Calcium plays a central part in processes like nerve signal transmission and muscle contraction, far beyond bone structure. The body maintains a tightly controlled balance of this mineral in the bloodstream, primarily through the parathyroid glands. When blood calcium levels rise above the normal range, the condition is known as hypercalcemia. This elevation is recognized as a serious condition that can be directly related to an underlying malignancy.
Defining Hypercalcemia and Key Thresholds
The measurement of calcium in the blood is typically reported as total serum calcium, which includes both the protein-bound and the free, active form. A healthy adult’s total serum calcium level usually falls within a narrow reference range of approximately \(8.5\) to \(10.2\) milligrams per deciliter (\(\text{mg/dL}\)). Hypercalcemia is defined when this level is consistently above \(10.2 \text{ mg/dL}\).
The severity is categorized by numerical thresholds. Mild hypercalcemia is generally \(10.5\) to \(11.9 \text{ mg/dL}\). Levels from \(12.0\) to \(13.9 \text{ mg/dL}\) are moderate, and \(14.0 \text{ mg/dL}\) or above is deemed a hypercalcemic crisis and a medical emergency. Malignancy is associated with pronounced elevations, particularly those above \(12 \text{ mg/dL}\), which tend to be rapidly progressive and symptomatic.
Ionized calcium is the free, physiologically active form. Since total calcium is affected by blood protein levels like albumin, the ionized measurement is often a more accurate reflection of true calcium status, especially in severely ill patients. If ionized calcium is not used, the total calcium value must be corrected for albumin level abnormalities.
Symptoms of Elevated Blood Calcium
Symptoms often become more pronounced as the level of calcium rises. Initial, milder symptoms frequently affect the gastrointestinal tract, presenting as nausea, vomiting, or persistent constipation. Increased calcium levels also affect the kidney’s ability to concentrate urine, leading to frequent urination and excessive thirst.
The skeletal system is impacted, causing bone pain and a greater risk of fractures as calcium is pulled from the bones. Neurological symptoms include fatigue, muscle weakness, and a foggy mental state. In severe cases, elevated calcium can lead to confusion, stupor, and even coma, indicating a life-threatening situation.
Mechanisms Linking Cancer and High Calcium
The connection between cancer and hypercalcemia is driven by two distinct biological mechanisms. The most frequent cause, accounting for up to \(80\%\) of malignancy-related cases, is Humoral Hypercalcemia of Malignancy (HHM). This occurs when tumor cells, such as those in squamous cell carcinomas of the lung or breast cancer, secrete Parathyroid Hormone-Related Peptide (\(\text{PTHrP}\)).
\(\text{PTHrP}\) mimics the action of the body’s natural parathyroid hormone (\(\text{PTH}\)) by binding to the same receptor in the bone and kidney. In the kidney, this action increases the reabsorption of calcium back into the blood, preventing its excretion in the urine. \(\text{PTHrP}\) also acts on bone cells to stimulate the \(\text{RANKL}\) pathway, which activates osteoclasts, the cells responsible for breaking down bone tissue. This results in a systemic increase in serum calcium, often characterized by a high \(\text{PTHrP}\) level and a suppressed \(\text{PTH}\) level.
The second major mechanism is Local Osteolytic Hypercalcemia, typically seen in cancers that have metastasized to the bone, such as multiple myeloma or metastatic breast cancer. In this scenario, the cancer cells infiltrate the bone marrow and release a variety of local signaling molecules, or cytokines. These local factors powerfully stimulate osteoclasts in the immediate vicinity of the tumor cells, causing intense, localized bone destruction.
This destruction releases a substantial amount of calcium directly into the circulation. Furthermore, the bone breakdown process releases growth factors that can stimulate the tumor cells to grow more aggressively, establishing a “vicious cycle” between the cancer and the bone. Unlike \(\text{HHM}\), this mechanism is localized to the bone and may not show the systemic elevation of \(\text{PTHrP}\).
Causes Other Than Cancer and Next Steps
Although malignancy is a common cause of high calcium, particularly in hospitalized patients, it is not the sole factor, and other conditions must be investigated. The most frequent non-malignancy cause is primary hyperparathyroidism (\(\text{PHPT}\)), which involves the overproduction of \(\text{PTH}\) by one or more of the parathyroid glands. In \(\text{PHPT}\), the lab results show an inappropriately high \(\text{PTH}\) level alongside the elevated calcium, which helps differentiate it from cancer-related hypercalcemia.
Other less common causes include:
- Certain medications, such as thiazide diuretics or lithium.
- Excessive intake of vitamin D, which increases calcium absorption from the gut.
- Granulomatous diseases like sarcoidosis, which increase the activation of vitamin D.
Once hypercalcemia is detected, detailed testing determines the root cause. A blood test for the \(\text{PTH}\) level is performed to distinguish between \(\text{PTH}\)-mediated causes (\(\text{PHPT}\)) and non-\(\text{PTH}\)-mediated causes (often cancer). Initial treatment focuses on stabilizing the patient through intravenous hydration with saline to restore fluid volume and promote calcium excretion. Medications like bisphosphonates are administered to inhibit osteoclast activity, slowing the breakdown of bone and the release of excess calcium.