Clinical Significance of Serum Bilirubin in Behçet's Disease

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Abstract

Background and Objective

Bilirubin (Bb) is the product of the intravascular compartment of catabolic pathway. In a small number of clinical trials, it has been shown that Bb molecules are associated with cardiovascular diseases, diabetes, cancer, autoimmune (lupus, rheumatoid arthritis) diseases and schizophrenia. Behçet's disease is a chronic, multisystemic, inflammatory vasculitis that was first described by Hulusi Behçet in 1937, which affects almost all organs and systems without any known aetiology. Here, we investigated the clinical significance of serum Bb as a biomarker in the patients with Behçet's disease.

Methods

Seventy-one (N = 71) patients with Behcet's diagnosis within the last 1 year were included retrospectively. Control group consisted of 75 subjects with similar age and sex distribution. Serum Bb, indirect Bb, total Bb, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data were recorded from the hospital records.

Results

In the Behçet group, direct Bb was significantly lower (P = 0.011), ESR and CRP were significantly higher (P = 0.00). No significant differences were observed in other parameters. In the whole group, total Bb and indirect Bb were negatively correlated with ESR (P = 0.025, P = 0.01). Direct Bb was negatively correlated with CRP (P = 0.002). For the diagnosis of Behçet, direct Bb with a threshold of < 0.14 can be used as a diagnostic test (P = 0.000) with 70% sensitivity, 68% specificity (area under the curve = 0.69; 95% confidence interval 0.59–0.80) in ROC curve analysis.

Conclusion

According to our study, we found that inflammatory markers were high and direct Bb values were low in patients with Behcet's disease. In addition, Bb parameters were negatively associated with acute phase reactants. As a practical biomarker with anti-oxidative properties, the direct Bb can be used to diagnose and clinical follow-up in cases with Behçet's disease.

Abstract

Background and Objective

Bilirubin (Bb) is the product of the intravascular compartment of catabolic pathway. In a small number of clinical trials, it has been shown that Bb molecules are associated with cardiovascular diseases, diabetes, cancer, autoimmune (lupus, rheumatoid arthritis) diseases and schizophrenia. Behçet's disease is a chronic, multisystemic, inflammatory vasculitis that was first described by Hulusi Behçet in 1937, which affects almost all organs and systems without any known aetiology. Here, we investigated the clinical significance of serum Bb as a biomarker in the patients with Behçet's disease.

Methods

Seventy-one (N = 71) patients with Behcet's diagnosis within the last 1 year were included retrospectively. Control group consisted of 75 subjects with similar age and sex distribution. Serum Bb, indirect Bb, total Bb, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data were recorded from the hospital records.

Results

In the Behçet group, direct Bb was significantly lower (P = 0.011), ESR and CRP were significantly higher (P = 0.00). No significant differences were observed in other parameters. In the whole group, total Bb and indirect Bb were negatively correlated with ESR (P = 0.025, P = 0.01). Direct Bb was negatively correlated with CRP (P = 0.002). For the diagnosis of Behçet, direct Bb with a threshold of < 0.14 can be used as a diagnostic test (P = 0.000) with 70% sensitivity, 68% specificity (area under the curve = 0.69; 95% confidence interval 0.59–0.80) in ROC curve analysis.

Conclusion

According to our study, we found that inflammatory markers were high and direct Bb values were low in patients with Behcet's disease. In addition, Bb parameters were negatively associated with acute phase reactants. As a practical biomarker with anti-oxidative properties, the direct Bb can be used to diagnose and clinical follow-up in cases with Behçet's disease.

Introduction

Behçet’s disease is a rare vasculitic disorder characterized by recurrent oral aphthous ulcers, genital ulcers and uveitis, a triple symptom complex.[1] Bb is a heme degradation product with anti-inflammatory, antioxidative, and immunosuppressive features.[2] Studies conducted in the previous two decades showed a strong antioxidative feature of Bb, in addition to its being a degradation product. Many hypotheses were put forth concerning the mechanism of action of Bb. The most well-known is the immunomodulatory effect that suppresses inflammation through its redox (antioxidative) capacity.3, 4,

Here, we investigated the clinical significance of serum Bb as a biomarker in patients with Behçet’s disease. To the best of our knowledge, there is no other study in the literature that analyzes serum Bb levels in patients with Behcet’s disease.

