Chronic toxicity can be triggered by a variety of factors that lead to decreased renal function, which in turn impairs the elimination of lithium from the body. Lithium is a monovalent cation and alkali earth metal; its mechanics of reabsorption are very similar to those of sodium, with reabsorption occurring in the proximal tubule, distal tubule, and collecting duct. Conditions that lead to greater sodium reabsorption also increase reabsorption of lithium. Illness that results in hypovolemia from fluid loss can cause an acute kidney injury and thereby decrease elimination. Drugs that lower the glomerular filtration rate (GFR), such as nonsteroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors, also reduce elimination. Medications that promote renal absorption, such as thiazide diuretics and spironolactone, cause reabsorption of both sodium and lithium via the same mechanisms. Other known risk factors include the presence of nephrogenic DI, age older than 50 years, and the presence of thyroid dysfunction.
Long-term use of lithium is associated with renal impairment. Nephrogenic DI is the most common adverse effect observed in patients who are receiving long-term lithium therapy.[10,11] Lithium interferes with the kidney's ability to concentrate urine, owing to a loss of responsiveness to vasopressin.[12,13] Polyuria leads to volume contraction and subsequent hypernatremia, hyperchloremic metabolic acidosis, and distal renal tubular acidosis.[6,13] These fluid losses trigger increased reabsorption of sodium and also lithium, reducing both the GFR and lithium excretion.
The mechanisms by which lithium affects the kidney's ability to concentrate urine can help shed light on the treatment of lithium-induced nephrogenic DI. Lithium enters the principal cells of the collecting duct via the epithelial sodium channel (ENaC), which is more permeable to lithium than to sodium.[8,10,12,13] Although sodium is removed from the cell by sodium/potassium adenosine triphosphatase (Na/K ATPase), lithium is not, causing intracellular levels of lithium to rise. This interferes with the cell's responsiveness to aldosterone and vasopressin, which, in turn, limits insertion of aquaporin-2 and leads to decreased water reabsorption. Amiloride, which blocks the ENaC, has a theoretical benefit by blocking lithium entry and thereby restoring urine concentrating ability. However, its onset of action is slow (weeks), and it does not significantly enhance lithium elimination, limiting its use in current practice.[2,14] Thiazide diuretics, which are useful in treating other forms of nephrogenic DI, should be avoided because they reduce lithium excretion, resulting in further toxicity.
Lithium also induces cyclooxygenase-2 (COX-2) expression in the kidney medulla. Increased COX-2 leads to the production of prostaglandin E2 (PGE2), which interferes with the ability of the collecting duct to concentrate urine by modulating the expression of aquaporin-2 (Figures 1 and 2). Treatment with indomethacin, which blocks PGE2, has been shown to enable the kidney to concentrate urine.[14 ]
Figure 2. Impaired function by lithium. Lithium enters the cell via the ENaC, which has a higher affinity for lithium than sodium. The Na/K ATPase at the basal surface cannot pump lithium out of the cell, causing lithium to build up intracellularly. Amiloride, which blocks the ENaC, has a theoretical benefit by blocking entry of lithium into the cell. Intracellular lithium interferes with the cell's ability to insert AQP-2 into the membrane, decreasing water reabsorption. Lithium stimulates production of PGE2, which interferes with the effect of vasopressin on the cell. This, in addition to the intracellular interference, reduces AQP-2 insertion and water reabsorption. Indomethacin, a PGE2 inhibitor, helps restore concentrating ability.
AQP = aquaporin; ENaC = epithelial sodium channel; Na/K ATPase = sodium/potassium adenosine triphosphatase; PGE2 = prostaglandin E2
Lithium has several endocrine effects. Hypothyroidism commonly occurs because of lithium's inhibitory effects on thyroid hormone production and secretion. Hypothyroidism can lower the GFR and thereby decrease lithium excretion. Although not directly caused by lithium, hyperthyroidism increases lithium reuptake, which can result in toxicity. Lithium also interferes with calcium sensing, which can lead to hyperparathyroidism.Hypercalcemia can cause osmotic diuresis, resulting in volume depletion.
The manifestations of lithium toxicity range from a lack of symptoms to profound neurotoxicity. Common symptoms include gastrointestinal (GI) distress (nausea, vomiting), muscle weakness, slurred speech, tremor, nystagmus, and ataxia. More severe intoxication can cause seizures, hyperthermia, delirium, and coma.
The workup includes obtaining and trending lithium levels and evaluation of electrolyte levels, kidney function, and thyroid function. Lithium levels should not be drawn in tubes containing lithium heparin because this can falsely elevate the level. Acetaminophen, salicylate, and ethanol levels should also be obtained in case of possible co-ingestion. An ECG may reveal nonspecific T-wave abnormalities, QTc prolongation, or bradycardia. Hypotension can occur in severe cases.
Treatment of lithium toxicity is aimed at preventing absorption and promoting elimination to lower serum levels and improve clinical symptoms. The first step in preventing absorption is to hold the patient's lithium and discontinue medications that can lead to increased lithium levels through impairment of kidney function. Although activated charcoal is useful in many types of overdoses, it has no role in lithium toxicity owing to its limited ability to bind metals. In cases of severe toxicity or toxicity from sustained-release formulations, whole-bowel irrigation with polyethylene glycol electrolyte solution (PEG-ES) can be considered to speed transit through the GI tract in an effort to limit absorption. The recommended regimen is 1-2 L/h of PEG-ES via nasogastric tube until the rectal effluent is clear.
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