Parathyroid

PARATHYROIDPARATHYROID

Mark Louie Lanting, MDMark Louie Lanting, MD

March 21, 2009March 21, 2009

HISTORYHISTORY

Indian rhinocerosIndian rhinoceros Ivar SandströmIvar Sandström glandulae parathyroideaeglandulae parathyroideae Felix Mandl Felix Mandl

EMBRYOLOGYEMBRYOLOGY

EMBRYOLOGYEMBRYOLOGY

EMBRYOLOGYEMBRYOLOGY Superior parathyroid glandsSuperior parathyroid glands from the from the fourth fourth

branchial pouchbranchial pouch Inferior parathyroid glandsInferior parathyroid glands and the thymus and the thymus from from

the the third branchial pouchthird branchial pouch Superior parathyroid glands – more consistent in Superior parathyroid glands – more consistent in

locationlocation 80% - near the posterior aspect of the upper and middle 80% - near the posterior aspect of the upper and middle

thyroid lobes, at the level of the cricoid cartilage. thyroid lobes, at the level of the cricoid cartilage. 1% - in the paraesophageal or retroesophageal space.1% - in the paraesophageal or retroesophageal space. Enlarged superior glands may "descend by gravity" in the Enlarged superior glands may "descend by gravity" in the

tracheoesophageal groove and come to lie caudal to the tracheoesophageal groove and come to lie caudal to the inferior glands. inferior glands.

ectopic superior parathyroid glands - rare, but may be found ectopic superior parathyroid glands - rare, but may be found in the middle or posterior mediastinum, commonly in the in the middle or posterior mediastinum, commonly in the aortopulmonary windowaortopulmonary window

EMBRYOLOGYEMBRYOLOGY As the embryo matures, the thymus and inferior As the embryo matures, the thymus and inferior

parathyroids migrate together caudally in the parathyroids migrate together caudally in the neck. neck.

Inferior parathyroid glands – more variable in Inferior parathyroid glands – more variable in position due to longer migratory pathposition due to longer migratory path most common location most common location within a distance of 1 cm from a within a distance of 1 cm from a

point centered where the inferior thyroid artery and point centered where the inferior thyroid artery and recurrent laryngeal nerve cross. recurrent laryngeal nerve cross.

15% found in the thymus. 15% found in the thymus. Undescended inferior glands may be found near the skull Undescended inferior glands may be found near the skull

base, angle of the mandible, or superior to the superior base, angle of the mandible, or superior to the superior parathyroid glands, along with an undescended thymus. parathyroid glands, along with an undescended thymus.

Intrathyroidal glands - 0.5 to 3% (upper glands Intrathyroidal glands - 0.5 to 3% (upper glands more likely)more likely)

ANATOMYANATOMY 4 parathyroid glands4 parathyroid glands

Superior glands - dorsal to the RLN at the level of the Superior glands - dorsal to the RLN at the level of the cricoid cartilagecricoid cartilage

Inferior parathyroid glands - ventral to the nerve. Inferior parathyroid glands - ventral to the nerve. Parathyroid color depends on numerous factors, Parathyroid color depends on numerous factors,

including cellularity, fat content, and including cellularity, fat content, and vascularity. vascularity. Newborns: gray and semitransparentNewborns: gray and semitransparent Adults: golden-yellow to light-brownAdults: golden-yellow to light-brown

Often embedded in and sometimes difficult to Often embedded in and sometimes difficult to discern from surrounding fat. Normal discern from surrounding fat. Normal parathyroid glands are located in loose tissue or parathyroid glands are located in loose tissue or fat and are ovoid. fat and are ovoid.

ANATOMYANATOMY Measure 5 to 7 mm in size and weigh Measure 5 to 7 mm in size and weigh

approximately 40 to 50 mg each. approximately 40 to 50 mg each. The parathyroid glands usually derive most The parathyroid glands usually derive most

of their blood supply from branches of the of their blood supply from branches of the inferior thyroid artery, although branches inferior thyroid artery, although branches from the superior thyroid artery supply at from the superior thyroid artery supply at least 20% of upper glands. least 20% of upper glands.

Branches from the thyroidea ima, and Branches from the thyroidea ima, and vessels to the trachea, esophagus, larynx, vessels to the trachea, esophagus, larynx, and mediastinum may also be found. and mediastinum may also be found.

The parathyroid glands drain ipsilaterally The parathyroid glands drain ipsilaterally by the superior, middle, and inferior by the superior, middle, and inferior thyroid veins.thyroid veins.

HISTOLOGYHISTOLOGY

Composed of Composed of chief cellschief cells and and oxyphil cellsoxyphil cells arranged in trabeculae, within a stroma arranged in trabeculae, within a stroma composed primarily of adipose cells composed primarily of adipose cells

Infants and children – mainly chief cells, which Infants and children – mainly chief cells, which produce parathyroid hormone (PTH). produce parathyroid hormone (PTH).

Adults – increase in acidophilic, mitochondria-Adults – increase in acidophilic, mitochondria-rich oxyphil cells which are derived from chief rich oxyphil cells which are derived from chief cellscells

Water-clear cellsWater-clear cells, also are derived from chief , also are derived from chief cells, are present in small numbers, and are cells, are present in small numbers, and are rich in glycogen. rich in glycogen.

PARATHYROID PARATHYROID PHYSIOLOGY & CALCIUM PHYSIOLOGY & CALCIUM

HOMEOSTASISHOMEOSTASIS Calcium is the most abundant cation in Calcium is the most abundant cation in

human beingshuman beings Extracellular calcium levels > intracellular Extracellular calcium levels > intracellular

levels levels Extracellular calcium Extracellular calcium for excitation– for excitation–

contraction coupling in muscle tissues, contraction coupling in muscle tissues, synaptic transmission in the nervous system, synaptic transmission in the nervous system, coagulation, and secretion of other hormones. coagulation, and secretion of other hormones.

Intracellular calcium Intracellular calcium important second important second messenger regulating cell division, motility, messenger regulating cell division, motility, membrane trafficking, and secretion. membrane trafficking, and secretion.

Calcium is absorbed from the small intestine Calcium is absorbed from the small intestine in its inorganic form. in its inorganic form.

Extracellular calcium (900 mg) accounts for only 1% Extracellular calcium (900 mg) accounts for only 1% of the body's calcium stores, the majority of which is of the body's calcium stores, the majority of which is sequestered in the skeletal system.sequestered in the skeletal system.

Serum calcium - range from 8.5 to 10.5 mg/dL (2.1 Serum calcium - range from 8.5 to 10.5 mg/dL (2.1 to 2.6 mmol/L) to 2.6 mmol/L) 50% in the ionized form (active component) - range from 50% in the ionized form (active component) - range from

4.4 to 5.2 mg/dL (1.1 to 1.3 mmol/L)4.4 to 5.2 mg/dL (1.1 to 1.3 mmol/L) 40% bound to albumin 40% bound to albumin 10% bound to organic anions such as phosphate and citrate 10% bound to organic anions such as phosphate and citrate

The total serum calcium level must always be The total serum calcium level must always be considered in its relationship to plasma protein considered in its relationship to plasma protein levels, especially serum albumin. levels, especially serum albumin. For each gram per deciliter of alteration of serum albumin For each gram per deciliter of alteration of serum albumin

above or below 4.0 mg/dL, there is a 0.8 mg/dL increase or above or below 4.0 mg/dL, there is a 0.8 mg/dL increase or decrease in protein-bound calcium, and thus in total serum decrease in protein-bound calcium, and thus in total serum calcium levels. calcium levels.

Total, and particularly ionized, calcium levels are Total, and particularly ionized, calcium levels are influenced by various hormone systems.influenced by various hormone systems.

PARATHYROID PARATHYROID PHYSIOLOGY & CALCIUM PHYSIOLOGY & CALCIUM

HOMEOSTASISHOMEOSTASIS

PARATHYROID PARATHYROID HORMONEHORMONE

Calcium-sensing receptor (CASR) - regulate PTH Calcium-sensing receptor (CASR) - regulate PTH secretion by sensing extracellular calcium levelssecretion by sensing extracellular calcium levels

PTH secretion also is stimulated by low levels of 1,25-PTH secretion also is stimulated by low levels of 1,25-dihydroxy vitamin D, catecholamines, and dihydroxy vitamin D, catecholamines, and hypomagnesemia. The PTH gene is located on hypomagnesemia. The PTH gene is located on chromosome 11. chromosome 11.

