PTH-DEPENDENT HYPERCALCEMIA

Besides PHPT, hypercalcemia due to excessive PTH secretion can be seen in the following conditions: chronic use of thiazide diuretics or lithium, end-stage renal disease (tertiary hyperparathyroidism), parathyroid cancer, or, very rarely, a tumor that secretes authentic PTH.

PHPT accounts for more than 90% of the cases of hypercalcemia in ambulatory settings. In the United States, PHPT has an estimated prevalence of 23 cases per 10,000 in women and 8.5 per 10,000 in men. PTH excess can arise from a benign, neoplastic change of one or more of the four parathyroid glands. Single parathyroid adenomas are the most common etiology of PHPT, accounting for approximately 80% of cases. Other causes include multiple adenomas (∼10%), hyperplasia of all four glands (less than 10%), and parathyroid carcinoma (less than 1%). Four-gland parathyroid disease is due to parathyroid cell hyperplasia. It can be sporadic or part of inherited syndromes, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, familial isolated hyperparathyroidism, and hereditary-jaw tumor syndrome. ^,

Tertiary hyperparathyroidism is characterized by elevated serum calcium and PTH in patients with end-stage, chronic kidney disease. Decreased phosphorus excretion, failure of the kidneys to synthesize 1,25-dihydroxyvitamin D, and hypocalcaemia in patients with kidney disease are together responsible for secondary hyperparathyroidism. At this stage, particularly when the creatinine clearance falls below 40 mL/minute, the PTH level will be elevated but the serum calcium will be normal. The chronic and progressive effects of these biochemical imbalances may lead to a semi-autonomous condition, akin to PHPT, with hyperplasia of all four parathyroid glands and eventual emergence of frank hypercalcemia. When the serum calcium rises in this setting, the terminology changes from secondary (high PTH but no hypercalcemia) to tertiary hyperparathyroidism (high PTH and hypercalcemia). The estimated prevalence of secondary or tertiary hyperparathyroidism in patients with a glomerular filtration rate below 20 mL/minute per 1.73 m ² is 80%. Tertiary hyperparathyroidism is reported in up to 30% of patients who are candidates for and have received kidney transplants.

Familial hypocalciuric hypercalcemia (FHH) is a clinical syndrome characterized by exceedingly low urinary calcium excretion in the setting of elevated serum calcium with inappropriately normal or elevated PTH. The genetic etiology in FHH, a mutation in the calcium-sensing receptor (CaSR) with reduced sensitivity to extracellular calcium, leads to a higher “set point” for calcium. Poor sensing by the mutant CaSRs in the kidney leads to excessive renal conservation and markedly reduced urinary calcium excretion. Three variants with generally similar phenotypes are known as FHH1, FHH2, and FHH3. FHH1 follows an autosomal dominant pattern of inheritance with complete penetrance, typically by the age of 30. Over 200 inactivating mutations in the CaSR have been described in FHH1. FHH2 is due to inactivating mutations in the GNA11 gene encoding the G-protein subunit α11. FHH3 is due to inactivating mutations in the AP2S1 gene encoding the adaptor-related protein complex 2, sigma 1 subunit (AP2σ). It is unusual for patients with FHH to develop end organ damage. The differentiation between PHPT and FHH usually rests with the familial inheritance pattern, the surfacing of the disease in young adulthood or before, and a urinary clearance ratio of Ca/Cr that is below 0.01. A cautionary note here is that many patients with PHPT, particularly those with low intake of calcium, can have urinary Ca to creatinine clearance ratios below 0.01. The diagnosis is unequivocally established by genetic analysis. It is important to recognize this genetic disease because patients with FHH should not undergo parathyroid surgery. It is not curative.

Lithium-induced hypercalcemia is characterized by elevated serum calcium levels with inappropriately normal or elevated PTH in patients. The mechanism remains elusive, but it has been suggested that lithium may alter the set point of CaSR. Thiazide-related hypercalcemia can also mimic PHPT. In both situations, stopping the drug, if possible, may lead to normalization of these biochemical indices. More often, however, the hypercalcemia and elevated PTH levels remain after stopping therapy for 3 to 6 months. The diagnosis of PHPT is then established. Some experts believe now that lithium and thiazides unmask latent PHPT that was not evident clinically prior to the administration of the drug. The majority of patients who are discovered to have hypercalcemia in the setting of lithium or thiazide use will be shown to have PHPT.

PTH-INDEPENDENT HYPERCALCEMIA

Suppressed PTH levels in the setting of hypercalcemia are consistent with non–PTH-mediated hypercalcemia as seen in patients with HOM, granulomatous diseases, milk alkali syndrome, hypervitaminosis D, and immobility.

HOM is a common complication of advanced cancer, with an estimated incidence of 20% to 30%. PTH-independent HOM is mediated through various mechanisms, including the development of focal osteolytic lesions; the secretion of parathyroid hormone-related peptide (PTHrP), also known as humoral HOM; or overproduction of 1,25-dihydroxyvitamin D (calcitriol). PTHrP-mediated HOM is usually associated with limited survival.

