Lithium-associated Hyperparathyroidism Research Articles

Lithium-associated hypercalcemia and hyperparathyroidism: A systematic review and meta-analysis.

We aimed to review and summarise the existing human literature on the association between lithium and hyperparathyroidism. A systematic literature search was carried out according to PRISMA guidelines (last search 27 February 2024), using MEDLINE, Web of Science, Embase and the Cochrane Library. A meta-analysis was performed to determine the prevalence of lithium-associated hypercalcemia (LAHca) in lithium-treated patients. The pooled prevalence of LAHca based on total calcium and ionised calcium was comparable, at 3.17% and 4.23%, respectively. Calcium, and PTH if the patient is hypercalcaemic, is insufficiently measured in lithium-treated patients in clinical practice. Lithium use is associated with higher calcium and PTH levels, as well as a higher incidence of hyperparathyroidism. There is a high prevalence of multiglandular disease in lithium-associated hyperparathyroidism (LAH), with a pooled prevalence of 51.28%. Parathyroid surgery and cinacalcet are effective treatments for LAH. Regarding lithium discontinuation, there is anecdotal but conflicting evidence suggesting that it can result in the resolution of LAH in selected cases. Lithium treatment increases the risk of hyperparathyroidism, a treatable complication with a pooled prevalence of around 4%, compared to 0.5% in the healthy population.

Surgical strategy in lithium-associated hyperparathyroidism: A population-based study.

The extent of parathyroidectomy (PTX) recommendation in patients with lithium-associated hyperparathyroidism (LAH) remains controversial. The primary objectives of this study were to analyze extent of surgery, complications, and long-term outcomes. A population-based study, including all primary hyperparathyroidism (PHPT) patients who underwent PTX in Sweden between 2008 and 2017. Data on exhibited lithium prescriptions, morbidity, surgical approach, and outcomes were collected from relevant national registers and the Scandinavian Quality Register of Thyroid, Parathyroid, and Adrenal Surgery. Patients with lithium exposure before PTX were defined as having LAH. Descriptive summary statistics and regression models were used to evaluate differences in comorbidities, surgical approach, and outcomes between LAH and PHPT not exposed to lithium (non-LAH). Lithium exposure was significantly more common among PHPT (n=202, 2.3%) than in controls (n=416, 0.5%); OR 5.0 (95% CI 4.2-5.9). The risk of LAH correlated to the length of lithium exposure. In the LAH-group, the surgical procedures were more extensive and associated with a higher risk of postoperative bleeding, wound infections, persistent hypercalcemia, and hypocalcemia that remained after adjustment for the higher percentage of multiglandular disease. However, the cumulative risk of re-admission for PHPT was similar the first years after PTX and primarily elevated for patients with >5years duration of lithium exposure prior to surgery. The findings support the perception of LAH as a complex entity. We recommend a functionally oriented approach, aimed to obtain and maintain normocalcemia for as long as possible, minimizing the risk of permanent hypoparathyroidism, and accepting some risk of recurrence.

Management of lithium-associated hyperparathyroidism with cinacalcet hydrochloride.