Methods

Seventy-one (N = 71) patients with Behcet’s diagnosis within the last 1 year were included retrospectively. Control group consisted of 75 patients of similar age and sex. Behçet’s diagnosis was based on the criteria of international study group.

Serum direct Bb, indirect Bb, total Bb, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data were recorded from the hospital records. The acute phase reactants (ESR and CRP) were used for disease activity. Patients with known inflammatory rheumatism disease, malignancy, infection and primary liver disease were not included in the study.

Statistical Analysis

Continuous variables were shown as means ± standard deviation, and categorical variables were presented as percentages. We used the Kolmogorov-Smirnov test to identify data normality. The t test and Mann–Whitney U test were used to analyze the data according to their distribution. The correlation between two continuous variables was analyzed using the Spearman approach. Statistical analysis was performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA); P < 0.05 was designated as statistically significant.

Results

The Behçet group consisted of 40 male and 31 female patients. The mean age was 42 ± 9.5 years. Mean direct Bb = 0.016 ± 0.08, Indirect Bb = 0.39 ± 0.2, total Bb = 0.5 ± 0.25, CRP = 8.1 ± 10.7 mg/dL, ESR = 14.9 ± 12.9 mm / h, AST = 23.5 ± 5.3, ALT = 24.4 ± 10.1, ALP = 79.2 ± 24.1.

The control group consisted of 44 males and 31 females. The mean age was 46 ± 10.5 years. The mean direct Bb = 0.19 ± 0.61, Indirect Bb = 0.33 ± 0.17, total Bb = 0.53 ± 0.17, CRP = 1.1 ± 1.6 mg / dL, ESR = 9± 8.3 mm / h. Sociodemographic and laboratory data of the groups are listed at Table1.

Table 1

Sociodemographic and laboratory data of the groups

TBb: total bilirubin; InBb: indirect bilirubin; DBb: Direct bilirubin; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase. *statistically significant.

Behçet groupControl groupP
Age (Year)42.0 ± 9.546.0 ± 10.50.45
Gender (M/F)40/3144/310.06
TBb (0–1.9; mg/dL)0.50 ± 0.250.53 ± 0.170.58
DBb*(0–0.3; mg/dL)0.016 ± 0.0080.19 ± 0.610.011
İnBb0.39 ± 0.20.33 ± 0.170.085
CRP* (mg/dL; 0-5)8.1 ± 10.71.1 ± 1.60.00
ESR* (mm/h; 0-20)14.9 ± 12.99.0 ± 8.30.00
AST (0-40 IU/L)23.5 ± 5.3-
ALT (0-56 IU/L)24.4 ± 10.1-
ALP (25–100 IU/L)79.2 ± 24.1-

In the Behçet group, direct Bb was significantly lower (P = 0.011) (Figure 1), ESR and CRP were significantly higher (P = 0.00). No significant differences were observed in the other parameters. In the whole group, total Bb and indirect Bb were negatively correlated with ESR (P = 0.025, P = 0.01) (Figure 2). Direct Bb was negatively correlated with CRP (P = 0.002). ALP were not related with any parameters (Bb and CRP, ESR) in the study group.

Figure 1

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Figure 1

The distribution of direct bilirubin (DBb) according to the groups

Citation: Journal of Translational Internal Medicine 6, 4; 10.2478/jtim-2018-0034

Figure 2

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Figure 2

The distribution of direct bilirubin (DBb) according to erythrocyte sedimentation rate (ESR)

Citation: Journal of Translational Internal Medicine 6, 4; 10.2478/jtim-2018-0034

For the diagnosis of Behçet, direct Bb with a threshold of < 0.14 can be used as a diagnostic test (P = 0.00) with 70% sensitivity, 68% specificity (area under the curve = 0.69; 95% confidence interval 0.59–0.80) in ROC curve analysis (Figure 3).

