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Functional Dyspepsia:Recent Advances In Pathophysiology

W H C Hu,* MBBS, MRCP, FHKAM(Med), FHKCP

S K Lam, MD, FRCP, FHKCPDepartment of Medicine

The University of Hong Kong

Summary

Functional (non-ulcer) dyspepsia is a common disease. With effective treatment now available for peptic ulcer;

functional dyspepsia remains a major therapeutic challenge in gastrointestinal medicine. Despite advances intechnology and diagnostic methods, the "true" underlying pathogenic abnormality in this disease remains elusive.

It is likely that functional dyspepsia is a heterogeneous disorder with multiple aetiological factors. In this articlevarious pathophysiological abnormalities in functional dyspepsia are discussed, and possible aetiological mechanisms

proposed. (HK Pract 1998;20:327-334)

Introduction

The discovery of Helicobacter

pylori and effective treatments for

peptic ulcer disease has resulted in a

focusing of research activity into

f u n c t i o n a l dyspepsia, a common

condition with l imited therapeutic

opt ions . Func t iona l (non-ulcer)

dyspepsia is a term generally applied

to p a t i e n t s who h a v e c h r o n i c

dyspepsia where oesophagogas-troduodenoscopy, considered the goldstandard test, has excluded pepticulceration, reflux oesophagitis andmalignancy.1 , 2 Patients with non-erosive gastritis and duodenitis, byconvention, are not excluded. Thecurrently accepted "Rome definitionof dyspepsia", based on the consensusopinion of an international panel ofclinical investigators, is persistent orrecurrent pain or discomfort centered

in the upper abdomen' (Table 1).Discomfort, in this context, may becharacterised by symptoms such asearly satiety, postprandial discomfortor fullness, bloating or nausea. On theother hand, symptoms referable to theoesophagus alone, such as heartburnor acid regurgitation, are no longerconsidered to constitute part of thedef in i t ion ; although patients withdyspepsia may concurrent ly havetypical reflux-like symptoms.12

* Address for correspondence: Dr Wayne Hu. Senior Medical Officer, Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong.

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Pathophysiology of Functional Dyspepsia

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Table 1: Definitions in dyspepsia

Functional dyspepsia

Ulcer-like dyspepsia

Dysmotility-like dyspepsia

Reflux-like dyspepsia

Unspecified dyspepsia(non-specific)

Pain or discomfort centered in the upper abdomen; and no clinical, biochemical orultrasonographic evidence of known organic disease that is likely to explain the symptoms.

Three or more of the following are necessary, but upper abdominal pain must be apredominant complaint:

1. Pain that is well localized in the epigastrium (i.e. can be localized to a single smallarea by pointing with one or two fingers);

2. Pain relieved by food, often (more than 25% of the time);3. Pain relieved by antacids and/ or H2 blockers, often;4. Pain occurring before meals or when hungry, often;5. Pain that at times wakes the patient from sleep;6. Periodic pain with remissions and relapses (periods of at least 2 weeks with no pain

interspersed with periods of weeks to months when there is pain).

Pain is not a dominant symptom. Upper abdominal discomfort should be present in all cases.This discomfort should be chronic and characterized by three or more of the following:

1. Early satiety;2. Postprandial fullness;3. Nausea;4. Retching and/ or vomiting that is recurrent;5. Bloating in the upper abdomen not accompanied by visible distension;6. Upper abdominal discomfort often aggravated by food.

Predominant dyspepsia with heartburn or acid regurgitation. Many of these patients mayactually have gastroesophageal reflux disease. (See text)

Dyspeptic patients whose symptoms do not fulfil the criteria for ulcer-like, dysmotility-likeor reflux-like dyspepsia.

Adapted from Drossman DA, Richter JE, Talley NJ. et al. Diagnostic criteria for functional gastrointestinal disorders (Ref. 40).

The classification of dyspepsiai n t o v a r i o u s s u b g r o u p s ( e . g . ,d y s m o t i l i t y - l i k e , u l ce r - l ike , orreflux-like)1-3 has been problematic.There is a considerable overlap ins y m p t o m s a n d p a t i e n t s m a ysimultaneously fall into different

subgroups. Also, symptoms appearto be poor discriminators of organicversus f u n c t i o n a l disease,4 andsimilar responses to treatment withc i sapr ide has been reported ind i f f e r e n t s y m p t o m g r o u p s . 5

H o w e v e r , more recent s tud ie sindicated that severe and relevant

p o s t p r a n d i a l f u l l n e s s , severev o m i t i n g and f e m a l e sex a rep r e d i c t o r s of de layed g a s t r i cemptying,6 and reflux-like symptomsmay be ind ica t ive of increasedgastro-oesophageal reflux.7

(Continued on page 330)

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Pathophysiology of func-tional dyspepsia

Helicobacter pylori, gastritis andduodenitis

A p o p u l a t i o n based s tudyexamined H. pylori positivity indyspeptics with normal endoscopicf i n d i n g s and no rma l con t ro l s .A l though there was a trend fordyspeptics to have a higher infectionrate, the d i f f e r e n c e s were notstatistically significant.8 In a Dutchs tudy , the apparent associa t ionbetween H. pylori and dyspepsia wasdue to subjects with a past ulcerhistory.9 From another perspective,most studies have failed to demon-strate any significant difference inthe symptom pattern in patients withand without the infection.10, 11 Also,H. pylori infection does not affectgastric sensitivity,12 antro-duodenalmot i l i ty 1 3 or gastric emptying1 4 indyspeptic patients. Thus, althoughhistological gastritis (usually causedby H. pylori) is found in between30% to 70% of p a t i e n t s w i t hfunctional dyspepsia,15, 16 it is unlikelyto be a s i g n i f i c a n t c ause fordyspeptic symptoms.