British Journal of Hospital MedicineVol. 84, No. 1 Case ReportManagement of lithium-associated hyperparathyroidism with cinacalcet hydrochlorideSarah Craus, Emma L Mifsud, Simon Mifsud, Sandro VellaSarah CrausDepartment of Diabetes and Endocrinology, Mater Dei Hospital, Msida, MaltaSearch for more papers by this author, Emma L MifsudDepartment of Medicine, Mater Dei Hospital, Msida, MaltaSearch for more papers by this author, Simon MifsudCorrespondence to: Simon Mifsud; E-mail Address: [email protected]Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, MaltaSearch for more papers by this author, Sandro VellaDepartment of Diabetes and Endocrinology, Mater Dei Hospital, Msida, MaltaSearch for more papers by this authorSarah Craus; Emma L Mifsud; Simon Mifsud; Sandro VellaPublished Online:3 Jan 2023https://doi.org/10.12968/hmed.2022.0330AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References Bilezikian JP, Brandi ML, Eastell R et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3561–3569. https://doi.org/10.1210/jc.2014-1413 Crossref, Medline, Google ScholarDixon M, Luthra V, Todd C. Use of cinacalcet in lithium-induced hyperparathyroidism. BMJ Case Rep. 2018;2018:bcr2018225154. https://doi.org/10.1136/bcr-2018-225154 Crossref, Medline, Google ScholarMallette LE, Khouri K, Zengotita H, Hollis BW, Malini S. Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume. J Clin Endocrinol Metab. 1989;68(3):654–660. https://doi.org/10.1210/jcem-68-3-654 Crossref, Medline, Google ScholarMarcocci C, Cetani F. Update on the use of cinacalcet in the management of primary hyperparathyroidism. J Endocrinol Invest. 2012;35(1):90–95. https://doi.org/10.3275/8112 Medline, Google ScholarMifsud S, Cilia K, Mifsud EL, Gruppetta M. Lithium-associated hyperparathyroidism. Br J Hosp Med (Lond). 2020;81(11):1–9. https://doi.org/10.12968/hmed.2020.0457 Link, Google ScholarNaramala S, Dalal H, Adapa S, Hassan A, Konala VM. Lithium-induced hyperparathyroidism and hypercalcemia. Cureus. 2019;11(5):e4590. https://doi.org/10.7759/cureus.4590 Medline, Google ScholarNordenström J, Strigård K, Perbeck L et al. Hyperparathyroidism associated with treatment of manic-depressive disorders by lithium. Eur J Surg. 1992;158(4):207–211 Medline, Google ScholarShapiro HI, Davis KA. Hypercalcemia and ‘primary’ hyperparathyroidism during lithium therapy. Am J Psychiatry. 2015;172(1):12–15. https://doi.org/10.1176/appi.ajp.2013.13081057 Crossref, Medline, Google ScholarSloand JA, Shelly MA. Normalization of lithium-induced hypercalcemia and hyperparathyroidism with cinacalcet hydrochloride. Am J Kidney Dis. 2006;48(5):832–837. https://doi.org/10.1053/j.ajkd.2006.07.019 Crossref, Medline, Google ScholarSzalat A, Mazeh H, Freund HR. Lithium-associated hyperparathyroidism: report of four cases and review of the literature. Eur J Endocrinol. 2009;160(2):317–323. https://doi.org/10.1530/EJE-08-0620 Crossref, Medline, Google Scholar FiguresReferencesRelatedDetails 2 January 2023Volume 84Issue 1ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 3 January 2023 Published in print 2 January 2023 Information© MA Healthcare LimitedPDF download

A Patient With Polyuria and Hypercalcemia

A Patient With Polyuria and Hypercalcemia

Lithium-associated hyperparathyroidism.

Lithium is a mood stabiliser widely used in the treatment and prophylaxis of mania, bipolar disorders and recurrent depression. Treatment with lithium can give rise to various endocrine and metabolic abnormalities, including thyroid dysfunction, nephrogenic diabetes insipidus and hypercalcaemia. Lithium may induce hypercalcaemia through both acute and chronic effects. The initial acute effects are potentially reversible and occur as a result of lithium's action on the calcium-sensing receptor pathway and glycogen synthase kinase 3, giving rise to a biochemical picture similar to that seen in familial hypocalciuric hypercalcaemia. In the long term, chronic lithium therapy leads to permanent changes within the parathyroid glands by either unmasking hyperparathyroidism in patients with a subclinical parathyroid adenoma or possibly by initiating multiglandular hyperparathyroidism. The latter biochemical picture is identical to that of primary hyperparathyroidism. Lithium-associated hyperparathyroidism, especially in patients on chronic lithium therapy, is associated with increased morbidity. Hence, regular monitoring of calcium levels in patients on lithium therapy is of paramount importance as early recognition of lithium-associated hyperparathyroidism can improve outcomes. This review focuses on the definition, pathophysiology, presentation, investigations and management of lithium-associated hyperparathyroidism.

A Case of Lithium-Associated Hypocalciuric Hypercalcemia

Lithium is the treatment of choice for acute manic, mixed, and depressive episodes of bipolar disorder, along with long-term prophylaxis. A significant proportion of patients taking lithium develop lithium-associated hypercalcemia. Most cases are due to lithium-associated hyperparathyroidism with underlying parathyroid adenoma or hyperplasia. We present a 67-year-old woman who presented with increasing lethargy and loss of concentration and was found to have slightly raised serum calcium levels with inappropriately low urinary calcium excretion levels characteristic of hypocalciuric hypercalcemia. She had been on lithium therapy for over 15 years for bipolar disease. She had no other cause for these findings and had no family history to suggest familial hypocalciuric hypercalcemia. Neck imaging ruled out any parathyroid adenoma or hyperplasia. A diagnosis of lithium-associated hypocalciuric hypercalcemia was discussed with the patient, and she remains stable under surveillance.

