Neuroendocrinology Letters No.3 June Vol.25, 2004
The beneficial effect of amalgam replacement on health in patients with autoimmunity
Jarmila Prochazkova, Ivan Sterzl, Hana Kucerova, Jirina Bartova and Vera DM Stejskal
Patients with certain autoimmune and allergic diseases, such as systemic lupus, multiple sclerosis, autoimmune thyroiditis or atopic eczema, often show increased lymphocyte stimulation by low doses of inorganic mercury in vitro. The patients often report clinical metal hypersensitivity, especially to nickel.
OBJECTIVE AND METHODS:
In this study we examined the health impact of amalgam replacement in mercury-allergic patients with autoimmunity. The suitability of MELISA®, an optimized lymphocyte stimulation test, for the selection of susceptible patients and monitoring of sensitization was also examined. Amalgam fillings were replaced with composites and ceramic materials. Follow-up health status and lymphocyte reactivity were assessed and evaluated half a year or later following amalgam removal.
Results of lymphocyte reactivity measured with MELISA® indicate that in vitro reactivity after the replacement of dental amalgam decreased significantly to inorganic mercury, silver, organic mercury and lead. Out of 35 patients, 25 patients (71%) showed improvement of health. The remaining patients exhibited either unchanged health (6 patients, 17%) or worsening of symptoms (4 patients, 11%). The highest rate of improvement was observed in patients with multiple sclerosis, the lowest rate was noted in patients with eczema. The initial mercury-specific lymphocyte reactivity was significantly higher in the responder group, than in the non-responders, whose health was not improved by amalgam removal. All patients with health improvement after amalgam replacement showed reduced proliferation to inorganic mercury in follow-up MELISA®. In vitro responses to phenylmercury and nickel did not differ between the groups.
Mercury-containing amalgam may be an important risk factor for patients with autoimmune diseases. MELISA® is a valuable tool for selection of patients for amalgam replacement and also for monitoring of metal allergies.
Metals, such as mercury and gold, can induce autoimmunity in susceptible strains of experimental animals [1–4]. Mercury and lead may also accelerate systemic autoimmunity in lupus-prone mice . In humans, certain metals may accelerate or worsen clinical autoimmune disease in susceptible populations [6–7]. High levels of autoantibodies were found in populations exposed to high doses of inorganic mercury [8–10]. El-Fawal et al.  studied workers in fluorescent light factories exposed to mercury vapor in a concentration of 0, 05 mg/m3. The titers of autoantibodies to neurofilament proteins and to myelin basic protein were significantly increased in exposed workers as compared with non-exposed workers. Antibodies were predominantly of the IgG type, indicating secondary antigen challenge or antigen persistence. The strong allergenic potential of mercury compounds is well recognized by dermatologists since thimerosal, thiosalicylate salt of ethylmercury, is the number one allergen in children . Many patients with autoimmune diseases have hypersensitivity to heavy metals in the anamnesis . In addition to mercury, well-known allergens such as gold, beryllium and nickel are frequently used in dental alloys [13–16]. Dental amalgam has been implicated as a risk factor in multiple sclerosis , in Alzheimer's disease [18–19] and recently in infertility .
Corrosion products from dental alloys may serve as triggers of chronic inflammation in susceptible subjects. Metal-induced allergy in man is caused by the contact of the metal with the surface of memory lymphocytes. Upon re-exposure to the same or structurally similar epitope, memory cells become activated and start to produce lymphokines. The resulting inflammation can occur in the skin or elsewhere in the body where metal ions are located [7, 12]. The activation of memory cells can be measured outside the body, in vitro, by so called lymphocyte stimulation test (LTT, LST). Lymphocytes from patients suffering from metal hypersensitivity (so called delayed type allergy) often show increased proliferation after exposure to metal salts in vitro [7, 12, 21–25]. Increased lymphocyte responses to inorganic mercury are frequent in patients with lichenoid changes and positive patch test to mercury , in patients with autoimmune thyroiditis  and in patients with atopic eczema and psoriasis [26–27].
In this study the impact of amalgam replacement on lymphocyte stimulation and health was studied in a subgroup of patients with various autoimmune diseases who showed lymphocyte reactivity to mercury in an optimized lymphocyte proliferation test, MELISA®.
This study shows the beneficial effect of amalgam replacement on the health of autoimmune patients with lymphocyte reactivity to low concentrations of inorganic mercury. Many patients showed short-term aggravation of symptoms 1–2 days after amalgam replacement. Since patients were selected into the study on the basis of lymphocyte reactivity to mercury, this reaction can be explained by systemic delayed type mercury hypersensitivity. To our knowledge this is the first time when a specific biomarker of mercury sensitivity was used for the selection of patients for amalgam replacement. It is important to realize that any risk factor maybe diluted if evaluated in heterogeneous population. As suggested by Weiss , analyses based on clinical markers of susceptibility (phenotypic markers) may be suitable for elucidation of causal pathways, identification of specific environmental risk factors and elimination of methodical flaws which exist in some studies concerning health risks of amalgam .
