#281 Hypercalcemia: Calci-fun! with Dr. Carl Pallais

June 28, 2021 | By Nora Taranto

Absorb all (but not too much) of the Calcium for your brain hole as Dr. Carl Pallais (Brigham and Women’s Hospital) walks us through his approach to Hypercalcemia. We learn about how tightly our body regulates calcium and what to do when that regulation goes awry.  Not to mention that PTH is the name to remember (and phosphorus, if you need a quick stand-in while that PTH is pending).  

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Credits

• Producer, Writer, Infographic, Cover Art: Nora Taranto MD 
• Hosts: Matthew Watto MD, FACP; Nora Taranto MD  
• Reviewer: Yan Emily Yuan MD, MSc
• Editor: Matthew Watto MD (written materials); Clair Morgan of nodderly.com
• Guest:  Carl Pallais MD, MPH 

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Show Segments

• Intro, disclaimer, guest bio
• Dr. Pallais One-Liner
• Case from Kashlak
• Definitions: What’s a Normal Calcium Level, and how to adjust for Albumin
• Causes of hypercalcemia
• How Lithium works! 
• Testing for Hypercalcemia: Get that PTH, and that phos 
• Symptoms of Hypercalcemia, and Questions on History 
• Indications for Surgery for Parathyroidectomy 
• Management of Hypercalcemia and Hypercalcemic Emergency 
• Outro

Hypercalcemia Pearls

1. In interpreting serum calcium, always correct for Albumin. Add 0.8 g/dL to the Calcium level for every point drop in Albumin. 
2. Only order ionized calcium levels in the inpatient setting (In ambulatory labs, samples may sit out for some time, which can artificially change the result). 
3. Ask your hypercalcemic patients about Calcium/Vitamin D supplementation, calcitriol, Thiazides, and Lithium.  Remember the stones (kidney), bones (fractures), groans (GI), and psychiatric overtones (depression, fatigue, coma) of hypercalcemia! 
4. When you see elevated calcium, check basic metabolic panel, phosphorus, albumin, PTH, and 25-OH Vitamin D to start. 
5. The first goal in working up hypercalcemia is to determine if it is PTH-mediated. A phosphorus level is a quick marker of whether PTH is turned on or off. (Phosphorus Low = PTH receptors may be activated, either by PTH or PTHrP; calcium supplements can also lower phosphorus levels). 
6. Check kidney function when you see hypercalcemia because kidney injury can prevent calcium excretion and make fluid resuscitation difficult. 
7. The mainstay of treatment for Hypercalcemia is Fluids. Use furosemide if needed to keep patients from becoming volume overloaded as you give fluids. 
8. Many medications will “unmask” primary hyperparathyroidism, which was brewing in the background before.  A true increase in Calcium on a Thiazide or Lithium with a normal to elevated PTH may represent hyperparathyroidism. Thus, monitoring and surgical intervention may be warranted. 
9. To Risk Stratify Asymptomatic Primary Hyperparathyroidism: Do a 24-hour urine collection (to measure urine calcium along with creatinine), renal imaging (to assess for stones), a bone density (include wrist/spine), and spine imaging (to assess for asymptomatic vertebral fractures). 
   

Hypercalcemia Show Notes 

Calcium: What’s Normal?  

A normal Calcium is 8.5 – 10.5 g/dL (varies a little by assay). You should correct for albumin, because only ~50% of that calcium is free (or ionized). The ionized calcium is the portion of the total body calcium that your body uses and cares about.  Approximately 40% is bound to albumin (an anion, binds to the positively charged calcium). By correcting for albumin, you approximate the amount of that total that is ionized.  

How to Adjust for Albumin: Add 0.8 mg/dL to the Calcium for every 1 g/dL Albumin drop below 4.  

You can measure ionized calcium (iCal) directly, and it’s an extremely useful test in the inpatient setting, where labs are processed more quickly (and results are therefore more consistent and accurate). But in the outpatient setting, the test results can be variable because samples may sit out for some time, acid may build up, and this may change the measured value.  Dr. Pallais does not recommend obtaining an iCal in the outpatient setting unless it is collected on ice and processed quickly. 

