Assessment of gastrointestinal involvement

P.J. Clements1, R. Becvar2, A.A. Drosos3, L. Ghattas4, A. Gabrielli4

Division of Rheumatology, Department ABSTRACT When a normal subject swallows a wet of , UCLA School of Medicine, The purpose of this paper is to identify meal, there is migration of increased 2 Los Angeles, California, USA; Institute a list of clinical, laboratory and instru - pressure as the attempts to of Rheumatology, Prague, Czech Republic; mental tools suitable to assess the pres - propel the bolus down into the stom- 3Section of Rheumatology, Department of Internal Medicine, University of Ioannina, ence of gastrointestinal involvement in ach. Also at the time of the swallow, Ioannina, Greece; 4Istituto di Clinica Med- SSc patients to be included in clinical there is relaxation of the lower esopha- ica Generale, Ematologia ed Immunologia i nve s t i gational studies. The pert i n e n t geal sphincter (LES) pressure in antici- Clinica, Università di Ancona, Ancona, literature was reviewed to select those pation of the arrival of the bolus. Once Italy. variables which have been demonstrat - the bolus arrives, the pressure in the Please address correspondence to: ed to be valid, reliable and feasible.A sphincter rises back to its baseline Philip J. Clements, MD, MPH, Division minimal core set of variables has been (usually 20-30 mm Hg) to close off the of Rheumatology/Medicine, Rm 32-59, identified to be used in clinical investi - from the esophagus, prevent- 1000 Veteran Avenue, UCLA School of gation for the assessment of esophagus, ing reflux. Medicine, Los Angeles, California, USA. E-mail: [email protected] s t o m a ch , , colon and When a scleroderma subject with eso- anorectum involvement in scleroderma p h ageal invo l vement swa l l ows a we t Clin Exp Rheumatol 2003; 21 (Suppl. 29): S15-S18. patients. m e a l , t h e re is an ab n o rmal pre s s u re response. Because the pharynx, which © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2003. Introduction is composed of skeletal muscle, usually Involvement of the gastrointestinal (GI) remains functional, manometry regis- Key words: , tract in systemic sclerosis (SSc) is sec- ters the swallow in the pharynx. Con- esophagus, stomach, small intestine, ond in fre q u e n cy only to the skin: versely manometry registers a reduced . e s o p h ageal dysmotility and its pro b- p re s s u re response from the smooth lems occur in 75-90% of SSc patients, muscle of the body of the esophagus stomach involvement in at least 50%, and a lack of relaxation of the lower small bowel invo l vement in 40-70%, e s o p h ageal sphincter (LES) pre s s u re. colon involvement in 20-50%, and ano- In many instances the LES pressure re- rectal invo l vement in 50-70% (1). mains reduced or low most of the time. Since there is often a disparity between Similar dysmotility pro blems occur the frequency of symptoms in contrast throughout the stomach and intestines to the frequency of objective signs of and with increasing frequency and se- organ involvement, patient symptoms verity, the longer the duration of SSc. alone cannot be relied upon to accu- In the fasting stat e, a n t ro d u o d e n a l rately and objectively document GI in- motility recordings show that there is volvement. spontaneous peristalsis in the form of m i grating myo e l e c t ric complexe s Pathophysiology (MMC). A c t ivity (increases in pre s- Although the manife s t ations of in- sure) begins in the antrum of the stom- vo l vement in the diffe rent GI orga n ach. The activity slowly migrates into systems may va ry considerably, t h e and down the . Within 10-15 underlying pathophysiology for the ga- minutes after eating, the normal MMCs strointestinal tract is the same.The pri- (which are seen during fasting) are re- mary abnormality involves dysmotility placed by irregular contractile activity of smooth muscles of the entire gas- (which at times can be quite intense). trointestinal tract. In this respect, rele- This irregular contractility is designed vant information has been provided by to move foods and liquids out of the manometry, which measures pressure stomach and into the intestine. cha n g es inside the gas t r ointestinal tube. In scleroderma, the MMCs are reduced These pressure changes are thought to or absent at rest. In their place high- reflect the state of muscle tone and per- amplitude, uncoordinated contractions istalsis (i.e. , i n c reased pre s s u re is are seen in the antrum and small intes- thought to rep resent increased tone). t i n e. After eat i n g, the uncoord i n at e d

