In this cross-sectional study, we found a significant higher prevalence of hypercalcemia in patients using lithium compared to that of the control group of patients without a current and previous history of lithium treatment (p = 0.001). In addition, the development of hypercalcemia was correlated to the cumulative time that lithium was taken regardless whether this was continuous or with one or more interruptions of various durations.
Strengths and weaknesses
This study is the first to determine the prevalence of hypercalcemia in a major cohort of psychiatric patients. Our results regarding the prevalence corroborates with previous studies (Bendz et al. 1996; Ananth and Dubin 1983; Davis et al. 1981; Järhult et al. 2010; Saunders et al. 2009; Christensson 1976; Hundley et al. 2005; Awad et al. 2003; Carchman et al. 2008). However, compared to previous studies, in our study, we included a large number of patients, and selection bias is less likely because we used a predefined search for patients that were currently treated in a large, non-academic psychiatric outpatient clinic. Patients attending this clinic reflect a regular sample of bipolar outpatients of varying severity and duration of illness. In most other studies, patients were selected from an endocrine surgery database instead of a psychiatric cohort. As a consequence, these cohorts included a highly selected subgroup of lithium-treated patients since the outcome, i.e., hyperparathyroidism, was already present.
In our study, patients were identified based upon their bipolar disorder, and calcium levels were measured as part of a routine monitoring schedule. In addition, using an upper limit for serum calcium levels of 2.60 mmol/L compared to that of the various lower upper limits uphold among different hospitals, psychiatric facilities, and laboratories, it is unlikely that our results overestimate the prevalence of hypercalcemia. All other factors such as medical history, use of other medications besides lithium, and possibly previous surgery were taken into account. None of these showed a significant difference that could distort our results.
Although our control group of lithium-naïve patients was very small compared to the group of lithium users reflecting the widespread use of lithium for bipolar disorder in the Netherlands, the range from low to high calcium levels seems to be higher in lithium users than that in the control patients. This may be an indication that the set point of serum calcium is higher in lithium users due to the binding of lithium to the calcium-sensing receptor of the parathyroid cell. This binding results in a lower threshold for the secretion of PTH, implicating that the serum calcium is also higher in all lithium users, and leading to hypercalcemia in approximately 15%. Our control group was small (n = 15), and therefore, such conclusions remain preliminary. Nonetheless, this cross-sectional study is the first including a control group of psychiatric patients, in this perspective. Because lithium is the mainstay for the long-term treatment of bipolar disorder, it is difficult to identify a larger cohort of control patients.
Whether lithium shifts the calcium set point to the right or that it uncovers a preexisting hyperparathyroidism remains the question. Because of the absence of PTH measurements, calcium in 24-h urine specimens, and proper imaging of patients with suspected LIH, we were unable to investigate this in our sample, which poses a limitation of our study.
In the absence of an evidence-based consensus on the optimal surgical approach in lithium-induced hyperparathyroidism, several studies have been published regarding the different treatment options (Bendz et al. 1996; Järhult et al. 2010; Saunders et al. 2009; Abdullah et al. 1999; Awad et al. 2003; Carchman et al. 2008). Some advocate removal of all four glands where others apply a more focused approach. In order to determine the optimal treatment for LIH, one has to understand its pathophysiology. However, the underlying mechanism by which lithium induces hyperparathyroidism has not been elucidated yet. Since lithium was thought to induce hyperplastic changes to all four glands (based on the idea that all glands are exposed equally) rather than the formation of one or multiple adenomas, (Abdullah et al. 1999), routine complete neck exploration was the surgical procedure of choice for a long time. The overall prevalence of multiglandular disease, however, has a broad variance ranging from only 13% to 52% (Järhult et al. 2010; Abdullah et al. 1999; Awad et al. 2003; Carchman et al. 2008). And therefore, the notion that the remaining parathyroid glands will render pathological with time is perhaps premature and lacks sufficient evidence (Järhult et al. 2010; Saunders et al. 2009). This would support a more selective approach and more extensive preoperative imaging as is common nowadays in primary hyperparathyroidism. At this moment, it is too early to advocate a certain surgical approach since both theories find equal supports in the literature. Furthermore, when there is reluctance to surgery, a relative new class of drugs called calcimimetics has been shown to lower the serum calcium level. Even though the results are promising, one must realize that this is not a definitive therapy (Houweling et al. 2012; Rothe et al. 2011).