eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Hyperparathyroidism

Author: Philip N Salen, MD, Clinical Professor, Department of Emergency Medicine, PA Program, Desales University; Adjunct Clinical Associate Professor, Department of Emergency Medicine, Temple University Medical School; Research Director, Emergency Medicine Education, Saint Luke's Hospital
Contributor Information and Disclosures

Updated: May 6, 2008

Introduction

Background

The parathyroid glands regulate serum calcium and phosphorus levels through the secretion of parathyroid hormone (PTH), which raises serum calcium levels while lowering the serum phosphorus concentration. The regulation of PTH secretion occurs through a negative feedback loop in which calcium-sensing receptors on the membranes of parathyroid cells trigger decreased PTH production as serum calcium concentrations rise.

Primary hyperparathyroidism, which accounts for most hyperparathyroidism cases, results from excessive release of PTH and manifests as hypercalcemia.¹ Patients with hypercalcemia who have normal renal function and no malignancy must be suspected of having primary hyperparathyroidism and must be subsequently tested for elevated PTH levels.

Hyperparathyroidism is often incidentally discovered during routine laboratory testing when hypercalcemia is noted. In 80% of patients with hyperparathyroidism, the symptoms of hypercalcemia are mild or are not notable at the time of discovery. Management of these patients is not clear-cut because routine laboratory tests have not been shown to assist in predicting development of overt manifestations of the disease. Conversely, patients with overtly symptomatic hyperparathyroidism (eg, those with urinary tract stones, bone pain, cognitive abnormalities) and those with marked hypercalcemia (calcium levels >10.2 mg/dL) must be referred for parathyroidectomy.²

Pathophysiology

Primary hyperparathyroidism is one of the most common causes of hypercalcemia and should be considered in any individual with an elevated calcium level.³  Primary hyperparathyroidism is usually the result of a single benign adenoma; a minority of patients have hyperplasia in all 4 parathyroid glands. Parathyroid carcinoma accounts for an insignificant minority (<0.5% of patients with hyperparathyroidism).

Asymptomatic primary hyperparathyroidism manifests with serum calcium concentrations only slightly elevated to within 1 mg/dL above the upper limit of the reference range. Within the setting of asymptomatic primary hyperparathyroidism, the PTH level is typically 1.5-2 times the upper limit of the reference range. Hypophosphatemia and hyperchloremia are typically seen only in patients who are highly symptomatic patients and have advanced hyperparathyroidism.

When hyperparathyroidism manifests with hyperplasia in all 4 glands, familial-genetic syndromes should be considered within the differential diagnosis. Syndromes to be considered include type I and type II multiple endocrine neoplasia (MEN) or, less commonly, familial hypocalciuric hypercalcemia and hyperparathyroidism–jaw tumor syndrome. Also, a syndrome of familial isolated hyperparathyroidism has been observed. Radiation therapy to the head and neck predisposes subjects to parathyroid tumors.

Secondary hyperparathyroidism occurs when the parathyroid glands become hyperplastic after long-term hyperstimulation and release of PTH. In secondary hyperparathyroidism, elevated PTH levels do not result in hypercalcemia. This has been classically attributed to an underlying state of hypocalcemia in those with chronic renal failure (CRF). However, hypocalcemia is not necessary for the development of secondary hyperparathyroidism in this setting. Additional risk factors for the development of secondary hyperparathyroidism include phosphorus retention, intrinsic parathyroid gland abnormalities, diminished serum calcitriol levels, and resistance to PTH by skeletal tissue. Rickets and malabsorption syndromes are rarer causes.

With long-term hyperstimulation, the glands function autonomously and produce high levels of PTH even after correction of chronic hypocalcemia. Tertiary hyperparathyroidism refers to hypercalcemia caused by autonomous parathyroid function after long-term hyperstimulation.

Frequency

United States

Primary hyperparathyroidism is a common endocrine disease that affects nearly 1 in 500 women and 1 in 2000 men per year, most often in the fifth, sixth, and seventh decades of life.⁴

Mortality/Morbidity

Most patients, who are predominantly elderly, present with mild elevations of serum calcium and are not overtly symptomatic. Usually, the rate of progression of hyperparathyroidism is slow, and monitoring these patients and medically managing the disease is usually safe.

