What does high serum manganese level indicate?

High Serum Manganese: Clinical Significance and Management

High serum manganese indicates potential manganese toxicity, which is primarily a neurotoxic condition that can cause irreversible brain damage, particularly affecting the basal ganglia and leading to a Parkinson-like syndrome called manganism. 1

Primary Clinical Significance

Manganese toxicity is a far greater clinical concern than deficiency, as the neurological damage can be permanent and treatment options are limited. 1 The brain is the main target organ, with manganese overexposure resulting in:

• Compromised mitochondrial function and oxidative stress 1
• Neuronal cell death in basal ganglia structures 1
• Irreversible neurological damage 1

Clinical Presentation

Early (Non-specific) Symptoms

• Headache, asthenia, irritability, fatigue, and muscular pains 1

Late (Neurodegenerative) Symptoms

• Manganism: A neurodegenerative syndrome with psychiatric symptoms resembling Parkinson's disease, including cognitive, motor, and emotional defects 1
• Initial "manganese madness" may present with compulsive behavior, emotional lability, and hallucinations 2

Somatic Effects

• Hypertension and increased heart rate (due to calcium channel blockade) 1
• Elevated cholesterol levels (reduced conversion to bile acids) 1
• Decreased fertility in men and increased fetal abnormalities 1

Common Causes of Elevated Serum Manganese

Iatrogenic Causes

• Long-term parenteral nutrition (>30 days), especially with manganese intake >55 μg/day 1
• Even "manganese-free" PN can cause elevation due to contamination 3
• IV intakes as low as 110 μg/day can elevate whole blood manganese 1

Medical Conditions

• Cholestasis, liver failure, or hepatic encephalopathy (manganese is excreted in bile) 1
• Iron deficiency (competing transport proteins lead to manganese accumulation) 1

Environmental/Occupational

• Occupational exposure to manganese oxides 1
• Environmental exposure (though dietary intake alone does not cause toxicity due to tight gut regulation) 1

Diagnostic Approach

When to Measure

Measurements should be made when manganese excess or toxicity is suspected, especially in:

• Long-term parenteral nutrition (>30 days, manganese intake >55 μg/day) 1
• Impaired liver function 1
• Iron deficiency 1

What to Measure

• Whole blood or RBC manganese concentrations (preferred, as majority of circulating manganese is within erythrocytes) 1
• Serum/plasma manganese can be measured but whole blood is more representative 1
• Brain MRI showing high intensity signals in globus pallidus correlates with elevated manganese levels and confirms diagnosis 1

Monitoring Frequency

• Not more frequent than 40-day intervals (biological half-life) 1

Treatment Thresholds and Management

Treatment Indication

Whole blood or serum manganese values greater than twice the upper limit of normal laboratory reference ranges should be treated. 1

Treatment Algorithm

Step 1: Remove Source

• Immediately remove any manganese-containing additives from parenteral nutrition 1
• Limit manganese contamination to <40 μg/day total in adult PN formulas 1

Step 2: Specific Interventions

• Iron supplementation if iron deficiency is present (corrects competitive transport protein binding) 1
• Chelation therapy: EDTA or para-aminosalicylic acid (PAS), though PAS has variable success 1

Step 3: Supportive Care

• Functional recovery is limited due to neuronal cell death in basal ganglia 1
• Future therapies may include stem cell therapy 1

Critical Pitfalls to Avoid

• Do not assume "manganese-free" PN is truly free of manganese: 30% of patients still develop elevated levels due to contamination and dietary intake 3
• Do not delay evaluation in patients with liver disease on PN: These patients are at highest risk due to impaired biliary excretion 1
• Do not overlook iron deficiency: This can independently cause manganese accumulation to toxic levels over time 1
• Do not use serum manganese alone: Whole blood manganese is more accurate as most manganese resides in erythrocytes 1
• Do not expect full recovery: Neurological damage from manganese toxicity is often irreversible, emphasizing the importance of prevention 1