eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hyperparathyroidism

Author: Gordon L Klein, MD, MPH, Professor, Departments of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Texas Medical Branch
Contributor Information and Disclosures

Updated: Aug 13, 2008

Introduction

Background

Hyperparathyroidism is defined as proliferation of the parathyroid hormone (PTH)–secreting cells, or chief cells, in one or more of the 4 parathyroid glands. Hyperparathyroidism may be caused by genetic mutations (as in primary hyperparathyroidism), various underlying conditions that produce secondary hyperparathyroidism due to hypocalcemia (eg, intestinal malabsorption), or high serum phosphorus levels (as is seen in chronic renal failure). Tertiary hyperparathyroidism usually occurs in situations of secondary hyperparathyroidism. Tertiary hyperparathyroidism occurs when parathyroid hyperplasia becomes so severe that removal of the underlying cause does not eliminate the stimulus for PTH secretion and hypertrophic chief cells become autonomous.

Pathophysiology

Although the exact mechanism that causes primary increased PTH secretion is not certain, a loss of sensitivity of these proliferating chief cells to normal extracellular calcium concentrations is observed. In 1996, Kifor et al showed that the parathyroid cell surface G protein–coupled calcium-sensing receptor is reduced by approximately 50% in parathyroid adenoma cells as compared to normal parathyroid controls.¹ This reduction is associated with an increased amount of circulating calcium, which is required to suppress PTH secretion. The reduction may be caused by genetic mutation (eg, familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism), multiple endocrine neoplasia (MEN), or conditions that would normally stimulate compensatory PTH secretion.

In addition, some genetic mutations have been described in primary hyperparathyroidism, including relocation of the PTH gene to a site next to an oncogene. Loss of one copy of a tumor suppressor gene on chromosome 11 has also been reported in some patients with MEN type 1 (MEN I) syndrome. Conditions leading to secondary hyperparathyroidism include calcium or vitamin D malabsorption, accumulation of phosphate with inability to excrete it (eg, chronic renal failure), and uremia.

PTH indirectly stimulates bone resorption by attaching to the osteoblast PTH receptor, which then signals the osteoblast to produce various substances, among them is the ligand of the receptor activator of the nuclear transcription factor NF-kappa B (RANK), known as RANK ligand or RANKL, which can stimulate osteoclast differentiation and proliferation. The osteoblast also acts as a brake on osteoclastic activity by producing osteoprotegerin. Exactly how the osteoblast governs osteoclastogenesis is not fully understood.

Frequency

United States

Frequency of primary hyperparathyroidism is reported to occur in adults with a frequency of 1 case in 500-1000 population. Its true prevalence in children is unknown, but it is considered rare. The frequency of secondary hyperparathyroidism depends on the frequency of the underlying disease.

International

No data indicate that international frequency differs from US frequency. One report from Libansky et al from a medical center in the Czech Republic reports that 10 children, aged 10-17 years, underwent surgical resection.² This provides a crude rate of a little less than 1 case per year that results in surgical treatment, although this does not suggest overall incidence of the condition. However, if nutritional rickets, a form of secondary hyperparathyroidism, is taken into account, occurrence of this condition in children in developing countries is much higher than in the United States, increasing overall frequency worldwide.

Mortality/Morbidity

The morbidity from primary hyperparathyroidism is most often due to hypercalcemia. This can take the form of bradycardia and heart block and dehydration due to polyuria, nausea, vomiting, and poor fluid intake. Pancreatitis has also been reported.

Other causes of morbidity observed with primary hyperparathyroidism may be due to effects of associated tumors, such as jaw tumors or Wilms tumor. In 1999, a population-based study by Khosla et al demonstrated that, even with mild disease, risk of fractures is increased, especially in adults.³ This appears directly related to age and sex (ie, older females have the highest incidence of fractures).

Morbidity from secondary hyperparathyroidism usually involves demineralization of bones with subsequent pain, fracturing, or deformity.

Race

No racial predominance is reported.

Sex

Primary hyperparathyroidism is most commonly observed in females, with a female-to-male ratio of 3:1. Females also have a greater risk of developing fractures.

Age

Postmenopausal women have the highest incidence of primary hyperparathyroidism and fractures. Additionally, they have an increase in secondary hyperparathyroidism because the skin of older persons is less efficient in converting the 7-dehydrocholesterol precursor to vitamin D with ultraviolet light exposure.

Because sporadic parathyroid tumors in children are rare, patients are relatively more likely to have tumors associated with MEN I, such as Zollinger-Ellison tumors of the pancreatic islet cells and pituitary tumors, or to have hyperparathyroidism fibro-osseous jaw tumors, which are associated with Wilms tumors in affected families.

Clinical

History

• Primary hyperparathyroidism
  • Most commonly, patients present without symptoms. Hyperparathyroidism may be diagnosed in an otherwise asymptomatic patient by incidental discovery during routine blood chemistry analysis of hypercalcemia.
  • Symptoms of early disease, when present, are specific to hypercalcemia. They include muscle weakness, depression, increased sleepiness, nausea, vomiting, acute abdominal pain (which might be the result of pancreatitis), constipation, and polydipsia. Frequent and occasionally painful urination and dysuria and/or back pain may be observed, the latter from nephrolithiasis. The most common presenting symptoms of the ten children reported by Libansky et al included urolithiasis, nephrolithiasis, nephrocalcinosis, and bone resorption, as well as fatigue and muscle weakness.
• Secondary hyperparathyroidism
  • Patients with secondary hyperparathyroidism usually present with a history of underlying disease such as renal or intestinal conditions.
  • Symptoms are musculoskeletal in nature, including bone pain, muscle weakness, and previous fracture.

Physical

• Primary hyperparathyroidism
  • Signs of dehydration due to hypercalcemia, such as tenting of skin, prolonged capillary refill time, and dry mucous membranes
  • Bradycardia, with or without irregular heartbeat
  • Decreased muscle tone and somnolence
• Secondary hyperparathyroidism
  • Skeletal deformity
  • Decreased muscle tone
  • Bone pain on palpation
  • Short stature

Causes

• Primary hyperparathyroidism is caused by a genetic mutation.
• Secondary hyperparathyroidism may develop as a response to hypocalcemia caused by intestinal disease resulting in calcium and vitamin D malabsorption.
  • Chronic renal insufficiency
  • Insufficient vitamin D and calcium intake: Insufficient intake in children may cause rickets. Although this is not as common in the United States, rickets are a major cause of secondary hyperparathyroidism in developing countries, especially those countries in which children are kept out of the sun while parents work. Moreover, a growing body of data suggest that many children and adolescents, especially in northern climates, are vitamin D insufficient and have a serum level of 25-hydroxyvitamin D between 20-30 ng/mL. Levels in this range are associated with increased circulating intact PTH.
  • Cholestatic liver disease: Contrary to previous belief, not all children with chronic cholestatic liver disease have secondary hyperparathyroidism. Many of these patients, as well as adults with chronic liver disease, have levels of PTH within the reference range.
  • Iatrogenic causes: Iatrogenic causes, such as lithium administration, may decrease the ability of circulating levels of calcium that are within the reference range to suppress PTH secretion. The mechanism for this is not presently clear.

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