Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
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
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_15_15

Rights and Permissions

The aim of this work was to explore the role prolactin (PRL) in hepatitis C (HCV)-related thrombocytopenia.
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.
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).
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 2020 Feb 28];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

Click here to view

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

Click here to view

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

Click here to view

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.

Click here to view
Table 4 Comparison between the studied groups as regards serum prolactin level

Click here to view

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.

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

Click here to view

  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


Conflicts of interest

There are no conflicts of interest.

  References Top

Matera L. Action of pituitary and lymphocyte prolactin. Neuroimmunomodulation 1997; 4:171–180.  Back to cited text no. 1
Orbach H, Shoenfeld Y. Hyperprolactinemia and autoimmune diseases. Autoimmun Rev 2007; 6:537–542.  Back to cited text no. 2
Vera-Lastra O, Jara LJ, Espinoza LR. Prolactin and autoimmunity. Autoimmun Rev 2002; 1:360–364.  Back to cited text no. 3
Sousa GM, Oliveira RC, Pereira MM, Parana R, Sousa Atta ML, Atta AM. Autoimmunity in hepatitis c virus carriers: involvement of ferritin and prolactin. Autoimmun Rev 2011; 10:210–213.  Back to cited text no. 4
Imbach P. Treatment of immune thrombocytopenia with intravenous immunoglobulin and insights for other diseases. A historical review. Swiss Med Wkly 2012; 142:13593–13599.  Back to cited text no. 5
Machin D, Campbell MJ, Walters JJ.P value and statistical interference. Chapter 7. In: Machin D, Campbell MJ, Walters JJ, editors. Medical statistics: a text book for health science. 4th ed. Sheffield, England: John Wiley and Sons Ltd; 2007. pp. 343–566.  Back to cited text no. 6
Kistanguri G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am 2013; 27:495–520.  Back to cited text no. 7
Saeidi S, Jaseb K, Asnafi AA, et al. Immune thrombocytopenic purpura in children and adults: a comparative retrospective study in IRAN. Int J Hematol Oncol Stem Cell Res 2014; 8:30–36.  Back to cited text no. 8
Zhang L, Li H, Zhao H, Ji L, Yang R. Hepatitis C virus related adult chronic idiopathic thrombocytopenic purpura: experience from a single Chinese center. Eur J Haematol 2003; 70:196–197.  Back to cited text no. 9
Cacoub P, Renou C, Rosenthal E, Cohen P, Loury I, Loustaud-Ratti V, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne etMaladies Infectieuses sur le Virus de l'Hepatite C. Medicine (Baltimore). 2000; 79:47–56.  Back to cited text no. 10
Pockros PJ, Duchini A, McMillan R, Nuberg LM, McHutchison J, Vierres E. Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection. Am J Gastroenterol 2002; 97:2040–2045.  Back to cited text no. 11
Chiao EY, Engels EA, Kramer JR, Bietz K, Henderson L, Giordano TP, et al. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection. Arch Intern Med 2009; 169:357–363.  Back to cited text no. 12
Al-Jafar H, Al-Khaldi J, Alduaij A, AlBanwan KH. Severe thrombocytopenia in a patient with hepatitis C treated with eltrombopag from off-label drug use to on-label drug use: a case report 4. J Med Case Rep 2014; 8:303.  Back to cited text no. 13
Rubtsov AV, Rubtsova K, Kappler JW, Marrack P. Genetic and hormonal factors in female-biased autoimmunity. Autoimmun Rev 2010; 9:494–498.  Back to cited text no. 14
Shahin D. Thrombocytopenia and leukocytosis are independent predictors of hyperprolactinemia in systemic lupus erythematosus patients. Egypt Rheumatol 2011; 33:77–83.  Back to cited text no. 15
Paraiba DP, Soares CR, Bartolini P, Arthuso FS, Borba EF, Bonfa E, et al. Lymphocytic prolactin does not contribute to systemic lupus erythematosus hyperprolactinemia. Clin Exp Rheumatol 2010; 28:2–7.  Back to cited text no. 16
Gazareen S, El-Najjar M, Lassien Y, Dawood A, El-Shebinie A, Soliman SE, et al. Prolactin hormone: a possible marker of the activity of systemic lupus erythematosus. Menoufia Med J 2009; 22:67–80.  Back to cited text no. 17
Shelly S, Boaz M, Orbach H. Prolactin and autoimmunity. Autoimmun Rev 2012; 11:465–470.  Back to cited text no. 18
Jara LJ, Cruz-Cruz P, Saavedra MA, Medina G, Gahcia-Flores A, Angeles U, et al. Bromocriptine during pregnancy in systemic lupus erythematosus: a pilot clinical trial. Ann N Y Acad Sci 2007; 1110:297–304.  Back to cited text no. 19
Velissaris D, Karanikolas M, Kalogeropoulos A, Solomou E, Polychronopoulos P, Thomopoulos K, et al. Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy. World J Gastroenterol 2008; 14:4190–4195.  Back to cited text no. 20
Eskander EF, Abd-Rabou AA, Yahya SM, Shaker OG, Mohamed MS. The impact of pegylated-interferon-a plus ribavirin on prolactinemia and testosteronemia among hepatitis C-genotype-4a patients. Open J Biochem 2014; 1:25–36.  Back to cited text no. 21
Gazareen S, Glal A, Shoeib S, Sonbol A, Abdelhafez M, Elkholy H. Serum prolactin in primary ITP. Menoufia Med J 2014; 4:99–117.  Back to cited text no. 22
Sandeep KR, Byron ME, Howard AL. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol 2005; 129:818–824.  Back to cited text no. 23
Giannini E, Borro P, Botta F, Fumagalli A, Malfatti F, Podesta E, et al. Serum thrombopoietin levels are linked to liver function in untreated patients with hepatitis C virus-related chronic hepatitis. J Hepatol 2002; 37:572–577.  Back to cited text no. 24


  [Figure 1], [Figure 2]

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


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Materials and Me...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded52    
    Comments [Add]    

Recommend this journal