Lithium toxicity: an iatrogenic problem in susceptible individuals

Lithium toxicity, manifesting primarily as neurotoxicity, is a significant health problem and is primarily iatrogenic in nature. Despite 50 years of medical experience with lithium, factors contributing to the development of severe neurotoxicity remain poorly documented. We hypothesized that severe neurotoxicity represents the most clinically significant manifestation of lithium toxicity. We proposed that this occurs primarily in the context of chronic therapeutic administration ('chronic poisoning'), rather than in the context of an overdose. Furthermore we hypothesized that patients who developed chronic poisoning did so in the presence of identifiable factors which predictably impair lithium clearance.

A retrospective analysis of 97 cases of lithium poisoning, treated at a regional centre over a 13-year period was performed. Demographic data and factors considered likely to relate to the risk of developing lithium toxicity were recorded. Patients were classified according to mode of poisoning (acute, acute on chronic, or chronic) and according to severity of neurotoxicity (nil, mild, moderate, severe). The risk of developing severe neurotoxicity as a result of each mode of poisoning was assessed. The association between various risk factors and the development of chronic poisoning was assessed using a logistic regression model.

Twenty-eight cases were rated as suffering severe neurotoxicity; in 26 this developed in the context of chronic poisoning and in two in the context of acute on chronic poisoning. All patients who developed severe neurotoxicity had at least one putative risk factor present, regardless of mode of poisoning. Length of stay was significantly longer for cases with severe neurotoxicity compared to those without severe neurotoxicity (12 vs. 2 days, P < 0.001). Peak serum lithium concentrations were significantly higher in cases with severe neurotoxicity compared to those without (2.3 vs. 1.6 mmol/L, P = 0.02). Patients presenting with chronic poisoning had a substantially higher risk of severe neurotoxicity than those presenting after an overdose of lithium (Odds Ratio [OR] 136, 95% CI 23-1300). A logistic regression model showed three factors contributed independently to the risk of chronic poisoning. These were: nephrogenic diabetes insipidus (adjusted OR 26.96, 95% CI 2.89-251.94), age over 50 years (adjusted OR 6.20, 95% CI 1.36-28.32) and thyroid dysfunction (adjusted OR 9.30, 95% CI 1.36-63.66). A fourth factor, baseline endogenous creatinine clearance below normal limits, was significant at the P = 0.05 level (adjusted OR 6.49, 95% CI 0.98-43.01). Hyperparathyroidism was noted in three cases of chronic poisoning suffering severe neurotoxicity.

Severe lithium neurotoxicity occurs almost exclusively in the context of chronic therapeutic administration of lithium, and rarely results from acute ingestion of lithium, even in patients currently taking lithium. As such it is an iatrogenic illness, occurring in patients who have identifiable clinical risk factors: nephrogenic diabetes insipidus, older age, abnormal thyroid function and impaired renal function. Although administration of drugs which impair lithium clearance appeared to contribute minimally to chronic lithium poisoning in the absence of other factors, these drugs may well 'uncover' the predisposing risk factors and certainly should not be considered safe to use as a consequence of this study. The serious morbidity suffered by lithium toxic patients, and the cost to society due to long hospital stays, might be reduced by careful prescribing, vigilant monitoring and awareness of these factors, as they develop in otherwise stable patients. Review of existing therapeutic guidelines may be warranted.