Case 22: Diagnosis & Conclusions

Case 22 Index

Diagnosis: Osteolytic hypercalcemia of malignancy

Case Summary: We’ll keep this summary short and sweet. Here, we have a 61 year old man presenting with acute kidney injury, hypercalcemia, and altered mental status. His urine studies reveal a urine sodium of less than 20 – consistent with both hypovolemia and vessel vasoconstriction due to hypercalcemia. We note dilute urine which may also be due to  hypercalcemia and impaired urine concentrating ability (remember that hypercalcemia can cause nephrogenic diabetes insipidus!).

Before we talk about hypercalcemia, let’s review how calcium levels are maintained. Briefly, low calcium levels stimulate intact parathyroid hormone (iPTH) release which leads to calcium release from the bone as well as increased calcitriol production and ultimately increased gut absorption of calcium.  iPTH also leads to increased urinary phosphorus excretion, as phosphorus is released with calcium from the bone.

So now – why is our patient so hypercalcemic? We can approach hypercalcemia cases algorithmically, taking advantage of known mechanisms of calcium homeostasis (Figure 1). Step 1: always start with the serum intact parathyroid hormone (iPTH) level! Then, investigate each of the potential mechanisms below: 

Mechanisms of hypercalcemia
The first step in the investigation hypercalcemia is looking at the iPTH level. If it’s not suppressed, there’s a problem. In the absence of chronic kidney disease (CKD), we’re looking at primary hyperparathyroidism. If there is CKD + elevated phosphorus levels, think about tertiary hyperparathyroidism.
PTH-related protein mediated (humoral hypercalcemia of malignancy)
If the PTH-rP is elevated in a patient with hypercalcemia, it’s likely being produced by a tumor. PTH-rP behaves just like PTH and mobilizes calcium from the bone and decreases urinary calcium excretion. PTH-rP increases receptor activator of nuclear factor kappa-B (RANK) ligand expression which leads to osteoclast activation. In rare cases, tumors can produce PTH and calcitriol (1,25 OH vitamin D).
Thiazides (impaired urine Ca excretion), familial hypocalciuric hypercalcemia (inactivation of calcium-sensing receptor), immobilization (Ca release from bone), hyperthyroidism (increased bone turnover), vitamin D intoxication (increased Ca bowel absorption), milk-alkali syndrome (increased ingestion)
Osteolytic hypercalcemia of malignancy
Malignancies that metastasize to the bone release cytokines that activate osteoclasts (which break down bone and lead to calcium release). Interleukin-6 and receptor activator of nuclear factor kappa-B (RANK) ligand have been implicated in osteoclast activation.
Granulomatous disease (calcitriol-mediated)
In granulomatous diseases, hypercalcemia is PTH-independent and thought to be mediated by calcitriol (calcidiol is converted to calcitriol by 1-α hydroxylase in macrophages usually in the lung or lymph nodes). Remember that calcidiol is 25 OH-vitamin D (hydroxylated by the liver) and calcitriol is 1,25 OH vitamin D (hydroxylated a 2nd time by the kidney). 

Figure 1. Etiologies of hypercalcemia

Our patient’s labs point to osteolytic hypercalcemia of malignancy, likely due to multiple myeloma given the presence of a monoclonal protein. The treatment for the hypercalcemia? Well first, volume resuscitation with isotonic fluids! The mechanism of hypercalcemia induced acute kidney injury is a combination of volume depletion and vessel vasoconstriction that leads to impaired glomerular filtration. Further, activation of calcium sensing receptor (CaSR) in the thick ascending loop of Henle leads to NKCC inhibition further contributing to volume depletion. Finally, generation of prostaglandin E2 by hypercalcemia may reduce sodium chloride reabsorption in the loop of Henle.

Other treatment options include loop diuretics in volume replete patients (increase urinary calcium excretion),  bisphosphonates and calcitonin (inhibit osteoclast activity), steroids (used for granuloma-mediated hypercalcemia), denosumab (RANK ligand inhibitor, used for hypercalcemia of malignancy), and ultimately dialysis when indicated.

For tertiary hyperparathyroidism in the setting of chronic kidney disease (look for elevated iPTH and high phosphorus levels), management consists of control of hyperphosphatemia, calcimimetics, and referral for parathyroidectomy.

Case 22 Index
Case 22 Introduction
Case 22 Physical Exam
Case 22 Diagnostic Testing
Case 22 More Diagnostic Testing