DISEASE OF THE MONTH 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 uric 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) (2–4). 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 steadystate 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. Physiology 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-toplasma concentration ratio would be approximately 10 to 30 because of the negative membrane potential (260 to 290 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. 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 physiologic conditions, Na/H exchange is responsible for the majority of sodium reabsorption across the proximal tubule. This protein will transport lithium in place of sodium, although the maximal transport rate is twofold slower for lithium than sodium (1,6,7), and is a major pathway for lithium transport into cells. Another candidate lithium transporter is the Na-K-2Cl cotransporter (NKCC2, BSC1), which is found in the apical membrane of the thick ascending limb of the loop of Henle and is inhibited by furosemide (1,6,7). NKCC2 (BSC1) catalyzes the electroneural transport of one sodium, one potassium, and two chloride ions. In this transport scheme, lithium can substitute for sodium, but this varies with tissue and species and has been demonstrated for membrane vesicles from rabbit medullar thick ascending limb, ascites tumor cells, and in the Madin-Darby canine kidney cell line (6). Finally, although the Na/K-ATPase (“the sodium pump”) is an obvious candidate for moving lithium across cell memCorrespondence to Dr. Jeff M. Sands, Emory University School of Medicine, Renal Division, WMRB Room 338, 1639 Pierce Drive, NE, Atlanta, GA 30322. Phone: 404-727-2435; Fax: 404-727-3425; E-mail: [email protected]