Lithium Intoxication (1999)

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 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 co-transporter (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 membranes, studies in human erythrocytes show that Na/K-ATPase has an affinity for lithium that is at least an order of magnitude less than that for sodium or potassium (1,6,7). Under normal physiologic conditions, it is unlikely that lithium is transported by the pump. Thus, this ubiquitously expressed protein that is localized to the basolateral membrane of tubule cells can be ruled out as pathway for lithium exit across the basolateral membrane. Another possible pathway for lithium transport into cells is by substitution of lithium for sodium on sodium-dependent cotransport pathways, such as sodium—glucose, sodium—amino acids, sodium—phosphate, or sodium—dicarboxylic acids. These cotransport systems are generally localized to the proximal tubule. Several sodium-amino acid cotransporters are activated by lithium, albeit at only 5 to 20% of the rate that sodium activates these same cotransport systems (6). However, lithium will not, or will only poorly, substitute for sodium on the renal forms of the sodium—glucose (6), sodium—dicarboxylic acid (8), and the sodium—phosphate cotransporters (9). In contrast, the intestinal sodium—dicarboxylate cotransporter readily accepts lithium as a substitute for sodium, showing approximately 50% of the transport activity compared with sodium (8), and the erythrocyte sodium—phosphate cotransporter is activated by lithium, showing approximately 20% of the activity compared with sodium (R. T. Timmer and R. B. Gunn, personal communication). One likely candidate for the extrusion of lithium from cells is via the sodium—sodium exchange protein (10,11). This sodium—sodium exchange process is well characterized in erythrocytes but is not described in the kidney. The transport mediated by this pathway is electroneutral exchange (in either direction) of sodium for sodium, lithium for lithium, and importantly, sodium for lithium (10,11). This transporter has been variously called the sodium—sodium exchanger, the sodium—lithium exchanger, and the sodium-lithium countertransporter. Its affinity for lithium is approximately 15- to 18-fold greater than that for sodium (10,11). Patients treated with lithium for a bipolar disorder typically have serum sodium and lithium concentrations of approximately 140 mEq/L and 0.6 to 1.5 mEq/L, respectively (10,11). Thus, the outside binding site would normally bind sodium and transport it down its electro-chemical gradient into the cell. On the intracellular side of the membrane, the concentration of sodium is much lower (approximately 10 mEq/L). Thus, the inside binding site would preferentially bind lithium (10,11), resulting in a secondary active transport pathway to pump lithium out of the cell. Although some findings suggested that sodium—sodium exchange in erythrocytes (and brain) is mediated by the Na/H exchanger, this is unlikely in light of current evidence (6,10,11). Hence, the molecular basis for this transport is currently unknown. It should be noted that the exchange activity must be a secondary property of whatever membrane protein is catalyzing this reaction because there is no teleologic reason for a cell to have a transporter that would normally catalyze the futile exchange of sodium on the outside for sodium on the inside of the cell. The biophysics and pathophysiology of the sodium—sodium exchanger has been recently reviewed in detail elsewhere (10,11). As discussed below, approximately 60% of filtered lithium is reabsorbed in the proximal tubule. It is possible that lithium is passively reabsorbed through a paracellular pathway. However, this seems unlikely because there is no substantial electrochemical driving force since the tubular fluid-to-plasma lithium concentration ratio is 1 and the transepithelial potential difference is negligible in the proximal tubule (6). Another mechanism for paracellular reabsorption in the absence of an electrochemical driving force would be if the proximal tubule had an extraordinarily high permeability to lithium. However, lithium and sodium have nearly identical diffusive rates in the proximal tubule, thus arguing against this possibility (6). The possibility of paracellular lithium reabsorption by solvent drag is also unlikely for two reasons (6): (1) it is highly improbable that the reflection coefficient of lithium is 0; and (2) although current evidence is controversial, it seems that a substantial amount of water movement in the proximal tubule is by a transcellular and not a paracellular pathway. If reabsorption in the proximal tubule is primarily via a transcellular pathway, then the details of this mechanism cannot be explained in terms of the current knowledge of lithium-transporting pathways. The movement of lithium into cells from the luminal fluid can be ascribed to several possible pathways, including Na/H exchange and sodium-dependent cotransport processes (e.g., sodium—glucose cotransport). However, the movement of lithium out of cells across the basolateral membrane cannot be reasonably described by any currently known basolateral transporter. This membrane normally has a low permeability to sodium, and there is no reason to expect that the permeability for lithium is appreciably different in lithium-treated individuals (6). Therefore, it is unlikely that lithium moves across the basolateral membrane by a passive leak pathway. As discussed above, it is equally unlikely that Na/K-ATPase is responsible for transporting lithium out of cells. One hypothesis to explain transit of lithium across the basolateral membrane is that a sodium—sodium exchange protein similar or identical to that found in erythrocytes is localized to this membrane. A similar conundrum exists to explain lithium reabsorption in the remainder of the kidney. Intracellular