Features of certain indicators of the vascular-platelet component of hemostasis and systemic inflammation markers in patients with inflammatory bowel diseases and non-alcoholic fatty liver disease

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Abstract

Objective. To assess the levels of homocysteine, thrombocytes and indicators of systemic inflammation in patients with inflammatory bowel disease, non-alcoholic fatty liver disease and their combination depending on the severity and phenotype of the disease.

Materials and methods. A total of 62 patients with non-alcoholic fatty liver disease (NAFLD), ulcerative colitis (UC), Crohn's disease (CD) at the onset and exacerbation of the disease were examined. The following hemostasis parameters were studied: vascular (homocysteine) and platelet (platelet count). The levels of CRP, fibrinogen, α-1 and α-2 globulin were assessed as markers of systemic inflammation.

Results. The CRP value in the IBD and NAFLD group was 4.4 times higher than in patients of the NAFLD group, p=0.03, and 1.8 times higher than in patients with IBD, p=0.121. No significant differences in acute phase protein levels were revealed in the IBD and NAFLD groups. No changes were observed depending on the disease phenotypes either. The proportion of individuals with hyperhomocysteinemia was 2.4 times higher in the IBD+NAFLD group than in patients with isolated NAFLD, p=0.055. A correlation between the homocysteine ​​level with the NAFLD phenotype and the homocysteine ​​level with the severity of an IBD attack was detected. In patients with IBD, the homocysteine ​​level correlated with the marker of systemic inflammation (a-1 globulin), r = 0.587, p = 0.05. Platelet values ​​were significantly higher in individuals with combined pathology of IBD and NAFLD than in patients of the group with isolated NAFLD, p = 0.000. There were no differences in platelet levels depending on the phenotypes of IBD and NAFLD.

Conclusions. The homocysteine ​​level and platelet count in patients with associated course of IBD + NAFLD are higher than those in the isolated groups. Moreover, the values correlate with the severity of an IBD attack and the degree of systemic inflammation and depend neither on IBD phenotype nor on NAFLD phenotype.

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Introduction

Inflammatory bowel diseases (IBD) are chronic, immune-mediated diseases that include Crohn's disease (CD) and ulcerative colitis (UC) [1–2].

IBD often occurs with extraintestinal manifestations, including non-alcoholic fatty liver disease (NAFLD) [3] and changes in the hemostatic system [3–7]. According to studies in Western countries, the prevalence of NAFLD in UC ranges from 1.5 to 39.5 % and from 1.5 to 39.5 % in CD [8–9]. According to Russian publications, the incidence of NAFLD among patients with IBD is observed in 40 % of patients with UC and in 55% of patients with CD [10].

The causes of NAFLD in patients with IBD remain poorly studied. The main triggers for the pathophysiological mechanisms of NAFLD development in patients with IBD include: intestinal microbiota imbalance, increased permeability, endotoxemia, and genetic factors [11–12]. A key role in the development of the association between IBD and NAFLD is played by obligatory disturbances in the system of proinflammatory and anti-inflammatory agents, as well as in the coagulation and fibrinolysis system, which are observed both in liver pathology and in IBD. In addition, these patients experience an increase in platelet count, especially during periods of high disease activity, and a decrease in natural anticoagulant factors, including antithrombin III, protein C, and protein S [12].

According to modern publications, the studied binding marker is homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, an essential amino acid obtained from dietary proteins [13–15].

Hyperhomocysteinemia, as well as pathological platelet modifications, are major factors in endothelial cell damage and the development of atherosclerosis. Certain homocysteine ​​metabolites, such as homocysteine ​​thiolactone, induce platelet aggregation and the release of thromboxane and prostacyclin [16]. The accumulation of these platelet aggregators, together with high concentrations of von Willebrand factor, which enhances platelet adhesion and coagulation, are important links in the development of a thrombophilic state [17].

The presence of unifying pathogenetic links in the comorbidity of IBD and NAFLD, as well as the high prevalence and social significance of both entities, explains the interest of scientists in this association. While isolated forms of IBD and NAFLD as thrombophilic conditions have been sufficiently studied, the hemostatic characteristics of associated diseases have not been described.

The aim of the study is to evaluate the levels of homocysteine, platelets, and systemic inflammation indicators in patients with IBD, NAFLD, and their combination, depending on the severity and phenotype of the disease.

