|Year : 2019 | Volume
| Issue : 4 | Page : 246-253
Reduced serum vitamin D levels in Egyptian adults with chronic primary immune thrombocytopenia (responders and nonresponders): an Egyptian single-center study
Walaa A Esalakawy MD 1, Abdel R.A Soliman1, Sana A Mohammed2, Alia M Saeed1
1 Department of Internal Medicine, Hematology and Clinical Oncology Division, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of General Internal Medicine, Faculty of Medicine, Misurata Univeristy, Misurata, Libya
|Date of Submission||31-Aug-2019|
|Date of Acceptance||26-Oct-2019|
|Date of Web Publication||20-Jul-2020|
Walaa A Esalakawy
Abbassia, Cairo 11241
Source of Support: None, Conflict of Interest: None
Introduction Immune thrombocytopenia (ITP) is a disorder characterized by immune-mediated accelerated platelet destruction and suppressed platelet production. Low vitamin D levels have been found in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and autoimmune gastritis. The mechanisms underlying the link between vitamin D and autoimmunity are not completely understood but probably are associated with its anti-inflammatory and immunomodulatory functions.
Patients and methods The study included 80 adult participants, comprising 40 patients with primary ITP (they were divided into 20 responders and 20 nonresponders), 20 cases of thrombocytopenia owing to non-ITP causes (eight acute myeloid leukemia, five myelodysplastic syndrome, and seven with aplastic anemia), and 20 healthy controls. All were subjected to measurement of serum 25-monohydroxyvitamin D level with ELISA.
Results We found that vitamin D levels were significantly lower in patients with ITP (range=2–40 ng/ml; mean±SD=17.29±10.96 ng/ml) and thrombocytopenia owing to non-ITP causes (range=10–40 ng/ml; mean±SD=21.05±8.31 ng/ml) in comparison with normal healthy controls (range=10–65 ng/ml; mean±SD=36.70±16.30 ng/ml) (P=0.000), but there was no statistically significant difference between levels in ITP vs non-ITP thrombocytopenia (P=0.225). When comparing vitamin D levels in patients with ITP in relation to response to first-line treatment with corticosteroids, there was no statistical significant difference regarding vitamin D levels (mean±SD=15.73±10.00 ng/ml in responders and mean±SD=18.85±11.89 ng/ml in nonresponders), with a P value of 0.374.
Conclusion Vitamin D levels are lower among patients with ITP in relation to healthy controls. Vitamin D may play a role in the pathogenesis of ITP.
Keywords: 25(OH) D, immune thrombocytopenia, response to treatment, thrombocytopenia
|How to cite this article:|
Esalakawy WA, Soliman AR, Mohammed SA, Saeed AM. Reduced serum vitamin D levels in Egyptian adults with chronic primary immune thrombocytopenia (responders and nonresponders): an Egyptian single-center study. Egypt J Haematol 2019;44:246-53
|How to cite this URL:|
Esalakawy WA, Soliman AR, Mohammed SA, Saeed AM. Reduced serum vitamin D levels in Egyptian adults with chronic primary immune thrombocytopenia (responders and nonresponders): an Egyptian single-center study. Egypt J Haematol [serial online] 2019 [cited 2020 Aug 8];44:246-53. Available from: http://www.ehj.eg.net/text.asp?2019/44/4/246/290231
| Introduction|| |
Immune thrombocytopenia (ITP) is a disorder characterized by immune-mediated accelerated platelet destruction and suppressed platelet production .
In patients with ITP, antiplatelet autoantibodies frequently appear to be directed against Group Ib/IX and Group IIb/IIIa expressed on platelets and megakaryocytes .
Abnormalities of cell-mediated immunity are known to contribute to the pathologic process. Like many other autoimmune diseases, ITP has a T helper cell type 1 bias and a reduced activity of T-regulatory cell .
Vitamin D, a steroid hormone, is known to play an essential role in calcium homeostasis, but as the receptor for vitamin D (VDR) is found in cells of almost every tissue, and the enzyme 1-α hydroxylase necessary for the final activation of vitamin D also has a widespread distribution, it appears obvious that vitamin D must have a multitude of function .