Although operative mortality is low, no evidence suggests that primary hyperparathyroidism with mild hypercalcemia has an adverse effect on survival.³ Conversely, parathyroidectomy remains the appropriate therapy for symptomatic or complicated primary hyperparathyroidism. Complication rates and symptom relief are the same in younger and older patients who undergo surgery.³

Sex

Most individuals with hyperparathyroidism are older women.³

Age

Although hyperparathyroidism can arise at any age, its occurrence rises markedly after age 40 years. Hyperparathyroidism is rare in children.

Clinical

History

Most patients with primary hyperparathyroidism are asymptomatic or minimally symptomatic. Because manifestations of hyperparathyroidism are subtle, the disease may run a benign course for years prior to detection. Symptomatic hyperparathyroidism is characterized by vague, nonspecific symptoms including generalized weakness, fatigue, poor concentration, and depression.

Nephrolithiasis that results in ureteral colic is secondary to serum calcium elevations. As many as 75% of patients who undergo surgical treatment for primary hyperparathyroidism present with nephrolithiasis. Furthermore, patients with primary hyperparathyroidism not only have a greater risk of renal stone disease, but this risk persists for 10 years after surgery.⁵  Overt bone disease, including subperiosteal bone resorption and osteitis fibrosa cystica, is a serious but rare manifestation of hyperparathyroidism. Proximal muscle weakness may occur, typically affecting the lower limbs more than the upper limbs. Chondrocalcinosis and pseudogout are other potential complications of hyperparathyroidism.

Rarely, hyperparathyroidism may abruptly worsen and may cause severe hypercalcemic complications such as profound dehydration, altered mental status, or coma. This is referred to as hypercalcemic parathyroid crisis.

• A helpful mnemonic, "painful bones, renal stones, abdominal groans, and psychic moans," can be used to recall the typical symptoms of hypercalcemia. Painful bones are the result of abnormal bone remodeling due to overproduction of parathyroid hormone (PTH). Nephrolithiasis occurs secondary to hyperparathyroid disease–induced hypercalcemia and resultant hypercalciuria. Abdominal groans refers to hypercalcemia-induced ileus. Psychic moans or depression may occur in the presence of persistently elevated serum calcium levels.
• The most frequent complication of primary hyperparathyroidism is nephrolithiasis, which occurs in about 20% of patients.⁴  Renal effects of the disease also include decreased glomerular filtration rate. Hypercalciuria (>300 mg daily calcium excretion) is observed in a significant subset of patients (£ 30%).
• Some patients suffer from easy fatigability, a sense of generalized weakness, or mild cognitive impairment.

Physical

No highly specific physical findings are present in hyperparathyroidism.

• CNS
  • Neuropsychiatric illness
  • Altered mental status
  • Coma (severe cases)
• Cardiovascular system
  • Signs of hypertension and congestive heart failure may be apparent, although little definitive evidence supports a causal relationship.
  • The association of primary hyperparathyroidism with hypertension has been well documented but remains poorly understood. Whether parathyroidectomy alters the long-term course of hypertension is unclear because surgery does not reliably result in improvement.³
• Musculoskeletal system
  • Osteoporosis
  • Osteopenia
  • Cystic bone lesions
  • Vertebral collapse
  • Chondrocalcinosis and pseudogout
  • Easily fatigued muscle (particularly proximal muscle groups)
• GI system
  • Pancreatitis, pancreatic calcification, or both
  • Peptic ulcer disease (may be present at a higher rate)
• Renal system: The renal manifestations of primary hyperparathyroidism include recurrent calcium nephrolithiasis, nephrocalcinosis, and impaired renal function.⁵

Causes

• A single parathyroid adenoma is the underlying pathology in 85% of cases.
• Diffuse hyperplasia of all parathyroid glands occurs in approximately 15% of cases. More than half of these are part of a familial syndrome.
• Parathyroid carcinoma is a very rare cause of primary hyperparathyroidism.
• Secondary hyperparathyroidism occurs when the parathyroid glands are chronically stimulated to release PTH.
  • Chronic renal failure
  • Malabsorption syndromes
  • Rickets
• Long-standing secondary hyperparathyroidism may progress into autonomous hypersecretion of PTH even after correction of chronic hypocalcemia; it is termed tertiary hyperparathyroidism.
• External radiation to the head, neck, and chest regions is associated with an increased likelihood of developing benign parathyroid tumors. Parathyroid adenomas reported after radiation exposure are usually hyperfunctioning and are usually detected upon manifestations of primary hyperparathyroidism.⁶  Patients with radiation-induced hyperparathyroidism are also more likely to have coexistent nodular goiter and thyroid gland carcinoma than patients with spontaneous hyperparathyroidism.⁷

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