Hyperparathyroidism in Otolaryngology and Facial Plastic Surgery 

Updated: Nov 16, 2015
Author: James LaBagnara, MD; Chief Editor: Arlen D Meyers, MD, MBA 

Overview

Background

Although parathyroid surgery can be rewarding for the otolaryngologist or head and neck surgeon, it also can be vexing. The vast majority of explorations proceed as planned, with rapid identification and removal of the abnormal gland. However, a particular case can be frustrating and beguiling if the number of glands is abnormal or inconsistent, if the pathologic abnormality lies in an anomalous location, or if the hyperparathyroidism is based on heredity factors.

Normal parathyroid glands as seen during a thyroid Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.

History of Hyperparathyroidism

Parathyroid glands, “the last major organ to be recognized in man,” were discovered in 1880 by a Swedish medical student, Ivar Sandstrom. However, the first-ever reference to the parathyroid gland was made in 1850 by Sir Richard Owen during the postmortem examination of a rhinoceros that died prematurely at the London Zoo.[1] Later, von Recklinghausen noted the relationship of the parathyroid glands to fibrocystic bone disease in 1891 (with the description of von Recklinghausen disease). Mandl reported the first successful removal of a parathyroid adenoma in 1925 in Vienna.[2] The patient had bone pain, osteitis fibrosa cystica, and calcium sediment in the urine.

The first reported removal of a parathyroid adenoma in the United States occurred in Massachusetts in 1926. The patient required 6 operations over 7 years until a substernal parathyroid adenoma was removed. Prior to 1932, all patients with hyperparathyroidism presented with osteitis fibrosa cystica. Before this relationship became clear, osteitis fibrosa cystica was thought to be a bone disease that caused parathyroid enlargement.

In 1934, Albright noted that nearly 80% of patients with osteitis fibrosa cystica had either renal stones (nephrolithiasis) or nephrocalcinosis.[3] For the subsequent 30 years, renal stones were considered the hallmark of hyperparathyroidism. Gout (due to hyperuricemia) and pseudogout (due to calcium phosphate crystals in the joints) were also commonly found. A relationship with peptic ulcer disease and pancreatitis was discovered in 1946.

These early concepts and surgical cures led to a detailed knowledge of calcium metabolism, pathophysiology of parathyroid hormone (PTH) and its many systemic manifestations, and the role of renal disease in secondary hyperparathyroidism, which has been further refined. Advances in imaging and surgical technique have elevated the current level of expertise in the management of simple and complex cases of hyperparathyroidism.

Problem

Hyperparathyroidism is a condition caused by excessive, inappropriate, and uncontrolled secretion of PTH by one or more parathyroid glands. Increased levels of PTH affect bone, the GI tract, and the kidneys, which causes elevation of the serum calcium level, generalized bone disease, decreased serum phosphorus levels. This occurs due to increased renal excretion and decreased reabsorption of calcium, and increased excretion of phosphorus. A variety of systemic conditions that involve various tissues result from changes in serum calcium and phosphorus levels. Skin, tendons, muscles, soft tissue, kidneys, eyes, nervous system, gut, and vascular systems can be involved.

A single adenoma causes primary hyperparathyroidism in most patients (80-90%). Multiple adenomas can occur, and diffuse hyperplasia can develop in one or more glands. Secondary and tertiary hyperparathyroidism are observed in patients with chronic renal disease and represent different diagnostic and treatment challenges. Parathyroid carcinoma may occur in 0.1-1% of patients with hyperparathyroidism. Hereditary hyperparathyroidism requires additional knowledge of the mode of genetic transmission as well as the different pathophysiologies and treatment modalities required for these sometimes very difficult clinical conditions.

The incidence of multigland disease is uncertain and varies based on the criteria used to define the condition. Certainly, a number of hereditary conditions can involve all parathyroid tissue. In nonhereditary conditions, the incidence can vary from 5-33%.[4] A study at the University of Miami reported that during 4-gland exploration, 10% of cases had multigland disease based on size, but only 3% had multigland disease when hormone secretion was measured.

Surgical treatment of hyperparathyroidism requires a thorough understanding of the pathophysiology of the disease and the embryologic basis of parathyroid gland surgical anatomy. The number of glands in any individual may vary, and the surgical anatomy may be inconsistent. Ectopic and extra glands present special challenges to the surgeon during exploration for primary hyperparathyroid. Chronic renal disease adds an additional level of complexity to the management of hyperparathyroidism and requires close and careful collaboration with the treating nephrologist.

Epidemiology

Frequency

Age-adjusted incidence of primary hyperparathyroidism was estimated to be 42 per 100,000 in an epidemiologic study in Minnesota over a 10-year period.

Hyperparathyroidism is most common between the fifth and seventh decades of life; the incidence is known to increase in persons older than 50 years. Hyperparathyroidism is 2-4 times more common in women than in men and is rare in children. In selected older populations, the prevalence of the disease may be as high as 1 in 1000 to 1 in 200. Approximately 100,000 new cases of hyperparathyroidism are reported in the United States annually.

Etiology

The etiology of hyperparathyroidism in sporadic cases is unknown; however, hereditary aspects of the disease have been identified. Details of the disorders, related conditions, and treatment considerations are discussed below.

In studies that screened for thyroid disease in patients with previous head and neck irradiation, the number of patients with primary hyperparathyroidism was found to be increased. As in thyroid disease, the latency period for the development of hyperparathyroidism ranges from 20-45 years after radiation is administered.