What’s Pseudohypercalcemia? 

It is not unusual to have a transiently elevated calcium in the setting of dehydration, because of an increased concentration of albumin, despite a normal ionized calcium.  

Rarely, in a subset of Multiple Myeloma, there is a negatively charged monoclonal globulin that is made in sufficient quantities that it binds to and subsequently increases the total Calcium, with a normal iCal.   

pH also changes the total proportion of calcium that is bound to Albumin (more acidotic → will displace some Calcium from the Albumin with the build up of hydrogen, and will affect the ionized calcium). 

What to do with elevated Calcium? 

History and Physical Exam 

As with any clinical problem, start with a good history:

1. Any changes in weight, diet or PO intake to suggest dehydration?
2. Any changes in height and recent fractures?
3. Any recent hospitalization or history of immobilization?
4. A detailed family history is important to consider syndromic endocrine disorders that could involve primary hyperparathyroidism like MEN1 and MEN2A.
5. Age and gender can increase the likelihood of primary hyperparathyroidism (think post-menopausal women, according to this JCEM 2013 article). 
6. Always ask about medications: Lithium is a primary offender to cause mild hypercalcemia. Thiazide diuretics as well.  Also, ask about Vitamin D and Calcium Carbonate supplementation (milk alkali syndrome is real! Ask about Tums!), and other vitamin or herbal supplements.  Ask specifically about activated vitamin D, Calcitriol, which is quite potent.  

On physical exam:

1. Look in the mouth to see if mucous membranes are dry.
2. Look in the eyes for any evidence of band keratopathy (corneal degeneration from calcium deposits, which may indicate a chronic process) 
3. Look at the skin for any calcinosis cutis (calcium salt deposition in the skin). 
4. Any abdominal pain?
5. Any bony pain, especially along the spine?
6. Any CVA tenderness to suggest kidney stones? 

The Symptoms 

Think Bones, Groans, Stones, and Psychiatric Overtones–primarily for severe hypercalcemia or quick increases. Specifically, you can get fractures if there is osteoporosis due to increased bone turnover. You can also get crystallization of calcium in the kidneys and subsequent stones, as well as vasoconstriction of the kidneys with severe hypercalcemia. Abdominal symptoms can range from constipation to pancreatitis or peptic ulcer disease (with high levels).  Mild psychiatric symptoms include fatigue, malaise and can escalate to coma(!) and delirium.  

We typically think of mild, asymptomatic hypercalcemia with a Calcium less than 12, with moderate and severe greater than 12 more likely to produce symptoms.  And remember, if a patient has an AKI, they won’t be able to get rid of that calcium, and are likely to develop symptoms more rapidly. 

Lab Workup 

First, repeat the lab. The Basic Metabolic Panel measures the total serum calcium level.  Always check the Albumin and Phosphorus and the kidney function (how much calcium are you able to pee out?).  Next, check the Intact Parathyroid Hormone and 25-OH Vitamin D.  

Quick Trick: Remember The Phos-PTH connection. PTH regulates both Calcium and Phosphorus. When hypercalcemia is PTH-mediated, the phosphate will be on the lower end of normal (and vice versa for PTH-independent hypercalcemia, with higher phosphates–except for PTHrP which also lowers Phosphate).  Per Dr. Pallais, the Phosphorus gives a quick idea of whether the hypercalcemia is PTH-mediated or not, far before the PTH level comes back. 

Always think about kidney function. We get rid of our excess calcium in urine, and folks with kidney disease (acute or chronic) will not be able to compensate as well. 

You may also want to think about workup for malignancy, if a patient presents with severe hypercalcemia and  PTH levels are low, suggesting the process is PTH-independent. This workup includes a skeletal survey to look for bone lesions, SPEP/Serum Free Light Chains to look for myeloma, and 1-25 (OH)2-Vitamin D to look for granulomatous disorders. Check a TSH as well. 

