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Gastrointestinal motility disorders in scleroderma.

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Number 9, September 1994, pp 1265-1282
0 1994, American College of Rheumatology
Arthritis & Rheumatism
Official Journal of the American College of Rheumatology
Scleroderma is a systemic disease characterized by excessive deposition of collagen and other
matrix elements by fibroblasts in skin and, sometimes,
in multiple internal organs. It is associated with prominent and often severe alterations of the microvasculature (l), the autonomic nervous system (2), and
the immune system (3). Scleroderma may exist as
either a localized or a systemic disease process. In its
localized form, linear scleroderma, or morphea, is
confined to the skin and adjacent tissues, and gastrointestinal (GI) tract involvement is minimal or absent
(4). This review will only deal with the systemic form
of scleroderma.
Shown in Table 1 is the classification of systemic sclerosis (SSc). The breakdown of SSc into
limited cutaneous and diffuse cutaneous forms is helpful in predicting onset of GI manifestations (5). Limited cutaneous SSc is characterized by skin involvement limited to the hands, face, feet, and forearms and
includes the CREST variant (calcinosis, Raynaud’s
phenomenon, esophageal dysmotility, sclerodactyly,
telangiectasias). When GI involvement occurs, it tends
to be late in the course of disease. Diffuse cutaneous
SSc is characterized by diffuse skin involvement and
early, significant visceral involvement. This second
variant is the one that principally affects the GI sysPresented in part at the 56th Annual Scientific Meeting of
the American College of Rheumatology, Atlanta, GA, October 1992,
and at the International Conference on Scleroderma, Sydney, Australia, February 1994.
Robert W. Sjogren, MD: Kaiser Permanente Medical Center, Falls Church, VA.
Address reprint requests to Robert W. Sjogren, MD, Gastroenterology Section, Kaiser Permanente Medical Center, 201
North Washington Street, Falls Church, VA 22046.
Submitted for publication April 7, 1993; accepted in revised
form May 3, 1994.
tem, and gut involvement may actually precede skin
manifestations. Unfortunately, many of the publications on gut involvement in SSc do not distinguish
between these two types, and esophageal involvement
is common in both variants.
Clinically symptomatic and significant GI involvement occurs in approximately 50% of all patients
with SSc (6). In addition, many patients with SSc who
do not have GI symptoms will have subclinical GI
involvement. Careful studies have revealed that as
many as 75-90% of patients with SSc have abnormalities noted on esophageal motility testing, although in
many, the involvement was not clinically significant
(7,8). Involvement of the anorectum was the next most
frequent, occurring in 5&70% (4), small bowel hypomotility in 40% (9), and colonic involvement (on
barium enema radiographic series) in l&SO% (10).
Until recently, delayed gastric emptying was only
occasionally reported. However, recent studies have
suggested that gastric involvement may be much more
common than previously thought (11,12). It has been
suggested that many of these patients are asymptomatic because of a concurrent visceral sensory
neuropathy , although visceral nerve involvement in
SSc is less well-studied than in other conditions such
as diabetes mellitus.
The pathology of SSc is similar throughout the
GI tract. Figure 1 shows a Masson trichrome stain of a
transmural section of duodenum. The villus structure
and epithelial cell morphology are normal ( 13,14).
There is a mild infiltration of the lamina propria with
Table 1. Subsets of systemic sclerosis*
Diffuse cutaneous systemic sclerosist
Onset of Raynaud’s phenomenon within 1 year of the onset of
skin changes (puffy or hidebound)
Truncal and acral skin involvement
Presence of tendon friction rubs
Early and significant incidence of interstitial lung disease,
oliguric renal failure, diffuse gastrointestinal disease, and
myocardial involvement
Absence of anticentromere antibodies
Nailfold capillary dilatation and capillary destruction$
Anti-topoisomerase antibodies (30% of patients)
Limited cutaneous systemic sclerosis
Raynaud’s phenomenon for years (occasionally, decades)
Skin involvement absent or limited to the hands, face, feet, and
Significant late incidence of pulmonary hypertension, with or
without interstitial lung disease, trigeminal neuralgia, skin
calcifications, or telangiectasias
High incidence of anticentromere antibodies (70430%)
Dilated nailfold capillary loops, usually without capillary
ies. Capillary basement membranes are thickened and
laminated. The veins are relatively spared (1,18). The
vascular changes appear to precede the muscle
changes (I).
Hypothesis: progressive GI involvement by SSc
Although there are no longitudinal studies, there
is circumstantial evidence that when SSc affects an
area of the GI tract, it does so by an orderly series of
steps that result in progressive dysfunction (6,19). This
concept has implications with regard to therapy. The
earliest GI lesion induced by SSc is neural dysfunction. The basis for this lesion is uncertain, although
there is some evidence in the esophagus, both physi-
* Reproduced, with permission, from Journal of Rheurnatology (5).
t Experienced observers have noted that some patients with diffuse
cutaneous systemic sclerosis do not develop organ insufficiency,
and they suggest using the term “chronic diffuse systemic sclerosis”
for such patients.
t Nailfold capillary dilatation and destruction may also be seen in
patients with dermatomyositis, overlap syndromes, and undifferentiated connective tissue disease. These syndromes may be considered part of the spectrum of scleroderma-associated disorders.
chronic inflammatory cells (15). In the submucosa
there is collagenous encapsulation of Brunner’s glands
and periglandular sclerosis (16). Also note the fibrous
replacement in the muscularis.
Figure 2, a hematoxylin and eosin-stained section from the colon of another SSc patient, shows the
muscle changes better. There is atrophy and fragmentation of the smooth muscle of the muscularis propria.
Initially, the distribution is patchy and later (as shown
here), it is extensive and leads to collagen infiltration
and fibrosis (16,17). These changes are more marked in
the circular than in the longitudinal layer (18) and
muscle atrophy exceeds fibrosis (9). In addition to
fibrosis, there are decreased numbers of gap junctions
between smooth muscle cells, a feature which impairs
transmission of peristalsis (17). There is thickening
and fibrosis of the serosa.
Autonomic nerves appear normal by light and
electron microscopy, but there are no sophisticated
studies using immunofluorescent markers for transmitters or specific silver stains for neural morpho~ogy.
Vascular abnormalities include myointimal Proliferation with narrowing and irregularity of the lumen and
disruption of the internal elastic lamina of small arter-
Figure 1. Masson trichrome-stained transmural section of duodenum from a patient with systemic sclerosis, showing normal villus
structure and epithelial cell morphology. There is mild infiltration of
the lamina propria with inflammatory cells. There is a collagenous
encapsulation of Brunner’s glands and periglandular sclerosis in the
submucosa. Also note fibrous replacement of the muscularis (magnification x 200).
invoked at this stage is partially reversible by prokinetic drugs.