Secondary hyperparathyroidism (better termed renal hyperparathyroidism) and tertiary hyperparathyroidism are seen in chronic renal insufficiency and represent, in part, a physiologic response to a lack of vitamin D. Renal conversion of vitamin D to its active form is reduced in persons with chronic renal failure. In addition, elevated serum phosphorus levels due to reduced renal function (lowered excretion of phosphorus) and lowered serum calcium levels further stimulate PTH production. Some dialysis solutions may contain little or no inorganic phosphate, which causes some phosphate loss during dialysis and a decline in serum phosphate levels.

Serum hyperphosphatemia is a potent stimulus for PTH production in renal failure (PTH ordinarily increases phosphate secretion when renal function is not impaired) and results in diffuse parathyroid hyperplasia of renal hyperparathyroidism. Tertiary hyperparathyroidism[5] is a condition in which unregulated PTH is produced in persons with progressive renal disease after parathyroidectomy has been performed for renal hyperparathyroidism. Autonomous hypercalcemic hyperparathyroidism can develop following a period of hypocalcemia after parathyroidectomy.

Hereditary hyperparathyroidism

Although cases of sporadic hyperparathyroidism are idiopathic and the etiology remains unknown, heredity plays an important role in familial hyperparathyroid disorders. Identifying conditions caused by genetic conditions is extremely important since the treatment differs from that used in patients with primary or secondary hyperparathyroidism.

Although primary hyperparathyroidism occurs sporadically, the familial disorders can occur with relatively high penetrance (approaching 95% in multiple endocrine neoplasia, type 1 [MEN1]).

The following facts originated in 2 landmark articles on the subject of familial and hereditary hyperparathyroid disorders.[6] These articles contain many more details about these conditions, but the extensive discussion has been summarized below for easy reference.

Stephen Marx, MD, of the National Institutes of Health (NIH) presented a detailed analysis of hereditary hyperparathyroidism disorders at a symposium on parathyroid disorders sponsored by the New York Head and Neck Society in March of 2005.

The following are definitions of hereditary hyperparathyroid disorders:

  • MEN1 -Multiple endocrine neoplasia, type 1 (previously Wermer syndrome); tumors of parathyroid, pituitary, and pancreas

  • MEN2A -Multiple endocrine neoplasia, type 2A (previously Sipple syndrome); medullary carcinoma of the thyroid, adrenal pheochromocytoma, and parathyroid tumors

  • HPT-JT - Hyperparathyroidism, jaw tumor syndrome

  • FIHPT - Familial isolated hyperparathyroidism

  • ADMH - Autosomal dominant mild hyperparathyroidism or familial hypercalcemia with hypercalcuria

  • FHH - Familial hypocalciuric hypercalcemia

  • NSHPT - Neonatal severe hyperparathyroidism

Importance of the CASR gene

Mutations of CASR (calcium receptor set gene) play a major role in ADMH, FHH, and NSHPT. CASR alters parathyroid sensitivity to elevated serum calcium levels and alters the serum calcium set level. The mutation of the CASR gene occurs at its cytoplasmic tail. The phenotypic features include hypercalcemia, elevated parathyroid hormone and magnesium levels, relative hypercalcuria and often nephrolithiasis or nephrocalcinosis. FHH is the syndrome with the mildest manifestations of the mutation. Although persons with FHH are hypercalcemic at birth, their urinary calcium level is normal, and little long-term morbidity develops. Parathyroidectomy is generally not indicated. However, persons with familial hyperparathyroid syndromes who have mutations of the CASR gene (ie, NSHPT) may require radical total or subtotal parathyroidectomy.

Table 1. Genetics, Findings, and Associated Conditions (Open Table in a new window)

Disorder

Inheritance

Gene

Chromosome

Penetrance and Findings

Associated

Conditions and

Cancers

MEN1

Autosomal

dominant

MEN1

11q13

90% penetrance,

multiple glands

Pituitary,

neuroendocrine,

pancreatic tumors;

foregut carcinoid

MEN2A

Autosomal

dominant

RET

10q21

Low penetrance, (approximately 20%),

usually single adenoma,

may be multiglandular

Medullary carcinoma

thyroid (C-cell)

pheochromocytoma

HPT-JT

Autosomal

dominant

HRPT2

1q21-q32

Cystic parathyroid

tumors, 15% risk of CA

Jaw tumors, renal

lesions

FIHPT

Autosomal

dominant

Autosomal

dominant

HRPT2

MEN1

1q21-q32

11q13

Adenoma, multiglandular

Adenoma, multiglandular

...

ADMH

Autosomal

dominant

CASR

3q13-q21

Multiglandular adenoma

...

FHH

...

CASR

heterozygous

3q13-q21

Mildly hyperplastic

Mildest form of

hyperparathyroidism

NSHPT

...

CASR

homozygous

3q13-q21

Markedly hyperplastic

Severest form of

hyperparathyroidism,

very high PTH level,

severe

hypercalcemia

 

Pathophysiology

In hyperparathyroidism, the release of excess PTH primarily causes hypercalcemia because of its direct effect on receptors in bone, the intestine, and the kidneys. Elevated ionized serum calcium levels suppress PTH production in the physiologic state. This negative feedback loop is inactive in the presence of an adenoma or glandular hyperplasia; therefore, PTH hypersecretion continues in the presence of hypercalcemia. Resorption of calcium from bone and increased absorption from the gut are direct effects of elevated PTH levels.

