Hyperparathyroidism

Does this patient have hyperparathyroidism?

Parathyroid function

There are four parathyroid glands which produce parathyroid hormone (PTH). PTH is the primary regulator of calcium homeostasis and vitamin D conversion. PTH maintains the calcium concentration (ionized) in the extracellular fluid within a narrow normal range due to calcium’s wide array of cellular functions. Secretion of PTH is normally stimulated by falls in the extracellular calcium concentration. To accomplish calcium homeostasis, PTH acts directly on the bone, kidney, and indirectly at the intestine via 1,25 (OH)2D to regulate calcium concentrations.

At the kidney, PTH actions stimulate renal calcium reabsorption in the cortical thick ascending limb. In the intestines it stimulates the hydroxylation of 25-hydroxyvitamin D allowing for calcium absorption. At bone, PTH acts to increase serum calcium by stimulating bone resorption via osteoclast-activating factors such as interleukin-6 from osteoblasts.

Hyperparathyroidism, the state of excess parathyroid hormone, is a common cause of hypercalcemia and the primary disorder is most commonly due to an autonomously functioning solitary adenoma (80-85%), gland hyperplasia (10-15%) or multiple adenomas (5%).

Secondary hyperparathyroidism

Secondary hyperparathyroidism occurs when there is partial resistance to the metabolic actions of PTH, leading to excessive production of the hormone. This is seen most commonly with renal failure. The topic of renal osteodystrophy will be discussed in subsequent sections.

Pseudohypothyroidism is an extremely rare genetic condition linked to dysfunctional G proteins (heterozygous loss of g alpha function) and is manifested by parathyroid hormone resistance. There are 3 types (1a, 1b, 2), and all present with low serum calcium, high phosphate and appropriate elevations in PTH.

Type 1a (Albright’s hereditary osteodystrophy), due to a maternal allelic mutation GNAS 1 on chromosome 20, has a distinct phenotypic appearance with short fourth and fifth metacarpals described as the “knuckle, knuckle, dimple, dimple” sign, rounded faces and is associated with thyroid stimulating hormone resistance.

Type 1b and type 2 lack phenotypic abnormalities but are biochemically similar. Pseudo-pseudohyperparathyroidsm presents with a phenotypic picture similar to psuedohyperparathyroidism type 1a, but subjects are biochemically normal. This is due to a paternal defect in the GNAS1 allele.

This topic will focus on primary hyperparathyroidism.

Epidemiology

The age adjusted incidence of primary hyperparathyroidism is estimated to 15.7 per 100,000 patient years, and this estimate has been in steady decline despite innovations in testing that have allowed for early detection. Possible explanations for the decline include the addition of calcium with vitamin D supplementation to the diet, supplemental estrogen use in post-menopausal females, and recognition of the complications of excessive radiation exposure that are implicated in causing parathyroid malignancies.

The estimated mean age at diagnosis based is between 52 – 56 years. Women account for the majority (74%) of the cases. At diagnosis the most common findings are serum calcium concentration within 1 mg/dL the upper limit of normal, and parathyroid hormone concentration 1.5 times the upper limit of normal. Hypercalciuria is seen in approximately 40% of patients and hypophosphatemia in less than 25% of patients.

Today, most patients are asymptomatic with few overt manifestations due to early detection. Hypercalcemia, an early laboratory finding in hyperparathyroidism, is often the impetus for checking parathyroid hormone (PTH) levels. The paradigm shift in clinical presentations from clinically symptomatic to asymptomatic can be attributed to the multichannel biochemical testing assay (1974) that includes serum calcium, thus allowing for early identification and treatment.

Rheumatological manifestations of primary hyperparathyroidism

Classically, effects of excess parathyroid hormone affected the kidney and musculoskeletal system giving rise to the well-known moniker for the clinical manifestations “bones, stones, and groans”.

Osteitis fibrosa cystica

Also referred to as osteitis fibrosa, osteodystrophia fibrosa and Von Recklinghausen’s disease of bone.

This was a term applied to the characteristic subperiosteal erosions that were initially identified in primary hyperparathyroidism. This is now an extremely rare complication in primary hyperparathyroidism in the United States (seen with severe disease, especially with parathyroid carcinoma), although in the developing world, where calcium and vitamin D nutrition is inadequate, it is still seen.

Clinically this is characterized by diffuse bone pain, bone tenderness, and skeletal deformities including bowing of the long bones and fractures. The skeletal changes are most prominent at the sites of highest bone turnover, the trabecular bones of the vertebrae, phalanges, the ends of long bones and in the skull.

