|Year : 2021 | Volume
| Issue : 4 | Page : 264-268
Long-term hydrochlorothiazide use and risk of cutaneous neoplasms
Heber Rew Bright1, Sujith J Chandy2, Renu George3, Meera Thomas4, Pradeep Rajkumar1, Anju George3
1 Department of Pharmacy, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pharmacology and Clinical Pharmacology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||16-Apr-2021|
|Date of Decision||30-May-2021|
|Date of Acceptance||16-Jun-2021|
|Date of Web Publication||07-Dec-2021|
Dr. Heber Rew Bright
Department of Pharmacy, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Hydrochlorothiazide is a diuretic commonly used in the treatment of hypertension. Recently, there have been published reports of hydrochlorothiazide-induced cutaneous neoplasms among Caucasians. We therefore investigated the risk for cutaneous neoplasms with hydrochlorothiazide use among the Indian population. Methods: We conducted a case–control study comparing hydrochlorothiazide use among patients diagnosed with cutaneous neoplasms between 2008 and 2017. Patients who underwent skin biopsy and had a pathological diagnosis of either nonmelanoma skin cancers or mycosis fungoides were matched with control patients without a skin cancer diagnosis in a 1:1 ratio. Hydrochlorothiazide use, its dose, and duration of use were compared between the groups. Odds ratio (OR) and 95% confidence intervals (CIs) for cutaneous neoplasms were calculated. Results: Among 90 patients in each group, 7 cases (7.78%) and 7 controls (7.78%) had hydrochlorothiazide exposure for at least 30 days, up to 1 year before cancer diagnosis (OR 1.0, 95% CI 0.34–2.98). Cumulative dose (P = 0.242) and duration of hydrochlorothiazide use (P = 0.08) did not differ between cases (n = 6) and controls (n = 5). There was a trend toward increasing risk of cutaneous neoplasms with high cumulative dose (≥25,000 mg) of hydrochlorothiazide (57.14% vs. 14.29%). The groups were similar with respect to comorbidities and concomitant drug intake; however, cases included more homemakers than controls (P = 0.008). Among hydrochlorothiazide-exposed cases, the body site of basal cell carcinoma involvement was predominantly the head/neck (n = 2; 66.67%), followed by the trunk (n = 1; 33.33%). Conclusion: The current findings did not find an association between long-term hydrochlorothiazide use and occurrence of cutaneous neoplasms.
Keywords: Basal cell carcinoma, hydrochlorothiazide, mycosis fungoides, skin cancer, squamous cell carcinoma
|How to cite this article:|
Bright HR, Chandy SJ, George R, Thomas M, Rajkumar P, George A. Long-term hydrochlorothiazide use and risk of cutaneous neoplasms. Curr Med Issues 2021;19:264-8
|How to cite this URL:|
Bright HR, Chandy SJ, George R, Thomas M, Rajkumar P, George A. Long-term hydrochlorothiazide use and risk of cutaneous neoplasms. Curr Med Issues [serial online] 2021 [cited 2022 Jan 22];19:264-8. Available from: https://www.cmijournal.org/text.asp?2021/19/4/264/331826
| Introduction|| |
Hydrochlorothiazide is a thiazide diuretic commonly used in the treatment of essential hypertension for several decades. Recently, there have been published reports on hydrochlorothiazide-induced nonmelanoma skin cancers (NMSCs),, and other cancers involving skin manifestations such as mycosis fungoides (MF). These cutaneous neoplasms were found to be associated with long-term and high cumulative usage of hydrochlorothiazide. Recent evidence has also prompted certain regulatory agencies including European Medicines Agency, Medsafe, Health Canada, and US FDA to strengthen the text regarding the risk of skin cancer on the package-inserts of hydrochlorothiazide-containing products.
Incidence rates of cutaneous neoplasms, in general, may vary across different geographical regions, and the risks are dependent on several factors including skin phenotypes. However, all available evidence supporting hydrochlorothiazide-induced skin cancer is based on observations predominantly from Caucasians. The generalizability of this finding across populations with varying skin phenotypes may therefore be inappropriate. Through this case–control study, we intended to identify the possible risk for skin cancer, if any, among the Indian population with a medication history of long-term hydrochlorothiazide use.
| Materials and Methods|| |
Study setting, population, and case ascertainment
The study was conducted in a large tertiary care teaching hospital that caters to patients from all parts of India and neighboring regions.
Eligible case patients included those with pathologically confirmed NMSCs including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) or MF. Cases were sequentially chosen from those patients who underwent skin biopsy between January 2008 and December 2017. The study protocol was approved by the institutional review board with waiver of informed consent due to the retrospective nature of data collection.
For all patients with a diagnosis of SCC, BCC, or MF, we manually reviewed their medical records. We excluded patients if they were less than 18 years at the time of skin biopsy and had a cancer diagnosis before or within 1 year of hydrochlorothiazide use, history of organ transplantation, diagnosis of HIV/AIDS, or azathioprine use.