Lower vitamin D levels have been found in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), systemic sclerosis, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and autoimmune gastritis .
The mechanisms underlying the link between vitamin D with autoimmunity are not completely understood but probably are associated with its anti-inflammatory and immunomodulatory functions .
Several studies confirm that vitamin D enhances the innate immune response, whereas it exercises an inhibitory action on the adaptive immune system by inhibiting the proliferation of type 1T helper cells, increasing the quantity of type 2T helper cells, increasing the quantity of CD4+/CD25+ T-regulator cells, and inhibiting B-cell proliferation, generation of B memory cells, plasma cell differentiation, and immunoglobulin production .
| Patients and methods|| |
The current case–control study was conducted on 80 adult participants (age ≥18 years), including 40 patients with ITP, 20 patients with thrombocytopenia secondary to non-ITP diseases, and 20 healthy controls. All procedures performed in our study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individuals who participated in the study. All patients were recruited from the Clinical Hematology Unit, Internal Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
An informed consent was taken from all participants participating in the present study according to the declaration of Helsinki.
The participants enrolled in this study were divided into the following groups:
- Group I: it included 40 adult patients diagnosed as having primary ITP who met the diagnostic criteria of ITP as previously described in the international consensus report published in 2010 . This group was subdivided into the following:
- Group Ia: it included 20 patients who were responders to treatment by first-line therapy (steroids).
- Group Ib: it included 20 nonresponder patients with ITP.
- Group II: it included 20 patients with secondary thrombocytopenia. This group included eight patients with acute myeloid leukemia (AML), five patients with myelodysplastic syndrome (MDS), and seven patients with aplastic anemia. All the patients with the aforementioned diseases were under treatment.
- Group III: it included 20 sex-matched and age-matched healthy controls with normal platelet count and no concurrent illnesses or medications at the time of blood withdrawal.
The following were the inclusion criteria:
- Adult (age ≥18 years).
- Primary ITP.
- Patients with ITP who received first-line steroid therapy.
The following were the exclusion criteria:
- Age less than 18 years.
- Secondary ITP.
- Patients with ITP on second-line therapy.
- Chronic renal disease.
- Chronic liver disease.
- Malnutrition and malabsorption.
Plan of treatment in patients with immune thrombocytopenia
Patients were treated by first-line steroid therapy (i.e. prednisolone 1 mg/kg) for 3–4 weeks followed by gradual tapering. Patients on second-line therapy (e.g. Azathioprine and danazol,) were excluded from this study, and the patients were subdivided into responders and nonresponders.
Definition of response
Patients were considered responders if they have platelet count above 30×109/l or doubling of the baseline platelet count and no clinically overt bleeding .
However, patients were considered resistant (nonresponders) if they have any platelet count lower than 30×109/l or less than doubling of the baseline count, active bleeding, or steroid dependence .
Assessment of serum level of 25(OH)D
For each participant, ∼5 ml of venous blood was drawn under complete aseptic conditions and dispensed into a labeled vacutainer containing gel and clot activator, and serum was separated by centrifugation for 5 min, then stored at temperature −20°C till assay. The measurement of 25(OH) vitamin D was done by ELISA assay using a commercially available ELISA kit (Calbiotech, A Life Science Company, El Cajon, CA, USA). The values were expressed in ng/ml.
Definition of vitamin D deficiency
Vitamin D deficiency is defined as a 25(OH) D level of 20 ng/ml or less, vitamin D insufficiency as 21–29 ng/ml, and vitamin D sufficiency as 30 ng/ml or greater .
Data were collected, revised, coded, and entered into the Statistical Package for the Social Sciences (IBM SPSS, Corporate headquarters 1 New Orchard Road Armonk, New York, United States) version 20. Qualitative data were presented as number and percentages, whereas quantitative data were presented as mean, standard deviations and ranges when parametric and median with interquartile ranges when nonparametric.
