Lithium Carbonate is a medication primarily prescribed as a mood stabilizer for the management of bipolar disorder, including the treatment of acute manic episodes and long-term maintenance therapy. While its effectiveness is well-established, its use requires careful attention to potential physiological side effects, particularly concerning calcium regulation in the body. Calcium is fundamental for muscle contraction, nerve impulse transmission, and the proper function of the circulatory system. The integrity of these bodily functions depends on maintaining calcium levels within a very narrow range, which explains why any drug affecting this balance warrants a thorough understanding.
The Body’s Natural Calcium Regulation System
The body employs a sophisticated feedback system, known as calcium homeostasis, to ensure serum calcium levels remain stable, typically between 8.5 and 10.5 mg/dL. This stability is maintained primarily through the coordinated actions of parathyroid hormone (PTH) and Vitamin D, along with their target organs: the bone, the kidneys, and the small intestine.
PTH acts as the central regulator, being secreted rapidly by the parathyroid glands when sensors detect a slight decrease in circulating calcium. This hormone signals the skeletal system to accelerate the breakdown of bone tissue, a process called resorption, which releases stored calcium into the bloodstream. Simultaneously, PTH acts upon the kidneys to increase the reabsorption of calcium back into the blood, minimizing its loss through urine.
In the kidneys, PTH also stimulates an enzyme to convert inactive Vitamin D into its most active form, calcitriol. Calcitriol then travels to the small intestine, where its primary role is to enhance the absorption of dietary calcium. Through this three-pronged approach, PTH and Vitamin D ensure that blood calcium levels are restored to the normal, healthy range. Any excess calcium triggers a suppression of PTH release to prevent overcorrection.
How Lithium Interferes with Parathyroid Hormone Production
Lithium’s impact on calcium levels stems from its direct interference with the regulatory mechanism within the parathyroid glands. The surface of parathyroid cells contains a specialized protein called the calcium-sensing receptor (CaSR), which functions as the primary monitor of blood calcium concentration. Under normal circumstances, when calcium levels rise, the CaSR is activated and signals the cell to stop producing and secreting PTH.
Lithium acts as an antagonist to the CaSR, meaning it changes the receptor’s behavior. The presence of lithium effectively reduces the sensitivity of the CaSR to extracellular calcium, making the parathyroid gland misinterpret the current calcium concentration as being too low. This physiological confusion raises the “set point”—the concentration of calcium required to switch off PTH production.
Because the gland now believes that normal calcium levels are insufficient, it continues to secrete PTH even when calcium is at or slightly above the healthy range, leading to lithium-induced hyperparathyroidism. This chronic overproduction of PTH initiates the same processes that occur during normal low-calcium states. The excess PTH pulls calcium from bone storage and increases its reabsorption in the kidneys, which eventually results in persistently elevated serum calcium levels, or hypercalcemia.
Recognizing and Managing Lithium-Induced Hypercalcemia
The presence of elevated calcium in the blood due to lithium use is often a subtle and insidious condition, as many patients remain without clear symptoms, particularly in the early stages. When symptoms do occur, they are frequently non-specific.
Symptoms
- Persistent tiredness
- A general feeling of weakness
- Increased thirst and more frequent urination
- Gastrointestinal changes like nausea and constipation
Diagnosis relies on routine laboratory testing, which is a standard part of monitoring for patients on long-term lithium therapy. The diagnosis of lithium-induced hypercalcemia is confirmed by finding elevated serum calcium levels alongside an inappropriately high or even normal PTH level. Under normal conditions, high calcium should suppress PTH entirely, so an active PTH signal in the presence of high calcium indicates a problem with the regulation system.
Management
The management strategy begins with a thorough clinical assessment to determine the severity of the hypercalcemia and whether the patient is experiencing any acute symptoms. For mild cases, the first consideration is often to see if the lithium dosage can be safely reduced or if the medication can be discontinued entirely under the guidance of a physician. If lithium cessation is possible, calcium and PTH levels may gradually return to the normal range in some patients, though this is not always the case.
For patients who cannot stop lithium due to psychiatric necessity, or whose hypercalcemia persists, medical and surgical alternatives are considered. A drug class known as calcimimetics, such as cinacalcet, can be utilized; these medications work by directly increasing the sensitivity of the CaSR, helping to suppress PTH release. In severe or long-standing cases, or if an adenoma (a benign tumor of the parathyroid gland) is suspected, surgical removal of the affected parathyroid gland, a procedure called parathyroidectomy, may be necessary and is considered the definitive treatment.