Am J Clin Dermatol (2014) 15:457–462 DOI 10.1007/s40257-014-0087-3
ORIGINAL RESEARCH ARTICLE
Relationship Between Helicobacter pylori Infection and Vitiligo: A Prospective Study ¨ zdemir • Meral Eks¸ iog˘lu Zeynal Dog˘an • Pınar O Levent Filik
•
Published online: 2 July 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Helicobacter pylori is a worldwide bacteria that may affect several extra-gastric systems, including the endocrine, hematologic, vascular, respiratory, immune, and skin. Several skin diseases, including chronic urticaria, alopecia areata, psoriasis, and systemic lupus erythematosis have been found to be associated with H. pylori infection. Aim To our knowledge, there are no data showing an association between H. pylori and vitiligo. Therefore, in this study, we wanted to evaluate the relationship between H. pylori and vitiligo. Methods This study is a prospective study carried out in our Gastroenterology and Dermatology and Venereology departments of the Ankara Education and Research Hospital (Ankara, Turkey) between July 2013 and December 2013. Seventy-nine consecutive patients with vitiligo and 72 patients with telogen effluvium (TE) were recruited from the dermatology outpatient clinic. A total of 133 patients with vitiligo (n = 68) and TE (n = 65) [excluding 18 patients who had suspicious urea breath test (UBT)
Z. Dog˘an (&) L. Filik Department of Gastroenterology, Ankara Training and Research Hospital, Sukriye District, Ulucanlar Street, Altındag˘, Ankara 06230, Turkey e-mail: [email protected] L. Filik e-mail: [email protected] ¨ zdemir M. Eks¸ iog˘lu P. O Department of Dermatology and Venereology, Ankara Training and Research Hospital, Ankara, Turkey e-mail: [email protected] M. Eks¸ iog˘lu e-mail: [email protected]
results] were included in the study. All individuals were tested for H. pylori IgG and CagA. Also, a UBT was performed to detect the presence of H. pylori infection. Results There were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05). The number of patients with dyspepsia was significantly higher in the vitiligo group than in the TE group. No statistically significant relationship was seen between H. pylori positivity, CagA, H. pylori IgG, dyspepsia, and the Vitiligo Disease Activity score (p [ 0.05). Also, when patients with vitiligo were divided into localized and generalized types of vitiligo, there was no association between vitiligo involvement pattern and H. pylori positivity, CagA, H. pylori IgG, and dyspepsia (p [ 0.05). Conclusion Additional studies are necessary to evaluate the effect of H. pylori eradication on the clinical course of vitiligo. Further studies are also needed to explain the relationship between H. pylori and the pathogenesis of vitiligo.
Key Points Helicobacter pylori infection and dyspepsia are common health problems for patients with vitiligo There appears to be a relationship between H. pylori infection and vitiligo as an acquired autoimmune skin disease H. pylori eradication could be considered in vitiligo patients with dyspepsia and new studies are necessary to reveal the effect of eradication treatment on the clinical course of vitiligo
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458
1 Introduction Helicobacter pylori is a worldwide bacterium that affects approximately 50–80 % of the world population [1]. H. pylori not only causes gastric mucosal disease but also affects extra-gastrointestinal systems leading to several manifestations, such as iron-deficiency anemia, idiopathic thrombocytopenic purpura, metabolic syndrome, dyslipidemia, and decreased liver to spleen ratio [2–6]. Also, several population-based and experimental studies have shown a relationship between H. pylori and skin diseases including chronic urticaria, psoriasis, Behc¸et’s disease, and Henoch-Schoenlein purpura [7–10]. Increased H. pylori prevalence associated with skin disease, or increased skin disease severity due to H. pylori and a favorable response to H. pylori eradication support the presence of a link between H. pylori and skin disease. Autoimmune mechanisms triggered due to H. pylori are mostly claimed to play a role in this pathogenesis. Vitiligo is an acquired autoimmune skin disease that is characterized by depigmentation of the epidermis due to loss of functional melanocytes. Infections have been known to be a potential triggering factor for developing autoimmunity over the years. Although the immunological basis of vitiligo has been known for a long time, there are no data examining the effect of H. pylori on vitiligo. Therefore, H. pylori should also be investigated as a predisposing factor for vitiligo. In this study, we wanted to evaluate the association between H. pylori and vitiligo.