The final lesion in SSc is muscle fibrosis and is
superimposed upon the two previous stages. At this
stage, the muscle is no longer capable of responding,
and restoration of function is not possible.
The esophagus
Figure 2. Hematoxylin and eosin-stained transmural section of
colon from a patient with systemic sclerosis, showing atrophy and
fragmentation of smooth muscle of the tunica muscularis. The
advanced muscle degeneration shown in this section is associated
with collagen infiltrationand fibrosis. These changes tend to be more
marked in the circular than in the longitudinal layer, and muscle
atrophy exceeds fibrosis (magnification x 100).
ologic and anatomic, that it is due to arteriolar changes
in the vasa nervorum (1,9,19). Compression of nerve
fibers by collagen deposits has been offered as an
alternate explanation (20). This produces abnormalities of function before smooth muscle contractility is
impaired by the infiltrative process. These functional
abnormalities may remain asymptomatic for prolonged
periods. Treatment with prokinetic drugs at this stage
is usually effective in reversing the functional abnormalities.
The second lesion is smooth muscle atrophy.
This is the stage during which symptoms most commonly first present. The muscle atrophy is superimposed on existing neural dysfunction. The muscle is
capable of responding, but it is weak. The dysfunction
The esophagus is the most commonly affected
area of the GI tract and is the most important clinically (2 1).
Motility. Esophageal motility in early-stage
SSc. Although esophageal motility is often abnormal
in SSc, it is usually normal in other connective tissue
disorders (except mixed connective tissue disease) and
this difference can be useful diagnostically (7,8). The
earliest esophageal abnormalities are located in the
distal two-thirds, or the smooth muscle portion, of the
esophagus (22), and are suggestive of neural dysfunction. Manometric studies show increased speed of the
peristaltic wave, incoordination between the arrival of
the peristaltic wave and relaxation of the lower esophageal sphincter (LES), and failure of the LES to relax to
gastric baseline (4,23,24). Some of these changes may
resemble achalasia (24), and they may be so subtle as
to require provocation with a cholinesterase inhibitor
such as edrophonium (25). Generally, the low LES
pressure in systemic sclerosis distinguishes it from
achalasia, which has a high LES pressure. Upper
esophageal sphincter (UES) function in SSc is variable. Early in SSc, UES pressures may be increased,
which may reflect stimulation by acid reflux (4).
At this stage of involvement, electrophysiologic
studies of esophageal smooth muscle show spontaneous disorganized spike bursts between swallows (26).
Sometimes this is associated with nonpropagating contractions. This type of activity is reminiscent of diffuse
esophageal spasm. With deglutition, there are repetitive, uncoordinated spike bursts of higher amplitude
and duration than normal (26). Normal esophageal
peristalsis and relaxation of the LES is shown in
Figure 3A. Esophageal manometry early in SSc (Figure 3B) shows low-amplitude peristaltic contractions,
a low LES pressure, and failure of the LES to relax.
Esophageal motility in mid-stage SSc. In moderately severe cases, manometric studies show decreased amplitude of peristalsis progressing to absent
peristalsis in the smooth muscle portion of the esophagus (6), delayed esophageal emptying of both liquids
(27) and solids (4,11,23,24), and decreased pressure of
20 mm Hg
I 2 0 mm Hg
ws wswsws ws w s w s
1 1 1 1 1 1 1
20 mm Hg
Figure 3. Esophageal manometry in A, a normal subject, B,a patient with early systemic sclerosis (SSc), and C, a patient with late SSC.The
distance above the lower esophageal sphincter (LES) is shown on the left and contraction amplitude on the right. WS marks ivet swallows. A,
In a normal subject, there are high-amplitude (>80 mm Hg), ordered peristaltic waves in all portions of the esophagus. Resting LES pressure
is 27 mm Hg above gastric baseline, and on swallowing, the LES relaxes to gastric baseline. LES relaxation precedes the arrival of the
peristaltic wave. B, In early SSc, peristaltic contractions are of low amplitude (20-30 m m Hg). Resting LES pressure is low (10 mm Hg), and
the LES fails to relax to gastric baseline on deglutition. The bottom 3 tracings are from radially oriented manometric tips placed in the LES.
C, In late SSc, there is preserved peristalsis in the proximal esophagus and absent peristalsis in the distal two-thirds. LES pressure is virtually
the lower esophageal sphincter. These manometric
findings have been shown to correlate with development of erosive esophagitis (28). Electrophysiologic
studies of smooth muscle show no myoelectric activity
between swallows and a markedly lower than normal
spike burst response after swallowing (26). Other
electrophysiologic studies at this stage suggest that
circular muscle function is more severely affected than
longitudinal muscle function (29).
Esophageal motility in late-stage SSc. Figure
3C is from a patient with advanced SSc. It shows
preserved peristalsis in the proximal esophagus and
absent peristalsis in the distal two-thirds. The LES
pressure is virtually absent. Very late in SSc, the
proximal skeletal muscle portion of the esophagus may
also be involved, with abnormal or absent peristalsis
(7,23). By the time there is abnormal function in the
proximal one-third of the esophagus, muscle atrophy
and fibrosis have occurred and the esophageal muscle
responds to neither neural (edrophonium) nor direct
(methacholine) stimulation. The UES may have diminished pressure (4). Decreased function of the upper
esophageal sphincter in conjunction with gastroesophageal reflux is particularly devastating because it removes the last barrier to aspiration of refluxed gastric
Clinical presentations. Raynaud’s phenomenon
and autoimmune markers. A longstanding adage has
bqen that Raynaud’s phenomenon is associated with
p or esophageal function (4). Some patients with SSc
h ve prolonged cold-induced vasospasm in the vessels
o the esophagus (“esophageal Raynaud’s”) as well as
in the vessels of the hand (30). Reversal of this
vasospasm by intraarterial injection of reserpine relieves both Raynaud’s phenomenon and abnormal
esophageal motility (31). However, isolated Raynaud’s
phenomenon may occur in 4 5 % of the general population (32), and repeated studies have convincingly
shown that the presence of Raynaud’s phenomenon
per se is not a predictor of abnormal esophageal
function, but rather, an association with existing
scleroderma (33).