PTH is synthesized in the parathyroid gland as a PTH is synthesized in the parathyroid gland as a precursor hormone, precursor hormone, preproparathyroid hormone preproparathyroid hormone cleaved first to cleaved first to proparathyroid hormone proparathyroid hormone 84-84-amino-acid PTHamino-acid PTH

Secreted PTH has a half-life of 2 to 4 minutes. Secreted PTH has a half-life of 2 to 4 minutes. In the liver, PTH is metabolized into the active N-In the liver, PTH is metabolized into the active N-

terminal component and the relatively inactive C-terminal component and the relatively inactive C-terminal fraction. The C-terminal component is terminal fraction. The C-terminal component is excreted by the kidneys and accumulates in chronic excreted by the kidneys and accumulates in chronic renal failure.renal failure.

PTHPTH PTH regulates calcium levels via its actions on three PTH regulates calcium levels via its actions on three

target organstarget organs Bone Bone

Increase in resorption of bone by stimulating osteoclasts and Increase in resorption of bone by stimulating osteoclasts and promotes the release of calcium and phosphate into the promotes the release of calcium and phosphate into the circulationcirculation

Kidney Kidney limit calcium excretion at the distal convoluted tubule via an limit calcium excretion at the distal convoluted tubule via an

active transport mechanismactive transport mechanism inhibits phosphate reabsorption (at the proximal convoluted inhibits phosphate reabsorption (at the proximal convoluted

tubule) and bicarbonate reabsorptiontubule) and bicarbonate reabsorption inhibits the Na+/H+ antiporter, which results in a mild inhibits the Na+/H+ antiporter, which results in a mild

metabolic acidosis in hyperparathyroid statesmetabolic acidosis in hyperparathyroid states Gut Gut

enhance 1-hydroxylation of 25-hydroxyvitamin D, which is enhance 1-hydroxylation of 25-hydroxyvitamin D, which is responsible for its indirect effect of increasing intestinal calcium responsible for its indirect effect of increasing intestinal calcium absorption.absorption.

CALCITONINCALCITONIN Produced by thyroid C cells and functions as an Produced by thyroid C cells and functions as an

antihypercalcemic hormone by inhibiting antihypercalcemic hormone by inhibiting osteoclast-mediated bone resorptionosteoclast-mediated bone resorption..

Production is stimulated most dramatically by Production is stimulated most dramatically by calcium and pentagastrin, and also by calcium and pentagastrin, and also by catecholamines, cholecystokinin, and glucagon. catecholamines, cholecystokinin, and glucagon. produces hypocalcemia, when administered produces hypocalcemia, when administered

intravenously to experimental animals. intravenously to experimental animals. At the kidney, calcitonin increases phosphate excretion At the kidney, calcitonin increases phosphate excretion

by inhibiting its reabsorptionby inhibiting its reabsorption Calcitonin plays a minimal, if any, role in Calcitonin plays a minimal, if any, role in

the regulation of calcium levels in humans. the regulation of calcium levels in humans. Useful as a marker of medullary thyroid cancer Useful as a marker of medullary thyroid cancer

and in treating acute hypercalcemic crisis.and in treating acute hypercalcemic crisis.

VITAMIN DVITAMIN D Vitamin D refers to vitamin D2 and vitamin D3, Vitamin D refers to vitamin D2 and vitamin D3,

both of which are produced by photolysis of both of which are produced by photolysis of naturally occurring sterol precursors. naturally occurring sterol precursors.

Vitamin D2 is available commerciallyVitamin D2 is available commercially Vitamin D3 is the most important physiologic Vitamin D3 is the most important physiologic

compound and is produced from 7-compound and is produced from 7-dehydrocholesterol, which is found in the skindehydrocholesterol, which is found in the skin

Vitamin D is metabolized in the liver to its primary Vitamin D is metabolized in the liver to its primary circulating form, 25-hydroxy vitamin D circulating form, 25-hydroxy vitamin D further further hydroxylation in the kidney results in 1,25-hydroxylation in the kidney results in 1,25-dihydroxy vitamin D, which is the most dihydroxy vitamin D, which is the most metabolically active form of vitamin Dmetabolically active form of vitamin D

Vitamin D stimulates the absorption of Vitamin D stimulates the absorption of calcium and phosphate from the gut and the calcium and phosphate from the gut and the resorption of calcium from the bone.resorption of calcium from the bone.

HYPERPARATHYROIDISHYPERPARATHYROIDISMM

Hyperfunction of the parathyroid Hyperfunction of the parathyroid glands may be classified as glands may be classified as primary, primary, secondary, or tertiarysecondary, or tertiary. .

Primary hyperparathyroidism Primary hyperparathyroidism (PHPT)(PHPT) increased PTH production from abnormal increased PTH production from abnormal

parathyroid glands parathyroid glands results from a disturbance of normal results from a disturbance of normal

feedback control exerted by serum calciumfeedback control exerted by serum calcium

HYPERPARATHYROIDISHYPERPARATHYROIDISMM

Secondary hyperparathyroidism (HPT)Secondary hyperparathyroidism (HPT) occur as a compensatory response to hypocalcemic occur as a compensatory response to hypocalcemic

states resulting from chronic renal failure or states resulting from chronic renal failure or gastrointestinal malabsorption of calciumgastrointestinal malabsorption of calcium

can be reversed by correction of the underlying can be reversed by correction of the underlying problem, (e.g., kidney transplantation for chronic problem, (e.g., kidney transplantation for chronic renal failure). renal failure).

Tertiary HPTTertiary HPT Due to chronic stimulation of parathyroid glands Due to chronic stimulation of parathyroid glands

causing it to become autonomous, resulting in causing it to become autonomous, resulting in persistence or recurrence of hypercalcemia after persistence or recurrence of hypercalcemia after successful renal transplantationsuccessful renal transplantation

PRIMARY HPTPRIMARY HPT 100,000 individuals annually in the US100,000 individuals annually in the US 0.1 to 0.3% of the general population0.1 to 0.3% of the general population more common in women (1:500) than in men more common in women (1:500) than in men

(1:2000)(1:2000) Increased PTH production leads to Increased PTH production leads to

hypercalcemia via increased gastrointestinal hypercalcemia via increased gastrointestinal absorption of calcium, increased production of absorption of calcium, increased production of vitamin D3 and reduced renal calcium vitamin D3 and reduced renal calcium clearance. clearance.

Characterized by Characterized by increased parathyroid cell increased parathyroid cell proliferation and PTH secretion which is proliferation and PTH secretion which is independent of calcium levels.independent of calcium levels.

PRIMARY HPT - PRIMARY HPT - ETIOLOGYETIOLOGY

Exact cause unknownExact cause unknown Predisposing factorsPredisposing factors

exposure to low-dose therapeutic ionizing radiation exposure to low-dose therapeutic ionizing radiation familialfamilial various diets various diets intermittent exposure to sunshine intermittent exposure to sunshine Other causes: renal leak of calcium and declining renal Other causes: renal leak of calcium and declining renal

function with age, as well as alteration in the sensitivity function with age, as well as alteration in the sensitivity of parathyroid glands to suppression by calciumof parathyroid glands to suppression by calcium

Lithium therapy has been known to shift the set-point Lithium therapy has been known to shift the set-point for PTH secretion in parathyroid cells, thereby resulting for PTH secretion in parathyroid cells, thereby resulting in elevated PTH levels and mild hypercalcemia. Lithium in elevated PTH levels and mild hypercalcemia. Lithium stimulates the growth of abnormal parathyroid glands stimulates the growth of abnormal parathyroid glands in vitro, and in susceptible patients in vivoin vitro, and in susceptible patients in vivo

PRIMARY HPT - PRIMARY HPT - ETIOLOGYETIOLOGY

PHPT results from the enlargement of a PHPT results from the enlargement of a single gland or parathyroid adenoma in single gland or parathyroid adenoma in approximately 80% of cases, multiple approximately 80% of cases, multiple adenomas or hyperplasia in 15 to 20% of adenomas or hyperplasia in 15 to 20% of patients and parathyroid carcinoma in patients and parathyroid carcinoma in 1% of patients. 1% of patients.

When more than one abnormal When more than one abnormal parathyroid gland is identified parathyroid gland is identified preoperatively or intraoperatively, the preoperatively or intraoperatively, the patient has hyperplasia (all glands patient has hyperplasia (all glands abnormal) until proven otherwise.abnormal) until proven otherwise.

