RHEUMATOLOGY
Rheumatology 2011;50:1596–1602
doi:10.1093/rheumatology/ker153
Advance Access publication 18 April 2011
Original article
Internal anal sphincter atrophy in patients with
systemic sclerosis
Nora M. Thoua1, Alexis Schizas1, Alastair Forbes2, Christopher P. Denton3 and
Anton V. Emmanuel1
Abstract
Objectives. SSc is a connective tissue, multisystem disorder of unknown aetiology. The gastrointestinal
tract (GIT) is affected in up to 90% of patients. The exact pathophysiology of GIT involvement is not
known, but it is related to both neurogenic and myogenic abnormalities as well as possible vascular and
ischaemic changes. Thinning of the internal anal sphincter (IAS) has been demonstrated in SSc with faecal
incontinence. We aimed to investigate anal sphincter structure in patients with SSc.
Methods. Forty-four SSc patients [24 symptomatic (Sx) and 20 asymptomatic (ASx)] and 20 incontinent
controls (ICs) were studied. Patients underwent anorectal manometry and endoanal US.
Results. In the ICs, external anal sphincter defects were more common, but the IAS was less atrophic,
evident by both atrophy scores and IAS thickness. There was no significant difference in atrophy scores
[Sx: 2 (1.5–3) vs ASx: 2 (1–2)] or IAS thickness [Sx: 1.85 (1.5–2.3) vs ASx: 1.8 (1.7–2.25)] between the
Sx and ASx SSc patients.
Conclusion. Patients with SSc (both Sx and ASx) have thin and atrophic IAS, suggesting that IAS atrophy
develops even in ASx patients and this may be amenable to treatment with sacral neuromodulation.
CLINICAL
SCIENCE
Key words: Internal anal sphincter, Atrophy, Faecal incontinence, Systemic sclerosis, Endoanal ultrasound,
Anorectal involvement.
Introduction
SSc is a connective tissue disorder of unknown aetiology
characterized by excess collagen deposition, chronic inflammation and vascular changes that affect multiple
organs [1]. The gastrointestinal tract (GIT) is affected in
up to 90% of patients [2]. The exact pathophysiology
of GIT involvement is not known, but it is related to
both neurogenic and myogenic abnormalities as well
as possible vascular and ischaemic changes [3–5].
Histologically, the main changes seen in the GIT are
smooth muscle atrophy and varying degrees of fibrosis
as the disease progresses [6]. Oesophageal involvement
is most common and upper gastrointestinal (GI) symptoms are frequently reported [7, 8]. Lower GI involvement
1
GI Physiology Unit, 2Department of Gastroenterology, University
College Hospital and 3Centre for Rheumatology, Royal Free Hospital,
London, UK.
Submitted 26 October 2010; revised version accepted 18 March 2011.
Correspondence to: Nora M. Thoua, Department of Gastroenterology,
St Mary’s Hospital, Praed Street, London W2 1NY, UK.
E-mail: [email protected]
can lead not only to constipation and evacuation difficulty
but also diarrhoea and faecal incontinence. The anorectum is affected in 50–70% of patients with SSc, with
>20% of patients developing faecal incontinence [9, 10].
In healthy subjects, faecal continence is maintained by
the coordinated function of pelvic floor, rectum and the
anal sphincters. The smooth muscle internal anal sphincter (IAS) is primarily responsible for the anal resting tone,
contributing 85% of the anal resting pressure. The
striated external anal sphincter (EAS) makes a small contribution towards the resting anal pressure, but is primarily
responsible for the voluntary contraction of the anal
sphincter [11]. Disruption or weakness of the IAS typically
leads to passive faecal incontinence, whereas that of the
EAS leads to urge faecal incontinence [12, 13]. The IAS,
being a smooth muscle, is more likely to be affected in
SSc [14] and it has been suggested that the changes are
similar to those seen in the lower oesophageal sphincter
(LOS).
The existing literature, none of which includes more
than 18 patients with SSc, suggests that the IAS is thinned
and hyperechoic on US in the majority of patients with
! The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
IAS atrophy in patients with SSc
SSc and faecal incontinence [15–17], although some patients may have a thickened hypoechoic sphincter, most
likely secondary to collagen deposition [16]. Whether
these differences relate to disease subtype or duration
has not been addressed. Even less is known about patients with SSc and no faecal incontinence. If the pattern
is similar to that seen in oesophageal involvement, we
would expect to see structural and functional changes
even in the absence of symptoms. This study aimed to
quantify the sonographic changes in the anal sphincters of
patients with SSc with and without faecal incontinence.
