Research: Kawasaki’s Disease, Acrodynia and Mercury

acrodynia (2) (140x105)Written and reproduced by kind permission of Dr Joachim Mutter MD PhD et al.

Click for the PDF of the complete, fully referenced version of this article about Kawasaki’s disease.

Abstract

A superantigen or autoimmunity has been hypothesised to be the main cause of the Kawasaki`s Disease but the aetiology is unknown. Medical literature, epidemiological findings, and some case reports have suggested that mercury may play a pathogenic role. Several patients with Kawasaki`s Disease have presented with elevated urine mercury levels compared to matched controls. Most symptoms and diagnostic criteria which are seen in children with acrodynia, known to be caused by mercury, are similar to those seen in Kawasaki´s Disease. Genetic depletion of glutathione S-transferase, a susceptibility marker for Kawasaki´s Disease, is known to be also a risk factor for acrodynia and may also increase sus- ceptibility to mercury. Coinciding with the largest increase (1985-1990) of thimerosal (49.6% ethyl mercury) in vaccines, routinely given to infants in the U.S. by 6 months of age (from 75µg to 187.5µg), the rates of Kawasaki´s Disease increased ten times, and, later (1985-1997), by 20 times. Since 1990 88 cases of patients developing Kawasaki´s Disease some days after vaccination have been reported to the Centers of Disease Control (CDC) including 19% manifesting symptoms the same day. The presented pathogenetic model may lead to new preventive and therapeutic strategies for Kawasaki´s disease.

Introduction

Kawaski’s Disease (KD), first described in Japan (1967), is an acute febrile multiorgan vasculitis, which predominantly (75 – 80%) affects children younger than 5 years. The disease has an increasing frequency and, in developed countries, has surpassed rheumatic fever as the leading cause of acquired heart disease in children. Early intravenous immunoglobulins in combination with acetyl-salicylic acid have significantly reduced the prevalence of coronary artery abnormalities.

There is no test for diagnosing KD; thus the diagnosis is based on clinical signs and symptoms. Despite of this, of all cases atypical ones amount to 10-45%. Interestingly, another childhood disease, acrodynia (AD) shares most of its diagnostic criteria with KD.

By now, the cause of KD is unknown. Antigens from infections as well as superantigens and genetic polymorphisms have been implicated in the etiological hypotheses. In this review of the literature and analysis of the U.S. Vaccine Adverse Effects Reporting System (VAERS), we hypothesise that prenatal and postnatal exposure to mercury (and synergistic toxins) may be a pathogenic factor in KD.

The VAERS database is an epidemiological database that has been maintained by the Centers for Disease Control (CDC) since 1990 as a surveillance tool to evaluate vaccine safety. An examination of the VAERS database (online public access version: http://vaers.hhs.gov/scripts/data.cfm) with reports entered through January, 31, 2008 was undertaken. The keywords: “kawasaki’s disease” and “kawasaki’s syndrome.” were used. An additional search for “mucocutaneous lymph node syndrome” did not yield any results. The strength of the VAERS database stems from its large reporting base. Its potential weakness is that all vaccine-associated adverse events experienced are not reported.

AD was considered a mysterious, systemic disorder, mainly affecting children under the age of five. At its epidemic height (1880-1950), it affected about one in 500 children in industrialised nations [1].

The onset of AD is characterised by high fever lasting more than 5 days; a varying rash such as erythematous plaques, or appearing as measles or scarlet fever; swollen lymph nodes, particularly in the neck; bright red, swollen hands and feet; red, irritated eyes without discharge; bright red, irritated mouth, lips, and throat [2,3]. Neurological, cutaneous, and cardiovascular symptoms are most commonly seen. However, the disease is highly variable; cutaneous symptoms may be mild or lacking while neurological symptoms always seem to be present. It was explained as an infection or nutritional deficiency and it occurred mostly in the teething period [4].

In 1953, as a result of work by Warkany and Hubbard, mercury – coming from teething powders, baby powders, and diapers treated with calomel (85% mercurous chloride) [2] – was accepted as the cause of AD [2]. After a federal ban of these mercury-containing products in 1954, AD disappeared [1]. It should be noted that, in vitro, mercurous chloride is one of the least toxic forms of mercury, about 100 times less toxic than are mercury vapour or ethyl mercury contained in vaccines [5]. In addition, it was reported that applications of vaccines (containing ethyl mercury in thimerosal) preceded the onset of AD in several cases [2,3].