As many as 95% of SSc patients have
Raynaud’s phenomenon, and the duration of Raynaud’s
phenomenon in a patient with SSc may be diagnostically helpful. Patients with diffuse cutaneous SSc and
a high risk of early visceral involvement usually have
a brief duration of Raynaud’s phenomenon before the
development of skin changes, whereas patients with
limited cutaneous SSc usually have many years of
Raynaud’s phenomenon before overt skin and visceral
involvement occur.
Use of markers such as abnormal nailfold capillaries (34) and the presence of antinuclear antibodies
may help predict which patients with new-onset
Raynaud’s phenomenon are at risk of scleroderma and
visceral involvement (35). Other autoantibodies are
also helpful. The anticentromere antibody is associated with limited cutaneous disease (sensitivity 60%,
specificity 98%) and the anti-Scl-70 antibody is associated with diffuse cutaneous disease (sensitivity 38%,
specificity 100%) (35).
Gastroesophageal reflux disease (GERD). The
big problem in SSc is the occurrence of GERD. It
stems from two physiologic defects (28,36). First,
decreased LES pressure results in an increased number of gastroesophageal reflux events. Second, once
acid is refluxed into the esophagus, poor peristaltic
function delays its clearance. Clearance of esophageal
acid is a 2-step process (37). First, immediately following a reflux event, 1 or 2 peristaltic contractions occur
which empty the esophagus of the majority of the
refluxate. Second, some residual acid clings to the
esophageal mucosa, and it takes 6-7 minutes more for
swallowed saliva to neutralize it. Poor esophageal
peristalsis inhibits both expulsion of refluxate and
delivery of saliva to the acid residue. In addition,
coexistence of the sicca syndrome with systemic sclerosis may reduce the acid-neutralizing capacity of
swallowed saliva.
To evaluate the relative importance of these
two factors, a recent report employed simultaneous
manometry, esophageal pH monitoring, and esophageal scintigraphy to study SSc and non-SSc patients
with severe gastroesophageal reflux (36). The SSc
group had significantly fewer reflux events than did the
non-SSc reflux group (although more than normal
controls), but once acid was refluxed, it took substantially longer to clear from the esophagus. In addition,
during these prolonged clearance intervals, additional
episodes of gastroesophageal reflux would occur, adding more acid to the esophagus. These “piggy back”
reflux events were not detected by the pH monitor
because the esophageal pH was already low. They
could be most reliably detected by manometry, which
showed an additional increase in resting intraesophageal pressure. It was concluded that decreased
smooth muscle peristalsis was the primary contributor
to acid exposure and esophageal injury in SSc, in
contrast to diminished LES pressure as the primary
cause of esophageal injury in non-SSc reflux. These
results are supported by previous findings that disordered motility is the primary abnormality contnbuting to GERD in scleroderma (28). Therefore, prokinetic agents may have a therapeutic niche in SSc,
particularly early in the disease.
Gastroesophageal reflux is especially severe in
SSc, and there is an increased incidence of complications including Candidu esophagitis, erosive esophagitis,, stricture, Barrett’s esophagus, and aspiration
(28,38). Strictures may be especially severe due to
both GERD and abnormal collagen synthesis by the
esophageal mucosa (39). As many as one-third of
patients with SSc may develop Barrett’s esophagus
with its accompanying potential for adenocarcinoma
(40). There are no clear predictors of risk for developing Barrett’s metaplasia, although the CREST syndrome, prolonged dysphagia, and very low LES pressure have been suggested (40).
The role of chronic aspiration in restrictive lung
disease in SSc is controversial. A recent report demonstrated a positive correlation between esophageal
pH scores and diffusing capacity for carbon monoxide
values, suggesting that aspiration may be an important
contributor to pulmonary disease in SSc (441).Others,
however, have not been able to reproduce these
Diagnosis. It is important to aggressively evaluate SSc patients with GERD because their reflux is
vicious, is associated with complications, and is often
resistant to therapy. Disordered esophageal motility
can be assessed using I of 3 modalities: esophageal
manometry, cine-esophagraphy, and esophageal transit scintigraphy. Early changes in esophageal function
are most accurately assessed with esophageal manometry (4,23). However, when evaluating an already
symptomatic patient, all 3 modalities are equally sensitive and specific (33). Esophageal manometry may
remain the choice because pH probes can be positioned for reflux testing at the same time. Although the
duration of SSc and the presence of dysphagia predict
abnormal findings on esophageal function tests (42)
and abnormal esophageal function predicts the presence of esophagitis (28), the degree of dysfunction
does not correlate with symptoms (33).
Which patients with SSc should undergo esophageal manometry and endoscopy? There is a wide
range of practice standards without a clear consensus.
Some would evaluate all patients with scleroderma,
while others would only evaluate those resistant to
standard doses of omeprazole. Since abnormal esophageal manometry has been shown to predict patients at
risk for erosive esophagitis and since symptoms do not
correlate with esophagitis, it has been suggested that
all patients with SSc receive baseline esophageal manometry and those with abnormal manometry undergo
upper GI endoscopy (28). If esophageal manometry is
unavailable, then periodic endoscopies might be warranted. It is unclear, however, whether minimally
symptomatic patients with esophagitis should be
treated. My approach is to evaluate all patients with
symptomatic reflux requiring prolonged H, blocker
therapy and all those with any symptom suggestive of
a complication (especially dysphagia or pulmonary
symptoms). This evaluation includes an endoscopy,
esophageal manometry, and 24-hour esophageal pH
Because of the high incidence of Barrett’s
esophagus in SSc, endoscopy should always be conducted as part of the esophageal evaluation for reflux.
In addition, all patients with dysphagia should undergo
endoscopy. Those with Barrett’s esophagus should
enter a program of periodic endoscopic surveillance
for development of dysplasia or adenocarcinoma and
should have either pH monitor-proven suppression of
acid reflux or suppression of inflammation demonstrated endoscopically and histologically. By this
scheme, most patients with diffuse cutaneous SSc will
be evaluated.
Treatment. Medical therapy can manage GERD
in most patients with SSc. As first-line therapy, there
are the general measures such as weight loss, elevation
of the head of the bed, multiple small meals, avoidance
of recumbency within 3 hours of eating, and cessation
of smoking. The major drugs used in the treatment of
GERD are the antisecretory drugs: H, blockers and
proton-pump inhibitors. H, blockers have been demonstrated to reduce GERD, improve symptoms, and
improve endoscopic evidence of esophagitis, both
acute (43) and chronic (44). Omeprazole, the protonpump inhibitor, has truly revolutionized the treatment
of GERD.