Materials and Methods

We conducted a cross-sectional study of patients with IBD and NAFLD. The study included 62 people: Group 1 (20 patients: 12 women, 8 men) with isolated IBD (8 with CD, 12 with UC), average age 52.30 ± 10.39 years;

Group 2 consisted of 22 patients with isolated NAFLD (17 with steatosis, 5 with non-alcoholic steatohepatitis (NASH)), average age 36.76 ± 10.84 years, including 13 women and 9 men; Group 3 (20 patients: 11 women, 9 men) – combined IBD + NAFLD (9 with CD, 11 with UC), average age 40.93 ± ± 12.89 years. Depending on the NAFLD phenotype in this group, steatosis was determined in 15 people and NASH in 5. The control group consisted of 20 practically healthy individuals (11 men, 9 women), average age 44.12 ± 10.74 years. All patients in the study groups were matched for gender and age.

Inclusion criteria were: a confirmed diagnosis of UC or CD in the acute or onset stage, and a verified diagnosis of NAFLD. The diagnoses of UC and CD were established in accordance with the clinical guidelines of the Russian working group on the diagnosis and treatment of UC and CD [1–2]. The diagnosis of NAFLD was verified based on the clinical guidelines of the Russian Society for the Study of the Liver [3].

The presence of hepatic steatosis was determined by ultrasound examination (US) based on the following criteria: liver heterogeneity, increased liver echogenicity compared to the kidneys, and depleted vascular pattern. NASH was diagnosed based on the presence of steatosis on liver ultrasound and elevated blood biochemical parameters: alanine aminotransferase (ALT) and/or gamma-glutamyl transferase (GGT) [18].

The exclusion criteria for the study were: hypertension, widespread atherosclerosis, acute myocardial infarction, diabetes mellitus; severe concomitant pathology: hepatitis, liver failure, cancer, congestive heart failure, unstable angina, cardiac arrhythmia, chronic kidney disease, myocarditis, severe pneumonia (respiratory failure), sepsis, life-threatening bleeding, HIV infection; use of hepatotoxic, anticoagulant, antiplatelet drugs; pregnancy, lactation; history of moderate to severe COVID-19; complications of IBD: intestinal bleeding, intestinal perforation, toxic dilatation of the colon; previous surgeries for UC and CD; genetic engineering biological therapy (GEBT); clostridial and cytomegalovirus infection; coagulopathy.

All patients underwent laboratory tests: complete blood count (CBC) with determination of erythrocyte sedimentation rate (ESR), biochemical blood test (BBC) and analysis of acute phase proteins: C-reactive protein (CRP), α1- and α2-globulin, fibrinogen. Complete blood count (CBC) values were assessed using a Beckman Coulter DxH-800 hematology analyzer (USA) with Beackman Coulter reagents (USA), and ESR was measured using the Panchenkov method. BAC values and acute-phase reactants were analyzed using an Architect-4000 automated biochemistry analyzer (USA) with Abbott reagents (USA). Additional tests included plasma homocysteine levels determined by ELISA using the CED984Ge diagnostic kit (Stavropol).

Statistical data processing was performed on a MacBook personal computer using the SPSS statistical program. Quantitative data were presented as the arithmetic mean (M) and standard deviation (σ). The Mann–Whitney test was used to assess the reliability of differences between two independent samples; for three or more samples, the Kruskal–Wallis test was used. The t-test was used to determine the significance of differences under these conditions. The strength of the association between features was measured by the Pearson contingency coefficient (Ki). Correlation analysis was conducted using the Pearson linear correlation coefficient (r).

Results and Discussion

When assessing the levels of acute phase proteins in patients with IBD, it was noted that the severity of the attack is associated with higher fibrinogen and ESR levels. Thus, the average fibrinogen level in a mild attack of IBD was 2.85 ± 0.57 versus 3.75 ± 0.94 g/l in moderate (p = 0.02) and 4.28 ± 0.84 g/l in severe (compared to mild, p = 0.001). The ESR value in a severe attack was 3.6 times higher than in a mild attack (37.6 ± 17.08 versus 10.33 ± 8.91 mm/h, respectively, p = 0,02). No significant differences were found between systemic inflammation indicators and IBD phenotype. Correlation analysis revealed a moderate positive association between attack severity and fibrinogen levels: r = 0.554, p = 0.009, and between attack severity and ESR: r = 0.584, p = 0.005.

According to the literature, 80% of patients with IBD have an increase in the level of ESR and CRP, and in some patients – fibrinogen, which correlates with the severity of the attack and the location of the lesion [19–20].