The control group consisted of patients with a history of skin disease of any pattern requiring a skin biopsy, but not resulting in a pathological diagnosis of any form of skin cancer. Subsequent to enrolment of a case, one eligible control patient who underwent skin biopsy during the same time period was enrolled and matched in a ratio of 1:1.
We considered cases and controls to be exposed to hydrochlorothiazide, if they had filled at least one prescription for any hydrochlorothiazide containing drug product for a minimum of 30 days and at least 1 year before skin biopsy or the occurrence of BCC, SCC, or MF in cases. The 1-year lag period was to allow for a reasonable induction period for an effect on cancer risk. Hydrochlorothiazide exposure was ascertained by reviewing pharmacy transactions of individual patients and by telephonic patient interview. We defined high use of hydrochlorothiazide use as, filled prescriptions equivalent to ≥25,000 mg, corresponding to at least 3 years of cumulative use (1000 defined daily doses [DDD]).
Patient demographics, date of cancer diagnosis, and comorbidities were obtained from the hospital's electronic medical records. Hydrochlorothiazide use including frequency, duration, and cumulative dose was obtained by reviewing pharmacy transactions and telephonic patient interviews.
We used conditional logistic regression analysis to compute OR with 95% CI, for the primary outcome of NMSCs or MF associated with hydrochlorothiazide use. We examined the dose–response relationship according to the predefined stratification of cumulative hydrochlorothiazide use: ≥25,000 mg (high use) corresponding to 3 years of use (1000 DDD) and <25,000 mg. We analyzed NMSCs and MF together as a group.
| Results|| |
A total of 90 patients with a diagnosis of either BCC (n = 53), SCC (n = 20), or MF (n = 17) were considered as cases. These patients were matched on time of skin biopsy with 90 control patients without skin cancer diagnosis. The mean age of cases (55.53 ± 13.24) and controls (45.16 ± 14.21) differed significantly (P < 0.001). Gender distribution of the patients between groups also differed significantly (P = 0.008). With respect to occupation, the group classified as homemakers registered a significantly higher risk for skin cancer than did the remaining occupations (OR 2.82, 95% CI 1.35–5.88). Cases and controls were similar with respect to comorbidities and concomitant drug intake [Table 1].
Eventually, 7 cases (7.78%) and 7 controls (7.78%) were found to have been exposed to hydrochlorothiazide for at least 30 days (OR 1.0, 95% CI 0.34–2.98). Although we observed a difference in high use of hydrochlorothiazide between the groups among 6 cases and 5 controls for whom the cumulative hydrochlorothiazide dose was known, this did not reach statistical significance (P = 0.242). Among hydrochlorothiazide users, we noted an upward trend of high use among cases (57.14% vs. 14.29%). Due to the limited statistical power, we precluded further dose–response analyses [Table 2]. Duration of hydrochlorothiazide use did not differ between groups (P = 0.08). Among cases exposed to hydrochlorothiazide, relatively, more patients had MF (n = 4; 57.14%), followed by BCC (n = 3; 42.86%). The four MF patients were staged as T1aN0M0, T1aN0M0B0, T2bN0M0, and T4N2M0B1. The body site of BCC involvement was predominantly the head/neck (n = 2; 66.67%), followed by the trunk (n = 1; 33.33%).
|Table 2 Association between hydrochlorothiazide use and cutaneous neoplasms|
Click here to view
| Discussion|| |
To the best of our knowledge, this is the first data on skin cancer risk with long-term use of hydrochlorothiazide among Indian population. Our findings reveal no evidence of increased risk of any of the skin cancers investigated. The body site of cutaneous BCC localization observed in our hydrochlorothiazide-exposed cases was predominantly the head/neck and limbs, which is more likely to be exposed to sunlight in comparison to the trunk. Although the preponderance of sun exposed skin supports the possibility of hydrochlorothiazide-induced skin cancer which is said to be mediated through its photosensitizing effect, this needs further investigation, as all these patients were either homemakers or professionals who are less likely to have had continuous sunlight exposure unlike those involving outdoor occupations. Although not statistically significant, there was some evidence of increased risk of skin cancer with high cumulative use of hydrochlorothiazide.
Friedman et al. in 2012 first reported an increased risk of lip cancer among non-Hispanic Whites who were on hydrochlorothiazide therapy for more than 1 year. However, this study did not account for the types of skin cancer such as BCC and SCC. Findings from a contemporary large prospective population-based study revealed no increased risk of BCC with hydrochlorothiazide use among Caucasians. In contrast, a prospective questionnaire-based study found an association between photosensitizing diuretics and BCC. That study, however, investigated the class effect rather than individual drugs among White Americans. Hence, it was not known if hydrochlorothiazide had an increased risk for BCC. Later, based on observations from four non-Hispanic White male patients, a publication by the American Society for Dermatologic Surgery reported hydrochlorothiazide use as a potential cause for SCC.
Recently, two large Danish case–control studies that obtained data from the same databases found a strong association between long-term hydrochlorothiazide use and NMSCs including both BCC and SCC., These studies carried out in Caucasians found hydrochlorothiazide to have increased the risk of skin cancer, in particular for SCC in a dose-dependent manner.
