Normocalcemic Primary Hyperparathyroidism

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What is normocalcemic primary hyperparathryoidism?

Normocalcemic primary hyperparathyroidism (nPHPT) is suspected when patients’ calcium level is within the normal range, but parathyroid hormone level is too high. (See Normal Calcium Levels) This condition is not well understood in the medical literature. This is simply because normal individuals do not have their parathyroid hormone levels checked.

Normocalcemic primary hyperparathyroidism (nPHPT) is hypothesized to be an “early” type of primary hyperparathyroidism. Primary hyperparathyroidism is when one or more of the parathyroid glands makes too much parathyroid hormone, which draws calcium from the bones into the blood, weakening bone density and raising blood calcium level. In normocalcemic PHPT, the parathyroid glands are releasing too much hormone, but the blood calcium level has not risen yet.

Primary hyperparathyroidism is typically diagnosed when patients are found to have high blood calcium during routine checkups. However, nPHPT cannot be detected through high blood calcium lab results, because these patients have normal calcium levels. Patients with nPHPT are often uncovered during work up for osteoporosis or low bone mineral density.

Proper diagnosis of normocalcemic primary hyperparathyroidism is challenging, because there are several other causes of high parathyroid hormone levels and normal calcium levels. Because several other conditions may mimic normocalcemic primary hyperparathyroidism, detailed blood and sometimes urine testing is required to establish the definitive diagnosis.

Does normocalcemic primary hyperparathyroidism cause bone problems such as osteopenia or osteoporosis?

Nearly half of patients diagnosed with normocalcemic primary hyperparathyroidism have been found to have osteoporosis. However, parathyroid hormone is more frequently performed in patients with osteopenia or osteoporosis. For this reason, it is possible these diagnoses are found together by coincidence. Therefore, normocalcemic primary hyperparathyroidism may cause bone loss.

Does normocalcemic primary hyperparathyroidism cause kidney stones?

The short answer is that we do not know for sure. We do know that primary hyperparathyroidism with high calcium levels does cause kidney stones. Current research tells us that 4-35% of patients normocalcemic primary hyperparathyroidism have kidney stones. However, since ~8% of people in the population have kidney stones for other reasons, it is unclear if nPHPT increases that risk even further.

What other conditions aside can cause high parathyroid hormone levels?

To diagnose normocalcemic primary hyperparathyroidism, other conditions that may cause high parathyroid hormone levels need to be ruled out. Here are other common causes of high parathyroid hormone levels:

  • Secondary hyperparathyroidism
    • Vitamin D deficiency
    • Not enough calcium in diet
    • Intestinal problems causing poor absorption of calcium
    • Kidney failure or kidney problems
  • Certain medications
    • Loop diuretics, such as Lasix aka furosemide
    • Lithium
    • Bisphosphonates
    • Denosumab
    • Anti-seizure medications

What is secondary hyperparathyroidism?

To diagnose nPHPT, we must rule out secondary hyperparathyroidism. Secondary hyperparathyroidism is different from primary hyperparathyroidism. In primary hyperparathyroidism, the parathyroid tissue is abnormal and making too much parathyroid hormone. In secondary hyperparathyroidism, the parathyroid gland is functioning normally and is only producing high levels of parathyroid hormone because the body is signaling that it needs more calcium in the blood.

One major cause of secondary hyperparathyroidism is vitamin D deficiency. Vitamin D is required for the body to absorb calcium from food. The normal range of Vitamin D is 30-80 ng/mL. With low levels of vitamin D, patients are not able to absorb calcium correctly and therefore the blood calcium is low. The parathyroid glands compensate by increasing PTH levels to increase blood calcium. Patients with normal levels of calcium, high levels of PTH, and vitamin D deficiency could have secondary hyperparathyroidism. Patients with low levels of calcium and high levels of PTH have secondary hyperparathyroidism.

After vitamin D supplementation, the patient’s PTH level should return to normal. If calcium levels become high and PTH remains high after Vitamin D supplementation, this establishes the diagnosis of primary hyperparathyroidism.

Kidney Stones Illustration
Kidney Stones Illustration

Another possible cause of secondary hyperparathyroidism is not eating enough calcium or the intestines not absorbing calcium. Both of these could also cause low body calcium, prompting the parathyroid glands to make extra parathyroid hormone. Intestinal problems such as celiac disease and previous weight loss surgeries could cause absorption problems.

Ruling out Chronic Kidney Disease and Urinary Calcium Leaks

Kidney failure, or an eGFR of less than 60, causes a problem with vitamin D metabolism. This also leads to the parathyroid glands appropriately compensating the loss of blood calcium by increasing PTH levels. Calcium in the blood can also be lost as blood filters through the kidneys and too much calcium leaks into the urine (called urinary calcium leak). Excess calcium in kidney filtration can lead to kidney stones.

MeasurePrimary HyperparathyroidismNormocalcemic Primary Hyperparathyroidism (nPHPT)Secondary Hyperparathyroidism
Blood CalciumHighNormalNormal or low
Parathyroid HormoneHighHighHigh
Vitamin DUsually normalMust be normalMay be low
GFR (kidney function)Usually normalMust be normalMay be low

What is the treatment for normocalcemic primary hyperparathyroidism?

Not everyone with normocalcemic primary hyperparathyroidism needs treatment. Many patients can be safely monitored over time. About 15% of people seem to progress to primary hyperparathyroidism and develop high blood calcium levels; these patients ultimately need surgery.

Our practice is to offer surgery selectively to patients with normocalcemic primary hyperparathyroidism. Currently, less than 1/3 of our patients with nPHPT undergo surgery. The typical patient who undergoes surgery at our center for nPHPT is selected for parathyroid surgery because they have progressive unexplained bone loss. After successful surgery, bone mineral density improves in approximately half of patients with nPHPT. At present there is no compelling evidence that non-specific symptoms (i.e. fatigue, lethargy, depression, forgetfulness, vague abdominal pain, loss of appetite) improve after parathyroid surgery for nPHPT.

Bone loss related to nPHPT may also be treated with medications used to treat osteopenia and osteoporosis. The combination of vitamin D and a type of medication called bisphosphonates can be used to improve bone health in patients with normocalcemic primary hyperparathyroidism. Other treatments for severe osteoporosis include injections that prevent breakdown of bone by bone cells (denosumab) and promoting bone formation (romosozumab). For patients with kidney stones, there is very limited evidence that cinacalcet may help reduce the size and number of kidney stones.

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Further reading and additional references

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