2 Patients and Methods This study is a prospective study carried out in the Gastroenterology and Dermatology and Venereology departments of the Ankara Education and Research Hospital (Ankara, Turkey) between July and December 2013. Seventy-nine consecutive patients with vitiligo were recruited from the dermatology outpatient clinic. The control group was composed of 72 consecutive patients who were admitted to the dermatology clinic due to telogen effluvium (TE) in the same time period. The TE group was defined as a patient group who had mental or physical stress for the past 2–4 months and were positive for hair pull tests. TE is a very well-defined clinical picture and has no immunological basis, which is why patients with TE were chosen as a control group from among dermatology outpatients. The classification of patients with vitiligo and TE was made by a specialist dermatologist. The Vitiligo Disease Activity (VIDA) score is a 6-point scale for assessing vitiligo activity that depends on the expansion of existing
lesions or appearance of new lesions, and was determined as follows: active 6 weeks or less (?4); active 6 weeks to 3 months (?3); active 3–6 months (?2); active 6–12 months (?1); stable 1 year or more (0); stable with spontaneous repigmentation 1 year or more (-1) [11]. The vitiligo involvement pattern was defined as types of vitiligo such as localized (focal, segmental, mucosal) or generalized (acrofacial, vulgaris, mixed, universal). To detect H. pylori infection, a urea breath test (UBT) was performed as follows: after an overnight fast, the patient swallowed a 14C-labeled urea-containing capsule (HelicapTM, Institute of Isotopes, Budapest, Hungary) with 50 mL water. After 15 min, the patient breathed out into a dry cartridge (HeliprobeÒ breath card, Kibion AB, Uppsala, Sweden) until the color of the card indicator changed from orange to yellow. Thereafter, the breath card was inserted into a small desktop Geiger Mu¨ller counter (HeliprobeÒ Analyser, Kibion AB, Uppsala, Sweden), and the radioactivity of the breath samples was read after 250 s of an automated process. Finally, the test results were expressed on the screen of the analyzer that showed radioactivity as count per minute (CPM): \25 CPM, patient not infected; 25–50 CPM, borderline or suspicious result; and [50 CPM, patient infected. We considered \25 CPM to be a negative result, [50 CPM to be a positive result, and 25–50 CPM to be a suspicious result in our study. Patients with a history of previous H. pylori eradication treatment, and those using NSAIDs, antibiotics, or proton pump inhibitors within 1 month were not included in the study. Patients were questioned about dyspeptic symptoms. Dyspepsia was defined as bloating, upper gastrointestinal discomfort, regurgitation, early satiety, and heartburn. The study was approved by the ethics committee of the hospital. Informed consent was obtained from all patients. 2.1 Statistical Analysis Numerical values were defined as means ± standard deviation. Chi-square test was used for categorical data differences between the two groups. p \ 0.05 was considered statistically significant. Statistical analyses were performed by SPSSÒ 16 statistical package (SPSS Inc., Chicago, IL, USA).
3 Results Eleven patients in the vitiligo group and seven patients in the TE group were not included in the study due to suspicious results in the UBT. In total, 133 patients (78 female and 55 male)—68 patients with vitiligo and 65 patients with TE—were included in the study. Twenty-four patients
H. pylori and Vitiligo
459
