Primary Hyperparathyroidism: Pathogenesis, Biochemical changes, C/F, D/D, Treatment
Primary hyperparathyroidism is caused by hypersecretion of parathyroid hormone (PTH), most commonly by the subset of four hyperplastic glands, less commonly by a parathyroid adenoma, or very rarely by a true carcinoma. Most cases today are identified by hypercalcemia (>10.5 mg/dL [2.6 mmol/L], after correction for serum albumin) on routine multipanel serum testing. Less than 5% of cases are recognized by the presence of an osteolytic defect with giant cells, histologically, the cyst-like areas are foci of osteoclasts in a highly vascular stroma. Extensive haemosiderin deposits cause the lesion to appear as a brown tumour. Some cases are suspected by the presence of renal “stones” (nephrocalcinosis); however, only 5% of people with nephrocalcinosis have primary hyperparathyroidism.
Primary hyperparathyroidism is more common in women and in those older than 50 years. Most gland hyperplasias are of unknown cause, but some are related to the multiple endocrine neoplasia syndrome of familial inheritance types I and IIa (MEN I and MEN IIa). Because most cases are due to an idiopathic hyperplasia of each gland, a neck mass is usually not palpable. In addition, most cases are asymptomatic. However, as serum calcium levels increase, symptoms may occur that are related to the hypercalcemia per se or to the disease’s effects on bone and on the urinary tract.
(1) increasing osteoclastic bone resorption,
(2) reducing renal excretion of calcium, and
(3) increasing calcium absorption in the small intestines.
The resultant abnormal laboratory test results are therefore hypercalcemia, a compensatory hypophosphatemia, and an alkaline phosphatase level that is usually normal but can be elevated in widespread lytic disease.
Biochemical findings in primary hyperparathyroidism
- Hypercalcemia-related signs and symptoms
The symptoms most commonly associated with hypercalcemia include thirst, nausea, and vomiting. In addition, constipation, weight loss, anemia, and peptic ulcer disease, as well as hypertension, may develop. If the hypercalcemia is severe (>15 mg/dL [3.75 mmol/L]) or long lasting, confusion, depression, and psychosis may result. Higher serum calcium levels also are associated with fatigability, muscle weakness, and paresthesia.
- Bone-related signs and symptoms
Bone pain is the main symptom and occurs primarily in the vertebrae, tibias, and joints. Long-standing disease can produce kyphosis and multiple small vertebral fractures that can lead to loss of height. Radiolucencies (brown tumors) may develop in bones, commonly in the jaws, or a diffuse demineralization, sometimes called osteitis fibrosa cystica, may result. Both entities evidence a fibrovascular stroma replacing mineralized bone while “giant cells,” which are presumably osteoclasts, are seen resorbing bone. These areas appear as a friable, red-brown mass, hence the term brown tumors. Clinicians often seek discrete unilocular or multilocular radiolucencies representing brown tumors in the jaws; however, these are rare. More common are subtle changes in the trabecular bone pattern resembling age-related osteoporosis. On occasion, tooth mobility occurs and sometimes loss of the lamina dura is seen, but this feature is rare and may be associated with only a few teeth.
- Urinary tract-related signs and symptoms
Polyuria and a resultant increase in thirst (polydipsia) are related to hypercalcemia. Renal calculi in the calyces or ureter or calcifications within the renal parenchyma (nephrocalcinosis) are deposits of calcium oxalate or calcium phosphate. Obstructive nephropathy or nephrocalcinosis leading to renal failure may develop in long-standing disease.
The most common presentation is one of hypercalcemia without radiographic evidence of bone lesions. Other entities that cause hypercalcemia and therefore must be ruled out are
- multiple myeloma
- hypercalcemia of malignancy
- overingestion of calcium and/or vitamin D
- adrenal insufficiency
- familial hypocalciuric hypercalcemia
Primary hyperparathyroidism should be confirmed by radioimmunoassays (RIAs) of the circulating parathyroid levels. Such RIAs are sufficiently specific to determine levels of normal PTH. Malignant tumor products of PTH-related polypeptides will not be registered on RIAs. If necessary, multiple myeloma can be ruled out by serum protein electrophoresis, sarcoidosis by an incisional parotid biopsy, overingestion of calcium or vitamin D by history, familial hypercalciuric hypercalcemia by history and by 24-hour urine collections showing more than 50 mg/24 hr (1.25 mmol/d) of calcium, and adrenal insufficiency by serum sodium levels and an adrenocorticotropic hormone (ACTH) challenge.
Jaw lesions of hyperparathyroidism exhibit a picture that is virtually identical to that of the central giant cell tumor. A proliferation of spindle cells with extravasated blood and haphazardly arranged, variably sized multinucleated giant cells is seen. These are osteoclasts, the action of which is influenced by PTH. Osteoid formation also may occur. All types of hyperparathyroidism present similar histologic findings.
the main effects are thinning of bone trabeculae, subperiosteal resorption of the bone of the fingers and resorption of the terminal phalangeal tufts. In severe disease, radiolucent cyst-like areas (osteitis fibrosa cystica) often with a multiloculated appearance are a typical but rare finding. Alveolar bone may also be resorbed but re-forms with treatment.
Medical treatment for primary hyperparathyroidism is indicated only in those in whom surgery is contraindicated and in those with mild hypercalcemia (< 11 mg/dL [2.75 mmol/L], albumin corrected) who show no evidence of organ dysfunction. Treatment consists of increased fluids, exercise, avoidance of prolonged inactivity, and avoidance of thiazide diuretics because these drugs decrease calcium excretion and raise serum calcium levels. For postmenopausal patients, estrogen hormone therapy also may be considered.
Most patients with primary hyperparathyroidism require surgery. Today, this surgery involves removal of at least three of the four glands and, in some cases, a subtotal resection of the fourth. The success of surgery is closely related to the experience level of the surgeon. If the disease has been isolated to a specific adenoma or carcinoma, excision of only that particular tumor is the rule. However, it should be noted that most pathologists report a diagnosis of adenoma for all parathyroid glands removed because of primary hyperparathyroidism. This does not mean that the glands were adenomatous—that is, that they were enlarged and would continue to grow if not removed. Instead, the use of the term is based on historical precedent, in which adenoma refers to any pathologic gland. In fact, primary hyperparathyroidism represents a more complex systemic disease of which hypersecretion of the parathyroid glands is a central component.
After surgery, most patients are expected to become hypocalcemic within 12 to 24 hours. This course should be checked with determination of serum calcium and serum albumin levels as well as eliciting a positive Chvostek sign. This assessment is required because a rapid fall in serum calcium to subnormal levels may produce a hypocalcemic tetany. A positive Chvostek sign is facial muscle twitching elicited by tapping a facial nerve component. It is also prudent to recall that early tetany may be manifested as carpopedal spasm and that hypocalcemic tetany is associated with reduced ionized calcium levels. Therefore, hyperproteinemia or respiratory alkalosis (hyperventilation) in particular may precipitate a tetanic episode by driving ionized calcium to a bound form.
Some patients require large amounts of calcium, vitamin D3 (cholecalciferol), and increased dietary magnesium in the first 1 week to 1 month following surgery while the residual parathyroid gland responds to the hypocalcemia with its own hyperplasia. Efforts should be made to keep serum calcium levels above 8.0 mg/dL (2 mmol/L).