Neuroendocrinology Letters. 1999;20(3-4):221-228.
Mercury and nickel allergy: risk factors in fatigue and autoimmunity.
Sterzl I, Procházková J, Hrdá P, Bártová J, Matucha P, Stejskal VD.
Source: Institute of Endocrinology, Prague, Czech Republic.
This study examined the presence of hypersensitivity to dental and environmental metals in patients with clinical disorders complicated with chronic fatigue syndrome. Three groups of patients were examined through medical history, dental examination, and by using a modified test of blast transformation for metals-MELISA(R). The three groups consisted of the following: 22 patients with autoimmune thyroiditis with or without polyglandular autoimmune activation; 28 fatigued patients free from endocrinopathy; and 22 fatigued professionals without evidence of autoimmunity. As controls, a population sample or 13 healthy subjects without any evidence of metal sensitivity was included. Healthy controls did not complain of marked fatigue and their laboratory tests did not show signs of autoimmunity and endocrinopathy.
We have found that fatigue, regardless of the underlying disease, is primarily associated with hypersensitivity to inorganic mercury and nickel. The lymphocyte stimulation by other metals was similar in fatigued and control groups.
To evaluate clinical relevance of positive in vitro findings, the replacement of amalgam with metal-free restorations was performed in some of the patients. At a six-month follow-up, patients reported considerably alleviated fatigue and disappearance of many symptoms previously encountered; in parallel, lymphocyte responses to metals decreased as well.
We suggest that metal-driven inflammation may affect the hypothalamic-pituitary-adrenal axis (HPA axis) and indirectly trigger psychosomatic multisymptoms characterizing chronic fatigue syndrome, fibromyalgia, and other diseases of unknown etiology.
Many patients with autoimmune polyglandular syndrome (APS) with manifestations of chronic fatigue syndrome (CFS) have hypersensitivity to heavy metals in the anamnesis. In addition to clinical hypersensitivity, laboratory findings indicate a marked increase in the activation of the TH1 and TH2 subpopulations of lymphocytes [1, 2]. A variety of health disorders such as contact dermatitis, stomatitis and parodontitis, oral lichen planus, mild renal dysfunction, pneumoconiosis, resistance to antibiotics, and male infertility have been reported following exposure to heavy metals [3–9].
The human body is constantly exposed to metals and metal-containing compounds. Some metals are in trace amounts crucial for normal functioning while others exert toxic effects. The key factors governing the harmfulness of metals are the cumulative concentration, duration of exposure, and genetic susceptibility. Many harmless metals may become allergens or exert toxicity if administered on a chronic basis .
Metal-induced hypersensitivity in man is based upon the reaction of the allergen with the surface of memory T- ymphocytes sensitized to a specific allergen previously. Upon contact with the allergen, memory cells become activated and begin to produce lymphokines. The resulting infl ammation can occur in the skin or elsewhere in the body where metal ions are deposited . The interaction of memory cells with antigen forms the basis of the Lymphocyte Stimulation Test (LST). The test has previously been used for the diagnosis of allergy to drugs, formaldehyde, epoxides and isothiazolinones [12–14]. MELISA® (Memory Lymphocyte Immuno Stimulation Assay), a further development of the test, measures immunological sensitization induced by mercury, gold, palladium and other metals [15–17].
In this article, cellular responses to metals in various groups of fatigued patients with or without autoimmunity were compared to those of healthy controls. The results indicate significantly increased lymphocytic reactivity to nickel and mercury in fatigued patients compared to healthy subjects.
The results of this study indicate significantly increased lymphocyte reactivity to inorganic mercury and nickel in patients with chronic fatigue syndrome and autoimmune thyroiditis as compared to healthy controls. The similar results were obtained in fatigued patients without endocrinopathies and in fatigued professionals with diffuse symptoms.
The major source of inorganic mercury is dental amalgam, as previously reported by Skare . Regarding the effect of mercury on thyroid function, Kawada and coworkers  demonstrated 50% inhibition of Na+Ka+ATPase in the membranous preparations from hog thyroid by mercuric chloride in 10-7 M concentration. A significant reduction in de novo synthesis of iodothyronines was demonstrated following an intraperitoneal injection of mercury into mice, thus suggesting that mercury may cause a coupling defect in the synthesis of iodothyronines.