You may also want to rule out familial hypocalciuric hypercalcemia (FHH), which is generally a benign disorder. You would want a 24-hour urine collection and measure calcium (along with creatinine). In FHH, you would expect the urine calcium to be low. 

The Li+/Ca2+ Connection: Lithium causes a mild hypercalcemia, in a PTH-dependent manner (see Meehan et al 2018’s work for more epidemiology). Lithium affects the Calcium-sensing receptor in the parathyroid glands and kidney (which can be mutated, as in Familial Hypocalciuric Hypercalcemia) which senses total Ca to be lower than it actually is, increases PTH production and Calcium reabsoprtion, and causes an increase in total Calcium. You can expect to see low Urine Calcium, elevated PTH, and elevated Calcium. Typically this is mild, but if you have any renal failure, the hypercalcemia can worsen due to impaired urinary calcium excretion. 

The Differential for Hypercalcemia

Break it down between PTH-dependent and PTH-independent causes. A suppressed PTH level suggests that the process causing the high calcium level is PTH-independent. Meanwhile, high or normal PTH levels with a high calcium suggests the process is PTH-mediated, and that the PTH is inappropriately elevated (and not suppressed by high circulating Calcium levels).  

PTH-Dependent: 

Primary hyperparathyroidism is incredibly common, and often found incidentally in asymptomatic patients. Remember that a high calcium with a normal PTH is also suggestive of primary hyperparathyroidism (PTH should be suppressed by hypercalcemia in normal parathyroid glands). 

Familial Hypocalciuric Hypercalcemia (FHH): If you see mild elevations in serum calcium, and normal to slightly elevated PTH, but low calcium in the urine, consider FHH.  Always look at prior labs, because this genetic condition will be present from birth (and genetic testing can confirm the diagnosis).  The mechanism is the same as with Lithium; the Calcium-Sensing Receptors in the parathyroid gland and kidneys think the body does not have enough calcium and cause the secretion of PTH and reabsorption of urinary calcium, respectively.  This condition is rare and reflects a reset of the calcium levels at a higher value. There’s actually nothing to do about this except monitor.  Primary Hyperparathyroidism is much more common, and Thiazides also cause low urinary Calcium. 

Clinical Pearl: Many medications will “unmask” primary hyperparathyroidism, which was brewing in the background before.  A true increase in Calcium on a Thiazide or Lithium may represent a true hyperparathyroidism, and monitoring and surgical intervention may be warranted. 

PTH-Independent: 

In the inpatient setting, think more about hypercalcemia of malignancy (PTH-independent), by a variety of mechanisms: PTHrP (PTH-related protein) which acts like PTH and causes increased bone turnover and calcium reabsorption in the kidney, increased bone turnover in the setting of metastases or lytic lesions (as in Multiple Myeloma), or rarely lymphoma-driven activation of Vitamin D.  Clinical pearl: If you’re thinking about PTHrP, think about solid tumor malignancies like breast cancer, squamous cell cancer, and other undifferentiated cancers.  

Other common causes of PTH-independent hypercalcemia include hormonal disorders (thyroid dysfunction, adrenal insufficiency), milk alkali due to excess calcium intake, Vitamin D or A toxicity,  granulomatous disorders resulting in unregulated activation of vitamin D, and prolonged immobilization and parenteral nutrition. 

Let’s talk management!  

Surgical Candidacy for Parathyroidectomy 

Think about surgical removal of the culprit parathyroid gland (usually an adenoma) for patients with elevated PTH levels and high calcium. Surgery is indicated for patients with a history of kidney stones or fragility fractures. The 2014 Guidelines (see Table 1) layout the indications for surgical removal of a parathyroid gland for asymptomatic patients. Indications for surgery include age < 50 (because of long expected duration of hypercalcemia), Calcium  level > 1 mg/dL above the upper limit of normal, renal dysfunction (CrCl < 60, predisposes to bone loss), presence of asymptomatic kidney stones on renal imaging or increased risk of kidney stone by 24h urine stone risk analysis, and and evidence of osteoporosis on DXA scan (get the wrist as well!) or asymptomatic vertebral fractures on spine films or vertebral fracture analysis (VFA) on DXA scan.  

