A 47-year-old woman underwent a comprehensive health evaluation as part of an application for a life insurance policy. She was noted to have a history of hypertension that was controlled with dietary modification. She was otherwise healthy, and no problems were identified. The results of her physical examination were unremarkable. Routine screening blood work was obtained, and she was noted to have a serum calcium level of 11.8 mg/dL (8.4-10.4 mg/dL), phosphate level of 1.9 mg/dL (2.5-4.8 mg/dL), and chloride level of 104 mmol/L (95-109 mmol/L). Other electrolytes, complete blood count, urinalysis, chest radiograph, and 12-lead electrocardiogram were all normal.
What is the most likely cause of this patient’s hypercalcemia?
How would you confirm the diagnosis?
What is the most appropriate therapy?
ANSWERS TO CASE 36: Hyperparathyroidism
Summary: A 47-year-old woman is found to have incidental hypercalcemia and hypophosphatemia.
• Most likely cause of hypercalcemia: Primary hyperparathyroidism.
• Confirmation of diagnosis: An elevated serum parathyroid hormone (PTH) level and the absence of a familial pattern of hypercalcemia.
• Most appropriate therapy: The treatment for primary hyperparathyroidism is surgery.
1. Formulate a differential diagnosis for hypercalcemia.
2. Describe the diagnosis and treatment of primary hyperparathyroidism.
3. Appreciate the natural history and long-term consequences of untreated primary hyperparathyroidism.
Primary hyperparathyroidism and malignancy account for 90% of all cases of hypercalcemia. In the ambulatory setting, primary hyperparathyroidism is by far the most common cause of hypercalcemia. In this patient, the chloride/phosphate ratio is greater than 33:1, suggesting hyperparathyroidism. The diagnosis can be confirmed by elevation of serum PTH and urinary calcium measurement demonstrating normal or increased calcium excretion in the urine. For this 47-year-old woman, if the serum PTH and urinary calcium levels confirm hyperparathyroidism, parathyroid localization and surgical exploration are indicated.
APPROACH TO: Hypercalcemia and Hyperparathyroidism
The differential diagnosis for hypercalcemia is extensive (Table 36–1). Primary hyperparathyroidism and malignancies account for 90% of all causes of hypercalcemia. In the ambulatory setting, primary hyperparathyroidism is the most common cause of hypercalcemia, accounting for 50% to 60% of all cases. Hypercalcemia is the hallmark of primary hyperparathyroidism. Patients may also have a low or low-normal serum phosphorus level, a high or high-normal serum chloride level, and mild metabolic acidosis. This is a result of the inhibitory effects of PTH on the reabsorption of phosphorus and bicarbonate in the renal tubule. Because of the increased amount of bicarbonate excreted, more chloride is reabsorbed with sodium to maintain electroneutrality. A chloride-to-phosphorus ratio of greater than 33:1 is consistent with a diagnosis of primary hyperparathyroidism. In malignancy-related hypercalcemia, phosphate may also be low or normal, but the chloride will generally be normal. Other causes of hypercalcemia are usually associated with normal to elevated phosphate levels.
Table 36–1 • DIFFERENTIAL DIAGNOSIS FOR HYPERCALCEMIA
A definitive diagnosis of hyperparathyroidism is made by documenting an elevated serum intact PTH level by an immunoradiometric or chemiluminescence assay. With the exception of familial hypocalciuric hypercalcemia, which may be associated with a mild increase in serum PTH levels, all other causes of hypercalcemia are associated with suppressed PTH levels.
Since the introduction of automated laboratory methods in the early 1970s, in most patients primary hyperparathyroidism has been diagnosed after incidental hypercalcemia is detected on routine blood testing. The clinical manifestations of primary hyperparathyroidism are protean (Table 36–2). Most patients admit to nonspecific symptoms such as weakness, fatigue, or constipation. Kidney stones are the most common metabolic complication, occurring in 15% to 20% of patients with primary hyperparathyroidism. The potential development of skeletal manifestations such as generalized demineralization, osteoporosis, and pathologic fractures are of particular concern for postmenopausal women. Gastrointestinal manifestations include peptic ulcer disease and pancreatitis. Patients may experience joint manifestations related to gout or pseudogout, as well as a wide variety of psychiatric symptoms. Hyperparathyroidism is also associated with certain well-described cardiovascular effects, including increased prevalence of hypertension, left ventricular hypertrophy, and calcifications of the myocardium and mitral and aortic valves.
Table 36–2 • CLINICAL MANIFESTATIONS OF PRIMARY HYPERPARATHYROIDISM
A hypercalcemic crisis may occur in 1.6% to 3.2% of patients with primary hyperparathyroidism. It is manifested by severe hypercalcemia with serum calcium levels usually greater than 15 mg/dL and an altered mental status. Patients may present with nausea, vomiting, dehydration, lethargy, and confusion or frank coma. The treatment of hypercalcemic crisis consists of hydration and forced diuresis with normal saline infusion and furosemide administration. Saline reduces serum calcium by blocking the proximal tubule calcium absorption while furosemide blocks distal tubule calcium absorption.
Untreated hyperparathyroidism reduces patient survival by approximately 10% when compared to age- and gender-matched control subjects without hyperparathyroidism. This increased risk for premature death is primarily related to cardiovascular causes and less frequently related to malignancy or renal failure, and it can be reversed with parathyroidectomy.
