Hypercalcaemia is one of the unrecognised side effect of lithium therapy. Lithium, also known as a mood stabiliser, has been used as a first-line therapy to treat mania, hypomania and bipolar disorder for decades. It causes hypercalcaemia, by increasing the reabsorption of calcium in the loop of Henle by its effect on calcium sensing receptors and hyperparathyroidism. Most of the patients with hypercalcaemia are asymptomatic. 

Acute symptomatic hypercalcaemia presents with confusion, stupor, lethargy, constipation, abdominal pain, polyuria and polydipsia. The definitive therapy for hypercalcaemia in these patients would be switching lithium with another mood stabiliser. We report a unique case of lithium-induced hypercalcaemia, in a 25-year-old patient. 

Case presentation

A 25-year-old male with bipolar disorder, successfully treated with lithium for more than three years, presented to the emergency department with 30 episodes of vomiting in a day, longstanding constipation deteriorated for two days and generalised abdominal pain that was relieved after three episodes of diarrhoea while in the ED. He had background history of Asperger’s disorder as a child and psychosomatic vomiting. 

Laboratory data revealed total corrected serum calcium level of 3.35mmol/L (normal range 2.2 to 2.7mmol/L), inorganic phosphate 0.70mmol/L, magnesium 1.21mmol/L, normal thyroid functions, WCC 27.9 x 10⁹/L, neutrophils 24.4 x 10⁹/L, neutrophil-to-lymphocyte ratio (NLR) 34.85, CRP 13.5, PTH 3.30pmol/L and lithium level 0.4mmol/L. ECG showed a QTc of 427 ms.

He was admitted for evaluation and management of hypercalcaemia. Lithium was stopped and intravenous fluids were started. Workup for malignancy was unremarkable. On day three, calcium level returned to within normal reference range. Interestingly all his inflammatory markers came down to normal with just intravenous fluid treatment. On day three, blood results reported calcium level of 2.48mmol/L, inorganic phosphate 0.93mmol/L, magnesium 0.83mmol/L, WCC 8.4 x 10⁹/L, neutrophils 5.1 x 10⁹, NLR 2.8 and CRP 12.1. The patient was restarted on a lower dosage of lithium, and referred to his psychiatrist for the adjustment of lithium dose or an alternative mood stabiliser. It was concluded that lithium was the contributing factor for hypercalcaemia. 

Discussion

As long-term lithium therapy can lead to hypercalcaemia, patients would be at high risk for the development of nephrolithiasis, renal insufficiency, diabetes insipidus, osteoporosis and short QT syndrome. To prevent these complications, calcium levels should be monitored regularly, at least every three months.

A study conducted by Meehan et al concluded that hypercalcaemia is not associated with bipolar disorder but is a common, though underestimated, characteristic of lithium treatment.¹ It was postulated that genetic factors, the duration and dosage of lithium therapy, gender, other medications and pathologies may – either together or separately – contribute to the development of this endocrinopathy.¹

Lithium, which has been in clinical use since 1950,^2,3,4 is one of the cornerstone treatments for bipolar disorder. Although lithium salts are known to disrupt thyroid function,³ lithium-induced parathyroid dysfunction is rare. The first case of lithium-induced hyperparathyroidism was reported in 1973.³ Although primary hyperparathyroidism usually arises from parathyroid adenomas, it is also essential to consider other factors that could be contributing to primary hyperparathyroidism.

In recent years, the identification of a calcium-sensing receptor (CaR) has provided new insight into disorders of calcium metabolism.⁵ As well as being located in numerous extra-renal tissues such as the parathyroid glands, gastrointestinal tract and bone,⁵ these CaRs are found on the basolateral aspect of the epithelial cells of the thick ascending limb of the loop of Henle.^5,6 Here they respond to a rise in serum calcium by reducing the diffusion of potassium back into the tubular lumen.⁵

Calcium secretion in the urine is increased due to reduced paracellular flow of calcium (magnesium and sodium) back into the blood stream as a result of reduced electrical gradient between the lumen and the blood.⁵ This shows the importance of CaR in maintaining the blood calcium level within the pre-determined range.⁵ To suppress parathyroid hormone (PTH) secretion, higher calcium levels are required in the peritubular space so as to down regulate the reabsorption of calcium in the renal tubule and the parathyroid gland; the predetermined target range of calcium is set higher than normal in certain conditions.⁵

One example is the asymptomatic presentation of hypercalcaemia and hyperparathyroidism on routine investigations.^5,6,7

Hyperparathyroidism-related cardiovascular complications may result from an increase in systemic inflammation.⁸ Previously it was reported that increased serum PTH levels are the mere indicators of systemic inflammation.⁸

The recent research demonstrated that NLR is an important marker of inflammation in patients with hyperparathyroidism.⁸ Lam et al assessed the longitudinal changes in NLR pre- and post-parathyroidectomy, and concluded that NLR significantly decreased after successful parathyroidectomy.⁸

In our case, the patient presented with symptoms and signs of hypercalcaemia. Laboratory data demonstrated the picture of hyperparathyroidism, with high calcium, low phosphate and high NLR, but the PTH level was within the reference range. 

Conclusion

An overlooked side effect of lithium is hypercalcaemia. To prevent the serious outcomes of hyperparathyroidism, calcium level should be regularly monitored in patients on long term lithium therapy. As the discontinuation of lithium can lead to the worsening of symptoms of bipolar disorder, commencement of an alternative mood stabiliser is recommended. 

References

1. Meehan AD, Udumyan R, Landén M, Järhult J, Wallin G. Lithium-associated hypercalcemia: pathophysiology, prevalence, management. World J Surg 2018; 42(2): 415-24
2. Naramala S, Dalal H, Adapa S, Hassan A, Konala VM. Lithium-induced hyperparathyroidism and hypercalcemia. Cureus 2019; 11(5): 4590
3. Brochier T, Adnet-Kessous J, Barillot M, Pascalis JG. Hyperparathyroidism with lithium. Encephale 1994; 20(1): 339-49
4. Garfinkel P, Ezrin C, Stancer H. Hypothyroidism and hyperparathyroidism associated with lithium. Lancet 1973; 302(1): 331-2
5. Caskey FJ, Pickett TM. Disturbed calcium metabolism in a patient with bipolar disorder and impaired renal function. Nephrology Dialysis Transplantation 2005; 20(8): 1752-5
6. Brown EM, Herbert SC. A cloned extracellular Ca(2+)-sensing receptor: molecular mediator of the actions of extracellular Ca2+ on parathyroid and kidney cells. Kidney Int 1996; 49(1):1042-6
7. Herbert SC. Extracellular calcium-sensing receptor: implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50(1): 2129-39
8. Lam HB, Chien MN, Lee JJ, Chao LF, Cheng SP. Association between neutrophil-to-lymphocyte ratio and parathyroid hormone in patients with primary hyperparathyroidism . Arch Med Sci 2019; 15(4): 880-6