Lithium Toxicity: Symptoms, Types, Causes and Treatment

Lithium, a mainstay in the treatment of bipolar disorder, has transformed countless lives. Yet, its use comes with a unique set of challenges due to its narrow therapeutic window. Lithium toxicity is a potentially dangerous complication that can affect multiple organ systems, requiring careful monitoring and rapid intervention. This comprehensive article will guide you through the symptoms, types, causes, and treatment of lithium toxicity, drawing on the latest scientific evidence.

Symptoms of Lithium Toxicity

Lithium toxicity can manifest in diverse and sometimes subtle ways, making it crucial for patients and clinicians to recognize the warning signs early. Symptoms may range from mild discomfort to life-threatening emergencies, affecting neurological, renal, gastrointestinal, and endocrine systems. Understanding these symptoms is vital for the timely identification and management of toxicity.

System	Symptom Example	Severity Range	Source(s)
Neurological	Confusion, tremor	Mild to severe	3 4 5
Gastrointestinal	Nausea, diarrhea	Mild to moderate	2 4 5
Renal	Polyuria, dehydration	Mild to severe	2 9 10
Endocrine	Hypothyroidism, hyperparathyroidism	Chronic, subtle to overt	1 2 3

Table 1: Key Symptoms of Lithium Toxicity

Neurological Manifestations

Lithium’s primary site of toxicity is the central nervous system. Symptoms can range from mild (fine tremor, mild confusion, lethargy) to severe (ataxia, coarse tremor, seizures, delirium, even coma) 3 4 5. Severe neurotoxicity is usually associated with chronic poisoning and is often linked to identifiable risk factors such as older age, hypothyroidism, and pre-existing kidney problems 3.

Gastrointestinal Symptoms

Early signs of lithium toxicity often include gastrointestinal upset—nausea, vomiting, and diarrhea—which can sometimes be mistaken for other illnesses. These symptoms are prevalent in both acute and chronic toxicity and may precede more severe neurological symptoms 2 4 5.

Renal Symptoms

Lithium is excreted almost entirely through the kidneys, and its toxicity frequently involves renal manifestations. Polyuria (excessive urination), polydipsia (excessive thirst), and dehydration are common, often due to lithium-induced nephrogenic diabetes insipidus 2 9 10. Chronic exposure may lead to decreased glomerular filtration rate and, rarely, chronic kidney disease 1 10.

Endocrine and Other Systemic Effects

Chronic lithium use increases the risk of hypothyroidism and hyperparathyroidism, which may present subtly as fatigue, weight gain, or muscle weakness 1 2 3. Weight gain and, less frequently, hypercalcemia (from hyperparathyroidism) are also observed 1 2. These symptoms can easily be overlooked unless specifically monitored.

Types of Lithium Toxicity

Lithium toxicity is not a single entity; rather, it is classified based on the pattern and context of exposure. Understanding the different types is essential for guiding treatment and anticipating complications.

Type	Description	Common Triggers	Source(s)
Acute	Large, single ingestion	Overdose, suicide attempt	3 4 5
Acute-on-chronic	Acute ingestion on background therapy	Adherence error, accidental	3 5
Chronic	Gradual accumulation over time	Impaired excretion, drug interactions	3 5 10

Table 2: Types of Lithium Toxicity

Acute Toxicity

Acute toxicity typically results from an intentional or accidental overdose in someone not previously taking lithium. In these cases, gastrointestinal symptoms dominate early, while neurotoxicity may be delayed due to slow lithium penetration into the brain 4 5. Surprisingly, severe neurotoxicity is less common in pure acute ingestions compared to chronic poisoning 3.

Acute-on-Chronic Toxicity

This type occurs when a patient already taking lithium chronically ingests an additional, often large, dose. Here, both acute GI symptoms and rapid-onset neurotoxicity may appear due to pre-existing tissue saturation with lithium 3 5.

Chronic Toxicity

Chronic toxicity is the most common and clinically significant form. It develops insidiously in patients on long-term therapy, usually because lithium intake exceeds renal elimination. This is often unintentional and may be triggered by factors like dehydration, intercurrent illness, or interactions with other drugs that impair kidney function 3 5 10. Chronic toxicity is closely associated with severe neurotoxicity and long hospitalizations 3 5.

Causes of Lithium Toxicity

Lithium toxicity arises when there is an imbalance between drug intake and the body's ability to eliminate it. Multiple factors can tip this balance, leading to dangerous accumulation.

Cause	Mechanism	Risk Factors	Source(s)
Impaired Renal Function	Reduced lithium excretion	Age, CKD, dehydration	3 5 9 10
Drug Interactions	Decreased lithium clearance	Diuretics, NSAIDs, ACE inhibitors	3 5
Nephrogenic Diabetes Insipidus	Volume depletion, increased serum lithium	Long-term lithium use	3 9
Thyroid Dysfunction	Impaired metabolism	Hypothyroidism	1 2 3

Table 3: Main Causes of Lithium Toxicity

Impaired Renal Excretion

Lithium is almost exclusively eliminated by the kidneys. Any condition that reduces renal function—such as chronic kidney disease, advanced age, or dehydration—increases the risk of toxicity 3 5 9 10. Even mild reductions in kidney function can significantly elevate lithium levels.