KD shares its diagnostic criteria with those of the onset of AD; the two diseases are similar in their clinical appearance. More than 150 symptoms and about 50 laboratory findings which are seen in KD were also described in cases with mercury poisoning (MP), too. (See Table 1) [2,3,6-57]. KD affects males twice as often as females. This may be explained by in vitro studies on human cells which have shown that testosterone synergistically increases the toxicity of mercury, while oestrogen protects against mercury toxicity [1].

KAWASAKI’S DISEASE MERCURY POISONING
Diagnostic Criteria Typical onset
Persistent high fever lasting >5 days Persistent high fever lasting >5 days
Varying rash such as erythematous plaques, or appearing as measles, scarlet fever Polymorphous exanthema such as erythematous plaques, morbilliform, scarlatiniform
Swollen lymph nodes, particularly in the neck Adenopathy, particularly cervical adenopathy
Bright red, swollen hands, feet Erythema, oedema of the hands, feet
Red, irritated eyes without discharge Bilateral conjunctivitis without discharge
Bright red, irritated mouth, lips, throat Stomatitis, erythema of the lips, pharyngitis
Mucocutaneous Mucocutaneous
Peeling of the hands, feet, nose, genitals Desquamation of the hands, feet, nose, genitals
Bright red, swollen cheeks, nose, genitals Erythema, oedema of the cheeks, nose, genitals
Bright red tongue with fungiform papillae Erythema of the tongue with blisters
Lesions, ulcers of the mouth Oral lesions, ulcers
Dry, cracked lips Fissured lips
Jaundice Icterus
Inflammation of the skin Dermatitis
Small, pink drops on the skin Guttate psoriasis
Painful, itching, burning sensations Painful, itching, burning sensations
Poor circulation to the fingers, toes, and other extremities, causing discolouration Reynaud’s syndrome
Beau’s lines, pale nails Beau’s lines, pale nails
Cardiovascular Cardiovascular
Rapid heart beat Tachycardia
Irregular heart beat Cardiac arrhythmia
Elevated or abnormally low blood pressure Hypertension, hypotension
Inflammation of the heart muscle, heart valve, pericardium, coronary arteries Myocarditis, valvulitis, pericarditis, coronary arteritis
Inflammation of the arterial walls, causing a thickening, hardening, loss of elasticity Arteriosclerosis, atherosclerosis
Coronary artery lesions Coronary arterial lesions
Abnormal fluid accumulation around the heart Pericardial effusion
Inflammation, narrowing of the blood vessels Stenosis
Blood clot Thrombosis
Reduced blood supply to the heart Myocardial  ischaemia
Enlargement of the blood vessels Arterial ectasia
Enlarged heart Cardiomyopathy, cardiomegaly
Coronary aneurysms, abnormalities Coronary aneurysms, abnormalities
Heart attack, cardiac failure Myocardial infarction, congestive cardiac failure
Respiratory Respiratory
Asthma Asthma
Chest pain Angina
Difficulty breathing, shortness of breath Dyspnoea
Inflammation of the nasal sinuses Sinusitis
Inflammation of the bronchi, lungs Bronchitis, pneumonitis
Blood clot in the lung Pulmonary embolism
Swelling, fluid accumulation in the lungs Pulmonary oedema
Interstitial thickening surrounding the bronchi Peribronchial cuffing
Abnormal tissue changes in the lungs Pulmonary nodules
Abnormal fluid accumulation around the lungs Pleural effusion
Collapse of part or the entire lung Atelectasis, emphysema
Respiratory tract infection Respiratory tract infection
Neurological Neurological
Marked personality change, severe irritability Marked personality change, severe irritability
Chronic fatigue, weakness Lethargy, aesthenia
General feeling of discomfort, unease Malaise
Headache, migraine Headache, migraine
Coma, stroke Coma, stroke
Convulsions, seizure Convulsions, seizure
Hearing loss, ringing of the ears Sensorineural hearing loss, tinnitus
Inflammation of the brain, meninges Encephalitis,  meningitis,  meningoencephalitis
Incoordination Ataxia
Facial paralysis Bell’s palsy
Musculoskeletal Musculoskeletal
Swollen joints, joint pain Arthritis, arthralgia
Muscle pain Myalgia
Inflammation of the muscles Myositis
Lower back pain, inflammation of the sacroiliac joint Sacroiliitis
Abnormally low muscle tone Hypotonia
Ocular Ocular
Drooping eyes Ptosis
Sensitivity to light Photophobia
Inflammation of the uvea Uveitis
Blurred vision, visual disturbances Blurred vision, visual disturbances
Immunological Immunological
Allergies, including nasal and eye allergies Allergies, allergic rhinitis, allergic conjunctivitis
Increased susceptibility to disease, infection Immunotoxic
Gastrointestinal Gastrointestinal
Loss of appetite, poor appetite weight loss Anorexia, poor appetite, weight loss
Nausea, vomiting Nausea, vomiting
Diarrhoea,  constipation Diarrhoea, ileus
Bowel obstruction Colonic obstruction
Ulcers, inflammation of the colon Colitis ulcerosa
Inflammation of the bile ducts Cholangitis
Enlarged liver Hepatomegaly
Kidney failure, nephritic syndrome Renal failure, nephrosis

