Lithium Toxicity

Etiology

Lithium is neither protein bound nor metabolized and is almost entirely eliminated by renal excretion through glomerular filtration and tubular sodium-coupled reabsorption. Consequently, even minor changes in volume status, renal perfusion, or sodium balance can produce clinically significant changes in serum lithium concentrations.[BJPsych Advances. Management of Lithium Intoxication]

Lithium toxicity most commonly results from reduced renal clearance rather than excessive ingestion, although both mechanisms may occur. Common causes include the following:

• Reduced renal function: Decreased glomerular filtration reduces lithium clearance. Examples include chronic kidney disease, acute kidney injury, and older age.
• Volume or sodium depletion: Because the kidney handles lithium similarly to sodium, states of sodium or volume depletion increase renal lithium reabsorption and decrease excretion. Examples include dehydration, vomiting, diarrhea, fever, lithium-induced nephrogenic diabetes insipidus, and low-sodium diets.
• Medication interactions: Certain medications alter renal hemodynamics or sodium handling, increasing lithium reabsorption or reducing clearance. Examples include nonsteroidal anti-inflammatory drugs, thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.
• Excess lithium intake: Acute overdose or excessive dosing may overwhelm renal elimination. Examples include suicide attempts, accidental ingestion, or dosing errors.[7]

Epidemiology

The true incidence of lithium toxicity is likely underestimated because mild or chronic cases may present with nonspecific symptoms, and serum lithium concentrations do not always correlate with clinical toxicity. Outpatient cases may therefore go unrecognized or unreported. Results from one retrospective cohort study of patients receiving lithium between 1997 and 2013 showed that 96 of 1340 patients (7%) experienced at least one episode with a lithium concentration greater than 1.5 mmol/L. A subgroup of 77 patients experienced a total of 91 episodes of toxicity, of which 34% required intensive care and 13% required hemodialysis. Renal function generally returned to baseline after the episode.[7] Results from another case-control study showed a lithium toxicity rate of approximately 2% over a 5-year period.[8] The risk of lithium toxicity is higher in certain populations, particularly older adults, individuals with impaired baseline renal function, and patients taking medications that change renal perfusion or sodium handling.[9] 

Pathophysiology

The precise mechanisms underlying lithium’s therapeutic and toxic effects remain incompletely understood.[4] Lithium modulates several intracellular signaling pathways, including inhibition of glycogen synthase kinase-3β (GSK-3β) and effects on inositol-dependent second messenger systems.[10] These actions influence neurotransmitter signaling, neurotrophic factors, oxidative metabolism, apoptosis, and neuronal and glial function. Results from studies showed that lithium also affects broader biological systems, including circadian regulation and the hypothalamic–pituitary–adrenal axis.[11]

Toxicokinetics

Absorption

Lithium is rapidly absorbed after oral administration, with bioavailability ranging from 80% to 100%. Time to peak serum concentration depends on the formulation, occurring approximately 1 to 2 h after immediate-release preparations and 4 to 5 h after sustained-release or controlled-release formulations. Complete absorption generally occurs within 6 to 8 h.[12][13]

Distribution

Lithium is widely but variably distributed throughout body tissues and is preferentially taken up by the thyroid and kidneys. Lithium does not bind to plasma proteins. Distribution into the central nervous system occurs slowly, and brain concentrations typically lag behind serum levels. Cerebrospinal fluid concentrations are generally estimated to be about half of serum concentrations but may approach 70% to 80%, depending on the timing of measurement and duration of exposure.[13]  Because lithium distribution into the central nervous system occurs slowly, neurologic symptoms may develop even as serum lithium concentrations decline.

Elimination

Lithium is eliminated almost entirely by the kidneys. The glomerulus freely filters lithium, and the proximal tubule reabsorbs 80% of it via sodium transport pathways, which explains why alterations in sodium balance and volume status can significantly affect lithium clearance. Small amounts may be excreted in sweat and feces, and lithium follows first-order kinetics.[BJPsych Advances. Management of Lithium Intoxication] The elimination half-life is typically 18 to 24 hours after a single dose but may extend to 48 to 58 hours in older adults or during chronic therapy because of increased tissue distribution and reduced renal clearance.[BJPsych Advances. Management of Lithium Intoxication] Ongoing gastrointestinal absorption, particularly after sustained-release preparations or large ingestions, may prolong the apparent elimination phase.[12][14]