Although there have been few studies on the
efficacy of omeprazole in SSc, it would appear that
most cases of severe, complicated GERD can be
managed with omeprazole (38,4547). Usually, twicea-day dosing is required (47). Median doses in most
studies in scleroderma are 40 mg/day, and individual
doses range as high as 80 mg/day (38,45,47,48). One
study by Hendel (45) found that omeprazole not only
healed esophagitis, but reduced elevated hydroxyproline levels to normal, suggesting reversal of esophageal
fibrosis. A second report from investigators at Thomas
Jefferson University (Philadelphia, PA) (49) has demonstrated that endoscopic ultrasonography reliably
documents both esophageal wall thickness and specific
degree of fibrosis in the muscularis propria. If probe
localization on repeated studies is reproducible, this
approach could permit assessment of the reversal of
fibrosis as an index of the adequacy of antireflux
therapy. Although the long-term safety of omeprazole
has yet to be determined, its use in doses up to 80
mg/day for periods of up to 5 years without serious
adverse effects in SSc has been reported (47). Once
started, it is frequently difficult to discontinue omeprazole in SSc patients.
One approach to such situations is to document
therapeutic efficacy by endoscopy and esophageal pH
testing. Once endoscopic healing is achieved, a prokinetic agent is added and attempts are made to switch
from omeprazole back to an H, blocker. If this fails, an
attempt is made to minimize the dosage of omeprazole
by concurrent use of cisapride. Often, however, longterm, high-dose omeprazole is required indefinitely.
The prokinetic drug cisapride was recently marketed in the United States as an effective single agent
for the treatment of GERD. In scleroderma, this may
not be the case. However, as adjuncts to the antisecretory drugs, metoclopramide and cisapride may
have a unique niche in the treatment of selected
patients because of the importance of disordered motility. These drugs work by increasing the LES pressure, by improving peristalsis (to aid esophageal emptying), and by increasing gastric emptying (50,51). In
addition, they seem to improve symptoms independent of their effects on motility (52). In this respect, it is interesting to note that they inhibit type 3
5-hydroxytryptamine (5-HT3) receptors, which are
present on vagal afferents (53). Bethanechol as a
prokinetic drug in scleroderma is usually ineffective.
Should other measures fail, antireflux surgery
should be a consideration (54-57). One must be cautious because impaired esophageal motor function can
result in esophageal obstruction if too “tight” an
antireflux procedure is performed, and such surgery
requires an experienced surgeon. A Collis gastroplasty
with fundoplication has been shown to significantly
reduce GERD in SSc patients (54). The recurrence of
symptoms following antireflux surgery in SSc, however, is high and may be related to delayed gastric
emptying (54).
All of these approaches are aimed at treating
the complications of systemic sclerosis, and not the
underlying cause. It would be appealing to arrest or
reverse the GI complications of SSc by treating its
underlying cause. However, esophageal function is
reported to continue to deteriorate in patients treated
with D-penicillamine (58,59) and with total lymphoid
irradiation (60).
The stomach and small intestine
Although the stomach has been said to be rarely
involved in systemic sclerosis (6), the small intestine is
commonly affected, and the two tend to function as a
unit (7). In addition, recent data suggests that gastric
emptying and antroduodenal motility are more frequently abnormal in SSc than previously known
Motility. Figure 4A shows a normal antral and
duodenal manometry during fasting. During the fasting
state, a cyclical pattern of contractile activity, the
migrating myoelectric complex (MMC), occurs at intervals of 1.5 to 2 hours. The MMC consists of regularly
recurring sequence of absent, irregular, and regular
peristaltic activity that originates in the stomach and
slowly progresses a variable distance down the small
intestine before stopping and recurring again in the
The MMC has been termed the “intestinal
housekeeper” by Charles Code (62). Teleologically,
its purpose is to clear remnants of digestion and
excessive bacterial colonization from the stomach and
small intestine. Patients with SSc often lack the MMC
and are therefore predisposed to developing bezoars
and bacterial overgrowth in the small intestine. Eating
disrupts the MMC and induces a marked increase in
contractile activity (Figure 4B). Gastric emptying and
intestinal transit occur primarily during the fed response.
Although the control of the MMC remains a
subject of controversy, hormones appear to be the key
in MMC generation. Endogenous cycling of motilin
appears to be related to MMC initiation. Once initiated, MMCs are transmitted distally in a coordinated
manner by the enteric nervous system. Should initiation or propagation of the MMC fail, the enteric
nervous system and endogenous enkephalins and
somatostatin are capable of generating an ectopic
distal MMC as backup. This neurohormonal control of
motility is directly reflected in the effects of drug
therapy of gastric and small bowel stasis with the
long-acting somatostatin analog, octreotide, with the
cholinergic agonist, cisapride, and with the motilin
agonist, erythromycin.
tracing is characterized by the absence of MMCs and
the presence of high-amplitude uncoordinated contractions in the distal antrum and small intestine (19).
Postprandially, uncoordinated activity may persist,
and often, there is an antral hypomotility, characterized by reduction of both the number and the amplitude of contractions (corresponding to delayed gastric
emptying) (19). This type of tracing with duodenal
hyperactivity is similar to that observed in ganglionectomized dogs (67) and in humans with diabetic neuropathy (68), and is suggestive of a neuropathic disorder
(19). Additional evidence of a primarily neuropathic
disorder comes from studies of duodenal myoelectric
activity, which show preserved slow-wave frequency
and propagation (a property of smooth muscle), but
diminished or absent response of the duodenum to
distention (an intrinsic neural reflex) (69).
Chronic intestinal pseudoobstruction in late
SSc. Late in the course of SSc, the gastrointestinal
muscle becomes refractory, the MMC is absent, and
there is dramatic hypomotility (19,63). In addition,
there is no contractile response of the stomach or
small intestine to a meal. Figure 6 is a postprandial
antroduodenal manometry tracing of a patient with
advanced intestinal SSc, demonstrating that the antral
and small intestinal contractions are few and of low
amplitude. This pattern suggests a myopathic disorder
Figure 4. Normal antroduodenal manometry in A, fasting and B,
postprandial states. The fasting tracing shows a typical migrating
myoelectric complex (MMC) slowly progressing from the stomach
through the proximal jejunum. The MMC has 3 phases: phase I,
during which contractile activity is nearly absent (end of each
tracing); phase 11, a period of irregular contractile activity (beginning of each tracing); and phase 111, a brief period of intense
contractile activity (middle of each tracing). The postprandial tracing shows irregular contractile activity induced throughout the small
intestine within 10-15 minutes of eating. Note the high-amplitude
contractions in the antrum. (Adapted, with permission, from
Malagelada J-R, Camilleri M , Stanghellini V : Manometric Diagnosis of Gastrointestinal Motility Disorders. New York, Thieme Medical Publishers, Inc., 1986.)
