Dermatology

Heavy Metal Dermatoses: Mercury(Mercury dermatosis: Hydrargyria, mercurialism, acrodynia, "pink disease," Mad Hatter’s disease, Hatter’s disease, Minamata disease)

Are You Confident of the Diagnosis?

What you should be alert for in the history?

The heavy metal dermatoses are a heterogeneous group of skin diseases related either to direct contact with or systemic absorption of heavy metals. Topical exposure can result in contact dermatitis. Dermatosis can also be due to systemic absorption (via skin, inhalation or ingestion). This report focuses on cutaneous manifestations associated with the two common metals of mercury and arsenic.

A history of exposure to cosmetic products or homeopathic regimen or contaminated seafood (fish) should prompt further investigations. Nevertheless, symptomatology of mercury poisoning is frequently not recognized, delaying effective therapeutic intervention.

Mercury is not required for any human physiologic process.

Characteristic findings on physical examination

Mercury exposure and cutaneous disease has been described. Stomatitis and systemic dermatitis are associated. Early cutaneous changes include pink color on tips of the fingers, toes and nose, and significant pain of the hands and feet. These two distinct features are responsible for the synonyms of “acrodynia” and “pink disease.” Pruritus can lead to excoriation and lichenification as children constantly rub and scratch at their skin. Scalp hair is often pulled out. Later, the hands and feet swell and become dusky pink. Eventually the palms and feet desquamate. Gums may be swollen, erythematous and focally eroded. Teeth and nail loss may occur.

Primary and intensely erythemato-exudative lesions of the pubic region and genitals were associated with inverted erythema of the upper inner thighs and, in severe cases, involvement of the face, neck, trunk and major flexures. Eruptions included exanthematic, papulo-vesicular, purpuric and erythema-multiforme-like clinical features. Patients also presented with general malaise and pyrexia.

Expected results of diagnostic studies

Blood is used to determine acute mercury exposure because the half-life of mercury in blood is short. Accurate diagnosis also requires analysis of 24-hour urine mercury by atomic absorption. Urine tests provide the best estimate of the current body burden of chronic mercury exposure. A positive patch test reaction to ammoniated mercury was often observed in patients with cutaneous manifestations. Nevertheless, patch testing for mercury hypersensitivity is associated with false-positive reactions due to the irritant nature of some of the mercury salts.

Therefore, simultaneous patch testing with several mercury compounds in petrolatum are recommended. They may include mercuric chloride, metallic mercury, ammoniated mercury, phenylmercuric acetate, thimerosal and amalgan powder. Mercurials are not included in the North American or the European standard patch test series.

The exposure of mercury over time can be estimated by measuring the mercury in long strains of hair as hair grows at a rate of approximately 1cm/month.

Blood samples must be collected in a heparinized container and refrigerated. A blood mercury level greater than or equal to 5mcg/dL is considered the toxic threshold in adults.

The range of urinary mercury that can be associated with adverse effects in adults has been determined. Urinary mercury less than 20mcg/L (<100nmol/L) is usually not associated with symptomatology.

Between 20 to 100mcg/L, decreased response on tests for nerve conduction, brain wave activity, and verbal skills may be observed; between 100 to 500mcg/L, irritability, depression, memory loss, minor tremor, and other nervous system disturbances. Kidney function may be disturbed. Between 500 to 1000 mcg/L, significant tremor and nervous system disturbances, kidney inflammation, swollen gums or gingivitis may develop.

Urinary or blood measurements in subjects who have chronic mercury exposure may not correlate with symptomatology of mercury toxicity because the mercury may be in an un-exchangeable tissue compartment. Some clinical features of mercury poisoning are irreversible, and the current body burdens of mercury may not represent past mercury exposure.

Diagnosis confirmation

Inflammatory and infectious conditions, such as Kawasaki disease and staphylococcal scalded skin syndrome may mimic the dermatologic manifestations of the disease. Intoxication with cocaine and hallucinogens may also have similar presentation. Transition group elements and highly electropositive heavy metals such as lead and cadmium, like mercury, can act as a coordination center for electronegative groups (SH groups and disulfide bridges, cysteinyl and histidyl residues) present in proteins, purines, and pteridines and cause immunogenicity with resultant contact hypersensitivity.

Who is at Risk for Developing this Disease?

Mercury is widespread in the environment, occurring in its elemental state (as a vapor), as inorganic mercurous or mercuric salts, and as methylmercury. The metal is toxic to humans in all its forms, and its presence in the body serves no known useful purpose. Methylmercury readily passes through cellular membranes and across the placenta and is the most toxic form of mercury.

Mercury is a common cause of heavy metal poisoning, and it can result in a wide range of organ dysfunction, including irreversible brain damage and death.

