Delayed gastric emptying determined using the 13C–octanoic acid breath test in patients with systemic sclerosis

Authors


Abstract

Objective

To determine the prevalence of delayed gastric emptying using the 13C–octanoic acid breath test in unselected patients with systemic sclerosis (SSc), to evaluate whether findings of the 13C–octanoic acid breath test are associated with clinical digestive manifestations, gastric mucosal abnormalities detected by gastroscopy, motor activity dysfunction detected by antroduodenal manometry, and esophageal motor impairment and extradigestive manifestations of SSc, and to develop a risk prediction score of gastric emptying in SSc.

Methods

Consecutive patients with SSc (n = 57) underwent the 13C–octanoic acid breath test. All of the patients with SSc completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated.

Results

The prevalence of delayed gastric emptying was 47.4% in patients with SSc. A marked correlation was observed between a GSS of digestive symptoms ≥5 and the presence of delayed gastric emptying (P < 0.00001). The sensitivity of a GSS ≥5 for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.73. Moreover, a GSS ≥5, mucosal gastric abnormalities, severe esophageal motor impairment, and interstitial lung disease were factors that were independently associated with the presence of delayed gastric emptying, and these variables were used to create a risk prediction score. The area under the receiver operating characteristic curve for the risk prediction score was 0.90; the sensitivity of this score for the prediction of delayed gastric emptying was 0.93, while the specificity was 0.77.

Conclusion

The results indicate that delayed gastric emptying occurs often in patients with SSc. Interestingly, using risk models with routine clinical characteristics, a simple risk prediction score can be calculated, allowing prediction of the occurrence of delayed gastric emptying in patients with SSc.

Systemic sclerosis (SSc; scleroderma) is a systemic inflammatory disorder affecting the skin and other organs, particularly the gastrointestinal tract. Studies have shown that scleroderma lesions may lead to motor activity impairment (1–11). Moreover, esophageal and anorectal abnormalities are frequent in patients with SSc (70–95% of cases) and have been described extensively (1–14). However, gastric involvement has been less frequently recognized in patients with SSc, occurring in 10–75% of patients (4, 7, 9, 12, 13). Gastrointestinal abnormalities may be responsible for the routine clinical symptoms in SSc, including dyspepsia, gastric hemorrhage related to antral vascular ectasia (known as “watermelon stomach”), and delayed gastric emptying (4, 7, 9, 12, 13).

Delayed gastric emptying may result in severe gastrointestinal symptoms, including an inability to ingest sufficient calories, leading to malnutrition and, at later stages, to cachexia and electrolyte disturbances, and worsening of gastroesophageal reflux (1, 5–7, 9–14). In previous studies, the prevalence of delayed gastric emptying has been reported to be 50–67% in patients with SSc exhibiting gastrointestinal symptoms, as determined using scintigraphy (15–23). Although the gold standard test for the diagnosis of delayed gastric emptying is scintigraphy, this is both a complex and an expensive technique for routine use. In clinical practice, the 13C–octanoic acid breath test represents a simple, noninvasive, nonradioactive and reliable method for the diagnosis of delayed gastric emptying (24–31). Results of this test have been shown to correlate with the findings from scintigraphy in the measurement of gastric emptying (32).

Currently, however, there are no studies assessing the prevalence of delayed gastric emptying using the 13C–octanoic acid breath test in patients with SSc. Therefore, the aims of the present prospective study were 1) to determine the prevalence of delayed gastric emptying in unselected patients with SSc, using the 13C–octanoic acid breath test, 2) to evaluate whether the findings of the 13C–octanoic acid breath test are associated with clinical digestive manifestations, findings of gastric mucosal abnormalities on gastroscopy and motor activity dysfunction on antroduodenal manometry, and esophageal motor impairment and extradigestive manifestations of SSc, and 3) to create a scoring system derived from routine clinical observations that would allow for estimation of the risk of delayed gastric emptying in patients with SSc.

PATIENTS AND METHODS

Patients.

From 2008 to 2010, 57 consecutive patients with a definite diagnosis of SSc were included in the study. The criteria used for the diagnosis of SSc were based on the American College of Rheumatology preliminary classification criteria (33). Ethics approval was obtained from our local ethics committee (Haute-Normandie, France).