Signaling Pathways The intracellular effects of lithium are multiple and have been the focus of considerable research, in part to provide a molecular basis for understanding the efficacy of lithium in the treatment of bipolar disorders. The effects of lithium in the brain on neuro-transmitter systems, neuropeptide systems, signal transduction pathways, and gene expression have recently been reviewed (1). The cAMP signal transduction pathway is a major for intracellular lithium effects and is important for several kidney including maintenance of normal water Lithium in a of cell including renal a lithium for 4 and a therapeutic serum lithium of have a 60% in cAMP in to (or This to be as cAMP activity and in lithium-treated is similar to The of lithium on may be and an with proteins that bind to the of the proteins Lithium also in the cultured renal cell line these cells in 10 lithium, the concentration found in lithium-treated intracellular concentration and in a in cAMP these cells with the of lithium The from these and other studies is that lithium, at least in renal the cAMP signal transduction pathway by with for of which the of These may at least in for the associated with lithium is also evidence that lithium in the (1). Lithium is a that must be with an Lithium is generally either as a or a A lithium of lithium (2). Lithium is from the in with serum levels 1 to 2 Lithium is also in serum levels generally 4 to 5 but can to for to 4 in patients with these In addition, some patients lithium as a at than as a a and may have lithium levels that are than with a (5). Thus, one must serum lithium levels a toxic to the that the Lithium is in body water and does not bind to serum proteins (2). It has a of of to (2). is a with in (e.g., (e.g., (5). in for some the in the brain is by approximately compared with (5). The concentration of lithium the fluid is only of serum levels due to its transport out of the fluid by brain (2). Lithium has a its include of lithium and of renal (2). Lithium has an of to a but its can to as as in individuals or patients lithium (2). Thus, one must lithium levels several a toxic because its rate of is and cannot be in any The of lithium is generally described as an and clinical by are made serum the at least 10 an (5). Lithium in the Lithium is excreted almost by the (2). Lithium is filtered by the since it is not to serum proteins (2). In the proximal tubule, lithium is to sodium (2). Thus, that or proximal tubule such as will serum lithium that proximal tubule sodium such as or will lithium and serum lithium 80% of the lithium that is filtered by the is the remainder is excreted in the (2). the filtered lithium, 60% is reabsorbed in the proximal tubule and 20% between the loop of Henle and the collecting duct (2). Lithium reabsorption can be by loop and by indicating that some lithium reabsorption in both the thick ascending limb of the loop of Henle and in the collecting duct (2). of Lithium are of lithium acute on and (3). in individuals are not treated with lithium. acute in in a with a treated with lithium and it such as a can also occur typically as a generally less and patients have symptoms than observed in other forms of lithium since the is in Lithium levels need to be and may be especially if renal is on in patients treated with lithium an (3). This may be or especially in patients with bipolar disorders are This of is generally more than acute due to the of the lithium (3). concentrations to 4 mEq/L are associated with symptoms and generally require toxicity in patients lithium (3). can occur in patients lithium dosage has been or in individuals renal has resulting in an in serum lithium levels (3). The of lithium intoxication with the serum lithium concentration and may be as to to or mEq/L) (5). symptoms may be present concentrations are well the therapeutic associated with include muscle and (Table toxicity is associated with and changes or which can be is associated with renal and However, the clinical of lithium toxicity is only with serum drug and there is in associated with a Thus, management of toxicity should be primarily by and not serum symptoms associated with lithium most of lithium toxicity is (2). Lithium in changes including and in the (2). patients and (2). Lithium toxicity may also including and (2). must be to symptoms from especially in patients also present with an Lithium can or (2). Lithium is the and and (3). Thus, lithium can and However, it can also and Lithium may also and (3). A of and lithium patients for an of yr and found an and of with a of and This also found that the was either or only in to of patients treated with lithium for 10 to yr in serum levels to normal 1 to 4 lithium was These findings an between the of lithium treatment and the of of can it could Lithium does not in and some patients normal levels elevated serum A patients and found that levels the of the However, there was no in serum or or in the tubular reabsorption of to The and the 2 yr of the that was for Lithium that the for toxicity in patients (Table include other and in potassium or sodium that alter renal can the for lithium toxicity and the reabsorption of lithium and in serum lithium concentrations (Table In one of an or steady-state lithium concentrations lithium was by and patients with symptoms of lithium toxicity The noted that was a to this and that patients may be to this a because many of these are now a and patients may potential for with that the for lithium with have a significant potential to serum lithium These a that to a in the reabsorption of sodium (and in the proximal tubule (5). This of has been suggested in many lithium toxicity to and has also been in a of studies (5). In therapeutic of in a to in lithium with a in serum lithium levels (5). The of this is and the most is to the use of if Another is a illness that in either true or effective A is a a such as a the or that in or The in will proximal tubule sodium