Could fecal calprotectin serve as an indicator of gastrointestinal (GI) complications in individuals with systemic sclerosis?

doi:10.21203/rs.3.rs-3230564/v1

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Research Article

Could fecal calprotectin serve as an indicator of gastrointestinal (GI) complications in individuals with systemic sclerosis?

https://doi.org/10.21203/rs.3.rs-3230564/v1

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Introduction

: Systemic sclerosis is a connective tissue disease with unpredictable symptoms. The GI tract is often affected, with calprotectin levels indicating inflammation. We are examining fecal calprotectin as a simple method to diagnose GI disorders and disease activity.

Materials and methods

We gathered information from the 39 patients by filling out a UCLA SCTS 2.0 questionnaire regarding their GI symptoms. Additionally, we examined their skin and determined their skin score. Blood samples were taken to assess malnutrition, and stool samples were collected to measure the calprotectin level. We also conducted a non-aggressive Barium Swallow and CT Enterography to check for GI disorders.

Results

Increased levels of FC didn’t have any correlation with age (P Value = 0.79), disease type (P Value = 0.59), slight intestine wall thickening (P Value = 0.10), esophageal dilatation (P Value = 0.18), skin score (P Value = 0.25), final GI score (P Value = 0.30) and none of the serum tests. In our study, just 5 cases had evidence of wall thickening in CT Enterography, and all those 5 cases had increased levels of calprotectin. Also, as most of our patients take vitamin and mineral supplements, we couldn’t find any signs of micronutrient deficiencies or correlation with FC level.

Discussion and Conclusion:

While no statistical correlation was found between FC level and the variables, the results suggest that FC might be a specific tool for assessing intestinal wall thickness. However, due to the limited sample size, further studies are necessary to validate these findings.

Systemic sclerosis

Fetal calprotectin

Systemic sclerosis (SSc), also referred to as scleroderma, is a complex and diverse inflammatory disease that affects various internal organs and the skin. It is characterized by the development of fibrosis and impairment of motor activity in the gastrointestinal (GI) tract due to lesions. It also leads to vascular dysfunction and autoimmunity. (1–3).

The GI system is heavily affected in patients with SSc, with more than 90 percent experiencing GI issues. While not the primary cause of death, these complications significantly impact patients' quality of life. The progressive fibrosis of smooth muscle in the muscular propria layer impairs normal motor function, leading to transit and nutrient absorption issues. Inflammation is also a significant contributor to GI disorders in SSc patients.

Calprotectin is a protein that binds to calcium and zinc and weighs 36-kDa. It makes up a considerable amount (40 to 60%) of the cytosolic proteins in neutrophils and is also present in other myeloid cells. Its composition comprises a heavy chain of 14 kDa and a light chain of 8 kDa.

When there's inflammation in the body and neutrophils are present, the levels of calprotectin elevate in the plasma, urine, saliva, and stool (25, 26). As a result, FC is a reliable indicator for detecting intestinal inflammation (28). The FC level stands out from other inflammatory markers such as the Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) because it is solely influenced by inflammation in the intestines and not affected by other sources of inflammation. (29).

In recent research, it has been found that SSc patients often exhibit high levels of FC (2, 11). As a result, fecal calprotectin has become a valuable tool in predicting the severity and recurrence of the disease, as well as assessing the efficacy of treatment (29). We faced a challenging issue, which led us to conduct a study aimed at exploring the effectiveness of fecal calprotectin in diagnosing GI disorders and assessing the disease activity among patients with such conditions.

Patients

The research was carried out at the rheumatology department of Sayyad Shirazi Hospital in Gorgan, Golestan Province, Iran. Prior to the study, it was approved by the regional ethical board at Golestan University of Medical Sciences, and all patients provided written informed consent.

To be included, patients had to meet the American College of Rheumatology (ACR) criteria for SSc, while exclusion criteria involved having other connective tissue diseases or vasculitis, a history of hepatic or GI diseases, diabetes or being alcoholic, a history of GI surgery or vagotomy, and a history of taking nonsteroidal anti-inflammatory drugs (NSAIDs).