P value was considered significant as follows:
- P greater than 0.05: nonsignificant.
- P less than 0.05: significant.
- P less than 0.01: highly significant.
| Results|| |
Demographic data and disease characteristics
The total number of participants enrolled into the study was 80 adult participants. They were divided into 40 patients with ITP (equally subdivided into responders and non-responders), comprising 36 females and four males, with a female : male ratio of 9 : 1, with mean age±SD of 33.41±9.67 years, ranging from 18 to 50 years; 20 cases of thrombocytopenia owing to other reasons, comprising 16 (80%) females and four (20%) males, with mean age±SD of 36.70±13.30 years, ranging from 19 to 60 years; and 20 adults apparently healthy controls, comprising 17 females and three males, with an age range of 18–44 years and mean±SD of 29.90±8.07 years.
The three groups were matched regarding age (P=0.123) and sex (P=0.560).
Demographic data and disease characteristics among the three studied groups are illustrated in [Table 1].
|Table 1 Comparison among the three studied groups regarding clinical characteristics|
Click here to view
Hemoglobin levels across the studied groups
Hemoglobin levels were significantly lower in patients with thrombocytopenia owing to other non-ITP causes (mean±SD=7.80±1.03 g/dl) than patients with ITP (mean±SD=11.31±1.48 g/dl) (P=0.000) or healthy normal controls (mean±SD=12.66±1.37 g/dl) (P=0.000).
Platelet counts across the studied groups
Regarding platelet counts, they were significantly reduced in patients with ITP and patients with thrombocytopenia owing to other causes as compared with healthy controls (P=0.000).
The mean platelet volumes (MPV) were significantly higher in patients with ITP (mean±SD=11.16±2.14 fl) than patients with thrombocytopenia owing to non-ITP causes (mean±SD=9.10±3.40 fl) and healthy controls (mean±SD=9.79±1.01 fl) (P=0.004).
Vitamin D levels across the studied groups
25-Monohydroxyvitamin D levels were significantly lower in patients with ITP (range=2–40 ng/ml; mean±SD=17.29±10.96 ng/ml) and thrombocytopenia owing to non-ITP causes (range=10–40 ng/ml; mean±SD=21.05±8.31 ng/ml) in comparison with normal healthy controls (range=10–65 ng/ml; mean±SD=36.70±16.30 ng/ml) (P=0.000), but there was no statistically significant difference between levels in ITP vs non-ITP thrombocytopenia (P=0.225), and this is well illustrated in [Figure 1].
|Figure 1 25(OH)D levels were significantly lower in patients with immune thrombocytopenia and patients with thrombocytopenia owing to other causes than healthy control (P=0.000).|
Click here to view
Calculating the degree of deficiency of vitamin D in the three groups, it was found that 27 (67.5%) patients with ITP were deficient in the vitamin levels, recording values less than or equal to 20 ng/ml. Of those 27 patients, 15 patients are severely deficient (i.e. ≤10 ng/ml). Other six (15%) patients with ITP were insufficient, and only seven (17.5%) had sufficient values of vitamin D.
When these data are compared with healthy normal controls, we observed that only four (20%) of them were deficient, and one of them had severe deficiency. Other four were insufficient, whereas 12 (60%) had normal levels.
In thrombocytopenia owing to non-ITP causes, half of them were deficient (10%), whereas five (25%) were insufficient, and only five (25%) had normal values.
Vitamin D levels in patients with immune thrombocytopenia in relationship to response
When further segregating patients with ITP into responders and nonresponders, we found that at enrollment time, the platelet count was significantly lower among nonresponders (median=64.5×109/l) than responders (median=200.5×109/l) (P=0.000). At the same time, there was no significant difference in hemoglobin level between nonresponders and responders (mean±SD=11.18±1.63 vs 10.65±1.56 g/dl, respectively; P=0.296).
The two subgroups (nonresponders and responders) showed no statistically significant difference regarding vitamin D levels (mean±SD=15.73±10.00 ng/ml in responders in relation to mean±SD=18.85±11.89 ng/ml in nonresponders, with a P value of 0.374).