Table 1 Demographic and laboratory characteristics of the vitiligo and telogen effluvium groups
Data are given as mean ± standard deviation unless specified otherwise ALT alanine aminotransferase, AST aspartate aminotransferase, BMI body mass index, Hb hemoglobin, TE telogen effluvium, TSH thyroidstimulating hormone
Characteristic
Vitiligo group (n = 68)
TE group (n = 65)
p value
\0.001
Gender Female [n (%)]
30 (44)
48 (74)
Male [n (%)]
38 (56)
17 (26)
Age (years)
40.27 ± 16.97
35.89 ± 15.1
[0.119
Height (m)
1.66 ± 0.07
1.67 ± 0.06
[0.564 [0.280
Body mass (kg)
72.80 ± 10.88
74.92 ± 11.60
BMI (kg/m2)
26.47 ± 4.50
26.92 ± 4.28
[0.555
Hb (g/dL)
14.04 ± 1.78
13.55 ± 1.22
[0.068
TSH (lIU/mL)
2.11 ± 0.35
1.76 ± 0.12
[0.358
Fasting glucose (mg/dL)
97.14 ± 21.52
91.58 ± 11.61
[0.065
AST (IU/L)
22.67 ± 5.07
21.89 ± 4.66
[0.356
ALT (IU/L)
19.80 ± 7.25
18.86 ± 9.06
[0.506
Creatinine (mg/dL)
0.92 ± 0.18
0.91 ± 0.16
[0.951
had localized (22 patients with focal and two patients with segmental) and 44 patients had generalized (37 patients with vulgaris and seven patients with acrofacial) types of vitiligo. Demographic and laboratory characteristics of the vitiligo and TE groups are shown in Table 1. There were no significant differences regarding demographic and laboratory characteristics between the two groups (p [ 0.05), except that the number of females in the TE group was found to be significantly higher than in the vitiligo group (p \ 0.05). There were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05) (Table 2). The Table 2 Presence of dyspepsia and laboratory tests for Helicobacter pylori in the vitiligo and telogen effluvium groups Vitiligo group (n = 68) [n (%)]
TE group (n = 65) [n (%)]
p value
H. pylori positive
41 (60.3)
27 (41.5)
\0.038
CagA positive
47 (69)
32 (49.3)
\0.023
H. pylori IgG positive
52 (76.5)
38 (58.5)
\0.041
Dyspepsia positive
26 (38.2)
12 (18.5)
\0.012
TE telogen effluvium
number of patients with dyspepsia was significantly higher in the vitiligo group than in the TE group (p \ 0.012). No statistically significant relationship was seen between positivity for H. pylori, CagA, H. pylori IgG, or dyspepsia and the VIDA score (p [ 0.05) (Table 3). Also, when patients with vitiligo were divided into localized and generalized types of vitiligo, there was no association between vitiligo involvement pattern and H. pylori positivity, CagA, H. pylori IgG, or dyspepsia (p [ 0.05).
4 Discussion Increasing data have supported the idea that H. pylori contributes to the pathogenesis of several dermatological disorders. Different mechanisms have been suggested to define the effects of H. pylori on autoimmune extra-gastric diseases (Table 4) [12–20]. Autoimmune diseases are characterized by an abnormal immune response of the body against normal tissues known as loss of tolerance to selfantigens. However, the precise etiology of these autoimmune diseases remains unclear. Genetic predisposition, gender, hormonal status, and environmental factors including diet, drugs, and infectious agents have been proposed in the pathogenesis [21]. Infectious agents may cause autoimmune diseases by several mechanisms,
Table 3 The association between Helicobacter pylori features and Vitiligo Disease Activity score ?4 (n = 14)
?3 (n = 5)
?2 (n = 10)
?1 (n = 8)
0 (n = 29)
-1 (n = 2)
p
8 (57.1)
3 (60)
6 (60)
6 (75)
17 (58.6)
1 (50)
[0.942
IgG positive
10 (71.4)
4 (80)
7 (70)
7 (87.5)
22 (75.9)
2 (100)
[0.580
CagA positive Dyspepsia positive
11 (78.6) 5 (35.7)
3 (60) 1 (20)
7 (70) 4 (40)
6 (75) 3 (37.5)
19 (65.5) 13 (44.8)
1 (50) 0 (0)
[0.428 [0.772
H. pylori positive
Data are given as n (%)
