Internal Medicine/Hypercalcemia and Hypocalcemia

Causes of Hypercalcemia

Hypercalcemia has various underlying causes, which can be classified based on disruptions in the body's normal mechanisms for regulating serum calcium levels. These causes include:

1. Excessive PTH Production: It occurs in conditions like primary parathyroid gland disorders (adenomas, hyperplasia, and rarely, carcinoma), as well as tertiary hyperparathyroidism due to long-term stimulation in renal insufficiency. In rare cases, ectopic PTH secretion can also lead to hypercalcemia. Familial hypocalciuric hypercalcemia (FHH) is another condition where PTH secretion is inappropriately high due to genetic mutations affecting calcium sensors in the body.
2. Hypercalcemia of Malignancy: Certain tumors produce a substance similar to PTH (PTHrP), leading to hypercalcemia. Additionally, cancer-related bone damage (lytic skeletal metastases) can result in elevated calcium levels.
3. Excessive 1,25(OH)2D Production: Conditions like granulomatous diseases (e.g., sarcoidosis), lymphomas, and vitamin D intoxication can lead to increased production of active vitamin D, which enhances calcium absorption.
4. Primary Increase in Bone Resorption: Hyperthyroidism, immobilization, and other factors can directly stimulate the release of calcium from bones, causing hypercalcemia.
5. Excessive Calcium Intake: Conditions like milk-alkali syndrome and total parenteral nutrition with high calcium supplementation can lead to an overload of calcium.
6. Other Causes: Certain endocrine disorders (e.g., adrenal insufficiency), medications (e.g., thiazides, vitamin A), and tumors (e.g., pheochromocytoma, VIPoma) can also contribute to hypercalcemia.

Clinical Symptoms of Hypercalcemia

The severity of hypercalcemia varies. Mild cases are often asymptomatic or may lead to subtle neuropsychiatric symptoms, while severe hypercalcemia can cause lethargy, gastrointestinal issues, and even life-threatening complications. Electrocardiographic changes may also occur.

Diagnostic Approach of Hypercalcemia

Diagnosing hypercalcemia involves several steps:

1. Check Serum Calcium and Albumin: Corrected calcium levels should be calculated if there are abnormalities in serum albumin concentrations.
2. Medical History: A detailed history can provide clues about the underlying cause, including any history of neck surgery, medication use, or systemic symptoms.
3. Parathyroid Hormone (PTH) Level: Measuring PTH levels, along with phosphate and creatinine levels, can help determine if primary hyperparathyroidism is present.
4. Calcium/Creatinine Clearance Ratio: This can be useful in diagnosing familial hypocalciuric hypercalcemia (FHH), a genetic disorder with mildly elevated PTH levels.
5. PTHrP Level: If malignancy is suspected as the cause, measuring PTHrP levels can be necessary.
6. 1,25(OH)2D Level: Elevated levels of active vitamin D can indicate granulomatous diseases or vitamin D intoxication.

Treatment of Hypercalcemia

Treatment depends on the underlying cause and the severity of hypercalcemia. In mild, asymptomatic cases, no immediate intervention may be needed. However, symptomatic hypercalcemia requires prompt management:

• Volume Expansion: Intravenous saline is administered to address dehydration, which often accompanies hypercalcemia.
• Bone Resorption Inhibitors: Bisphosphonates like zoledronic acid and pamidronate are used to inhibit calcium release from bones.
• Denosumab: This antibody to RANKL can be effective in treating hypercalcemia, especially when bisphosphonates are not sufficient.
• Gallium Nitrate: In some cases, gallium nitrate is used, but it has potential nephrotoxicity.
• Glucocorticoids: These are used to lower 1,25(OH)2D production in cases where it is the cause of hypercalcemia.
• Other Medications: In rare instances, drugs like ketoconazole, chloroquine, or hydroxychloroquine may be prescribed to reduce 1,25(OH)2D production.
• Dialysis: In severe cases, dialysis may be necessary to remove excess calcium from the bloodstream.

Overall, the treatment approach depends on the specific cause and clinical condition of the patient.

Causes of Hypocalcemia

Hypocalcemia has various causes, and they can be categorized based on whether the levels of serum parathyroid hormone (PTH) are low (hypoparathyroidism) or high (secondary hyperparathyroidism). The primary culprits for hypocalcemia are typically impaired PTH production and impaired vitamin D production. Hypoparathyroidism, often arising from unintended damage during thyroid or parathyroid surgery or autoimmune endocrine diseases, can lead to severe hypocalcemia, which can be life-threatening. Impaired PTH secretion can result from magnesium deficiency or genetic mutations affecting calcium sensing receptors, suppressing PTH production (autosomal dominant hypocalcemia). Vitamin D deficiency, impaired 1,25(OH)2D production (usually due to kidney problems), or vitamin D resistance can also cause hypocalcemia, but it is generally less severe compared to hypoparathyroidism because the parathyroids can try to compensate for the low calcium levels.

Clinical Symptoms of Hypocalcemia

The symptoms of hypocalcemia vary depending on its severity. Mild chronic hypocalcemia may not cause noticeable symptoms and might only be detected through routine calcium tests. More severe cases can lead to neuropsychiatric symptoms, gastrointestinal issues, and an increased risk of conditions like peptic ulcers and kidney stones. In extreme cases, hypocalcemia can result in life-threatening symptoms, including seizures, muscle spasms, and cardiac abnormalities.

Hypocalcemia: Diagnostic Approach

When evaluating hypocalcemia, the first step is to confirm that changes in serum calcium levels are not influenced by abnormal albumin concentrations. A significant portion of calcium in the blood binds to albumin, so it's essential to correct for this when interpreting results. To determine the cause of hypocalcemia, measuring PTH levels is crucial. Low PTH levels (or "inappropriately low") suggest hypoparathyroidism, while high PTH levels point toward issues in the vitamin D axis. Other factors, such as serum magnesium and phosphate levels, also play a role in the diagnosis.

Treatment of Hypocalecmia

The treatment approach for hypocalcemia depends on its severity, rate of development, and associated complications. In cases of acute, symptomatic hypocalcemia, calcium gluconate is administered intravenously, typically over a short period. Continuous infusion may be required for ongoing hypocalcemia. If hypomagnesemia is present, it should also be treated with magnesium supplements.

For chronic hypocalcemia due to hypoparathyroidism, treatment involves calcium supplements and vitamin D supplementation, either with vitamin D2 or D3. PTH (1-84) (Natpara) is an approved treatment for refractory hypoparathyroidism. Vitamin D deficiency is addressed with vitamin D supplementation, with the dose adjusted based on the severity of the deficiency and the underlying cause.

The goal of treatment is to raise serum calcium levels into the lower normal range and prevent hypercalciuria, which can lead to kidney stone formation. The specific treatment approach is tailored to the individual's condition and needs.