The study cohort consisted of 12 men and 45 women with a median age of 56 years (range 23–82 years). The median duration of the disease, considered from the onset of the first non–Raynaud's phenomenon clinical manifestations, was 4 years (range 1–37 years). Patients were grouped into disease subsets according to the criteria of LeRoy et al (34), with 26 patients (45.6%) classified as having diffuse cutaneous SSc (dcSSc) and 31 (54.4%) as having limited cutaneous SSc (lcSSc). Among the 57 patients with SSc, the median Scleroderma Health Assessment Questionnaire (SHAQ) score (35) was 0.2 (range 0–2.6). None of the patients with SSc had other connective tissue disorders (systemic lupus erythematosus, Sjögren's syndrome, polymyositis/dermatomyositis) or a history of liver or digestive system diseases, diabetes mellitus, gastric surgery, or vagotomy. Furthermore, no patient had received nonsteroidal antiinflammatory drugs. Pulmonary involvement in the patients with SSc included interstitial lung disease (ILD) in 22 patients (38.6%) and pulmonary arterial hypertension in 6 patients (10.5%). Thirty-three patients (57.9%) had digital pitting scars.

All patients had undergone esophageal manometry. Based on the findings from manometry, the Hurwitz criteria for the degree of esophageal involvement was applied, as follows: stage I = normal esophageal motility, stage II = uncoordinated peristalsis with normal pressure-wave amplitude, stage III = uncoordinated peristalsis with low pressure-wave amplitude, and stage IV = both aperistalsis and decreased pressure in the low esophageal sphincter (5, 6). According to the Hurwitz criteria, 33 patients had severe esophageal motor impairment (stage IV) and 24 had normal/mild/moderate esophageal motor impairment (stages I/II/III).

All patients had also undergone gastroscopy to detect gastric mucosal abnormalities. In our patients, gastroscopy revealed the following gastric mucosal damage: antral erythematous gastritis (n = 8), watermelon stomach (n = 5), diffuse erythematous gastritis (n = 3), gastric micropolyps (n = 3), antral ulcer unrelated to Helicobacter pylori (n = 1), and gastric bezoar (n = 1). In the 5 patients with watermelon stomach, the endoscopic pattern was characterized by both parallel and longitudinal red folds within the distal antrum radiating to the pylorus; results of biopsy in these 5 patients revealed capillary ectasia with focal intravascular thrombi and fibromuscular hyperplasia in the lamina propria (4).

Among the 57 patients with SSc, 27 had undergone antroduodenal manometry, as described previously (8, 10). With this technique, computerized analyses are used to characterize gastric motility abnormalities. In analyses of manometric tracings during the fasting period, the phase III characteristics (number, duration, amplitude, and migration velocity of phase III) of the migrating motor complex (MMC) are determined from the recording chart (8, 10). In analyses of tracings during the postprandial period (i.e., following a 750-kcal meal), the number of pressure waves and the area under the curve on the whole tracing and on every half-hour of recording are calculated to determine the motility index (8, 10).

Thus, antroduodenal manometry yielded abnormal findings in 18 of the 27 SSc patients analyzed. Among these 18 patients, the findings were classified according to the extent of motor impairment, into categories of either severe impairment or mild impairment, as reported previously (8, 10). A motor disorder with severe impairment was characterized as either an absence of motility during both the fasting and postprandial periods or abnormal interdigestive motility (decreased amplitude and/or velocity of phase III MMC) associated with postprandial hypomotility. A motor disorder with mild impairment was defined as either abnormal interdigestive motility (decreased amplitude and/or velocity of phase III MMC) or a low-amplitude postprandial pattern (8, 10). According to these classifications, 15 patients had severe antroduodenal motor impairment and 3 had mild antroduodenal motor impairment.

Scoring of digestive symptoms.