PRIMARY HPT - PRIMARY HPT - GENETICSGENETICS

Occur within the spectrum of a Occur within the spectrum of a number of inherited disorders such number of inherited disorders such as MEN1, MEN2A, isolated familial as MEN1, MEN2A, isolated familial HPT, and familial HPT with jaw-HPT, and familial HPT with jaw-tumor syndrome tumor syndrome autosomal autosomal dominantdominant

PRIMARY HPT – PRIMARY HPT – CLINICAL CLINICAL

MANIFESTATIONSMANIFESTATIONS "classic" pentad of symptoms "classic" pentad of symptoms

kidney stoneskidney stones painful bonespainful bones abdominal groansabdominal groans psychic moanspsychic moans fatigue overtonesfatigue overtones

With the advent and widespread use of With the advent and widespread use of automated blood analyzers in the early automated blood analyzers in the early 1970s, there has been an alteration in the 1970s, there has been an alteration in the "typical" patient with PHPT, who is more "typical" patient with PHPT, who is more likely to be minimally symptomatic or likely to be minimally symptomatic or asymptomatic.asymptomatic.

PRIMARY HPT – PRIMARY HPT – CLINICAL CLINICAL

MANIFESTATIONSMANIFESTATIONS Currently, most patients present with weakness, Currently, most patients present with weakness,

fatigue, polydipsia, polyuria, nocturia, bone and fatigue, polydipsia, polyuria, nocturia, bone and joint pain, constipation, decreased appetite, joint pain, constipation, decreased appetite, nausea, heartburn, pruritus, depression, and nausea, heartburn, pruritus, depression, and memory loss. memory loss.

Patients with PHPT also tend to score lower than Patients with PHPT also tend to score lower than healthy controls when assessed by general healthy controls when assessed by general multidimensional health assessment tools, such multidimensional health assessment tools, such as the Medical Outcomes Study Short-Form as the Medical Outcomes Study Short-Form Health Survey (SF-36), 55,56 and by other Health Survey (SF-36), 55,56 and by other specific questionnaires, such as those designed by specific questionnaires, such as those designed by Pasieka and associatesPasieka and associates

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS –

RENAL DISEASERENAL DISEASE 80% of patients with PHPT 80% of patients with PHPT Kidney stonesKidney stones were previously found in up to 80% of were previously found in up to 80% of

patients, but now occur in approximately 20 to 25%. The patients, but now occur in approximately 20 to 25%. The calculi are typically composed of calculi are typically composed of calcium phosphate or oxalatecalcium phosphate or oxalate

In contrast, primary HPT is found to be the underlying In contrast, primary HPT is found to be the underlying disorder in only 3% of patients presenting with disorder in only 3% of patients presenting with nephrolithiasis. nephrolithiasis.

Nephrocalcinosis more likely to lead to renal dysfunction. Nephrocalcinosis more likely to lead to renal dysfunction. Chronic hypercalcemia can also impair concentrating Chronic hypercalcemia can also impair concentrating

ability, thereby resulting in polyuria, polydipsia, and ability, thereby resulting in polyuria, polydipsia, and nocturia. nocturia.

Incidence of hypertension is variable ~ occur in up to Incidence of hypertension is variable ~ occur in up to 50% 50% more common in older patients more common in older patients correlate with the magnitude of renal dysfunctioncorrelate with the magnitude of renal dysfunction

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS – BONE BONE

DISEASEDISEASE Osteopenia, osteoporosis, and osteitis fibrosa Osteopenia, osteoporosis, and osteitis fibrosa

cysticacystica - found in ~15% - found in ~15% Increased bone turnover Increased bone turnover elevated blood alkaline elevated blood alkaline

phosphatase level phosphatase level Advanced PHPT and/or vitamin D deficiency leads to Advanced PHPT and/or vitamin D deficiency leads to

osteitis fibrosa cysticaosteitis fibrosa cystica, a condition that previously , a condition that previously was more common, but which now occurs in less than was more common, but which now occurs in less than 5% of patients5% of patients characterized by pathognomonic radiologic findings, which are characterized by pathognomonic radiologic findings, which are

best seen on x-rays of the hands that demonstrate best seen on x-rays of the hands that demonstrate subperiosteal resorption (most apparent on the radial subperiosteal resorption (most apparent on the radial aspect of the middle phalanx of the second and third aspect of the middle phalanx of the second and third fingers), bone cysts, and tufting of the distal phalanges fingers), bone cysts, and tufting of the distal phalanges

Skull may also be affected and appears mottled (salt and Skull may also be affected and appears mottled (salt and pepper) with a loss of definition of the inner and outer cortices. pepper) with a loss of definition of the inner and outer cortices.

Brown or osteoclastic tumors and bone cysts may also be Brown or osteoclastic tumors and bone cysts may also be present. present.

Severe bone disease, resulting in bone pain and tenderness Severe bone disease, resulting in bone pain and tenderness and/or pathologic fractures, is rarely presently observed. and/or pathologic fractures, is rarely presently observed.

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS – BONE BONE

DISEASEDISEASE Hyperparathyroidism Hyperparathyroidism loss of bone mass at loss of bone mass at

sites of cortical bonesites of cortical bone, such as the radius and , such as the radius and relative preservation of cancellous bone relative preservation of cancellous bone such as that located at the vertebral bodies such as that located at the vertebral bodies

Patients with PHPT, however, may also have Patients with PHPT, however, may also have osteoporosis of the lumbar spine (trabecular osteoporosis of the lumbar spine (trabecular bone) that improves dramatically following bone) that improves dramatically following parathyroidectomy. parathyroidectomy.

Fractures occur more frequently Fractures occur more frequently incidence of fractures decreases beginning 1 year incidence of fractures decreases beginning 1 year

after parathyroidectomyafter parathyroidectomy Bone disease correlates with blood PTH and Bone disease correlates with blood PTH and

vitamin D levels.vitamin D levels.

Associated with Associated with peptic ulcer diseasepeptic ulcer disease An increased incidence of An increased incidence of pancreatitis pancreatitis

occur only in patients with profound occur only in patients with profound hypercalcemia (Cahypercalcemia (Ca2+2+ 12.5 mg/dL) 12.5 mg/dL)

Increased incidence of Increased incidence of cholelithiasischolelithiasis consequence of an increase in biliary consequence of an increase in biliary

calcium calcium leads to the formation of leads to the formation of calcium bilirubinate stonescalcium bilirubinate stones

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS – GASTROINTESTINAL GASTROINTESTINAL

COMPLICATIONSCOMPLICATIONS

Neuropsychiatric manifestations: Neuropsychiatric manifestations: florid psychosisflorid psychosis ObtundationObtundation ComaComa Other findings: depression, anxiety, and fatigueOther findings: depression, anxiety, and fatigue

In patients with only mild hypercalcemia. In patients with only mild hypercalcemia. The etiology of these symptoms is unknown. The etiology of these symptoms is unknown. Studies demonstrate that levels of certain neurotransmitters Studies demonstrate that levels of certain neurotransmitters

(monoamine metabolites 5-hydroxyindoleacetic acid (monoamine metabolites 5-hydroxyindoleacetic acid [5-HIAA]) and homovanillic acid [HVA]) are reduced [5-HIAA]) and homovanillic acid [HVA]) are reduced in in the cerebrospinal fluid of patients with primary HPT when the cerebrospinal fluid of patients with primary HPT when compared to controls. compared to controls.

Electroencephalogram abnormalities also occur in patients Electroencephalogram abnormalities also occur in patients with primary and secondary HPT and normalize following with primary and secondary HPT and normalize following parathyroidectomy.parathyroidectomy.

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS –

NEUROPSYCHIATRIC NEUROPSYCHIATRIC MANIFESTATIONSMANIFESTATIONS

Fatigue and muscle weaknessFatigue and muscle weakness prominent in the proximal muscle groupsprominent in the proximal muscle groups muscle biopsy studies show that weakness muscle biopsy studies show that weakness

results from a neuropathy, rather than from a results from a neuropathy, rather than from a primary myopathic abnormalityprimary myopathic abnormality

Increased incidence of Increased incidence of chondrocalcinosis chondrocalcinosis and and pseudogoutpseudogout, with deposition of calcium , with deposition of calcium pyrophosphate crystals in the joints. pyrophosphate crystals in the joints.

Calcification at ectopic sites such as blood Calcification at ectopic sites such as blood vessels, cardiac valves, and skin, also has vessels, cardiac valves, and skin, also has been reported, as has hypertrophy of the been reported, as has hypertrophy of the left ventricle independent of the presence of left ventricle independent of the presence of hypertensionhypertension

CLINICAL CLINICAL MANIFESTATIONS – MANIFESTATIONS – OTHER FEATURESOTHER FEATURES

Neck: masses and/or lymphadenopathyNeck: masses and/or lymphadenopathy Parathyroid tumors are seldom palpable, except in Parathyroid tumors are seldom palpable, except in

patients with profound hypercalcemia. patients with profound hypercalcemia. A palpable neck mass in a patient with PHPT is more A palpable neck mass in a patient with PHPT is more

likely to be thyroid in origin or a parathyroid cancer. likely to be thyroid in origin or a parathyroid cancer. Band keratopathy, a deposition of calcium in Band keratopathy, a deposition of calcium in

Bowman's membrane just inside the iris of the eyeBowman's membrane just inside the iris of the eye generally caused by chronic eye diseases such as uveitis, generally caused by chronic eye diseases such as uveitis,

glaucoma, and traumaglaucoma, and trauma may also occur in the presence of conditions associated may also occur in the presence of conditions associated

with high calcium or phosphate levelswith high calcium or phosphate levels Fibro-osseous jaw tumors, or the presence of Fibro-osseous jaw tumors, or the presence of

familial disease in patients with PHPT and jaw-familial disease in patients with PHPT and jaw-tumors, if present, should alert the physician to tumors, if present, should alert the physician to the possibility of parathyroid carcinoma. the possibility of parathyroid carcinoma.