We hypothesized that defects in the sphincter mechanism
would be less common in incontinent SSc patients than in
incontinent controls (ICs) without SSc. We further
hypothesized that atrophic sphincter changes would
occur more often in symptomatic (Sx) than asymptomatic
(ASx) SSc patients.
Methods
Patients
Forty-four patients with SSc, 24 Sx (with anorectal symptoms) and 20 ASx (without anorectal symptoms) patients,
were recruited to the study. Twenty patients, age and sex
matched to the Sx SSc patients, referred to our GI physiology unit for investigations of faecal incontinence, were
used as ICs. All patients gave informed consent to participate in the study, which was approved by the University
College Hospital research ethics committee. Incontinence
was assessed by using the Wexner incontinence score, a
validated questionnaire assessing incontinence based on
frequency and stool consistency.
Questionnaires
SSc patients were asked to complete the following questionnaires on the day of their assessments.
(i) Scleroderma GI tract 1.0 questionnaire: a 52-item
self-completed instrument that provides a profile for
GI symptoms in five broad categories and their
effect on social and emotional well-being.
(ii) Short form-36 (SF-36) general health questionnaire:
a multi-purpose, short-form health survey with 36
questions that yields an eight-scale profile of functional health and well-being scores.
(iii) EuroQol: a six-item self-completed instrument that
provides a simple descriptive profile for health
status by asking if the patient has no problems,
some problems or significant problems in domains
of: mobility, self-care, usual activities, pain/discomfort and anxiety/depression (scoring 1, 2 or 3,
respectively).
Anorectal manometry
No bowel preparation was given before testing. An eightchannel radial water-perfused manometry system with a perfusion rate of 0.6 ml/min (MMS, Enschede, The Netherlands)
was utilized. A latex-free balloon with 500 ml capacity
was attached at the end of the manometry catheters
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(Ardmore Healthcare Limited, Amersham, UK, external diameter 3.9 mm). With the subject in the left lateral position, the
station pull-through technique was employed to assess
anal canal length, anal resting pressure and anal squeeze
pressure.
Endoanal US
Endoanal US (EAUS) was performed to assess the integrity of anal sphincters and possible presence of sphincter
infiltration and atrophy. A conventional Hitachi EUB 8500
US machine was used with an EUP R54AW-19 endoanal
probe covered with a lubricated condom was inserted
into the anus with the patient in the prone position.
Conventional anal endosonography was performed according to a standard technique [18]. Images of the anal
sphincters were taken at proximal, mid- and distal canal
levels. Images were acquired by a trained radiographer
and assessed independently by two experts. The anal
sphincter complex was examined and the integrity and
atrophy of the internal and external sphincters were
described as follows, and scored 1–3 for analysis purposes [19].
Integrity
Integrity score: 1 = intact, 2 = focal thinning and 3 = defect/
scar; focal thinning: thinning in muscle thickness, but
fibres in continuity; and defect/scar: discontinuity of
muscle fibres with or without replacement by lower
echogenicity scar tissue.
Atrophy
Atrophy score: 1 = normal, 2 = mild atrophy, 3 = severe
atrophy; mild internal sphincter atrophy: abnormal
increased echogenicity and/or measurement 1.5–2 mm;
severe internal sphincter atrophy: measurement
<1.5 mm; mild external sphincter atrophy: muscle structure visible but abnormal high echogenicity suggestive of
fatty replacement; and severe external sphincter atrophy:
muscle structure very poorly or not defined suggestive
of marked fatty replacement.
The IAS was measured at the level of greatest thickness
at the 3, 6, 9 and 12 o’clock positions and the average
thickness was calculated.
Statistics
Statistical analysis was performed using GraphPad Prism.
As some of the values measured were non-normally
distributed, results are expressed as median and interquartile range. The non-parametric Mann–Whitney and
Kruskal–Wallis tests were used for comparisons of two
and three groups, respectively. Correction for multiple
comparisons was done using the Dunn’s correction.