Table 1. Symptoms Shared Between Kawasaki’s Disease and Mercury Poisoning

Probably, cases with symptoms similar to KD were designated as Feer disease or AD before the discovery of KD [6]. One case of AD mimicked KD and was induced through inhalation of mercury vapour [7]. In another report, published in 2004, two brothers (3 and 20 months of age) presented with similar symptoms and were first diagnosed as having KD. Laboratory testing revealed that both had ele- vated urinary mercury levels, so a diagnosis of AD was made [8].

Mercury’s possible role in KD was first suggested by Donald Cheek (Australia, 1975) after he noticed clinical similarities to AD [56]. In addition, Orlowski and Mercer found mercury levels in the urine of six patients with KD elevated, compared to controls. One patient was treated successfully through mercury detoxification with D-Penicillamine [58].

Possible source of human mercury exposure

According to the U.S. Environmental Protection Agency (EPA) and the National Academy of Science, about 8-10% of American women have mercury levels sufficiently high to cause neurological disorders in most of their children [1]. Numerous studies have suggested that maternal dental amalgam is one of the main sources of prenatal mercury exposure [58,99]. Dental amalgam fillings contain at least 50% elemental mercury, which is continuously emitted as mercury vapour and is easily absorbed by human tissues. Mercury vapour is acknowledged as one of the most toxic forms of mercury, as it penetrates into the cells with great ease, which is not possible for inorganic forms of mercury. Other prenatal sources of mercury include vaccines, immune globulin, and fish. Postnatal sources of mercury include thimerosal from vaccines and mercury from breast milk. During childhood, dental amalgam fillings and, especially in populations with great fish consumption, fish are the main sources of mercury. According to the pharmaceutical company Eli Lilly, the inventor and producer of thimerosal since 1928, this ethyl mercury antiseptic may cause severe mental and motor retardation in children and the unborn [59]. Thimerosal is the form of mercury particularly capable of inducing cutaneous symptoms and diseases, such as those seen in KD [1,9].

The US Food and Drug Administration (FDA) compiled a list of medical products still containing mercury (See Table 2) [62]. Several medical tests, too, may expose a patient to thimerosal, such as those for hepatitis or strep [63].

While some experiments have shown that methyl-mercury-iodide or methyl-mercury-chloride, commonly used in experiments, may be more toxic than ethyl-mercury, still exposure to the form of methyl-mercury found in fish may be less toxic, possibly because it has already reacted in fish tissues and is tightly bound to sulphur groups or selenium [1,61]. Also, mercury vapour (e.g., from dental amalgam) seems to have even stronger toxic effects to the offspring of animals than does methyl-mercury-chloride [62].

Genetic susceptibilities or sensitivities

Mercury toxicity is primarily retention toxicity, and its adverse effects depend largely on how much is retained in cells and tissues as opposed to being excreted. After a given quantity of intake, high urine mercury levels tend to be a sign of healthy excretion, while low levels tend to indicate an inability to effectively excrete mercury. This may be influenced by genetic susceptibilities or synergistic toxins, which increase the retention and, thereby, the toxicity of mercury [1,85].

According to a recent study of 67 Korean children with KD and 252 healthy controls, genetic depletion of glutathione S-transferase (GST) may be a susceptibility factor for KD. The frequency of the doubly deleted genotype (-/-) of GSTM1 and GSTT1 was found to be significantly elevated compared to the intact genotype (+/+) in KD patients [99] (cont) …

Click for the PDF of the complete, fully referenced version of this article about Kawasaki’s disease.

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