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Evaluation of central nervous system symptoms similar to Parkinson disease in manganese miners and processors
Characterization of liver cirrhosis
Therapeutic monitoring in treatment of cirrhosis, parenteral nutrition-related Mn toxicity and environmental exposure to Mn
Evaluation of Behcet disease
Manganese (Mn) is a trace element that is an essential cofactor for several enzymes, including 1 form of superoxide dismutase and the gluconeogenic enzymes: pyruvate carboxylase and isocitrate dehydrogenase. It circulates in the serum as a metalloprotein complex with any of several proteins. The +2 and +3 states are of biological significance, but speciation in the analysis has not been studied sufficiently to determine its value. The required daily intake of 1 to 6 mg is readily supplied by a normal diet with a diverse mixture of fruits and vegetables.
Manganese ores and alloys are refined and used in the making of batteries, welding rods, and high-temperature refractory materials. Environmental exposure occurs from inhalation and ingestion of manganese-containing dust and fumes occurring from the refinement processes. It is likely that inhaled Mn is mobilized up the trachea and swallowed; uptake through the gut is inefficient, about 10%.
The major compartment for circulating Mn is the erythrocytes, bound to hemoglobin, with whole blood concentrations of Mn (in patients with normal levels) being 10 times that of the serum. Mn passes from the blood to the tissues quickly. Concentrations in the liver are highest, with 1 mg Mn/kg to 1.5 mg Mn/kg (wet weight) in normal individuals. The half-life of Mn in the body is about 40 days, with elimination primarily through the feces. Only small amounts are excreted in the urine.
Environmental sources of Mn can lead to toxicity. The primary sites of toxicity are the central nervous system (CNS) and the liver. Acute exposure to Mn fumes gives rise to symptoms common to many metal exposures including fever, dry mouth, and muscle pain. Chronic exposure of several months or more gives rise to CNS symptoms and rigidity, with increased scores on tremor testing and depression scales, as well as generalized parkinsonian features. Confined-space welders have been extensively studied because of their ongoing exposure to metal fumes, but the reported results are difficult to assign to any single metal as the origin of symptoms because of worksite variability, lack of adequate controls, and analytical issues.(1) Nevertheless, reports frequently describe significant increases in Mn levels in the whole blood (or erythrocytes) and in the CNS of these workers, with some evidence that circulating levels decrease following removal of individuals from sources of exposure.
The mechanism of Mn-induced neurotoxicity is not clear. While Parkinsonlike symptoms are found, the damage to nerve cells appears to be to the globus pallidus, while the nigrostriatal pathway (the focus of abnormality in Parkinson disease) is intact (although some claim it is dysfunctional). Increased levels of Mn in the CNS are not necessarily found in manganism, but this could be due to the use of inadequate analytical methodology. Animal studies, while plentiful and useful for pharmacokinetic modeling and possibly for studying mechanisms of hepatotoxicity, are of little value in extrapolation to CNS aberrations in humans because of species-to-species variability in absorption and distribution, and widely divergent psychological means of evaluation.(2)
Elevated levels of whole blood Mn have been reported, with and without CNS symptoms, in patients with hepatitis B virus-induced liver cirrhosis, in patients on total parenteral nutrition (TPN) with Mn supplementation, and in infants born to mothers who were on TPN. The studies in cirrhotic patients with extrapyramidal symptoms indicate a possible correlation between whole blood Mn and that measured by T1-weighted magnetic resonance in the globus pallidus and midbrain, with whole blood Mn levels being 2-fold or more, higher than normal. Increases in whole blood Mn over time may be indicative of future CNS effects. The data on TPN patients is based on anecdotes or small studies and is highly variable, as is that obtained in infants.(3)
Behcet disease, a form of chronic systemic vasculitis, has been reported to exhibit 4-fold increase in erythrocyte Mn and it is suggested that increased activity of superoxide dismutase may contribute to the pathogenesis of the disease.
Mn has been reported as a contaminant in "garage" preparations of the abused drug methcathinone. Continued use of the drug gives rise to CNS toxicity typical of manganism.(4)
Reports of suspected toxicity due to gustatory excess, even the drinking of large quantities of Mn-rich tea, may be dismissed as anecdotal and largely due to chance.
For monitoring therapy, whether of environmental exposure, TPN, or cirrhosis, whole blood levels have been shown to correlate well with neuropsychological improvement, although whether the laboratory changes precede the CNS or merely track with them is unclear as yet. It is recommended that both CNS functional testing and laboratory evaluation be used to monitor therapy of these patients. Long-term monitoring of Behcet disease has not been reported, and it is not known if the Mn levels respond to therapy.
Whole blood levels above the normal range are indicative of manganism. Values between 1 and 2 times the upper limit of normal may be due to differences in hematocrit and normal biological variation, and should be interpreted with caution before concluding that hypermanganesemia is contributing to the disease process. Values greater than twice the upper limit of normal correlate with disease. For longitudinal monitoring, sampling no more frequently than the half-life of the element (40 days) should be used.
Contamination of the collection site and of the specimen must be avoided. In the case of environmental evaluation, do not collect specimens in the workplace. Failure to use metal-free collection procedures and devices may cause falsely increased results. See Specimen Required and Trace Metals Analysis Specimen Collection and Transport in Special Instructions for collection and processing information.
1. Jiang Y, Zheng W, Long L, et al: Brain magnetic resonance imaging and manganese concentrations in red blood cells of smelting workers: search for biomarkers of manganese exposure. NeuroToxicology 2007;28:126-135
2. Guilarte T, Chen M, McGlothan J, et al: Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 2006;202:381-390
3. Choi Y, Park J, Park N, et al: Whole blood and red blood cell manganese reflected signal intensities of T1-weighted magnetic resonance images better than plasma manganese in liver cirrhotics. J Occup Health 2005;47:68-73
4. Sanotsky Y, Lesyk R, Fedoryshyn L, et al: Manganic encephalopathy due to "Ephedrone" abuse. Mov Disord 2007;22:1337-1343