Clinical Assessment:

We gathered various patient data, including age, gender, disease type, skin and GI symptom scores, the small bowel wall thickness in CT-Enterography, esophageal dilation in barium swallow examination, and their blood serum test results. The patients were classified according to whether they had diffused or limited cutaneous SSc (7), and their skin involvement was measured using the modified Rodnan skin score (mRSS) (36). Based on the European Scleroderma Trials and Research Group (EUSTAR) SSc activity score, a skin score above 14 was considered a sign of active skin involvement, and a score of less than 14 was considered as a sign of inactive skin involvement (37). To assess esophageal function and small bowel wall thickness, we utilized barium swallow and CT-Enterography, respectively, and both were evaluated by a radiologist as usual or affected.

Assessment of medical records

Medical records were studied carefully and patients with any of the exclusion criteria did not enter the study.

Questionnaire

Patients were asked to complete the UCLA SCTC 2.0 (University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0) (38). This questionnaire consists of 7 parts, including Reflux, bloating/abdominal distension, fecal spoilage, diarrhea, social function, emotional well-being, and constipation, each with specific questions. The score for each question was calculated individually, and at the end, the total was divided into six parts (excluding the constipation score), which was considered as the final score. Each patient received a score between zero and 2.83.

Laboratory examinations

To determine the FC level in patients, we used the BÜHLMANN CAL® EK-CAL (96 test) kit and the ELISA method. According to established classifications, FC levels above 50µg/g were deemed elevated (24, 29), and levels above 200µg/g were classified as significantly elevated (39). Since none of the patients had negative FC levels (less than 50µg/g), we divided them into two groups based on their levels: elevated (greater than 50µg/g and less than 200µg/g) and significantly elevated (greater than 200µg/g). We considered the first group a positive result and the second group a negative result. Additionally, we conducted laboratory tests for Albumin, Magnesium, Zinc, ESR, CRP, Folic Acid, Vitamin B12, and Ferritin in all patients.

Statistical analyses

We analyzed the collected data using SPSS software version 16, utilizing the Chi-square test to determine the correlation between FC level, age, disease type, and radiography results. The t-student test was used to examine the correlation of FC level with quantitative variables such as skin score and GI symptoms, magnesium, and ESR, while the Mann-Whitney test was used for other serum tests with abnormal distribution (CRP, Albumin, Ferritin, folic acid, Vitamin B12, and zinc). A two-tailed P-value < 0.05 was considered significant in the study.

A total of 46 patients were admitted to our medical department. However, seven patients, including two men and five women, were excluded from the study due to various reasons such as diabetes, history of esophagectomy, and simultaneous diabetes and polymyositis. The remaining 39 patients were all female and had a mean age of 43.23 years with a standard deviation of 11.75 years.

Table 1 presents the frequency distribution of positive and negative cases after analyzing disease types, skin involvement, increased thickness of the small intestine wall, and esophageal dilation. Some patients were excluded from the analysis because of insufficient information or inability to undergo the barium swallow test.

Table 1

Frequency distribution of positive cases of Disease types, skin involvement, increased thickness of the small intestine wall, and esophageal dilation.
Variables		Abundance	Percentage
Disease type	Diffuse	22	59.50
Disease type	Limited	15	40.50
Skin involvement	Positive	19	57.57
Skin involvement	Negative	14	42.43
Increased small intestine wall thickness	Positive	6	16.70
Increased small intestine wall thickness	Negative	30	83.30
Esophageal dilation	Positive	13	36.10
Esophageal dilation	Negative	23	63.90

* Unspecified cases were removed.

Table 2 also shows the mean and standard deviation of laboratory tests conducted on the studied subjects. According to the table, the mean and standard deviation for ESR, CRP, albumin, ferritin, folic acid, vitamin b12, magnesium, and zinc were 36.58 and 22.13, 4.65 and 7.12, 4.03 and 0.41, 65.07 and 82.38, 15.16 and 7.01, 435.77 and 1.86, 2.06 and 0.14, 49.43 and 28.94 respectively.