An interesting finding is also denaturation of hog thyroglobulin in the presence of 8 x 10-3 M mercuric chloride suggesting that thyroglobulin may carry a large binding capacity against mercurials. Barregåd and coworkers  studied functional impairments of thyroid in occupationally exposed workers.
The results indicated inhibitory effects of mercury vapor on 5′- deiodinases which are responsible for the conversion of T4 to the active hormone T3. Nickel is an ubiquitous metal and the re-exposure is difficult to avoid by sensitized individuals. Most of our patients were females and the increased prevalence of metal sensitivity may be due to the use of nickel-containing earrings. High-quality stainless steel in cooking utensils may release enough nickel to provoke dermatitis in sensitized subjects .
Significant amounts may be released by sweat or household detergents . This release is accelerated by an acid pH and thus, in the handling and cooking of acid fruit and vegetables, nickel may be released . Another source of exposure is cigarette smoke. Last but not least, nickel may be found as an impurity in amalgam or as a component of dental crowns and bridges [24 and unpublished observations].
The prevalence of metal sensitivity in patients with CFS and other disorders with unclear etiology has not been studied to a greater extent. Swedish researchers have reported on the increased prevalence of nickel-positive patch tests in patients with fi bromyalgia and CFS . Further, in 397 patients referred for metal patch testing, over 50% of the patients exhibited systemic symptoms such as fatigue and muscular pain while the local oral symptoms were less frequent . The patch test data confirmed the results of increased lymphocyte responsiveness to metals in vitro in this patient category [15–17].
Positive lymphocyte responses were clinically relevant since patients often reported intolerance to metal earrings and other metallic devices such as jeans buttons, watches and intrauterine devices. Some of them also reported worsening of fatigue and other symptoms following a visit to the dentist. Two patients with clinical and in vitro metal reactivity underwent the replacement of amalgam fillings. Both patients reported significant improvement of health as compared to the time prior to amalgam removal. Parallelly, the lymphocyte responses to metals decreased as well.
Similar results were observed in 10 other patients participating in an ongoing long-term study and in a recently reported Swedish study .
The improved health observed in many patients following amalgam replacement has been observed by others [28 – 30]. In a recent study of 6,744 consecutive patients from 34 dental offices in Germany, a higher number of symptoms as well as higher intensity of symptoms were found in patients before amalgam removal compared to the remaining patients . There was no correlation between the intensity of complaints and the number of amalgam-fillings.
These findings suggest an immunological rather than a toxicological basis of amalgam-induced side effects.
The fatigue and total “burn out” in dentists in numerous countries has been previously published [32, 33]. In 1976 Cheraskin  observed an increased prevalence of fatigue in dentists with low intake of vitamin C. An analysis of the data on vitamin C intake and fatigue in 411 dentists and their wives revealed a negative relationship.
It is generally recognized that immune activation resulting in cytokine release may cause severe psychosomatic symptoms [35, 36]. Since chronic immune activation could be a plausible explanation of CFS and other alleged psychosomatic disorders, the demonstration of immune activation in CFS patients generated considerable interest in the scientific community. Thus, Buchwald and coworkers reported the increased serum markers of infl ammation and immune activation in patients with CFS and chronic fatigue, compared to controls .
In a recent review article, Komaroff and Buchwald emphasized that CFS is a definite entity characterized by chronic activation of the immune system, abnormalities of the HPA-axis, and abnormal changes in the brain . The pathological MRI findings in multi-symptomatic patients exhibiting lymphocytic sensitization to metals and disregulation of phenotypic lymphocyte markers have been reported previously .
The chronic exposure to corrosion products of dental metals or to metals generally could serve as a trigger of chronic infl ammation in sensitized individuals. The disregulation of HPA-axis in CFS has been described by Demitrack et al. in 1991  and in autoimmune thyroiditis by Sterzl and coworkers . The symptoms of fatigue are frequent in other autoimmune disorders, for instance in multiple sclerosis .
Allelic components of the major histocompatibility complex (MHC) are associated with various immunological diseases, including allergies to heavy metals. In man, hypersensitivity to heavy metals is more frequent in patients with HLA DR4 antigens [43, 44], and monozygous twins with CFS display an identical pattern of metal sensitization . Hence, in agreement with the animal findings , sensitization to metals in man seems to be determined by an individual genetic predisposition.
The introduction of the new method MELISA® is a major step in the improvement of the diagnosis of hypersensitivity to heavy metals, thus allowing the identification of the patients where simple removal of metal fillings will markedly enhance the quality of life.