Authors: Ai-bo Qin, Li Liu, Bi-xia Gao, Tao Su
Categories: Letter to the Editor
Source: Renal Failure
Mercury is a toxic heavy metal in elemental, inorganic, and organic forms. However, non-occupational chronic mercury poisoning remains a poorly understood health problem in developing countries [1,2]. Chronic inorganic mercury exposure can lead to systemic accumulation with associated neurotoxicity, nephrotoxicity, and gastrointestinal toxicity. Diagnosis is easily missed or delayed because of its insidious onset, subtle manifestations, and lack of recognition in traditional examinations, even when multiple organs are involved. Here, we present a case of chronic inorganic mercury poisoning associated with nephrotic syndrome, recurrent abdominal pain, and progressive neuropsychiatric symptoms.
A 73-year-old man was admitted to the department of nephrology for investigation of nephrotic syndrome. The patient complained of progressive peripheral edema and neuropsychiatric symptoms including hypersomnia, slow reactions, memory loss, and agitated delirium over the past months. Unexplained abdominal pain occurred irregularly. His medical history included three years of hypertension and chronic dermatitis of the lower extremities bilaterally, with no history of diabetes mellitus, chronic glomerulonephritis, inflammatory bowel disease, or cerebrovascular disease. The patient denied alcohol abuse. Home medication included metoprolol for hypertension and a self-made ointment for dermatitis used during the past 6 months. He was a farmer and denied the history of mercury exposure.
Physical examination revealed normal blood pressure. No abnormalities were observed in oral or gingival mucosa. Moderate edema was observed in both legs. The abdomen was soft. Laboratory tests showed a daily urinary protein of 10.8 g, serum albumin of 19.0 g/L, and normal serum levels of creatinine, electrolytes, and glycosylated hemoglobin (Table 1). No monoclonal immunoglobulins were detected. Antibodies against PLA2R, ANCA, and ANA were also absent. The patient was initially admitted with the aim of performing a renal biopsy, but he suffered from multiple episodes of abdominal pain accompanied by frequent irregular occurrence of diarrhea throughout the day during the first week of hospital stay. However, no significant abnormalities were found on abdominal contrast-enhanced CT tomography or cerebral magnetic resonance imaging. Toxicological tests using inductively coupled plasma mass spectrometry (ICP-MS) detected very high levels of mercury in the blood, urine, and ointment samples at concentration of 24.7 ng/ml (blood, < 2.5 ng/ml), 33.4 ng/ml (urine, < 15 ng/ml), and 7.5 × 10^3^ mg/kg (national standard < 1 mg/kg), respectively. Based on the multi-organ symptoms of kidney, gastrointestinal, and neuropsychiatric disorders, chronic mercury poisoning was diagnosed. We planned to assess the patient’ cognitive function using the Mini-Mental State Examination Scale. However, communication barriers prevented him from cooperating to complete the scale. The patient was administered losartan 50 mg daily and five courses of chelation therapy with 2,3-dimercapto-1-propanesulfonic acid intravenously (0.25 g once daily for three consecutive days, followed by a 4-day interval). Blood and urinary mercury concentrations declined rapidly to 4.2 ng/ml and 1.9 ng/ml in five weeks, respectively. The symptoms of hypersomnia and abdominal pain were relieved, and the symptoms of unresponsiveness and agitated delirium partially improved. Three months after post-chelation therapy, the daily urinary protein level declined to 3.2 g (Figure 1). Unfortunately, laboratory tests were not repeated after the symptoms resolved. The patient self-reported that he was completely free of edema, had no trouble walking, had no obstacles in language communication, and was in a good condition.