PRIMARY HPT – PRIMARY HPT – PHYSICAL FINDINGSPHYSICAL FINDINGS

DIFFERENTIAL DIFFERENTIAL DIAGNOSISDIAGNOSIS

PHPT and malignancy account for PHPT and malignancy account for more than 90% of all cases of more than 90% of all cases of hypercalcemia. hypercalcemia. PHPT more common in the outpatient PHPT more common in the outpatient

settingsetting Malignancy - in hospitalized patientsMalignancy - in hospitalized patients

Patients with solid tumors of the lung, breast, Patients with solid tumors of the lung, breast, kidney, head and neck, and ovary often have kidney, head and neck, and ovary often have humoral hypercalcemia of malignancy without humoral hypercalcemia of malignancy without any associated bony metastases. any associated bony metastases.

Hypercalcemia also can be associated with Hypercalcemia also can be associated with hematologic malignancies such as multiple hematologic malignancies such as multiple myeloma. myeloma.

Humoral hypercalcemia of malignancy is Humoral hypercalcemia of malignancy is known to be mediated primarily by parathyroid known to be mediated primarily by parathyroid hormone-related peptide (PTHrP), which also hormone-related peptide (PTHrP), which also plays a role in the hypercalcemia associated plays a role in the hypercalcemia associated with bone metastases and multiple myeloma. with bone metastases and multiple myeloma.

Thiazide diuretics cause hypercalcemia by Thiazide diuretics cause hypercalcemia by decreasing renal clearance of calciumdecreasing renal clearance of calcium corrects in normal patients within days to weeks corrects in normal patients within days to weeks

after discontinuing the diuretic but patients with after discontinuing the diuretic but patients with PHPT continue to be hypercalcemicPHPT continue to be hypercalcemic

Benign familial hypocalciuric hypercalcemia Benign familial hypocalciuric hypercalcemia (BFHH) (BFHH) rare autosomal dominant condition with nearly rare autosomal dominant condition with nearly

100% penetrance 100% penetrance results from inherited heterozygous mutations in results from inherited heterozygous mutations in

the CASR gene located on chromosome the CASR gene located on chromosome result in neonatal hypercalcemia, a condition that result in neonatal hypercalcemia, a condition that

can rapidly prove fatal. can rapidly prove fatal. Patients with BFHH have lifelong hypercalcemia, Patients with BFHH have lifelong hypercalcemia,

which is not corrected by parathyroidectomy.which is not corrected by parathyroidectomy.

Hypercalcemia is also found in Hypercalcemia is also found in approximately 10% of patients with approximately 10% of patients with sarcoidosis secondary to increased 25-sarcoidosis secondary to increased 25-hydroxy vitamin D 1-hydroxylase activity hydroxy vitamin D 1-hydroxylase activity in lymphoid tissue and pulmonary in lymphoid tissue and pulmonary macrophages, which is not subject to macrophages, which is not subject to inhibitory feedback control by serum inhibitory feedback control by serum calcium. calcium.

Thyroid hormone also has bone-Thyroid hormone also has bone-resorption propertiesresorption properties, thus causing , thus causing hypercalcemia in thyrotoxic stateshypercalcemia in thyrotoxic states, , especially in immobilized patients. especially in immobilized patients.

Hemoconcentration appears to be an important Hemoconcentration appears to be an important factor in the hypercalcemia associated with adrenal factor in the hypercalcemia associated with adrenal insufficiency and pheochromocytoma, although the insufficiency and pheochromocytoma, although the latter patients may have associated parathyroid latter patients may have associated parathyroid tumors (MEN2A) and some pheochromocytomas are tumors (MEN2A) and some pheochromocytomas are known to secrete PTHrP. known to secrete PTHrP.

Vasoactive intestinal peptide-secreting tumors Vasoactive intestinal peptide-secreting tumors (VIPomas)(VIPomas) hypercalcemia due to increased secretion of PTHrPhypercalcemia due to increased secretion of PTHrP

Milk–alkali syndrome requires the ingestion of large Milk–alkali syndrome requires the ingestion of large quantities of calcium with an absorbable alkali such quantities of calcium with an absorbable alkali such as that used in the treatment of peptic ulcer disease as that used in the treatment of peptic ulcer disease with antacidswith antacids

DIAGNOSTIC DIAGNOSTIC INVESTIGATIONINVESTIGATION

Biochemical StudiesBiochemical Studies The presence of an The presence of an elevated serum elevated serum

calcium and intact PTH (iPTH) or calcium and intact PTH (iPTH) or two-site PTH levels two-site PTH levels establishes the establishes the diagnosis of PHPT with virtual diagnosis of PHPT with virtual certainty.certainty. distinguish primary HPT from other distinguish primary HPT from other

causescauses


Biochemical StudiesBiochemical Studies Patients with PHPT also typically have Patients with PHPT also typically have

decreased serum phosphate decreased serum phosphate (approximately (approximately 50%) and 50%) and elevated 24-hour urinary calcium elevated 24-hour urinary calcium concentrations concentrations (approximately 60%). (approximately 60%).

A A mild hyperchloremic metabolic acidosis mild hyperchloremic metabolic acidosis is also present (80%) is also present (80%) elevated elevated chloride:phosphate ratio (>33)chloride:phosphate ratio (>33)

Urinary calcium levels need not be measured Urinary calcium levels need not be measured routinely, except in patients who have not had routinely, except in patients who have not had previously documented normocalcemia, or previously documented normocalcemia, or who have a family history of hypercalcemia, in who have a family history of hypercalcemia, in order to rule out BFHH. order to rule out BFHH.


Biochemical StudiesBiochemical StudiesBFHHBFHH

The biochemical profile of BFHH is similar to primary HPT, The biochemical profile of BFHH is similar to primary HPT, except that the except that the hypercalcemia is mild hypercalcemia is mild and and PTH levels are PTH levels are high-normal or only slightly elevatedhigh-normal or only slightly elevated

24-hour urinary calcium excretion is characteristically low 24-hour urinary calcium excretion is characteristically low (<100 mg/d)(<100 mg/d)

Serum calcium to creatinine clearance ratio is usually less Serum calcium to creatinine clearance ratio is usually less than 0.01 than 0.01 in patients with BFHH (typically greater than 0.02 in in patients with BFHH (typically greater than 0.02 in patients with PHPTpatients with PHPT

Elevated levels of alkaline phosphatase in 10% of patients with Elevated levels of alkaline phosphatase in 10% of patients with PHPT PHPT indicative of high-turnover bone diseaseindicative of high-turnover bone disease patients are prone to developing postoperative hypocalcemia as a patients are prone to developing postoperative hypocalcemia as a

consequence of bone hungerconsequence of bone hunger Blood urea nitrogen and creatinine levels should be obtained to Blood urea nitrogen and creatinine levels should be obtained to

determine the extent of damage to the kidneys. determine the extent of damage to the kidneys. Serum and urine protein electrophoresis may be necessary to Serum and urine protein electrophoresis may be necessary to

exclude multiple myeloma.exclude multiple myeloma.

Occasionally, patients present with Occasionally, patients present with normocalcemic normocalcemic PHPTPHPT caused by vitamin D deficiency, a low serum caused by vitamin D deficiency, a low serum albumin, excessive hydration, a high phosphate diet, albumin, excessive hydration, a high phosphate diet, or a low normal blood calcium set-point.or a low normal blood calcium set-point.

These patients have These patients have increased total PTH levels increased total PTH levels with or without increased blood ionized calcium with or without increased blood ionized calcium levelslevels and must be distinguished from patients with and must be distinguished from patients with renal leak hypercalciuria who also have increased renal leak hypercalciuria who also have increased PTH levels as a result of excessive calcium loss in PTH levels as a result of excessive calcium loss in the urine. the urine. accomplished by administering thiazide diuretics. accomplished by administering thiazide diuretics.

