Hypercalcemia
March  2016


A 28 year-old male applied for life insurance. Medical history revealed that he had a general physical about 9 months prior to the application. His BMI was 33.9.
On the screening blood work he had an elevated serum calcium of 10.7 mg/dl (8.7-10.2 mg/dl) or 2.67 mmol/L (2.17- 2.54 mmol/L). His albumin was 5.0 g/dl (3.6-5 g/dl) or 50 g/L (36-50 g/L) and the total protein was 7.6 g/dl (6.1-8.2 g/dl) or 76 g/L (61-82 g/L).

A repeat blood test showed his serum calcium remained elevated at 11 mg/dl or 2.74 mmol/L, his serum albumin was 4.7 g/dl, and his ALT was slightly elevated at 61 (0-45 UL). He was feeling well, was on no medication, and taking no supplements or vitamin D. There was no history of endocrine tumors, fracture or kidney stones in him or his family. Other than obesity, his physical examination was normal. 

He was referred to an endocrinologist. These records showed that his corrected calcium was 10.1 mg/dl, 24-hour calcium in the urine was 218 mg (100-300 mg). Other values included Parathyroid hormone related protein (PTHrP) < .74 pmol/L, Vitamin D 25 Hydroxy 19.9 ng/ml (30-100 ng/ml), PTH 30 pg/ml (15-65 pg/ml). The tentative diagnosis was familial hypocalciuric hypercalcemia. He was placed on a diet with adequate hydration and moderate calcium restriction and prescribed 800 IU of vitamin D daily. Follow-up was scheduled for 1 month, but records were not included. 
 

Is the work-up sufficient to diagnose familial hypocalciuric hypercalcemia (FHH)? What are the mortality implications of hypercalcemia?
Hypercalcemia is a serious finding as over 90% of individuals will have either hyperparathyroidism or malignancy as the cause. Calcium is absorbed in the intestine, deposited in bone and excreted by the kidneys. Excessive absorption from the gut, resorption from bone, decreased excretion by the kidneys or any combination of the three can result in hypercalcemia.

One caveat should be noted when considering serum calcium: 40%-45% is bound to serum proteins, mostly to albumin. The free or ionized calcium is considered to be physiologically important. For the most part, normal laboratory ranges account for this. However, an adjustment sometimes is made when the serum albumin levels are exceptionally high or low. One common formula (US units) for this correction is:

Corrected calcium = Serum calcium + 0.8 * (normal albumin – patient albumin)

(Note: normal albumin is often 4.0 for women and 4.4 g/dl for men.)

For SI units the formula is:

Corrected calcium = Serum Calcium+0.02 * (normal albumin – patient albumin)

(Normal albumin is often 40 for women and 44 g/L for men.)

Evaluation
Laboratory evaluation of hypercalcemia typically begins with the measurement of parathyroid hormone (PTH). Produced in the parathyroid gland, PTH increases bone resorption and intestinal absorption of calcium. A common cause of elevated PTH and consequent hypercalcemia is parathyroid adenoma.

 

This is the most common cause of primary hyperparathyroidism. Typically, primary hyperparathyroidism will elevate serum calcium minimally, less than 11 mg/dl (2.75 mmol/L). And in some cases the hypercalcemia of primary hyperparathyroidism will cause intermittent hypercalcemia or high normal serum calcium, requiring repeated measurements.

If the PTH measures low (<20 pg/ml), measurement of Vitamin D metabolites (1,25-dihydroxyvitamin D) and parathyroid hormone related protein (PTHrP) is recommended. If PTHrP is elevated, then malignancy should be strongly considered and sought. In that setting, vitamin D is usually normal or low. PTHrP increases bone resorption and reduces renal excretion of calcium, resulting in relatively higher levels of hypercalcemia.

Hypercalcemia is relatively common in cancer, occurring in 20%-30% of cases. Cancer can elevate serum calcium by several mechanisms. The most common (~80%) is humoral hypercalcemia of malignancy (HHM) mediated by secretion of PTHrP. The more common tumors associated with HHM are squamous cell carcinomas of the lung, head, neck, breast, bladder, renal or ovarian carcinomas.