Re: Three Patients with Lithium-Associated Hyperparathyroidism: Literature Review Regarding Medical and Surgical Management.

Re: Three Patients with Lithium-Associated Hyperparathyroidism: Literature Review Regarding Medical and Surgical Management.

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

IntroductionPrevalence studies demonstrate that a significant proportion of lithium-treated patients develop hypercalcaemia (3–30%). Lithium-associated hyperparathyroidism (LHPT) is poorly defined, and calcium homeostasis may be affected in a more complicated fashion than purely by elevated PTH secretion. The current study aims to examine in detail calcium homeostasis principally with regard to lithium duration.MethodsMedical records of 297 lithium-treated patients (193 women, 104 men; median age 58 years) were examined, and information on gender, age, lithium treatment duration and calcium homeostasis was obtained. The median treatment duration with lithium was 16 (1.5–45) years.ResultsA total of 8504 calcium values were retrieved. Before initiation of lithium treatment, serum calcium was on average 2.33 mmol/l (2.02–2.60). During the treatment period, 178 patients (60%) remained normocalcaemic, 102 (34%) developed hypercalcaemia or were strongly suspected of LHPT, 17 (6%) had 3 or more intermittent episodes of hypocalcaemia. Forty-one per cent of patients with suspected or confirmed LHPT had low (<4 mmol) 24-h urine calcium levels. The success rate after 33 parathyroidectomies was 35%, hyperplasia being diagnosed in 75% of extirpated glands.ConclusionsThe prevalence of hypercalcaemia during lithium treatment is very high. In addition, hypocalcaemic episodes appear to occur frequently, possibly reflecting a more complicated parathyroid dysfunction than previously known. Long-term surgical results are unsatisfactory. LHPT biochemical profile is different from that of primary hyperparathyroidism and is in some ways similar to familial hypocalciuric hypercalcaemia.

The Effects of Lithium on Calcium and Parathormone Levels: A Cross-sectional Study with Healthy Controls

Despite lithium associated hyperparathyroidism (LAH) can lead to many complications, little notice has been paid to this sideeffect. The aim of this study was to investigate the effects of lithium on calcium and parathyroid hormone levels and the relation between lithium use and thyroid diseases. This cross-sectional study was carried out with 87 lithiumtreated patients and 65 volunteers who had a similar age and gender distribution with the lithium group. Serum levels of corrected calcium, intact parathormone, phosphorus, magnesium, alkaline phosphatase, free thyroxine, thyroid stimulating hormone, thyroid autoantibodies and creatinine were assessed, and also, thyroid and parathyroid ultrasonography was conducted. Further detailed investigations were made depending on the elevation of the initially measured calcium and/ or parathormone levels. Median values of serum levels of the corrected calcium and the intact parathormone were significantly higher in the lithium group. Calcium levels had a mild correlation with the duration of lithium treatment. In the first assessment, while all control individuals had values within the normal reference range, 11 lithium-treated patients had corrected calcium and/or intact parathormone levels above the normal reference levels. All of the five patients, who were diagnosed with LAH after further investigation, were also diagnosed with a thyroid disorder. These results demonstrate that lithium treatment has a relationship with calcium and parathormone levels. The 5.7% prevalence of LAH and potential life-threatening conditions associated with LAH necessitates the use of available low-cost METHODS to monitor blood calcium levels of lithium-treated patients for early diagnosis.

May cinacalcet improve psychiatric symptoms by decreasing calcium levels in lithium-associated hyperparathyroidism?

May cinacalcet improve psychiatric symptoms by decreasing calcium levels in lithium-associated hyperparathyroidism?

Lithium-associated Hyperparathyroidism in a Filipino woman presenting as recurrent ischemic stroke: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #714 Lithium Associated Hyperparathyroidism: Symptom Relief and Improved Quality of Life After Parathyroidectomy

Abstract #714 Lithium Associated Hyperparathyroidism: Symptom Relief and Improved Quality of Life After Parathyroidectomy

Lithium associated Hyperparathyroidism (LAH): Cinacalcet is an effective alternative treatment option

Lithium associated Hyperparathyroidism (LAH): Cinacalcet is an effective alternative treatment option

A Comparative Analysis of the Initial East European Center Experience with a Western High-volume Center for Open Minimally Invasive Parathyroidectomy (OMIP) as Treatment of Primary Hyperparathyroidism

