Characterization of Calcium Homeostasis in Lithium-Treated Patients Reveals Both Hypercalcaemia and Hypocalcaemia

Data were collected from all hospital and primary healthcare charts from the start of each patient’s lithium medication until the inspection period between January and April 2017. Verbal informed consent was obtained from all patients, and consent was witnessed and formally recorded. Demographic details including age, gender, lithium duration, thyroxine medication, principal psychiatric diagnosis and laboratory findings were recorded.

Calcium homeostasis was assessed on all available calcium values, predominantly total serum calcium concentration (TCa); when only ionized serum calcium concentration (iCa) values were available, the TCa was estimated arithmetically according to validated formulae [15]. Hypocalcaemia and hypercalcaemia were defined, respectively, according to national recommendations [16], where the agreed reference value for TCa = 2.15–2.50 mmol/l and for iCa 1.15–1.33 mmol/l. All calcium determinations were performed using the same biochemical assay and reference range. Every attempt was made to retrieve calcium values before the initiation of lithium treatment and was successful in 196 individuals (66%). Of those 101 individuals where calcium values were not retrieved, six had elevated calcium determinations in the first three-year period of lithium medication (6%), and it cannot be completely rejected that these patients had pHPT already at the start of lithium medication. On the other hand, 17 of the 188 patients with normocalcaemia before the start showed elevated calcium levels during the first 3 years (9%). Since the general belief is that the development of LHPT accumulates with time, we chose time periods of 3 years to be clinically relevant in the monitoring and assessment of any disturbances in calcium homeostasis. For each three-year period, all available calcium values were retrieved per patient and the lowest, highest and mean values were registered. In addition, the number of calcium values which were below or above the reference value was also noted. Further, all currently available laboratory parameters (including TCa, iCa, PTH, vitamin D as well as creatinine and phosphate), and any information concerning thyroid and/or parathyroid surgery were documented. In 66 cases (22%), in whom LHPT was established or highly suspected, additional biochemistry was retrieved further to understand antecedent calcium disturbances or with a diagnostic aim. This included the assessment of 24-h urine calcium levels in 29 cases.

Fifty-one of the 66 patients with strongly suspected LHPT were referred to the team of endocrine surgery at Ryhov Hospital for operative evaluation. The indication for surgery was primarily intermittent hypercalcaemia in combination with an inappropriate increase in serum PTH concentration; however, preoperative investigations revealed that three individuals (all women) had osteopenia. Twenty-two were considered unsuitable for surgery due to high age, additional chronic diseases, marginally elevated calcium and/or the reluctance to be operated.

A total of 29 patients underwent parathyroidectomy performed by four separate surgeons experienced in endocrine surgery. Ten were investigated preoperatively with Sestamibi scintigraphy which revealed large adenomas in three patients (two remained cured at last follow-up), though there were indeterminate findings in seven cases. Focused parathyroidectomy was performed in the three cases with adenomas, and in the remaining 26 patients, the intention was to carry out a traditional four-gland exploration. All macroscopically enlarged parathyroid glands, as judged by the individual surgeon, were removed, and when doubt arose, a biopsy was conducted. Biopsy revealed normal parathyroid tissue in seven patients. Intraoperative PTH determinations were not used. No patient was subject for autotransplantation.

The normocalcaemic group was defined as patients having all calcium values within the normal range or, at most, two hypocalcaemic and/or two hypercalcaemic determinations during the complete period of lithium medication.

The hypocalcaemic group was defined as patients with three or more hypocalcaemic values during the study period. A maximum of two hypercalcaemic determinations were accepted.

The hypercalcaemic group consisted of patients with three or more hypercalcaemic values during the study period. Once again, a maximum of two hypocalcaemic determinations were accepted.

Established LHPT was defined as patients with hypercalcaemia and elevated PTH levels, in whom neck surgery had removed pathological parathyroid tissue.

Suspected LHPT was defined as patients with 5 or more increased calcium levels during lithium treatment, in the majority of cases combined with elevated PTH values.

Of those patients who had undergone surgery, cure was defined as normal calcium and PTH at the latest follow-up. Aberrant calcium and/or PTH suggested surgical failure and was further classified as persistent (elevated calcium 6 months postoperatively), recurrent (normal calcium at 6 months postoperatively but elevated values at the later follow-up), and Normocalcaemic Hyperparathyroidism (NCHPT, normal calcium but elevated PTH at the follow-up).

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. All procedures involving patients were approved by the Central Ethics Review Board at The University of Uppsala, Sweden (Dnr 2014/435). Any additional laboratory tests were performed on a voluntary basis with full consent of participants.

Descriptive statistics included frequencies (percentages) and median values (ranges). Regression analysis was used to identify any correlation between calcium values and treatment duration. Normocalcaemic patients were compared to the two groups with pathological calcium values using Chi-squared test for categorical variables and from a median test for continuous variables. Two-tailed Student’s unpaired t test was also utilized. Statistical significance was set at p < 0.05. Data were processed using SPSS (version 22).

