Evaluation of CNS symptoms similar to Parkinson disease

Characterization of liver cirrhosis

Therapeutic monitoring in treatment of cirrhosis, TPN-related

Mn toxicity and environmental exposure to Mn

Supportive of diagnosis of Behcet disease

Manganese (Mn: atomic number 25, atomic weight 54.938 g/mole)

is a trace element that is an essential cofactor for several

enzymes, including one 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 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.

4.7-18.3 ng/mL (85-333 nmol/L; conversion factor 18.202)

Whole blood levels above the normal range are indicative of

likely manganism. Single 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 are much more highly correlated with

symptoms. 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 "Metals Analysis - 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 enceph-

      alopathy due to "Ephedrone" abuse. Mov Disord

      2007;22:1337-1343