Z. Dog˘an et al.
460 Table 4 Proposed mechanisms related to Helicobacter pylori in autoimmune conditions Autoimmune condition
Proposed mechanism
Rheumatoid arthritis Sjo¨gren’s syndrome
B cell activation by chronic H. pylori infection resulting in increased rheumatoid factor IgM
Idiopathic thrombocytopenic purpura
Molecular mimicry between CagA and peptides on platelets
Autoimmune thyroiditis
Molecular mimicry between CagA and thyroid peroxidase
Primary biliary cirrhosis
Higher prevalence of anti-H. pylori antibodies
Increased H. pylori antibodies
Primary sclerosing cholangitis
Detectable H. pylori species in liver samples
Atopic dermatitis
Increased IgE by H. pylori resulting in chronic allergic inflammation
Autoimmune bullous disease
Higher prevalence of H. pylori IgG antibodies
including antibody production, molecular mimicry, high levels of cytokines, major histocompatibility complex activation, regulatory T cell dysfunction, immune complex formation, and chronic inflammatory damage [22–28]. Similarly, several mechanisms have been proposed to explain the pathogenesis of H. pylori-induced autoimmunity. In a population-based study, H. pylori infection was found to be associated with higher levels of C-reactive protein (CRP), supporting a chronic inflammatory condition [29]. This chronic inflammation may trigger autoantibody production and antigenic stimulation and induce a systemic inflammatory response resulting in extra-gastric diseases. Molecular mimicry between H?, K?-adenosine triphosphatase, and H. pylori antigens has been demonstrated to play a role in the pathogenesis of autoimmune gastritis by activated cross-reactive gastric CD4? T cells [30, 31]. Several immune-mediated skin disorders, such as psoriasis, Behc¸et’s disease, and alopecia areata, have been considered to have a relationship with H. pylori infection. Psoriatic patients were found to have more prevalent antiH. pylori antibodies compared with a healthy control group [8]. Also, eradication therapy in patients with psoriasis and H. pylori has resulted in more rapid improvement of the skin disease [32]. H. pylori eradication in chronic urticaria has resulted in an improvement of the clinical course of the skin disease, breaking resistance to antihistamine medications [33]. Also, reinfection with H. pylori has resulted in activation of urticaria symptoms [34]. In several studies, comparable or higher rates of H. pylori infection have been found in patients with Behc¸et’s disease [35, 36]. Of interest, an important result from one study is that eradication of H. pylori was associated with improvement of Behc¸et’s disease features, including cutaneous lesions, articular complaints, and oral and genital ulcers [37]. In this regard, we did not find any association between H. pylori infection or the presence of H. pylori IgG and the Vitiligo Disease Activity Score, or between the vitiligo involvement pattern and H. pylori positivity or H. pylori IgG. Although CagA strains of H. pylori are responsible for more serious gastric
disease and clinical outcomes, we did not find any association between the presence of H. pylori CagA and VIDA score, or skin involvement of vitiligo in the present study (Table 3). However, dyspepsia was much more common in vitiligo patients infected with H. pylori than in controls (Table 3). Also, similar to other studies, there were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05) (Table 2). Vitiligo is an acquired autoimmune skin disease that is characterized by depigmentation of the epidermis due to loss of functional melanocytes. However, its immunopathogenesis is not totally explained. Several mechanisms, including cytotoxic, oxidant–antioxidant, neural, and autoimmune, have been proposed to contribute to the pathogenesis of vitiligo [38–43]. H. pylori-induced autoimmunity based on higher levels of CRP, chronic inflammatory condition, auto-antibody production, and antigenic stimulation may be responsible for the pathogenesis of vitiligo. The proposed autoimmune pathogenesis of vitiligo is destruction of functional melanocytes by autoimmune triggering factors, including cytotoxic T cells or autoantibodies against melanocyte surface peptides as a result of self-tolerance loss [44, 45]. Therefore, it can be speculated that H. pylori might alter cellular immunity resulting in development of a similar autoimmune process, e.g., cytotoxic T cell activation against melanocyte antigens. Besides H. pylori causing local gastric inflammation, it is also responsible for systemic inflammation by producing tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-8, and IL-1b [46–50]. Systemic inflammation of H. pylori causes pancreatic b cell injury resulting in pancreatitis with higher levels of IL-1b and IL-10 [51]. By a similar mechanism, chronic systemic inflammation induced by H. pylori may affect the microenvironment of the dermis, resulting in detrimental effects on melanocytes. The exact pathogenesis of skin diseases related to H. pylori remains unclear. Most studies are based on the prevalence and eradication of H. pylori to explain the
H. pylori and Vitiligo
relationship between H. pylori and skin disease. Because the detection of H. pylori was made only by serological tests, including H. pylori IgG and CagA, there may be conflicting and controversial results. In our study, the presence of H. pylori was confirmed by a UBT, which has a success rate of more than 98 % in detecting H. pylori infection, in addition to serological tests. Therefore, the present study provides better evidence supporting the relationship between ongoing H. pylori infection and vitiligo.
5 Conclusions There is a significant association between UBT-proven H. pylori infection and vitiligo. Additional studies are necessary to evaluate whether H. pylori eradication has a favorable effect on the clinical course of vitiligo. Further studies are also needed to explain the relationship between H. pylori and the pathogenesis of vitiligo. Acknowledgments No sources of funding were used to conduct this ¨ zdemir, study or prepare this manuscript. Zeynal Dog˘an, Pinar O Meral Eks¸ iog˘lu, and Levent Filik have no conflicts of interest that are directly relevant to the content of this study.
