Clinical Manifestations

Most patients diagnosed with primary hyperparathyroidism today do not have the classic or historical clinical manifestations of this disorder such as osteitis fibrosa cystica, nephrolithiasis, nephrocalcinosis, peptic ulcer disease, gout, or pseudogout. The pentad of symptoms—painful bones, kidney stones, abdominal groans, psychic moans, and fatigue overtones—is more common, although most patients have few dramatic symptoms. The symptoms and other associated complications of primary hyperparathyroidism are listed in Table 40-3. Several investigators have documented that manifestations such as fatigue, weakness, exhaustion, polydipsia, polyuria, nocturia, joint pain, bone pain, constipation, depression, anorexia, nausea, heartburn, and several associated conditions such as nephrolithiasis and hematuria occur more often in patients with primary hyperparathyroidism than in those with thyroid nodules.8"10 Furthermore, only symptoms of fatigue, bone pain, and weight loss seemed to correlate with the severity of hypercalcemia.8 Younger patients are more likely to present with nonspecific complaints such as fatigue and lethargy.11 The pathophysiologic mechanisms explaining why many of these manifestations occur more often in patients with even mild primary hyperparathyroidism are unknown. However, studies have documented changes in neurotransmitters in the cerebrospinal fluid of patients with primary hyperparathyroidism.12

Several groups have used a standardized health status assessment tool such as the SF-36 (the Medical Outcomes Study Short-Form Health Survey) to assess symptoms and

TABLE 40-1. Differential Diagnosis of Hypercalcemia

Primary hyperparathyroidism Malignancy

Granulomatous disorders—sarcoidosis, tuberculosis, berylliosis

Endocrine disorders—Addison's disease, hyperthyroidism, hypothyroidism, pheochromocytoma, vasoactive intestinal peptide tumor (VTPoma) Benign familial hypocalciuric hypercalcemia Medications—thiazide diuretics, calcium supplements, lithium

Increased dietary intake—vitamin D, vitamin A Milk-alkali syndrome Immobilization Paget's disease

TABLE 40-3. Symptoms and Associated Conditions in Patients with Primary Hyperparathyroidism


Associated Condition







Bone pain

Back pain


Increasing constipation


Memory loss

Joint pain

Loss of appetite





Hematuria from passage of stone

Bone fracture


Joint swelling Weight toss Duodenal ulcer Gastric ulcer Pancreatitis Hypertension

From Chan AK, Duh QY, Katz MH, et al Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: A case-control study. Ann Suig 1995; 222:402.

health state in patients with primary hyperparathyroidism. This multidimensional health assessment tool has several domains that evaluate physical function, role limitation (physical and emotional), social function, bodily pain, mental health, energy, and general health perception.13 Burney and colleagues first demonstrated that patients with primary hyperparathyroidism scored lower than healthy control subjects in all domains of the SF-36.14 Other studies confirm that these patients are indeed impaired in several domains15"17 and have also shown that the impairments in functional status are independent of the degree of elevation of serum calcium levels.16 Even patients with minimal hypercalcemia and parathyroid hormone elevation benefit from parathyroidectomy.17 More recently, Pasieka and Parsons designed and validated a disease-specific surgical outcome tool for patients with primary hyperparathyroidism. The items in their Visual Analog Scale (VAS) questionnaire include symptoms of bone and joint pain, fatigue, mood swings, depression, abdominal pain, weakness, irritability, memory loss, headaches, pruritus, increased thirst, and proximal muscle weakness. The study group of patients with primary hyperparathyroidism had significantly more symptoms than a comparison group of patients with nontoxic thyroid disease.18

Studies have also documented that patients with primary hyperparathyroidism have an increased incidence of fractures,19 muscle weakness,20 and cardiovascular disease.21,22

TABLE 40-2. Comparison of Biochemical Characteristics of Humoral Hypercalcemia of Malignancy (HHM) and Primary Hyperparathyroidism (PHPT)


Plasma calcium Very high High

Plasma phosphorus Low Low or normal

Plasma chloride Low High

Plasma bicarbonate High Low

Urinary cyclic adenosine High High monophosphate (cAMP)

Modified from Grill V, Martin TJ. Hypercalcemia of malignancy. Rev Endocr Metab Disord 2000; 1:253.

Rarely, patients may be completely asymptomatic. We documented truly asymptomatic hyperparathyroidism in only 2% to 4.6% of consecutive patients referred for parathyroidectomy.810

On physical examination, patients may demonstrate signs such as band keratopathy, a deposition of calcium in Bowman's membrane just inside the iris of the eye. This condition is caused by chronic eye diseases such as uveitis and glaucoma and by trauma but also occurs in systemic conditions associated with high calcium or phosphate levels. It is therefore not specific for primary hyperparathyroidism.23 Evidence of fibro-osseus jaw tumors should be sought. Patients with this manifestation are more likely to develop parathyroid carcinoma.24 The neck should be examined for masses, thyroid nodules, and concurrent lymphadenopathy. Parathyroid tumors are seldom palpable, except in patients with profound hypercalcemia (>14 mg/dL). A palpable neck mass in a patient with primary hyperparathyroidism is more likely to be a thyroid lesion. However, approximately 50% of parathyroid cancers are palpable.25

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