One of the important factors for a beneficial outcome of amalgam replacement seems to be an initially strong reactivity of lymphocytes to low concentrations of inorganic mercury (0, 5 μg of HgCl2 per ml and 1x106 lymphocytes). Low concentrations of mercury have been found to activate lymphocytes of patients with oral lichen adjacent to amalgam fillings. In addition to oral problems, patients also suffered from arthralgia, myalgia, eczema, diabetes and chronic malaise. Under these conditions, lymphocytes from healthy amalgam bearers and from amalgam-free subjects were not activated . Inorganic mercury is the second most common sensitizer in patients with central nervous symptoms and suspected intoxication from dental amalgam , in patients with CFS syndrome  and in a group of patients with Hashimoto thyroiditis . As mentioned previously, thimerosal, an organic mercury compound, ranks as the most frequent allergen in children and adolescent men, probably due to repeated exposure to thimerosal-containing vaccines in the past [11,32]. Positive patch test to inorganic mercury is also frequent in dermatological praxis [33–34].
One important observation in this study is a decrease of lymphocyte reactivity to inorganic mercury half a year after amalgam removal in patients with health improvement but not in patients with unchanged or worsened health. All patients with multiple sclerosis showed improved health and reduction of mercury-specific reactivity in vitro. All patients with thyroiditis who improved showed a decrease of mercury-induced activity to half or less of original SI value.
The non-responder group, whose health was unchanged or worsened after amalgam replacement, consisted of eight patients, four with systemic lupus, two with thyroiditis and the remaining two with atopic eczema. Only two patients from this group (25%) responded strongly to inorganic mercury in vitro prior to amalgam replacement as compared to 17 out of 27 (63%) of the patients in the responder group. In the majority of patients, lymphocyte responses to inorganic mercury were low and did not change significantly after amalgam replacement.
With regards to smoking habits, all patients with worsened health after amalgam replacement were smokers. As reported previously, nickel, mercury, cadmium and lead are present in cigarette smoke .
Some patients started smoking again after the initial health improvement and this could unfavorably affect their health. Patient no.32 had been a heavy smoker and the persisting reactivity to mercury which was not affected by amalgam removal could be possibly explained by continuous exposure to mercury from the cigarettes. Another source of nickel exposure, often not discussed, is that nickel may be present as an impurity in certain amalgams, so called copper amalgams. Nickel is the most common metal allergen [36–37] and its ubiquitous presence makes complete avoidance difficult. The beneficial effect of a nickel-free diet on the health of patients with chronic fatigue syndrome has been reported (38).
It has been postulated that chronic metal-driven inflammation may through cytokine release up regulate the hypothalamus-pituitary-adrenal axis (HPA-axis) resulting in unspecific multi-symptoms such as chronic fatigue, depression, sleep disturbances and other psychosomatic symptoms . The reduction of mercury-specific responses after amalgam replacement has been published previously in patients with autoimmune thyroiditis , and in patients with chronic fatigue syndrome . Similarly, Valentine-Thon and Schiwara demonstrated marked reduction of lymphocyte reactivity to titanium dioxide in patients with abnormal fatigue who used titanium-containing cosmetics on a daily basis . Avoidance of exposure resulted in disappearance of fatigue and reduction of lymphocyte reactivity to titanium in vitro. Thus, the decrease of the exposure to metals in susceptible patients may result in down-regulation of inflammation and reduced symptomatology. In this respect, metal-induced inflammation resembles the inflammation caused by bacteria, viruses and other allergens. It is known that patients with metal sensitivity may experience influenza-like symptoms following the dental treatment.
In contrast to strong lymphocyte responses to inorganic mercury, only a few patients responded to phenylmercury, an organic form containing a benzene ring. Phenylmercury is used as a preservative in ointments, cosmetics and lotions. In the dental praxis, phenylmercury is present in root filling materials, such as N2 ("Nerve second"), together with arsenic and lead. In Sweden, N2 is banned since several years but is still illegally used by some dentists. Inorganic mercury and phenylmercury are structurally different and are therefore both used in patch testing. The same is true for thimerosal. The marked reduction of phenylmercury-specific responses in some patients suggests decreased exposure, possibly through avoidance of phenylmercury-containing pharmaceutical products.
No significant health risks of mercury in an unselected population were described in a report written on behalf of the European Union (40). However, such risks may become apparent when the effect of mercury exposure is studied in susceptible groups, such as children and patients with autoimmunity. This article will hopefully create an interest for larger studies on metal-susceptible populations in the future.
This is the first time when the selection of patients for amalgam removal was based on initial sensitivity to inorganic mercury at lymphocyte level as measured by the MELISA® test. The results show that mercury-containing amalgam may be an important risk factor for patients with autoimmune diseases who are sensitized to mercury. Hence, the removal of amalgam fillings is a useful complementary treatment for such patients. Nickel sensitivity was found to be another risk factor that may negatively affect the chance of regaining health.