Inhalation of mercury vapors, ingestion, and contact by skin and mucosa of all types of mercury can result in systemic toxicity leading to a variety of hypersensitivity reactions and to suppressed immunoreactivity.

Acrodynia, or pink disease, is childhood mercury poisoning as a result of prolonged exposure to mercury. Inhalation of household products is a major source of poisoning. Elemental mercury may be percutaneously absorbed. Direct skin contact in children exposed to mercurial antibacterial agents has been reported. Other sources include calomel-containing teething and diaper powder, repeated gamma-globulin injections, anthelminthics, termite-protected wood, ingestion of watch batteries, and laxative use. Mercury poisoning has also been of concern in cosmetic products.

Body burden of mercury is associated with acute atopic eczema and total IgE in children from southern Germany. Environmental agents as cause of health disorders in children can be difficult to prove. One report describes a 9-month-old child who suffered from subclinical mercury poisoning caused by adulterated homeopathic medication and developed bullous pemphigoid (BP) while she was being treated for presumptive atopic eczema with a homeopathic regimen comprising sulfur, mercury, cantharides, and Rhus (Toxicodendron). She had generalized bullae and a progressive worsening of her general condition with asthenia, dehydration, malnutrition.

While the role of homeopathy in triggering the disease remains unclear, their observation attests to the potential life-threatening course of childhood BP in instances where appropriate treatment is withheld and homeopathic products are used instead.

Systemic dermatitis from mercury in amalgam dental restorations and localized lichenoid contact stomatitis have also been reported.

What is the Cause of the Disease?

Etiology

Direct exposure or systemic absorption. Mercury as amalgam is a moderate topical sensitizer. Both cell-mediated type IV or contact dermatitis and humoral type I or urticarial types of hypersensitivity are induced by mercury compounds. The most characteristic is mercury exanthema, which is a generalized eruption due to exposure to either mercury or a variety of its compounds.

Pathophysiology

The mechanisms of disease may involve adrenocortical hyperfunction and catecholamine excess. Organic forms, specifically methylmercury, are the most toxic of the three classes of mercurials: 1) elemental, mainly as a vapor; 2) inorganic mercurous or mercuric salts; 3) methylmercury.

The GI tract absorbs more than 90% of the methylmercury ingested, which then enters the bloodstream. Because mercury binds to the body’s ubiquitous sulfhydryl groups, toxicity involves multiple organ systems. Structural proteins, membranes, and enzymes are all disrupted. Methylmercury exerts its most devastating effect on the CNS by causing psychiatric disturbances, ataxia, visual loss, hearing loss, and neuropathy. Methylmercury is lipophilic and readily crosses the blood-brain and placentofetal barriers. Neurologic damage in the form of diffuse and widespread neuronal atrophy is most severe in patients exposed in utero. Necrosis of the proximal tubules is a common direct renal toxic effect.

Systemic Implications and Complications

Initial systemic manifestations include anorexia, lethargy, hypotonia, irritability, and personality changes. Increased drooling and profuse perspiration, hypertension, tachycardia, and intermittent low-grade fever may be present.

Methylmercury concentrates in red blood cells (RBCs). Consequently, a direct determination of the blood mercury concentrations is essential. The normal range of mercury concentrations in whole blood is 0 to 10mcg/L. Early signs and symptoms may occur with concentrations greater than 35mcg/L.

The severity of mercury poisoning is not always correlated with the blood concentration because of the redistribution of mercury in the tissues. The detection of mercury in the urine demonstrates that exposure has occurred; however, it does not indicate the severity of mercury poisoning. The severity of mercury’s toxic effects depends on the form and concentration of mercury and the route of exposure.

Presence of neurologic symptoms usually reflects severe elemental or methylmercury poisoning. Severe elemental mercury as a vapor causes acute lung injury and respiratory failure. Severe inorganic mercury causes caustic gastroenteritis. Renal impairments with neuropsychiatric disturbances also indicate severe methylmercury poisoning.

Treatment Options

Removal of the source of exposure, and decontamination efforts are necessary to prevent further exposure. Because of the high propensity for neurologic impairment, patients with acute mercury ingestion should undergo gastric lavage with solutions that contain proteins such as those from milk or egg whites. In addition, activated charcoal should be administered although it does not absorb heavy metals well in general.

Whole bowel irrigation, along with the administration of polyethylene glycol solution, has been shown to be useful in clearing residual mercury, as depicted on serial abdominal radiography. Depending on symptomatology and confirmative blood tests, systemic therapy may be indicated with the use of chelating agents.

Optimal Therapeutic Approach for this Disease

The local poison control facility should be contacted and care coordinated with physicians who are familiar with the use of the chelators and the necessary support and follow-up of these poisoned patients. A toxocologist should be consulted. The mainstay of treatment is chelation with substrates that contain sulfhydryl groups, which bind the mercury to facilitate its excretion in urine and stool. Nevertheless, chelation for methylmercury poisoning is not efficacious.