History and Physical

Lithium toxicity presents with a range of symptoms and physical examination findings affecting multiple organ systems and may range from asymptomatic to clinically severe poisoning. The pattern of toxicity can influence the clinical presentation. Patients with acute toxicity are more likely to be asymptomatic despite high lithium concentrations and may initially present with gastrointestinal symptoms.[BJPsych Advances.[Management of Lithium Intoxication][14] Chronic and acute-on-chronic toxicity are associated with sustained tissue accumulation and prolonged exposure, leading to greater toxicity. This pattern is more often associated with neurologic impairment even at relatively lower lithium concentrations. Severe toxicity may lead to life-threatening complications and long-term sequelae.[14]

Neurologic

The central nervous system is the most commonly affected organ system, particularly in chronic toxicity. Findings may include drowsiness, coarse tremor, slurred speech, hyperreflexia, agitation, muscle weakness, nystagmus, and ataxia. More severe toxicity may cause progressive mental status changes and seizures, progressing to delirium and eventually coma.[5][7][5][BJPsych Advances. Management of Lithium Intoxication]

Gastrointestinal

Gastrointestinal symptoms include nausea, vomiting, and diarrhea. These symptoms are often the earliest manifestations of acute toxicity and typically occur soon after ingestion.[5]

Renal

Renal manifestations include polyuria and polydipsia due to impaired urinary concentrating ability.[15] Acute kidney injury may occur, although sustained renal impairment is uncommon.[15]

Cardiac

Cardiac manifestations include bradycardia, prolonged corrected QT intervals, and arrhythmias. Cardiovascular collapse may occur in patients with severe toxicity.[16]

Evaluation

Clinical Assessment

Key clinical factors requiring assessment include:

• Acute, acute-on-chronic, or chronic ingestion
• Time since acute ingestion
• Time of last lithium intake
• Regular lithium dose, formulation, and duration of use
• Lithium dose changes
• Signs and symptoms and time since onset
• Prior lithium concentration measurements (if available)
• Medical conditions
• Medications (regular and recently taken, including over-the-counter agents)
• Additional drugs ingested in cases of intentional ingestion [BJPsych Advances. Management of Lithium Intoxication]

Evaluation

Clinical findings of toxicity commonly occur at lithium concentrations greater than 1.5 mmol/L. Toxicity has traditionally been categorized as mild (1.5–2.5 mmol/L), moderate (2.5–3.5 mmol/L), and severe (> 3.5 mmol/L).[17] However, serum lithium concentrations should be interpreted cautiously. Initial concentrations may not represent peak concentrations, and serum lithium concentrations should always be interpreted in conjunction with clinical findings because levels may not correlate with severity, particularly in cases of chronic toxicity. For example, falsely elevated lithium concentrations may occur if blood samples are collected in tubes containing lithium heparin. [18]

Any patient who is prescribed or has access to lithium and develops vomiting, confusion, or cerebellar signs should be presumed to have lithium toxicity until proven otherwise. Clinicians should maintain a low threshold for measuring serum lithium concentrations when concerning symptoms occur. Evaluation of suspected lithium toxicity includes assessment of vital signs, serial serum lithium measurements, renal function, electrolytes, and evaluation for potential coingestants.[19]

Bedside assessment:

• Vital signs
• Temperature (hypothermia or hyperthermia)
• Blood pressure (hypotension or hypertension)
• Respiratory rate
• Oxygen saturation
• Point-of-care glucose measurement
• Pregnancy test [BJPsych Advances. Management of Lithium Intoxication]

Laboratory studies:

• Serum lithium concentration
• Initial measurement and every 2-4 hours during treatment
• Every 6-12 hours once levels are decreasing
• The pattern may help distinguish acute from chronic intoxication
• Renal function
• Electrolytes
• Serum sodium level
• Monitor every 6-12 hours
• Monitor more frequently if:
• Symptomatic hyponatremia
• Nephrogenic diabetes insipidus
• Abnormal sodium results on initial testing
• Anion gap (may be low)
• Urine specific gravity (evaluation for nephrogenic diabetes insipidus)
• Thyroid-stimulating hormone [BJPsych Advances. Management of Lithium Intoxication][5][20]

Toxicology testing (coingestion):

• Acetaminophen level
• Salicylate level
• Additional toxicology testing may be considered depending on clinical suspicion 

Cardiac evaluation: 

• Electrocardiogram findings may include:
• Corrected QT interval prolongation
• Atrioventricular block
• T-wave flattening
• Bradycardia [BJPsych Advances. Management of Lithium Intoxication]

Imaging

• Neuroimaging may be considered when alternative neurologic diagnoses such as stroke are suspected.