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ORIGINAL RESEARCH ARTICLE
Relationship Between Helicobacter pylori Infection and Vitiligo: A Prospective Study ¨ zdemir • Meral Eks¸ iog˘lu Zeynal Dog˘an • Pınar O Levent Filik
•
Published online: 2 July 2014 Ó Springer International Publishing Switzerland 2014
Abstract Background Helicobacter pylori is a worldwide bacteria that may affect several extra-gastric systems, including the endocrine, hematologic, vascular, respiratory, immune, and skin. Several skin diseases, including chronic urticaria, alopecia areata, psoriasis, and systemic lupus erythematosis have been found to be associated with H. pylori infection. Aim To our knowledge, there are no data showing an association between H. pylori and vitiligo. Therefore, in this study, we wanted to evaluate the relationship between H. pylori and vitiligo. Methods This study is a prospective study carried out in our Gastroenterology and Dermatology and Venereology departments of the Ankara Education and Research Hospital (Ankara, Turkey) between July 2013 and December 2013. Seventy-nine consecutive patients with vitiligo and 72 patients with telogen effluvium (TE) were recruited from the dermatology outpatient clinic. A total of 133 patients with vitiligo (n = 68) and TE (n = 65) [excluding 18 patients who had suspicious urea breath test (UBT)
Z. Dog˘an (&) L. Filik Department of Gastroenterology, Ankara Training and Research Hospital, Sukriye District, Ulucanlar Street, Altındag˘, Ankara 06230, Turkey e-mail: [email protected] L. Filik e-mail: [email protected] ¨ zdemir M. Eks¸ iog˘lu P. O Department of Dermatology and Venereology, Ankara Training and Research Hospital, Ankara, Turkey e-mail: [email protected] M. Eks¸ iog˘lu e-mail: [email protected]
results] were included in the study. All individuals were tested for H. pylori IgG and CagA. Also, a UBT was performed to detect the presence of H. pylori infection. Results There were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05). The number of patients with dyspepsia was significantly higher in the vitiligo group than in the TE group. No statistically significant relationship was seen between H. pylori positivity, CagA, H. pylori IgG, dyspepsia, and the Vitiligo Disease Activity score (p [ 0.05). Also, when patients with vitiligo were divided into localized and generalized types of vitiligo, there was no association between vitiligo involvement pattern and H. pylori positivity, CagA, H. pylori IgG, and dyspepsia (p [ 0.05). Conclusion Additional studies are necessary to evaluate the effect of H. pylori eradication on the clinical course of vitiligo. Further studies are also needed to explain the relationship between H. pylori and the pathogenesis of vitiligo.
Key Points Helicobacter pylori infection and dyspepsia are common health problems for patients with vitiligo There appears to be a relationship between H. pylori infection and vitiligo as an acquired autoimmune skin disease H. pylori eradication could be considered in vitiligo patients with dyspepsia and new studies are necessary to reveal the effect of eradication treatment on the clinical course of vitiligo
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1 Introduction Helicobacter pylori is a worldwide bacterium that affects approximately 50–80 % of the world population [1]. H. pylori not only causes gastric mucosal disease but also affects extra-gastrointestinal systems leading to several manifestations, such as iron-deficiency anemia, idiopathic thrombocytopenic purpura, metabolic syndrome, dyslipidemia, and decreased liver to spleen ratio [2–6]. Also, several population-based and experimental studies have shown a relationship between H. pylori and skin diseases including chronic urticaria, psoriasis, Behc¸et’s disease, and Henoch-Schoenlein purpura [7–10]. Increased H. pylori prevalence associated with skin disease, or increased skin disease severity due to H. pylori and a favorable response to H. pylori eradication support the presence of a link between H. pylori and skin disease. Autoimmune mechanisms triggered due to H. pylori are mostly claimed to play a role in this pathogenesis. Vitiligo is an acquired autoimmune skin disease that is characterized by depigmentation of the epidermis due to loss of functional melanocytes. Infections have been known to be a potential triggering factor for developing autoimmunity over the years. Although the immunological basis of vitiligo has been known for a long time, there are no data examining the effect of H. pylori on vitiligo. Therefore, H. pylori should also be investigated as a predisposing factor for vitiligo. In this study, we wanted to evaluate the association between H. pylori and vitiligo.
