – 1996; an ageing problem? Gut 1999 44 Suppl 1:125A

11 Bardhan KD, Williamson M, Lyon?C et al. The changing pattern of duodenal ulcer (DU) in the Trent regional Authority (TRHA), UK 1972 – 1996. Gut 1999 44

Suppl 1:124A,

12 Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1995;90:206–210

13 Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996;38:316–321

14 Higham J, Kang JY, Majeed A. Recent trends in admissions and mortality due to peptic ulcer in England: increasing frequency of haemorrhage among older subjects. Gut 2002;50:460-464

15 Predicting Trends in Helicobacter pylori Emerging Infectious Diseases 2000;6(3). Centers for Disease Control and Prevention (CDC)

16 Prescription Pricing Division. Analgesics and NSAIDs Prescribing. 2006:?PPD www.ppa.nhs.uk

17 Rodriguez L, Hernandez-Diaz S. Risk of uncomplicated Peptic Ulcer among users of aspirin

and nonaspirin nonsteroidal anti-inflammatory drugs Am J Epidemiol 2004;159(1):23-31

18 Rostom A, Dube?C, Wells G et al. Prevention of NSAID-induced gastroduodenal ulcers Cochrane Database Syst Rev 2002;(4):CD002296

19 National Prescribing Centre. NSAIDs and gastroprotection. MeReC Briefing 2002;20:1-4

20 Stevenson GW, Norman G, Frost?R et al. Barium meal or endoscopy? A prospective randomized study of patient preference and physician decision making. Clin Radiol 1991;44:317-321

21 National Institute for Health and Clinical Excellence. Dyspepsia: managing adult patients in primary care. Clinical Guideline 17. London:NICE 2004

22 Houben M, van de Beek D, Hensen EF, et al. A systematic review of Helicobacter pylori eradication therapy – the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther 1999;13(8):1047-55

23 Cavallaro L, Egan B, O'Morain?C, et al. Treatment

of Helicobacter pylori Infection. Helicobacter 2006;11:36-38

24 Roberts AP, Childs SM, Rubin?G, et al. Tests for Helicobacter pylori infection: a critical appraisal from primary care. Fam Pract 2000;17(suppl 2):S12-S20

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