Lithium-Induced Hyperparathyroidism: An Ill-defined Territory

Abstract

Lithium is the gold standard treatment for bipolar disorder. Studies have shown an association between lithium and hyperparathyroidism. However, there is limited data regarding the management of lithium-induced hyperparathyroidism. We present a clinical conundrum which physicians frequently encounter—an excellent lithium responder refractory to other treatments who developed lithium-induced hyperparathyroidism. Medical treatment with cinacalcet was successful in management of hyperparathyroidism without discontinuing lithium maintenance therapy.

Introduction

Lithium (Li) is a gold-standard treatment for acute mania and maintenance treatment in Bipolar Disorder (BD). Despite comprehensive data on the efficacy of Li, it is consistently underutilized in patients with BD.¹ One of the reasons postulated for decreased prescription of Li is the potential side effects from long-term Li therapy (LTLT).² Li is known to cause 3 endocrine adverse effects namely (i) Thyroid dysfunction,³ (ii) Hypercalcemia due to hyperparathyroidism (HPT),⁴ and (iii) Nephrogenic Diabetes Insipidus.⁵ HPT is the leading cause of hypercalcemia in patients on Li therapy.⁶ Li is known to cause an increased set- point of calcium for parathyroid hormone (PTH) suppression, and results in parathyroid hyperplasia.⁶ It is also known to worsen pre-existing primary HPT. HPT is reported to cause musculoskeletal and neuro-psychiatric symptoms.⁷ Untreated long-standing HPT is a risk factor for developing nephrolithiasis and osteoporosis.⁷ Hence, timely diagnosis and treatment of HPT is critical for a good quality of life and prevention of complications. Unfortunately, optimal management of Li-induced HPT (Li-HPT) is challenging and not well defined in the literature.

We present a case of a 70-year-old female with BD euthymic on LTLT presenting with hypercalcemia due to HPT. We have reviewed literature on the pathophysiology and management of HPT in patients on LTLT.

Case History

A 70-year-old female with history of Bipolar-I disorder (BD-I) was referred for evaluation of hypercalcemia. Since her diagnosis of BD-I, she had several manic and depressive episodes, with one of these episodes leading to hospitalization for suicidal attempt. She was euthymic on LTLT (Li Carbonate 300 mg PO three times a day) for 28 years. She had a medical history of hypothyroidism prior to initiating Li and was adequately treated with Levothyroxine PO 75 μg daily. She endorsed polyuria, but otherwise was asymptomatic. She did not report fragility fractures or kidney stones. She had not been screened for osteoporosis. She was not on thiazide therapy. Routine laboratory studies in the past 3 years showed mildly elevated calcium levels.

Laboratory studies (Table 1) showed hypercalcemia, with elevated PTH consistent with primary HPT. Renal function, 25-Hydroxy Vitamin D, and thyroid stimulating hormone (TSH) were in the normal range. Twenty-four urine calcium was normal (daily calcium intake was approximately 1000 mg). Li level was in the therapeutic range. Dual-energy X-ray Absorptiometry (DXA) reported low bone density (osteopenia), not meeting threshold for prescription treatment (World Health Organization 10-year fracture risk; major osteoporotic fracture: 9.3% and hip fracture: 1.9%).⁸ The Parathyroid Technetium 99m Sestamibi (SPECT)- CT scan showed a 7 mm parathyroid adenoma with increased radiotracer uptake near the inferior margin of the left thyroid lobe (Fig 1 and Fig 2).

Table 1. Lab Panel Before and After Treatment with Cinacalcet.

						Post-treatment with cinacalcet
		Normal reference range		Pre-treatment		After 1 weeka		After 3 weeksb
Plasma Labs
Sodium (mEq/L)		137–145		138
Potassium (mEq/L)		3.5–5.1		4.8
Chloride (mEq/L)		98–107		109
Albumin (g/dL)		3.5–5		4.3		4.3		4.5
Calcium (mg/dL)		8.4–10.2		11.4		11.2		10.3
Ionized Calcium (mg/dL)		4.57–5.43		NA#		6.15		5.43
Phosphorus (mg/dL)		2.5–4.5		NA#		2.5
Magnesium (mg/dL)		1.6–2.3		2.2
Creatinine (mg/dL)		0.7–1.2		0.9
Parathyroid hormone (pg/mL)		16.7–77.4		161.5		75.9		110.4
25-hydroxy vitamin D (ng/mL)		30–100		27.4
Urine Labs
Creatinine (mg/day)		15–25 mg/kg*		663
Calcium (mg/day)		150–250		90
Fraction excretion of Calcium		>2% in hypercalcemia		1%

#: Not available; *: Body weight 80kg; a: Cinacalcet 30 mg daily; b: Cinacalcet 30 mg twice daily.

Figure 1.

Coronal Section of Parathyroid Technetium 99m Sestamibi (SPECT)- CT Scan

Figure 2.

Transverse Section of Parathyroid Technetium 99m Sestamibi (SPECT)- CT Scan

Arrow points towards the left inferior parathyroid adenoma.