Before undergoing the 13C–octanoic acid breath test, patients with SSc were systematically interviewed using a standardized questionnaire, in which patients were asked whether they had experienced any small-bowel symptoms, i.e., nausea, vomiting, abdominal pain/discomfort, bloating, diarrhea, constipation, abdominal tenderness, dysuria, tenesmus, fever, or general illness. Each symptom was assigned a symptom score ranging from 0 (no symptoms) to 3 (severe) (7, 36). A global symptom score (GSS) of digestive symptoms, calculated as the sum of all symptom scores, was then assigned to each patient (maximum score of 33), as has been described and validated in previous studies (7, 36). The GSS was compared between SSc patients with and those without delayed gastric emptying.

Biochemical tests.

Patients with SSc also underwent biochemical tests. These included measurements of the serum total protein levels (in gm/dl), serum albumin levels (in gm/dl), ferritin levels (in μmoles/liter), plasma folic acid levels (in nmoles/liter), vitamin B12 levels (in pmoles/liter), hemoglobin levels (in gm/dl), erythrocyte sedimentation rate (in mm/hour), and C-reactive protein levels (in mg/liter). Laboratory findings were compared between SSc patients with and those without delayed gastric emptying.

13C–octanoic acid breath test.

Medication that might affect gastric motility (e.g., metoclopramide, anticholinergics, calcium channel antagonists, macrolide antibiotics) was discontinued at least 72 hours before the13C–octanoic acid breath test was administered. After 12-hour fasting, patients with SSc underwent the 13C–octanoic acid breath test under standard conditions. The breath testing started between 8:30 AM and 9:00 AM.

All patients with SSc ingested a 250-kcal test meal (19% protein, 43% carbohydrate, 38% fat) consisting of white bread (50 gm), butter (17 gm), and an egg doped with 91 mg 13C–octanoic acid (Euriso-Top) (26, 27). Breath samples were obtained immediately before the meal and every 15 minutes after the meal for up to 8 hours. All samples were analyzed for the presence of 13CO2 by isotope-selective nondispersive infrared spectrometry (IRIS; Wagner/Analysen Technik) (26, 37), with results evaluated using an IRIS analyzer as described by Ghoos et al (38). The increase in breath 13CO2 after ingestion of 13C–octanoic acid was used to calculate the 13CO2 exhalation rate, assuming a mean endogenous 13CO2 production of 5 mmoles/minute/m2 body surface area (39); body surface was estimated from each patient's weight and height (40).

The solid half-time rate (T½) for gastric emptying is defined as the period of time (number of minutes) during which the first half of the 13C-labeled substrate is metabolized, i.e., when the cumulative excretion of 13C in the breath is one-half the ingested amount (26, 27, 37, 41). In our patients, the T½ was calculated by linear regression analysis using the IRIS software GE2.DEM (Wagner/Analysen Technik) (26, 27, 41). Thus, gastric emptying was considered delayed when the T½ exceeded 166 minutes (26). In the current study, the 13C–octanoic acid breath test was not performed on healthy subjects, as normal ranges have been previously validated in 37 healthy volunteers in the Department of Digestive Physiology at Rouen University Hospital (26).

Comparison of gastrointestinal and other systemic manifestations in SSc patients with and those without delayed gastric emptying.

We compared various clinical characteristics between SSc patients with delayed gastric emptying and those with normal gastric emptying. First, digestive manifestations were compared between SSc patients in these 2 groups. Manifestations included the findings from gastroscopy, findings from esophageal manometry (according to the Hurwitz criteria for the degree of esophageal involvement on manometry, i.e., patients with severe esophageal motor impairment [stage IV] versus patients without severe esophageal motor impairment [stages I/II/III]), and the severity of antroduodenal motor impairment according to the findings from antroduodenal manometry.

Second, SSc patients with delayed gastric emptying and those with normal gastric emptying were compared for the following characteristics: median age, median duration of SSc, distribution of SSc subsets, median SHAQ score, prevalence of digital pitting scars, ILD, and pulmonary arterial hypertension, antibody status (anticentromere and anti–Scl-70 antibodies), and findings from biochemical tests, i.e., erythrocyte sedimentation rate, C-reactive protein level, presence of anemia (defined as a hemoglobin level of <13 gm/dl in men and <12 gm/dl in women), serum total protein level, presence of hypoalbuminemia (serum albumin level <37 gm/liter), ferritin level, plasma folic acid level, and vitamin B12 level.