In addition to BCC and SCC, a prospective analysis which predominantly included Caucasians found increased hydrochlorothiazide use among patients who developed MF. This study also noted a causal relationship in which a substantial number of patients (28.8%) at least had a marked improvement of their lesions after discontinuation of hydrochlorothiazide. The findings of our study are in contrast to all the above findings from Europe and America, probably due to the ethnic difference in study population. Although not very common, disparities in adverse reactions among different ethnic groups have been previously reported with other drugs such as ACE inhibitors, where Black patients are more likely to develop adverse reactions than others. Darker skinned populations including Asians are generally less likely to develop cutaneous neoplasms primarily due to photo-protection provided by increased epidermal melanin. This protective effect of melanin would probably help mitigate any skin cancer inducing potential of photosensitizing drugs such as hydrochlorothiazide.
The risk of hydrochlorothiazide-induced skin cancer among ethnic groups other than Caucasians was not studied until recently where hydrochlorothiazide was found to be safe in Taiwanese population with an odds ratio of 0.86 (95% CI 0.09–7.81) and Korean population with a hazard ratio of 0.96 (95% CI 0.91–1.02). Our findings also corroborate with these Asian data, thereby together implying a potential role of ethnicity in hydrochlorothiazide-induced skin cancer.
There are certain limitations of importance in our study. First, the deficiency of a nationwide and comprehensive patient data system restricted analysis of data from only a relatively small sample size at a single tertiary care center. However, to negate any negative effect due to this, we calculated and included the minimum sample size required to find any statistical difference. Second, the increased risk of skin cancer with hydrochlorothiazide observed in previous studies was significantly more pronounced for SCC compared with other types of skin cancer, and hence, the combined analysis of BCC, SCC, and MF in our study might mask a true increased risk of any one of these. Third, confounders such as age and gender that significantly differed between our study groups could have influenced the results.
| Conclusion|| |
The study did not find an association between long-term hydrochlorothiazide use and occurrence of cutaneous neoplasms. This important finding will help dermatologists in decision-making on hypertensive patients with a medication history of hydrochlorothiazide use and newly diagnosed with cutaneous neoplasms.
We thank C. Nivetha, M. Ramya, Neha Mary Dilson, and Beyona Baby for their contribution during patient interviews.
Research Quality and Ethics Statement
The authors of this manuscript declare that this scientific work complies with reporting quality, formatting and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board, and the corresponding protocol/approval number is 11239. We also certify that we have not plagiarized the contents in this submission and have done a plagiarism check.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Arnspang S, Gaist D, Johannesdottir Schmidt SA, Hölmich LR, Friis S, Pottegård A. Hydrochlorothiazide use and risk of non-melanoma skin cancer: A nationwide case-control study from Denmark. Am Acad Dermatol 2018;78:673-681.e9.
Pottegård A, Hallas J, Olesen M, Svendsen MT, Habel LA, Friedman GD, et al.
Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med 2017;282:322-31.
Jensen AØ, Thomsen HF, Engebjerg MC, Olesen AB, Sørensen HT, Karagas MR. Use of photosensitising diuretics and risk of skin cancer: A population-based case-control study. Br J Cancer 2008;99:1522-8.
Jahan-Tigh RR, Huen AO, Lee GL, Pozadzides JV, Liu P, Duvic M. Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series. Cancer 2013;119:825-31.
Bradford PT. Skin Cancer in Skin of Color. Dermatol Nurs Dermatol Nurses Assoc 2009;21:170-8.
Friedman GD, Asgari MM, Warton EM, Chan J, Habel LA. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med 2012;172:1246-51.
Ruiter R, Visser LE, Eijgelsheim M, Rodenburg EM, Hofman A, Coebergh JW, et al.
High-ceiling diuretics are associated with an increased risk of basal cell carcinoma in a population-based follow-up study. Eur J Cancer 2010;46:2467-72.
McDonald E, Freedman DM, Alexander BH, Doody MM, Tucker MA, Linet MS, et al.
Prescription diuretic use and risk of basal cell carcinoma in the nationwide U.S. radiologic technologists cohort. Cancer Epidemiol Biomarkers Prev 2014;23:1539-45.
Cognetta AB Jr., Wolfe CM, Heinrichs E. Hydrochlorothiazide use and skin cancer: A mohs surgeon's concern. Dermatol Surg 2016;42:1107-9.
Ogedegbe G, Shah NR, Phillips C, Goldfeld K, Roy J, Guo Y, et al.
Comparative effectiveness of angiotensin-converting enzyme inhibitor-based treatment on cardiovascular outcomes in hypertensive blacks versus whites. J Am Coll Cardiol 2015;66:1224-33.
Pottegård A, Pedersen SA, Schmidt SAJ, Lee CN, Hsu CK, Liao TC, et al.
Use of hydrochlorothiazide and risk of skin cancer: A nationwide Taiwanese case-control study. Br J Cancer 2019;121:973-8.
Park E, Lee Y, Jue MS. Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: A nationwide retrospective cohort study from Korea. Korean J Intern Med 2020;35:917-28.
[Table 1], [Table 2]