Manganese and chronic hepatic encephalopathy

doi:10.1016/S0140-6736(95)92164-8

The Lancet

Volume 346, Issue 8970, 29 July 1995, Pages 270-274

https://doi.org/10.1016/S0140-6736(95)92164-8 Get rights and content

Abstract

Summary

Clinical observations and animal studies have raised the hypothesis that increased concentrations of manganese (Mn) in whole blood might lead to accumulation of this metal within the basal ganglia in patients with end-stage liver disease. We studied ten patients with liver failure (and ten controls) by magnetic resonance imaging (MRI) and measurement of Mn in brain tissue of three patients who died of progressive liver failure (and three controls) was also done.

Whole blood Mn concentrations in patients with liver cirrhosis were significantly increased (median 34·4 μg/L vs 10·3 μg/L in controls; p=0·0004) and pallidal signal intensity indices correlated with blood Mn (R_s=0·8, p=0·0058). Brain tissue samples reveal highest Mn concentrations in the caudate nucleus, followed by the quadrigeminal plate and globus pallidus.

Mn accumulates within the basal ganglia in liver cirrhosis. Similarities between Mn neurotoxicity and chronic hepatic encephalopathy suggest that this metal may have a role in the pathogenesis of chronic hepatic encephalopathy. Further studies are warranted because the use of chelating agents could prove to be a new therapeutic option to prevent or reverse this neuropsychiatric syndrome.

References (28)

Ja Brunberg et al.
Chronic acquired hepatic failure: MR imaging of the brain at 15 T
AJNR
(1991)
Sa Mirowitz et al.
Basal ganglia signal intensity alterations: reversal after discontinuation of parenteral manganese administration
Radiology
(1992)
K. Nelson et al.
Manganese encephalopathy: utility of early magnetic resonance imaging
Br J Ind Med
(1993)
A. Pujol et al.
Hyperintense globus pallidus on T₁-weighted MRI in cirrhotic patients is associated with severity of liver failure
Neurology
(1993)
Mc Newland et al.
Visualizing manganese in the primate basal ganglia with magnetic resonance imaging
Exp Neurol
(1989)
D. Krieger et al.
Clinical significance of hyperintense globus pallidus on T1-weighted MRI in patients with liver failure
Neurology
(1995)
GC. Cotzias
Manganese in health and disease
Physiol Rev
(1958)
Ag Devenyi et al.
Dystonia, hyperintense basal ganglia, and whole blood manganese levels in Alagille's syndrome
Gastroenterology
(1994)
M. Ashner et al.
Manganese uptake and efflux in cultured rat astrocytes
J Neurochem
(1992)
Vl Schramm et al.
The manganese (II) economy in rat hepatocytes
Fed Proc
(1986)

Fc Wedler et al.

Glutamine synthetase: the major Mn (II) enzyme in mammalian brain

Curr Top Cell Regul

(1984)

Md Norenberg et al.

Hepatic encephalopathy: a disorder in glial-neuronal communication

Progr Brain Res

(1992)

Fc Wedler et al.

Interactions of Mn (II) with mammalian glutamine synthetase

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Although manganese (Mn) is a trace metal essential for humans, chronic exposure to Mn can cause accumulation of this metal ion in the brain leading to an increased risk of neurological and neurobehavioral health effects. This is a concern for welders exposed to Mn through welding fumes. While brain Mn accumulation in occupational settings has mostly been reported in the basal ganglia, several imaging studies also revealed elevated Mn in other brain areas. Since Mn functions as a magnetic resonance imaging (MRI) T1 contrast agent, we developed a whole-brain MRI approach to map in vivo Mn deposition differences in the brains of non-exposed factory controls and exposed welders. This is a cross-sectional analysis of 23 non-exposed factory controls and 36 exposed full-time welders from the same truck manufacturer. We collected high-resolution 3D MRIs of brain anatomy and R1 relaxation maps to identify regional differences using voxel-based quantification (VBQ) and statistical parametric mapping. Furthermore, we investigated the associations between excess Mn deposition and neuropsychological and motor test performance. Our results indicate that: (1) Using whole-brain MRI relaxometry methods we can generate excess Mn deposition maps in vivo, (2) excess Mn accumulation due to occupational exposure occurs beyond the basal ganglia in cortical areas associated with motor and cognitive functions, (3) Mn likely diffuses along white matter tracts in the brain, and (4) Mn deposition in specific brain regions is associated with exposure (cerebellum and frontal cortex) and motor metrics (cerebellum and hippocampus).
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The CNS manifestation of chronic liver disease can include magnetic resonance (MR) signal hyperintensities in basal ganglia structures. Here, relations between liver (serum-derived fibrosis scores) and brain (regional T1-weighted signal intensities and volumes) integrity were evaluated in a sample of 457 individuals including those with alcohol use disorders (AUD), people living with human immunodeficiency virus (HIV), those comorbid for AUD and HIV, and healthy controls. Liver fibrosis was identified from cutoff scores as follows: aspartate aminotransferase to platelet ratio index (APRI) > 0.7 in 9.4% (n = 43) of the cohort; fibrosis score (FIB4) > 1.5 in 28.0% (n = 128) of the cohort; and non-alcoholic fatty liver disease fibrosis score (NFS) > -1.4 in 30.2% (n = 138) of the cohort. Presence of serum-derived liver fibrosis was associated with high signal intensities selective to basal ganglia (i.e., caudate, putamen, and pallidum) structures. High signal intensities in the pallidum, however, explained a significant portion of the variance in APRI (25.0%) and FIB4 (23.6%) cutoff scores. Further, among the regions evaluated, only the globus pallidus showed a correlation between greater signal intensity and smaller volume (r = -0.44, p <.0001). Finally, higher pallidal signal intensity correlated worse ataxia (eyes open ρ = -0.23, p =.0002; eyes closed ρ = -0.21, p =.0005). This study suggests that clinically relevant serum biomarkers of liver fibrosis such as the APRI may identify individuals vulnerable to globus pallidus pathology and contribute to problems with postural balance.
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Manganese and chronic hepatic encephalopathy

Abstract

Chronic acquired hepatic failure: MR imaging of the brain at 15 T

AJNR

Basal ganglia signal intensity alterations: reversal after discontinuation of parenteral manganese administration

Radiology

Manganese encephalopathy: utility of early magnetic resonance imaging

Br J Ind Med

Hyperintense globus pallidus on T1-weighted MRI in cirrhotic patients is associated with severity of liver failure

Neurology

Visualizing manganese in the primate basal ganglia with magnetic resonance imaging

Exp Neurol

Clinical significance of hyperintense globus pallidus on T1-weighted MRI in patients with liver failure

Neurology

Manganese in health and disease

Physiol Rev

Dystonia, hyperintense basal ganglia, and whole blood manganese levels in Alagille's syndrome

Gastroenterology

Manganese uptake and efflux in cultured rat astrocytes

J Neurochem

The manganese (II) economy in rat hepatocytes

Fed Proc

Glutamine synthetase: the major Mn (II) enzyme in mammalian brain

Curr Top Cell Regul

Hepatic encephalopathy: a disorder in glial-neuronal communication

Progr Brain Res

Interactions of Mn (II) with mammalian glutamine synthetase

Hyperintense globus pallidus on T₁-weighted MRI in cirrhotic patients is associated with severity of liver failure