Calculation of the risk prediction score of delayed gastric emptying.

The possible role played by selected variables with respect to the presence of delayed gastric emptying was first examined by single-variable analysis, in which all collected variables were considered. Variables identified as significant in the single-variable analysis, i.e., those for which the P value was less than 0.10, were entered into a logistic regression model with a retention threshold of significance of P values less than 0.05. The risk prediction score was calculated as the sum of the products of these variables and their beta coefficients from the final model, i.e., (β1 × variable 1) + (β2 × variable 2) + (β3 × variable 3), etc.

Statistical analysis.

Statistical analyses were conducted using SAS software (version 8.02; SAS Institute). For group comparisons involving binary data, we used either the chi-square test or Fisher's exact test, depending on the expected sample size (≥5 or <5, respectively). Comparisons involving continuous data were performed using the Mann-Whitney test. In addition, logistic regression analyses were performed to identify the predictive factors for delayed gastric emptying. These results are reported as the odds ratio (OR) and 95% confidence interval (95% CI). Receiver operating characteristic (ROC) curves were constructed to examine the predictive value of the score in the detection of delayed gastric emptying. The overall diagnostic accuracy of this test was assessed using the area under the ROC curve. P values less than 0.05 were considered significant in all performed tests.

RESULTS

Prevalence of delayed gastric emptying.

In our whole population of 57 patients with SSc, the median T½ for gastric emptying was 202 minutes (range 101–558 minutes). Of these 57 unselected patients with SSc, 27 patients (47.4%) exhibited delayed gastric emptying, as shown by a T½ of >166 minutes, which was determined using the 8-hour 13C–octanoic acid breath test.

Digestive symptoms in SSc patients.

SSc patients reported the occurrence of the following digestive symptoms: nausea (54.4% of patients), vomiting (17.5% of patients), abdominal pain/discomfort (68.4% of patients), bloating (66.7% of patients), diarrhea (29.8% of patients), constipation (33.3% of patients), abdominal tenderness (49.1% of patients), and tenesmus (5.3% of patients). In our 57 patients with SSc, the median GSS of digestive symptoms was 5 (range 0–23).

The pattern of digestive symptoms was further compared between SSc patients with and those without delayed gastric emptying (Table 1). All of the patients with delayed gastric emptying exhibited digestive symptoms, compared to 90% of the patients without delayed gastric emptying. The prevalence of the following symptoms was higher in patients with delayed gastric emptying compared with patients who exhibited normal gastric emptying: vomiting (37% versus 0%), abdominal pain/discomfort (92.6% versus 46.7%), abdominal tenderness (85.2% versus 20.7%), and postprandial bloating (81.5% versus 43.3%).

Table 1. Clinical digestive symptoms in systemic sclerosis patients with delayed gastric emptying compared with those without delayed gastric emptying*
Clinical parameterPatients with delayed gastric emptying (n = 27)Patients without delayed gastric emptying (n = 30)P
  • *

    Except where indicated otherwise, values are the percentage of patients. GSS = global symptom score of digestive symptoms.

Nausea66.743.30.11
Vomiting3700.0001
Abdominal pain92.646.70.0001
Postprandial bloating81.543.30.005
Diarrhea3723.30.39
Constipation44.423.30.10
Abdominal tenderness85.220.70.000001
Fever14.83.30.18
Tenesmus7.43.30.59
GSS, median (range)8 (2–25)3 (0–12)0.000003

Furthermore, the median value for the GSS of digestive symptoms was significantly higher in SSc patients with delayed gastric emptying than in those without (median score 8 versus 3; P = 0.000003). We observed a marked correlation between a GSS of digestive symptoms ≥5 and the presence of delayed gastric emptying (P < 0.00001) as illustrated by the ROC curve (Figure 1), with an area under the ROC curve of 0.86. The sensitivity of a GSS of digestive symptoms ≥5 for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.73. The positive predictive and negative predictive values of a GSS of digestive symptoms ≥5 were 0.76 and 0.92, respectively.

Figure 1.

