Lithium Intoxication

Normally, lithium is not present in significant amounts in body fluids (<0.2 mEq/L). However, lithium salts have been used therapeutically for almost 150 years, beginning with its use for the treatment of gout (or urice acid diathesis) in the 1850s (1). Although gout was believed to include symptoms of mania and depression, it wasn't until the 1880s that John Aulde and Carl Lange observed that lithium could be used to treat symptoms associated with depression, independent of gout (1). However, the use of lithium became problematic and was discarded due to the serious toxicity associated with the widespread use of lithium in tonics, elixirs, and as a salt substitute (1). The modern era of lithium usage as a pharmacologic agent began with its “rediscovery” in 1950 by Cade and the clinical studies by Schou in the 1950s that established lithium as an effective treatment of manic-depressive illness (1). Lithium is now the drug of choice for treating bipolar affective disorders. It is successful in improving both the manic and depressive symptoms in 70 to 80% of patients (2). Lithium may also be used to treat alcoholism, schizoaffective disorders, and cluster headaches (3). Thus, lithium is an indispensable pharmaceutical component of modern psychiatric therapy. Unfortunately, lithium also has a narrow therapeutic index, with therapeutic levels between 0.6 and 1.5 mEq/L (Table 1) (2,3,4). The optimal steady-state concentration of lithium for maintenance treatment of bipolar disorders is generally considered to be 0.6 to 1.2 mEq/L, with slightly elevated steady-state concentrations (0.8 to 1.5 mEq/L) indicated for the acute management of manic episodes (5). Because toxicity can occur at levels >1.5 mEq/L, lithium levels must be carefully monitored and lithium dosage adjusted as necessary. This is especially true following changes in other medications that alter renal function, such as angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAID). Nephrologists require a thorough understanding of lithium since it is excreted by the kidney and its toxic side effects commonly affect renal function. In addition, the treatment of lithium intoxication usually requires consideration of the need for acute hemodialysis, a decision that should only be made by a nephrologist.Table 1: Lithium pharmacologyaPhysiology Lithium physiology has been studied extensively for almost 50 yr because of its use in treating manic-depressive illness. Lithium can substitute for sodium or potassium on several transport proteins that normally transport sodium or potassium, thus providing a pathway for lithium entry into cells. The pathways for transporting lithium out of cells are more limited, resulting in lithium accumulating intracellularly. It is important to realize that lithium does not equilibrate passively between intracellular and extracellular compartments. If lithium equilibrated passively across cell membranes, the lithium cell-to-plasma concentration ratio would be approximately 10 to 30 because of the negative membrane potential (-60 to -90 mV) of most cells. However, the measured cell-to-plasma lithium concentration ratio is actually much lower. For example, a ratio of 2 to 4 is found in rat vascular smooth muscle cells, rat brain slices, cultured neuroblastoma cells, and rat skeletal muscle cells (6). Thus, lithium must be actively transported out of most cells. Two of the major lithium transporting proteins are the sodium channel and the sodium—proton exchanger. Both transporters are inhibited by amiloride (1,6,7). The amiloride-sensitive sodium channel (ENaC) is a key transporter that is involved in sodium homeostasis in the collecting duct (Figure 1). This channel has approximately equal permeability to lithium and sodium (1,6,7) and is a major pathway for lithium accumulation in collecting duct cells.Figure 1: . Lithium transport pathways in proximal and distal tubule cells. (A) A schematic view of a proximal tubule cell is shown indicating putative apical and basolateral transport pathways for lithium. A transporter is indicated by a shaded oval buried in the membrane, with an arrow indicating the direction of lithium movement; however, an “X” adjacent to the arrow indicates that experimental evidence suggests that the transport pathway is unlikely for lithium. The apical transporters illustrated are the sodium—hydrogen exchanger (NHE), and two sodium-dependent cotransporters: The sodium—glucose shown with lithium and glucose moving on the transporter; the sodium-phosphate cotransporter with lithium and monohydrogen phosphate. However, the latter is not a likely pathway for lithium transport. The paracellular pathway is indicated as lithium movement through an intercellular junction. However, this is an unlikely pathway for lithium. The basolateral transporters illustrated are the sodium—potassium ATPase, which, as discussed in the text, is an unlikely lithium transport pathway and the putative sodium—lithium exchanger. (B) A schematic view of a distal tubule cell is shown indicating putative apical and basolateral transport pathways for lithium. A transporter is indicated by a shaded oval buried in the membrane, with an arrow indicating the direction of lithium movement; however, an “X” adjacent to the arrow indicates that experimental evidence suggests that the transport pathway is unlikely for lithium. The amiloride-sensitive sodium channel (ENaC) is indicated by the two parallel lines bisecting the apical membrane with lithium movement indicated by the arrow through the “channel.” The paracellular pathway is indicated as lithium movement through an intercellular junction. However, this is an unlikely pathway for lithium. The basolateral transporters illustrated are the same as those indicated for the proximal tubule cell.The Na/H exchanger is a ubiquitous transport system that is present on many cells in the body and is inhibited by amiloride (1,6,7). Under normal ph