Indications and Preparation for Parathyroidectomy
Currently, the only definitive treatment for primary hyperparathyroidism is parathyroidectomy. A National Institutes of Health (NIH) Consensus Panel in 2002 identified the following criteria as indications for parathyroidectomy: symptomatic patients and asymptomatic patients younger than 50 years with a serum calcium greater than 11.5 mg/dL, a 24-hour urine calcium greater than 400 mg (to rule out familial hypocalciuric hypercalcemia), a creatinine clearance reduction greater than 30% for the age group in the absence of another cause, or a bone mineral density greater than two standard deviations below normal for age-, gender-, and race-matched controls (Table 36–3). Because parathyroidectomy may improve the vague nonspecific symptoms and render survival benefits in patients with primary hyperparathyroidism, many experts advise that in the absence of prohibitive operative risk, all patients with primary hyperparathyroidism be treated with parathyroidectomy.
Table 36–3 • INDICATIONS/CONTRAINDICATIONS: NIH DEVELOPMENT CONFERENCE’S INDICATIONS FOR SURGICAL INTERVENTION IN PATIENTS WITH ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM
The 2002 NIH Consensus Workshop recommended that all patients under consideration for parathyroidectomy undergo preoperative localization studies to determine the feasibility of minimum invasive parathyroidectomy or unilateral explorations. In various institutions, the preferred localization modality can vary based on local expertise and technology availability. Some of the common localization modalities that have been applied are ultrasonography, nuclear imaging (sestamibi scan), MRI, and CTs. When patients have biochemically documented primary hyperparathyroidism and preoperative sestamibi scans that do not localize the disease, these patients have increased probability of having parathyroid hyperplasia as opposed to having parathyroid adenomas and may require more extensive parathyroid explorations, subtotal parathyroidectomies, and may experience lower chances of cure from their hypercalcemia. It is therefore important to have more extensive discussions of risks/benefits prior to the planning of surgery in these patients.
With unilateral parathyroid exploration or the minimum invasive approach, intraoperative PTH assay is generally used to verify removal of the parathyroid gland(s) responsible for the hyperparathyroidism. Another variation of the minimally invasive approach to parathyroidectomy utilizes intravenous injection of radiolabeled sestamibi, followed by a limited exploration directed by localization of highest radioactivity using a handheld gamma probe.
Published results show that a greater than 95% cure rate can be expected for primary hyperparathyroidism when parathyroid exploration is performed by an experienced surgeon after obtaining appropriate preoperative evaluations and localization studies.
36.1 A 60-year-old postmenopausal woman with osteoporosis has a serum calcium level of 11.4 mg/dL, a serum phosphorus level of 2.0 mg/dL, and a 24-hour urine calcium excretion of 425 mg. Which of the following serum tests is most likely to establish the cause of her hypercalcemia?
A. Chloride-phosphorus ratio
B. PTH-related polypeptide
C. Urine calcium clearance
D. Intact PTH level
E. A sestamibi scan
36.2 You are asked to evaluate a patient in the hospital with hypercalcemia. A diagnosis of hyperparathyroidism has been excluded. Which of the following is the most likely cause?
A. Familial hypocalciuric hypercalcemia
C. Induced by medication
D. Nephrogenic diabetes insipidus
36.3 Which of the following is the most common metabolic complication of primary hyperparathyroidism?
A. Kidney stones
36.4 Which of the following abnormalities is most likely to be caused by hyperparathyroidism?
D. Elevated serum bicarbonate
E. Elevated serum creatinine
36.1 D. An intact PTH level is highly specific for hyperparathyroidism. A chloride-phosphorus ratio greater than 33:1 is only suggestive of hyperparathyroidism, while an elevated PTH is confirmatory. A sestamibi scan is a localization study most useful to localize the parathyroid adenoma prior to operative resection.
36.2 E. Malignancy is the most common cause of hypercalcemia encountered in patients in the inpatient setting, particularly when hyperparathyroidism is ruled out. Familial hypocalciuric hypercalcemia, medications, and sarcoidosis are all less common causes of hypercalcemia. Nephrogenic diabetes insipidus is not a cause of hypercalcemia but can be seen in patients with hyperparathyroidism, as increased serum calcium inhibits the kidneys’ response to antidiuretic hormone.
36.3 A. Kidney stones are the most common metabolic complications associated with hyperparathyroidism, occurring in 15% to 20% of patients with the disease.
36.4 C. Hyperparathyroidism is associated with a high secretion of calcium in urine (hypercalcinuria), low serum phosphate, high serum chloride, and low serum bicarbonate levels. Increased serum creatinine is generally not seen in patients with primary hyperparathyroidism unless there is damage to the kidneys from long-standing nephrocalcinosis. Elevated creatinine or chronic renal insufficiency causes increased serum phosphorous and lead to the increase in PTH levels (secondary hyperparathyroidism).
Hypercalcemia with hypophosphatemia is suggestive of hyperparathyroidism. The diagnosis is confirmed by an elevated PTH level.
The two most common causes of hypercalcemia are hyperparathyroidism and malignancy.
Surgical indications for primary hyperparathyroidism include a markedly elevated serum calcium or a hypercalcemic crisis, kidney stones, decreased kidney function, and reduced bone density. The best treatment for primary hyperparathyroidism is surgery.
Support for parathyroidectomy in an asymptomatic patient is based on the increase in cardiovascular complications and 10% survival reduction associated with patients with untreated primary hyperparathyroidism. This survival advantage is most notable in younger patients (age <50 years).
Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007;92:3114-3121.
Biliezikian JP, Potts JT, Fuleihan EH, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87: 5353-5361.
Caron NR, Pasieka JL. What symptom improvements can be expected after operation for primary hyperparathyroidism? World J Surg. 2009;33:2244-2255.
Chen H. Primary hyperparathyroidism. In: Cameron JL, Cameron AM, eds. Current Surgical Therapy. 10th ed. Philadelphia, PA: Mosby Elsevier; 2011:610-613.