Pathologically there is an increase in the giant multinucleated osteoclasts on the surface of bone and a replacement of the normal bone elements with fibrous tissue. Brown tumors are severe manifestations of this turnover with areas of necrosis and focal hemorrhage with hemosiderin deposition. They are lytic lesions that become sclerotic as they heal, mimicking blastic metastasis on imaging.

Crystalline arthropathies

Pseudogout

The clinical event of pseudogout is defined as an acute attack of calcium pyrophosphate crystal induced inflammatory synovitis. Asymptomatic chondrocalcinosis is evidence of pseudogout crystal deposition. This is seen on x-ray imaging as calcifications at sites including fibrocartilage or joint capsules. Typical sites of deposition include the knee, symphysis pubis and the triangular fibrocartilage of the radioulnar joint. Both pseudogout and chondrocalcinosis are described to occur at a greater incidence in patients with untreated primary hyperparathyroidism. The majority of the affected joints are however asymptomatic, with just evidence of chondrocalcinosis.

In the setting of parathyroid hormone excess, it is postulated that proteoglycans, which act to inhibit crystallization, may be impaired by the elevated calcium. Additionally, altered pyrophosphate metabolism or alterations (increase) in nucleoside triphosphate pyrophosphohydrolase enzymes which catalyze the production of pyrophosphate, may promote the formation of calcium pyrophosphate crystals. This is postulated to increase the risk of a pseudogout flare.

In the postoperative period after a parathyroidectomy, there is an increased incidence of pseudogout flares. This is attributed to the nadir in the serum calcium seen postoperatively. In this setting, the calcium pyrophosphate crystals have increased solubility and have a tendency to be released into the synovial space resulting in a flare.

Hyaluronic acid injections can precipitate attacks and is postulated that the preparation may decrease intra-articular calcium concentrations leading to calcium pyrophosphate shedding. Interestingly, treatment for osteoporosis with the recombinant human parathyroid hormone Teriparatide does not confer an increased risk of pseudogout flares.

Gout

Gout is characterized by acute attacks of inflammatory arthritis due to monosodium urate crystal deposition. Hyperuricemia has been observed to occur more frequently in small studies of patients with hyperparathyroidism compared to controls. It is known that there is a higher incidence of gout attacks in the setting of hyperuricemia, thus ultimately increasing the risk for clinically significant gout in the primary hyperparathyroidism population.

Although the pathophysiology is not known, it is suggested that PTH or calcium deposition may inhibit uric acid excretion in the proximal renal tubule. Interestingly, the use of recombinant human parathyroid hormone Teriparatide in trials have demonstrated that, although there is a mild increase in serum uric acid above the normal threshold, the increase in hyperuricemia did not result in increased gout attacks.

Bone density

The effect of mild excesses of parathyroid hormone on bone density exemplifies the anabolic and catabolic actions of this hormone. PTH acts to decrease cortical bone with relative preservation of cancellous bone. At the lumbar, femoral and radial sites, bone densitometry declines.

The largest decrease occurs at the distal third of the radius, a site of predominantly cortical bone. Loss is estimated to be 80% of expected, compared to aged matched controls. At the lumbar spine, a site of predominantly cancellous bone, bone density estimates are within the 90% of expected. At the lumbar spine, a site of admixture of cortical and cancellous bone, there is a moderate decrease in bone density estimated between 80-90%.

In postmenopausal females, there is a protective effect of excess parathyroid hormone demonstrated by an increase in cancellous bone volume compared to age matched controls. Fracture risk data however both supports and conflicts the protective effect of excess parathyroid hormone in primary hyperparathyroidism. Further information is necessary to estimate incidence risk for fracture at all sites in this clinical setting.

Neuromuscular manifestations

Myalgia is a common feature, affecting the proximal muscles in the upper and lower extremities. There can be features of tenderness and malaise. The occurrence and severity of muscle symptoms do not correlate with severity of hypercalcemia. Arthralgias can occur at the medium and large joints. The features may mimic polymyalgia rheumatica. Weakness, easy fatigability, and atrophy can occur, particularly at the lower extremities.

Electromyograms are variable; both short duration, low amplitude motor unit potential, as well as abnormally high amplitude, long duration polyphasic potentials in others. Motor nerve conduction velocities and distal sensory latencies are normal. On muscle biopsy, typical myopathic features are absent and atrophy is seen greater in type II fibers than in type 1 fibers. Serum creatinine phosphokinase and aldolase values are typically within normal limits.