With idiopathic hypercalciuria, the urinary calcium level falls, With idiopathic hypercalciuria, the urinary calcium level falls, and the secondary increase in the blood PTH level also and the secondary increase in the blood PTH level also decreases to normal, decreases to normal,

With normocalcemic hyperparathyroidism continue to have With normocalcemic hyperparathyroidism continue to have elevated urine calcium and blood PTH levels, and may in fact elevated urine calcium and blood PTH levels, and may in fact become hypercalcemic.become hypercalcemic.

RADIOLOGIC TESTSRADIOLOGIC TESTS Routine hand x-rays are Routine hand x-rays are only only

recommended in patients with an recommended in patients with an elevated bone alkaline phosphatase levelelevated bone alkaline phosphatase level

Bone mineral density studies using dual-Bone mineral density studies using dual-energy absorptiometry are, however, being energy absorptiometry are, however, being increasingly used to assess the effects of increasingly used to assess the effects of PHPT on bone.PHPT on bone.

Abdominal ultrasound examination is used Abdominal ultrasound examination is used selectively to document renal stones. selectively to document renal stones.

Parathyroid localization studies are not used Parathyroid localization studies are not used to confirm the diagnosis of PHPT, but rather to confirm the diagnosis of PHPT, but rather to aid in identifying the location of the to aid in identifying the location of the offending gland(s)offending gland(s)

TREATMENTTREATMENTRationale for Rationale for

Parathyroidectomy and Parathyroidectomy and Guidelines for Operative Guidelines for Operative

TreatmentTreatment Most authorities agree that patients who have Most authorities agree that patients who have developed complications such as kidney developed complications such as kidney stones, osteoporosis, or renal dysfunction, stones, osteoporosis, or renal dysfunction, have the "classic" symptoms of PHPT, or have the "classic" symptoms of PHPT, or who are younger than age 50 years, who are younger than age 50 years, should undergo parathyroidectomy. should undergo parathyroidectomy.

However, the treatment of patients with However, the treatment of patients with asymptomatic PHPT has been the subject of asymptomatic PHPT has been the subject of controversy, partly because there is little controversy, partly because there is little agreement on what constitutes an agreement on what constitutes an "asymptomatic" patient. "asymptomatic" patient.



TreatmentTreatment At the National Institutes of Health (NIH) At the National Institutes of Health (NIH) consensus conference in 1990, consensus conference in 1990, "asymptomatic" "asymptomatic" PHPTPHPT was defined as was defined as "the absence of common "the absence of common symptoms and signs of PHPT, including no symptoms and signs of PHPT, including no bone, renal, gastrointestinal, or bone, renal, gastrointestinal, or neuromuscular disorders.“neuromuscular disorders.“

The panel advocated The panel advocated nonoperative management nonoperative management of these patients with mild PHPTof these patients with mild PHPT Based on observational studies Based on observational studies which suggested which suggested

relative stability of biochemical parameters over time. relative stability of biochemical parameters over time. Cohort studies by Silverberg and associates (patients with Cohort studies by Silverberg and associates (patients with

asymptomatic HPT followed without surgery) asymptomatic HPT followed without surgery) levels of levels of serum and urinary calcium, PTH, alkaline phosphatase, serum and urinary calcium, PTH, alkaline phosphatase, and vitamin D metabolites remained relatively stable over and vitamin D metabolites remained relatively stable over a 10-year period in most patients. a 10-year period in most patients.



TreatmentTreatment Parathyroidectomy is now recommended for Parathyroidectomy is now recommended for patients with smaller elevations in serum patients with smaller elevations in serum calcium levels (<1 mg/dL above the upper limit calcium levels (<1 mg/dL above the upper limit of normal) and if bone mineral density measured of normal) and if bone mineral density measured at any of three sites (radius, spine, or hip) is at any of three sites (radius, spine, or hip) is greater than 2.5 SD below those of gender- and greater than 2.5 SD below those of gender- and race-matched, but not age-matched, controls race-matched, but not age-matched, controls (i.e., peak bone density or T-score [rather than (i.e., peak bone density or T-score [rather than Z-score] <2.5). Z-score] <2.5).

The panel still recommends exercising caution in The panel still recommends exercising caution in using neuropsychologic abnormalities, cardiovascular using neuropsychologic abnormalities, cardiovascular disease, gastrointestinal symptoms, menopause, and disease, gastrointestinal symptoms, menopause, and elevated serum or urine indices of increased bone elevated serum or urine indices of increased bone turnover as sole indications for parathyroidectomy. turnover as sole indications for parathyroidectomy.

PREOPERATIVE PREOPERATIVE LOCALIZATION TESTLOCALIZATION TEST

Identify location of the enlarged Identify location of the enlarged gland(s) gland(s) Classified into noninvasive or invasive Classified into noninvasive or invasive

modalitiesmodalities

Minimally-invasive procedures include Minimally-invasive procedures include unilateral and focused neck exploration, unilateral and focused neck exploration, radio-guided parathyroidectomy, and radio-guided parathyroidectomy, and several endoscopic or video-assisted several endoscopic or video-assisted approaches. approaches.

Use of localization studies associated with Use of localization studies associated with lower morbidity rates (hypoparathyroidism and lower morbidity rates (hypoparathyroidism and

recurrent laryngeal nerve injury)recurrent laryngeal nerve injury) decreased operative timesdecreased operative times reduced duration of hospital stayreduced duration of hospital stay improved cosmetic outcomesimproved cosmetic outcomes may be more cost-effective.may be more cost-effective.

little consensus on which localization studies should be little consensus on which localization studies should be used. used.

The performance characteristics of these studies vary with The performance characteristics of these studies vary with institutional and radiologist experienceinstitutional and radiologist experience

99mTechnetium-labeled sestamibi99mTechnetium-labeled sestamibi is the most widely is the most widely used and accurate modality, with a sensitivity greater than used and accurate modality, with a sensitivity greater than 80% for detection of parathyroid adenomas. 80% for detection of parathyroid adenomas.

Sestamibi, also known as Cardiolite, was initially introduced Sestamibi, also known as Cardiolite, was initially introduced for cardiac imaging and is concentrated in mitochondria-for cardiac imaging and is concentrated in mitochondria-rich tissuerich tissue useful for parathyroid localization because of the delayed useful for parathyroid localization because of the delayed

washout of the radionuclide from hypercellular parathyroid washout of the radionuclide from hypercellular parathyroid tissue when compared to thyroid tissue. tissue when compared to thyroid tissue.

Sestamibi scans are generally complemented by neck Sestamibi scans are generally complemented by neck ultrasound ultrasound identify adenomas with greater than 75% sensitivity in identify adenomas with greater than 75% sensitivity in

experienced centersexperienced centers most useful in identifying intrathyroidal parathyroidsmost useful in identifying intrathyroidal parathyroids

Single-photon emission computed tomography Single-photon emission computed tomography (SPECT), when used with planar sestamibi, has (SPECT), when used with planar sestamibi, has particular utility in the evaluation of ectopic particular utility in the evaluation of ectopic parathyroid adenomas, such as those located deep in parathyroid adenomas, such as those located deep in the neck or in the mediastinum. Specifically, SPECT the neck or in the mediastinum. Specifically, SPECT can indicate whether an adenoma is located in the can indicate whether an adenoma is located in the anterior or posterior mediastinum (aortopulmonary anterior or posterior mediastinum (aortopulmonary window), thus enabling the surgeon to modify the window), thus enabling the surgeon to modify the operative approach accordingly. operative approach accordingly.

CT and MRI scans are less sensitive than sestamibi CT and MRI scans are less sensitive than sestamibi scans, but are helpful in localizing mediastinal glands. scans, but are helpful in localizing mediastinal glands.

Intraoperative parathyroid hormone was initially Intraoperative parathyroid hormone was initially introduced in 1993, and is used to determine the introduced in 1993, and is used to determine the adequacy of parathyroid resection adequacy of parathyroid resection According to one commonly used criterion, According to one commonly used criterion, when the PTH when the PTH

falls by 50% or more in 10 minutes after removal of a falls by 50% or more in 10 minutes after removal of a parathyroid tumor, as compared to the highest parathyroid tumor, as compared to the highest preremoval value, the test is considered positive and the preremoval value, the test is considered positive and the operation is terminated.operation is terminated.

OPERATIVE OPERATIVE APPROACHESAPPROACHES

Unilateral parathyroid exploration was first carried Unilateral parathyroid exploration was first carried out using intraoperative staining of a biopsy from out using intraoperative staining of a biopsy from the normal parathyroid gland with Sudan black dye the normal parathyroid gland with Sudan black dye to rule out a double adenoma. to rule out a double adenoma.

