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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 1  |  Page : 162-167

Prolactin contributes to the pathogenesis of thrombocytopenia in patients with hepatitis C virus


1 Department of Internal medicine, Faculty of Medicine, Menofia University, Menofia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menofia University, Menofia, Egypt

Date of Submission15-Jan-2015
Date of Acceptance14-Apr-2015
Date of Web Publication25-Jul-2017

Correspondence Address:
Walaa M Elgheriany
Department of Internal Medicine, Faculty of Medicine, Menoufia University, Shebin Al-Kom, Menoufia, 32843
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_15_15

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  Abstract 


Objective
The aim of this work was to explore the role prolactin (PRL) in hepatitis C (HCV)-related thrombocytopenia.
Background
PRL is involved in the activation of a number of immunological responses. It enhances the progression of the immune process in autoimmune diseases. Autoimmunity is a common finding in chronic hepatitis C, and a significant association between hyperprolactinemia (HPRL) and infection with HCV genotype 4 has been reported.
Materials and methods
This study was carried at the Internal Medicine Department, Menoufia University Hospital, in the period between May 2014 and December 2014. Three groups were involved: group I, which included 41 chronic hepatitis C patients with thrombocytopenia; group II, which included 35 chronic hepatitis C patients without thrombocytopenia; and group III, which included 25 healthy individuals with matched age and sex.
Results
Patients with HCV-related thrombocytopenia had HPRL and their serum PRL levels were significantly higher compared with HCV patients with normal platelet count and compared with normal controls (P = 0.02 and 0.001, respectively). We demonstrated negative correlation between HPRL and platelet count (r = 0.32 and P = 0.04). In addition, there was a significant difference in platelet count among different stages of liver fibrosis as the platelet count dropped steadily in line with the stage of fibrosis (P = 0.004).
Conclusion
This study shows that HPRL is present in a subset of patients with HCV-related thrombocytopenia and can be a contributing factor in the pathogenesis of thrombocytopenia in those patients. Thus, anti-PRL may be a treatment option in this category of patients.

Keywords: hepatitis C virus, hyperprolactinemia, immune thrombocytopenia


How to cite this article:
Glal AZ, Shoeib SA, Abdelhafez MA, Osman NF, Eldin WS, Abdelsala AE, Elgheriany WM. Prolactin contributes to the pathogenesis of thrombocytopenia in patients with hepatitis C virus. Menoufia Med J 2017;30:162-7

How to cite this URL:
Glal AZ, Shoeib SA, Abdelhafez MA, Osman NF, Eldin WS, Abdelsala AE, Elgheriany WM. Prolactin contributes to the pathogenesis of thrombocytopenia in patients with hepatitis C virus. Menoufia Med J [serial online] 2017 [cited 2019 Aug 22];30:162-7. Available from: http://www.mmj.eg.net/text.asp?2017/30/1/162/211482




  Introduction Top


Prolactin (PRL) is a versatile hormone produced not only by the anterior pituitary gland but also by various extrapituitary sites as neurons, prostate, decidua, mammary epithelium, skin, and immune cells. PRL is considered as a cytokine, due to structural homology, and plays an important role in modulating the immune response in animals and humans. PRL exerts its influence on the immune system by endocrine, paracrine, and autocrine mechanisms. This role is mediated by binding to specific receptors expressed on the membrane of all immune and hemopoietic cells [1].

Elevated serum PRL levels interfere with induction of B-cell tolerance by impairing B-cell receptor-mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B-cells, thereby promoting autoreactivity [2].

In addition, PRL is involved in regulating both T-helper cells type 1 (Th1) and type 2 (Th2); altered PRL levels are associated with either Th1 or Th2 dominance, which is a feature of autoimmune disorders. Hyperprolactinemia (HPRL) has been described in many autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Interestingly, human PRL gene is located on the short arm of the chromosome 6 close to the HLA region [2],[3].

Autoimmunity is a common finding in hepatitis C virus (HCV) infection; B-cell dysfunction may be caused by the interaction of B-cells with HCV, which modulates the function of these cells, and thus promotes its polyclonal activation and expands CD5+ cells. HPRL was found in 10.1% of HCV patients and that was independent of cryoglobulinaemia or nonorgan-specific autoantibodies [4].

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by an increased rate of platelet destruction caused by autoantibody binding to platelet surface glycoproteins, leading to platelet clearance by reticuloendothelial system macrophages in the spleen. The pathogenesis of ITP is complex, involving alterations in humoral and cellular immunity [5].

This study aimed to assess the role of PRL in HCV-related thrombocytopenia.


