Domperidone use and risk of primary liver cancer in the Clinical Practice Research Datalink
Introduction
Liver cancer is the sixth most commonly occurring cancer in the world and the second leading cause of cancer mortality [1]. In almost all areas of the world, the incidence of liver cancer is three- to four-fold higher among men than women [2]. Men also have higher recurrence rates and poorer survival after diagnosis of liver cancer than do women [3,4]. Reasons for this gender disparity are not clear. While some major risk factors, such as infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), excessive alcohol consumption, and cigarette smoking, are more common among men, these factors do not fully account for the gender differences in liver cancer incidence and survival [2].
A role for endogenous hormones in the gender discrepancy in liver cancer risk has been hypothesized, with most speculation focusing on testosterone or estradiol [[5], [6], [7], [8]]. However, the role of estrogenic exposures remains unclear, as studies have reported mixed results for parity [[9], [10], [11], [12], [13], [14], [15]], oral contraceptive use [16], and menopausal hormone therapy [15,17,18], although two studies have shown an increased liver cancer risk associated with bilateral oophorectomy [15,18]. Other hormones could also play a role in liver cancer development. Prolactin is an estrogen-responsive hormone secreted by the pituitary gland that is expressed at higher levels among women than among men [19]. While its role in reproduction, including lactation, menstruation, and sexual behavior, is well characterized, prolactin also plays extensive roles in numerous other processes including immune response regulation [20]. Prolactin exhibits immunostimulatory properties and protects against inflammation under severe stress, such as trauma [21].
Whether the higher levels of prolactin found in women could underlie the gender difference in liver cancer risk is not known. Prolactin secretion, however, can be increased by domperidone, a dopamine antagonist that is commonly prescribed for the amelioration of nausea and vomiting [22,23]. Experiments in mice, one of which employed domperidone, have reported that stimulation of prolactin production decreased liver tumorigenesis [24,25]. As liver cancer rates are rising and survival rates remain poor, identification of possible chemopreventive agents could provide an effective intervention in high-risk populations. Thus, to examine the hypothesis that domperidone use, and by extension higher prolactin levels, is associated with decreased liver cancer risk in humans, a large study in a medical records database was undertaken.
Section snippets
Study population
A nested case-control study was conducted within the Clinical Practice Research Datalink CPRD, a United Kingdom (UK) database of anonymized, population-based electronic medical records. In the UK, universal health coverage is provided by the National Health Service, and the age and gender distributions in the CPRD are representative of the general UK population [26,27]. The CPRD contains medical data on approximately 8.5% of the population. Data, including demographic information, medical
Results
Overall, the median length of enrollment in CPRD was 10.3 years (range 6.5–14.6 years), with the median being slightly longer among men (10.4 years) than among women (9.9 years). Characteristics of the cases and controls are shown in Table 1. Among both men and women, cases were more likely than controls to be current smokers, have chronic HBV and/or HCV infection, have diabetes, have an alcohol related-disorder and have a rare genetic disorder. Male cases, compared to female cases, were more
Discussion
This study comprehensively evaluated the association between domperidone use and liver cancer, utilizing medical data recorded by general practitioners. Overall, no association between use of domperidone and liver cancer risk was identified. There was, however, a significantly increased risk among women who received the greatest number of prescriptions. There was no evidence of heterogeneity in the gender specific results, however, suggesting that the results among women will need confirmation
Conflict of interest
The authors declare no potential conflicts of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The research was approved by the Institutional Review Board of the National Cancer Institute. This study does not contain any animal experiments performed by any of the authors.
Submission declaration
This manuscript has not been published and is not under consideration for publication elsewhere.
Authorship contributions
Conception and design: Baiyu Yang, Barry I. Graubard, Katherine A. McGlynn
Financial and administrative support: Katherine A. McGlynn
Collection and assembly of data: Jake E. Thistle, Baiyu Yang, Jessica L. Petrick, Katherine A. McGlynn
Data analysis: Jake E. Thistle, Baiyu Yang, Katherine A. McGlynn
Data interpretation: All authors
Manuscript writing: Jake E. Thistle, Katherine A. McGlynn
Review and approval of manuscript: All authors
Grant support
NIH Intramural Research Program, National Cancer Institute
Acknowledgements
The authors wish to thank Drs. Michael B. Cook, Shahinaz Gadalla and Julia Gage of DCEG, NCI for participating in covariate creation. The authors wish to thank Emily Carver and David Ruggieri of Information Management Systems, Inc. for assistance with data curation and file preparation.
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