Table 2

The mean and standard deviation of laboratory tests in the studied subjects.
Variable	Mean	Standard deviation
ESR	36.58	22.13
CRP	4.65	7.12
Albumin	4.03	0.41
Ferritin	65.07	82.38
Folic acid	15.16	7.01
Vitamin B12	435.77	1.86
Magnesium	2.06	0.14
Zinc	49.43	28.94

* Unspecified cases were removed.

The FC test was completed successfully in 38 individuals, with a positive result for 26 (68.4%) patients and a negative result for 12 (31.6%).

Table 3 shows the distribution of FC results by age category, disease type, the presence of wall thickening, and the presence or absence of esophageal dilation in the studied subjects. According to the calculated p-values, it appears that the relationship between FC and any of these variables is not statistically significant.

Table 3

The distribution of FC results by age category, disease type, the presence of wall thickening, and the presence or absence of esophageal dilation in the subjects.
Variables		Negative FC		Positive FC		Total	P-value
Variables		No.	%	No.	%	No.	P-value
Age category	Young	5	29.40	12	70.60	17	0.79
Age category	Middle age	7	33.30	14	66.70	21	0.79
Disease type	Diffused	6	27.30	16	72.70	22	0.59
Disease type	Limited	5	35.70	9	64.30	14	0.59
Increased small intestine wall thickness	Positive	11	36.70	19	63.30	30	0.10
Increased small intestine wall thickness	Negative	0	0.00	5	100	5	0.10
Esophageal dilation	Positive	8	36.40	14	63.60	22	0.18
Esophageal dilation	Negative	2	15.40	11	84.60	13	0.18

Table 4. shows the mean and standard deviation of the skin score, the final score for GI symptoms, ESR and magnesium, serum CRP, albumin, ferritin, folic acid, vitamin B12, and zinc in terms of both positive and negative FC. The calculated p-values showed that the relationship of FC with any of these variables was not significant.

Table 4

To calculate the data, normal frequency distribution was used for the mean and standard deviation of skin score, GI symptoms final score, ESR, and magnesium, followed by the application of the student t-test. Meanwhile, the Mann-Whitney test was utilized to determine the mean and standard deviation of serum CRP, albumin, ferritin, folic acid, vitamin B12, and zinc for both positive and negative FC.
Variable	Negative FC		Positive FC		P Value^*
Variable	Mean	SD	Mean	SD	P Value^*
Skin score	11.38	7.00	15.92	10.08	0.25
GI score	0.39	0.24	0.49	0.28	0.30
ESR	39	22.96	35.46	22.11	0.65
Magnesium	2.06	0.07	2.06	0.16	0.94
CRP	3.32	1.78	5.26	1.48	0.21
Albumin	3.94	0.11	4.07	0.08	0.22
Ferritin	73.32	19.56	61.26	17.51	0.10
Folic acid	12.60	2.02	16.33	1.33	0.11
Vitamin B12	453.85	40.23	427.41	40.34	0.45
Zinc	44.75	3.08	51.58	6.71	0.84

According to Table 3, there was no notable variation in the occurrence of FC-positive cases between the young group (70.6%) and the middle-aged group (66.7%) in relation to age (P. Value = 0.79). There was no significant correlation found, but it was observed that the younger age group had a higher number of positive FC cases. This could possibly be due to the increased digestive tract activity in younger individuals. A previous study (40) on elderly patients with IBD and normal endoscopic findings found that the mean FC level was not higher, and there was no significant relationship between age and FC level. In contrast, a study by D'Angelo in 2017 demonstrated that FC levels increase with age (41).

In regards to the different types of SSc, Table 3 offers data on the occurrence of FC-positive cases. The results show that there was no significant difference (P. Value = 0.59) between the frequency of positive FC cases in the diffused type (72.7%) and the limited type (64.3%). However, due to the higher probability of digestive tract disorder in the diffuse type (42), the number of positive FCs was significantly higher than in the limited type, which confirms the link between FC levels and digestive tract involvement in patients with SSc.