Sensitivity and specificity of a global symptom score of digestive symptoms ≥5 (solid square on the receiver operating characteristic curve) for predicting delayed gastric emptying in patients with systemic sclerosis. The sensitivity was as high as 0.93 and the specificity was 0.73.

Gastrointestinal involvement in SSc patients.

Gastric mucosal involvement was more common in SSc patients with delayed gastric emptying than in those without (55.6% versus 13.3%; P = 0.001) (Table 2). In addition, all of the patients with delayed gastric emptying exhibited motor dysfunction according to the findings from antroduodenal manometry, compared to only 10% of those with normal gastric emptying. Furthermore, we found that the motor impairment was more severe in the group of patients with delayed gastric emptying (determined using the 13C–octanoic acid breath test) (Table 2). Indeed, among the 17 patients with delayed gastric emptying who underwent antroduodenal manometry, 15 had findings of severe motor dysfunction, whereas mild motor dysfunction was demonstrated in only 2 of the patients.

Table 2. Findings of gastrointestinal involvement in systemic sclerosis patients with delayed gastric emptying compared with those without delayed gastric emptying*
Test, findingPatients with delayed gastric emptying (n = 27)Patients without delayed gastric emptying (n = 30)P
  • *

    Values are the percentage of patients.

Gastroscopy   
 Gastric mucosal abnormalities55.613.30.001
 Watermelon stomach11.16.70.66
 Gastritis (unrelated to Helicobacter pylori)29.613.30.21
 Gastric bezoar3.700.47
Antroduodenal manometry   
 Antroduodenal abnormalities100100.000002
Esophageal endoscopy   
 Esophageal abnormalities55.623.30.016
 Esophagitis33.3200.37
 Barrett's esophagus18.56.70.24
Esophageal manometry   
 Severe esophageal motor impairment70.4400.03

Predictive factors for delayed gastric emptying.

General clinical characteristics.

Severe esophageal motor disorders (stage IV) were significantly more frequent in SSc patients with delayed gastric emptying than in those without (70.4% versus 40%) (Table 2). We further found that gastroscopy showed esophageal mucosal damage in more of the SSc patients with delayed gastric emptying than in those without (55.6% versus 13.3%; P = 0.001).

We failed to show any statistically significant difference in the presence or absence of delayed gastric emptying between the subsets of scleroderma (each P = 0.293) (Table 3). However, delayed gastric emptying occurred earlier in patients with dcSSc than in patients with lcSSc, in that the median duration of dcSSc was shorter than that of lcSSc before the onset of delayed gastric emptying (median 4 years [range 1–9] versus 5 years [range 1–37]; P = 0.04).

Table 3. Clinical characteristics of systemic sclerosis (SSc) patients with delayed gastric emptying compared with those without delayed gastric emptying*
Clinical parameterPatients with delayed gastric emptying (n = 27)Patients without delayed gastric emptying (n = 30)P
  • *

    Except where indicated otherwise, values are the percentage of patients. lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; SHAQ = Scleroderma Health Assessment Questionnaire.

Age, median (range) years57 (23–73)51.5 (25–82)0.24
Sex, male/female22.2/77.820/801.00
SSc duration, median (range) years5 (1–37)3.5 (1–20)0.27
SSc subset   
 lcSSc44.4600.29
 dcSSc55.6400.29
Digital pitting scars59.356.71.00
Interstitial lung disease51.926.70.06
Pulmonary arterial hypertension14.86.70.41
SHAQ score, median (range)0.3 (0–2.55)0.05 (0–2.2)0.006

Furthermore, the group of patients with delayed gastric emptying exhibited a higher median SHAQ score (0.3 versus 0.05 in those without delayed gastric emptying; P = 0.006). In addition, patients with delayed gastric emptying had a higher prevalence of ILD (51.9% versus 26.7% of those without delayed gastric emptying; P = 0.06).

Laboratory findings.

As shown in Table 4, the group of SSc patients with delayed gastric emptying, compared to those without, exhibited a significantly higher ESR (17 mm/hour versus 10 mm/hour; P = 0.03) and significantly higher incidence of anemia (55.6% versus 26.7%; P = 0.03).