Results
Patients
Forty-four SSc patients were studied. Twenty-four patients were Sx, reporting faecal incontinence, and 20 patients were ASx. Sex- and age-matched patients with
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Nora M. Thoua et al.
TABLE 1 Demographic characteristics of three patient groups and disease characteristics of
the SSc patients
Patient characteristics
ASx SSc
Sx SSc
ICs
Age, median (IQR)
Female : male ratio
Parity, median (IQR)
Wexner incontinence, median (IQR)
Disease duration, median (IQR)
lcSSc/dcSSc, n
Autoantibodies, n (%)
ACA
SCL-70
Internal organ involvement, n (%)
Pulmonary
Cardiac
Renal
Oesophageal
57.5 (53.5–65.5)
20 : 0
1 (0–2)
2 (0.5–3.5)
5.5 (3.3–11)
13/7
61 (53–66)
20 : 4
2 (1–2)
10 (8–16)*
10.5 (4.5–18)
20/4
50.5 (44–64)
20 : 0
2 (2–3.5)*
14 (11.5–16)*
N/A
N/A
N/A
8 (40)
2 (10)
17 (71)
3 (13)
5 (25)
1 (5)
2 (10)
14 (70)
10 (42)
2 (8)
2 (8)
23 (96)
N/A
Comparisons made using Mann–Whitney and Kruskal–Wallis tests. *P < 0.05 compared with ASx.
IQR: interquartile range.
TABLE 2 Questionnaire scores in SSc patients
Questionnaires
SF-36
Total score
Physical health score
Mental health score
EuroQol (EQ-5D)
Mobility
Self-care
Usual activities
Pain/discomfort
Anxiety/depression
VAS score
SSc-GIT 1.0
Reflux
Distension
Diarrhoea
Constipation
Abdominal pain
Social
Emotional
ASx SSc, median (IQR)
Sx SSc, median (IQR)
62.43 (54.45–77.84)
60.4 (42.8–75.1)
65.15 (53.95–70.9)
54.01 (39.74–73.57)
50.8 (27–68.5)
62.35 (35.63–72.95)
1 (1–2)
1 (1–1.5)
1 (1–2)
1.5 (1–2)
1 (1–2)
80 (60–80)
1
1
2
2
2
62
92.6 (81.5–96.5)
83.3 (72.2–94.35)
100 (77.75–100)
100 (77.7–100)
100 (83.3–100)
100 (100–100)
100 (94.45–100)
(1–2)
(1–2)
(1–2)
(2–2)
(1–2)
(53–80)
55.6 (42.55–77.75)*
50 (36.1–63.85)*
61.1 (27.75–100)*
66.65 (22.2–100)*
66.7 (50–100)*
81.7 (65–95)*
55.6 (31.45–77.75)*
Comparisons made using the Mann–Whitney test. *P < 0.05. IQR: interquartile range; VAS: visual
analogue scale.
incontinence were used as controls. Table 1 summarizes
the demographics and incontinence scores of the three
patient groups. The median disease duration was 5.5 and
10.5 years for ASx and Sx patients, respectively. Five
(25%) ASx patients and 4 (17%) Sx patients had disease
duration of 43 years. There was no significant difference
in the percentage of oesophageal symptoms between Sx
and ASx SSc patients. Unfortunately, oesophageal manometry results were available for only two patients, and
therefore we could not assess for correlation between abnormal oesophageal and anorectal manometry. Incontinence scores were higher in the IC and Sx groups
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compared with the ASx group. Although many patients
reported both urge and passive faecal incontinence,
urge incontinence was more common in the IC group
(16/20 IC vs 12/24 SSc Sx patients). SSc patients more
commonly reported passive incontinence or soiling (20/24
patients). Parity was higher in the IC group. Table 2 summarizes the quality-of-life questionnaire scores in SSc
patients.
Anorectal manometry
The resting pressure was below the normal range in both
the Sx and the IC groups and was the lowest in the IC
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IAS atrophy in patients with SSc
group [IC: 42.2 (33–57.4) vs ASx: 63.8 (53.7–73.9);
P < 0.05 vs Sx: 50.8 (40.7–61)]. The squeeze pressure
was lower in the IC group, and below the normal range,
compared with both the ASx and Sx groups [IC: 46.95
(30–63.9) vs ASx: 104.6 (81–128.3) vs Sx: 121.4
(101.3–141.6); P < 0.05 for both]. There was no significant
difference in the resting or squeeze pressures between
the ASx and Sx SSc patient groups. Subset analysis of
patients with dcSSc and lcSSc did not show any difference in anorectal manometry nor IAS atrophy between the
two subsets, although this analysis is limited by the small
number of patients in each subset.