When analyzing systemic inflammation parameters in patients with NAFLD, it was found that the mean values of CRP and α1-globulin exceeded the reference values, and the CRP concentration was 2 times higher in patients with NASH than in individuals with steatosis (7.87 ± 11.49 and 3.98 ± 2.11 mg/L), without statistically significant differences by NAFLD phenotype. Our results are consistent with literature data demonstrating an association of some acute-phase proteins and cytokines with NASH [21–24].

In patients with IBD and NAFLD, fibrinogen levels during a severe attack were 4.61 ± 1.68 versus 3.29 ± 0.11 g/L in a mild attack, p = 0.041. There were no differences in the levels of systemic inflammation markers depending on the disease phenotypes. Correlation analysis revealed a moderate positive relationship between attack severity and fibrinogen levels: r = 0.438; p = 0.054. No significant differences were found in the levels of other acute-phase reactants (ESR, CRP, α1- and α2-globulins.

The results of a comparative analysis of the levels of systemic inflammation proteins in patients with associated disease, isolated IBD and NAFLD, and the control group are presented in Table 1.

Thus, the analysis of the level of markers of systemic inflammation in patients in the studied groups showed that the CRP value in the IBD and NAFLD group was 4.4 times higher than in patients with NAFLD: 32.45 ± 63.20 versus 7.25 ± 10.45 mg/l, p = 0.03, and 1.8 times higher than in patients with isolated IBD: 17.17 ± 35.44 mg/l, р = 0.121.

An analysis of vascular hemostasis parameters in patients with isolated forms of IBD revealed that their average values did not exceed reference values. Thus, homocysteine levels in IBD patients were 38.71 ± 7.43 μmol/L. No differences in homocysteine levels were observed depending on the extent of the lesion, the severity of the attack, and the phenotypes of IBD and NAFLD. However, correlation analysis showed that in patients in the IBD group, increased homocysteine levels were associated with α1-globulin levels (r = 0.587; p = 0.05).

In patients with NAFLD, the homocysteine level was 11.74 ± 4.32 μmol/L: with steatosis 7.72 ± 3.26 μmol/L, with NASH 13.63 ± 4.25 μmol/L, p = 0.04. The data were confirmed by correlation analysis: a positive moderate relationship was revealed between NAFLD phenotypes and homocysteine levels (r = 588; p = 0.04).

According to the literature, higher homocysteine levels are observed in patients with NASH than in patients with steatosis, and correlate with both the degree of activity and the stage of liver fibrosis in patients with NAFLD [25].

In patients with IBD+NAFLD, the average homocysteine concentration was 24.86 ± 20.54 μmol/L. It was noted that in the subgroup of patients with severe IBD, the level of the studied parameter was significantly higher than in those with mild and moderate disease severity. Thus, the average homocysteine ​​concentration during a severe attack was 57.8 ± 3.27 μmol/l, during a moderate attack – 14.05 ± 8.98 μmol/l, during a mild attack – 13.63 ± 4.42 μmol/l. In addition, correlation analysis showed a positive relationship between homocysteine ​​levels and the severity of an IBD attack: r = 0.783, р = 0.000. No statistically significant differences were found depending on the localization of the pathological process in the intestine and the phenotypes of IBD and NAFLD.

 

Table 1. Results of a comparative analysis of systemic inflammatory protein levels in patients with IBD, NAFLD, IBD+NAFLD and the control group

Indicator

Patients with IBD, n = 20

Patients with IBD+NAFLD, n = 20

Patients with NAFLD, n = 22

Control group, n = 20

p

 

 

 

ESR, mm/h

24.28 ± 17.37

21.25 ± 17.41

21.25 ± 17.41

10.33 ± 8.91

р1–2 = 0.711

р2–3 = 0.347

р1–3 = 0.711

p1–4 = 0.055*

p2–4 = 0.078

p3–4 = 0.091

 

 

 

SRP, mg/l

17.17 ± 35.44

 32.45 ± 63.20

7.25 ± 10.45

3.66 ± 2.05

р1–2 = 0.121

р2–3 = 0.03*

р1–3= 0.976

p1–4 = 0.02*

p2–4 = 0.001*

p3–4 = 0.081

a1-globulin, %

9.93 ± 1.60

6.02 ± 2.28

4.30 ± 0.72

3.02 ± 0.89

р1–2 = 0.841

р2–3 = 0.490

р1–3 = 0.357

p1–4 = 0.003*

p2–4 = 0.012

p3–4 = 0. 869

a2-globulin, %

11.99 ± 3.73

12.56 ± 3.41

9.94 ± 1.25

8.01 ± 3.94

р1–2 = 0.548

р2–3 = 0.303

р1–3 = 0.610

p1–4 = 0.133

p2–4 = 0.219

p3–4 = 0.788

Fibrinogen, g/l

3.62 ± 0.96

3.72 ± 1.10

3.52 ± 1.28

2.85 ± 0.57

р1–2 = 0.596

р2–3 = 0.703

р1–3 = 0.872

p1–4 = 0.347

p2–4 = 0.899

p3–4 = 0.941

Note: * – differences in indicators are statistically significant (p < 0.05).