Overproduction of calcitriol is a well-recognized complication of lymphomas and granulomatous diseases and is thought to be driven by increased activity of 1-alpha-hydroxylase in macrophages. ^, Hypercalcemia in the setting of elevated calcitriol levels in patients with solid tumors has been described recently and was shown to be associated with failure to normalize serum calcium after antiresorptive therapy. Hypercalcemia, independent of PTH, can also be due to vitamin D toxicity as was reported in patients who took excessive amounts of an over-the-counter product, Soladek.

PATHOPHYSIOLOGY OF SYMPTOMATIC HYPERCALCEMIA

The sequence of pathophysiologic events that lead to symptomatic hypercalcemia is common to virtually all causes of hypercalcemia. The central mechanism is the activated osteoclast, the bone-resorbing cell. It is activated in PHPT, in HOM, and even in vitamin D toxicity. The activated osteoclast excessively resorbs bone and releases calcium into the circulation. In patients with normal renal function who are not dehydrated, the calcium challenge will initially be met by increasing urinary calcium excretion. The hypercalcemia also impairs the kidneys’ water-conserving mechanisms, leading to polyuria. In turn, polydipsia follows. As the serum calcium rises further, the polydipsia cannot keep up with the polyuria, and anorexia develops. Dehydration follows and is worsened by vomiting, at times. Rapidly worsening hypercalcemia follows as the kidneys can no longer keep up with the need to excrete the additional calcium presented to them. Central nervous system features become prominent with lethargy and other indices of altered mental status.

MANAGEMENT

The degree of hypercalcemia along with associated symptoms determines the urgency of therapy. Symptoms are determined both by the level of the corrected serum calcium per se as well as its rate of rise. For the same hypercalcemic value, if the serum calcium has risen slowly, symptoms tend to be less severe.

Patients with mild hypercalcemia, such as in the typical patient with PHPT, tend to be asymptomatic. If symptoms are present, they tend to be nonspecific and do not require immediate treatment. In contrast, most patients with moderate to severe hypercalcemia present urgently and require immediate attention. The first step in the management of symptomatic hypercalcemia is to address the dehydration that inevitably accompanies symptomatic hypercalcemia. Intravenous fluid with isotonic saline is the fluid of choice because it helps to facilitate urinary calcium excretion. Within the first few hours 500 mL can be administered, followed by a more moderate rate of 150 to 200 mL/hour. Once hypovolemia is corrected, administration of furosemide can be considered in certain situations to further increase urinary calcium excretion. Furosemide is often not necessary in someone whose renal and cardiac functions are normal, but if there are concerns about the ability of the patient to handle the fluid load, the loop diuretic can be helpful. Another useful initial step is subcutaneous or intramuscular calcitonin, given as 200 units every 8 to 12 hours. Calcitonin reduces bone resorption, the central pathophysiologic feature of most severe hypercalcemic states. Although calcitonin works rapidly, within 12 hours, it is not very potent and will reduce the serum calcium by no more than 1 to 2 mg/dL. In addition, the effects of calcitonin are short-lived. Patients with severe hypercalcemia typically require more potent and long-lasting agents.

As the major “culprit” inciting the severe hypercalcemic state is the osteoclast, the most specific management approach is to use an inhibitor of osteoclast-mediated bone resorption. The bisphosphonates are the classic drugs used in this setting. Because intravenous or parenteral therapy is required, the two choices are pamidronate (30, 60, or 90 mg) or zoledronic acid (4 mg). Both agents are effective and generally follow the same time course, with the serum calcium falling 24 to 48 hours after administration. In the study of Major et al., zoledronic acid had a greater effect both in terms of the reduction of the serum calcium and the duration of the effect. Both agents do carry a warning about their use in patients with renal insufficiency. However, in the setting of acute hypercalcemia, and without preexisting renal disease, the renal dysfunction is usually “pre-renal” due to dehydration. It is not, therefore, an absolute contraindication to the use of bisphosphonates. However, renal function should be taken into consideration in the decision to use a bisphosphonate.

Another mechanism by which hypercalcemia is induced is by RANK ligand, a powerful bone-resorbing cytokine. It is often stimulated in the context of acute hypercalcemia. The RANK ligand inhibitor, denosumab, is, therefore, another option. ^, An advantage of denosumab (60 or 120 mg given subcutaneously; 120 mg is the approved dose for HOM) over the bisphosphonates is that renal dysfunction is not a contraindication. Denosumab, like the bisphosphonates, requires 24 to 48 hours for an effect to be appreciated.

Because both the bisphosphonates and denosumab are not immediately acting, a standard of many practitioners faced with this situation is to use combination therapy with calcitonin and either a bisphosphonate or denosumab. In this way one takes advantage of the rapid but weak effects of calcitonin while waiting for the more delayed but more powerful anticalcemic effects of pamidronate, zoledronic acid, or denosumab to manifest themselves.

If hypercalcemia is associated with elevated 1,25 dihydroxyvitamin D, such as occurs in some lymphomatous malignancies or granulomatous diseases, corticosteroids or other inhibitors of 1-alpha-hydroxylase (e.g., ketoconazole) can be considered. Multiple myeloma and some breast cancers may be responsive to glucocorticoids. In extreme situations, hemodialysis can be used in patients with life-threatening hypercalcemia, refractory to the approaches listed above.