Table 4. Biochemical findings in systemic sclerosis patients with delayed gastric emptying compared with those without delayed gastric emptying*
Biochemical parameterPatients with delayed gastric emptying (n = 27)Patients without delayed gastric emptying (n = 30)P
  • *

    Except where indicated otherwise, values are the percentage of patients. Anemia was defined as a hemoglobin level of <13 gm/dl in men and <12 gm/dl in women. Hypoalbuminemia was defined as a serum albumin level of <37 gm/liter. ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

ESR, median (range) mm/hour17 (2–78)10 (2–40)0.03
CRP, median (range) mg/liter1 (1–27)1 (1–23)0.60
Presence of anemia55.626.70.03
Serum total protein, median (range) gm/liter67 (50–77)68 (55–76)0.35
Presence of hypoalbuminemia3713.30.06
Vitamin B12, median (range) pmoles/liter249 (30–738)306 (106–730)0.64
Folic acid, median (range) nmoles/liter11 (2–40)13 (6.5–50)0.44
Ferritin, median (range) μg/liter55 (2–358)60 (5–730)0.85
Anticentromere antibodies33.336.71.00
Anti–Scl-70 antibodies33.316.70.22

Results of logistic regression analysis to identify risk factors for delayed gastric emptying.

Logistic regression analyses identified independent risk factors for delayed gastric emptying in the SSc patients. These included a GSS of digestive symptoms ≥5 (OR 32.1, 95% CI 4.99–206, P = 2 × 10−7), gastric mucosal abnormalities detected by gastroscopy (OR 7.2, 95% CI 1.13–45.75, P = 0.036), severe esophageal motor disorders (OR 7.09, 95% CI 1.11–45.7, P = 0.039), and ILD (OR 6.96, 95% CI 1.10–44.1, P = 0.04).

Risk prediction score of delayed gastric emptying.

We found a marked correlation between the presence of delayed gastric emptying and a GSS of digestive symptoms ≥5, gastric mucosal abnormalities revealed by gastroscopy, severe esophageal motor disorders, and ILD, as shown by the ROC curve in Figure 2, with an area under the ROC curve of 0.90. The sensitivity of this score for predicting delayed gastric emptying was as high as 0.93, while the specificity was 0.77. The positive predictive and negative predictive values of this score were 0.78 and 0.92, respectively. The risk prediction score of delayed gastric emptying was calculated as follows: 3.5 (if GSS of digestive symptoms ≥5) + 2 (if ILD present) + 2 (if severe esophageal motor disorders present) + 2 (if mucosal abnormalities present on gastroscopy).

Figure 2.

Sensitivity and specificity of the risk prediction score of delayed gastric emptying (solid circle and asterisk on the receiver operating characteristic curve) obtained from logistic regression analyses of independent factors (global symptom score of digestive symptoms ≥5, gastric mucosal abnormalities, severe esophageal motor impairment, and interstitial lung disease) showing an association. The sensitivity was as high as 0.93 and the specificity was 0.77.

DISCUSSION

Delayed gastric emptying is a severe condition in SSc patients. Nevertheless, previous studies of delayed gastric emptying are rare and have included only a small number of patients with symptomatic SSc, who were evaluated using either radioscintigraphy or ultrasonography (15–23). Among 12 symptomatic patients with advanced SSc who underwent radioscintigraphy, 75% were found to have delayed gastric emptying (18). In other small series of SSc patients evaluated by scintigraphy, 50–67% of the patients showed delayed gastric emptying (16, 19–23).

Our present study of a prospective series of SSc patients is, to the best of our knowledge, the first to evaluate SSc patients who were not selected according to their clinical digestive presentation. In this instance, we observed a high frequency (47.4%) of gastric emptying disturbances. We considered a sample of 57 consecutive SSc patients without any prior selection based on clinical presentation, and thus the sample appeared to be representative of the entire SSc population. Our findings showed that delayed gastric emptying was prevalent in our whole population of SSc patients.