FIG. 1 (A) IAS atrophy scores in the three groups. (B) IAS
thickness in the three groups.
EAUS
SSc patients had more atrophic IAS sphincter (atrophy
median score 2), but largely intact IAS and EAS compared
with ICs. The age- and sex-matched ICs were more likely
to have EAS defects; they also had less IAS atrophy,
evidenced by both atrophy scores and IAS thickness.
Figure 1 show the IAS atrophy scores and IAS thickness,
respectively, in the three patient groups. Surprisingly,
there was no significant difference in atrophy scores
[Sx: 2 (1.5–3) vs ASx: 2 (1–2)] or IAS thickness [Sx: 1.85
(1.5–2.3) vs ASx: 1.8 (1.7–2.25)] between the Sx and ASx
SSc patients. EAUS images of IAS atrophy and sphincter
defects are seen in Fig. 2.
There was no significant correlation between incontinence scores and atrophy and integrity scores or IAS
thickness. In subgroup analysis, there was a positive correlation between Wexner incontinence score and IAS
atrophy in the SSc patient groups (r = 0.38, P = 0.01).
There was no correlation between IAS thickness or IAS
atrophy scores and disease duration in SSc patients.
P<0.05
A
IAS atrophy
3
2
1
ASx
IC
P<0.05
B 4
IAS thickness, mm
Sx
3
Discussion
Anorectal involvement is reported in 50–70% of patients
with SSc [10]. Faecal incontinence is probably
under-reported in view of the stigmatizing nature of the
symptom and its social implications. In an anonymous
questionnaire study, 24% of patients reported faecal soiling [9]. As the anorectum is the second most commonly
affected site of the GI tract, after the oesophagus, there
have been a number of studies that investigated anorectal
symptoms mainly with physiological measurements
2
1
0
ASx
Sx
IC
FIG. 2 EAUS images showing (A) EAS and IAS defect ( ), IAS (
A
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), EAS (
) and (B) IAS atrophy (
).
B
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Nora M. Thoua et al.
such as anorectal manometry, sensation and reflexes.
Typically, it is the smooth muscle IAS that is affected in
SSc, thus resulting in lower resting pressure [20–23],
whereas squeeze pressure is usually normal as the EAS
is largely unaffected [20, 22–24]. In our study, we found
slightly lower resting pressure in the Sx SSc patients when
compared with the ASx patients, but the ICs had significantly lower resting pressures. This is probably a reflection of the presence of both internal and external sphincter
defects in the latter group of patients. As in a number of
previous studies, the squeeze pressure in the SSc patients was normal.
Although well recognized that the anal sphincters are
likely to be affected in scleroderma, there are only few
studies that have assessed the anal sphincter structure.
Engel et al. [12] were the first to report morphological
changes of the internal sphincter in SSc patients. They
described two female patients with SSc and passive
faecal incontinence with very thin, hyperechoeic IAS
[14]. deSouza et al. [17], in an MRI study of 18 patients
with SSc and 19 controls with and without incontinence,
showed that the SSc patients with incontinence had thinner IASs than controls, but not in those without incontinence, suggesting that incontinence is related to smooth
muscle atrophy in this group. They further found reduced
gadolinium enhancement of the IAS in all SSc patients,
suggesting an ischaemic origin of IAS atrophy. They did
not find any significant difference in the EAS thickness in
SSc patients [17]. Koh et al. [16] described 11 SSc patients with incontinence and suggested two distinct types
of morphological changes in the IAS. Patients had either
very thinned, difficult to delineate and hyperechoic internal
sphincters or, less commonly, a thickened, homogeneous
and uniformly hypoechoic IAS [16].
In our study, we aimed to investigate the morphology of
anal sphincters in SSc patients. We compared SSc patients with and without anorectal symptoms and specifically faecal incontinence with controls that were being
investigated for faecal incontinence. We showed that patients with SSc, both those with faecal incontinence and
the ASx ones, had thinned and atrophic IAS compared
with the ICs. In contrast, the ICs had more common evidence of EAS defects. We did not find any SSc patients
with thickened IAS in our unselected sequential cohort of
patients.