Chronic intestinal pseudoobstruction in early
SSc. Both fasting and postprandial gastric and small
bowel motility are abnormal in systemic sclerosis
(12,19,63-65). Intestinal transit is delayed (66). Figure
5 shows fasting antroduodenal motility in a patient
early in the course of intestinal SSc. The fasting
Figure 5. Fasting antroduodenal manometry of a patient with early
gastrointestinal systemic sclerosis, showing high-amplitude, uncoordinated contractions in the distal antrum and small intestine.
There are no migrating myoelectric complexes. Similar patterns can
be seen in early diabetes and amyloidosis and are suggestive of a
neuropathic process. (Adapted, with permission, from Gastroenterology [191.)
(19). At this stage, the intestinal myoelectric response
to the regulatory hormones secretin and gastrin is
impaired (69). In addition, while endogenous cycling
of motilin and pancreatic polypeptide continues in
patients with SSc, the levels of both are increased,
which suggests end-organ refractoriness (65).
Clinical presentations. Symptoms suggestive of
gastric and small bowel involvement include anorexia,
early satiety, halitosis, nausea, vomiting, intestinal
distention, abdominal pain, weight loss, steatorrhea,
diarrhea, and obstipation (6). Although there are no
good epidemiologic data, several authors have reported a high frequency of gastroparesis in SSc
(1 1,12,61). Many of these patients were asymptomatic,
but even a mild delay in gastric emptying can worsen
GERD (11,12). In one report, Maddern et a1 (1 1) found
that 75% of symptomatic SSc patients have gastroparesis (11). Solid emptying is affected earlier and
more severely than is liquid emptying.
Chronic intestinal pseudoobstruction. Even
when gastroparesis is present, small bowel symptoms
usually dominate the clinical picture, with nausea,
vomiting, distention, abdominal cramps, malabsorption, and diarrhea and constipation. Various degrees
of intestinal pseudoobstruction may occur in as many
as 40% of patients with SSc. Figure 7 is an upper GI
radiographic film of a patient with intestinal pseudo-
Figure 6. Postprandial antroduodenal manometry of a patient with
advanced intestinal pseudoobstruction due to systemic sclerosis.
Even after eating, there is dramatic hypomotility of the stomach and
proximal small intestine. Similar patterns are seen in hereditary
visceral myopathy and are suggestive of a myopathic disorder.
(Adapted, with permission, from Gastroenterology [Is].)
Figure 7. Upper gastrointestinal radiograph of a patient with intestinal pseudoobstruction due to systemic sclerosis. The duodenum
and proximal jejunum are dilated and mildly edematous.
obstruction due to SSc. Note the dilated duodenum
and proximal jejunum.
Malabsorption. Nutrition may be a major management problem in advanced SSc, and malabsorption
can be the immediate cause of death (70-72). Malabsorption in SSc may result from 3 causes: bacterial
overgrowth of the small intestine, abnormalities of the
intestinal absorptive surface, and pancreatobiliary insufficiency (6). The first 2 stem from disordered motility. By far the most clinically important cause is
bacterial overgrowth.
In 1977 Vantrappen et al(63) demonstrated that
small bowel bacterial overgrowth was associated with
absent MMCs. Subsequent studies in rats suggested
that restoration of MMCs reduces bacterial colony
counts (73). The presence of small bowel bacterial
overgrowth is strongly suggestive of disordered motility. In addition, use of omeprazole can induce achlorhydria, increase bacterial colony counts in the stomach, and may predispose patients to enteric infection
with ingested pathogens such as Salmonella, cholera,
and mycobacteria. Whether achlorhydria also worsens
small bowel bacterial overgrowth, which represents
colonization from below with colonic gram-negative
and anaerobic flora, is unknown. Overgrowing bacteria compete for essential nutrients (such as vitamin
B12) and deconjugate bile acids, inducing fat malabsorption.
Even in the absence of small bowel bacterial
overgrowth, some patients have persistent malabsorption. Tests of passive mucosal uptake, such as the
D-xylose absorption test and the glucose tolerance
test, may show abnormal results (15,74). In addition,
folic acid levels are sometimes low. Bacteria synthesize folic acid, which is passively absorbed by the
mucosa, giving rise to increased serum levels of folic
acid in the presence of bacterial overgrowth. These
findings suggest there is a mucosal defect inhibiting
absorption in SSc.
Morphologically, the intestinal mucosa is intact, and two possible explanations for this malabsorption have been offered (6). First, increased submucosal
collagen deposition could interfere with permeation
across the intestinal wall. Alternatively, lack of motility
may result in an increased depth of the unstirred water
layer. The unstirred water layer is a stagnant layer of
luminal contents immediately adjacent to the mucosa.
All absorbed materials must cross it to enter the enterocyte. By reducing luminal flow, disorders of motility
increase the width of the unstirred water layer. The
clinical significance of this layer is uncertain. For
caloric intake, it is probably not important. However,
it may account for deficiencies of certain water-soluble
vitamins such as folic acid and pyridoxine.
Finally, abnormalities of pancreatobiliary secretion have been described in SSc. An increased
frequency of primary biliary cirrhosis has been suggested, although its incidence is still uncommon (75).
Associated with primary biliary cirrhosis is a decrease
in bile acid excretion, leading to fat malabsorption.
Pancreatic secretion of digestive enzymes such as
trypsin and lipase may also be impaired. With sophisticated pancreatic testing, such as the Lundh test meal
and the secretin-cholecystokinin test, abnormal pancreatic exocrine function has been demonstrated in
-30% of unselected patients with SSc (76). Although
these abnormalities are usually mild, they may be
clinically significant in 10-15% of patients.
In addition to gastroparesis, pseudoobstruction, and malabsorption, the following other intestinal
presentations of SSc have been reported: pneumatosis
cystoides intestinalis, small intestine telangiectasia,
and small bowel diverticula. In many circumstances,
pneumatosis cystoides intestinalis is a benign condition, but in SSc, it may be associated with rapidly
Figure 8. Spot film of the mid-jejunum from a small bowel followthrough radiographic series in a patient with gastrointestinal systemic sclerosis (SSc). Multiple diverticula are characteristic of SSc
and may be a source of small bowel bacterial overgrowth.
progressive SSc and death (77). It is important to
distinguish benign intraperitoneal gas associated with
pneumatosis from that associated with an intraabdominal catastrophe for which emergent surgery is indicated (78). Cutaneous telangiectasias are part of the
CREST syndrome. Gastric, small bowel, and colonic
telangiectasias also occur and are indistinguishable
from those in Osler-Weber-Rendu disease. They may
be a cause of GI bleeding and iron deficiency, and
endoscopic sclerosis or cautery may be required (7981). As shown in Figure 8, small bowel diverticula may
be extensive and may contribute significantly to bacterial overgrowth in the small intestine.