Initially, the choice of side to be explored was Initially, the choice of side to be explored was random, but the introduction of preoperative random, but the introduction of preoperative localization studies has enabled a more directed localization studies has enabled a more directed approach. approach.

In contrast, the focused approach identifies only the In contrast, the focused approach identifies only the enlarged parathyroid gland and no attempts are enlarged parathyroid gland and no attempts are made to locate other normal parathyroid glands. made to locate other normal parathyroid glands.

Unilateral neck explorationsUnilateral neck explorations have several have several advantages over bilateral neck explorationadvantages over bilateral neck exploration reduced operative times and complications, such as injury reduced operative times and complications, such as injury

to the recurrent laryngeal nerve and hypoparathyroidism.to the recurrent laryngeal nerve and hypoparathyroidism.


Argument against a unilateral exploration Argument against a unilateral exploration the the risk of missing another adenoma on the risk of missing another adenoma on the opposite side opposite side of the neck. of the neck. incidence of double adenomas: 0 to 10%incidence of double adenomas: 0 to 10%

increased incidence in elderly patientsincreased incidence in elderly patients Upper parathyroid glands involved more frequentlyUpper parathyroid glands involved more frequently

Risk of missing a second adenoma is higher in populations Risk of missing a second adenoma is higher in populations with a higher incidence of multiple adenomas, such as with a higher incidence of multiple adenomas, such as those with familial HPT, MEN syndromes, and the elderly. those with familial HPT, MEN syndromes, and the elderly.

Another difficulty inherent with unilateral Another difficulty inherent with unilateral exploration exploration inability to discern whether the inability to discern whether the combination of an abnormal gland and a combination of an abnormal gland and a normal gland on the initial side constitute a normal gland on the initial side constitute a single adenoma or asymmetric hyperplasiasingle adenoma or asymmetric hyperplasia


Radio-guided parathyroidectomy takes advantage of Radio-guided parathyroidectomy takes advantage of the ability of parathyroid tumors to retain sestamibi the ability of parathyroid tumors to retain sestamibi and uses a hand-held gamma probe to guide the and uses a hand-held gamma probe to guide the identification of the offending gland. identification of the offending gland. rarely used now, largely because it offers little advantage rarely used now, largely because it offers little advantage

over preoperative sestamibi scans over preoperative sestamibi scans associated with increased operative times associated with increased operative times reduced accuracy in the presence of multiglandular diseasereduced accuracy in the presence of multiglandular disease

Various videoscopic and video-assisted techniques Various videoscopic and video-assisted techniques of parathyroidectomy currently are in use, of parathyroidectomy currently are in use, associated with increased operating timesassociated with increased operating times require more personnelrequire more personnel ExpensiveExpensive not been useful for patients with multiglandular disease or not been useful for patients with multiglandular disease or

a large thyroid mass, or in patients who have had previous a large thyroid mass, or in patients who have had previous neck surgery and irradiation. neck surgery and irradiation.

greatest utility has been in patients with tumors at ectopic greatest utility has been in patients with tumors at ectopic sites, such as the mediastinum.sites, such as the mediastinum.


The recommended practice involves obtaining both a The recommended practice involves obtaining both a sestamibi scan and neck ultrasound in patients with sestamibi scan and neck ultrasound in patients with PHPTPHPT. .

Studies show that if both studies independently identify the Studies show that if both studies independently identify the same enlarged parathyroid gland, and no other gland, it is same enlarged parathyroid gland, and no other gland, it is indeed the abnormal gland in approximately 95% of cases. indeed the abnormal gland in approximately 95% of cases.

These patients with sporadic PHPT are candidates for a focused These patients with sporadic PHPT are candidates for a focused neck exploration. neck exploration.

A A standard bilateral neck explorationstandard bilateral neck exploration is planned is planned if parathyroid localization studies or intraoperative parathyroid if parathyroid localization studies or intraoperative parathyroid

hormone are not available; hormone are not available; if the localizing studies fail to identify any abnormal parathyroid if the localizing studies fail to identify any abnormal parathyroid

gland, or identify multiple abnormal glands, in patients with a family gland, or identify multiple abnormal glands, in patients with a family history of PHPT, MEN1, or MEN2A; history of PHPT, MEN1, or MEN2A;

or if there is a concomitant thyroid disorder that requires bilateral or if there is a concomitant thyroid disorder that requires bilateral exploration. exploration.

finding a minimally abnormal parathyroid gland on the side finding a minimally abnormal parathyroid gland on the side indicated by localization studies during focal exploration should indicated by localization studies during focal exploration should prompt a bilateral exploration or at least the identification of a prompt a bilateral exploration or at least the identification of a normal parathyroid gland on the same side. normal parathyroid gland on the same side.

Conduct of Conduct of Parathyroidectomy Parathyroidectomy (Standard Bilateral (Standard Bilateral

Exploration)Exploration) An experienced parathyroid surgeon An experienced parathyroid surgeon performed under general anesthesiaperformed under general anesthesia The patient is positioned supine on the operating The patient is positioned supine on the operating

table with the neck extended and the arms table with the neck extended and the arms tucked on either side. tucked on either side.

For a bilateral exploration, the neck is explored For a bilateral exploration, the neck is explored via a 3- to 4-cm incision just caudal to the cricoid via a 3- to 4-cm incision just caudal to the cricoid cartilage. The initial dissection and exposure is cartilage. The initial dissection and exposure is similar to that used for thyroidectomy. similar to that used for thyroidectomy.

dissection during a parathyroidectomy is dissection during a parathyroidectomy is maintained lateral to the thyroid, making it maintained lateral to the thyroid, making it easier to identify the parathyroid glands and not easier to identify the parathyroid glands and not disturb their blood supply.disturb their blood supply.

Identification of the Identification of the Parathyroid GlandsParathyroid Glands

A bloodless field is important A bloodless field is important The middle thyroid veins are ligated and divided, thus The middle thyroid veins are ligated and divided, thus

enabling medial and anterior retraction of the thyroid enabling medial and anterior retraction of the thyroid lobe. This may be facilitated by a peanut sponge or lobe. This may be facilitated by a peanut sponge or placement of 2-0 silk sutures into the thyroid placement of 2-0 silk sutures into the thyroid substance. The space between the carotid sheath and substance. The space between the carotid sheath and thyroid is then opened by gentle sharp and blunt thyroid is then opened by gentle sharp and blunt dissection, from the cricoid cartilage superiorly to the dissection, from the cricoid cartilage superiorly to the thymus inferiorly and the RLN is identified. thymus inferiorly and the RLN is identified.

Approximately 85% of the parathyroid glands are Approximately 85% of the parathyroid glands are found within 1 cm of the junction of the inferior found within 1 cm of the junction of the inferior thyroid artery and recurrent laryngeal nervesthyroid artery and recurrent laryngeal nerves. . upper parathyroid glands are usually superior to this junction upper parathyroid glands are usually superior to this junction

and dorsal (posterior) to the nerve, and dorsal (posterior) to the nerve, lower glands are located inferior to the junction and ventral lower glands are located inferior to the junction and ventral

(anterior) to the recurrent nerve. (anterior) to the recurrent nerve.


Because parathyroid glands are partly surrounded Because parathyroid glands are partly surrounded by fat, by fat, any fat lobule at typical parathyroid any fat lobule at typical parathyroid locations should be explored, because the locations should be explored, because the normal or abnormal parathyroid gland may be normal or abnormal parathyroid gland may be concealed in the fatty tissueconcealed in the fatty tissue. .

The thin fascia overlying a "suspicious" fat lobule The thin fascia overlying a "suspicious" fat lobule should be incised using a sharp, curved hemostat should be incised using a sharp, curved hemostat and scalpel. This maneuver often causes the and scalpel. This maneuver often causes the parathyroid gland to "pop" out. Alternatively, parathyroid gland to "pop" out. Alternatively, gentle, blunt peanut sponge dissection between the gentle, blunt peanut sponge dissection between the carotid sheath and the thyroid gland often reveals carotid sheath and the thyroid gland often reveals a "float" sign, suggesting the site of the abnormal a "float" sign, suggesting the site of the abnormal parathyroid gland.parathyroid gland.


Parathyroid tissue can be confused with Parathyroid tissue can be confused with normal or brown fat tissue, thyroid normal or brown fat tissue, thyroid nodules, lymph nodes, and ectopic thymus. nodules, lymph nodes, and ectopic thymus. Lymph nodes are generally light beige to Lymph nodes are generally light beige to

whitish-gray in color, and appear glassy, whitish-gray in color, and appear glassy, Thyroid nodules are generally more vascular, Thyroid nodules are generally more vascular,

firm, dark or reddish-brown in color, and have firm, dark or reddish-brown in color, and have a more variegated appearance. a more variegated appearance.

