Introduction
Lithium is a chemical element located in group one (alkali metal) of the periodic table. This specific location enables it to ionize into a cation and easily interact with other functional groups. In addition, it is the lightest metal (74 Daltons), making it easy to be distributed throughout the body[1]. It's use in the treatment of mental disorders began in 1948 by Doctor John Cade in Australia[2]. Since then, lithium salts were classified as mood stabilizers due to its positive empiric impact on the treatment of bipolar affective disorders with a success rate of 80% in the treatment of both maniac and depressive symptoms[3,4].
Case report
A 77 year old woman, with personal history of affective bipolar disorder in treatment with lithium, presented into our hospital with functional declination, somnolence, fever and tremor, for 5 days approximately . The physical examination showed altered consciousness state, normal blood pressure, tachycardia, tachypnea, grade II dehydration, neck rigidity, tremor and hyperreflexia with clonus. The rest was normal.
Because the hospital was of first level, basic laboratories were available, so initially there was focus like meningitis, so antibiotics are started after blood and urine samples were collected. We observed leukocytosis with neutrophilia, altered renal function with GFR in 27.08 ml/ min/1.73 m2 with MDRD formula (figure 1), proteinuria, hematuria and massive bacteriuria in the urine sediment. Also glycemic levels and an electrocardiogram were realized, finding in the last one sinus tachycardia, normal ventricular axis, interval PR of 180 milliseconds, but a corrected interval QT of 510 milliseconds.
In this moment, with these findings, acute lithium intoxication was suspected associated with acute kidney injury and urinary tract infection, considered like an emergency dialysis. Immediately the patient was translated to a hospital with the service of nephrology and dialysis, and realized serum lithium levels finding an abnormal value of 2.85 mmol/L (Figure 1) (normal value 0.6 - 1.2 mmol/L). So, it was decided to initiate dialysis femoral via and antibiotic, presenting good response. In urine culture was isolated Proteus Mirabilis, so regimen antibiotic with Aztreonam was gave during 10 days with resolution of the infection.
After three days of treatment, renal function and serum lithium level were normal.
Discussion
Lithium distribution volume ranges between 0.6-0.9 L/Kg in the average adult. It has no protein or tissue binding, making it a substance with a therapeutic index that ranges between 0.6-1.5 mEq/L, which is very narrow[3]. Particularly, the optimal steady-state concentration of lithium for treatment of bipolar disorders is 0.6-1.2 mEq/L. Lithium acts with inositol and glycogen synthase kinase 3, by inhibiting an enzyme called inositol monophosphatase, decreasing inositol levels and altering first and second messenger system. With the chronic administration, stabilize GABA reuptake, explaining the effect on mania. Also antagonize 5HT1A and 5HT1B receptors, increasing levels of serotonin, explaining the effect on depression symptoms. Maintaining these exact ranges may be challenging and chances of toxicity remain high. Lithium is excreted in its vast majority by the kidneys and because of its chemical resemblance to sodium; they are handled in a very similar way. It is freely filtered and 60% of it is reabsorbed in the proximal tubule[5]. Due to its high rate of reabsorption and distribution throughout the body, lithium's half-life may be as high as 18 and 36 hours in the adult and the elderly, respectively[5].
As explained in the pharmacokinetics section, lithium has several biological interactions that may lead to lithium toxicity. The average patient on chronic lithium treatment may experience at least one episode of toxicity during his lifetime-. Lithium toxicity is classified by most authors in three different types: Acute, which includes manifestations that are predominantly gastrointestinal, such as nausea, vomiting and diarrhea, but neuromuscular manifestations may also be present; Acute on chronic, in which both gastrointestinal and neurologic manifestations occur; and Chronic that includes manifestations primarily neurological, including sluggishness, ataxia and neuromuscular excitability[7].
Toxicity is explained mostly by abnormally reduced excretion in the kidneys, overdose, prescribing errors and drug-to-drug interactions. Lithium has no protein or tissue binding, therefore, hemodialysis provides a useful therapeutic strategy[8].
At the intracellular level, lithium ion is transported from the lumen to the intracellular space by different protein channels, by means of an exchanging cation pump, in substitution of either sodium or potassium. The H+/Na+ exchanger accounts for most of the lithium transported into the cytosol and posteriorly to the blood. Particularly, lithium entrance is handled by passive transports compared to its exit, which is handled by pumps involving active transport and energy use. Secondary to this pump imbalance, lithium tends to accumulate throughout the body: Other channels might also contribute to the accumulation of Lithium, such as Glucose/Na channel or Na/K ATPase[9].
Back to our patient: Our patient developed an urinary tract infection (UTI), particularly a pyelonephritis, as manifested by its systemic symptoms, clinical findings and urinalysis findings. According to classification criteria, our patient met criteria urosepsis etiology. Its urine culture was found to be positive for Proteus Mirabilis, a facultative anaerobe bacteria, urease positive with increasing rates of antibiotics resistance[10]. Because of the pyelonephritis, induced renal impairment manifested as reduced GFR and an increased reabsorption (secondary to its sepsis induced vasodilation and dehydration), leading to increased lithium levels up to 2.85 mEq/L.
The main stem for treatment of acute lithium toxicity relies on following the ABC protocols (Airway, Breath, Circulation) and supportive care, followed by aggressive hydration in order to guarantee appropriate lithium clearance. Hydration should be done with normal saline (0.9%). Sodium levels should be assessed prior to treatment because these patients may develop induced nephrogenic diabetes insipidus, which makes it important to have a baseline serum sodium level upon hydration. Treatment with oral charcoal is not recommended by most authors[11]. Some studies have shown a benefit of giving high doses of kayexelate (oral sodium polystyrene sulfonate) is reducing lithium levels, however, its use is not recommended secondary to the side effects of hypokalemia[12]. Ultimately, the gold standard treatment when these therapies fail is the use of hemodialysis as an extracorporeal measure. Consensus guidelines for the use of hemodialysis in this setting are controversial. Some authors suggest using hemodialysis in patients with lithium levels greater than 5 mEq/L and a normal renal function. In those with impaired renal function (creatinine higher than 2 mmol/L) and lithium levels of 4 mEq/L, therapy can be considered as well[13]. Finally, those patients who don't respond to previous treatment and in whom signs of toxicity persist, hemodialysis remains as a reasonable option. More studies are needed to provide guidelines with a stronger degree of recommendation[14].
In our patient, the lithium levels quickly fell after hemodialysis, from 2.85 to 0.89 mEq/L in a 24-hour period. Additionally, the BUN and creatinine levels also fell down to normal after the prerenal acute kidney injury was solved. Creatinine and BUN decreased from 1.89 to 0.85mg/dl and from 43 to 17mg/dl respectively, in a 48-hour period.
Conclusion
Patients treated for bipolar affective disorder with lithium must be specifically warned on how to early identify possible triggers that may induce acute kidney injury, such as UTI, systemic infections, volume depletion states patients must stop medication and seek medical care.
Detailed clinical history of patients initial neurological disorders before initiating Lithium therapy is required, since lithium intoxication symptoms tend to be mostly neurological, so there must be a clear differentiation between the treated pathology symptoms and the newly acquired intoxication symptoms for the diagnosis to be possible and timely. In this case, there were three potential triggers for the GFR drop: Pyelonephritis, prerenal acute kidney injury and prolonged lithium exposure. The summation of these caused Lithium serum levels to increase to toxic levels and resulted in an intoxication, however, the dehydration had the most evident repercussions.