  Materials and Methods Top


This study was performed on 101 individuals aged from 30 to 60 years recruited from the inpatient wards and outpatient clinics of Menoufia University hospitals during the period from May 2014 to December 2014.

Study groups

Following groups were included in the study: group I, including 41 compensated HCV patients with thrombocytopenia and a positive antiplatelet antibodies; group II, including 35 compensated HCV patients without thrombocytopenia; and group III, including 25 healthy individuals of matched sex and age as a control group.

Inclusion criteria

Clinical diagnosis and laboratory findings of chronic hepatitis C as diagnosed by a positive anti-HCV and positive RNA-PCR.

Exclusion criteria

The following patients were excluded from the study:

  • Patients with known cause for HPRL, such as pregnancy, lactation, etc.
  • Patients with hypothyroidism, polycystic ovary syndrome, or other endocrinopathies
  • Patients taking medications known to increase PRL (e.g., phenothiazines, isoniazid, danazol, verapamil, metoclopramide, methyldopa, H2-blockers, etc.)
  • Patients with renal failure or chronic illnesses other than HCV infection
  • Patients with splenomegaly, portal hypertension, and decompensate liver disease
  • Patients with thrombocytopenia attributed to non-HCV causes (e.g., drugs, irradiation, heparin-induced thrombocytopenia, disseminated intravascular coagulation, etc.).


All included participants were subjected to a thorough medical history taking and complete physical examination. They also underwent routine investigations complete blood count (Sysmex XN-1000; Sysmex Corporation, Kobe, Hyogo Prefecture, Japan) and blood film; liver profile [alanine transaminase, aspartate transaminase, serum bilirubin (total and direct), prothrombin time and concentration, serum albumin]; fasting blood glucose; blood urea; serum creatinine; and serum electrolytes (Beckman AU480 chemistry analyzer; Beckman Coulter Inc., Carlsbad, California, USA). Bone marrow examination was not required for diagnosis unless the patient had unusual manifestations or age greater than 60. Erythrocyte sedimentation rate was carried out by using the Westergren's method and antinuclear antibody test was done by using the indirect immunofluorescence assay (Inova diagnostics, San Diego, California, USA). In addition, the participants were subjected to abdominal ultrascan and fibroscan (done in fewer hospitals), and specific investigations (serum PRL assay: PRL was measured directly in the serum samples by AXSYM (A Microparticle Enzyme Chemiluminescence Immunoassay; Abbott Laboratories Inc., Abbott Park, Illonis, USA).

Statistical analysis

Results were collected, tabulated, and statistically analyzed by using an IBM compatible personal computer with statistical package for the social sciences version 20 (IBM SPSS Statistics for Mac, Released 2011; IBM Corp., Armonk, New York, USA; SPSS Inc., Chicago, Illinois, USA). Descriptive statistics were expressed as number, percentage, mean, and SD. Qualitative data were analyzed by using the c2-test. Quantitative data were analyzed by using one-way analysis of variance test for comparison of more than two parametric groups. In this case, post-hoc test was used to show which group is statistically different. Kruskal–Wallis test was used for comparison of more than two non-parametric groups. Pearson's correlation coefficient test (r-test) was used to study the correlation between normally distributed quantitative variables. P value less than 0.05 was considered statistically significant [6].


  Results Top


The demographic data of the three groups are shown in [Table 1]. There was no significant difference in age or sex among the studied groups (P > 0.05).
Table 1 Sociodemographic characteristics of the studied groups

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There was statistically significant difference in the degree of liver fibrosis (as assessed by fibroscan) between the two HCV groups, being higher in group I (P < 0.05) [Table 2].
Table 2 Comparison between the studied groups of hepatitis C patients as regards fibroscan

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Comparison of the laboratory parameters among the three groups is shown in [Table 3]. There was a statistically significant difference in platelet count among the three groups (P < 0.001). Platelet count was significantly lower in group I (83.41 ± 17.64 × 103) compared with group II (195.97 ± 62.45 × 103, P < 0.001) and group III (267.2 ± 36.43 × 103, P < 0.001). There was also statistically significant difference in prothrombin concentration (P = 0.001), alanine transaminase (0.002), aspartate transaminase (P < 0.001), albumin (P < 0.001), and bilirubin (P = 0.002) among the three groups. On the other hand, no significant difference in hemoglobin level, white cell count, serum creatinine, or blood urea nitrogen was demonstrated among the three groups [Table 3].
Table 3 Comparison between the studied groups as regards laboratory parameters

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Our data showed statistically significant difference in serum PRL level among the three groups (P = 0.008). Serum PRL was significantly higher in group I (15.32 ± 11.32 ng/ml) when compared with group II (10.49 ± 9.66, P = 0.02) and group III (8.06 ± 3.35, P = 0.001) [Figure 1] and [Table 4].
Figure 1: Serum prolactin level (ng/ml) among the studied groups.