Chelation therapy should be used in subjects who are symptomatic from mercury or have toxic blood or urine concentrations. Chelation therapy only removes a very small percentage of the total body burden of mercury, and the efficacy of chelation in chronic elemental exposure is questionable. Chelation in acute exposures is most effective when given as soon as possible (within 3 hours) after the ingestion of mercury salts.

Currently available chelation drugs for acute mercurial poisoning include N-acetyl-D, L-penicillamine (NAP), British Anti-Lewisite (BAL), 2,3-dimercapto-1-propanesulfonic acid (DMPS), and dimercaptosuccinic acid (DMSA). DMSA is the chelator of choice in subjects who can ingest oral medications. It is efficacious with the least amount of adverse effects. BAL must be given by deep intramuscular injection and is the chelator of choice in subjects who cannot take oral medications.

Chelation with DMSA should be given for several days and then stopped several days, and repeated until the patient is symptom free. The recommended dose is 10mg/kg orally administered every 8 hours for 5 days, then every 12 hours for 14 days. Adverse drug reactions include vomiting, nausea, diarrhea, appetite loss, and transient elevations of serum aminotransferases. Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiencies has been reported, and the drug should be avoided in these patients.

BAL in oil can be used to chelate inorganic mercury (but not methylmercury). BAL is usually given 3 to 5mg/kg intramuscularly on days 1 and 2; 2.5 to 3mg/kg every 6 hours on days 3 and 4; and 2.5 to 3mg/kg every 12 hours for 1 week. Adverse reactions occur in about 50% of the patients receiving BAL; they include hypertension, tachycardia, nausea and vomiting, and headache.

Inorganic mercury can be removed from the gastrointestinal tract by emesis, catharsis, or lavage. It is important to keep the patient well hydrated to reduce the concentration of mercury in the kidneys. Chelation should be initiated as soon as possible. Peritoneal dialysis or hemodialysis should be considered in potentially lethal ingestion.

Phlebotomy has been used for iron overloading but does not remove metals from the brain. It is not used for mercury poisoning

Methylmercury damage is irreversible. Treatment is determined by the severity of the condition. The patient should be removed from the source of exposure. Treatment may involve:

--Activated charcoal (if mercury is swallowed)

--Fluids and electrolytes

--Dialysis

--DMSA

Patient Management

When patients with mercury hypersensitivity have been treated with chelation therapy and their symptoms have improved:

--Monitor the patient’s blood mercury concentrations for several months to ensure that the exposure is not ongoing. There have been no evidence-based recommendations on these. Monthly assessments for 1 to 2 months sounds reasonable.

--Maintenance therapy: Some patients may need repeated courses of treatment, a minimum of 2 weeks between courses is recommended.

Key information for family: Decontamination of the environment by state departments of health is mandatory.

Unusual Clinical Scenarios to Consider in Patient Management

Vigilance is warranted in any patients receiving homeopathic treatments, as such therapy may be adulterated with mercury.

Tunnessen et al reported the case of a 23-month boy with acrodynia following exposure to mercury from fluorescent light bulbs.

What is the Evidence?

Nakayama, H, Niki, F, Shono, M, Hada, S. "Mercury exanthem". Contact Dermatitis. vol. 9. 1983. pp. 411-7.

(We experienced 15 patients with generalized rash, mostly appearing a day or two after breaking a clinical thermometer or during dental treatment. Similar skin manifestations were revealed, suggestive at first glance of mercury exanthem, ie, diffuse symmetrical erythema predominantly on major fluxural areas. An inverted triangular or V-shaped erythema on both upper antero-medial thighs was a common feature. Severe cases had miliary pustules and/or purpura on erythematous skin. Pruritus or burning sensation was relatively mild. Pyrexia or malaise was a complaint of more than half the patients.)Most of the patients had a previous history of contact dermatitis to Mercurochrome, and by patch-testing were found to have contact allergy to several mercurials, especially inorganic ones. Until recently, Mercurochrome had been most widely used as a topical disinfectant in Japan. This seems to be a possible cause of the high incidence of contact allergy to mercurials in this country. From our findings we feel that our patients had developed systemic contact dermatitis due to inhalation of mercury vapor.)

Vena, GA, Foti, C, Grandolfo, M, Angelini, G. "Mercury exanthem". Contact Dermatitis. vol. 31. 1994. pp. 214-6.