2 Patients and Methods This study is a prospective study carried out in the Gastroenterology and Dermatology and Venereology departments of the Ankara Education and Research Hospital (Ankara, Turkey) between July and December 2013. Seventy-nine consecutive patients with vitiligo were recruited from the dermatology outpatient clinic. The control group was composed of 72 consecutive patients who were admitted to the dermatology clinic due to telogen effluvium (TE) in the same time period. The TE group was defined as a patient group who had mental or physical stress for the past 2–4 months and were positive for hair pull tests. TE is a very well-defined clinical picture and has no immunological basis, which is why patients with TE were chosen as a control group from among dermatology outpatients. The classification of patients with vitiligo and TE was made by a specialist dermatologist. The Vitiligo Disease Activity (VIDA) score is a 6-point scale for assessing vitiligo activity that depends on the expansion of existing
lesions or appearance of new lesions, and was determined as follows: active 6 weeks or less (?4); active 6 weeks to 3 months (?3); active 3–6 months (?2); active 6–12 months (?1); stable 1 year or more (0); stable with spontaneous repigmentation 1 year or more (-1) [11]. The vitiligo involvement pattern was defined as types of vitiligo such as localized (focal, segmental, mucosal) or generalized (acrofacial, vulgaris, mixed, universal). To detect H. pylori infection, a urea breath test (UBT) was performed as follows: after an overnight fast, the patient swallowed a 14C-labeled urea-containing capsule (HelicapTM, Institute of Isotopes, Budapest, Hungary) with 50 mL water. After 15 min, the patient breathed out into a dry cartridge (HeliprobeÒ breath card, Kibion AB, Uppsala, Sweden) until the color of the card indicator changed from orange to yellow. Thereafter, the breath card was inserted into a small desktop Geiger Mu¨ller counter (HeliprobeÒ Analyser, Kibion AB, Uppsala, Sweden), and the radioactivity of the breath samples was read after 250 s of an automated process. Finally, the test results were expressed on the screen of the analyzer that showed radioactivity as count per minute (CPM): \25 CPM, patient not infected; 25–50 CPM, borderline or suspicious result; and [50 CPM, patient infected. We considered \25 CPM to be a negative result, [50 CPM to be a positive result, and 25–50 CPM to be a suspicious result in our study. Patients with a history of previous H. pylori eradication treatment, and those using NSAIDs, antibiotics, or proton pump inhibitors within 1 month were not included in the study. Patients were questioned about dyspeptic symptoms. Dyspepsia was defined as bloating, upper gastrointestinal discomfort, regurgitation, early satiety, and heartburn. The study was approved by the ethics committee of the hospital. Informed consent was obtained from all patients. 2.1 Statistical Analysis Numerical values were defined as means ± standard deviation. Chi-square test was used for categorical data differences between the two groups. p \ 0.05 was considered statistically significant. Statistical analyses were performed by SPSSÒ 16 statistical package (SPSS Inc., Chicago, IL, USA).
3 Results Eleven patients in the vitiligo group and seven patients in the TE group were not included in the study due to suspicious results in the UBT. In total, 133 patients (78 female and 55 male)—68 patients with vitiligo and 65 patients with TE—were included in the study. Twenty-four patients
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459
Table 1 Demographic and laboratory characteristics of the vitiligo and telogen effluvium groups
Data are given as mean ± standard deviation unless specified otherwise ALT alanine aminotransferase, AST aspartate aminotransferase, BMI body mass index, Hb hemoglobin, TE telogen effluvium, TSH thyroidstimulating hormone
Characteristic
Vitiligo group (n = 68)
TE group (n = 65)
p value
\0.001
Gender Female [n (%)]
30 (44)
48 (74)
Male [n (%)]
38 (56)
17 (26)
Age (years)
40.27 ± 16.97
35.89 ± 15.1
[0.119
Height (m)
1.66 ± 0.07
1.67 ± 0.06
[0.564 [0.280
Body mass (kg)
72.80 ± 10.88
74.92 ± 11.60
BMI (kg/m2)
26.47 ± 4.50
26.92 ± 4.28
[0.555
Hb (g/dL)
14.04 ± 1.78
13.55 ± 1.22
[0.068
TSH (lIU/mL)
2.11 ± 0.35
1.76 ± 0.12
[0.358
Fasting glucose (mg/dL)
97.14 ± 21.52
91.58 ± 11.61
[0.065
AST (IU/L)
22.67 ± 5.07
21.89 ± 4.66
[0.356
ALT (IU/L)
19.80 ± 7.25
18.86 ± 9.06
[0.506
Creatinine (mg/dL)
0.92 ± 0.18
0.91 ± 0.16
[0.951
