Approach to hypercalcemia: Clinical sciences

Chapters:

Watch video only

Introduction0:00–0:42

Hypercalcemia refers to a serum calcium level above the upper limit of normal, which varies among different labs but is often considered greater than 10.5 mg/dL.
Calcium plays a vital role in various body functions, such as myocardial contractility and nerve signaling. So, calcium imbalances, such as hypercalcemia, can result in cardiac and neurologic dysfunction.
Some important causes of hypercalcemia that you should keep in mind include medications, malignancy, as well as different endocrine conditions like hyperparathyroidism or hyperthyroidism.Now, if your patient presents with a chief concern suggesting hypercalcemia, you should first perform an ABCDE assessment to determine if your patient is unstable.

Unstable Patient0:42–1:52

If the patient is unstable, stabilize the airway, breathing, and circulation. Next, obtain IV access and put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry, as well as cardiac telemetry.
Finally, if needed, provide supplemental oxygen.Now, here’s a high-yield fact to keep in mind! Patients with severe or rapidly progressing hypercalcemia can present with lethargy, stupor, or even coma.
Additionally, an ECG may reveal bradycardia, atrioventricular block, or a shortened QT interval. In this case, you should normalize calcium levels by starting intravenous hydration, as well as diuretics like furosemide or bisphosphonates like zoledronic acid.Now that we're done with unstable patients, let’s go back to the ABCDE assessment and discuss the stable ones.

Stable Patient1:52–4:18

First, obtain a focused history and physical examination, and obtain labs to check their serum calcium levels. Your patient may report personality and mood changes, as well as trouble concentrating, and even altered mental status.
They might also experience gastrointestinal issues, such as abdominal pain, nausea, anorexia, and constipation. Additionally, history might reveal musculoskeletal pain; renal symptoms like polyuria; polydipsia; and nephrolithiasis.
On the flip side, physical exam findings are typically nonspecific and might include weakness and signs of dehydration, like dry mucous membranes and poor skin turgor.
To remember the classic presentation of hypercalcemia, you can think of the mnemonic “groans, bones, stones, thrones, and psychiatric overtones.” Groans represent constipation and muscle weakness, which occur due to decreased muscle contractions.
Bones is for bone pain resulting from chronic bone demineralization. Next, stones refer to a history of nephrolithiasis, since hypercalcemia will typically lead to hypercalciuria in an attempt to excrete the excess calcium; whereas thrones serve as a reminder of polyuria.
Finally, psychiatric overtones include symptoms like mood changes or altered mental status.Finally, labs will reveal a serum calcium level that’s above the upper limit of normal, so, at this point, you should consider, not diagnose yet, hypercalcemia.
This is because approximately half of the calcium in the blood is bound to plasma proteins, mainly albumin, while the other half circulates as ionized calcium.
Although ionized calcium reflects the body's calcium stores accurately, measuring it is more complex than measuring total serum calcium.
Also, keep in mind that, when measuring total serum calcium in the setting of low serum albumin, there's a chance of getting false results, since the albumin-bound calcium is also affected.So to avoid false results and truly diagnose hypercalcemia, you might need to calculate the corrected total serum calcium level.

Corrected Calcium Levels4:18–4:51

Do this by subtracting the patient's serum albumin level from 4 and multiplying the difference by 0.8. Next, add the product to the measured serum calcium, and you will obtain the corrected calcium level.
If the corrected serum calcium level is above the reference range, you can confirm the diagnosis of hypercalcemia!Once you’ve diagnosed hypercalcemia, your next step is to identify the cause.

Medication-induced Hypercalcemia4:51–5:19

Start by reviewing your patient’s medication list, since certain medications may lead to or worsen their hypercalcemia. These include vitamin D supplements, thiazide diuretics, lithium, and calcium-containing antacids.
If a causative medication is identified, you can diagnose medication-induced hypercalcemia. On the other hand, let’s see what to do if your patient is not taking any medications associated with hypercalcemia.

PTH High5:19–7:12

First, check serum parathyroid hormone or PTH for short. If PTH is elevated, diagnose hyperparathyroidism.
Primary hyperparathyroidism is caused by inappropriately high production of PTH by the parathyroid glands. In contrast, secondary hyperparathyroidism is caused by an appropriate rise in PTH levels, as the parathyroid glands attempt to correct hypocalcemia.
Finally, there’s tertiary hyperparathyroidism, which is usually caused by long-standing secondary hyperparathyroidism that eventually ends up with parathyroid hyperplasia and subsequently PTH overproduction.Now, here’s a clinical pearl to keep in mind!
Hypercalcemia is present in individuals with Familial Hypocalciuric Hypercalcemia or FHH for short, which is an autosomal dominant genetic disorder impacting the calcium-sensing receptor on cell membranes.
This receptor plays a crucial role in calcium regulation. In FHH, a genetic mutation reduces sensitivity to high calcium levels, which would normally be sensed by the calcium-sensing receptors on parathyroid cells and turn off the parathyroid’s PTH production.
As a result, these patients will have elevated PTH secretion despite hypercalcemia. If you suspect FHH, order a urine test to evaluate the calcium-to-creatinine ratio.
If the ratio is low, proceed with genetic testing to confirm the diagnosis.Alright, now, let's take a step back and take a look at what to do if PTH is not elevated.

PTH Low/Normal7:12–7:59

In this case order labs, including PTH-related peptide, or PTHrP; 1,25-dihydroxy vitamin D; and alkaline phosphatase. If the PTH-related peptide is elevated, your patient might have a solid tumor such as lung cancer.
On the other hand, if there’s high alkaline phosphatase, think of lytic bone metastases, such as those seen in breast cancer or multiple myeloma.
Finally, elevated 1,25-dihydroxy vitamin D is highly suggestive of lymphoma or granulomatous conditions, such as Hodgkin lymphoma or sarcoidosis, respectively.
However, if PTH-related peptide, alkaline phosphatase, and 1,25 dihydroxy vitamin D are all normal, consider hyperthyroidism.
Your next step is to order labs, including a TSH and free T4. If the TSH is low and the free T4 is high, you can diagnose hyperthyroidism.

Hyperthyroidism7:59–8:49

Now, here’s one last clinical pearl! If the diagnosis is still not clear, other tests should be considered, including serum protein electrophoresis or SPEP and urinary protein electrophoresis or UPEP, to look for the presence of monoclonal proteins, which would indicate a disease like multiple myeloma.
Alright, as a quick recap… Hypercalcemia refers to a serum calcium level above the upper limit of normal. If you suspect hypercalcemia, first perform a focused history and physical exam, and order serum calcium and correct it for the albumin if it’s low.

Review8:49–9:49

Some important causes of hypercalcemia include medications, such as vitamin D supplements, thiazide diuretics, lithium, and calcium-containing antacids.
If you rule out medication-induced hypercalcemia, check PTH levels. If the PTH is elevated, diagnose hyperparathyroidism.
However, if PTH is not elevated, order a PTH-related peptide, alkaline phosphatase, and 1,25 dihydroxy vitamin D. These labs will help you diagnose conditions such as solid tumors, lytic bone metastasis, as well as lymphoma and granulomatous conditions.
If these labs are normal, consider hyperthyroidism. pth related peptide alkaline phosphatase and 1 25 dihydroxy vitamin D these labs will help you diagnose conditions such as solid tumors lytic bone metastasis as well as lymphoma and granulomatous conditions If these labs are normal consider