To compare results of treatment of primary hyperparathyroidism (PHPT) in two teaching hospitals (eastern and western Europe) and to establish conclusions regarding quality of surgery for PHPT in Romania. We reviewed two prospectively collected databases of patients submitted to open minimally invasive parathyroidectomy (OMIP) for symptomatic PHPT in two centers from Romania and the United Kingdom (UK). We included patients with biochemically proven PHPT and positive pre-operative localization studies. We excluded patients with negative localization studies, suspected multiglandular disease, concomitant thyroid disorders and chronic renal failure. 60 patients were included, 27 in group A (Romanian cohort) and 33 in group B (UK cohort). We noted significant differences between groups in pre-operative serum calcium and phosphorus levels (p<0.5). There were no differences between groups regarding the presence of symptoms; in group A we had significantly more patients with renal calculi history (p=0.02), digestive symptoms (p=0.006) and osteitis fibrosa cystica (p=0.01). Two patients from the UK group had lithium associated hyperparathyroidism and 2 patients had genetic disease. Intraoperative parathyroid hormone measurement (ioPTH) was available only for group B and frozen sections were selectively used in both groups. Both the adenoma size and weights were significantly higher in group A. The median operative time was significantly longer in Romanian group (p=0.001); in this group we noted the single conversion to traditional cervicotomy (3.7%) from all studied patients. In group A we noted two patients (7.4%) with failed parathyroidectomy and persistent PHPT; the cure rate was 92.5% for Romanian group and 97% for the UK group. OMIP can be performed safe with a high cure rate in "small" volume endocrine centres with results comparable to western experienced endocrine centres. Romanian patients presented with more severe PHPT with more frequent end-organ damage, due probably to late diagnosis.

Reply to Comments From Dr Lozano, et al—Concerning the Prevalence of Lithium-Associated Hyperparathyroidism

Meehan, Adrian David MA, MD; Humble, Mats B. MD; Yazarloo, Payam MD; Järhult, Johannes MD, PhD; Wallin, Göran MD, PhD Author Information

Lithium-Associated Hyperparathyroidism: A Pooled Analysis

Background: Lithium treatment has been associated with hyperparathyroidism (HPT). However, there are conflicting data regarding the rate of single- (SGD) versus multiple-gland disease (MGD) as well as the optimum surgical approach in these cases. Methods: Published data were identified through systematic electronic literature searches. Studies that fulfilled the preset inclusion criteria were analyzed (n = 12). Results: These studies documented 210 lithium-associated HPT (LAH) cases. Of these, 103 (49%) were due to SGD and 107 (51%) due to MGD. The unadjusted odds ratio of having multiple LAH compared to sporadic HPT was 3.44 (95% confidence interval 2.5907-4.5633; p < 0.0001). The sensitivity of preoperative sestamibi and sonography for SGD was 66-100 and 75-82%, respectively. The sensitivity for MGD was 9-67% for both. Intraoperative parathyroid hormone monitoring was utilized in 6 studies. Three studies recommended minimally invasive parathyroidectomy (MIP), while the other 3 recommended bilateral exploration. Conclusion: LAH is a relatively frequent condition among patients on lithium, and calcium monitoring should be performed initially and longitudinally. Almost half of the LAH cases are due to SGD. MIP should be the optimum surgical approach.

The prevalence of lithium-associated hyperparathyroidism in a large Swedish population attending psychiatric outpatient units.

This retrospective study determined the prevalence of lithium-associated hyperparathyroidism (LHPT) in 2 geographically defined, equivalent populations in Sweden, with no other selection bias. The medical journals of all patients receiving lithium treatment were examined specifically regarding their biochemistry: calcium, parathyroid hormone (PTH), creatinine, and vitamin D. The condition LHPT was defined biochemically. All patient data were noted, and the prevalence of the condition could thereby be calculated. A total of 423 patients were included (251 women and 172 men; 3:2), treated over a mean of 13.5 years (range, 1-46 years), aged 19 to 92. 77 patients (18%) were identified with LHTP whose median serum calcium was 2.55 mmol/L and PTH was 99 ng/L. A further 21% showed tendencies toward hypercalcemia. Forty-three percent had vitamin D insufficiency. Five patients (approximately 1%) had undergone parathyroidectomy. The prevalence of LHPT is high and often goes undetected. Vitamin D insufficiency is common as is polypharmacy. Surgery, for unclear reasons, has not been performed extensively, possibly because of limited knowledge of the underlying pathophysiology or surgery's significance. We present standard recommendations on patient management and suggest continual, specific follow-up including the monitoring of calcium, PTH, and vitamin D at least annually. Surgery should be considered with intention to improve psychiatric well-being and provide multiorgan protection.

