Primary hyperparathyroidism is a metabolic disorder resulting from overproduction of parathyroid hormone (PTH) by one or more enlarged parathyroid glands causing persistent hypercalcemia. At least 50% of patients with primary hyperparathyroidism are asymptomatic, and approximately 1% of cases go undiscovered. Estimates of incidence rates vary; the National Institutes of Health (NIH) estimate that 28 new cases per 100,000 persons occur annually in the United States (U.S.). Primary hyperparathyroidism affects women at least twice as often as men. Peak incidence occurs between the third and sixth decades; however, it can also affect children. Parathyroidectomy is 95% effective in symptomatic and progressive cases.

Primary hyperparathyroidism:

• Adenoma (single or multiple)
• Parathyroid hyperplasia
• Type I and II multiple endocrine neoplasia (MEN) syndromes
• Parathyroid malignancies (rare)—less than 2% of cases of hyperparathyroidism

Incidence rates increase with age. New cases occur in approximately 2 of every 1,000 women over age 60 annually. Hyperparathyroidism can be hereditary in the form of autosomal dominant MEN syndromes.

As stated in the section entitled Overview, at least 50% of primary hyperparathyroid patients are asymptomatic and the diagnosis is made following discovery of an incidental finding of elevated calcium on routine exam. When symptoms do occur, they are generally attributable to the persistently elevated calcium.

Bones:

• Osteopenia and osteoporosis
• Osteitis fibrosa cystica—although rarely occurs, pathognomonic for elevated PTH

Gastrointestinal:

• Dyspepsia
• Ulcers
• Nausea and vomiting
• Pain
• Constipation
• Pancreatitis
• Chondrocalcinosis
• Pseudogout
• Anorexia

Renal:

Improvements in detection of early hyperparathyroidism has significantly lessened renal complications.

• Excessive thirst and polydipsia
• Polyuria
• Kidney stones; repeated nephrolithiasis may cause urinary tract obstruction, infection, and impaired kidney function over time

Neuromuscular:

• Muscle weakness and fatigue, particularly proximal
• Hypotonia; atrophy
• Joint pains

CNS effects:

• Drowsiness; may even progress to lethargy, stupor, or coma
• Memory loss; altered cognitive function
• Depression and anxiety
• Psychosis

Other:

• Pruritis

• Adrenal insufficiency or crisis (Addison's disese)
• Hyperthyroidism, thyroid storm, and Graves' disease
• Hypothyroidism and myxedema coma
• Sarcoidosis
• Vitamin D or vitamin A toxicity 
• Tuberculosis
• Hypercalcemia of malignancy, particularly multiple myeloma; tumors secreting PTH-like substances
• Immobilization, particularly with Paget's disease or paraplegia
• Use of thiazide diuretics
• Milk-alkali syndrome from excessive ingestion of calcium and absorbable antacids

Diagnosis is often made based on test results given that a high percentage of patients with primary hyperparathyroidism are asymptomatic. Clinical manifestations of the disease are extremely variable (see section entitled Signs and Symptoms). Once diagnosis is considered or suspected, physical exam should include complete neuromuscular, mental status, and abdominal exams.

• Elevated total serum calcium concentration along with elevated serum PTH concentration; this combination is also present with malignancies secreting PTH-like substance
• Multiphasic screening for decreased serum phosphate level (<2.5 mg/dl), elevated serum chloride levels, low bicarbonate, and high alkaline phophatase concentrations; alkaline phosphatase is particularly elevated in the case of osteitis fibrosa cystica
• Immunoassays for intact PTH are reliable and cost effective
• 24–hour urine collection for calcium

• Single photon absorptiometry to check cortical bone mass
• CT scan and quantitative digital radiography (DEXA) used to assess spinal bone density
• Neck ultrasonography
• MRI
• Technetium-sestimibi scanning—may be done if radiographic tests of the neck and/or surgical exploration have not identified diseased parathyroid glands; may find parathyroid gland in aberrant location

