Introduction

Primary hyperparathyroidism is a relatively common disorder that may cause significant renal and skeletal complications, although most patients diagnosed in recent decades have mild degrees of hypercalcemia and are often asymptomatic. Surgery remains the definitive treatment. However, conservative observation or medical therapy may be appropriate for selected patients.[1] A basic understanding of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism.

Etiology

 PTH-dependent Causes of Hypercalcemia

• Primary Hyperparathyroidism

  • Single adenoma

  • Multigland disease

    • Familial causes of hyperparathyroidism

      • Multiple endocrine neoplasia Type 1

      • Multiple endocrine neoplasia Type 2

      • Familial hyperparathyroidism

      • Hyperparathyroidism-jaw tumor syndrome

  • Parathyroid carcinoma

• Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor

• Adverse effect of treatment with lithium

PTH Independent Causes of Hypercalcemia

• Malignancy

• Granulomatous diseases

• Hyperthyroidism

• Thiazide therapy

• Vitamin D intoxication

• Milk-alkali syndrome

• Adrenal insufficiency

• Vitamin A intoxication

Epidemiology

Once considered a relatively rare disease associated with significant morbidity, primary hyperparathyroidism is now a relatively common disorder that is often asymptomatic. Prior to 1970, the diagnosis went unsuspected until patients presented with specific symptoms, typically nephrolithiasis or bone pain. Since then most patients are diagnosed with hyperparathyroidism when a serum calcium is incidentally discovered to be increased on a chemistry profile ordered as screening tests or for an unrelated problem. The current incidence in the United States has been estimated at a mean of 66 per 100,000 person-years in women, and from 13 to 36 per 100,000 person-years in men.[2]

Pathophysiology

Normal Calcium Homeostasis

Under physiologic circumstances, the concentration of calcium in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in bone, kidney, and the gastrointestinal tract.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion is complexed to anions such as phosphate and citrate. It is only the ionized calcium that is biologically active, yet most laboratories report total serum calcium levels. Measurements of ionized calcium are available. However, an approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin)

Caution must be exercised in evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia. 

Parathyroid Hormone

Secretion of parathyroid hormone is inversely related to the concentration of ionized calcium in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in the types of serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated and parathyroid cells decrease secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases and parathyroid hormone secretion increases as calcium levels decline. Mutations that inactivate the CaSR are the etiology of familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disorder characterized by increased parathyroid hormone secretion, hypercalcemia, and hypocalciuria.

Parathyroid hormone activates the parathyroid hormone receptor increasing resorption of calcium and phosphorus from bone, enhancing the distal tubular resorption of calcium, and decreasing the renal tubular resorption of phosphorus. Also, parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.

History and Physical

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, or bone deformity. Now, most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile. Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products, vitamin D supplements, or other symptoms associated with the multiples etiologies of hypercalcemia.[3] A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age, or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can be helpful in finding abnormalities that could suggest other etiologies of hypercalcemia. Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of a parathyroid carcinoma.

Evaluation

Patients with primary hyperparathyroidism and other causes PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia. PTH levels should be very low in those patients with PTH-independent hypercalcemia.

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and an elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy appearing individual to be hypercalcemic for more than a few years without becoming clinically obvious.[3]

List of tests for primary hyperparathyroidism: 

• Total calcium

• Albumin

• Calculation of the “corrected” serum calcium. Approximately 50% of total serum calcium is protein-bound, principally to albumin and only free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin) (calcium measured in mg/dL; albumin measured in g/dL)

• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium

• Parathyroid hormone

• Phosphorus

• BUN and creatinine

• Alkaline phosphatase

• 25-hydroxyvitamin D

• Urine calcium and creatinine

• Imaging to screen for renal calcifications or urolithiasis

• Bone densitometry (DXA) including measurement at the distal 1/3 radius

• EKG

• Genetic testing in selected individuals if there is suspicion of a genetic syndrome

• Parathyroid scan and neck ultrasound. These tests are not considered diagnostic because there can be false negative results. They should not be ordered when there are no plans for surgery. They should be ordered when there are plans for surgery to assist the surgeon as a “roadmap” in localizing enlarged parathyroid gland.

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxyvitamins D levels, thyroid tests, bone scans, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.[4]

Differential Diagnosis

• Berylliosis

• Cancers producing parathyroid hormone-related protein

• Exogenous calcium intake 

• Histoplasmosis

• Immobilization

• Leprosy

• Lytic bone metastasis

• Milk-Alkali syndrome

• Multiple endocrine neoplasms

• Pheochromocytoma

Pearls and Other Issues

Primary hyperparathyroidism preferentially reduces cortical bone density and increases fracture risk at sites where cortical bone predominates, such as the distal forearm, with relative sparing of trabecular bone. For this reason, those with hyperparathyroidism should have a dual-energy x-ray absorptiometry that includes the distal third radius, a site composed almost exclusively of cortical bone, in addition to measurements at the spine and hip.

Primary hyperparathyroidism is associated with some psychological complaints including depression, anxiety, fatigue, irritability, lassitude, and sleep disturbance. There is an inconsistent improvement in psychological parameters, and quality of life following parathyroidectomy and patient numbers in high-quality studies are small.[9]

When there is a family history of hyperparathyroidism consider the possibility of multiple endocrine neoplasia types 1 or 2a or familial hypocalciuric hypercalcemia (FHH), an autosomal dominant inactivating mutation of the calcium-sensing receptor. Urine calcium excretion with the calculation of the fractional excretion of calcium is the best initial test to differentiated familial hypocalciuric hypercalcemia from primary hyperparathyroidism. Patient with familial hypocalciuric hypercalcemia is typically asymptomatic without renal stones or osteoporosis. Subtotal parathyroidectomy does not cure this problem and total parathyroidectomy results in hypoparathyroidism.[10]

Enhancing Healthcare Team Outcomes

Primary hyperparathyoidism is a relatively common disorder. Because hypercalcemia can affect many organs, the condition is best managed by an interprofessional team that includes a radiologist, endocrinologist, surgeon, internist and a nephrologist. Patients who are asymptomatic can be observed but all symptomatic patients need surgery. Follow up can be by the primary care provider or nurse practitioner and should involve renal function, bone density, calcium levels and mood changes.

If hypercalcemia is left untreated it can have severe adverse effects on many organs. After surgery, most patients have a good outcome.