High Calcium in the Blood (Hypercalcemia): Causes, Symptoms and Tests

Blood calcium is kept within a very narrow range by three organs and two hormones. Bone is the store (about 99% of the body's calcium), the gut determines absorption from food, and the kidneys decide how much calcium returns to the blood and how much goes into urine. Parathyroid hormone (PTH), secreted by the parathyroid glands, raises calcium: it stimulates the release of calcium from bone, reduces its excretion in urine and activates vitamin D to its active form (1,25-dihydroxyvitamin D), which increases calcium absorption in the gut. Parathyroid cells have calcium-sensing receptors (CaSR); when calcium rises, PTH secretion should fall. In a healthy body this negative feedback works like a thermostat.

That is why the first question in hypercalcemia is: is PTH behaving normally, that is, is it suppressed by the high calcium? If so (low PTH, in many assays below about 20 pg/ml depending on the method), the cause lies outside the parathyroids: calcium is 'pouring' into the blood from another source, for example from bone in cancer, from the gut with excess vitamin D, or from another tissue. If PTH is raised or within the normal range despite high calcium, it is a sign that the parathyroids are working inappropriately, which is typical of primary hyperparathyroidism. According to the authors of the JAMA review, this simple division is the most important initial diagnostic step.

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in people who are neither oncology patients nor hospitalized. It is usually caused by an adenoma of one parathyroid gland, less often by enlargement of several glands. As an epidemiological review in the Journal of Bone and Mineral Research summarizes, the disease typically affects postmenopausal women, and how often it is detected depends largely on whether calcium and PTH are measured as screening in a given country; in Western countries the asymptomatic form, found by chance, now predominates. A genetic basis is identified in about 10% of cases (MEN1–MEN4 syndromes, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism).

In the past, PHPT was diagnosed mainly from its complications: kidney stones, bone changes and marked complaints. Today most patients have no obvious symptoms and the consequences are subtler: accelerated loss of bone mass, an increased risk of fractures and kidney stones, and in some patients fatigue, low mood and poor concentration. The Fifth International Workshop on PHPT (2022) updated the guidelines on evaluation and management, including criteria for referring the asymptomatic form for surgery; in practice, treatment (parathyroidectomy or observation) is decided by age, calcium level, and kidney and bone status.

An interesting entity that must be distinguished from PHPT is familial hypocalciuric hypercalcemia (FHH): a mild, inherited hypercalcemia with an inappropriately normal PTH but low urinary calcium excretion. Unlike PHPT, it usually does not need surgery, and a wrong diagnosis and an operation bring no improvement. Differentiation rests on urinary calcium and, in unclear cases, on genetic testing. A separate matter is lithium-induced hyperparathyroidism: a review in the British Journal of Hospital Medicine notes that chronic lithium treatment can 'unmask' a subclinical adenoma or cause enlargement of several glands, so regular calcium monitoring is necessary in people taking lithium.

From the point of view of a reader of our site, this is one of the most important sections. Excess calcium or vitamin D from supplements is a real, though rare, cause of hypercalcemia, and the fashion for high doses of vitamin D3 means the problem may occur more often. A team of Polish and international authors described this issue in a clinical review: severe hypercalcemia is a manifestation of vitamin D toxicity, and the most common cause of exogenous toxicity is the improper use of very high doses of pharmacological preparations.

A practical lesson follows: if you use high doses of vitamin D3 (especially multiples of the doses recommended for the general population), calcium supplements or vitamin A, calcium and 25(OH)D are worth checking periodically, and if a result is above range, first stop the supplement after consulting your doctor and repeat the test. Thiazides (which reduce urinary calcium excretion), lithium and, less often, other drugs can lead to similar effects. The JAMA review mentioned above also lists among rare causes (together under 1%) a ketogenic diet, extreme exercise, SGLT2 inhibitors and checkpoint inhibitors, which shows that almost any factor can contribute to hypercalcemia, but in practice PHPT and cancer almost always have to be excluded first.

The second most common group of causes is malignant disease. Hypercalcemia in cancer arises in two main ways: the tumor secretes a PTH-like protein (PTHrP), which acts in bone and kidney like PTH, or metastases and myeloma destroy bone and release calcium. Less often the tumor produces active vitamin D (some lymphomas). In both main scenarios PTH is suppressed. Cancer-related hypercalcemia usually develops quickly, produces marked symptoms (thirst, polyuria, nausea, confusion) and, as the JAMA review summarizes, is associated with a poor prognosis because it is a marker of advanced disease. It is worth saying so plainly, while stressing that cancer is the cause of a minority of cases of hypercalcemia found by chance in otherwise healthy people.