25(OH)D levels when correlated to age, disease duration, dose of steroids given, and platelet counts in patients with ITP showed no significant correlation.
| Discussion|| |
ITP is an autoimmune disorder characterized by accelerated platelet destruction and suppression of platelet production, resulting in low platelet count .
Vitamin D is recognized as a true steroid hormone that exerts several biological activities, including the regulation of the immune system .
The aim of this study is to check vitamin D status in adult patients with primary ITP and to correlate it with response to first-line treatment.
The present study included 40 patients with ITP (36 females and four males), 20 patients with thrombocytopenia secondary to other diseases (16 females and four males), and 20 normal healthy participants (17 females and three males). There were no statistically significant differences among the three groups regarding sex and age (with P values of 0.560 and 0.123, respectively).
In this study, 90% of the patients with ITP were females and only 10% were males, with female to male ratio of 9 : 1, which reflects a higher incidence of ITP in females in comparison with males. This observation is consistent with the results of Schoonen et al.  who found that the incidence of ITP was statistically significantly higher in women compared with men. Moreover, Saeidi et al.  found that the ITP prevalence was higher in females aged above 16 years compared with males of the same age, with a ratio of 7 : 3. However, ITP is an autoimmune disease, and it is well known that women for unclear reason are more likely to develop autoimmune diseases than men.
The mean age of patients with ITP in our study was 33.41±9.67 years. This was the same as that described by Cines and Bussel  who stated that the incidence of ITP is more common in women aged between 18 and 40 years. On the contrary, Neylon et al.  estimated a higher incidence of ITP among those aged 60 years and older.
The platelet counts in patients with ITP (median of 114×109/l) and in the patients with thrombocytopenia owing to non-ITP causes (median of 36.5×109/l) were significantly decreased in comparison with healthy controls (296×109/l) (P<0.001). On the contrary, the hemoglobin levels were significantly lower in patients with thrombocytopenia owing to non-ITP causes (mean±SD=7.80±1.03) than in normal healthy controls (mean±SD=12.66±1.37) and patients with ITP (mean±SD=11.31±1.48), with P value of 0.000. This finding was owing to the nature of the diseases included in this group of patients (AML, aplastic anaemia, and MDS), which were characterized by the manifestation of bone marrow failure. The patients with ITP showed mean hemoglobin level around the normal because it is the disease of isolated thrombocytopenia.
In this study, we observed that the MPV were significantly higher in patients with ITP (mean±SD=11.16±2.14 fl) than that in patients with thrombocytopenia owing to non-ITP causes (hypoproductive thrombocytopenia) (mean±SD=9.10±3.40 fl) and in normal controls (mean±SD=9.79±1.01 fl), with P value of 0.002 and 0.035, respectively. This result agrees with the finding reported by Ntaios et al.  and Negash et al.  who found that the MPV is significantly elevated in patients with ITP than in patients with A4 thrombocytopenia. In disagreement with this result, a study conducted by Borkataky et al.  found no significant difference in the MPV between the destructive thrombocytopenia groups and the control group. However, larger platelets have more granules, aggregate more rapidly with collagen, have a higher thromboxane A2 level, and express more glycoprotein Ib and IIb/IIIa receptors than smaller platelets, which may explain the lower bleeding tendency in patients with ITP .
Results in the present study revealed decreased serum 25(OH)D levels in female patients with ITP than those of males; however, this decrease was nonsignificant. In concordance with our results, a study by Elsammak et al.  evaluated the vitamin D status of a cohort of healthy young Saudi Arabians in the Eastern region of Saudi Arabia. A sample of 139 blood donors were studied. They found that serum 25(OH)D levels did not differ significantly between males and females. This result is consistent with the findings of Amital et al.  who conducted their study on patients with SLE from several European and Israeli cohorts and found that vitamin D level did not differ between sexes. However, the results of this present study did not agree with the results of a study by Wright et al.  conducted on patients with SLE who found that female sex was a predictor for vitamin D deficiency. To our knowledge, no similar studies were conducted on patients with ITP before.