In nonhyperparathyroid hypercalcemia such as paraneoplastic syndromes, compensatory renal and intestinal loss of calcium occurs. This compensation is inoperative in the presence of elevated PTH levels, compounding the hypercalcemic state. As the serum calcium level approaches 12 mg/dL, renal tubular reabsorption of calcium is exceeded and hypercalciuria develops. Although this is of some aid in reducing serum calcium levels, the incidence of nephrolithiasis and nephrocalcinosis increases, which may eventually lead to reduced creatinine clearance and renal failure. Excess extracellular calcium may be deposited in the soft tissues, causing painful calcified nodules in skin, subcutaneous tissue, tendons (calcific tendonitis), and cartilage (chondrocalcinosis).

Vitamin D plays an important role in calcium metabolism because its presence is required for the actions of PTH on its target organs. Body stores of vitamin D may rapidly become exhausted in the hyperparathyroid state, which may reduce the level of circulating calcium. Vitamin D metabolism is disrupted further in chronic renal disease, which inhibits calcium absorption from the GI tract. Progressive depletion of calcium from bone by PTH and the reduced GI absorption from the gut lead to osteomalacia and advanced osteitis fibrosa cystica, which is rarely seen today.

The role of serum and urinary phosphate is also important. PTH decreases renal tubular reabsorption and increased secretion of phosphate, leading to hyperphosphaturia and decreased serum phosphate levels. Hypophosphatemia can worsen the hypercalcemia by increasing the production of the active form of vitamin D in the kidney.

Effects of elevated serum ionized calcium are:

See the list below:

  • Central nervous system - Mental alterations, impaired memory, emotional instability, depression, sleepiness, and coma

  • Neuromuscular - Proximal muscle weakness, joint and muscle pain due to calcium deposition, pruritus, and abnormal leg movements during sleep

  • Gastrointestinal - Peptic ulcer, pancreatitis, nausea, vomiting, reflux, and loss of appetite

  • Renal - Kidney stones, polyuria, nocturia, and renal failure with uremia

  • Cardiovascular - Hypertension, left ventricular hypertrophy unrelated to hypertension[7]

  • Eye – Conjunctivitis, band keratopathy

  • Skin – Pruritus

Presentation

Currently, a routine blood analysis that detects an elevation of serum calcium levels identifies most cases of primary hyperparathyroidism. (Serum calcium levels were first measured in 1909.) These patients are, for the most part, asymptomatic or may have vague nonspecific symptoms such as weakness and fatigue. When the disease is detected late in its course, the related signs and symptoms are directly attributed to hypercalcemia, increased urinary calcium levels or bone changes, and, specifically, osteitis fibrosa cystica (now rare). In 1957, Walter St Goer first described the mnemonic to note the triad of "stones, bones, and abdominal groans" in persons with hyperparathyroidism. Today's mnemonic may be better stated as "stones, bones, groans and psychological overtones". Prior to the 1970s, the diagnosis was most often made based on the presentation of bone disease and other late manifestations.

Normocalcemic hyperparathyroidism[8] is present in approximately 20% of patients with hyperparathyroidism. This group of patients has normal serum calcium levels in the presence of an elevated parathyroid hormone level. It is generally believed these patients have a milder form of hyperparathyroidism and a milder elevation of PTH. In addition, patients with normocalcemic hyperparathyroidism may be manifesting bone and renal tubular resistance to the normal actions of PTH. When normocalcemic and hypercalcemic patients are matched on the basis of serum PTH concentration, age, and sex, the normocalcemic group has the following:

  • Lower urinary calcium excretion

  • Lower renal tubular calcium absorption

  • Less bone turnover

  • Lower plasma 1,25 dihydroxyvitamin D levels

  • Higher renal phosphate thresholds

In addition, since many patients with primary hyperparathyroidism are postmenopausal females, it has been suggested that estrogen deficiency may play a role in unmasking hypercalcemia.

Renal (secondary) hyperparathyroidism develops in patients with chronic renal disease and dramatic elevations of the PTH level (usually >1000 pg/mL and, at times, >3500 pg/mL), normal or low serum calcium levels, marked bone demineralization related to renal osteodystrophy, soft tissue calcifications, and intense pruritus. These patients may experience severe bone and joint pain and painful calcifications in soft tissue and tendons. Serum phosphate levels rise in these patients as calcium levels drop, a potent stimulus for PTH production. The renal disease inhibits renal production of vitamin D. Aluminum can reach toxic levels in bone if it is present in the dialysate, compounding the osteomalacia and further stimulating PTH production.

Tertiary hyperparathyroidism presents similarly to secondary hyperparathyroidism, with pain and PTH elevations in patients who have had near-total parathyroidectomy in the past. The remaining gland may begin to function autonomously after parathyroidectomy. Progressive hyperphosphatemia of renal disease stimulates PTH, which causes hypercalcemia.

Parathyroid carcinoma is rare (0.1-1%) and often presents with serum calcium levels greater than 14 mg/dL, markedly elevated serum PTH levels, and a palpable mass in the neck, which is semifixed to the adjacent neck structures. The palpable mass is the major sign that suggests the preoperative diagnosis.

Cystic parathyroid adenoma may also present as a palpable neck mass and is diagnosed by ultrasound and needle aspiration of the fluid, which reveals extremely high PTH levels.

