If you asked me to name the most important cutaneous adverse reactions to the thiazide diuretic hydrochlorothiazide (HCTZ), my immediate response would be a photolichenoid eruption (1) and subacute cutaneous lupus (2). Non-melanoma skin cancer (NMSC) would not have been mentioned – increasing data suggests that it should.
As Pedersen et al note, HCTZ is one of the most frequently used diuretic and antihypertensive drugs in the United States and Western Europe. It is a known photosensitizer. Because of prior reports linking HCTZ to lip cancer, the authors examined the association of HCTZ and the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The authors identified patients with NMSC from the Danish Cancer Registry (2004-2012). Controls were matched 1:20 by age and sex. Cumulative hydrochlorothiazide use was assessed. Using conditional logistic regression, they calculated odds ratios (ORs) for BCC and SCC associated with hydrochlorothiazide use. A high use of hydrochlorothiazide (≥50,000 mg) was associated with ORs of 1.29 for BCC and 3.98 for SCC. A clear dose-response relationship between hydrochlorothiazide use and both BCC and SCC was noted; the highest cumulative dose category (≥200,000 mg of HCTZ) had ORs of 1.54 and 7.38 for BCC and SCC, respectively. Use of other diuretics (including furosemide – which also has a sulfa moiety) and antihypertensives was not associated with NMSC. Patients under age 50 had the highest ORs, which further supports the association. The authors concluded that HCTZ use is associated with a substantially increased risk of NMSC, especially SCC. (3)
In their search of EMBASE and MEDLINE, Cognetta et al found 3 studies demonstrating an increased risk of SCC or lip cancer. Using HCTZ for more than 5 years was associated with the highest risk. (4)
In a study of 58,213 white patients, of whom 2,291 had BCCs, a significantly increased risk of BCC associated with diuretic use (hazard ratio 1.22) was found. Interestingly, this was noted in overweight and obese patients, suggesting that those patients may have required higher dosages for a longer duration. (5). Unfortunately, there was no breakdown of which diuretics were used.
Not all authors have reached the same conclusions.
Gandini et al performed a meta-analysis to determine which antihypertensive drugs might be associated with skin cancer. They found that calcium channel blocker (CCB) users were at increased NMSC risk with a summary relative risk (SRR) of 1.14, and beta-blocker users were at increased risk of developing cutaneous melanoma (SRR) 1.21 (Melanoma risk is worthy of a separate discussion). There was no association between thiazide diuretics, angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) use and skin cancer risk. The authors concluded that family doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and beta-blockers and instruct them to perform periodic skin self-examination (6)
Although these are conflicting data, if you accept the proposition that HCTZ is associated with NMSC, the proposed mechanism for the drug to cause cancer is UV-induced dissociation of its chlorine substituent leading to free radical formation and DNA damage. (4)
As practicing dermatologists, what should do with this information? That answer will become clearer when prospective studies are performed in people of all skin types with different classes of antihypertensive agents. Every day I have multiple patients taking HCTZ. While I have no qualms requesting discontinuation of the drug for those patients with severe cutaneous adverse reactions, should we recommend that other patients be cease taking HCTZ?
I believe that Cognetta et al articulated the right approach by stating that “it may be prudent to recommend alternative antihypertensive medications in non-Hispanic whites with a strong history of skin cancer until further studies delineate the correlation. For patients who may not be taken off HCTZ, or those with lower risk, counseling on the possible association between HCTZ and lip cancer/SCC to reinforce the need for sun protection to include the use of lip products that contain sunscreen may be warranted.” (4)
I asked Dr. Daniel Hyman, head of General Internal Medicine at Cooper Medical School of Rowan University, to read the article by Pedersen et al. He commented that “I was aware of the photosensitivity aspect of HCTZ but not the association with NMSC. The present guidelines recommend first line pharmacologic treatment choices for HTN being either thiazides, ARBs, ACEI or CCB. I think the majority of us are going with ACEI now unless there is a contraindication. I will generally use HCTZ as an add on later if control is inadequate. I will use HCTZ more often in African American patients. I would be curious whether HCTZ increases risk in AA pts. After reading this article, I will likely prescribe thiazides less in first line treatment of HTN. The heading for the latest guidelines is below. [J Am Coll Cardiol. 2017 Nov 7. pii: S0735-1097(17)41519-1].” Two outstanding internists at Cooper, Drs. Nancy Beggs and Rosemarie Leuzzi agreed with Dr. Hyman’s assessment.
- Johnston GA, Coulson IH. Thiazide-induced lichenoid photosensitivity. Clin Exp Dermatol 2002; 27: 670-2.
- Lowe G, et al. A systematic review of drug-induced subacute cutaneous lupus. Br J Dermatol 2011; 164: 465-72.
- Pedersen SA, et al. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-contol study from Denmark. 2018; 78: 673-81.
- Cognetta AB, et al. Hydrochlorothiazide use and skin cancer: A Mohs surgeon’s concerns. Dermatol Surg 2016; 1107-9.
- McDonald E, 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.
- Gandini S, et al. Anti-hypertensive drugs and skin cancer risk: A review of the literature and meta-analysis. Crit Rev Oncol Hematol 2018; 122: 1-9.
Point to Remember: Recent studies suggest that long-term exposure to HCTZ increases the risk of NMSC, especially SCC.
*The image of the structure of HCTZ is from Wikimedia Commons; the blood pressure cuff is from Pixabay
Dermatology Insights and Inquiries (DI&I) is the 2017 Recipient of the AAD Sulzberger Dermatologic Institute and Education Grants Committee’s Program for Innovative Continuing Medical Education in Dermatology (PICMED) Grant. The PICMED project and DI&I are funded by an endowment established by the Skin Disease Education Foundation and the Elsevier Foundation.