Normal parathyroids are light beige and Normal parathyroids are light beige and only slightly darker or more brown than only slightly darker or more brown than adjacent fat. adjacent fat.


Intraoperatively, a suspicious nodule may be Intraoperatively, a suspicious nodule may be aspirated using a fine needle attached to a aspirated using a fine needle attached to a syringe containing 1 mL of saline. syringe containing 1 mL of saline. Very high Very high PTH levels in the aspirate are diagnostic PTH levels in the aspirate are diagnostic in in the intraoperative identification of parathyroid the intraoperative identification of parathyroid glands.glands.

Several characteristics, such as size (>7 mm), Several characteristics, such as size (>7 mm), weight, and color, are used to distinguish weight, and color, are used to distinguish normal from hypercellular parathyroid glands. normal from hypercellular parathyroid glands. Hypercellular glands are generally darker, Hypercellular glands are generally darker,

more firm, and more vascular than more firm, and more vascular than normocellular glands. normocellular glands.


An An intraoperative density test intraoperative density test was was developed to take advantage of the developed to take advantage of the fact that fact that hypercellular glands sink hypercellular glands sink in saline solutions because of in saline solutions because of their low fat contenttheir low fat content, whereas , whereas normal parathyroid glands float, but normal parathyroid glands float, but few surgeons use this test today. few surgeons use this test today.

LOCATION OF LOCATION OF PARATHYROID GLANDSPARATHYROID GLANDS

The majority of lower parathyroid glands are The majority of lower parathyroid glands are found in found in proximity to the lower thyroid poleproximity to the lower thyroid pole

If not found at this location, the thyrothymic ligament and If not found at this location, the thyrothymic ligament and thymus should be mobilized as follows: The thymus extends thymus should be mobilized as follows: The thymus extends into the mediastinum as a tongue of tissue that is sometimes into the mediastinum as a tongue of tissue that is sometimes indistinguishable from the perithymic fat, except that it is indistinguishable from the perithymic fat, except that it is slightly firmer with more discrete margins. The upper end is slightly firmer with more discrete margins. The upper end is gently grasped with a right-angle clamp and the distal portion gently grasped with a right-angle clamp and the distal portion is bluntly dissected from perithymic fat with a peanut sponge. is bluntly dissected from perithymic fat with a peanut sponge. One can then "walk down" the thymus with successive right-One can then "walk down" the thymus with successive right-angle clamps (Fig. 37-50B). Applying light tension along with angle clamps (Fig. 37-50B). Applying light tension along with a "twisting" motion helps to free the upper thymus. The a "twisting" motion helps to free the upper thymus. The carotid sheath should also be opened from the bifurcation to carotid sheath should also be opened from the bifurcation to the base of the neck if the parathyroid tumor cannot be found. the base of the neck if the parathyroid tumor cannot be found. If these maneuvers are unsuccessful, an intrathyroidal gland If these maneuvers are unsuccessful, an intrathyroidal gland should be sought by using intraoperative ultrasound, incising should be sought by using intraoperative ultrasound, incising the thyroid capsule on its posterolateral surface, or by the thyroid capsule on its posterolateral surface, or by performing an ipsilateral thyroid lobectomy and "bread-performing an ipsilateral thyroid lobectomy and "bread-loafing" the thyroid lobe. loafing" the thyroid lobe.

LOCATION OF LOCATION OF PARATHYROID GLANDSPARATHYROID GLANDS

Preoperative or intraoperative ultrasonographyPreoperative or intraoperative ultrasonography can be can be useful for identifying intrathyroidal parathyroid glands. useful for identifying intrathyroidal parathyroid glands.

Rarely, the third branchial pouch may maldescend and be Rarely, the third branchial pouch may maldescend and be found high in the neck (undescended parathymus), anterior to found high in the neck (undescended parathymus), anterior to the carotid bulb, along with the missing parathyroid gland. the carotid bulb, along with the missing parathyroid gland.

Upper parathyroid glands are more consistent in Upper parathyroid glands are more consistent in position and are usually found near the junction of the position and are usually found near the junction of the upper and middle thirds of the gland, at the level of the upper and middle thirds of the gland, at the level of the cricoid cartilage cricoid cartilage

Ectopic upper glands may be found Ectopic upper glands may be found in the carotid sheathin the carotid sheath tracheoesophageal groovetracheoesophageal groove in the retroesophagealin the retroesophageal in the posterior mediastinumin the posterior mediastinum

Every attempt must be made to identify all four glands. Every attempt must be made to identify all four glands. Treatment depends upon the number of abnormal Treatment depends upon the number of abnormal glands.glands.

A single adenoma is presumed to A single adenoma is presumed to be the cause of a patient's primary be the cause of a patient's primary HPT if only one parathyroid tumor HPT if only one parathyroid tumor is identified and the other is identified and the other parathyroid glands are normalparathyroid glands are normal, , present in 80%present in 80%

Adenomas typically have an atrophic Adenomas typically have an atrophic rim of normal parathyroid tissue, but rim of normal parathyroid tissue, but this characteristic may be absent. this characteristic may be absent.

If two abnormal and two normal glands are If two abnormal and two normal glands are identified, the patient has double adenomasidentified, the patient has double adenomas. .

Triple adenomas are present if three glands Triple adenomas are present if three glands are abnormal and one is normal.are abnormal and one is normal.

Multiple adenomas Multiple adenomas more common in older patients more common in older patients incidence of up to 10% in patients more than 60 years incidence of up to 10% in patients more than 60 years

old old The abnormal glands should be excised, provided The abnormal glands should be excised, provided

the remaining glands are confirmed as such, the remaining glands are confirmed as such, thus excluding asymmetric hyperplasia, after thus excluding asymmetric hyperplasia, after biopsy and frozen section.biopsy and frozen section.

If all parathyroid glands are enlarged or hypercellular, If all parathyroid glands are enlarged or hypercellular, patients have parathyroid hyperplasiapatients have parathyroid hyperplasia, which has been shown , which has been shown to occur in approximately 15% of patients in various series. to occur in approximately 15% of patients in various series. These glands are often lobulated, usually lack the rim of normal These glands are often lobulated, usually lack the rim of normal parathyroid gland seen in adenomas, and may be variable in size. parathyroid gland seen in adenomas, and may be variable in size.

It is often difficult to distinguish multiple adenomas from It is often difficult to distinguish multiple adenomas from hyperplasia with variable gland size. Hyperplasia may be of the hyperplasia with variable gland size. Hyperplasia may be of the chief cell (more common), mixed, or clear-cell type. chief cell (more common), mixed, or clear-cell type.

Patients with hyperplasia may be treated by subtotal Patients with hyperplasia may be treated by subtotal parathyroidectomy or by total parathyroidectomy and parathyroidectomy or by total parathyroidectomy and autotransplantation, with the choice of procedure being autotransplantation, with the choice of procedure being determined by rates of recurrence, postoperative hypocalcemia, determined by rates of recurrence, postoperative hypocalcemia, and failure rates of autotransplanted tissue. and failure rates of autotransplanted tissue. Initial studies demonstrated equivalent cure rates and postoperative Initial studies demonstrated equivalent cure rates and postoperative

hypocalcemia for the two techniques, with the latter having the hypocalcemia for the two techniques, with the latter having the added advantage of avoiding recurrence in the neck. added advantage of avoiding recurrence in the neck.

However, subtotal parathyroidectomy is preferred because However, subtotal parathyroidectomy is preferred because autotransplanted tissue may fail to function in approximately 5% autotransplanted tissue may fail to function in approximately 5% of cases.of cases.

All four parathyroid glands are identified and All four parathyroid glands are identified and carefully mobilized. For patients with hyperplasia, a carefully mobilized. For patients with hyperplasia, a titanium clip is placed across the most normal gland, titanium clip is placed across the most normal gland, leaving a 50-mg remnant and taking care to avoid leaving a 50-mg remnant and taking care to avoid disturbing the vascular pedicle, and resecting the disturbing the vascular pedicle, and resecting the gland with a sharp scalpel. gland with a sharp scalpel.

The authors' preference, if possible, is The authors' preference, if possible, is to subtotally to subtotally resect an inferior gland, which is more easily resect an inferior gland, which is more easily accessible in case of recurrence because of its accessible in case of recurrence because of its anterior location with respect to the recurrent anterior location with respect to the recurrent laryngeal nerve. laryngeal nerve.

The resected parathyroid tissue is confirmed by The resected parathyroid tissue is confirmed by frozen section or PTH assay. If the remnant appears frozen section or PTH assay. If the remnant appears to be viable, the remaining glands are resected. to be viable, the remaining glands are resected.