A multidisciplinary care team recommended medical management due to high risk for persistent HPT after resection of the solitary parathyroid adenoma. Patient was treated with Cinacalcet hydrochloride 30 mg PO daily for 1 week and the dose was then increased to 30 mg PO twice daily. Ionized calcium normalized in 3 weeks to 5.43 mg/dL, with total calcium at 10.3 mg/dL and albumin 4.5 g/dL (Table 1). The patient tolerated cinacalcet without any adverse effects. Her mood stayed euthymic.

Discussion

HPT is one of the endocrine adverse effects in patients on LTLT. The prevalence of Li-HPT has been found to be variable based on the study methodologies. A recent Swedish study of 423 patients maintained on LTLT, reported a prevalence rate of Li-PHT as high as 18%.⁹ Albert et al.¹⁰ enrolled 112 patients with BD and studied PTH and calcium levels in the patients treated with Li. 8.6% of patients exposed to Li developed HPT and 24.1% developed hypercalcemia. Approximately 40% of patients with Li-HPT are over 60 years of age with a mean serum calcium levels reported to be higher in comparison to younger patients treated with Li.¹¹ The time to hypercalcemia and HPT after initiation of Li therapy has been reported to be variable, seen both with short-term and long-term use of Li.¹¹ Mak et al.¹² followed 53 patients receiving Li therapy, prospectively for 2 years and measured PTH levels at baseline, 1, 6, 12 and 24 months intervals. The PTH levels were higher at 1 month—though not statistically significant; but were higher and statistically significant at 6, 12 and 24 months. They also found a significant increase in urinary absorption of calcium which was concordant with the PTH change. The plausible mechanism of hypercalcemia with Li treatment included (a) interaction with the calcium sensing receptor to shift set point or calcium-PTH curve to the right or (b) inhibition of renal c-AMP.¹³ Li therapy mimics findings of Familial benign Hypocalciuric Hypercalcemia, by decreasing urinary calcium excretion or (c) inhibition of glycogen synthase kinase 3b.¹⁴ In our patient, we observed decreased fractional excretion of calcium of 1% (usually >2% in hypercalcemia and HPT). Further, Li is reported to decrease sensitivity of parathyroid gland to calcium and hence shift the set-point of the calcium-PTH curve to the right.¹³ Optimal management of Li-HPT is not well defined. Prospective randomized studies to evaluate appropriate management strategies for Li-HPT are lacking. Resolution of hypercalcemia can be achieved if Li can be safely discontinued, provided Li therapy was used short term for less than 5 years.¹⁵ Although a trial of Li discontinuation may seem reasonable the risk of relapse with mood episodes is extremely high after Li discontinuation.¹⁶ LTLT has been reported to exert chronic stimulatory effect on the parathyroid gland to cause parathyroid hyperplasia or adenoma.¹⁷ Surgical excision of parathyroid adenomas is a definitive management in primary HPT. The risk of recurrence after surgical management for primary HPT unrelated to Li is reported to be around 5%.¹⁸ However the risk of recurrence after surgical management of Li associated HPT is reported to be very high. Meehan et al.¹⁹ found a remarkably high rate of recurrence of HPT after surgical resection in patients with Li-HPT. They performed exploratory parathyroidectomy in 7 patients on long-term Li therapy who had hypercalcemia and HPT (5 patients underwent multi-gland resection). Histopathology showed multi-gland hyperplasia in 4 patients, adenoma in 1 patient, lipoadenoma in 1 patient and normal gland in 1 patient. One patient with lipoadenoma had persistent hypercalcemia post-operatively, while remaining 6 patients developed recurrent disease. The average follow-up was 10 years (range 5–12 years).¹⁹

Since multi-gland disease is common in Li treated patients, the risk of recurrence following surgery is very high. Li dose reduction or discontinuation and switching to other mood stabilizers or atypical antipsychotics can be considered if mood stays stable. However, the risk of decompensation stays high after Li discontinuation in patients maintained on LTLT.^20,21 In addition, discontinuation is less likely to reverse the HPT in patients on LTLT.¹⁷ If Li cannot be discontinued safely or if Li has been used long-term, use of cinacalcet seems to be a safe reasonable option while parathyroid surgery can be considered for patients not responding to or intolerant to cinacalcet. Cinacalcet is a calcimimetic which increases the sensitivity of the calcium-sensing receptor to extracellular calcium, thus reducing calcium and parathyroid hormone levels.²²

In our patient, after consultation with psychiatry and discussing with the patient, discontinuation of Li was not considered safe. Moreover, our patient had used Li for 28 years (expected to have multi-gland disease) and also had an evident parathyroid adenoma, which decreases the likelihood of response to Li discontinuation. Therefore, cinacalcet was considered the most appropriate treatment for her, considering the high risk of recurrence with surgical option and high risk of relapse of BD with Li discontinuation. The patient tolerated cinacalcet without any adverse effects on her mood.

Conclusion

Lithium induced hyperparathyroidism is a potential complication of long-term lithium therapy. We recommend regular monitoring of calcium and parathyroid hormone levels every 6 months in patients using Li. Appropriate guidelines for optimal treatment of Li-HPT are lacking. We believe that treatment decisions should be individualized and a multidisciplinary team involving patient’s psychiatrist and an endocrinologist is essential for optimal outcomes. Cinacalcet seems to be reasonable pharmacotherapy for Li-HPT associated with long-term Li use, especially when trial of Li discontinuation is not feasible or surgical treatment is not appropriate.