(We have observed nine male patients with a generalized rash following the topical use of an over-the-counter antiparasitic powder [MOM], containing ammoniated [11.2g%] and metallic [4.2g%] mercury, to treat phthiriasis [lice infestation]. Primary and intensely erythemato-exudative lesions of the pubic region and genitals were associated with inverted erythema of the upper inner thighs and, in severe cases, involvement of the face, neck, trunk and major flexures. Eruptions included exanthematic, papulovesicular, purpuric and erythema-multiforme-like clinical pictures. Seven of the nine cases presented with general malaise and pyrexia. A positive patch test reaction to ammoniated mercury was observed in all cases. There are probably three routes of powder exposure behind this type of rash: direct skin contact; airborne skin contact; inhalation.)

Curtis, HA, Ferguson, SD, Kell, RL, Samuel, AH. "Mercury as a health hazard". Arch Dis Child. vol. 62. 1987. pp. 293-5.

(Pink disease has virtually disappeared since teething powders were withdrawn. We describe a case in a boy who was exposed to metallic mercury vapor. We discuss the potential health hazard of spilled elemental mercury in the house and the difficulties of removing it from the environment.)

Tunnessen, WW, McMahon, KJ, Baser, M. "Acrodynia: exposure to mercury from fluorescent light bulbs". Pediatrics. vol. 79. 1987. pp. 786-9.

(Medical attention was sought for a 23-month-old toddler because of anorexia, weight loss, irritability, profuse sweating, peeling and redness of his fingers and toes, and a miliarial rash. The diagnosis was mercury poisoning, and an investigation of his environment disclosed that he had been exposed to mercury from broken fluorescent light bulbs. Acrodynia resulting from fluorescent bulbs has not been previously reported.)

Dinehart, SM, Dillard, R, Raimer, SS, Diven, S, Cobos, R, Pupo, R. "Cutaneous manifestations of acrodynia (pink disease)". Arch Dermatol. vol. 124. 1988. pp. 107-9.

(A 14-month-old girl who presented with multiple systemic complaints was found to have gingivitis, peeling of her palms and soles, and a peculiar acral eruption. A diagnosis of acrodynia, or pink disease, was confirmed by elevated levels of mercury in the urine. The many cutaneous manifestations of this once common disease are discussed.)

Am Fam Physician. vol. 46. 1992. pp. 1731-41.

(Because mercury has several forms and because it produces subtle effects at chronic low-level exposures, mercury toxicity can be a difficult diagnosis to establish. Elemental mercury vapor accounts for most occupational and many accidental exposures. The main source of organic methylmercury exposure in the general population is fish consumption. Children are at increased risk of exposure to elemental mercury vapor in the home because it tends to settle to the floor. The chemical and physical forms of mercury determine its absorption, metabolism, distribution and excretion pathways. The central nervous system and kidneys are key targets of mercury toxicity. Chelation therapy has been used successfully in treating patients who have ingested mercury salts or inhaled elemental mercury. There is no antidote for patients poisoned with organic mercury.)

Mucklow, ES. "Mercury as a health hazard". Arch Dis Child. vol. 63. 1988. pp. 1416-7.

(A case of ammoniated mercury intoxication)

Graeme, KA, Pollack, CV. "Heavy metal toxicity, Part I: arsenic and mercury". J Emerg Med. vol. 16. 1998. pp. 45-56.

(This review is Part I of a two-part series focusing on heavy metal toxicity. Part I will cover arsenic and mercury toxicity. Acute and chronic arsenic toxicity, as well as arsine gas toxicity, will be reviewed. The clinical presentation, with focus on the nervous, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, hematopoietic, and dermatologic systems, is delineated. Mercury exposure, including exposure to short chain alkyl mercury, elemental mercury, and acute inorganic salt, is reviewed. The discussion of clinical toxicity focuses on the nervous, cardiovascular, pulmonary, gastrointestinal, and renal systems, as well as on the teratogenic effects of mercury. Recommendations for diagnostic tests and management plans are discussed, including chelation regimens.)

Boyd, AS, Seger, D, Vannucci, S, Langley, M, Abraham, JL, King, LE. "Mercury exposure and cutaneous disease". J Am Acad Dermatol. vol. 43. 2000. pp. 81-90.

(Human contact with mercury has been ongoing for centuries and was previously considered a legitimate means of treating different cutaneous and systemic conditions. Toxicity from this heavy metal may occur from exposure to elemental, inorganic, and organic forms of mercury. This article outlines the signs and symptoms of mercury poisoning and the different clinical conditions with assorted cutaneous findings.)

Swaiman, KF, Flagler, DG. "Mercury poisoning with central and peripheral nervous system involvement treated with penicillamine". Pediatrics. vol. 48. 1971. pp. 639-42.

(The report summarizes the case of a 14-year-old boy who developed acrodynia during the first year of life from topical ammoniated mercury ointment, and developed the Guillain Barre syndrome from chronic mercury vapor poisoning beginning at age eleven. The patient was successfully treated with penicillamine, which prompts mercury excretion and reduces symptoms.)
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