Several studies have been conducted to evaluate the use of FC levels in different diseases. Bonnin et al (43) found that the level of FC in children with IBD is significantly higher than in children with functional type of disease or healthy children. Similarly, Andreasson et al (11) discovered that the level of FC in SSc patients was significantly higher compared to people with Sjögren's disease, rheumatoid arthritis, and healthy ones, indicating specificity of FC in diagnosing digestive tract problems in SSc patients. Ozseker et al (44) also found that FC levels can be used as a tool to identify GI tract problems in patients with Behcet’s disease, as patients with ulcers in terminal ileum or colon in endoscopic examinations exhibited significantly higher levels of FC compared to those with no digestive tract abnormalities (P. Value = 0.01).

However, Montalto et al (24) reviewed recent studies on the diagnostic use of FC levels in various GI disorders and concluded that FC level should not be used as a marker for structural digestive tract diseases but rather as a sign of inflammation of the GI wall. These findings contradict the results of other studies.

The prevalence of FC-positive cases in patients with SSc was determined by analyzing the thickness of the intestinal wall in CT-enterography. Table 3 shows that there was no statistically significant difference in the frequency of FC-positive cases between those with normal small intestine wall thickness (63.3%) and those with increased thickness (100%) (P. Value = 0.10). However, it's worth noting that only five cases showed evidence of increased small intestinal wall thickness in their CT-enterography, and all five had FC levels of more than 200 g/gµ. Since endoscopic access to the small intestine can be difficult, expensive, and painful, determining FC levels can serve as a predictive tool for the presence of GI disorders in the small intestine in patients with SSc.

Various studies have established a link between FC levels and GI issues. For instance, in 2011 (2) and 2014 (11), Anderson et al. conducted two studies that revealed a strong correlation between FC levels and GI pathology, which was proven by Cine-radiography. Similarly, in 2015, Cerrillo et al. (45) tested 112 patients with Crohn's disease involving the ileum using magnetic resonance elastography. They compared the results with their FC levels and observed that the magnetic resonance index of activity score was significantly associated with FC levels (p-value < 0.01). Additionally, in 2017, Shimoyama et al. (46) evaluated FC levels as a marker for small bowel inflammation in patients with Crohn's disease. They discovered a significant positive correlation between FC level and CT-enterography score (P < 0.0001).

Further research with a larger sample size is needed to determine if FC levels can indicate inflammation in the small intestine, as our current study did not yield significant results.

In patients with SSc, the esophagus is commonly affected, with 90% of patients experiencing this issue (47). Our study aimed to compare the frequency of FC-positive cases in patients with and without esophageal dilation during a barium swallow test. The results showed no significant relationship between positive cases of FC in patients with and without esophageal dilation (P. Value = 0.18). However, FC levels were numerically higher in patients with esophageal dilation, indicating a possible correlation between elevated FC levels and upper GI tract disorders. Previous studies (40) have shown that FC can be a useful marker for detecting abnormalities in both the upper and lower GI tract. Though it is more useful in colon disorders, FC levels have been found to be significantly higher in children with reflux compared to healthy children (0).

Based on the data presented in Table 4, individuals with a positive FC response had a mean skin score of 15.92, while those with a negative FC response had an average skin score of 11.38. However, the difference was not deemed statistically significant with a P-value of 0.25. This finding is supported by a study conducted by Andreasson et al. (2) in 2011, which also found no significant correlation between FC levels and skin score in SSc patients. Therefore, subsequent studies did not compare these two parameters. In 2015, Marie et al. (1) also conducted a study on the role of FC level in SSc and found no correlation between FC levels and average skin score, with a P-value of 0.79.