• ECG to detect shortened QT interval (severe hypercalcemia)
• Surgical frozen section

A recent survey of endocrine surgeons found that surgery to lower serum calcium was successful in 95% of patients. Another study has shown that bone mineral density is increased after surgery for primary hyperparathyroidism. Nonsurgical management is recommended only in asymptomatic patients and in patients with only mildly elevated serum calcium (<11.5 mg/dl), no previous life-threatening episodes of hypercalcemia, and normal renal and bone status. Surgery may be beneficial in younger asymptomatic patients because of potential negative long-term outcomes from primary hyperparathyroidism and need for long-term surveillance. Hospitalization and intravenous hydration prior to surgery are recommended in patients with significant symptoms and elevations of calcium levels; although, surgery is generally the quickest way to lower calcium levels.

• Loop diuretics (e.g. lasix) to increase urinary calcium excretion in well-hydrated patients with hypercalcemia
• Calcitonin 4 to 8 Units/kg SC or IM q 6 to 12 hours to reduce calcium levels
• Estrogen for postmenopausal women who are unwilling or unable to undergo surgery; may prevent bone demineralization and reduce calcium levels
• Bisphosphonates, such as tiludronate and alendronate, for postsurgical cases with documented decreases in bone density; not a substitute for surgery
• Oral phosphate has been used in the past; although this lowers calcium levels, oral phosphate increases PTH further and may worsen end organ damage

Conservative parathyroidectomy (removal of one enlarged parathyroid gland) is often favored over near total removal of parathyroid tissue, although there is some controversy as well as pros and cons to each approach. Many surgeons will do frozen sections of each parathyroid gland at the time of the surgery and make a determination about which glands need to be removed. In familial cases involving multiple gland hyperplasia, surgical management generally entails total removal of three glands, with a partial excision of the fourth. Total parathyroidectomy is sometimes required. A portion of one gland may be left in place or a segment of a normal parathyroid gland may be implanted. Complications are rare.

Dietary, nutritional, and herbal support of normal bone development and endocrine function have not been extensively studied, but may prove beneficial as adjunctive treatments for prevention of complications from hyperparathyroidism, particularly bone demineralization.

Soy Ipriflavone:

There is a fair amount of scientific literature studying the effect of ipriflavone (an isoflavone synthesized from the soy isoflavone daidzein) in patients with osteoporosis. To date, a variety of studies document the effectiveness of ipriflavone in one or more of the following:

• Inhibiting bone resorption
• Enhancing bone formation
• Increasing bone density in humans and animals.

Because bone remodeling is dependent upon the interaction of osteoclasts and osteoblasts as old bone is reabsorbed and new bone is formed, ipriflavone's dual effects seem especially applicable to the prevention of skeletal damage, which may complicate primary hyperparathyroidism (Head 1999).

In one study investigating the use of ipriflavone specifically for hyperparathyroidism, researchers looked at the effectiveness of this isoflavone on a small group of nine patients with primary hyperparathyroidism. The patients were administered oral ipriflavone 1200 mg/day for either 21 or 42 days. The study evaluated serum and urinary parameters of bone remodeling for all patients. Treatment significantly reduced markers of bone turnover without affecting bone formation. Further studies are needed to confirm these findings (Mazzuoli et al. 1992).

The Ipriflavone Multicenter European Fracture Study investigating effects on osteoporosis was begun in 1997; results are expected in 2001 (Head 1999). The research group is not examining hyperparathyroidism specifically; however, information about the mechanisms of action of ipriflavone on bone resorption and formation in the case of osteoporosis may have relevance for this particular complication of hyperparathyroidism.

Certain nutrient deficiencies may contribute to development of bone disorders:

• Vitamin C
• Manganese 
• Vitamin K 

Both manganese and vitamin C aid in the cross-linking of collagen and contribute to the integrity of the bone matrix. Vitamin K is necessary for cellular uptake of calcium. Supplementation with any of these substances is generally only necessary in the case of anorexia or borderline nutritional status, either of which may occur in the case of primary hyperparathyroidism (see section entitled Signs and Symptoms).