Figure 3

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Figure 3

Direct bilirubin with a threshold of < 0.14 can be used as a diagnostic test (P = 0,00) for Behçet disease with 70% sensitivity, 68% specificity (area under the curve = 0,69; 95% confidence interval:0.59–0.80). Diagonal segments are produced by ties

Citation: Journal of Translational Internal Medicine 6, 4; 10.2478/jtim-2018-0034

Discussion

Behçet’s disease is a chronic, multisystemic, inflammatory vasculitis that was first described by Hulusi Behçet in 1937, which affects almost all organs and systems without any known aetiology. Behçet’s is most common along the Silk Road. It is particularly common among persons who have the HLA-B51 major histocompatibility type It is thought that exposure to infectious agents plays a role

in the genetically susceptible person in the pathogenesis of the disease. There is no pathognomonic laboratory test, but there are clinical criteria to assist in establishing the diagnosis.[1, 2, 3, 4, 5] Mortality may occur as a result of neurologic or vascular disease or gastrointestinal perforation.[4, 5]

Clinical findings of Behçet’s disease show great differences from one patient to another. In addition, there are also changes in organ involvement and clinical course of the disease, exacerbation and recovery periods. Clinical manifestations tend to decline as age progresses.[4, 5]

The diagnosis of Behçet’s disease is based on clinical findings, and there are no specific laboratory findings of the disease.[6, 7] The ESR and CRP are mostly moderately increased, but do not directly correlate with disease activity. Main routine laboratory tests give information about organ functions and helps in differential diagnosis. It should be remembered that drugs may have high toxic effects on liver. Rarely amyloidosis, glomerulonephritis, interstitial nephritis, renal vein thrombosis proteinuria, hematuria, pyuria, renal failure laboratory findings can be detected. There is no autoantibody specific for Behcet’s disease (rheumatoid factor, antinuclear antibody, anticardiolipin, and antineutrophil cytoplasmic antibody, anti-endothelial antibodies and antibodies against the oral mucosa may be positive).[6, 7]

In Behcet’s disease, gastrointestinal tract involvement is known as intestinal Behçet’s disease or entero-Behçet. Gastrointestinal system involvement of Behcet’s disease differs between countries. Oral aphthous, gastric, duodenal ulcer, esophagitis, small and large intestine ulcers.

Hepatobiliary complications of Behcet’s disease are fatty liver, acute or chronic hepatitis, cholelithiasis, cholecystitis, primary biliary cirrhosis, hepatic abscess. In 11% of patients with Behçet’s disease, liver ALP levels were increased and correlated with the disease activity.[9]

Several biomarkers have been studied in early stage vascular involvement in Behçet’s disease.[10] In the study of Balta et al., mean platelet volume (MPV) was significantly associated with increased arterial stiffness in Behçet disease[11]; besides, there were found no significant difference in the study of Şenel et al.; and Balkarli et al. found that neutrophil/lymphocyte ratio may be a simple, inexpensive, and convenient diagnostic marker for activity in Behçet disease.[12, 13]

Bilirubin (Bb) is the major product of intravascular compartment of hem catabolic pathways. Research in the last few decades has revealed a strong antioxidant. There are a number of hypotheses about the mechanism of action of Bb. The most known is redox (antioxidative) capacity with

immunomodulatory effect by suppressing inflammation. In a few clinical trials, Bb molecule has been shown to be associated with cardiovascular diseases, diabetes, cancer, autoimmune (lupus, rheumatoid arthritis) diseases and schizophrenia.[2, 3]

Peng et al. found lower serum Bb values in all patients with polymyositis than in a healthy control group; a possible relationship with disease activity was also detected.[14] Zheng et al. found higher serum CRP values and lower TBb values in diabetic patients and in patients with impaired insulin tolerance.[15] For the patients with psoriasis, a negative relation was found between TBb values and inflammatory parameters.[16] Peng et al. detected lower DBb values and higher CRP values when assessing neurogenic inflammation in patients with migraine. [17] CRP and DBb were found negatively correlated. In recent years, simple, cheap and practical biomarkers as indicators of inflammation have been the subject of various investigations.[18] Firstly, in the literature, we found that direct Bb values were low in patients with Behcet’s disease and correlated negatively with acute phase reactants.

Limitation of the study

Because the study data were collected retrospectively, those with high ESR and CRP values were evaluated as active disease. However, as we have already mentioned, these parameters mostly increase in Behçet’s disease but are not always correlated with disease activity.

