Approach to Hypercalcemia

Before reading this approach we highly recommend you read these 2 short articles first, to get a background on calcium:

• What are the types of calcium and how can we measure it?
• How are calcium levels levels controlled in the blood?

Hypercalcemia can be due to a variety of reasons, some (e.g. malignancy) more ominous than others (e.g. primary hyperparathyroidism).

What does the hypercalcemia patient look like?

Mnemonic for hypercalcemia:

1. Wet – polyuria, polydipsia, nausea/vomiting
2. Wacky – confused
3. Writhing – kidney stones, abdominal pain
4. Waste – constipation
5. Weak muscles
6. Weak reflexes

QT interval is inversely proportional to Ca levels:

• Hypercalcemia – short QT interval
• Hypocalcemia – long QT interval

Steps for Hypercalcemia

Let’s break it down into steps

1. Measure serum Ca. Serum Ca is elevated!
2. Look at albumin, see if it is normal range.
   1. If normal range, then hypercalcemia is confirmed
   2. If hyperalbuminemia, then correct total Ca using formula, and then see if corrected value falls outside the range for normal Ca
3. After hypercalcemia is confirmed, next you want to measure PTH (PTH released by parathyroid gland increases serum Ca levels)
   1. Serum PTH is elevated or normal
      1. Get a urine calcium to creatinine clearance ratio to differentiate between FHH and PHPT
   2. Serum PTH is low
      1. Measure PTHrp (rule out PTHrP from malignancy)
      2. Measure 25-hydroxyvitamin D (precursor of active vitamin D) and 1,25-dihydroxyvitamin D (active vitamin D)
      3. Measure SPEP and serum free light chain assay (rule out multiple myeloma)

Types of vitamin D

• Vitamin D2 – ergocalciferol
• Vitamin D3 – cholecalciferol

Vitamin D3 comes from 2 sources: dietary supplements and sun. When ultraviolent rays hit the skin it results in the conversion of the pre-vitamin D into vitamin D3 (cholecaiferol).

Cholecalciferol and ergocalciferol are then taken to the liver where they are converted to the inactive precursor of vitamin D, called calcidiol

• Calcidiol – 25-hydroxyvitamin D

Calcidiol is then taken to the kidneys where it is converted into calcitriol which is active vitamin D

• Calcitriol – 1,25-hydroxyvitamin D

Calcitriol then acts on the intestine to increase calcium and phosphorous absorption.

Hypercalcemia with elevated or normal PTH

• Primary hyperparathyroidism
• Familial hypocalciuric hypercalcemia

Primary hyperparathyroidism (PHPT) means that the reason the Ca is so elevated is because for some reason there is overproduction of PTH. The role of PTH is to break down bone in order to release the Ca into the blood. It does so through acting on PTH receptors on osteoblasts (the cells that build bone).

PHPT can be caused by an adenoma in one of the parathyroid glands (most common), non-cancerous overgrowth of normal cells in more than one parathyroid gland, parathyroid cancer (rare), and at younger ages, familial hyperparathyroidism syndrome.

Familial hypocalciuric hypercalcemia (FHH) is a bit more of a complicated story.

In order to understand FHH we first have to understand calcium sensing receptors (CaSR).

What does CaSR have to do with FHH then?

In FHH, there is an inactivating mutation of the CaSR gene. That means the receptor is insensitive to Ca and is not working as well as it should. So that means that a higher than normal level of Ca is required at the CaSR in the parathyroid gland before PTH production is suppressed. Similarly, a higher than normal level of Ca is required at the CaSR receptor at the kidney before Ca reabsorption is inhibited.

How can we distinguish between FHH and PHPT if both have high Ca and high PTH?

The answer is to use the urine calcium to creatinine clearance ratio

• FHH ratio < 0.01 LOW
• PHPT ratio > 0.02

If you have PHPT, you have excess PTH, but your CaSR receptors are working normally, so you should be able to pee out that Ca, so urine Ca is high resulting in the ratio being > 0.02

If you have FHH, you have excess PTH, but you are unable to pee out the extra Ca, so urine Ca is low resulting in the ratio being < 0.02

Hypercalcemia with low PTH

When you have high Ca levels with low PTH, it means that the hypercalcemia is not related to levels of PTH. The hypercalcemia is PTH-independent.

One potential cause of hypercalcemia is due to the secretion of PTH-related protein (PTHrP). PTHrP is usually secreted in the context of renal, bladder, breast, ovarian and squamous cell carcinomas of the lung, head and neck. PTHrP acts in a very way to PTH, in that it can raise serum Ca levels. Because these individuals have raised Ca levels, you would also expect to find low levels of normal PTH as well.

Another potential cause of hypercalcemia is due to elevated levels of vitamin D or vitamin D metabolites.

• Elevated levels of 25-hydroxyvitamin D (inactive precursor) can indicate vitamin D toxicity due to over ingestion of cholecaiferol or ergocalciferol
• Elevated levels of active vitamin D may also be due to overingestion but it can also be due to
  • Increased renal production (remember the kidneys are where the last step of the formation of active vitamin D takes place)
  • Extrarenal production in lymphoma

Finally a third cause of hypercalcemia, which you never want to forget especially in the elderly is multiple myeloma. For that reason we want to do a serum protein electrophoresis and serum free light chain assay.