A second mechanism, accounting for most of the remainder of the cases of hypercalcemia in malignancy, is osteolytic metastasis. The tumor stimulates osteoclast production and activity, releasing calcium into the blood. Breast cancer and multiple myeloma often cause hypercalcemia by this method.

A less common mechanism is an increased production of 1,25-dihydroxyvitamin D (calcitriol) which can be seen with Hodgkin’s and non-Hodgkin’s lymphomas. This elevation can also be seen in non-malignant granulomatous disease like tuberculosis or sarcoidosis.

Rarely, tumors such as small cell lung cancer, ovarian cancer, papillary cancer of the thyroid and pancreatic cancer can independently produce excess PTH. Quite often, hypercalcemia is a late finding in malignancy, and it often portends a poor prognosis.

If the PTHrP is not elevated, physicians turn to the Vitamin D levels in the evaluation of hypercalcemia. An elevated blood level of vitamin D leads one to consider vitamin or supplement intake, lymphoma or chronic granulomatous disease (TB or Sarcoid), and order a chest x-ray.

In the setting of hypercalcemia and low PTH with low/normal PTHrP and Vitamin D levels, other causes including medications (Figure 1), hyperthyroidism, acromegaly, adrenal insufficiency, immobilization, parenteral nutrition, or milk alkali syndrome should be investigated.

Figure 1 - Medications that can cause hypercalcemia

​Medication​Mechanism of hypercalcemia
​Lithium​Raises the calcium "setpoint" to suppress PTH release
​Thiazide Diuretics​Reduces urinary calcium excretion (rare cause)
​Theophylline (toxicity)​Mild elevations, subsides
​Hypervitaminosis D or Calcitrol or Calcidiol Rx​Increases gut absorption and bone resorption
​Hypervitamininosis A​Increased bone resorption

Certain drugs unrelated to typical mechanisms of hypercalcemia can nevertheless cause the condition to manifest.

For completeness, secondary hyperparathyroidism should be considered, although serum calcium levels are typically normal. This disorder is characterized by elevated PTH to maintain serum calcium levels in response to another disorder. Renal failure and intestinal malabsorption (e.g., bariatric surgery, Celiac disease) are among the more common causes.

Causes
The most common cause of asymptomatic hypercalcemia is primary hyperparathyroidism (PHPT), and after malignancy has been excluded attention can be focused on this.  Symptomatic PHPT is characterized by the mnemonic:

  • Bones (bone pain from calcium resorption)
  • Stones (nephrolithiasis)
  • Abdominal Moans (anorexia, nausea, constipation)
  • Psychic Groans (anxiety, depression, cognitive changes)

However, symptomatic PHPT is much rarer than the asymptomatic variant. Subclinical muscle weakness may also be detected with appropriate testing. Laboratory findings for the most common causes of hypercalcemia are listed in Figure 2.

Figure 2 - Typical hypercalcemia lab test results and likely diagnosis

Diagnosis​PTH​24-hour urinary calcium​250H
Vitamin D
​PHPT​^^ or high normal​Elevated (40%)
or normal
​Normal or elevated
​Cancer​Low (<20 pg/ml)​High​Depends on intake and type of malignancy
​Familial hypocalcuric hypocalcemia (FHH)​Normal in majority, slightly elevated in 15%​Low
(<100 mg/24 hrs)
​Normal

Each diagnosis has a unique, distinguishing series of values.

PHPT diagnosis is related to routine measurement of serum calcium on multichannel screening blood tests. The majority of diagnoses are made between ages 50 and 65. Women are affected twice as often as men. PHPT is usually (80%-85%) caused by a solitary benign adenoma, although double adenomas or diffuse hyperplasia does occur. Parathyroid carcinoma is the cause in < 1% of cases.

Research indicates that PHPT may be associated with other disorders like multiple endocrine neoplasia, obesity, type 2 diabetes, anemia and monoclonal gammopathy, although some studies are conflicting for some disorders.
 