Treatment / Management

The approach to management of lithium toxicity varies depending on the degree of toxicity. Discontinuation of lithium may be sufficient for mild toxicity. Management of moderate toxicity generally includes supportive care and intravenous isotonic fluids to promote renal lithium clearance. After recent large ingestions, gastrointestinal decontamination, such as gastric lavage or whole-bowel irrigation with polyethylene glycol, particularly for sustained-release preparations, may be considered.[BJPsych Advances. Management of Lithium Intoxication][20] General measures used in poisoning management, including airway protection, should be implemented when clinically indicated. Lithium does not bind to activated charcoal, although charcoal may be administered when coingestion of other substances is suspected. In severe lithium toxicity, extracorporeal treatment is recommended.[19](A1)

Indications for Extracorporeal Treatment

Current recommendations for extracorporeal treatment described below are largely based on the Extracorporeal Treatments in Poisoning Workgroup guidelines.[19] However, clinical judgment remains essential when applying these recommendations, and more recent work has sought to refine patient selection by considering factors such as the pattern of toxicity (acute versus chronic).[20][21](A1)

Extracorporeal treatment is recommended when:

• Kidney function is impaired, and the serum lithium concentration exceeds 4.0 mmol/L
• Decreased level of consciousness, seizures, or life-threatening dysrhythmias are present, regardless of lithium concentration

Extracorporeal treatment is suggested when:

• The serum lithium concentration exceeds 5.0 mmol/L
• Significant confusion is present
• The expected time to reduce the serum lithium concentration to < 1.0 mmol/L exceeds 36 hours 

Hemodialysis is the preferred extracorporeal treatment, although continuous renal replacement therapy is an acceptable alternative. When hemodialysis is required, repeated sessions may be necessary because of lithium redistribution and rebound after dialysis.[BJPsych Advances. Management of Lithium Intoxication][22] Careful monitoring of volume status and serum sodium levels is important to correct common contributors to chronic lithium toxicity and prevent hypernatremia during fluid resuscitation.

Disposition

Hospital admission should be considered for individuals with clinical signs and symptoms of toxicity and for those receiving chronic lithium therapy with a serum lithium concentration greater than 2.0 mmol/L. Intensive care unit admission is indicated for individuals with severe or life-threatening manifestations, including cardiovascular collapse, respiratory depression, severe neurologic symptoms, severe hyperthermia, or renal failure, or those with serum lithium concentrations greater than 4.0 mmol/L. Discharge may be considered once clinical improvement has occurred and serum lithium concentrations remain less than 1.5 mmol/L, which may require several days depending on the lithium formulation. Patients with intentional lithium overdose should undergo evaluation and treatment of acute suicidality, typically through a psychiatric or combined medical and psychiatric service.[BJPsych Advances. Management of Lithium Intoxication]

Reintroduction of Lithium

No standardized guidelines address the reintroduction of lithium after lithium toxicity. Decisions should be individualized and ideally involve an interdisciplinary team in collaboration with the patient.

Differential Diagnosis

Clinicians must distinguish lithium toxicity from other conditions that may present with altered mental status and neurologic findings. Neuroleptic malignant syndrome and serotonin syndrome warrant particular consideration because both may occur in patients receiving lithium and can be life-threatening. Additional conditions to consider include the following:

Toxicologic Causes

• Serotonin syndrome • Neuroleptic malignant syndrome • Anticholinergic toxicity • Sedative-hypnotic intoxication

Metabolic and Endocrine Causes

• Hypoglycemia • Thyrotoxicosis • Electrolyte abnormalities

Neurologic Causes

• Stroke • Central nervous system infection • Traumatic brain injury [BJPsych Advances. Management of Lithium Intoxication]

Prognosis

The prognosis of lithium toxicity is generally favorable with prompt recognition and treatment, and mortality rates have decreased and are currently estimated to be less than 1%.[23] Nevertheless, significant morbidity may still occur because lithium toxicity can affect multiple organ systems, including the central nervous system, thyroid, cardiovascular system, and kidneys.[24] Most signs and symptoms do resolve as serum lithium concentrations decline. Older adults and individuals with impaired renal function or significant medical comorbidities may experience a more prolonged clinical course due to reduced lithium clearance and increased susceptibility to neurologic sequelae.[25]

The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) has been described in the literature since 1965 and includes permanent neurologic damage following lithium treatment, even without toxic serum concentrations or after treatment discontinuation. [26] The syndrome predominantly manifests as cerebellar dysfunction, with features of ataxia, dysarthria, and dysmetria. Although rare, SILENT is likely underreported.

Complications

Although complications of lithium toxicity are uncommon, persistent neurologic dysfunction may occur in rare cases, including cerebellar abnormalities described in the syndrome of irreversible lithium-induced neurotoxicity. Acute kidney injury may also occur but is typically reversible with appropriate treatment.