Differential for hypercalcemia

Other less common causes of hypercalcemia include:

Humoral hypercalcemia of malignancy due to parathyroid hormone related protein (seen in malignancy and differing from primary hyperparathyroidism by normal to low serum PTH.)
Lithium therapy.
Thiazide diuretics.
Jansen’s disorder (metaphyseal chondrodysplasia).
Familial hypocalciuric hypercalcemia.
Direct bone invasion malignancies.
Excess vitamin D ingestion.
Sarcoidosis.
Granulomatous diseases (tuberculosis, fungal).
Williams’ syndrome (autosomal dominant disorder seen rarely in infancy).
Hyperthyroidism (both primary and secondary).
Immobilization.
Aluminum intoxication.
Vitamin A intoxication.
Milk Alkali syndrome.
Pheochromocytoma.
Rhabdomyolysis.
Theophylline toxicity.
Multiple endocrine neoplasia syndrome 1 (MEN 1) that includes pancreatic islet cell, pituitary and carcinoid tumor.

What tests to perform?

Laboratory testing

All patients suspected of hyperparathyroidism or with hypercalcemia of unknown significance, should be screened with parathyroid hormone immunoassay (second or third generation assays), 25-hydroxyvitamin D, serum calcium, ionized calcium, creatinine clearance (calculated), and bone mineral densitometry. Twenty four hour urine calcium should be used to screen for familial hypocalciuric hypercalcemia if suspected.

If present, Vitamin D deficiency should be addressed and repleted. The goal is to achieve a serum level of 25-hydroxyvitamin D greater than 20 ng/dl (50 nmol/liter). Calcium supplementation recommendations are the same as in healthy patients: 1000 mg/day for males ages < 70 years and females < 50 years, 1200 mg/day for females > 51 years and males >71 years. This is based on the Institute of Medicine guidelines.

In primary hyperparathyroidism annual monitoring of serum calcium and serum creatinine is recommended. Bone density should be repeated every 1-2 years.

Formerly, 24 hour urine calcium, 24 hour urine collections for creatinine clearance and abdominal imaging (x-ray or ultrasound) were recommended for monitoring based on the 1990 guidelines. Some practitioners will still utilize these modalities in clinical practice.

Imaging

Parathyroid gland imaging

Imaging of the parathyroid gland is essential for localization prior to certain surgical procedures, but not indicated for diagnosis.

Radionucleotide imaging using TC-99m sestamibi SPECT imaging with magnetic resonance imaging (MRI) of the neck provides a high success rate of localization. Standard practice often incorporates initial localization with Tc-99m sestamibi SPECT imaging, with or without CT image fusion, and ultrasound techniques to mark the skin surface entry site.

CT, MRI, Positron emission tomography scanning, arteriography and selective venous sampling for PTH are often reserved for patients who have not been cured by previous explorations or for whom other localization techniques are uninformative or discordant.

In the event that surgery is planned with a standard neck dissection, preoperative imaging is not recommended as gross dissection will frequently reveal the pathologic focus. If minimally invasive surgery is planned, Tc -99m SPECT sestamibi imaging and ultrasound are recommended for localization.

Musculoskeletal imaging

Regarding skeletal imaging, the late stages of hyperparathyroidism are not commonly seen today due to early diagnosis and treatment. Without musculoskeletal symptoms, standard x-ray imaging is not indicated. If advanced disease is suspected, x-ray imaging of the affected area can be useful.

In advanced disease radiographic findings will show a spectrum of changes related to osseous resorption. The earliest finding is often subperiosteal resorption along the radial aspect of the second and third phalanges. This resembles a long curved erosion along the length of the phalanx. Acro-osteolysis can occur at the tufts of the distal phalanges.

Periosteal resorption can also be seen at multiple sites, with erosions affecting the medial metaphysis of the tibia, humerus, superior surface of the ribs. Subchondral bone resorption occurs at the sacroiliac, acromioclavicular sternoclavicular, temporomandibular, pubis symphysis and patella. Subligamentous and subtendinous resorption occurs at the femoral trochanters, ischial tuberosity, calcaneous, clavicle and humeral tuberosities.

Late disease manifestations include trabecular resorption at the skull leading to the classically described “salt and pepper” appearance. Brown tumors are lytic lesions of the bone due to extremes of bone resorption and are seen in severe cases. Brown tumors often contain hemosiderin, which gives it a classic hypointense (dark) signal on T2 weighted and T1 weighted MRI sequences. After parathyroidectomy, brown tumors heal and become sclerotic, and have the appearance of blastic metastases.