In the past, when hyperparathyroidism was discovered in an advanced state, significant bone disease was usually present. Prior to 1932, all patients with hyperparathyroidism had osteitis fibrosa cystica, the hallmark of the disease. For the subsequent 30 years, renal stones were the most common finding. In that era, brown tumors, osteoclastomas, and bone cysts were frequently seen. Subperiosteal bone resorption was often observed radiographically. In 1937, Albright described jawbone manifestations of hyperparathyroidism, which include fibrous osseous dysplasia, cystic bone lesions, and giant cell lesions.[3] Hyperparathyroidism has been demonstrated to occur in 5-10% of patients with fibrous dysplasia.

Indications

Indications for surgery in primary hyperparathyroidism

Surgery is recommended for patients who have one or more of the following indications:

  • Bone pain

  • Depression

  • Gastric symptoms

  • Serum calcium levels greater than 11.4 mg/dL

  • Creatinine clearance reduced by 30%

  • A 24-hour urinary calcium excretion of more than 400 mg

  • Bone mass of more than 2 standard deviations less than that of age, race, and sex-matched controls

Surgery is also indicated for patients who are not expected to comply with periodic follow-up appointments, who find retesting inconvenient, and who request surgery. Surgery is also the treatment of choice in younger persons (< 50 y) because of the potential risk of bone demineralization over ensuing decades.

Primary hyperparathyroidism

Parathyroidectomy is indicated in the presence of such manifestations of hyperparathyroidism as stones and bone disease, pancreatitis, peptic ulcer, muscle weakness, fatigue and changes in mental status. Surgery is also indicated when the serum calcium level exceeds 11.4 mg/dL. However, even patients with early asymptomatic hyperparathyroidism who have minimally elevated serum calcium levels can obtain metabolic benefit from early surgical intervention.

Currently, most cases of primary hyperparathyroidism are discovered during routine screening, and the individuals are relatively asymptomatic; serum calcium levels may be mildly elevated (10-11.5 mg/dL), depending on the serum albumin levels. Upon further questioning, these patients often admit to fatigue and muscle weakness or pain in bones or joints. Early surgery in these patients is indicated if they develop progressive hypercalcemia, renal calculi, or osteitis fibrosa.

Serum calcium levels, parathyroid hormone (PTH) levels, and bone density can be evaluated biannually in patients who remain asymptomatic or who are poor surgical candidates. Surgery becomes an option for these patients when periodic retesting is inconvenient or impossible, or when the patient's emotional well-being becomes a factor. The NIH consensus conference statement in 1991 recommended surgery for asymptomatic patients with markedly elevated serum calcium levels, low bone density, reduced creatinine clearance, and hypercalciuria (>400 mg in 24 h) who were age 50 years or younger and who had inadequate follow-up care.[9]

Indications for surgery in renal hyperparathyroidism

Indications for parathyroidectomy in patients with renal (secondary) hyperparathyroidism are bone pain, intractable pruritus, soft tissue calcifications, and, occasionally, calciphylaxis in the presence of elevated PTH and serum calcium levels. In most patients, whether to perform subtotal or total parathyroidectomy with reimplantation depends on the comfort level of the nephrologist who manages the postoperative hypoparathyroidism.

Tertiary hyperparathyroidism

Indications for surgery in patients with tertiary hyperparathyroidism are the same as for those with secondary hyperparathyroidism; however, since subtotal parathyroidectomy was already performed, completion parathyroidectomy is necessary.

Relevant Anatomy

In most patients with primary hyperparathyroidism, the surgical procedure, in experienced hands, should be straightforward, uncomplicated, and swift. If the adenoma has been localized preoperatively, the appropriate quadrant is explored and the specimen removed. Frozen section can be requested if necessary.

A detailed knowledge of the embryology of parathyroid glands is helpful when only 3 normal glands have been found and the pathologic gland has not been located. The development of the parathyroid glands and thymus gland is specifically related to the embryology of the third and fourth branchial arches. Since the 2 inferior parathyroid glands are derived from the third branchial arch, they are pulled caudally with the migrating thymus in the fifth week of development and may descend into the mediastinum. If an adenoma is suspected in a lower gland that has not been found, it is probably located in the superior mediastinum or thymus. Occasionally, the lower gland can be located as low as the aortic arch. Parathyroid adenomas occur in the inferior glands twice as often as in the superior glands.

The location of the superior parathyroid glands is more variable. At times, they can even be located inferior to the inferior glands and have been identified in locations between the skull base and the aortopulmonary window in the posterior mediastinum. A missing superior gland, derived from the fourth branchial arch, is embryologically related to the cricothyroid muscle, pharyngeal constrictors, and superior laryngeal nerve, since the superior gland is embryologically located in the wall of the pharynx.

Since the fourth arch vessel is the common carotid artery, the ectopic superior gland may be located in the retroesophageal space, posterior mediastinum, or retropharyngeal areas (if still attached to the pharynx) or within the carotid sheath. This knowledge is also useful when 4 normal glands have been identified and the adenoma remains at large, necessitating exploration of an ectopic site to locate the missing adenoma. It may also be located within the posterior thyroid capsule or the parenchyma of the thyroid lobe, requiring hemithyroidectomy.