Chronic inorganic mercury-associated nephrotoxicity has been reported to involve glomerular podocytes. Common pathological findings include minimal change disease, membranous nephropathy, and focal segmental glomerular sclerosis [3]. It is well-known that immune mechanisms play important roles. The kidneys are the major sites of inorganic mercury deposition; however, mercury itself has not been identified within immune complexes, suggesting that the deposition of immune complexes is secondary to the activation of the immune system by mercury [1]. In highly susceptible mice, mercury-induced membranous glomerulonephritis is characterized by T cell-dependent polyclonal B cell activation, which is induced mainly by increased levels of IgG and IgE antibodies, production of ANA, and the formation of immune complex deposits in the kidneys [4, 5]. Electron micrographs of glomerular capillaries revealed that patients with mercury-associated minimal change disease had mild podocyte effacement. They had a lower relapse rate despite sharing similar clinical and routine pathological characteristics with patients with primary minimal change disease [6]. High mercury concentrations over a short duration directly damage podocytes and tubular epithelial cells, whereas chronic exposure to low mercury concentrations induces membranous nephropathy via immune mechanisms. Another opinion is based on the influence of increasing atmospheric mercury pollution on the development of kidney diseases [7]. More importantly, nephrologists should keep in mind that mercury is a reversible cause of glomerular diseases and that toxicological tests should not be ignored when investigating proteinuria.
Neurotoxicity associated with mercury is predominantly triggered by its elemental and organic forms [8]. This is because inorganic mercury salts demonstrate inadequate penetration of the blood-brain barrier. However, sustained exposure to inorganic mercury may lead to its accumulation in the central nervous system, thereby eliciting various symptoms [9]. Damage to the nervous system induced by inorganic mercury poisoning can manifest in various forms, including fatigue, headache, insomnia, polyneuropathy, myalgia, irritability, tremors, memory loss, and depression. Experimental data from in vivo and in vitro studies on Alzheimer’s disease strongly suggest that inorganic mercury can adversely affect the nervous system [S1]. Mercury ions react with the sulfhydryl groups to form mercaptides. It is an important protective element that maintains the balance between oxidation and reduction in the brain. Consequently, this reaction potentially interferes with cellular metabolism by inactivating sulfhydryl enzymes. Given the high consumption of oxygen by the brain and the need for antioxidants, prolonged cerebral accumulation of inorganic mercury could exacerbate neurodegenerative disorders due to its strong affinity for selenium and selenoprotein and its potential for inducing oxidative stress [S2]. In a previous study, a 91-year-old man diagnosed with Alzheimer’s disease exhibited cognitive decline and dangerously elevated mercury levels as a result of consuming fish with high mercury levels. Fascinatingly, his cognitive impairment resolved significantly as the methylmercury level decreased after adjusting his diet and undergoing detoxification [S3]. In our study of a Chinese patient cohort with mercury-associated glomerulonephritis, the majority of patients were female, had a history of exposure to facial creams containing excessive mercury, and a few reported nervous system disorders [3]. In particular, our current patient exhibited memory loss, slow response times, and agitated delirium, similar to the symptoms associated with Alzheimer’s disease. However, the neuropsychiatric symptoms significantly improved after chelation therapy. The characteristics of the reported cases of inorganic mercury-induced neuropsychiatric diseases are summarized in Table 2.
The public has access to commercial products containing dangerously high levels of mercury chloride and mercurous oxide (both forms of inorganic mercury). These include non-compliant skin-lightening creams and medical ointments, particularly in developing countries. In this case report, we highlight the importance of thoroughly investigating the patients’ home medication use and performing the necessary toxicological tests if the patient demonstrates symptoms of glomerular diseases and unexplained neuropsychiatric conditions. This is crucial, because chronic mercury poisoning is ultimately treatable and preventable. Therefore, this issue warrants greater attention from the public and clinicians to avoid misdiagnosis.
This study was supported by the Scientific Research Seed Fund of Peking University First Hospital (2021SF28) and CAMS Innovation Fund for Medical Sciences (Grant Number:2019-I2M-5-046). The funders played no role in the study design, data collection, analysis, interpretation of data, decision to publish, or manuscript preparation.
Studies involving human participants were reviewed and approved by the Ethics Committee of Peking University First Hospital. Written informed consent was obtained from the patient for publication of this case report.
No potential conflict of interest was reported by the author(s).