In Table 4, the mean GI symptoms score was found to be 0.49 in individuals with a positive FC response, and 0.39 in those with a negative FC response. However, the association between FC and GI symptoms was not statistically significant (P. Value = 0.30). One possible reason for this is that the questionnaire used may not have been specialized for the Iranian population. Another factor to consider is the use of anti-acid drugs, such as proton pump inhibitors (PPIs). It is important to note that the questionnaire included questions about fear of digestive problems in different social situations, which may not have been relevant to our patient population, consisting mostly of middle-aged, illiterate, and housewife women who did not encounter diverse social situations. Similarly, questions about fear of digestive problems while traveling were not applicable to many of our patients due to financial or physical constraints. Furthermore, a study by Andreasson et al. in 2011(2) found that the relationship between FC level and GI symptom score, as measured by a Swedish questionnaire (GSRS), was also not statistically significant (P. Value = 0.44). The authors attributed this to the questionnaire's lack of specialization for patients with SSc.

Malnutrition is a significant symptom of acute GI disease (49), which is often linked to a low number of bacteria in the small intestine, where nutrients are absorbed (50). Small intestinal bacterial overgrowth (SIBO) can lead to food being consumed by bacteria, causing damage to the mucosa and impairing absorption in the small intestine, ultimately resulting in malabsorption (51). Laboratory tests can be used to identify micronutrient deficiencies, which are common symptoms of malnutrition (52). In a study by Polkowska-Pruszyńska (53), fecal calprotectin (FC) was found to be a reliable indicator of SIBO in SSc patients, but further tests are necessary to confirm a diagnosis. The study also found that SIBO treatment for more than three months can affect fecal calprotectin levels and other micronutrients (15). However, a statistical analysis of serum tests (ESR, magnesium, CRP, albumin, ferritin, folic acid, vitamin B12, and zinc) in patients with positive and negative FC responses showed no significant relationship between FC level and micronutrient levels. Surprisingly, the albumin level was higher in the positive FC group, indicating that further research is necessary to determine the relationship between FC and micronutrient deficiencies. Overall, these findings suggest that malabsorption and GI involvement are not necessarily correlated with lower micronutrient levels.

Through our research, we have determined that receiving prescribed vitamin and mineral supplements is a crucial factor in the elevated levels of micronutrients found in the FC-positive group. Andreasson et al. (2011) (2) conducted a similar study and came to the same conclusion, demonstrating that patients who received micronutrient supplements for deficiencies had higher FC levels compared to those who did not receive any supplemental medication. In another study conducted by the same researchers in 2014 (11), levels of folic acid, vitamin B12, iron, and zinc were measured in SSc patients. It was discovered that those with a deficiency in more than one micronutrient had higher FC levels than those with only one deficiency. Additionally, the FC levels in the second group were higher than in normal subjects (P. Value = 0.001), which suggests that GI disorders in SSc patients result in increased FC levels.

Based on the findings of the study, FC levels higher than 200µg/g were not significantly correlated with age, sex, disease type, GI complaints, skin score, or micronutrient deficiencies. However, a correlation was found between a thickening of the small bowel wall and esophageal dilation. This suggests that FC can be used as a marker for diagnosing GI tract involvement in SSc patients, reducing costs and avoiding invasive procedures. Patients with FC levels over 200µg/g should be further examined using an alternative method like endoscopy. The majority of our patients opted for vitamin and mineral supplements to prevent malnutrition, and as a result, none of them exhibited any signs of micronutrient deficiency.

Our study's lack of statistical significance may be attributed to the limited sample size. Therefore, future researchers should prioritize using a larger sample size to obtain more accurate results.

Ethical approval and consent to participate: The study and all experimental protocols were approved by the Professional Ethics Committee of the Golestan University of Medical Sciences. The informed consent was also obtained from the patient for the implementation of this project.

All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication: Not applicable

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author, Nafiseh Abdolahi, on reasonable request.

Competing interests: The authors declare no competing interests.

Funding: The Golestan University of Medical Sciences financially supported this work.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Authors contribution:

A.F: Manuscript writing and Data entry.

H.H: Design of the work

M.A., and N.A.: Data interpretation and substantial manuscript revision.

MHG and S.L: Radiologic analysis and interpretation.

Acknowledgment: Special thanks to all the fellow authors who contributed to this article.

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No competing interests reported.

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Could fecal calprotectin serve as an indicator of gastrointestinal (GI) complications in individuals with systemic sclerosis?

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