Lithium-associated hyperparathyroidism and hypercalcaemia: A case-control cross-sectional study

BackgroundLithium is recommended as a first-line treatment for Bipolar Disorder (BD). Thyroid and renal alterations are well known lithium side-effects, while effects on parathyroids are less studied. The aim of this case-control cross-sectional study is to compare parathyroid hormone (PTH) and calcium levels in lithium-exposed bipolar patients and in subjects who had never been exposed to lithium. Methods112 BD patients were enrolled, 58 on lithium since at least 1 month (mean exposure 60.8±74.8 months) and 54 in the control group. Blood exams included complete blood count, PTH, total and ionized calcium, TSH, T3 and T4, creatinine, urea, sodium and potassium, and lithium serum levels. The Student's t-test and the Pearson's Chi-square test were used for bivariate analyses. A linear regression model was used to analyze the relationship between the duration of exposure to lithium and PTH and calcium levels. ResultsPTH and ionized calcium levels were significantly higher in lithium-exposed patients; the proportions of subjects with hyperparathyroidism (8.6%) and hypercalcaemia (24.1%) were significantly greater in lithium-exposed patients. The linear regression analyses showed a significant effect of exposure to lithium in months on ionized calcium levels but not on PTH levels. LimitationsGiven the cross-sectional design of the study we could not identify the exact time of occurrence of hyperparathyroidism. ConclusionsOur results indicate that lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation and during long-term lithium maintenance, calcium (and eventually PTH) should be added.

Do current screening recommendations allow for early detection of lithium-induced hyperparathyroidism in patients with bipolar disorder?

BackgroundCurrent screening recommendations for early detection of lithium-associated hyperparathyroidism propose an exclusive measurement of serum albumin-adjusted calcium (Aac) concentration as a single first step. However, longitudinal data in patients with recurrent affective disorders suggest that increases in serum intact parathyroid hormone (iPTH) levels in lithium-treated patients may not necessarily be accompanied by a parallel increase in the concentration of Aac. If true, patients with an isolated increase in iPTH concentration above the reference range might be missed following current screening recommendations. Therefore, this study set out to examine key parameters of calcium metabolism, including iPTH and 25-hydroxycholecalciferol concentrations in patients with bipolar disorder that was or was not managed with lithium.MethodsSixty patients with bipolar disorder according to DSM-IV were enrolled, 30 of whom had received long-term lithium treatment (lithium group), whereas the other 30 patients were on psychopharmacological treatment not including lithium (non-lithium group) at the time of the study. Owing to exclusion criteria (e.g., lithium < 6 months, laboratory results indicative of secondary hyperparathyroidism), 23 bipolar patients composed the final lithium group, whereas 28 patients remained in the non-lithium group for statistical analyses.ResultsPatients in the lithium group showed a significantly higher concentration of iPTH compared to the non-lithium group (p < 0.05). Similarly, Aac concentrations were significantly increased in the lithium group compared to the non-lithium group (p < 0.05). However, in a multivariate linear regression model, group affiliation only predicted iPTH concentration (p < 0.05). In line with this, none of the four patients in the lithium group with an iPTH concentration above the reference range had an Aac concentration above the reference range.DiscussionThis study suggests that the biochemical characteristics between primary hyperparathyroidism and lithium-induced hyperparathyroidism differ substantially with regard to regulation of calcium homeostasis. As such, current screening practice does not reliably detect iPTH concentrations above the reference range. Therefore, further research is needed to elucidate the consequences of an isolated iPTH concentration above the reference range in order to develop the most appropriate screening tools for hyperparathyroidism in lithium-treated patients with bipolar disorder.

Lithium-associated hyperparathyroidism: a case report

Lithium carbonate therapy has continued to be a mainstay treatment for bipolar disease and schizoaffective disorders. Hypercalcemia and hyperparathyroidism (HPT) is an underappreciated, but relatively common occurence, with a prevalence ranging from 6,3 to 50 % in patients requiring long-term lithium therapy. It is still unclear whether lithium initiates HPT or promotes an underlying subclinical state. Lithium antagonizes the calcium-sensing receptor (CASR) resulting in an increase in the threshold level of calcium required for suppression of serum PTH. This is validated by the fact that many patients with lithium associated hyperparathyroidism (LAH) have inappropriately low-normal urinary calcium excretion. LAH reflects a spectrum of disease from single to multigland involvement with a variable responce of each parathyroid gland to the continous PTH stimulation.