Bilirubin levels reflected hepatic and gall bladder involvement in pathology. It would be appropriate to analyze bilirubin shifts in association with venous thrombosis. The timing of the laboratory studies and the presence of venous thrombosis weren’t taken into account. Direct bilirubin being low may be secondary to chronic inflammation, so it may not be specific to Behçet’s disease, but it is necessary to investigate it in other inflammatory rheumatic diseases.

Behçet’s disease has a heterogeneous clinical manifestation, but there is no information on disease involvement in the patient group, for example, mucocutaneous Behçet and neurobehçet.

Conclusion

Bilirubin values decrease as the inflammation increases in the serum. As a practical biomarker, serum direct Bb levels can be used for diagnosis and clinical follow-up in Behçet’s disease.

Conflict of Interest The authors have no conflicts of interest to declare.

Financial Disclosure The authors received no financial support for the research and/ or authorship of this article.

References

  • 1

    Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view. Nat Rev Rheumatol 2018;14: 119.

  • 2

    Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol 2013; 45: 2843-51.

  • 3

    Khan NM, Poduval TB. Immunomodulatory and immunotoxic effects of bilirubin: molecular mechanisms. J Leukoc Biol 2011; 90: 997-1015.

  • 4

    Holzınger D, Föll D. Biomarkers for chronic inflammatory diseases. Z Rheumatol 2015; 74: 887-97.

  • 5

    Lee LA. Behçet disease. Semin Cutan Med Surg 2001; 20: 53-7.

  • 6

    Suzuki Kurokawa M, Suzuki N. Behcet’s disease. Clin Exp Med 2004; 4: 10-20.

  • 7

    Ko LN, Alloo A, Lin WM, Hoang MP, Kroshinsky D. A 25-Year-Old Male with Orogenital Ulcers, Rash, and Difficulty Swallowing. Dermatopathology (Basel) 2017; 4: 7-12.

  • 8

    Keogan MT. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Clin Exp Immunol 2009; 156: 1-11.

  • 9

    Zhu Z, Shu X, Long S, Jiang X, Lu N, Zhu X, et al. Ulcerative colitis followed by the development of typical intestinal Behçet disease: A case report. Medicine (Baltimore) 2018; 97: e9882.

  • 10

    Protogerou AD, Nasothimiou EG, Sfikakis PP, Tzioufas AG. Non-invasive vascular biomarkers in patients with Behçet’s disease: review of the data and future perspectives. Clin Exp Rheumatol 2017; 35 Suppl 108: 100-7.

  • 11

    Balta I, Balta S, Koryurek OM, Demirkol S, Celik T, Akbay G, et al. Mean platelet volume is associated with aortic arterial stiffness in patients with Behçet’s disease without significant cardiovascular involvement. J Eur Acad Dermatol Venereol 2014; 28: 1388-93.

  • 12

    Şenel E, Acar B, Demir E. Mean Platelet Volume: A Reliable Marker of Inflammation in Recurrent Apthous Stomatitis and Behçet Disease? Indian Dermatol Online J 2017; 8: 468-70.

  • 13

    Balkarli A, Kucuk A, Babur H, Erbasan F. Neutrophil/lymphocyte ratio and mean platelet volume in Behçet’s disease. Eur Rev Med Pharmacol Sci 2016; 20: 3045-50.

  • 14

    Peng YF, Zhang L, Pan GG, Wei YS. A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis. Eur Rev Med Pharmacol Sci 2016; 20: 631-5.

  • 15

    Zheng J, Wu Y, Li Z, Wang H, Xiao W, Shi Y, et al. Low Serum Total bilirubin Concentration was Associated with Increased High Sensitive C Reactive Protein Level in Patients with Impaired Glucose Tolerance and Type 2 Diabetes Mellitus Subjects. Clin Lab 2016; 62: 901-7.

  • 16

    Zhou ZX, Chen JK, Hong YY, Zhou R, Zhou DM, Sun LY, et al. Relationship Between the Serum Total bilirubin and Inflammation in Patients With Psoriasis Vulgaris. J Clin Lab Anal 2016; 30: 768-75.

  • 17

    Peng YF, Xie LQ, Xiang Y, Xu GD. Serum bilirubin and Their Association With C-Reactive Protein in Patients With Migraine. J Clin Lab Anal 2016; 30: 982-5.