In straightforward cases, an inferior adenoma is quickly identified relatively superficially in the space just lateral to the veins at the inferior thyroid pole. The most common location of the inferior gland is caudal to the inferior thyroid artery (ITA) and medial and anterior to the recurrent laryngeal nerve (RLN). The superior gland is typically located on the undersurface of the thyroid lobe superior to the ITA and lateral to the plane of the RLN.

Contraindications

Surgery is complex and may be contraindicated in patients with certain familial parathyroid disorders.

 

Workup

Laboratory Studies

See the list below:

  • Diagnosis is made based on hypercalcemia and elevated parathyroid hormone (PTH) levels. Other abnormal laboratory findings may include elevated BUN and creatinine levels, hyperchloremic acidosis, reduced serum bicarbonate levels due to renal bicarbonate casting, hypophosphatemia, elevated alkaline phosphatase levels and hypercalciuria.

  • Other causes of hypercalcemia (eg, paraneoplastic syndromes, malignancies, Paget disease, drug-induced causes, dietary causes) are not associated with PTH level elevation. However, occasionally, primary hyperparathyroidism and malignancy-related hypercalcemia may coexist.

Imaging Studies

See the list below:

  • The importance of preoperative localization studies can substantially reduce operative time, cost, and patient morbidity. This is important in the era of managed care and operating room cost containment. Without preoperative localization, a parathyroid adenoma is successfully identified and removed in more than 95% of patients, although this may require exploration of all 4 glands.

  • Accurate localization can limit exploration to the identified side, allowing rapid removal of the adenoma. If a second adenoma is present, both adenomas are frequently identified with preoperative ultrasonography and sestamibi scan, even if the lesion is in an ectopic location. Localization may not reduce the need for a later reexploration for a mediastinal adenoma. A list of noninvasive imaging modalities and their usefulness and ease of performance appears below, in order of increasing cost, as follows:

    • High-resolution ultrasonography: In the hands of an experienced ultrasonographer, this method is the most economic and may provide maximum information. It shows enlarged parathyroid glands and their relationship to relevant neck anatomy, thyroid nodules, and lymph nodes. High-resolution ultrasonography can reveal multiple adenomas, hyperplasia of all 4 glands, and glands in ectopic cervical locations such as within the carotid sheath or thyroid. However, high-resolution ultrasonography can not identify mediastinal adenomas.

    • Technetium-99m labeled sestamibi scan

      • This nuclear material has a specific affinity for abnormal parathyroid tissue. Although uptake also occurs in thyroid tissue, technetium-99m rapidly diminishes in the thyroid but is retained in the parathyroid mitochondria.

      • Sestamibi scan is useful in identifying single and multiple parathyroid adenomas and hyperplasia. Sestamibi also can reveal ectopic glands.

      • Although sestamibi is most often used preoperatively, it can also be used intraoperatively. Intrathoracic adenomas can also be identified despite the overlying sternum. A sestamibi scan that fails to reveal an adenoma in a patient with hypercalcemia and elevated PTH levels may suggest diffuse hyperplasia of all 4 glands or the presence of an adenoma that has a cell population that consists mainly of chief cells.

      • Although sestamibi is very sensitive with single adenomas, it fails to reveal 17% of second adenomas and 55% of hyperplastic glands. The outcome of the sestamibi scan is most influenced by the size of the adenoma; scans of lesions less than 2 cm in size are often difficult to interpret. Since sestamibi is concentrated in mitochondria, the sensitivity of sestamibi has histopathologic considerations that vary by the predominant cell type within the adenoma.

      • Adenomas that are rich in Oxyphil cells have a higher mitochondrial content, greater metabolic activity, and increased radiotracer uptake. Adenomas that are predominantly chief cells have minimal mitochondrial content and minimal radiotracer uptake.

    • CT scan: CT scanning provides excellent spatial resolution and greater detail than the images obtained in a single plane. CT scans can be reconstructed for additional views. The location of an enlarged gland can be precisely defined in relation to adjacent anatomy. CT scan is helpful in locating mediastinal adenomas as well.

    • MRI: MRI provides excellent contrast resolution; images can be formatted in multiple planes (ie, axial, coronal, sagittal). Increased vascularity of the adenomas is ideal for identification with this modality. MRI may be useful in locating mediastinal adenomas.

  • Combination of ultrasonography and sestamibi scan provides maximum information and is cost effective.

  • CT scan or MRI for mediastinum adenomas may be required when an adenoma is suspected in the thorax.

Histologic Findings

In primary hyperparathyroidism, the adenomas represent true neoplasms. Diffuse hyperplasia occurs in the absence of an adenoma. Hyperplasia of all 4 glands is often dramatic in renal (secondary) hyperparathyroidism with significantly increased gland volumes and weights.

Frozen section differentiation of an adenoma from hyperplasia is difficult for the pathologist. In the operating room, the surgeon primarily wishes to know that the specimen contains parathyroid tissue. An adenoma can be identified on permanent section if the surrounding halo or rim of fat is visible along with certain cellular characteristics. An experienced surgeon can usually identify an adenoma in situ based on its size and color as compared with a normal parathyroid gland, lymph node, or globule of fat.

 

Treatment

Medical Therapy

Controversy exists regarding the need and timing of surgery in asymptomatic patients who have slow progressive parathyroid disease. If patients are to be medically observed, the potential renal and bone disease should be periodically assessed.

In patients who are not candidates for surgery, ultrasound-guided alcohol ablation and angiographic embolization are considerations.