Managing that Calcium 

With mild hypercalcemia (<12), patients will often be asymptomatic. If they have preserved kidney function, tell them to drink a lot of fluid (at least 2L/day), and stop vitamin D or calcium supplementation.  

Do we need to stop Lithium? If it’s an old medication on which a patient is stable, and the calcium level is in the mild range, you may not need to stop it. You can start Cinacalcet, which activates the Calcium-Sensing Receptor and down-regulates PTH secretion. 

Severe Hypercalcemia (>14): Think lethargy, confusion, and coma, as well as renal dysfunction (from calcium-induced vasoconstriction).  The most common cause of severe hypercalcemia is malignancy, but you can also see this with primary hyperparathyroidism plus calcium/vitamin D supplementation and pre-renal acute kidney injury. 

The mainstay of treatment for those who can tolerate it is fluids (to wash out the calcium). Volume is the key (whatever the fluid type), and loop diuretics are useful to allow for more fluid administration in select patients. Beware of overzealous diuretic use, which can dehydrate and worsen the process. 

Also give Calcitonin (though you can only use this for 2 days due to tachyphylaxis) to stop bone turnover, and anti-resorptive medications such as an intravenous  bisphosphonates, which start working after a day or two. With impaired renal function, use denosumab instead of bisphosphonates. Prior to using anti-resorptive medications, remember to replete Vitamin D (if deficient) to reduce the risk of post-treatment hypocalcemia, which can be severe.  

For hypercalcemia that is due to Vitamin D toxicity or mediated by 1,25 (OH)2-Vitamin D, such as in granulomatous disease, treatment with glucocorticoids should also be considered. 

Check out this 2018 Summary of Treatment Options. 

Take Home Points 

1. Don’t let schooling interfere with your education. Take ownership of your education, allow yourself to deviate to learn what you need to know for your own interest. 
2. Don’t miss primary hyperparathyroidism, with high calcium and an inappropriately normal PTH (It doesn’t have to be elevated!). 
3. Send a 24-hour urine collection to measure urine calcium and creatinine for asymptomatic primary hyperparathyroidism, as well as a renal US or CT to evaluate for kidney stones, and the bone density to include the wrist and spine imaging to look for asymptomatic vertebral fractures. These tests will help you to risk stratify and decide who to send for surgery.  

Links*

1. Dr. Pallais’s Book Recommendation: A Confederacy of Dunces
2. Yeh et al, Incidence and Prevalence of Primary Hyperparathyroidism in a Racially Mixed Population, 2013, JCEM
3. Meehan et al, Lithium-Associated Hypercalcemia: PAthophysiology, PRevalence, Management, 2018, World J Surg. 
4. Bilezikan et al, Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary statement from the Fourth International Workshop, 2014, J Clin Endocrinol Metab.
5. Rare Diseases FHH: https://rarediseases.info.nih.gov/diseases/10828/familial-hypocalciuric-hypercalcemia 
6. Reneghan et al, Hypercalcemia: etiology and management, 2018, Nephrology, Dialysis, Transplantation 
7. Stephen et al, Severe Hypercalcemia. In: Garg R., Hennessey J., Malabanan A., Garber J. (eds) Handbook of Inpatient Endocrinology. Springer, Cham. (2020) https://doi.org/10.1007/978-3-030-38976-5_10 

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Goals

Listeners will understand the workup and management of hypercalcemia. 

Learning objectives

After listening to this episode listeners will…

1. Calculate adjusted calcium levels 
2. Identify medications that can contribute to hypercalcemia 
3. Create appropriate differentials, and interpret diagnostic tests to identify etiology
4. Identify when to treat hypercalcemia, and treat hypercalcemia emergencies 

Disclosures

Dr Pallais reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Pallais JC, Williams PN, Brigham SK, Watto MF. “#281 Hypercalcemia: Calci-fun! with Dr Carl Pallais”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date June 28, 2021.