Granulomatous diseases such as sarcoidosis or tuberculosis cause hypercalcemia differently: macrophages in granulomas produce active vitamin D regardless of the body's needs, which increases calcium absorption in the gut. In such cases PTH is low and 1,25(OH)2D may be raised. Importantly, people with sarcoidosis may develop hypercalcemia after sun exposure or after vitamin D supplementation, so supplementation advice for them requires particular caution and calcium monitoring.

Rarer causes include hyperthyroidism (accelerated bone turnover), adrenal insufficiency, immobilization and, in people with kidney disease, disturbances of calcium-phosphate balance, including tertiary hyperparathyroidism after years of kidney failure. In nephrology patients calcium should be interpreted together with phosphate, PTH and vitamin D, not as an isolated result. We write about phosphate in a separate article in this series.

Calcium in the blood exists in three forms: bound to albumin (about 40–45%), bound to anions (for example citrate) and ionized, which is biologically active. The standard test measures total calcium, so it depends on the albumin concentration. With low albumin (malnutrition, liver disease, severe illness) total calcium may be underestimated despite normal ionized calcium, and with high albumin (dehydration) overestimated. That is why a correction formula is often used in practice: corrected calcium (mg/dl) = total calcium + 0.8 × (4.0 − albumin in g/dl). The formula is widely described in textbooks, but it has limitations.

Practical conclusion: when total calcium is borderline and albumin departs from normal, direct measurement of ionized calcium, done in a properly collected sample (without a long tourniquet, analyzed quickly), is the most reliable. More detailed interpretation rules are described in the entry on total and ionized calcium. A raised result may also reflect dehydration, which increases albumin and thus total calcium; after rehydration the value may fall. Rarely, in paraproteinemia, pseudohypercalcemia occurs, so in people with suspected gammopathy it is worth confirming the result with ionized calcium.

The classic textbook description of hypercalcemia symptoms is: 'stones, bones, groans and psychic moans'. Stones means kidney stones and polyuria (calcium impairs the kidneys' ability to concentrate urine, so thirst and dehydration appear), bones means bone pain and osteoporosis, groans means nausea, constipation, loss of appetite and abdominal pain, and psychic moans means fatigue, depression, apathy and, at high values, confusion. High calcium can also shorten the QT interval on the ECG and disturb heart rhythm.

Importantly, most people with mildly raised calcium have no complaints at all, or the complaints are nonspecific and easily put down to stress, age or menopause. That is why a calcium result above range always deserves a repeat and follow-up tests, even if you feel well. Sound diagnostics prevent both dismissal and unnecessary procedures.

First hypercalcemia should be confirmed: repeat total calcium with albumin and, if in doubt, do ionized calcium. The doctor then orders PTH, which decides the direction of the work-up. The list below presents a typical set of tests and their purpose.

The current guidelines on primary hyperparathyroidism (Fifth International Workshop, J Bone Miner Res 2022) are the result of the work of more than 50 experts and updated the previous 2014 recommendations, taking into account new imaging, genetics, pregnancy and the results of randomized trials. For the patient this means one thing: the diagnosis of hyperparathyroidism is now well organized, and the decision about surgery depends on age, calcium level, kidney function, bone status and the patient's preferences, not solely on the calcium value itself.

At the same time, keep a sense of proportion. Mild hypercalcemia in asymptomatic PHPT, especially in a person over 50 with calcium only slightly above the upper limit (per the JAMA review: less than 1 mg/dl above the upper limit, without bone and kidney disease), may be managed by observation. It does, however, need periodic checks of calcium, creatinine and bone density, not disregard.

Equally doubtful is the popular opinion that 'calcium must always be taken with vitamin K2 so that it does not deposit in the arteries'. That is a separate topic, which we discuss in the articles on vitamins K2 and D3. In the context of this text, the more important reminder is that high doses of vitamin D with calcium can simply raise blood calcium in susceptible people, and K2 does not prevent this.

High calcium is a result that is hard to dismiss and yet should not cause panic. The best plan is three simple steps: repeat the test (with albumin or ionized calcium), go through the list of supplements and drugs with your doctor, and order PTH together with 25(OH)D, creatinine and phosphate. From these few results the cause usually emerges, and only then is treatment or observation chosen.

If you use high doses of vitamin D3, calcium supplements or take drugs affecting calcium balance, plan periodic calcium measurement together with 25(OH)D. It is a cheap and simple safety check that can catch hypersensitivity to vitamin D before symptoms appear. Remember also that asymptomatic primary hyperparathyroidism is a real, often overlooked diagnosis in postmenopausal women with unexplained osteoporosis or kidney stones.