Although radioscintigraphy is still considered by many to be the gold standard for the diagnosis of delayed gastric emptying, this method has several limitations. First, scintigraphy is expensive and can only be performed in a hospital environment, because it requires complex equipment and highly qualified technicians; this test also requires that the patients occupy the gamma camera for several hours. Second, the administration of radioisotope-labeled substrates induces a substantial radiation burden. Finally, some methodologic problems may also influence the results of radioscintigraphy, including count attenuation, comptor scatter, downscatter, septal penetration, or imaging overlap (30, 31).

More recently, a breath test using test meals labeled with 13C–octanoic acid has been reported to be a practical and attractive alternative to scintigraphic studies for the assessment of gastric emptying (24–31). Thus, the 13C–octanoic acid breath test is easy to perform and safe, as it does not involve any radiation exposure (24, 26, 27, 37, 41–43). However, to date, there is still no expert consensus regarding the duration of the 13C–octanoic acid breath test (i.e., 4 hours, 6 hours, or 8 hours) that would be considered optimal to assess gastric emptying (24–31, 41–48).

Some investigators have, in fact, evaluated gastric emptying, both in healthy controls and in patients, using either the 4- or 6-hour 13C–octanoic acid breath test. Those investigators have observed that the 6-hour 13C–octanoic acid breath test seems to be more accurate in assessing gastric emptying in patients (44–47). In addition, two other groups of investigators have, interestingly, shown that the 13C–octanoic acid breath test can correctly assess both normal and delayed gastric emptying; those authors showed, in patients and healthy subjects, a marked correlation between the findings of gastric scintigraphy (using technetium-99–labeled test meals) and the findings of the 8-hour 13C–octanoic acid breath test (26, 37). In the present study, we also assessed gastric emptying using the 8-hour 13C–octanoic acid breath test.

Results of a study by Keller et al (47) suggested that the 13C–octanoic acid breath test may serve as a reliable marker of gastric emptying velocity in both healthy volunteers and mixed patient populations. To date, functional dyspepsia and autonomic diabetic neuropathy have, in fact, been the main conditions targeted in investigations of gastric emptying disorders in which the 13C–octanoic acid breath test has been used (24, 26, 27, 37, 42–49). However, until now, no researchers have evaluated gastric emptying impairment using the 13C–octanoic acid breath test in SSc patients. The findings of the current study interestingly suggest that the 13C–octanoic acid breath test may be a reliable method for noninvasive disclosure of delayed gastric emptying in SSc patients.

Only a few previous studies have demonstrated that digestive symptoms are predictors of delayed gastric emptying in SSc patients; these studies involved evaluations using radioscintigraphy or ultrasonography (17, 21). Other series have shown a poor correlation between gastric emptying and digestive symptoms (16, 50). The results of the present study underline the pathogenic role of delayed gastric emptying in the development of digestive symptoms in SSc patients. Taken together, our results show that delayed gastric emptying is associated with a greater prevalence of vomiting and dyspeptic manifestations (i.e., epigastric pain/discomfort, epigastric tenderness, and postprandial bloating).

The pathologic mechanisms of small-intestine dysmotility in SSc remain unknown. It has been postulated that impairment of the small bowel in SSc may result from the progressive development of histologic lesions, similar to those found in the skin (13, 14). Sjögren (13, 14) has proposed the following stages of sclerodermatous involvement: 1) vascular damage (grade 0), 2) neurogenic involvement (grade 1), and 3) myogenic involvement with replacement of normal smooth muscle by collagenous fibrosis and atrophy of muscle fibers within the circular muscle layer (grade 2). It is possible to classify intestinal motor disorders as either myogenic (hypomotility) or neurogenic (abnormally propagated phasic contractions and failure of fed-pattern response development). Myogenic abnormalities are characterized by low-amplitude intestinal contractions (7, 8, 10).

In the present series, 27 patients with SSc underwent antroduodenal manometry. In total, 18 of the 27 patients had abnormal findings on antroduodenal manometry. Interestingly, antroduodenal motor impairment detected by manometry was more common in patients with delayed gastric emptying (assessed using the 13C–octanoic acid breath test) than in those without delayed gastric emptying (100% versus 10%). Moreover, our findings also show that SSc patients with delayed gastric emptying more frequently exhibited severe antroduodenal motor impairment; in total, 68.8% of these patients had a myogenic pattern on manometry. Taken together, our findings suggest that there is a marked correlation between antroduodenal manometry findings and delayed gastric emptying, when the 8-hour 13C–octanoic acid breath test is used.