S-15 Assessment of gastrointestinal involvement in SSc / P.J. Clements et al. activity may persist but there may be Phase 1: There is neurological dysfunc- t ive info rm ation about stru c t u re (i.e. , no contractile response of the stomach tion, but the muscle can still respond to strictures, diverticulae, masses, etc.). or intestine to a meal. In advanced in- prokinetic agents. testinal scl e ro d e rma dra m atic hy p o- Phase 2: As smooth muscle atrophies, Gastric involvement motility of the stomach and small intes- the response to prokinetic agents be- G a s t ric dysmotility occurs in a high tine can occur, which at times gives rise comes less reliable. proportion of patients with sclerodema to pseudo-obstruction. Phase 3: Finally, when muscle atroph- (6), but the methods to assess it are few In 1971 Cohen et al. published a report ies completely, the smooth muscle can and mainly represented by: that greatly advanced our understand- no longer respond to prokinetic stimuli. 1. Gastric emptying.The results can be ing of the pathophysiology of gut prob- given quantitatively as the percent of lems in scleroderma (2). Using esopha- Candidate variables radioactivity remaining in the stomach geal manometry, t h ey studied LES Esophageal involvement “x” minutes after the patient (who is in pressures in normal subjects, healthy Hypomotility in the esophagus results the supine position) swallows a radio- subjects who had an incompetent LES, in delayed transit down the esophagus active meal. subjects with Raynaud’s phenomemon, and in a weakened lower esophageal 2. .This test gives only qua- and two groups of scleroderma patients sphincter.The repeated bathing of the litative information about the structure (one with normal peristalsis in the body distal esophagus by hydrochloric acid of the esophagus and the stomach. of the esophagus and the second with may result in erosive esophagitis and abnormal peristalsis). Cohen found that stricture. Esophageal involvement can Small intestinal involvement LES pressure was lower in scleroderma be assessed by the following methods Hypomotility results in delayed transit populations than in normals. More im- (3-5): of food and liquids through the small portantly they studied the response of 1. Manometry. Assessment of esopha- intestine.The stagnation of flow from LES pressures to stimulation by several geal motility can be made dire c t ly this hypomotility allows colonic bacte- d i ffe rent pharm a c o l ogic age n t s : o n e using manometry. During manometry, ria to migrate upstream into the small agent which directly stimulated smooth wave amplitude (in mm Hg) and lower i n t e s t i n e, wh e re the bacteria bre a k- muscle (methacholine) and two agents esophageal sphincter pressure (in mm down bile acids necessary for the ab- which stimulated smooth muscle indi- Hg) can be determined on a continuous sorption of . The inability to absorb rectly through stimulation of choliner- scale. Motility in the body of the eso- fats may lead to , weight gic nerves (edrophonium and Gastrin p h ag u s , h oweve r, is usually gra d e d loss and . In some instances the I). The studies showed that esophageal q u a l i t at ive ly as normal or ab n o rm a l hypomotility may be so severe that it muscle could and did respond to direct (hypomotile). When motility is abnor- p roduces re c u rre n t , p e rsistent ileus stimulation with methacholine. On the mal, the degree of hypomotility can be ( p s e u d o - o b s t ruction). Intestinal invo l- other hand stimulation of cholinergic f u rther graded as mild, m o d e rat e, o r vement can be assessed by several me- n e rves by edrophonium and ga s t ri n severe. thods, depending on which pathophy- failed to lead to stimulation of the LES. 2. pH monitoring of the distal esopha - siologic aspect is more prevalent (1, 3, The conclusion was that the cholinergic gus. This test can produce quantitative 7-9): nerves were not transmitting the mes- data by