Treatment
Treatment of PHPT consists of observation or surgical removal of parathyroid tissue. Surgery for symptomatic patients is recommended, while some asymptomatic patients may be observed. In asymptomatic PHPT patients followed for 10 years, 27% had progression of serum calcium and PTH, while 37% progressed over 15 years of follow-up. It was noted that younger patients were more likely to progress.

Criteria to be considered that make asymptomatic patients candidates for surgery include: serum calcium 1 mg/dl or more above the upper limit of normal; eGFR < 60 ml/min; nephrolithiasis or nephrocalcinosis, elevated 24-hour urinary calcium excretion (>400 mg/day); severely reduced bone density or frailty fractures; and age < 50 years.

In patients in which surgery is recommended, but who cannot or will no undergo surgery, medications are available that can mimic calcium’s effect on parathyroid tissue while others will reduce bone resorption. A detailed discussion is beyond the scope of this case study.

PHPT-related mortality in some reports is related to the severity of the hypercalcemia, with higher levels having higher mortality. In various Scandinavian studies the range of relative risk of all-cause mortality in PHPT was 1.2-2.0. However, these studies were done before the availability of PTHrP testing.

US studies have not shown an increase in mortality above the general population in association with mild PHPT, even among those who did not undergo surgery, although these patients generally had lower levels of serum calcium.

One more recent study from the UK compared populations having elevated calcium and elevated PTH to an age and gender-matched cohort from the area, who had either normal or no calcium measurements. The study group did not fit the NIH criteria for surgical referral. They found hazard ratios (HR) of 2.24 for all-cause mortality in the PHPT group. They further adjusted for higher rates of underlying morbidity and propensity for calcium testing and obtained a HR of 1.64 (1.43-1.87) for all-cause mortality.

Familial hypocalciuric hypocalcemia (FHH) is a rare condition due to at least partial inactivation of the calcium-sensing receptors (CaSR). The familial form is due to a genetic mutation. CaSR are present on cells of the parathyroid and kidneys, and allow those cells to adjust PTH levels and urinary calcium secretion and calcitriol levels to maintain serum calcium in a tight range.

Approximately 200 mutations to the CaSR have been identified. The severity of the hypercalcemia is related to the particular mutation, penetrance and hetero versus homozygosity. If the clinical picture is unclear, mutational analysis tests for the more common mutations are available commercially.

Clinically, FHH is usually a benign, asymptomatic condition, without complications. Hypercalcemia remains mild and stable and surgical removal of parathyroid tissue is not helpful or indicated.

Returning to the Case
As this discussion illustrates, the evaluation of hypercalcemia can be challenging. In this particular case the normal PTH levels combined with the normal 24-hour urinary calcium secretion would make FHH a strong possibility. But FHH is much less common than PHPT, and the low Vitamin D levels confuse the picture somewhat.

Once Vitamin D is replenished, the clinical picture may shift to one of PHPT with normal levels of PTH and increased urinary calcium excretion. One could not be faulted for awaiting completion of the work-up and stability of the serum calcium to be established prior to consideration. However, it would also be reasonable to offer at a minimal to mildly elevated mortality rating with reconsideration possible upon further clinical diagnosis.


References
Leifsson BG et al. “Serum calcium and survival in a large health screening program.” J Clin Endocrinol Metab. 1996 Jun;81(6):2149-53.
Siireide JA et al. “Survival after surgical treatment for primary hyperparathyroidism.” Surgery, 1997;122:1117-23.
Yu N et al. ”A record linkage study of outcomes in patients with mild primary hyperparathyroidism: The Parathyroid Epidemiology and Audit Research Study (PEARS).” Clinical Endocrinology, 2011 75:169–176.
Alfadda TI et al. “Calcium-sensing receptor 20 years later.” Am J of Physio Cell Physio, 2014 307(3):C221-31.
Saini B et al. “What is the Diagnosis? Familial Hypocalciuric Hypercalcemia or Primary Hyperparathyroidism with Vitamin D Deficiency?” Poster Abstracts / JAMDA 14 2013:B3-B26.
UpToDate – www.uptodate.com, last accessed March 8, 2016.