Lithium toxicity occurs when lithium levels in the body rise above the therapeutic range, leading to harmful effects on various organs, especially the nervous system. The causes of lithium toxicity are multifactorial and often relate to how lithium is absorbed, distributed, metabolized, and excreted, as well as interactions with other medications and underlying health conditions.
At its core, lithium is a medication primarily used to treat mood disorders such as bipolar disorder. It has a narrow therapeutic window, meaning the difference between an effective dose and a toxic dose is small. Because lithium is almost entirely excreted by the kidneys, any factor that reduces kidney function or alters lithium clearance can cause lithium to accumulate to toxic levels.
One common cause of lithium toxicity is **decreased renal clearance**. The kidneys filter lithium out of the blood, so conditions that impair kidney function—such as dehydration, kidney disease, or reduced blood flow to the kidneys—can cause lithium to build up. For example, dehydration from vomiting, diarrhea, or excessive sweating reduces blood volume, which in turn decreases kidney filtration and lithium elimination, raising lithium levels dangerously.
Certain medications also interfere with lithium clearance by the kidneys. **Nonsteroidal anti-inflammatory drugs (NSAIDs)**, commonly used for pain and inflammation, reduce renal blood flow and lithium excretion, increasing the risk of toxicity even if the lithium dose remains unchanged. Similarly, **thiazide diuretics** (like hydrochlorothiazide), used to treat high blood pressure, decrease lithium clearance by reducing glomerular filtration rate and increasing lithium reabsorption in the kidney tubules. Other drugs such as ACE inhibitors and some calcium channel blockers can have similar effects.
Another cause of lithium toxicity is **excessive lithium intake**, either from accidental overdose or from taking lithium supplements or medications in amounts higher than prescribed. Because lithium is absorbed through the gastrointestinal tract, taking too much lithium at once can rapidly raise blood levels.
Changes in body sodium levels also influence lithium toxicity. Lithium and sodium compete for reabsorption in the kidneys. When sodium levels are low, the kidneys reabsorb more lithium to compensate, increasing lithium retention and toxicity risk. This is why low-salt diets or conditions causing sodium loss (like sweating or certain illnesses) can predispose to lithium toxicity.
Lithium toxicity can be **acute**, occurring shortly after a large dose, or **chronic**, developing gradually due to accumulation over time. Acute toxicity often presents with gastrointestinal symptoms like nausea, vomiting, diarrhea, and abdominal pain. Chronic toxicity tends to affect the nervous system more, causing symptoms such as tremors, confusion, dizziness, muscle weakness, and in severe cases, seizures or coma.
At the cellular level, lithium affects multiple neurotransmitter systems and intracellular signaling pathways. While therapeutic lithium stabilizes mood by modulating neurotransmitters like serotonin and norepinephrine and promoting neuroprotective factors, excessive lithium disrupts normal neuronal function. It can interfere with ion transport, enzyme activities, and mitochondrial function, leading to oxidative stress and cellular damage, particularly in the brain.
Other factors contributing to lithium toxicity include **age-related changes** in kidney function, as older adults naturally have reduced renal clearance, making them more susceptible. Additionally, conditions like hyperparathyroidism, which can be induced or worsened by lithium, may complicate the clinical picture by altering calcium metabolism and further affecting kidney function.
In summary, lithium toxicity arises mainly from impaired elimination due to kidney dysfunction, drug interactions that reduce lithium clearance, excessive intake, and changes in sodium balance. Its effects are most pronounced on the nervous system but can involve multiple organ systems. Careful monitoring of lithium blood levels, kidney function, hydration status, and concurrent medications is essential to prevent toxicity.