• Black cohosh (Cimicifuga racemosa) has a history of traditional use for estrogenic effects raising question about possible benefit in potentiating estrogenic functions such as inhibition of osteoclastic activity. 
• Ginkgo biloba is rich in flavones, such as quercetin, raising the question about whether this would have similar value to the isoflavone daidzen from soy in bone protection (Blumenthal 1998).

Mineral-rich herbs are used in traditional preparations to support normal bone growth; examples include:

• Horsetail (Equisetum avense)
• Oat straw (Avena sativa)

In addition to those mentioned above, some naturopaths and herbal specialists may consider other remedies to balance the endocrine system.

Although not studied scientifically, tissue salts that are used by experienced homeopaths for the treatment of dysfunctional calcium metabolism and slow development of bones may be useful in hyperparathyroidism. These include:

• Calcarea carbonica 
• Calcarea phosphorica 

Calcium levels should be monitored periodically for several months after parathyroidectomy. Increased calcium levels indicate the need for further evaluation of the parathyroid gland. Nonsurgical patients require periodic monitoring (at least semi-annually over the first 3 years) to identify increased hypercalcemia, deteriorating bone or renal status, and other complications, including patient self-reports of weakness, depression, and skeletal and gastrointestinal symptoms. Providers should assess blood pressure, serum calcium, serum creatinine, and creatinine clearance. Other procedures include annual abdominal radiographs, 24-hour urinary calcium in some patients, and repeat bone mass measurement after 1 to 2 years.

Early detection of rickets or vitamin D deficiency may help prevent secondary hyperparathyroidism. There are no known preventive measures for primary hyperthyroidism. However, the following approaches are advised for patients who are at risk:

• Avoid dehydration
• Avoid restricted or excess calcium diet
• Treat hypertension even when mild

• Skeletal damage (e.g., pathologic fracture)
• Urinary tract infections
• Renal damage
• Peptic ulcers
• Pancreatitis
• Hypertension
• Nervous system symptoms
• Rare surgical complications (e.g., hypoparathyroidism)

Patients who undergo parathyroidectomy and those who are asymptomatic have excellent prognoses. Poor prognosis is associated with secondary hyperparathyroidism due to chronic renal failure.

Hyperparathyroidism in pregnant women can cause hypocalcemia and tetany in newborns.

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Berkow R, Fletcher AJ, Beers MH, eds. The Merck Manual. Rahway, NJ: Merck & Co.; 1992:1010-1011, 1015, 1100-1103.

Blumenthal M, ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, Mass: Integrative Medicine Communications; 1998.

Endocrine Web, Inc. Hyperparathyroidism. Accessed at www.EndocrineWeb.com/hyperpara.html on January 20, 2000.

Fauci AS, Braunwald E, Isselbacher KJ, et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998.

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NIH Consensus Statement. Diagnosis and Management of Asymptomatic Hyperparathyroidism. National Institutes of Health. Accessed at www.odp.od.nigh.gov/consensus/cons/082/082 statement.htm on January 20, 2000.

Mazzuoli G, Romagnoli E, Carnevale V, et al. Effects of ipriflavone on bone remodeling in primary hyperparathyroidism. Bone Miner. 1992;19:S27-S33.

NIH Osteoporosis and Related Bone Diseases National Resource Center. Information for Patients about Primary Hyperparathyroidism. National Institutes of Health. Accessed at www.osteo.org/prpara.html on August 28, 2000.

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Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab. 1996;81(11):4007-4012.

SIU Division of Otolaryngology. Hypercalcemia with emphasis on hyperparathyroidism. Southern Illinois University School of Medicine. Accessed at www.siumed.edu/surgery/otol/hyperparathyroid.html on January 25, 2000.

Sosa JA, Powe NR, Levine MA, Udelsman R, Zeiger MA. Profile of a clinical practice: Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: a national survey of endocrine surgeons. J Clin Endocrinol Metab. 1998;83(8):2658-2665.