In the present study, we did not find a significant correlation between vitamin D levels and age or disease duration in patients with ITP. This finding is in line with the results of a study by Emam et al.  who studied a comparable number of Egyptian patients with SLE (40 patients with SLE and 20 age-matched and sex-matched controls) and did not find significant correlation between vitamin D level and age or disease duration. Another study by Rossini et al.  conducted on patients with rheumatoid arthritis did not find an association between vitamin D level and disease duration. Moreover, Dias de Castro et al.  in their study on patients with inflammatory bowel disease found no correlation between vitamin D and age or disease duration. However, Karatay et al.  studied 32 patients with Behcet’s disease and found that age was one of the predictors of 25(OH)D levels.
In the present study, we have found significantly lower mean 25(OH)D levels among ITP cases compared with healthy control group (17.29±10.96 vs 36.70±16.30 ng/ml, respectively), with P value less than 0.001.
When patients with ITP and controls were classified according to vitamin D status, 33 of 40 patients with ITP (82.5%) had inadequate (insufficient and deficient) 25(OH)D levels (<30 ng/ml), of which six (15%) patients being insufficient (21–29 ng/ml) and 27 (67.50%) being deficient (≤20 ng/ml). In contrast, four of 20 healthy controls (20%) were found to be insufficient and four (20%) being deficient. To our knowledge, there were no previous studies evaluating vitamin D levels in patients with ITP in an Arab country, but there were on other autoimmune disorders such as SLE disease. The frequency of 25(OH)D deficiency among patients with ITP in our study is similar to that reported in a study conducted by Emam et al.  on 40 Egyptian patients with SLE and 20 controls, which revealed low vitamin D levels in patients with SLE compared with healthy controls, and 85% of patients with SLE had inadequate (insufficient and deficient) vitamin D levels.
Despite Egypt being a sunny country, many contributing factors lead to low vitamin D level in our population in general as in most middle east countries, including the dark skin, use of sun screen, the cultural and religious practice of wearing clothes that cover the entire body, and the limited amount of vitamin D obtained from dietary sources due to lack of fortification and even lack of measures to confirm adequacy of fortification of fortified staple foods . Moreover, Fragoso et al.  explained this to be a result of increased modern indoor life activities.
In the present study, the result is concordant to a study by Fattizzo et al.  conducted on 103 patients with autoimmune cytopenia (included 44 patients with ITP, 35 with primary autoimmune hemolytic anemia, five with Evans’ syndrome, and 19 patients with chronic idiopathic neutropenia) and 40 controls, which revealed low 25(OH)D level in patients with ITP compared with healthy controls (mean±SD=2.3±1.8 vs 6±6 ng/ml, P<0.001). They also found that 25(OH)D levels were significantly lower in patients with primary autoimmune hemolytic anemia, Evans’ syndrome, and chronic idiopathic neutropenia than in controls (mean±SD=2.4±1.6, 1.3±0.5, 2.1±1.3, and 6±6 ng/ml, respectively; P<0.001).
Moreover, in agreement with our results, a Chinese study conducted on 45 patients with ITP showed that the levels of 25(OH)D (10.6±7.7 ng/ml) and 1α,25(OH)2D (69.9±29.0 pg/ml) of the patients with ITP were lower than those of healthy controls (13.7±9.1 and 87.3±19.9 pg/ml) (P<0.05) .
In the present study, there was no statistically difference between the patients with ITP and patients with thrombocytopenia secondary to other causes (non-ITP) regarding vitamin D levels. Serum 25(OH) D levels were significantly lower in patients with thrombocytopenia owing to non-ITP causes than normal healthy controls (mean±SD=21.05±8.31 vs mean±SD=36.70±16.30 ng/ml; P<0.001). In fact, the patients included in this group (patients with thrombocytopenia secondary to other causes) unfortunately were patients with AMLs, MDSs, and aplastic anemia, and vitamin D deficiency has been implicated in the pathogenesis of these hematological and oncohematological disorders. However, many of the diseases with thrombocytopenia were associated with vitamin D deficiency, and we could not enroll patients with thrombocytopenia secondary to hepatitis C virus or hepatitis B virus because patients with liver diseases were excluded from this study as liver disease is one of the causes of vitamin D deficiency.