similar to the of and also in an in proximal lithium reabsorption and serum lithium include in serum potassium or sodium the renal tubular reabsorption of lithium thus to toxic serum levels of lithium. potassium concentrations can have effects on serum lithium For example, acute lithium reabsorption in In potassium from to mEq/L water reabsorption and lithium reabsorption However, in potassium can in lithium reabsorption in the rat In a low potassium lithium is reabsorbed by an amiloride-sensitive transport mechanism in the distal and of lithium is by almost 50% compared with that of The most side of lithium is with an of to Patients present with and an to treatment with lithium in a in the water channel in the apical membrane of cells in the collecting and a of water serum lithium levels are therapeutic This side is important since patients with must fluid to with to will proximal reabsorption and serum lithium the at for acute on lithium Because of the of some treating to One is to lithium dosage to a serum of to mEq/L that the psychiatric symptoms can be by this lower The lower lithium levels can the Another is to treat the with similar to the used for other forms However, as discussed above, may since the must a for to be and can lithium levels and its toxicity may also and can or One the successful use of for the treatment of in a However, the use of any for has not been and may serum lithium levels by is currently the treatment of choice for does not and does not require the to be on sodium thus the of can also lithium into cells since it lithium transport by the amiloride-sensitive sodium channel can to lithium-treated patients However, lithium dosage should be amiloride since it can alter lithium levels The of lithium In several studies in which renal in lithium-treated either for or found that with These findings tubular and and and These patients either had no or only a in A of patients renal treated with lithium for 10 yr at in these patients serum from to 1.2 The that there was a significant between the of lithium and the of serum but the was only and the serum was the normal The studies used as studied psychiatric patients as not treated with lithium and found that on renal in these patients similar to those treated with lithium This the of from a psychiatric disorder than from lithium Another found that patients treated with both lithium and had more and more changes on renal than patients treated with lithium However, these patients also had more psychiatric disorders and had been treated with lithium for of studies a that in lithium-treated patients but not in psychiatric The distal and collecting have with and Thus, the of lithium a serious for and renal is patients have been to the or from lithium the most is to serum levels in lithium-treated patients and to lithium levels as low as possible to the of toxicity the psychiatric must be carefully the of treatment with lithium since the of and is lithium is Thus, it is important to in renal that lithium can be or the serious of renal Lithium may present in several different However, the management is similar (Table If the has with the must be A lithium and an should be to the of intoxication and renal function. A should be and of activated is not because it does not bind lithium Several studies to lithium from the and to its This is especially important for patients a lithium of lithium in management is Patients with may present with may also to of the of patients should normal to and and to a of normal patients must be monitored to especially in those with the management to lithium from the In patients with normal renal function, the can lithium at a rate of 10 to (2). In normal should lithium by proximal However, clinical studies have shown no in lithium with in patients present with true (2). Thus, this is not Another is the use of the exchange sodium to lithium in exchange for sodium This has shown some in clinical studies However, the of has not been studied and may The for lithium is only to of lithium and is not for treating lithium can lithium by 1 mEq/L 4 of treatment (3). should be of more lithium of hemodialysis, but are not The should be in place because treatment must be since does not intracellular lithium Thus, serum lithium levels as the intracellular lithium cells and the Lithium levels may also in patients a lithium due to lithium from the Thus, lithium levels must be (3). for should be in any with lithium intoxication with or renal (Table (3). should also be in lithium is this is by lithium If the lithium to due to or of lithium from cells, then should be (3). Another for is if more lithium can be by a treatment than by the in (3). One should also for any on lithium with serum lithium levels 4 mEq/L, or for patients with lithium levels between and 4 mEq/L serious or symptoms (3). Patients on lithium are at for from lithium than patients with acute since intracellular lithium levels are to be responsible for toxicity Thus, individuals may not need until lithium levels to mEq/L (3). is in patients with serum lithium levels mEq/L (3). However, several lithium levels must be measured as the may A decision to should be made approximately to This decision should be made on lithium the of renal function, and the clinical Because is effective at lithium from the and has side it should be the has any not should be a and not with an as lithium from intracellular is an is used (2). A the use of a high to for lithium intoxication serum should be and hemodialysis, lithium levels must to be because at least two are in patients lithium levels can for to to 4 In one lithium levels began to the was to due to of lithium from the These the need for of especially those lithium renal have been used on a basis for treating lithium and can to of lithium lithium not lithium levels as as and are by the need for may be for patients with in intracellular lithium accumulation a substantial for This was by of and and from the