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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 mg 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 normals) 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 on-going exposure to metal fumes, but the reported results are difficult to assign
to any 1 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 Parkinson-like 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.
Useful For: 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
Interpretation: 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
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