In our study, there was no statistically significant difference in 25(OH)D levels between responders and nonresponders (median=15.5 vs 19 ng/ml, respectively; P=0.327). This result is in concordance with the results of a study by Fattizzo et al.  in which all patients with ITP were treated with steroids; rituximab was administered in one case, cytotoxic immunosuppressors in seven, and splenectomy performed in eight. Overall, five cases unsuitable for or refractory to splenectomy were treated with thrombopoietin receptor agonists, and they found no significant association among the number of therapy lines and vitamin D levels. This observation may indicate that vitamin D deficiency has a role in ITP pathogenesis, but did not contribute in disease activity and treatment response. However, more studies with larger populations may be required to define the actual role of vitamin D in treatment response and the activity of disease in patients with ITP.
However, vitamin D was inversely correlated with disease activity in many other studies. In a study conducted by Haga et al.  on 302 patients with rheumatoid arthritis, they found that very low serum 25(OH)D levels (≤6 ng/ml) were associated with very high disease activity and with increased requirement of treatment with at least three disease-modifying antirheumatic drugs. Furthermore, a case–control study by Ricceri et al.  conducted on 68 patients with chronic plaque psoriasis and 60 healthy controls demonstrated a statistically significant inverse linear correlation between patient’s vitamin D levels and their Psoriasis Area Severity Index scores. Moreover, Mok et al.  in their study on patients with SLE found that 25(OH)D level correlated inversely and significantly with SLE activity. On the contrary, Ruiz-Irastorza et al.  found no association between vitamin D levels and SLE disease activity. D’Aurizio et al.  found that low serum levels of vitamin D did not correlate with Hashimoto’s thyroiditis or with Grave’s disease activity. Moreover, no correlation between vitamin D levels and disease activity was observed in a cross-sectional study conducted by Levin et al.  on children with inflammatory bowel diseases.In the present study, there was no significant correlation between vitamin D levels and platelet counts at enrollment time. Our observations are consistent with the findings of Fattizzo et al.  who found no significant association among vitamin D levels and hemoglobin, platelets, and absolute neutrophil counts values at enrollment for AIHA, ITP, and chronic idiopathic neutropenic patients, respectively. However, 20 patients with ITP with very low vitamin D levels (<1.3 ng/ml) displayed reduced platelets counts compared with the remaining 24. However, the majority of our patients were enrolled from the outpatient clinic and their platelet counts were not severely deficient at time of enrolment.
Despite corticosteroid use is thought to increase the catabolism of vitamin D by activating the expression of the Steroid and Xenobiotic nuclear receptor, which induces the destruction of 25(OH)D and 1α,25(OH)2D through the expression of CYP3A4 . We found no correlation between use of steroids/steroid doses and vitamin D levels. Our observations are consistent with the findings of Fattizzo et al.  where no relationship was found between serum 25(OH) D levels and steroid doses in patients with ITP. Also, in a study conducted on SLE patients by Schoindre et al.  they did not find an association between corticosteroid use or dose and vitamin D status. This finding may indicate that vitamin D deficiency in our patients was not owing to steroid therapy itself. However, Toloza et al.  found that cumulative corticosteroid exposure in patients with SLE was associated with low vitamin D levels.
Additional support for our results, two refractory thrombocytopenic patients with concomitant lupus-like syndrome responded to hydroxychloroquine and high-dose vitamin D replacement therapy . Moreover, in a case study, a 48-year-old female patient with refractory ITP was found to have an inadequate level of 25(OH) D, and significantly responded to high dose vitamin D 
Thus, the present findings conclude that vitamin D deficiency may have an important role in the pathogenesis of primary ITP, and vitamin D supplementation might reduce the risk of the disease by modulating the immune system.
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Conflicts of interest
There are no conflicts of interest.
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