Medical management of hyperparathyroidism is generally reserved for patients with poor medical conditions, advanced age with mild hypercalcemia, no evidence of dementia, and no significant bone demineralization. Serum calcium levels should be only mildly elevated, and renal status, bone density, and bone mass should be normal. Severe hypercalcemia (> 14mg/dL) may be a medical emergency, and the initial treatment requires intravenous saline infusions, diuresis, calcium binders and bisphosphonates.) Medical follow-up care may also be indicated when neck exploration has not been successful.

Medical follow-up care should include biannual measurements of serum calcium levels, parathyroid hormone (PTH) levels, and bone mass, as well as assessment of renal status. Ask patients specifically about symptoms of weakness, fatigue, and depression.

Surgical Therapy

The surgical procedure selected to remove the pathologic gland or glands depends on the philosophy and experience of the surgeon and the nature of the disease in each patient.[10] A focused parathyroidectomy is effective in most cases; however, some controversy exists regarding the following procedures:

  • Unilateral versus bilateral explorations in patients with primary hyperparathyroidism

  • Total parathyroidectomy versus seven-eighth parathyroidectomy in patients with chronic renal failure or diffuse, nonrenal hyperplasia.

Intraoperative Details

Adenoma and hyperplasia

Parathyroid adenomas vary in size and shape and are often bilobed. A halo of fat, at least at one pole, usually surrounds parathyroid adenomas and aids in identification. The gland often turns red-brown when manipulated, probably because of vasospasm of its feeding artery.

Classical surgical approach

This technique was most often performed between 1930 and 1960. The standard, time-honored (but dated) approach uses a typical thyroidectomy collar incision with wide exposure. The upper and lower subplatysmal flaps are raised, and the anterior cervical veins are not ligated and are left on the anterior surface of the strap muscles. The strap muscles are separated in the midline, exposing the thyroid isthmus. On the side to be dissected, the area lateral to the inferior thyroid veins is explored first, and an inferior adenoma is often visible with minimal dissection. If an inferior adenoma is not visible, the lateral aspect of the thyroid lobe is rotated anteromedially and the superior gland is usually seen on the posterior superior surface of the lobe. When present, the middle thyroid vein may require ligation.

The inferior thyroid artery (ITA) is identified just medial to the carotid artery, and a vessel loop is placed on the ITA. The artery is followed medially, and the recurrent laryngeal nerve (RLN) is always identified passing either over or under the artery. With careful dissection, the distal branches of the artery can be seen feeding each normal or pathologic parathyroid gland. Before the gland is removed, the RLN is followed to its point of entry into the cricothyroid membrane. Bleeding is usually minimal with this technique; minimal bleeding is controlled with bipolar cautery. The distal arterial branches are tied, when necessary.

Once the adenoma has been removed and sent for frozen section diagnosis of parathyroid tissue, the ipsilateral gland is identified. If the gland appears normal, it is not disturbed. If the gland is enlarged, biopsy is performed, and the specimen sent to confirm the presence of hyperplasia. If both glands are found to be hyperplastic, the opposite side of the neck is explored. If the 2 contralateral glands are confirmed as hyperplastic, most surgeons perform either a seven-eighth parathyroidectomy or a total parathyroidectomy with autotransplantation of a small fragment into forearm musculature for easy access in the future.

General endotracheal anesthesia was standard. Operative time was longer since a bilateral exploration was done. A postoperative drain was routinely used and an overnight stay was typical.

Minimally invasive approach (targeted parathyroidectomy, focused parathyroidectomy, selective parathyroidectomy)

This technique became popular in the 1990s and is most often used today. This approach was pioneered by the noted Norman Parathyroid Center in Tampa, Florida. A small transverse incision is placed in the lower neck, in the midline, or off the midline on the side of the adenoma. Both ipsilateral parathyroid glands can be reached through a small incision off the midline incision with aggressive retraction. A bilateral exploration can be performed through the small midline incision. The dissection is minimal and exposure may be limited. The amount of dissection may be further reduced if intraoperative PTH monitoring or intraoperative radioguidance is used. In the off-midline approach, instead of separating the strap muscles in the midline, the lateral aspect of the sternothyroid and sternohyoid muscles are separated from the medial border of the sternocleidomastoid muscle. The carotid sheath is exposed and the adenoma removed.

This approach can easily be performed with laryngeal mask anesthesia or under local anesthesia with intravenous sedation in carefully selected patients. This approach has been proven to be safe in adult patients of all ages, including elderly persons.[11] Morbidity is reduced. A drain is not required. Operative time is further reduced, and often the patient can be discharged from the same-day unit or postoperative care unit within an hour or 2 after surgery, even in morbidly obese patients. Preoperative loading and postoperative administration of oral calcium citrate makes postoperative hypocalcemia extremely unlikely.[12]

There is no learning curve for this technique in the hands of an experienced parathyroid surgeon.

In 2009, the Norman Parathyroid Center presented their findings and recommendations regarding unilateral and bilateral exploration in primary hyperparathyroidism.[13] That center is devoted to parathyroid surgery and performs 1800 parathyroidectomies per year (13/day, 3 days/wk). They have a first-operation cure rate of 99.5%. They reviewed 3000 consecutive primary parathyroid operations over a 20-month period and listed 18 objective factors that influence the decision for unilateral versus bilateral surgery. Their surgical approach is worth noting and includes the following:

  • Laryngeal mask anesthesia (no endotracheal intubation)

  • No use of local anesthesia

  • Propofol and midazolam as priming agents

  • No recurrent laryngeal monitoring

  • Two- to 2.5-cm midline horizontal incision in the lower neck

  • All operations take place within 2 hours of sestamibi scanning on the morning of surgery (no preoperative scanning).