Biopsy

Biopsy of the parathyroid gland is performed with surgery. In the event of a brown tumor, the findings include medullary fibrosis, thickened trabecular bone, extensive loose medullary fibrosis and numerous osteoblasts and osteoclasts lining the trabecular bone. This can histologically be differentiated from giant cell tumors by the presence of intratrabecular ditches and tunnels.

How should patients with hyperparathyroidism be managed?

Asymptomatic patients who do not meet surgical guidelines can be followed safely without surgery. In this situation, annual monitoring is critical as it is estimated that one third of patients will experience progressive disease. Young age at diagnosis (<50 years) is correlated to progression risk.

Guidelines for parathyroid surgery

Surgery is indicated in all symptomatic patients and whom medical surveillance is neither desired nor possible. Parathyroid surgery should be performed only by surgeons highly experienced in this operation, as failure and complication rates can be unacceptably high.

In asymptomatic patients indications for surgery include:

Serum calcium >1.0 mg/dL (0.25 mmol/liter) above the upper limit of normal.
Creatinine clearance (calculated) reduced to < 60 ml/min. Some physicians will utilize a 24 hour urinary calcium excretion > 400 mg/day as an indication for surgery.
Bone mineral density T score < -2.5 at any site (lumbar spine, total hip, femoral neck or the 33% radius). In male patients younger than 50 years and pre-menopausal females, Z scores are recommended, using a cut off of -2.5 as an indication for surgery.
Age less than 50 years.

Guidelines for normocalcemic primary hyperparathyroidism have not been established.

Postoperatively, improvement in bone mineral density at the spine and hip should occur over a 3-4 year period.

Pharmacological management includes Vitamin D and Calcium supplementation.

At this time there is inconclusive data to recommend additional pharmacotherapy in the asymptomatic patient currently in the monitoring phase, or as an alternative to surgery in patients fulfilling the above guidelines.

What happens to patients with hyperparathyroidism?

Pathophysiology

Understanding the actions of PTH will allow better insight into dysregulation of the hormone. PTH secretion is normally stimulated by a fall in the extracellular calcium concentration. Conversely, elevated blood ionized calcium directly suppresses PTH secretion by activating parathyroid calcium sensing receptors, which inhibit PTH secretion and parathyroid cell growth.

Skeletal

PTH acts on bone by increasing the rate of bone mineral dissolution, which ultimately changes the concentration of calcium by shifting it from bone to blood, both directly and indirectly. Ninety nine percent of the human body calcium store resides in the osseous skeleton. Elevated PTH and 1,25(OH)2D indirectly activate osteoclastic bone resorption via osteoclast activating factors, such as interleukin-6 and other cytokines from osteoblasts, to obtain calcium from bone. The effects of PTH on bone can be seen within minutes in the setting of hypocalcemia with preformed PTH.

Within hours in the setting of hypocalcemia, PTH mRNA expression is upregulated and overtime will lead to gland hyperplasia. Chronic effects on bone include increased osteoblasts, osteoclasts and remodeling. Continuous exposure to elevated PTH leads to increased osteoclast mediated bone resorption. Intermittent administration of PTH (1-2 hours daily) leads to net stimulation of bone formation of trabecular bone. Osteoblasts have PTH receptors and are responsible for the bone forming effects of PTH.

Renal

PTH acts by reducing the renal clearance of calcium and results in increased extracellular fluid calcium. Approximately 8-10 g/day of calcium is filtered by the glomeruli, with only 2-3% found in the urine. Approximately 65% of filtered calcium is passively reabsorbed. Another 20% is reabsorbed in the cortical thick ascending limb of Henle’s loop, via a paracellular mechanism with paracellin-1. This is regulated by serum calcium and magnesium concentrations. The remainder, approximately 10%, is reabsorbed in the distal convoluted tubules by a transcellular mechanism that is regulated by PTH.

Additionally, the renal actions include inhibition of phosphate transport at the proximal tubule, and stimulation of renal 25(OH)D-1-alpha-hydroxylase at the proximal convoluted tubule. This enzyme catalyzes the hydroxylation of calcidiol pr 25(OH)D), to the active form calcitriol or 1,25 (OH)2D.

Intestinal

Parathyroid hormone increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)2D. Active calcium transport via activated vitamin D occurs mainly in the proximal small bowel. At high levels of calcium intake, synthesis of 1,25(OH)2D is reduced, which decreases the rate of active intestinal calcium absorption. Of importance, absorption of calcium requires gastric acid. Calcium supplementation can further be poorly absorbed due to the neutralizing effect on gastric acid from the supplements, like protein pump inhibitors and H2 receptor blockade. The use of calcium citrate may be preferable to calcium carbonate due to the weakly dissociable properties of the latter.