had localized (22 patients with focal and two patients with segmental) and 44 patients had generalized (37 patients with vulgaris and seven patients with acrofacial) types of vitiligo. Demographic and laboratory characteristics of the vitiligo and TE groups are shown in Table 1. There were no significant differences regarding demographic and laboratory characteristics between the two groups (p [ 0.05), except that the number of females in the TE group was found to be significantly higher than in the vitiligo group (p \ 0.05). There were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05) (Table 2). The Table 2 Presence of dyspepsia and laboratory tests for Helicobacter pylori in the vitiligo and telogen effluvium groups Vitiligo group (n = 68) [n (%)]
TE group (n = 65) [n (%)]
p value
H. pylori positive
41 (60.3)
27 (41.5)
\0.038
CagA positive
47 (69)
32 (49.3)
\0.023
H. pylori IgG positive
52 (76.5)
38 (58.5)
\0.041
Dyspepsia positive
26 (38.2)
12 (18.5)
\0.012
TE telogen effluvium
number of patients with dyspepsia was significantly higher in the vitiligo group than in the TE group (p \ 0.012). No statistically significant relationship was seen between positivity for H. pylori, CagA, H. pylori IgG, or dyspepsia and the VIDA score (p [ 0.05) (Table 3). Also, when patients with vitiligo were divided into localized and generalized types of vitiligo, there was no association between vitiligo involvement pattern and H. pylori positivity, CagA, H. pylori IgG, or dyspepsia (p [ 0.05).
4 Discussion Increasing data have supported the idea that H. pylori contributes to the pathogenesis of several dermatological disorders. Different mechanisms have been suggested to define the effects of H. pylori on autoimmune extra-gastric diseases (Table 4) [12–20]. Autoimmune diseases are characterized by an abnormal immune response of the body against normal tissues known as loss of tolerance to selfantigens. However, the precise etiology of these autoimmune diseases remains unclear. Genetic predisposition, gender, hormonal status, and environmental factors including diet, drugs, and infectious agents have been proposed in the pathogenesis [21]. Infectious agents may cause autoimmune diseases by several mechanisms,
Table 3 The association between Helicobacter pylori features and Vitiligo Disease Activity score ?4 (n = 14)
?3 (n = 5)
?2 (n = 10)
?1 (n = 8)
0 (n = 29)
-1 (n = 2)
p
8 (57.1)
3 (60)
6 (60)
6 (75)
17 (58.6)
1 (50)
[0.942
IgG positive
10 (71.4)
4 (80)
7 (70)
7 (87.5)
22 (75.9)
2 (100)
[0.580
CagA positive Dyspepsia positive
11 (78.6) 5 (35.7)
3 (60) 1 (20)
7 (70) 4 (40)
6 (75) 3 (37.5)
19 (65.5) 13 (44.8)
1 (50) 0 (0)
[0.428 [0.772
H. pylori positive
Data are given as n (%)
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460 Table 4 Proposed mechanisms related to Helicobacter pylori in autoimmune conditions Autoimmune condition
Proposed mechanism
Rheumatoid arthritis Sjo¨gren’s syndrome
B cell activation by chronic H. pylori infection resulting in increased rheumatoid factor IgM
Idiopathic thrombocytopenic purpura
Molecular mimicry between CagA and peptides on platelets
Autoimmune thyroiditis
Molecular mimicry between CagA and thyroid peroxidase
Primary biliary cirrhosis
Higher prevalence of anti-H. pylori antibodies
Increased H. pylori antibodies
Primary sclerosing cholangitis
Detectable H. pylori species in liver samples
Atopic dermatitis
Increased IgE by H. pylori resulting in chronic allergic inflammation
Autoimmune bullous disease
Higher prevalence of H. pylori IgG antibodies
including antibody production, molecular mimicry, high levels of cytokines, major histocompatibility complex activation, regulatory T cell dysfunction, immune complex formation, and chronic inflammatory damage [22–28]. Similarly, several mechanisms have been proposed to explain the pathogenesis of H. pylori-induced autoimmunity. In a population-based study, H. pylori infection was found to be associated with higher levels of C-reactive protein (CRP), supporting a chronic inflammatory condition [29]. This chronic inflammation may trigger autoantibody production and antigenic stimulation and induce a systemic inflammatory response resulting in extra-gastric diseases. Molecular mimicry between H?, K?