  • Ultrasound is not performed (but may have been performed by the referring endocrinologist).

  • No intraoperative PTH monitoring is performed.

  • The gamma probe is used ex vivo and is not used in the wound; any gland that is physiologically overactive is marked for removal. Abnormal activity by the probe is the only criterion used for gland removal.

  • No frozen sections are performed.

  • At least 2 glands are always assessed and a biopsy specimen it taken from the ipsilateral gland for permanent section.

  • Ipsilateral thyroid abnormalities are always examined and pathology is removed.

  • If a unilateral exploration becomes a bilateral exploration, the operative time increases by only 5 minutes.

  • All patients are discharged from the recovery room.

Using these techniques, 21% of patients had more than 1 gland removed, most commonly a second adenoma (9.8%), followed by a clinically enlarged, nondormant gland (9.3%), followed by 4-gland hyperplasia (2.1%), followed by 3 adenomas (0.6%). They achieved a 99.9% cure rate, which could never be obtained with a focused, single-gland exploration. There were certain preoperative criteria that always indicated a bilateral exploration. The most common were the following:

  • Multiple endocrine neoplasia syndromes

  • Teenagers (high risk of multiple adenomas)

  • Familial hereditary hyperparathyroidism

Renal (secondary) hyperparathyroidism

Generally, but not always, diffuse hyperplasia of all 4 glands is present. The glands may be voluminous and weigh in excess of 100 grams. The classic surgical approach is used. Each RLN is identified. All abnormal parathyroid tissue is removed. When fewer than 4 glands are hyperplastic, the normal sized glands may be left intact. When 4 large hyperplastic glands are removed, a small fragment of one gland may be reimplanted into a forearm muscle or strap muscle. The treating nephrologist often prefers reimplantation in order to preserve some parathyroid function. Total postoperative hypoparathyroidism is more debilitating and more difficult to medically manage than an autotransplanted patient with a small fragment of revitalized parathyroid tissue.

Tertiary hyperparathyroidism

In patients with tertiary hyperparathyroidism, the residual tissue or adenoma is usually identified preoperatively with ultrasonography and sestamibi scan, allowing rapid access to the involved area. Scarring from prior surgery can be problematic and may place the RLN at risk of iatrogenic injury. The surgical approach in this situation is to proceed to the localized site immediately and to remove the lesion with as little dissection as possible. The RLN may not be routinely exposed, especially if severe scarring is present from prior surgery. This surgery usually removes all remaining parathyroid tissue and results in permanent hypoparathyroidism.

Parathyroid carcinoma

When the rare parathyroid carcinoma is encountered, the goal is wide local excision with selective neck dissection, which allows removal of metastatic nodal disease and all involved soft tissues. The mass is usually large, gray-white, and locally invasive. Aggressively removing the mass, along with the ipsilateral thyroid gland and adjacent soft tissue, is required. Postoperative radiotherapy may be necessary in cases with residual tumor. Patients with recurrent parathyroid carcinoma can be identified based on rising PTH levels.

Familial parathyroid disorders

As mentioned above, the hereditary parathyroid disorders require an advanced knowledge of the genetics of transmission, associated conditions, and special treatment considerations (see Table 2).

Table 2. Surgical Therapy in Patients With Hereditary Parathyroid Disorders (Open Table in a new window)

Disorder

Dominant Feature

Treatment

Notable Facts

MEN1

 

Hyperparathyroidism

Total parathyroidectomy with search

for ectopic

supernumerary glands;

transcervical

thymectomy;

autotransplantation

Recurrence inevitable

MEN2A

Medullary carcinoma

Removal of single

adenoma,

normal-appearing

glands left in situ

Milder

hyperparathyroidism;

often asymptomatic

HPT-JT

Severe hypercalcemia;

cystic parathyroid tumors

Uniglandular but

total parathyroidectomy

(may reduce risk of cancer)

Only 30 families

reported; 15% risk of

carcinoma

FIHPT

...

Complex

management.

Single adenoma treated with resection;

multiglandular disease treated with subtotal parathyroidectomy

Linked to MEN1 gene,

HRPT gene and CASR

gene mutation

ADMH

...

Subtotal parathyroidectomy

CASR mutation

FHH

Usually asymptomatic;

hypercalcemia at birth but little long-term

morbidity

No benefit from

parathyroid surgery

of mildly enlarged

glands; total parathyroidectomy with autotransplantation for severe forms

CASR mutation

NSHPT

Very high PTH level, severe

hypercalcemia

Total parathyroidectomy within first

months of life (condition often lethal)

CASR mutation

Ancillary intraoperative tools

See the list below:

  • Intraoperative rapid PTH monitoring (i-PTH): Although intraoperative rapid PTH monitoring is not necessary for routine cases in which the location of the adenoma is preoperatively known, it may have special value in reexplorations and when a second adenoma is suspected. The chemoluminescent immunoreactive technique has demonstrated PTH to have a half life of 3-5 minutes. The circulating PTH level has been shown to be reduced by 50% within 10 minutes following successful removal of an adenoma. Additional equipment, time, and expense are necessary. A venous baseline sample is taken prior to the skin incision and then at 5 and 10 minutes after specimen removal. The turnaround time for results, in the best of hands, is 10-15 minutes.