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Table 4 Comparison between the studied groups as regards serum prolactin level

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In addition, we demonstrated negative correlation between serum PRL level and platelet count (r = −0.32 and P = 0.04).

The study of the platelet count in relation to the stage of fibrosis in HCV groups (groups I and II) showed steady decrease in platelet count as fibrosis progressed, as platelet count was normal in F0 (191.64 ± 84.52) and showed a progressive decline to be the lowest in F5 (105.21 ± 35.06). The difference in platelet count among patients with different stages of fibrosis was significant (P = 0.004) [Figure 2] and [Table 5].
Figure 2: Platelets count (×103) among groups I and II according to fibroscan results.

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Table 5 Correlation between serum prolactin and other assessed laboratory parameters in group I (n=41)

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  Discussion Top


ITP is caused by antibodies that react with glycoproteins expressed on platelets and megakaryocytes (glycoprotein IIb/IIIa, Ib/IX, and others). Diminished numbers and function of regulatory T-cells as well as the effects of cytotoxic T-cells also contribute to the pathogenesis of ITP [7].

ITP is not a single disorder, but a syndrome in which thrombocytopenia may be primary or secondary to underlying infectious or immune disorders [8]. Many studies [9],[10],[11],[12] have described an association between ITP and HCV infection as it was shown to present in up to 20% of ITP cases, with a higher incidence in certain geographical areas [7].

The pathogenesis of HCV-associated ITP may involve activation of B-cells and antibodies cross-reactive with HCV and platelet GPIIIa. Over 90% of patients with chronic HCV infection develop high levels of immunoglobulin (Ig) G-associated thrombocytes called platelet-associated IgG [13].

PRL has an important role in modulating the immune response, both the innate and adaptive immune systems [14]. PRL has an immune stimulatory effect and promotes autoimmunity and was implicated in the pathogenesis of a number of autoimmune diseases like SLE and rheumatoid arthritis. Among others [15],[16],[17], reported HPRL in patients with autoimmune diseases such as SLE [18]. Jara et al. [19] demonstrated a good response to bromocriptine, a dopaminergic agonist, in active SLE patients. Elevated PRL was described in liver disease and was attributed mainly to the fall in dopamine levels in the tuberoinfundibular tract [20].

Our study aimed to determine the contribution of PRL in HCV-related ITP.

Serum PRL level was significantly higher in our HCV patients compared with normal controls, being higher in patients with HCV-related thrombocytopenia, where HPRL coexisted in 15.3% of these patients. Furthermore, we demonstrated a significant correlation between platelet count and PRL level in that group.

Eskander et al. [21] also found that Egyptian chronic HCV genotype-4a-infected patients have a significant increase of PRL concentrations compared with healthy controls, regardless of sex. Besides, PRL concentrations decreased significantly after antiviral therapy [21].

In a case–control study by Gazareen et al. [22], HPRL was detected in 20% of ITP patients and PRL level correlated with the severity of ITP as 36.4% of their patients with platelet count below 30 000/μl had HPRL.

HPRL may mediate thrombocytopenia through interfering with B-cell tolerance induction, enhancing proliferative response to antigens, and increasing the production of autoantibodies and cytokines, as it was shown to induce the production of interleukin-1 and interferon-γ and promote the expression of IL-2 receptor [18],[21].

In this study, correlation analysis showed a significant relation between the platelet counts and stage of fibrosis. Lower platelet counts were detected in patients with higher stages of fibrosis. This observation was reported in previous studies [23],[24]. This was thought to be due to decrease in thrombopoietin production by hepatocytes [24].

To summarize, our findings suggest that HCV-related thrombocytopenia is multifactorial as decreased thrombopoietin production due to liver disease as well as immune dysregulation secondary to HCV infection and HPRL are likely contributing factors to the development of thrombocytopenia in these patients. We recommend trials of bromocriptine in the treatment of thrombocytopenia associated with high serum PRL, particularly when response to other therapies is unsatisfactory.


  Conclusion Top


HPRL occurs in a subset of patients with HCV-related thrombocytopenia and correlates with the degree of thrombocytopenia in this group of patients. Further studies involving larger number of patients with HCV-related thrombocytopenia are needed to clarify the actual role of PRL in immune regulation and to test the efficacy of PRL-lowering agents as a therapeutic option in these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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