  • 18

    Koca TT. Does obesity cause chronic inflammation? The association between complete blood parameters with body mass index and fasting glucose. Pak Jour of Med Sci 2017; 33: 65-9.

1

Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view. Nat Rev Rheumatol 2018;14: 119.

2

Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol 2013; 45: 2843-51.

3

Khan NM, Poduval TB. Immunomodulatory and immunotoxic effects of bilirubin: molecular mechanisms. J Leukoc Biol 2011; 90: 997-1015.

4

Holzınger D, Föll D. Biomarkers for chronic inflammatory diseases. Z Rheumatol 2015; 74: 887-97.

5

Lee LA. Behçet disease. Semin Cutan Med Surg 2001; 20: 53-7.

6

Suzuki Kurokawa M, Suzuki N. Behcet’s disease. Clin Exp Med 2004; 4: 10-20.

7

Ko LN, Alloo A, Lin WM, Hoang MP, Kroshinsky D. A 25-Year-Old Male with Orogenital Ulcers, Rash, and Difficulty Swallowing. Dermatopathology (Basel) 2017; 4: 7-12.

8

Keogan MT. Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Behçet’s syndrome. Clin Exp Immunol 2009; 156: 1-11.

9

Zhu Z, Shu X, Long S, Jiang X, Lu N, Zhu X, et al. Ulcerative colitis followed by the development of typical intestinal Behçet disease: A case report. Medicine (Baltimore) 2018; 97: e9882.

10

Protogerou AD, Nasothimiou EG, Sfikakis PP, Tzioufas AG. Non-invasive vascular biomarkers in patients with Behçet’s disease: review of the data and future perspectives. Clin Exp Rheumatol 2017; 35 Suppl 108: 100-7.

11

Balta I, Balta S, Koryurek OM, Demirkol S, Celik T, Akbay G, et al. Mean platelet volume is associated with aortic arterial stiffness in patients with Behçet’s disease without significant cardiovascular involvement. J Eur Acad Dermatol Venereol 2014; 28: 1388-93.

12

Şenel E, Acar B, Demir E. Mean Platelet Volume: A Reliable Marker of Inflammation in Recurrent Apthous Stomatitis and Behçet Disease? Indian Dermatol Online J 2017; 8: 468-70.

13

Balkarli A, Kucuk A, Babur H, Erbasan F. Neutrophil/lymphocyte ratio and mean platelet volume in Behçet’s disease. Eur Rev Med Pharmacol Sci 2016; 20: 3045-50.

14

Peng YF, Zhang L, Pan GG, Wei YS. A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis. Eur Rev Med Pharmacol Sci 2016; 20: 631-5.

15

Zheng J, Wu Y, Li Z, Wang H, Xiao W, Shi Y, et al. Low Serum Total bilirubin Concentration was Associated with Increased High Sensitive C Reactive Protein Level in Patients with Impaired Glucose Tolerance and Type 2 Diabetes Mellitus Subjects. Clin Lab 2016; 62: 901-7.

16

Zhou ZX, Chen JK, Hong YY, Zhou R, Zhou DM, Sun LY, et al. Relationship Between the Serum Total bilirubin and Inflammation in Patients With Psoriasis Vulgaris. J Clin Lab Anal 2016; 30: 768-75.

17

Peng YF, Xie LQ, Xiang Y, Xu GD. Serum bilirubin and Their Association With C-Reactive Protein in Patients With Migraine. J Clin Lab Anal 2016; 30: 982-5.

18

Koca TT. Does obesity cause chronic inflammation? The association between complete blood parameters with body mass index and fasting glucose. Pak Jour of Med Sci 2017; 33: 65-9.

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Figures

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    The distribution of direct bilirubin (DBb) according to the groups

  • View in gallery

    The distribution of direct bilirubin (DBb) according to erythrocyte sedimentation rate (ESR)

  • View in gallery

    Direct bilirubin with a threshold of < 0.14 can be used as a diagnostic test (P = 0,00) for Behçet disease with 70% sensitivity, 68% specificity (area under the curve = 0,69; 95% confidence interval:0.59–0.80). Diagonal segments are produced by ties

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