assessing pH in the distal eso- 1. Small bowel barium follow through sage to the smooth muscle. A further phagus (i.e., the number of episodes of x-ray.The test tends to produce qualita- conclusion was that the earliest defect pH < 4, longest episode of pH < 4, per- t ive data (dilat at i o n , p s e u d o s a c c u l a- in the dismotility disorder of scleroder- cent of study time with pH < 4, etc.). tions), but the duodenal diameter (at ma is in the cholinergic nerves which 3. Scintigraphy.The results can be giv- the 2nd portion of the duodenum) and supply the muscle rather than a process en quantitatively as the percent of ra- transit time can be measured quantita- primary to the muscle itself. dioactivity remaining in the esophagus tively. Pathologic studies support this obser- “x” minutes after the patient (who is in 2. 72-hour fecal determination. This vation. Early in scl e ro d e rm a , t h e a supine position) swallows a radioac- incommodious test re q u i res a 100- smooth muscle of the esophagus may tive meal. gram fat diet during and for 5 meals appear normal structurally but its func- 4. Endoscopy.This test gives primarily prior to the 72-hour collection of feces. tion may be decreased. Later, progres- qualitative information about the struc- The entire stool sample is then homog- s ive at ro p hy develops and wh at re- ture of the esophagus and stomach. enized and processed before a sample mains of the muscle fails to respond to 5. Cine/video barium esophagra m. is tested for fat contents. It is consid- drugs. In addition the mucosal surfaces This test, when performed in the supine ered by many to be the “gold standard” may become atrophic and the muscle position, gives qualitative information for evaluating malabsorption. It gives and adventitial layers become fibrotic. about motility (normal or ab n o rm a l ; quantitative data. These data have given rise to a 3-phase abnormal tracings can further be grad- 3. Jejunal culture s. Obtaining these hypothesis that has practical implica- ed as mild, moderate or severe hypo- cultures requires passing a tube or cap- tions for the evaluation and manage- motility or as spasm of gastroesopha- sule orally and verification that the cul- ment of GI tract problems in SSc. geal sphincter). It also can give qualita- ture device is actually in the jejunum.

S-16 Assessment of gastrointestinal involvement in SSc / P.J. Clements et al.

Table I. List of potential tests for evaluating gastrointestinal involvement in the SSc patient t e chniques give pri m a ri ly qualitat ive (and whether they give primarily quantitative or qualitative results). structural data. They are also expen- sive. Organ Quantitative Qualitative 9. Serum carotene can be used as a sur- Esophagus Manometry Manometry rogate for absorption/malabsorption. LESP* Motility patterns 10. Pre-albumin can be used to assess Wave amplitude Endoscopy s t a rvation and nu t rition. Low leve l s PH monitor Endoscopic ultrasound Scintigraphy Cine/video barium esophagram m ay result from pro blems with the s t ru c t u re, ab s o rption and function of Stomach Scintigraphic emptying Endoscopy the gut. Upper gastrointestinal barium x-ray 11. Body weight (particularly changes Small intestine Duodenal diameter (x-ray) Manometry over time) and the body mass index (as- 72-hour fecal fat Abdominal x-ray (plain) Hydrogen breath test Small bowel follow-through (x-ray) suming height remains constant) can be Schilling’s test Abdominal CT used to assess nutritional status, starva- D-xylose Endoscopy tion and weight loss. Jejunal culture Large intestine Sitz marker (transit) Motility Large intestine involvement Barium enema S eve ral ab n o rmalities have been de- monstrated to occur in the colon of SSc patients and the anorectum is the most Anorectum —- Motility affected part. Manometric studies have *Low esophageal sphincter pressure. documented that prolonged pancolonic transit time more than functional ob- struction at the anorectum is responsi- The results are qualitat ive in nat u re growth. When the test is repeated after ble for constipation (10). The internal ( p resence or absence of bacteri a l a course of antibiotics, the absorption and ex t e rnal sphincters may become growth). of vitamin B12 may have increased. hy p o t o n i c. We a kened sphincters may 4. H y d roge n - b re ath test. This test is 6. D-xylose test. When swallowed, this give rise to fecal incontinence. Investi- used as a surrogate for assessing small n o n - m e t ab o l i z able sugar will be ab- gation of the colon may be performed b owel bacterial ove rgrowth. The test sorbed and excreted unchanged into the with: subject swallows a non-absorbable sug- urine and can be measured chemically. 