Drug Interactions

Medications that affect renal blood flow or tubular function can reduce lithium excretion. The most common culprits are thiazide diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), and ACE inhibitors 3 5. These drugs should be avoided or used with extreme caution in patients taking lithium.

Volume Depletion and Nephrogenic Diabetes Insipidus

Lithium can induce nephrogenic diabetes insipidus (NDI), leading to excessive urination and chronic mild dehydration. This, in turn, decreases lithium clearance and can precipitate toxicity, especially during intercurrent illnesses that cause vomiting or diarrhea 3 9.

Thyroid and Parathyroid Dysfunction

Lithium-induced hypothyroidism and, less commonly, hyperparathyroidism, not only have direct effects but also influence lithium metabolism and excretion, further increasing toxicity risk 1 2 3.

Other Contributing Factors

Other risk factors include older age (over 50), baseline low creatinine clearance, and episodes of elevated lithium levels due to dosing errors or nonadherence 3 10. These factors often act in combination, creating a “perfect storm” for toxicity.

Treatment of Lithium Toxicity

Prompt recognition and management of lithium toxicity can be lifesaving. Treatment strategies are tailored based on the type and severity of toxicity, kidney function, and the patient’s overall clinical status.

Approach	When Used	Key Actions	Source(s)
Supportive Care	All cases	Airway, fluids, monitoring	4 5 8
Discontinue Lithium	Any toxicity	Stop further absorption	4 5 8
Enhance Elimination	Moderate–severe cases	IV fluids, dialysis	4 5 8
Hemodialysis	Severe/prolonged toxicity	Rapid lithium removal	4 5 8

Table 4: Treatment Approaches for Lithium Toxicity

Immediate Supportive Measures

The first step in managing suspected lithium toxicity is to discontinue lithium and provide supportive care. This includes ensuring airway protection, intravenous hydration (to correct dehydration and promote lithium excretion), and close cardiac and neurological monitoring 4 5 8.

Enhancing Lithium Elimination

For mild cases, aggressive intravenous fluids may suffice to enhance renal clearance of lithium. In moderate-to-severe toxicity, especially when kidney function is impaired or neurological symptoms are pronounced, more advanced measures are needed 4 5 8.

Role of Hemodialysis

Hemodialysis is highly effective at removing lithium from the body and is the treatment of choice for severe cases. Indications for dialysis include:

• Impaired kidney function with lithium levels >4.0 mmol/L
• Decreased consciousness, seizures, or life-threatening arrhythmias (regardless of lithium level)
• Persistent or severe symptoms, or lithium level >5.0 mmol/L
• Failure to rapidly reduce lithium concentration by conservative means 4 5 8

Dialysis should continue until the patient shows clinical improvement or lithium levels fall below 1.0 mmol/L 8. Continuous renal replacement therapy is an alternative if hemodialysis is unavailable.

Monitoring and Follow-Up

Patients recovering from lithium toxicity require ongoing monitoring of lithium levels, renal function, thyroid, and parathyroid status. Long-term follow-up is crucial, especially in those who have sustained chronic or severe toxicity, due to the risk of persistent neurological or renal impairment 1 2 3 10.

Special Considerations

• Nephrogenic Diabetes Insipidus: Amiloride (an ENaC inhibitor) may help manage lithium-induced NDI, though its ability to prevent long-term damage is still under investigation 9.
• Hypothyroidism/Hyperparathyroidism: These should be diagnosed and managed appropriately; hypothyroidism responds well to levothyroxine supplementation 1 2 3.
• Drug Interactions: Review and adjust concomitant medications that may impair lithium clearance 3 5.

Conclusion

Lithium remains an invaluable treatment for mood disorders, but its safe use requires vigilance and proactive management. Here’s a summary of the key points about lithium toxicity:

• Symptoms: Can involve neurological, gastrointestinal, renal, and endocrine systems, ranging from mild to life-threatening.
• Types: Classified as acute, acute-on-chronic, or chronic, with chronic toxicity being most common and dangerous.
• Causes: Primarily due to impaired renal clearance, drug interactions, dehydration, and thyroid or parathyroid dysfunction.
• Treatment: Ranges from supportive care and stopping lithium to aggressive measures like hemodialysis in severe cases.
• Monitoring: Regular assessment of kidney, thyroid, and parathyroid function is essential during lithium therapy.

By understanding the warning signs, risk factors, and appropriate interventions, both patients and healthcare providers can work together to minimize the risks and maximize the benefits of lithium therapy.