Pharmacologic considerations

At this point, surgery is the standard of care in patients meeting criteria for intervention. Other possible modalities which require further study include:

Bisphosphonates, which have been shown to increase bone density at the lumbar spine and hip regions in patients with primary hyperparathyroidism without alterations to the serum calcium. This is an area of interest of future study.
Cinacalcet – a calcimemetic that is used in secondary hyperparathyroidism and for hypercalcemia in parathyroid carcinoma. It is effective in reducing serum calcium concentrations but has not shown significant changes to bone density. This is approved in Europe for the management of primary hyperparathyroidism.
Estrogen replacement therapy in post-menopausal females is associated with a slight improvement in bone mineral density, small reductions in serum calcium and stable parathyroid hormone levels. Raloxifene, a selective estrogen receptor modulator, when used in postmenopausal females has shown similar improvements to estrogen replacement therapy, with modest serum calcium improvements, stable serum parathyroid hormone levels, and improvement in markers of bone turnover

How to utilize team care?

Specialty consultations

Otolaryngology or surgical subspecialty in head and neck surgery for the parathyroidectomy. Endocrinology for management of hyperparathyroidism.

Dietitians

Patients should maintain daily recommend intake for both calcium (1000-1200 mg/day based on age/sex) and vitamin D (600-800 IU/day), either by diet or supplementation.

Are there clinical practice guidelines to inform decision making?

Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop.

What is the evidence?

Wermers, RA, Khosla, S, Atkinson, E. “Incidence of Primary Hyperparathyroidism in Rochester, Minnesota, 1993-2001: An update on the Changing Epidemiology of the Disease”. Journal of Bone and Mineral Research. vol. Vol 21. 2006. (Population based descriptive study using the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System.)

Aldred, MA, Trembath, RC. “Activating and inactivation mutations in the human GNAS1 Gene”. Hum Mutat. vol. 6. 2000 Sep. pp. 183-9.

Silverberg, SJ, Shane, E, de la Cruz, L. “Skeletal disease in primary hyperparathyroidism”. J Bone Miner Res. vol. 4. 1989. pp. 283-291.

Rubin, Mishaela, Silverberg. “Rheumatic Manifestations of Primary Hyperparathyroidism and Parathyroid Hormone Therapy”. Current Rheumatology Reports. vol. 4. 2002. pp. 179-185.

Cusano, N, Silverberg, S, Bilezikian, J. “Primary hyperparathyroidism:rheumatologic manifestations and bone disease”. Rheumatology.

Helliwell, M. “Rheumatic symptoms in primary hyperparathyroidism”. Postgraduate Medical Journal. vol. 59. April 1983. pp. 236-240.

Grahame, R, Sutor June Mitchener, M.B. “Crystal Deposition in hyperparathyroidism”. Ann. Rheum Dis. vol. 30. 1971. pp. 597

Silverberg, SJ. ” Natural history of primary hyperparathyroidism Endocrinol Metab Clin”. North Am. vol. 29. 2000. pp. 451-464

Bilezikian, J, Khan, A, Potts, J. ” Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Third International Workshop”. J Clin Endocrinol Metab, February. vol. 94. 2009. pp. 335-339.

Patten, B, Bilezikian, J, Mallette, LE. “Neuromuscular Disease in Primary Hyperparathyroidism”. Ann Intern Med. vol. 80. 1974. pp. 182-193.

Potts, J. “Diseases of the Parathyroid Gland and Other Hyper-Hypocalcemic Disorders”. Harrison's Principles of Internal Medicine. 2005.

Bennett, D.L, El-Khoury, G.Y. “Imaging in Hyperparathyroidism and Renal Osteodystrophy”. Imaging of Arthritis and Metabolic Bone Disease.

Rubin, M, Lee, K, McMahon, D, Silverberg, S. “Raloxifene Lowers Serum Calcium and Markers of Bone Turnover in Postmenopausal Women with Primary Hyperparathyroidism”. J Clin Endocrinol Metab. vol. 88. March 2003. pp. 1174-1178.

Bassler, T, Wong, E, Brynes, R. “Osteitis Fibrosa Cystic Stimulating Metastatic Tumor; An Almost Forgotten Relationship”. American Journal of Clinical Pathology. vol. Vol 100. 1993.

“New Recommended Daily Amounts of Calcium and Vitamin D, Institute of Medicine”. Winter. vol. Volume 5. 2011.

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