The gastrointestinal smooth muscle may be involved
early in patients with SSc, before the onset of clinical
symptoms. This is seen in the oesophagus where physiological, mainly motility abnormalities are seen even in patients with no oesophageal symptoms [25, 26]. The IAS
shares similarities with the LOS in that they both are a
smooth muscle continuation of the circular muscle layer
of the gut that maintains chronic tone. The oesophageal
abnormalities in SSc are low basal LOS pressure resulting
in loss of competence and also lack of peristalsis of the
lower oesophageal body [27–29]. These abnormalities are
thought to be secondary to collagen deposition, resulting
in smooth muscle atrophy and fibrosis [30]. Although collagen deposition and smooth muscle atrophy are well
1600
recognized in GIT involvement in SSc, there is evidence
that these abnormalities are preceded by vascular insufficiency and neural dysfunction [31, 32]. Vasculopathy of
arterioles is common in SSc. Decreased oesophageal
blood flow has been found in patients with RP and
reduced gastric and duodenal blood flow has been
demonstrated in SSc patients [31, 33]. In the anorectum,
deSouza et al. [17] showed that SSc patients with faecal
incontinence had reduced gadolinium enhancement of the
IAS. The pathogenesis of neuropathy may be caused
by compression of nerve fibres by collagen deposits or
secondary to arteriolar changes in the vasa nervorum.
Another possible mechanism is autoantibody related.
Antibodies to muscarinic M3 receptors have been found
to inhibit enteric cholinergic neurotransmission and to be
associated with severe GI involvement [34–36]. The evidence of neuropathy in the anorectum comes from
evidence of reduced sensation and more so by evidence
of absent or impaired rectoanal inhibitory reflex (RAIR)
found in 70% of SSc patients with anorectal involvement
[20, 22, 37]. Malandrini et al. [38] found evidence of nerve
degeneration in rectal mucosa of SSc patients with faecal
incontinence.
Oesophageal involvement is found in up to 90% of patients with SSc, and even patients with no oesophageal
symptoms when investigated are found to have oesophageal dysmotility [29, 39]. Only a small number of SSc patients with no anorectal symptoms have been investigated
and therefore there are little data on anorectal physiology
abnormalities in ASx SSc patients. deSouza et al. [17]
studied four SSc patients without incontinence and did
not find reduced IAS thickness as found in the SSc incontinent patients. We found that although SSc continent patients did not have reduced resting pressure, they did
have IAS atrophy and reduced IAS thickness. Although
different imaging modalities were used in these two studies, MRI and EAUS, this is unlikely to account for the
difference in findings as the relationship between the
two modalities for IAS and EAS thickness is excellent
[40]. It is possible that this early finding of IAS atrophy
may be secondary to vascular or neurological dysfunction
and not secondary to fibrosis, which tends to occur later
in the disease process. Confirmation of such a hypothesis
requires histological evidence from full thickness biopsy,
which is not ethically justifiable. Interestingly, a histological study of oesophageal tissue in SSc patients and controls found smooth muscle atrophy in 94% of SSc patients
and only 5% of controls. The pathological findings
seemed to be either secondary to loss of neural function
or a primary smooth muscle lesion [41]. We have previously found reduced anal sensation and impaired RAIR in
this ASx SSc patient group, suggestive of a neural cause
for those changes [42]. These findings are significant
with regard to management of anorectal symptoms as it
is possible that sacral neuromodulation [15] may be more
successful than other therapies and that it may be worth
considering early, minimal treatment of Sx or even ASx
patients, if anorectal physiology abnormalities are
present.
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IAS atrophy in patients with SSc
In summary, we have shown that patients with SSc
have thin and atrophic IAS. This finding is evident in
both Sx and ASx patients and development of symptoms
seems to be dependent on other factors. With the development of better treatments such as sacral neuromodulation, screening for anorectal dysfunction may be worth
considering.
Rheumatology key messages
Anorectal involvement is common in SSc and
evident even in ASx patients.
. The IAS is thin and atrophic in SSc patients.
. Development of faecal incontinence is multifactorial.
.
Acknowledgements
Funding: This work was supported by the Raynaud’s
and Scleroderma Association, UK.
Disclosure statement: The authors have declared no
conflicts of interest.
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