  • Intraoperative total serum calcium monitoring: In all cases, the serum calcium level has been shown to drop within 5 minutes of successful removal of a parathyroid adenoma. Calcium monitoring is less expensive than i-PTH monitoring and is readily available in all hospitals.

  • Intraoperative sestamibi radiomonitoring (gamma probe):[14] Minimally invasive radioguided parathyroidectomy requires that surgery be performed within 1.5-3 hours after the injection of sestamibi so that the adenoma still has a high gamma emission. The hand-held probe guides the surgeon to the area of increased activity. The excised specimen still emits radioactivity greater than 20% of the background check.

  • Endoscopic parathyroidectomy

    • The pure endoscopic approach requires preoperative localization of a single adenoma. The technique is contraindicated in patients with a history of prior neck surgery, prior neck radiation, abnormal anatomy, and multigland disease. Reported complications include dramatic subcutaneous emphysema from chin to scrotum. Hypercapnia and tachycardia have also been reported. Exposure is limited and the working space is small.

    • A video-assisted technique uses carbon dioxide insufflation for only 3 minutes at the start of the procedure and begins the dissection under the strap muscles. A small skin incision (1.5 cm) in the midline is made and used to perform the parathyroidectomy on the video monitor.

    • Gasless video-assisted robotic parathyroidectomy is being performed, but reference is made to a substantial learning curve and mean exposure and docking times ranging from 31-51 minutes, which exceeds the normal time for other approaches by experienced parathyroid surgeons. This technique avoids the problems of carbon dioxide insufflation of the neck and complications related to insufflation. Robotic console times ranged from 25-105 minutes for single adenoma removal.[15]

  • Transaxillary and submammary endoscopic approaches: More reports now describe transaxillary and submammary endoscopic approaches to parathyroid disease that use laparoscopic techniques.

Postoperative Details

Monitoring of serum calcium levels and management of hypocalcemia were the traditional tasks of postoperative care. This is minimized by preoperative calcium and vitamin D loading. This author also adds calcium carbonate to the intravenous solution being administered in the operating room. In addition, modern minimally invasive techniques, even with bilateral explorations, now allow all but the most complicated patients to be discharged within hours of surgery. Prevention of a wound seroma with an appropriate closed suction drain may be necessary if bleeding has been encountered, but this is usually not necessary. The skin is approximated with a skin adhesive (Dermabond). Wound healing is delayed in patients with renal disease.

Transient hypocalcemia in patients with primary hyperparathyroidism is generally mild, and the serum calcium level slowly drops and gradually returns to normal without tetany. Oral calcium supplements may be given for a period of weeks with calcitriol (Rocaltrol) 0.25 mg 2 or 3 times per day to enhance GI absorption.

Dramatic hypocalcemia due to severe bone hunger is observed in patients with secondary and tertiary parathyroidectomy due to marked calcium depletion from bone, which is often rapidly and acutely reversed in the first few hours postoperatively in patients with chronic renal disease. Hungry bone uptake of ionized serum calcium is so swift that a continuous calcium infusion is often needed to avoid tetany. Continuous calcium infusion is required until oral calcium and vitamin D supplements begin to maintain the serum calcium levels near the reference range. Calcitriol (Calcijex) injection during dialysis is often required.

Calcitriol (the active form of vitamin D-3) injection in patients with renal disease, a population in whom treatment proves difficult, stimulates intestinal calcium absorption and aids in the treatment of chronic hypocalcemia.

Follow-up

A primary care physician or surgeon observes patients with primary hyperparathyroidism annually to monitor serum calcium levels; patients with genetic parathyroid disorders may develop a second adenoma or recurrent hyperparathyroidism.

Patients with chronic renal disease are monitored indefinitely because of the nature of their disease and its intimate relationship to kidney disease and phosphorus retention.

Complications

Transient hypocalcemia is anticipated but may be mild and without clinical signs. This is especially true if the patient is preloaded with calcium citrate and vitamin D for 1-2 weeks prior to surgery. Difficult-to-manage severe hypocalcemia can lead to tetany if not treated. Permanent hypoparathyroidism and recurrent laryngeal nerve injury are also potential complications. If the adenoma is not found or if a second adenoma is not identified, hypercalcemia will persist.

Outcome and Prognosis

Successful exploration and removal of an adenoma is curative, and the abnormal calcium metabolism is quickly reversed. However, soft tissue calcifications may resorb very slowly. Nephrolithiasis requires continued urologic management. Somatic symptoms such as fatigue, joint pain, and mental changes are often quickly eliminated. Some patients report an excellent and dramatic sense of well-being shortly after surgery.

Successful treatment of secondary and tertiary hyperparathyroidism is equally rewarding for both surgeon and patient. These patients generally feel much stronger and less depressed and are pleased with the elimination of pain from bones, joints, and soft tissue calcifications. Relief from disabling pruritus is an additional benefit.

Future and Controversies

As with all surgical modalities, improvements and refinements are always on the horizon. Although innovations may have value in specific cases, most patients with hyperparathyroidism can be successfully managed with the standard methods described above (see Treatment).

CT scan or ultrasound-guided needle localization and ablation of adenomas with alcohol may have value in elderly patients with severe hypercalcemia who are very ill and who cannot endure parathyroidectomy under local or general anesthesia.