 

Homocysteine levels in the groups with associated course, with isolated IBD and NAFLD are presented in Table 2. The proportion of individuals with hyperhomocysteinemia was 2.4 times higher in the group of patients with IBD+NAFLD than in patients with isolated NAFLD, p = 0.055.

The platelet count in the IBD group during a mild attack was (336.5 ± 99.74)·109/l, during a moderate attack (407.55 ± 138.34)·109/L, during a severe attack (369.4 ± 106.50)·109/L, without statistically significant differences depending on the severity of the attack. No statistically significant changes in platelet count were observed across IBD phenotypes.

The platelet count in individuals with NAFLD was (235.31 ± 38.93)·109/l. No statistically significant differences were found depending on the degree of fibrosis or NAFLD phenotype.

 

Table 2. Results of a comparative analysis of homocysteine and platelets in patients with IBD, NAFLD, IBD+NAFLD, and a control group

Indicator

Patients with IBD, n = 20

Patients with IBD+NAFLD, n = 20

Patients with NAFLD, n = 22

Control group,

n = 20

p

Homocystei,

µmol/l

38.71 ± 7.43

24.86 ± 20.54

11.74 ± 4.32

9.8 ± 3.72

р1–2 = 0.638

р2–3 = 0.055*

р1–3 = 0.661

p1–4 = 0.031*

p2–4 = 0.005*

p3–4 = 0.091*

Platelets,

109/l

384.61 ± 121.05

383 ± 123.19

235.31 ± 38.93

241.45 ± 56.37

р1–2 = 0.833

р2–3 = 0.0001*

р1–3 = 0.0008*

p1–4 = 0.006*

p2–4 = 0.003*

p3–4 = 0.763

Note: * – differences in indicators are statistically significant (p < 0.05).

 

The average platelet count in patients with IBD+NAFLD was (383 ± 123.19)·109/L. No statistically significant differences were observed depending on the severity of the IBD attack and the phenotypes of IBD and NAFLD.

Some studies have reported that in patients with CD, a significant relationship was found between platelet levels and the presence of NASH. In patients with UC, there were no statistically significant differences in platelet levels between patients with and without NAFLD [9].

Changes in the platelet component of hemostasis were observed to a greater extent in patients with IBD than in patients with NAFLD: (384.61 ± ± 121.05)·109/l versus (235.31 ± ± 38.93)·109/l, p = 0.000. Also, in individuals with combined pathology of IBD and NAFLD, platelet values were significantly higher than in patients in the group with isolated NAFLD: (383 ±123.19)·109/l versus (235.31 ± 38.93)·109/l, p = 0.000) (Table 1). No statistically significant differences in platelet levels were found between the IBD and IBD-NAFLD patient groups.

Our data indicate that patients with associated IBD and NAFLD are characterized by hyperhomocysteinemia and thrombocytosis, unlike those in the isolated groups. Furthermore, these values significantly correlate with the severity of the IBD attack.

Conclusions

  1. In patients with IBD and IBD+NAFLD, statistically significant increases in homocysteine, platelets, and inflammatory cytokines (CRP, fibrinogen, and ESR) were observed. The maximum values of these markers were observed during a severe IBD attack. No significant differences in the markers studied were found depending on the IBD phenotype.
  2. Homocysteine levels vary depending on the type of NAFLD. Higher values were observed in patients with steatohepatitis. Given that this marker is a prothrombotic factor, patients with steatohepatitis are at risk for thrombophilic disorders.
  3. The level of homocysteine, CRP and platelet count are increased to a greater extent in patients with the associated course of IBD + NAFLD, which suggests the presence of an unfavorable mutual pathogenetic influence of these diseases on the risk of developing thrombophilia.
×

About the authors

Alena А. Trapeznikova

Ye.A. Vagner Perm State Medical University

Author for correspondence.
Email: trapeznikovagastro@yandex.ru
ORCID iD: 0009-0001-6844-1780

Postgraduate Student of the Department of Hospital Therapy and Cardiology

Russian Federation, Perm

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