What are the differential diagnoses for a patient presenting with hypercalcemia and hypomagnesemia?

Differential Diagnosis of Hypercalcemia with Hypomagnesemia

The most common causes of concurrent hypercalcemia and hypomagnesemia are primary hyperparathyroidism (PHPT), malignancy-related hypercalcemia, and familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC).

Primary Hyperparathyroidism

Primary hyperparathyroidism is strongly associated with hypomagnesemia, occurring in approximately 24% of PHPT patients, and this combination predicts more severe symptomatic disease. 1

• Hypercalcemia in PHPT inhibits renal magnesium reabsorption, leading to urinary magnesium wasting and hypomagnesemia 1
• Patients with PHPT and hypomagnesemia have significantly higher rates of symptomatic disease (80% vs 48% in those with normal magnesium) 1
• These patients demonstrate higher PTH levels, lower bone mineral density (lumbar and femur T-scores), and lower vitamin D levels compared to PHPT patients with normal magnesium 1
• Kidney stones occur more frequently (34% vs 21%) and osteoporosis is substantially more common (74% vs 32%) when hypomagnesemia coexists with PHPT 1
• Multivariate analysis confirms hypomagnesemia independently predicts symptomatic disease in PHPT (OR: 6.88,95% CI: 5.20-11.27) 1

Malignancy-Related Hypercalcemia

Hypercalcemia of malignancy occurs in 10-25% of patients with lung cancer and is most commonly seen with squamous cell carcinomas, with hypomagnesemia developing as a consequence of hypercalcemia-induced renal losses. 2

• PTHrP-mediated hypercalcemia is characterized by suppressed intact PTH and low/normal calcitriol levels, distinguishing it from primary hyperparathyroidism 2
• Common malignancies include squamous cell lung cancer, head and neck cancers, renal cell carcinoma, breast cancer, and multiple myeloma 2
• Diagnostic evaluation should include serum iPTH, PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, calcium, albumin, magnesium, and phosphorus 2
• Median survival after discovery of hypercalcemia of malignancy in lung cancer patients is approximately 1 month 2

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC)

FHHNC due to CLDN16 gene mutations presents with primary renal magnesium wasting, hypercalciuria, nephrocalcinosis, and can paradoxically present with either hypercalcemia or hypocalcemia depending on the stage of disease. 3

• Biallelic loss-of-function mutations in CLDN16 cause primary renal magnesium and calcium wasting 3
• Clinical presentation is diverse: some patients present with hypercalcemia and elevated PTH in early stages, while others present with hypocalcemia, hypophosphatemia, and rickets-like features 3
• Bilateral medullary nephrocalcinosis is a hallmark finding 3
• Progressive chronic kidney disease is common, with end-stage renal disease occurring in children or young adults 4
• Persistent hypercalciuria despite treatment, along with inability to normalize serum magnesium, characterizes this condition 4

Iatrogenic Causes

Excessive vitamin D or calcium supplementation combined with magnesium oxide therapy can produce concurrent hypercalcemia and hypermagnesemia (though hypermagnesemia is the opposite of what the question asks, this highlights the iatrogenic risk). 5

• Calcitriol treatment for osteoporosis combined with magnesium oxide for constipation can lead to hypercalcemia with altered magnesium homeostasis 5
• This combination may precipitate acute kidney injury and consciousness disturbance 5

Kidney Disease-Related Electrolyte Disturbances

Patients on intensive kidney replacement therapy (KRT) commonly develop hypomagnesemia (60-65% incidence) due to dialysate losses, which can coexist with hypercalcemia from underlying conditions. 2

• Continuous KRT causes substantial magnesium losses in the effluent, particularly when regional citrate anticoagulation is used (magnesium-citrate complexes are lost) 2
• Hypomagnesemia prevalence reaches 60-65% in critically ill patients on KRT 2
• Electrolyte abnormalities including hypophosphatemia (60-80%), hypokalemia (25%), and hypomagnesemia are common complications 2

Critical Diagnostic Considerations

When evaluating hypercalcemia with hypomagnesemia, measure ionized calcium corrected by pH, serum magnesium, PTH, PTHrP (if malignancy suspected), vitamin D metabolites, phosphate, and renal function. 6, 7

• Less than 1% of total body magnesium is extracellular, so patients can have significant magnesium deficiency despite normal serum concentrations 7
• Check for nephrocalcinosis on renal imaging, as this suggests FHHNC or chronic hypercalciuria 4, 3
• Assess for horizontal nystagmus and myopia, which may indicate FHHNC 4
• Evaluate medication history for vitamin D, calcium supplements, magnesium oxide, diuretics, and chemotherapy agents 5

Neurologic Manifestations

Both hypercalcemia and hypomagnesemia produce CNS depression (encephalopathy) and PNS irritability (tetany), creating overlapping neurologic symptoms. 8

• Hypercalcemia causes CNS depression with obtundation as the major manifestation 8
• Hypomagnesemia produces both CNS irritability (seizures) and PNS irritability (tetany) 8
• The combination may present with confusion, muscle weakness, paresthesias, muscle cramps, irritability, and anxiety 6