Diagnosis. Radiographic assessment. Radiographic evidence of involvement of the stomach and
small bowel occurs late in intestinal scleroderma. The
most commonly affected area is the duodenum and
proximal jejunum, which may show edematous, dilated loops and pooling of barium. Multiple small
bowel diverticula are suggestive of scleroderma, but
may be seen in other conditions. Finally, gastroparesis, if severe, may result in retention of barium on
upper GI films. Radioisotope gastric emptying studies
are readily available and are more sensitive and quantitative than barium studies for demonstrating gastro-
paresis. Solid emptying is affected earlier and more
severely than liquid emptying, and solid-phase studies
are the gastric emptying studies of choice.
Antroduodenal and small bowel manometry.
The diagnostic tests of choice for demonstrating abnormal motility of the stomach and small intestine and
for differentiating neuropathic from myopathic involvement are antroduodenal and small bowel manometry. These tests are most useful in patients with
significant upper GI symptoms, but without dilatation
on upper GI series. In addition, they are important in
the functional assessment of intestinal segments when
resection is contemplated. There are multiple protocols for the conduct of these tests, and at present, they
are only available in a limited number of referral
centers. In general, these tests require intubation of
the stomach and small intestine for periods ranging
from 5 to 24 hours, and manometry is recorded in both
the fasting and postprandial states. Sometimes, the
motor response to prokinetic drugs is also monitored.
Tube placement is often difficult in patients with poor
motility, and radiographic confirmation of recording
site location is necessary. The introduction of ambulatory manometry may make these tests both more
acceptable to patients and more available to clinicians.
There are many tests used to diagnose small
bowel bacterial overgrowth including culture, breath
H, levels, abnormal Schilling test result corrected with
antibiotics, and increased serum levels of unconjugated bile acids. Culture of duodenal or jejunal aspirates can be done at the time of endoscopy. Cultures of
>lo3 organisms/ml are suggestive, and those > lo5
organisms/ml diagnostic, of small bowel bacterial
The breath H, is probably the most widely used
test and is noninvasive. In this test, the patient ingests
a nonabsorbable carbohydrate, such as lactulose, and
breath H, levels are determined every 15 minutes for 3
hours. Normally, the carbohydrate takes 2-3 hours to
reach the cecum, where bacteria degrade the carbohydrate, releasing H,, which is picked up as a rise in
H, levels in the expired air. A premature H, spike
suggests bacterial overgrowth. The Schilling test is
excellent, but expensive and involves the use of an
isotope. Increases in serum bile acids result from
bacterial deconjugation of bile acids in the small
intestine. However, in many clinical settings, this test
tends to be unreliable.
Treatment. For chronic intestinal pseudoobstruction, the prokinetic drugs are a central element
to therapy: metoclopramide, cisapride, octreotide, and
erythromycin. Metoclopramide was the first truly efficacious prokinetic drug (82). It is both a dopaminergic antagonist and a cholinergic agonist (82). It facilitates acetylcholine release in the myenteric plexus,
probably by interaction with serotonergic receptors on
nerves. Metoclopramide can decrease symptoms of
GERD even in the absence of endoscopic healing. This
may be due to inhibition of 5-HT3receptors on sensory
neurons. Metoclopramide crosses the blood-brain barrier and has a central antiemetic effect. Because metoclopramide is a dopamine antagonist, it has important
extrapyramidal side effects and may cause irreversible
tardive dyskinesia.
Metoclopramide has been shown to increase
LES pressure, to increase gastric emptying, to induce
MMCs, and to increase antral and small bowel peristalsis and transit (65,83). Its effects on esophageal
transit and on esophageal contraction amplitude are
inconsistent (82,83). Unlike cisapride, metoclopramide has little effect on the colon. Metoclopramide is
indicated in the treatment of gastroparesis and small
bowel stasis, and it has minor effects in GERD.
Cisapride was released in the United States in
1993 for use in gastroesophageal reflux. It is chemically related to metoclopramide, but is devoid of
antidopaminergic effects and therefore does not cause
extrapyramidal side effects or prolactin secretion
(84,85). The primary mechanism of cisapride is to
facilitate release of acetylcholine in the myenteric
plexus by stimulation of 5-HT, receptors (85). Like
metoclopramide, cisapride decreases symptoms of
GERD even in the absence of endoscopic healing.
Finally, recent data have demonstrated the persistence
of prokinetic effects in the presence of atropine and
tetrodotoxin, suggesting that cisapride may have direct smooth muscle effects.
In the esophagus, cisapride increases the LES
pressure (50,86), increases the amplitude of peristaltic
contractions (87), but has little effect on esophageal
emptying (50,51). In the stomach, cisapride increases
both liquid and solid emptying via increasing both
fundic and antral contractions and improving
antroduodenal coordination (87-89). In an uncontrolled trial, 1 month of oral cisapride at a dosage of 10
mg 4 times a day reduced symptom scores in SSc
patients (51). In the small intestine, cisapride speeds
transit time, induces frequent propagating contractions, and restores the MMC. In the colon, it speeds
transit time and increases contractions. The effects of
cisapride appear to be more prolonged than those of
metoclopramide, and side effects appear to be fewer.
It is the only drug for which symptomatic improvement sometimes correlates with demonstrated prokinetic effects.
A new addition to the prokinetic armamentarium is the long-acting somatostatin analog, octreotide
(90). In conventional high doses, octreotide is an
antidiarrheal and may be used for this purpose in SSc
patients. However, at low doses (50 pg at bedtime),
octreotide has been shown to induce MMCs, to increase intestinal peristalsis, to decrease bacterial overgrowth, and to relieve symptoms of nausea, bloating,
vomiting, and abdominal pain in a study of 5 patients
(90). Because octreotide does not increase gastric
emptying and because the motor and pancreatic responses to eating may be impaired in scleroderma, it is
important to limit doses to once at bedtime (90,91).
Hence, octreotide has limited usefulness for mealrelated symptoms. It is also important to remember
that prolonged use of octreotide is associated with
impaired gall bladder emptying and increased incidence of cholelithiasis.