While pHPT remains the third most common endocrinopathy, LHPT as a form of parathyroid pathology is by far more prevalent. Typically, pHPT is characterized by moderate-to-high serum calcium and PTH, hypercalciuria and reduced levels of phosphate, though other variants exist such as normocalcaemic hyperparathyroidism [7, 17]. Biochemically, LHPT is somewhat different: serum calcium can range from normal to moderately elevated, PTH ranges from normal to high (and often inappropriately high in relation to serum calcium), phosphate is normal to moderately elevated, and lastly, urinary secretion of calcium is low or very low (Table 2) [5, 9, 18, 19]. Many individuals with pHPT have osteopenia or even osteoporosis, while it is suggested that lithium may have a protective effect on the skeleton [20]. While fatigue may be the most common symptom of pHPT, in Western countries nephrolithiasis is still the most prevalent complication of pHPT demanding medical care, with prevalence rates ranging from 7 to 15% [21]. No occurrences of lithiatic medical conditions were detected through retrospective inspection of the present patient material, as observed in other studies [5, 22]. The current study is the first, to our knowledge, to report the occurrence of hypocalcaemia as a possible side-effect of lithium treatment. Seventeen patients (5.7%) met the arbitrary requirement of having at least three hypocalcaemic values during the follow-up, and though small, the population did differ significantly from the normocalcaemic group (Table 1, Fig. 1b). No ascertainable explanation for hypocalcaemia was apparent from the inspection of medical records (e.g. use of diuretics), and unfortunately no PTH was taken coincidentally. Considering that normal physiological conditions are elegantly attuned to limited changes in inter- and extracellular calcium, larger fluctuations might have clinical implications for individuals [23]. Hypothetically, it may reflect a general parathyroid dysfunction due to chronic lithium medication.

However, there are similarities in these parathyroid pathologies (pHPT vs LHPT). Both conditions predominantly affect females, particularly post-menopausal women (Tables 1 and 2) [24, 25], and both are caused by either parathyroid adenomas or hyperplasia, although multiglandular disease (MGD) is more frequent in LHPT [14, 26, 27]. Both conditions are difficult to diagnose, with pHPT and LHPT typically debuting with diffuse symptoms, which in the case of LHPT can be clinically challenging to differentiate from the lithium-treated patients’ affective condition [25, 28]. Existing anomalies may suggest other mechanisms in the development of LHPT, possibly necessitating another medical approach.

The present study confirms that surgical results in LHPT are poor and distinct from the admirable results obtained in pHPT [8, 11, 17, 29]. The cure rate in this study was found to be 35%, a rate that potentially may decrease with time since the follow-up was relatively short in cured patients (Group A). There may be several reasons for this. Preoperative imaging gave accurate results in only 30%, allowing for focused surgery in few cases. Norlén et al. [30] and Marti et al. [31] report levels of accuracy with Sestamibi in over 50%, and better results with concordant ultrasound assessment, in particular regarding adenomas. In addition, Carchman et al. [12] present preoperative imaging that could predict ten adenomas in a case material of 16 patients, though two were later found to have MGD. Largely, the role of imaging is contentious, possibly because of the high proportion of MGD [11, 17], and Skandarajah et al. [27] actually argue, “the sole indication for preoperative imaging…is to exclude concomitant thyroid disease”. While most centres now use intraoperative PTH (IOPTH) monitoring, that was not the case at the current centre during most of the time period studied. Its utility in LHPT is questionable. While Carchman et al. [12] contend satisfactory correlation between IOPTH and subsequent cure, Hundley et al. [26] dispute its reliability and predictive value in lithium-treated patients, where six of 12 patients had MGD, concluding IOPTH could not “supplant good surgical judgement”. It is also interesting to note that in this study, preoperative PTH values were not useful in establishing suitable surgical management. An important explanation to the discrepancy in cure rate in our study is possibly due to the histopathological background of LHPT and subsequent surgical strategy. Once again, dichotomous evidence emerges in the literature where some surgical studies present incidences of adenomas comparable to pHPT [12, 26, 32], while others report higher incidences of MGD (Table 3) [10, 14, 27, 33]. Another contributing factor to the exceptionable results of surgery in LHPT might be the inappropriate surgical strategy performed at the primary operation, as in the present study [14, 32, 34]. Macroscopic assessment of parathyroid gross morphology can be difficult, leading to insufficient excision of parathyroid tissue. Bilateral neck exploration (BNE) has found wide support as the appropriate surgical strategy [8, 11, 13, 35], though Saunders et al. [8] stress that sufficient evidence is lacking to fully endorse this method universally. These are questions we are attempting to address in our ongoing randomized study comparing surgery with watchful waiting.

LHPT’s biochemical similarity to familial hypocalciuric hypercalcaemia (FHH) raises the question as to what the correct management of suspected LHPT might be: active observation, medication with calcimimetics or surgery, and, if surgery is deemed appropriate, what degree of surgical radicality should be implemented.

The strengths of this study consist in the homogeneity of the patient material from a well-defined geographical area. The Swedish Social and Health Care system, through identification numbers, registers and computerized medical records, allow for clear identification of individual patients, facilitating the follow-up. The same researchers (JJ & AM) collaborated closely in data collection according to a predetermined protocol. The manual collection of data is in itself a self-generating mark of quality. The study also has some limitations. The study is retrospective and cannot, therefore, guarantee the absence of any unforeseen bias. The absence of PTH and vitamin D at synchronous periods of calcium fluctuations would have greatly facilitated the understanding of these disturbances, making any conclusions more reliable. While the authors only found calcium values for 66% of patients before lithium-treatment initiation, the coverage rate for the follow-up was an admirable 88%.