Lithium Toxicity Clinical Presentation

As with all toxic ingestions, it is important to determine the amount, time, co-ingestants, and reason for ingestion. Toxicity does not often correlate with the measured lithium level since clinical toxicity is affected by the type of the poisoning.

Clinical features

Three main categories of lithium poisoning are as follows: acute, acute-on-chronic, and chronic.

Acute poisoning

These patients usually do not have a tissue body burden. SIgns and symptoms are predominantly gastrointestinal (GI), including nausea, vomiting, cramping, and sometimes diarrhea. Progression of acute toxicity can involve neuromuscular signs such as tremulousness, dystonia, hyperreflexia, and ataxia. Cardiac dysrhythmias have been reported but rarely occur. ^[5] The most common electrocardiographic finding is T-wave flattening.

Acute-on-chronic poisoning

These patients take lithium regularly and have taken a larger dose recently. These patients may display both GI and neurologic symptoms, and serum levels can be difficult to interpret. Patients should be treated according to their clinical manifestations.

Chronic poisoning

These patients typically have a large body burden of lithium and may be difficult to treat. Chronic lithium toxicity is usually precipitated by introduction of a new medication that may impair kidney function/excretion or cause a hypovolemic state. Cases have also been reported following bariatric surgery, which results in alteration of the pharmacokinetics of lithium. ^[6]

Lithium toxicity has been reported in association with COVID-19. The likely association in these cases is acute kidney injury from the COVID-19. ^[7]

Signs and symptoms of chronic lithium toxicity are primarily neurologic. Mental status is often altered and progression to coma and seizures may occur if the diagnosis is unrecognized.

Severely poisoned patients can develop the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). The presentation in these cases includes both neurologic and neuropsychiatric signs and symptoms, such as cognitive impairment, cerebellar dysfunction, brainstem dysfunction, extrapyramidal symptoms, choreoathetoid movements, myopathy, nystagmus, and even blindness. Risk factors for SILENT are age above 50 years, chronic lithium therapy, development of nephrogenic diabetes insipidus, hyperthyroidism, and impaired renal function. ^{[4, 8]}

Drug interactions

The following three major drug classes have been identified as potential precipitants of lithium toxicity:

• Diuretics that promote renal sodium wasting
• Angiotensin-converting enzyme (ACE) inhibitors that reduce glomerular filtration rate (GFR) and enhance the tubular reabsorption of lithium
• Nonsteroidal anti-inflammatory drugs (NSAIDs) that reduce the glomerular filtration rate (GFR) and interrupt of renal prostaglandin synthesis

Systemic effects

Kidney toxicity is common with chronic lithium therapy, and may take any of the following forms:

• Nephrogenic diabetes insipidus (NDI)
• Renal tubular acidosis
• Chronic tubulointerstitial nephritis
• Nephrotic syndrome.

NDI is the most severe manifestation. Lithium inhibits the action of antidiuretic hormone (ADH) on the distal renal tubule, impairing sodium and water reabsorption. Following a cross-sectional study showing that use of statins is associated with lower NDI risk, an international group has initiated a randomized controlled study in lithium users who have indicators of NDI, to determine whether atorvastatin improves urine osmolality and aquaporin excretion. ^[9]

The most common endocrine disorder secondary to chronic toxicity is hypothyroidism. Lithium is taken up avidly by thyroid cells and blocks thyroid hormone release from thyroglobulin, which inhibits adenylate cyclase and prevents thyroid-stimulating hormone (TSH) from activating thyroid cells via the TSH receptor. ^[10] It may also affect thyroid hormone synthesis. Myxedema coma has been reported as a complication of toxicity.

Acute exposure to lithium can cause leukocytosis, whereas chronic exposure can produce aplastic anemia.

Patients who are on long-term lithium therapy can develop localized edema, dermatitis, and skin ulcers.

Neurologic effects of lithium toxicity include the following:

• Tremors
• Lethargy
• Confusion
• Seizures
• Coma

Gastrointestinal effects of lithium toxicity include the following:

• Nausea
• Vomiting
• Crampy abdominal pain
• Diarrhea

Mild-to-moderate lithium toxicity is characterized by tremor, weakness, and mild confusion. Moderate-to-severe lithium toxicity is characterized by the following:

• Altered mental status
• Muscle fasciculations
• Stupor
• Seizures
• Coma
• Hyperreflexia
• Cardiovascular collapse