The macrolide antibiotics, such as erythromycin, are motilin agonists and can increase gastric
emptying, induce MMCs, increase the peristaltic response of the small bowel to eating, and speed colonic
transit. Erythromycin has been reported as therapy in
a variety of conditions including SSc (92). Most notably, a 1990 paper in the New England Journal of
Medicine reported that both intravenous and oral
erythromycin were effective in increasing gastric emptying and in increasing postprandial spike responses in
diabetic patients with autonomic neuropathy (93).
However, the current dosage recommendation (250
mg with meals) often causes abdominal cramps and is
poorly tolerated, and its prolonged use as a prokinetic
agent is often disappointing.
For the motility disorders, the current suggested, but untested, therapeutic algorithm is as follows. For neuropathic early SSc, prokinetic drugs are
the treatment of choice. In SSc, cisapride has been
shown to increase solid and liquid gastric emptying
and to decrease GI symptom score (51). In chronic
idiopathic pseudoobstruction, cisapride increases
small intestine peristalsis and transit, and is the drug of
choice (64). Metoclopramide is inconsistently effective, has neurologic side effects, but might also be tried
(65). Both cisapride and metoclopramide also have
some antireflux effects. Parenteral use of prokinetic
drugs may be required if there is concern about
absorption from a paretic gut. A limitation to the use of
cisapride is its lack of a parenteral formulation.
For late myopathic pseudoobstruction, prokinetic drugs are usually ineffective (although often
tried), and surgery is the only option beyond nutritional support. Venting enterostomy , whether surgical
(94), laparoscopic ( 9 9 , or endoscopic (96), is a relatively new approach that is short of resection (97-99).
It is used to decompress distended bowel, relieve pain
and bloating, and may enable prokinetic drugs to be
effective in less severe cases. When other forms of
therapy fail, surgical resection to remove localized
disease because of obstruction or for pain control may
be considered (17,100-102). Such an approach requires careful localization of the atonic segment to
conserve intestine and to assure that newly apposed
segments are functional (103). Examples of such surgical procedures include jejunostomy , with or without
decompressing gastrostomy , and total or partial colectomy. Simple pyloroplasty or antrectomy and gastrojejunostomy usually fail. As a group, patients with
advanced SSc tolerate surgery very poorly, and a
conservative stance should be taken when surgery is
contemplated. In the future, small bowel transplantation may become an option.
Malabsorption. Although many patients with
SSc will have abnormal intestinal function, treatment
of malabsorption should be restricted to patients with
significant signs and symptoms. This should be a
minority of patients. Intestinal SSc is a long-term,
chronic disease, and nutritional support and pain control are major problems. There is no predictably
effective therapy other than treatment of bacterial
overgrowth and nutritional support.
For all stages of intestinal SSc, antibiotics for
bacterial overgrowth and dietary supplements (such as
vitamins, low-residue and elemental diets, and
medium-chain triglycerides) are mainstays of therapy.
The usual treatment of small bowel bacterial overgrowth is antibiotics such as ciprofloxacin, amoxicillin, metronidazole, tetracycline, and oral vancomycin.
Rotating monthly courses of different antibiotics and
providing antibiotic holidays are believed by some to
help prevent emergence of resistant strains and to
preserve antibiotic efficacy (15). In most cases, antibiotics alone are sufficient. It should be noted, however, that antibiotics can worsen constipation, and
abrupt cessation may exacerbate obstructive symptoms.
If bacterial overgrowth persists, addition of a prokinetic
agent may help, but may also increase diarrhea.
Nutritional supplementations with fat-soluble
vitamins, vitamin C, low-residue and elemental diets,
and medium-chain triglycerides are mainstays of nu-
tritional support. A recent study from Sweden (72)
compared 30 patients with GI manifestations of SSc
with matched healthy control subjects. It demonstrated that 43% of scleroderma patients had fat malabsorption and 50% had malnutrition, according to
anthropometric measurements (72). Deficiencies of
vitamin C and of all fat-soluble vitamins were noted.
Selective avoidance of dietary fruits and fiber and fat
malabsorption appeared to be a greater problem than
insufficient caloric intake. However, during a 1-year
followup, supplementation of oral intake did not alter
these parameters.
If correction of dietary deficiencies remains a
problem after apparent successful treatment of bacterial overgrowth and nutritional supplementation, a
trial of replacement pancreatic enzymes is worth considering. Such replacement therapy in cases of suspected or proven pancreatic insufficiency is logical,
but there are no studies demonstrating efficacy.
Antiemetics may afford symptomatic relief, although addressing the underlying GERD or gastroparesis is usually more rewarding. Use of prokinetic
agents may improve absorption by increasing mucosal
contact and decreasing bacterial overgrowth, although
there are no studies documenting this. For an acute
exacerbation, nasogastric suction, intravenous fluids,
and antibiotics may be used.
In severe, refractory cases, long-term parenteral nutrition may be required (104). This has been
associated with complicatioddeath rates as high as
40%. Grabowski and Grant (104) established the following guidelines for nutritional support in scleroderma patients: 1) absence of rapid disease progression, 2) adequate pulmonary function, 3) adequate
renal function, 4) adequate cardiac and circulatory
function, 5 ) adequate mobility and manual dexterity,
and 6 ) an adequate home support system.
The colon
Involvement of the colon in SSc is surprisingly
common. The anorectum is the most commonly affected area, and recent studies suggest that it is almost
as commonly involved as the esophagus (4). Careful
manometric studies have documented that patients
with abnormal esophageal manometry almost always
also have abnormal anorectal motility (4). Although
fecal incontinence is very common, clinically significant colonic presentations are usually related to colonic pseudoobstruction (105).
Figure 9. Anorectal manometry using a Schuster balloon, in a
healthy volunteer and a patient with scleroderma and fecal incontinence. Arrow marks inflation of the rectal balloon. The normal
tracing demonstrates an intact rectoanal inhibitory reflex, with
relaxation of the internal anal sphincter and contraction of the
external anal sphincter. The patient with scleroderma has an absent
rectoanal inhibitory reflex, with no response of the internal anal
sphincter to balloon distention and a weak contraction of the
external anal sphincter. (Adapted, with permission, from Wald A :
Anorectum, Atlas of Gastrointestinal Motility in Health and Disease. Edited by MM Schuster. Baltimore, Williams and Wilkins,
Motility. Colonic transit in SSc is prolonged and
often shows decreased right colonic or pancolonic
transit in SSc patients with constipation as compared
with healthy control subjects and with SSc patients
without constipation (61,106). This would suggest that
colonic inertia, rather than functional obstruction at
the anorectum, is the primary cause of constipation
in SSc.