1. Sitz marker.When swallowed, these ar (i.e. , lactulose) and the subject’s If the intestinal mucosa is not function- opaque markers can be used to measure breath hydrogen levels are determined ing pro p e rly, lesser than norm a l transit times in the large intestine. every 15 minutes for 3 hours. Early ap- amounts of the sugar will be absorbed 2. Intestinal manometry. In the large in- pearance of a hydrogen spike suggests and ex-creted into the urine. testine and , manometric studies that bacteria have metabolized the sug- 7. Intestinal manometry. In the intes- tend to give qualitative rather than qua- ar high in the small intestine. It gives tine, manometric studies tend to give ntitative data, which may or may not be quantitative data but is subject to a ple- qualitative rather than quantitative data, reproducible. In addition, these tech- thora of technical problems, which may which may or may not be reproducible. niques are not always readily available invalidate the results. In add i t i o n , the techniques are not in the community or study centers. The 5. Schilling’s test. Usually thought of always readily available in the commu- test tends to be expensive and the re- as the test for clinching the diagnosis of nity or study centers. The test tends to sults are often operator dependent. p e rnicious anemia, it also can show be expensive and the results are often 3. S i g m o i d o s c o py and colonoscopy. poor absorption of vitamin B12 in the operator dependent. These methods give primarily qualita- presence of small bowel bacterial over- 8. Abdominal x-ray and CT. Th e s e tive information about the structure of the colon and recto-sigmoid region. Table II. Core set variables 4. Barium enema.This procedure can show pseudodiverticulae. Organ Recommended Core Set Variables Table I summarizes the candidate vari- ables considered above. Esophagus Symptoms of dysphagia, heartburn Cine/video barium esophagram Discussion Stomach Symptoms of early satiety, bloating, vomiting Identification of core set variables Small intestine Symptoms of diarrhea, constipation, intestinal distention Table II lists the core set vari a bles need- Large intestine Symptoms of intestinal distention, constipation ed to assess the presence of GI involve- ment in the SSc patient enrolled in clin- Anorectum Symptoms of fecal incontinence ical investigational studies.

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Rationale for the selection of the re l i ab i l i t y. In part i c u l a r, e s o p h age a l References variables sc i n t i g raph y using a semi-solid bolus is 1. SJOGREN RW: Review: Gastrointestinal dis- Since impaired peristalsis (often appre- both quantitat ive and sensitive with, orders in scleroderma. Arthritis Rheum 1994; c i ated as distal dy s p h agia for solid ho wever , a 20% false positive rate (12) 37: 1265-82. 2. COHEN S , RISHER R, LIPSHUTZ W, TURNER fo o d s ) , ga s t ro e s o p h ageal re fl u x , e ro- whi c h ren d e r s this technique inapp r o- R,MYERS A,SCHUMACHER R: The pathoge- sive esophagitis (resulting in heartburn) pri a te for scree n i n g . Furth e rm o r e, es o - nesis of esophageal dysfunction in scleroder- and esophageal strictures are likely to ph a geal manometry has been shown to ma and Ray n a u d ’s disease. J Clin Inve s t occur in this sequence in SSc patients pr edict patients at risk of eros i ve eso- 1972; 51: 2663- 8. 