A retired 80-year-old man presented to the emergency department after 10 days of increasing polydipsia, polyuria, dry mouth, confusion, and slurred speech. He also reported that he had gradually and unintentionally lost 20 pounds and had loss of appetite, constipation, and chronic itching. He denied fevers, chills, night sweats, nausea, vomiting, and abdominal pain.
Medical history. He had type 2 diabetes mellitus that was well controlled by oral hypoglycemics, hypothyroidism treated with levothyroxine in stable doses, and chronic hepatitis C complicated by liver cirrhosis without focal hepatic lesions. He also had hypertension, well controlled with hydrochlorothiazide and losartan. For his long-standing pruritus he had tried prescription drugs including gabapentin and pregabalin without improvement. He had also seen a naturopathic practitioner, who had prescribed supplements that relieved the symptoms.
Examination. The patient was in no acute distress. He appeared thin, with a weight of 140 lb and a body mass index of 21 kg/m2. His temperature was 36.8°C (98.2°F), blood pressure 198/82 mm Hg, heart rate 72 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 97%. His skin was without jaundice or rashes. The mucous membranes in the oropharynx were dry.
Neurologic examination revealed mild confusion, dysarthria, and ataxic gait. Sensation to light touch, pinprick, and vibration was intact. Generalized weakness was noted. Cranial nerves II through XII were intact. Deep tendon reflexes were symmetrically globally suppressed. Asterixis was absent. The remainder of the physical examination was unremarkable.
Laboratory values in the emergency department. We initially suspected he had symptomatic hyperglycemia, but a bedside blood glucose value of 113 mg/dL ruled this out. Other initial laboratory values:
- Blood urea nitrogen 31 mg/dL (reference range 9–24)
- Serum creatinine 1.7 mg/dL (0.73–1.22; an earlier value had been 1.0 mg/dL)
- Total serum calcium 14.4 mg/dL (8.6–10.0)
Complete blood cell counts were unremarkable. Computed tomography of the head was negative for acute pathology.
In view of the patient’s hypercalcemia, he was given aggressive intravenous fluid resuscitation (2 L of normal saline over 2 hours) and was admitted to the hospital. His laboratory values on admission are shown in Table 1. Fluid resuscitation was continued while the laboratory results were pending.
CAUSES OF HYPERCALCEMIA
1. Based on this information, which is the most likely cause of this patient’s hypercalcemia?
- Primary hyperparathyroidism
- Hypervitaminosis D
Traditionally, the workup for hypercalcemia in an outpatient starts with measuring the serum parathyroid hormone (PTH) level. Based on the results, a further evaluation of PTH-mediated vs PTH-independent causes of hypercalcemia would be initiated.
Primary hyperparathyroidism and malignancy account for 90% of all cases of hypercalcemia. The serum PTH concentration is usually high in primary hyperparathyroidism but low in malignancy, which helps distinguish the conditions from each other.1
In primary hyperparathyroidism, there is overproduction of PTH, most commonly from a parathyroid adenoma, though parathyroid hyperplasia or, more rarely, parathyroid carcinoma can also overproduce the hormone.
PTH increases serum calcium levels through 3 primary mechanisms: increasing bone resorption, increasing intestinal absorption of calcium, and decreasing renal excretion of calcium. It also induces renal phosphorus excretion.
Typically, in primary hyperparathyroidism, the increases in serum calcium are small (with serum levels of total calcium rising to no higher than 11 mg/dL) and often intermittent.2 Our patient had extremely high serum calcium, low PTH, and high phosphorus levels—all of which are inconsistent with primary hyperparathyroidism.
In some solid tumors, the major mechanism of hypercalcemia is secretion of PTH-related peptide (PTHrP) through promotion of osteoclast function and also increased renal absorption of calcium.3 Hematologic malignancies (eg, multiple myeloma) produce osteoclast-activating factors such as RANK ligand, lymphotoxin, and interleukin 6. Direct tumor invasion of bone can cause osteolysis and subsequent hypercalcemia.4 These mechanisms are usually associated with a fall in PTH.
Less commonly, tumors can also increase levels of 1,25-dihydroxyvitamin D or produce PTH independently of the parathyroid gland.5 There have also been reports of severe hypercalcemia from hepatocellular carcinoma due to PTHrP production.6
Our patient is certainly at risk for malignancy, given his long-standing history of hepatitis C and cirrhosis. He also had a mildly elevated alpha fetoprotein level and suppressed PTH. However, his PTHrP level was normal, and ultrasonography done recently to screen for hepatocellular carcinoma (recommended every 6 months by the American Association for the Study of Liver Diseases in high-risk patients) was negative.7
Multiple myeloma screening involves testing with serum protein electrophoresis with immunofixation in combination with either a serum free light chain assay or 24-hour urine protein electrophoresis with immunofixation. This provides a 97% sensitivity.8 In this patient, these tests for multiple myeloma were negative.