ABSTRACT
Background: Pruritus has been reported as an adverse drug
reaction to arsenic trioxide, but the association of arsenic exposure
with pruritus has not been systematically investigated. To investigate
the association of arsenic exposure with pruritus, we performed
observational, interventional, and Mendelian randomization studies.
Methods: A cross-sectional study was conducted in Shimen,
China. A Mendelian randomization study was conducted to confirm the
causal relationship between susceptibility to arsenic toxicity, in terms
of genetically predicted percentages of monomethylated arsenic (MMA%)
and dimethylated arsenic (DMA%) in urine, and chronic pruritus in the
UK Biobank participants. Then, a
case-control study in Shimen
participants was conducted to determine the biomarker for pruritus, and
arsenite-treated mice were used to confirm the biomarker. Last, a
randomized, double-blind, placebo-controlled trial was conducted to test
the efficacy of naloxone, a μ-opioid receptor antagonist, in
arsenic-exposed patients with pruritus in Shimen.
Results: Hair arsenic showed a dose-response relationship with
the intensity of itch in 1092 participants. The Mendelian randomization
analysis confirmed the causal relationship in the UK Biobank
participants, with odds ratios of 1.043 for MMA% and 0.904 for DMA%
above versus under median. Serum β-endorphin was identified as a
significant biomarker associated with the intensity of itch.
Consistently, treatment with arsenite in mice upregulated the level of
β-endorphin. The randomized controlled trial showed that treatment with
sublingual naloxone significantly relieved the intensity of itch in
arsenic-exposed participants.
Conclusion: Arsenic exposure is associated with
pruritus, and β-endorphin serves as
a biomarker of pruritus. Naloxone relieves pruritus in patients with
arseniasis.
Key words: arsenic exposure; β-endorphin; Mendelian
randomization; pruritus; randomized controlled trial.
INTRODUCTION
High arsenic is found in groundwater in parts of the United States,
Chile, Mexico, China, Argentina, India, and
Bangladesh1, where inorganic arsenic exposure is
reported to be associated with cancers, cardiovascular diseases,
neurological diseases, and arsenic-related skin lesions (ArSL) including
hyperkeratosis, skin cancers, and pigmentary
changes2-4. Even in low-exposure populations (water
arsenic <1 μg/L) in the US, rice consumption was associated
with higher risk of squamous cell carcinoma of skin5.
Arsenic-related pruritus was reported in very limited number of
literatures, as an adverse drug reaction
of
arsenic trioxide (As2O3) therapy among
patients with acute promyelocytic leukemia6 and
patients with multiple myeloma7, as well as a highly
frequent symptom among occupational workers with
arseniasis8. Among the epidemiologic studies in
arsenicosis regions worldwide, however, pruritus, a possible consequence
of arsenic exposure, remained nearly unstated.
After decades of economic development in China, concerns about
environmental consequences have been raised, and remarkable ecological
improvements have been achieved in recent years. Shimen, a county
located in central south China, had the largest realgar mineral in Asia.
Mines and plants mushroomed in the realgar-rich area near Heshan village
from the 1950s until 2011 when they were completely shut down by the
government due to the pollution they caused. The local government
embarked on a massive environment improvement project since 2012. In
1994, the arsenic concentration in river (the main source of drinking
water before 1985) was reported to be 14531±1232 µg/L near
Heshan9; while in 2014, the peak arsenic concentration
in river was 765 µg/L10. In spite of the successful
environmental governance, adverse health outcomes after arsenic exposure
continue to occur.
Arsenic-related cutaneous symptoms are underappreciated, and
comprehensive identification of exposure and outcomes may improve
patient prognosis. During the epidemiologic investigation in Shimen, we
noticed that many of the participants claimed unrelieved chronic
pruritus during the dermatological examination. Owing to a lack of
evidence, we performed a series of studies to confirm the causal
relationship between arsenic exposure and chronic pruritus.
METHODS