Several studies have attemptedto study the effects of Helicobactereradication, but in many the designsare f l a w e d . 1 7 There are severalreports tha t H. pylori p o s i t i v edyspep t ics r ece iv ing succes s fu le r a d i c a t i o n t h e r a p y h a d l e s ss y m p t o m s t h a n n o n - e r a d i c a t e dcontrols after 6 to 12 months,al though short term response rateswere similar in both groups.18-20 Onthe other hand, another double-blind6-month s tudy us ing a v a l i d a t e d

symptom questionnaire showed nodifference in dyspeptic symptomsafter Helicobacter eradication.21 Atthe present state of knowledge, node f in i t e l i nk between H. pylorigastritis and functional dyspepsia canbe established.

Gastric acid

A recent s tudy us ing gastrinreleasing peptide as a secretogogueto s imula te meal-s t imulated acido u t p u t suggested tha t H. pyloriposi t ive dyspeptics have a higheracid o u t p u t t h a n a s y m p t o m a t i cinfected volunteers.22 However, moststudies have found normal basal andgastrin-stimulated peak acid outputin f u n c t i o n a l dyspep t i c s , whencompared to healthy controls.23

Various studies have attemptedto reproduce pain with intragastricacid p e r f u s i o n . A l t h o u g h somepat ients may experience a typica ldiscomfort, similar symptoms mayoccur af ter pe r fu s ion of normalsaline.2 4 Moreover, while patientswith functional dyspepsia are morel i k e l y to exper ience p a i n a f te rpentagastrin injection, blocking ofacid secretion did not reduce pain.25

Acid p r o b a b l y does not p l a y asignificant role in the pathogenesis offunc t iona l dyspepsia but may bemore re levant in the subgroup ofdyspeptic patients with ref lux- l ikesymptoms.7

Dysmotility

Delayed gastric emptying26 andant ra l h y p o m o t i l i t y 2 7 have beend e m o n s t r a t e d in up to 50% of

patients with functional dyspepsia.However, the correlation betweendyspeptic symptoms and the gastrice m p t y i n g rate is poor.2 8 Morerecently, abnormal distribution ofsolids in the stomach has beendemonst ra ted in pat ients 2 9 wi thincreased postprandial accumulationin the distal stomach. Also, a studyhas reported a lower number ofduodenal migrating motor complexeswith an increased proportion of timein phase II of the cycle dur ingsleep.30 However, in most patientsstudied, there was poor temporalcorrelation between episodes of painand abnormal motor activity.

Altered sensory function

Recent s tudies have focusedmore on abnorma l perception infunctional gastrointestinal disorders.Decreased perception thresholds toi n t r a l u m i n a l d i s t e n s i o n in the 'gastric fundus 3 1 - 3 3 and duodenum34

has b e e n d e m o n s t r a t e d in ap r o p o r t i o n of p a t i e n t s ; and adecreased gastric relaxatory responseto duodenal d i s t ens ion has alsobeen observed." It is possible thatabnormal fundal tone and gastricrelaxation may act synergisticallywith lowered visceral pain thresholdsto produce postprandial pain andbloating in patients.

Increased visceral sensi t ivi tyappears to be a generalised phenom-enon in the gastrointestinal tract.Dyspeptic patients also have loweredsensory thresholds in the oesophagusand rectum.35 Interestingly, despitethe widespread nature of visceralh y p e r s e n s i t i v i t y , somat ic p a i nt h r e s h o l d s are not a f f ec t ed in

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ey messages

1. Functional dyspepsia is a common disease with heterogeneous pathophysiology.

2. Although firmly implicated in peptic ulcer disease, the role of Helicobacter pylori in functional dyspepsia is less

clear. Only some studies have shown a long-term benefit in dyspeptic symptoms after H. pylori eradication.

3. Gastric acid is probably not related to dyspeptic symptoms.

4. Dyspeptic patients may have disordered gastrointestinal motility and abnormal fundal tone.

5. Patients may have abnormal visceral hypersensitivity.

6. Increased anxiety and depression are present in dyspeptic patients attending medical clinics.

f u n c t i o n a l dyspepsia . The painthreshold to transcutaneous nervestimulation remains normal, despite alower pain th re sho ld to bal loondistension in the stomach.33

Psychosocial factors

Several studies have shown ah i g h e r l e v e l o f a n x i e t y a n ddepression in patients with functionaldyspeps i a , when compared tohealthy controls.36-38 However, theirlevel of anxiety may not be differentf rom p a t i e n t s w i t h n o n l i f e -t h r e a t e n i n g o r g a n i c b o w e ldiseases.36,39 Co-existing depressionand anxiety may act as a catalyst fora patient to seek medical care, ratherthan being the cause of symptoms.

Conclusions

Much advance has been made inthe unders tanding of func t iona ldyspepsia. It is probably hetero-

geneous in nature and the lack ofdiagnostic markers restrict precisestudy. It remains to be determinedwhether the various physiologicalabnormalities observed are markerso f t he c o n d i t i o n o r m e r e l yepiphenomena . Truly e f fec t ivemanagement strategies can only beformulated when the true underlyingaetiology has been made clear. •

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