In patients with SSc, esophageal mucosal abnormalities are principally related to both low pressure in the low esophageal sphinter and abnormal peristalsis, leading to decreased acid clearance and prolonged acid–mucosal contact time (6). In this instance, because patients with delayed gastric emptying were more frequently observed to have more severe esophageal mucosal abnormalities, our findings suggest that gastric emptying disorders are likely to result in the deterioration of gastroesophageal reflux.

Furthermore, we demonstrated a strong relationship between delayed gastric emptying and severe motor impairment involving both the esophagus and ILD. Therefore, our findings suggest that this subgroup of patients will most likely have some distinguishing characteristics. First, they may exhibit a more severe concomitant involvement of the digestive tract in the processes of SSc, resulting in fibrosis of the gastric and esophageal smooth muscle. Indeed, in previous series of patients evaluated by manometry, esophageal motor dysfunction has been noted to be associated with antral hypomotility in patients with SSc (51), and our findings are in accordance with these data. Second, this subgroup of patients may have an increased risk of ILD related to increased occurrence of gastroesophageal reflux (related to delayed gastric emptying and severe esophageal motor involvement). From a practical point of view, complete knowledge of the predictive factors for delayed gastric emptying appears to be essential in order to improve the management of patients with SSc.

The findings from our study also reveal that the prevalence of delayed gastric emptying tended to be higher in patients with lcSSc than in those with dcSSc, although the differences were not significant. Moreover, our findings suggest that delayed gastric emptying occurs earlier in dcSSc compared with lcSSc. Previous authors have also observed that delayed gastric emptying tends to be more prominent in patients with dcSSc (16, 20).

A main finding in the present study was the observation of a marked correlation between a GSS of digestive symptoms ≥5 and the presence of delayed gastric emptying (P < 0.00001), with a sensitivity of 0.93 and a specificity of 0.73. Because the median GSS was 5 in our whole population, this could serve as a cutoff value for predicting the risk of delayed gastric emptying. Our findings therefore suggest that delayed gastric emptying should be considered in SSc patients exhibiting a GSS of digestive symptoms ≥5.

Furthermore, we observed a strong relationship between the presence of delayed gastric emptying and the following signs: a GSS of digestive symptoms ≥5, gastric mucosal abnormalities on gastroscopy, and severe esophageal motor impairment and ILD. The risk prediction score derived from these variables showed a sensitivity and specificity of 0.93 and 0.77, respectively. Interestingly, these data underscore the importance of routinely performing evaluations for delayed gastric emptying in the subgroup of SSc patients with severe esophageal motor impairment and ILD, even if they do not exhibit a GSS of digestive symptoms ≥5.

Thus, the results of our study highlight the usefulness of the noninvasive 13C–octanoic acid breath test for identifying delayed gastric emptying in patients with SSc, although, to date, the optimal duration of the 13C–octanoic acid breath test to assess gastric emptying in SSc patients remains unknown. In addition, our findings show that the GSS of digestive symptoms in SSc patients should be routinely calculated. In fact, the 13C–octanoic acid breath test should be performed (if available) in the subgroup of SSc patients exhibiting a GSS of digestive symptoms ≥5, since GSS values ≥5 were markedly associated with the presence of delayed gastric emptying in our patients with SSc.

We also identified a simple risk prediction score, based on characteristics observed on medical examinations that are routinely performed, to predict the risk of delayed gastric emptying in SSc patients. Indeed, our findings emphasize the importance of evaluating SSc patients for the presence of delayed gastric emptying when gastric mucosal abnormalities are detected on gastroscopy or when severe esophageal motor impairment and/or ILD is present.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Marie had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Marie, Ducrotté.

Acquisition of data. Marie, Gourcerol, Leroi, Levesque, Ducrotté.

Analysis and interpretation of data. Marie, Gourcerol, Leroi, Ménard, Ducrotté.

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