-adenosine triphosphatase, and H. pylori antigens has been demonstrated to play a role in the pathogenesis of autoimmune gastritis by activated cross-reactive gastric CD4? T cells [30, 31]. Several immune-mediated skin disorders, such as psoriasis, Behc¸et’s disease, and alopecia areata, have been considered to have a relationship with H. pylori infection. Psoriatic patients were found to have more prevalent antiH. pylori antibodies compared with a healthy control group [8]. Also, eradication therapy in patients with psoriasis and H. pylori has resulted in more rapid improvement of the skin disease [32]. H. pylori eradication in chronic urticaria has resulted in an improvement of the clinical course of the skin disease, breaking resistance to antihistamine medications [33]. Also, reinfection with H. pylori has resulted in activation of urticaria symptoms [34]. In several studies, comparable or higher rates of H. pylori infection have been found in patients with Behc¸et’s disease [35, 36]. Of interest, an important result from one study is that eradication of H. pylori was associated with improvement of Behc¸et’s disease features, including cutaneous lesions, articular complaints, and oral and genital ulcers [37]. In this regard, we did not find any association between H. pylori infection or the presence of H. pylori IgG and the Vitiligo Disease Activity Score, or between the vitiligo involvement pattern and H. pylori positivity or H. pylori IgG. Although CagA strains of H. pylori are responsible for more serious gastric
disease and clinical outcomes, we did not find any association between the presence of H. pylori CagA and VIDA score, or skin involvement of vitiligo in the present study (Table 3). However, dyspepsia was much more common in vitiligo patients infected with H. pylori than in controls (Table 3). Also, similar to other studies, there were significantly higher rates of H. pylori positivity, H. pylori CagA, and IgG in serum in the vitiligo group than in the TE group (p \ 0.05) (Table 2). Vitiligo is an acquired autoimmune skin disease that is characterized by depigmentation of the epidermis due to loss of functional melanocytes. However, its immunopathogenesis is not totally explained. Several mechanisms, including cytotoxic, oxidant–antioxidant, neural, and autoimmune, have been proposed to contribute to the pathogenesis of vitiligo [38–43]. H. pylori-induced autoimmunity based on higher levels of CRP, chronic inflammatory condition, auto-antibody production, and antigenic stimulation may be responsible for the pathogenesis of vitiligo. The proposed autoimmune pathogenesis of vitiligo is destruction of functional melanocytes by autoimmune triggering factors, including cytotoxic T cells or autoantibodies against melanocyte surface peptides as a result of self-tolerance loss [44, 45]. Therefore, it can be speculated that H. pylori might alter cellular immunity resulting in development of a similar autoimmune process, e.g., cytotoxic T cell activation against melanocyte antigens. Besides H. pylori causing local gastric inflammation, it is also responsible for systemic inflammation by producing tumor necrosis factor (TNF)-a, interleukin (IL)-6, IL-8, and IL-1b [46–50]. Systemic inflammation of H. pylori causes pancreatic b cell injury resulting in pancreatitis with higher levels of IL-1b and IL-10 [51]. By a similar mechanism, chronic systemic inflammation induced by H. pylori may affect the microenvironment of the dermis, resulting in detrimental effects on melanocytes. The exact pathogenesis of skin diseases related to H. pylori remains unclear. Most studies are based on the prevalence and eradication of H. pylori to explain the
H. pylori and Vitiligo
relationship between H. pylori and skin disease. Because the detection of H. pylori was made only by serological tests, including H. pylori IgG and CagA, there may be conflicting and controversial results. In our study, the presence of H. pylori was confirmed by a UBT, which has a success rate of more than 98 % in detecting H. pylori infection, in addition to serological tests. Therefore, the present study provides better evidence supporting the relationship between ongoing H. pylori infection and vitiligo.
5 Conclusions There is a significant association between UBT-proven H. pylori infection and vitiligo. Additional studies are necessary to evaluate whether H. pylori eradication has a favorable effect on the clinical course of vitiligo. Further studies are also needed to explain the relationship between H. pylori and the pathogenesis of vitiligo. Acknowledgments No sources of funding were used to conduct this ¨ zdemir, study or prepare this manuscript. Zeynal Dog˘an, Pinar O Meral Eks¸ iog˘lu, and Levent Filik have no conflicts of interest that are directly relevant to the content of this study.
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