3. ZAMOST BJ, HIRSCHBERG J, IPPOLITI A F, (11), the presence of dysphagia and/or ph a gitis. It has been suggested that all FURST DE, CLEMENS PJ, WEINSTEIN W M: heartburn is to be considered sufficient pa tients with SSc should undergo base- Esophagitis in scleroderma: Prevalence and to suggest esophageal involvement on line esophageal manometry and those risk factors. Gastroenterology 1987; 92: 421- 8. clinical grounds. Howeve r, ap p rox i- with abn o r mal manometry should sub- 4. KLEIN HHA, WALD A, GRAHAM TO, CAMP- mat e l y 30% to 40% of SSc patients with se q u e n t l y have endoscopy (3). Howev- BELL WL, STEEN VD: Comparative studies ab n o rmalities of esophageal function er , the latter app ro a c h is to be rec o m - of esophageal function in systemic sclerosis. are asymptomatic. In these patients a mended only for special studies. Gastroenterology 1992; 102: 1551-6. 5. MURPHY JR, MCNALLY P, PELLER P, SHAY baseline motility examination by cine/- Tests for gastric dysmotility including a SS: Prolonged clearance is the primary abnor- video barium esophagram is a minimal barium study should be reserved to pa- mal reflux parameter in patients with progres- re q u i rement to ex clude or establ i s h tients in whom gastroparesis needs to sive systemic sclerosis and esophagitis. Dig esophageal dysfunction. be demonstrated in the single patient in Dis Sci 1992; 37: 833-41. 6. WEGENER M, A DAMEK RJ, WEDMANN J, Early satiety and/or bloating and/or vo- clinical practice. Evaluation of gastric JERGAS M, A LT M E Y E R P: G a s t ro i n t e s t i n a l miting can be considered suggestive of emptying after a ra d i o a c t ive meal is t ransit through esophag u s , s t o m a ch , s m a l l gastric dysfunction. Although we lack m o re sensitive and quantitat ive than and large intestine in patients with progres- epidemiological data, a high frequency barium studies, but since it is less feasi- sive systemic sclerosis. Dig Dis Sci 1994; 39: 2209-15. of gastroparesis is thought to be present ble it should presently be considered 7. MADSEN JL, HENDEL L: G a s t ro i n t e s t i n a l in mostly asymptomatic patients. only for therapeutic trials. transit time of radio-labeled meal in progres- Symptoms indicati ve of small bowel in- Small bowel involvement, in dubious sive systemic sclerosis. Dig Dis Sci 1992; 37: vol v ement should be one of the fol l o w- cases, could be assessed by abnormal 1404-8. 8. C LE M E N T S P J, L AC H E N B RU C H PA , S T E R Z in g : weight loss, cha n g es of body mass X - ray (pseudo-obstru c t i o n ) , s m a l l - M et al.: Cyclosporine in systemic sclerosis. in d e x (as evidence of malabs o rp t i o n ) , bowel barium follow-through study, ca- Results of a fo rty-eight week open safe t y co n s t i p at i o n , di a r rhea (as evidence of rotene and pre - a l bumin (ab s o rp t i o n- study in ten patients. Arthritis Rheum 1993; 36: 75-83. motility dys f u n c t i o n ) , and/or intestinal /malabsorption) and, if leading to bac- 9. GREYDANUS MP, CAMILLERI M: Abnormal distension (pseudo-obstruction). t e rial ove rgrowth and malab s o rp t i o n , postcibal antral and small bowel motility due Involvement of the lower digestive tract can be inve s t i gated by the hy d roge n to neuropathy or myopathy in systemic scle- is common and is suggested by abnor- breath test, the D-xylose absorption test rosis. Gastroenterology 1989; 96: 110-5. 10. METCALF A M , PHILLIPS SF, Z I N S M E I S T E R mal distension (related to colonic pseu- and the 72-hour fecal fat test. However, AR, MACCARTY RL, BEART RW, WOLFF BG : doobstruction) and constipation due to it is suggested by signs and symptoms. Simplified assessment of segmental colonic colonic inertia. A colonic transit study could be per- transit. Gastroenterology 1987; 92: 40-7. Disorders of anorectal function are pre- formed in clinical practice in patients 11. COHEN S, LAUFER I, SNAPE WJ, SHIAUY-F, LEVINE GM, JIMENEZ S: The gastrointesti- sent early in the course of SSc and are with uncertain clinical symptoms, but nal manifestations of scleroderma. Pathogen- responsible for fecal incontinence. is unnecessary to improve comparabili- esis and management. G a s t ro e n t e ro l ogy ty in clinical investigation. 1980; 769: 155-66. Rationale for the exclusion of other , defecatography 12. EDENBRANDT L, THEANDER E, HOGSTROM M, SCHEJA A, AKESSON A, PALMER J: Eso- variables and electromyography are specialized phageal scintigraphy of systemic sclerosis. J Other vari a bles have been exc luded be- t e chniques and should be employe d Nucl Med 1995; 36: 1533-8. cause of their poor feasibility or low only as research tools.

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