Rectosigmoid function is abnormal in patients
with SSc. Fasting rectosigmoid motility in SSc is
normal (including slow waves, spike bursts, and contractions) (107). In normal subjects, rectosigmoid motility increases after eating. This is mediated by a
cholinergic pathway (108). Patients with SSc lack this
postprandial increase in motility (109). Administration
of the anticholinesterase, neostigmine, restores the
postprandial motility response in patients with early
SSc, but not in those with longstanding disease (109).
Disordered anorectal function occurs early in
the course of scleroderma and is a major factor in the
development of fecal incontinence. The most common
manometric abnormality is an absent or diminished
rectoanal inhibitory reflex (see Figure 9) (4,110). If a
balloon is distended in the rectum, normal subjects
will show a relaxation of the internal anal sphincter
(which is smooth muscle) and a contraction of the
external anal sphincter (which is skeletal muscle). In
the early stages of SSc, the response of the internal
anal sphincter is diminished or absent and the response of the external anal sphincter is either normal
or increased (4,111). These changes correlate with
reduction in the amplitude of relaxation of the LES in
the esophagus (4). These findings are reminiscent of
those seen in Hirschsprung’s disease and are consistent with a neural defect in the myenteric plexus.
In the later phases of SSc, decreases in resting
pressures of the internal and external anal sphincters,
decreased length of the anal canal, decreased maximum squeeze pressure, and finally, decreased rectal compliance due to collagen deposition occur
(4,106,107,110,111). The only changes that correlate
with symptoms are decreased squeeze pressures (106)
and decreased rectal compliance (107), which correlate with diarrhea. Presence of a rectal prolapse further decreases anal sphincter pressures and can contribute to incontinence (110,111).
Clinical presentations. Symptoms of constipation are extremely common (6). Constipation, defined
as 5 2 spontaneous stools/week, may be severe, and
barium impaction (112) and stercoral ulceration and
perforation (1 13) of the colon have been reported in
SSc. Fecal incontinence is probably the most common
colonic presentation of SSc (4,110). Other presentations of colonic involvement in SSc include diarrhea
(109), rectal prolapse (1lo), spontaneous perforation
(114), and colonic infarction (115). Diarrhea is most often
a symptom of small intestine bacterial overgrowth.
Diagnosis. Radiographic assessment. The incidence of pancolonic involvement identified on barium
enema radiographic series in patients with SSc varies
from 10% to 50% (6). Dilatation of the large bowel is
common, and wide-mouthed antimesenteric pseudodiverticula in the colon are highly suggestive of SSc
(18). These diverticula contain all layers of the intestinal wall, but the muscularis propria is atrophic.
Colonic transit assessment. Total and regional
colonic transit can be measured simply and inexpensively using the “Sitz marks” method according to the
Mayo Clinic protocol (116). Patients ingest capsules
containing 20 radiopaque markers on each of 3 consecutive days and an abdominal radiograph is obtained
on day 4 and on day 7. The marks in the left colon,
right colon, and rectosigmoid are counted, and by a
simple formula, transit times are calculated.
Anorectal manometry, defecatography, and
anal electromyography . These are specialized techniques designed to assess the function of the anal
sphincters and pelvic sling muscles. These techniques
are useful in evaluating incontinence and colonic outlet obstruction and in the consideration of surgical
approaches (110).
Treatment. As in other intestinal areas, treatment of colon and anorectal disorders in SSc is symptomatic. Fecal incontinence is due to anal sphincter
involvement. The first line of treatment is to treat
diarrhea. Diarrhea is principally due to small intestinal
causes. In addition to treatment of small bowel bacterial overgrowth, nonspecific measures including a
low-residue diet, antidiarrheals (such as loperamide),
and bile acid-binding resins (such as cholestyramine)
may be tried. If this fails to work, biofeedback measures can be tried, although there are no studies of
biofeedback in the management of SSc. Finally, surgical measures may be helpful. If proximal colonic
motility is shown to be normal and decreased pressures of the anal sphincters are shown with an absent
rectoanal inhibitory reflex, then a posterior anal repair
may be helpful (1 I 1).
Treatment of constipation is somewhat more
complicated. Nonspecific measures should be tried
first, although they often fail: increased fluids, increased fiber/Metamucil (psyllium hydrophilic mucilloid), and bowel training. If these fail, the next step is
to quantitate total and regional colonic transit. The
most common finding in SSc is generalized slow
transit, consistent with colonic inertia or pseudoobstruction. If this is the case, the algorithm discussed
for the small intestine should be used: first, prokinetic
drugs, then venting or surgical resections. Of note,
metoclopramide is usually not effective in the colon;
cisapride and erythromycin are reported effective.
There are no data on the effect of octreotide on colonic
If the colonic transit is normal except for delay
at the rectosigmoid, colonic outlet obstruction should
be considered. An evaluation of pelvic floor function
should be initiated with anorectal manometry, defecatography, and anal electromyography (110). The
purpose of this evaluation is to determine the function
of the anal sphincter and the skeletal muscles in the
pelvic sling. If pelvic floor dysfunction can be diagnosed, specific surgical reconstructions can be performed.
After the skin, the gastrointestinal tract is the
second most common target of systemic sclerosis. The
major clinical manifestations include gastroesophageal
reflux, small bowel bacterial overgrowth, malnutrition, and intestinal pseudoobstruction. Treatment is
symptomatic and supportive. Gastroesophageal reflux
can usually be adequately managed with prokinetic
drugs, omeprazole, and judicious use of antireflux
surgery. If Barrett’s esophagus is present, periodic
endoscopic monitoring for development of dysplastic
changes or adenocarcinoma is indicated. Bacterial
overgrowth usually responds to rotating antibiotics
and prokinetic drugs. Malnutrition and intestinal
pseudoobstruction remain the major problems and
often home total parenteral nutrition is required. Intestinal pseudoobstruction occurs in two phases: an
early, neuropathic phase and a late, myopathic phase.
The early neuropathic phase may respond to prokinetic drugs (metoclopramide, cisapride, octreotide,
and erythromycin) and dietary modification (lowresidue diets, vitamin supplementation). In the late
myopathic phase, therapy is usually ineffective. Treatment consists of nutritional support. Careful manometric and radiographic localization of affected segments of stomach and small and large intestines may
allow judicious surgical resection or venting procedures to reduce symptoms in this unfortunate group of
T h e author wishes to thank Dr. Barbara White,
Division of Rheumatology a n d Immunology, University of
Maryland, Baltimore, for her encouragement and advice.
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