Bilateral upper cervical thymectomy is also routinely Bilateral upper cervical thymectomy is also routinely performed because supernumerary glands occur in up performed because supernumerary glands occur in up to 20% of patients. Whenever multiple parathyroids are to 20% of patients. Whenever multiple parathyroids are resected, it is preferable to cryopreserve tissue, so that resected, it is preferable to cryopreserve tissue, so that it may be autotransplanted should the patient become it may be autotransplanted should the patient become hypoparathyroid. hypoparathyroid.

Parathyroid tissue is usually transplanted into the Parathyroid tissue is usually transplanted into the nondominant forearm. nondominant forearm. A horizontal skin incision is made overlying the brachioradialis A horizontal skin incision is made overlying the brachioradialis

muscle a few centimeters below the antecubital fossa. muscle a few centimeters below the antecubital fossa. Pockets are made in the belly of the muscle and one to two Pockets are made in the belly of the muscle and one to two

pieces of parathyroid tissue, measuring 1 mm each, are placed pieces of parathyroid tissue, measuring 1 mm each, are placed into each pocket. into each pocket.

Twelve to 14 pieces are transplanted. Twelve to 14 pieces are transplanted. Autotransplanted tissue also has been reported to function Autotransplanted tissue also has been reported to function

when transplanted into fat when transplanted into fat

INDICATIONS FOR INDICATIONS FOR STERNOTOMYSTERNOTOMY

Generally, a median sternotomy is performed Generally, a median sternotomy is performed to to locate a missing gland only after a complete locate a missing gland only after a complete search has been conducted in the necksearch has been conducted in the neck. A . A bilateral upper thymectomy also has been bilateral upper thymectomy also has been performed. performed.

A sternotomy is A sternotomy is not usually recommended at the not usually recommended at the initial operation, unless the calcium level is initial operation, unless the calcium level is greater than 13 mg/dL.greater than 13 mg/dL.

Rather, it is preferred to biopsy the normal glands Rather, it is preferred to biopsy the normal glands and subsequently close the patient's neck and and subsequently close the patient's neck and obtain localizing studies, if they were not obtained obtain localizing studies, if they were not obtained previously. Intraoperative PTH assay during the previously. Intraoperative PTH assay during the operation from large veins may be helpful. Using operation from large veins may be helpful. Using selective venous catheterization postoperatively selective venous catheterization postoperatively may also be needed when noninvasive localization may also be needed when noninvasive localization studies are negative, equivocal, or conflicting.studies are negative, equivocal, or conflicting.

INDICATIONS FOR INDICATIONS FOR STERNOTOMYSTERNOTOMY

Lower parathyroid glands tend to migrate into the Lower parathyroid glands tend to migrate into the anterior mediastinum in the thymus or perithymic anterior mediastinum in the thymus or perithymic fat fat and can usually be and can usually be approached via a cervical approached via a cervical incisionincision. A sternotomy is needed to deliver these tumors . A sternotomy is needed to deliver these tumors in approximately 5% of cases. in approximately 5% of cases.

Generally, the gland can be approached by a partial Generally, the gland can be approached by a partial sternotomy to the third intercostal space. The midline sternotomy to the third intercostal space. The midline sternotomy can be extended to the left or right side as sternotomy can be extended to the left or right side as required. required.

Upper glands tend to migrate to the posterior Upper glands tend to migrate to the posterior mediastinum in the tracheoesophageal groove, and, mediastinum in the tracheoesophageal groove, and, therefore require a complete sternotomy for therefore require a complete sternotomy for exposureexposure. Mediastinal glands may also be found in the . Mediastinal glands may also be found in the aortopulmonary window, pericardium, or attached to the aortopulmonary window, pericardium, or attached to the ascending aorta, aortic arch, or its branches. Tumors ascending aorta, aortic arch, or its branches. Tumors identified in the aortopulmonary window are ideal for identified in the aortopulmonary window are ideal for attempted removal via a thoracoscopic approach.attempted removal via a thoracoscopic approach.

Special SituationsSpecial SituationsPARATHYROID PARATHYROID CARCINOMACARCINOMA

Parathyroid cancer ~1% of the cases of PHPT. Parathyroid cancer ~1% of the cases of PHPT. It may be suspected preoperatively byIt may be suspected preoperatively by

the presence of severe symptomsthe presence of severe symptoms serum calcium levels greater than 14 mg/dLserum calcium levels greater than 14 mg/dL significantly elevated PTH levels (five times normal)significantly elevated PTH levels (five times normal) a palpable parathyroid gland.a palpable parathyroid gland.

Local invasion is most common; approximately 15% of patients Local invasion is most common; approximately 15% of patients have lymph node metastases and 33% have distant metastases have lymph node metastases and 33% have distant metastases at presentation. at presentation.

Intraoperatively, parathyroid cancer is Intraoperatively, parathyroid cancer is suggested by the suggested by the presence of a large, gray-white to gray-brown presence of a large, gray-white to gray-brown parathyroid tumor that is adherent to or invasive into parathyroid tumor that is adherent to or invasive into surrounding tissues such as muscle, thyroid, recurrent surrounding tissues such as muscle, thyroid, recurrent laryngeal nerve, trachea, or esophaguslaryngeal nerve, trachea, or esophagus. Enlarged lymph . Enlarged lymph nodes also may be present.nodes also may be present.

Accurate diagnosis necessitates histologic examination, which Accurate diagnosis necessitates histologic examination, which reveals local tissue invasion, vascular or capsular invasion, reveals local tissue invasion, vascular or capsular invasion, trabecular or fibrous stroma, and frequent mitoses.trabecular or fibrous stroma, and frequent mitoses.

Special SituationsSpecial SituationsPARATHYROID PARATHYROID CARCINOMACARCINOMA

Treatment of parathyroid cancer consists of Treatment of parathyroid cancer consists of bilateral bilateral neck exploration, with en bloc excision of the neck exploration, with en bloc excision of the tumor and the ipsilateral thyroid lobetumor and the ipsilateral thyroid lobe. .

Modified radical neck dissection is recommended in Modified radical neck dissection is recommended in the presence of lymph node metastases. the presence of lymph node metastases.

Prophylactic neck dissection is not advised because it Prophylactic neck dissection is not advised because it is associated with an increased risk of complications is associated with an increased risk of complications and does not appear to have a significant impact on and does not appear to have a significant impact on survival. survival.

Reoperation is indicated for locally recurrent or Reoperation is indicated for locally recurrent or metastatic disease because uncontrolled metastatic disease because uncontrolled hypercalcemia is the major cause of death in these hypercalcemia is the major cause of death in these patients, but is associated with significant morbidity. patients, but is associated with significant morbidity.

Radiation and chemotherapy can be considered in Radiation and chemotherapy can be considered in patients with unresectable disease. Bisphosphonates patients with unresectable disease. Bisphosphonates and calcimimetic drugs may also be effective in long-and calcimimetic drugs may also be effective in long-term palliation.term palliation.

Special SituationsSpecial SituationsFAMILIAL HPTFAMILIAL HPT

usually sporadicusually sporadic may occur as a component of various inherited may occur as a component of various inherited

syndromes such as MEN1 and MEN2A. syndromes such as MEN1 and MEN2A. Inherited primary hyperparathyroidism also can Inherited primary hyperparathyroidism also can

occur as isolated familial hyperparathyroidism (non-occur as isolated familial hyperparathyroidism (non-MEN), or familial hyperparathyroidism with jaw MEN), or familial hyperparathyroidism with jaw tumors.tumors.

The diagnosis of familial HPT is known or suspected The diagnosis of familial HPT is known or suspected in approximately 85% of patients preoperatively. in approximately 85% of patients preoperatively.

Furthermore, patients with hereditary Furthermore, patients with hereditary hyperparathyroidism generally have a higher hyperparathyroidism generally have a higher incidence of multiglandular disease, supernumerary incidence of multiglandular disease, supernumerary glands, and recurrent or persistent disease. glands, and recurrent or persistent disease.

Special SituationsSpecial SituationsFAMILIAL HPTFAMILIAL HPT

It is recommended to obtain a preoperative It is recommended to obtain a preoperative sestamibi scan and ultrasound in patients with sestamibi scan and ultrasound in patients with inherited hyperparathyroidism to identify inherited hyperparathyroidism to identify potential ectopic glands. potential ectopic glands.

A standard bilateral neck exploration is A standard bilateral neck exploration is performed, along with a bilateral cervical performed, along with a bilateral cervical thymectomy, regardless of the results of thymectomy, regardless of the results of localization studies. Both subtotal localization studies. Both subtotal parathyroidectomy and total parathyroidectomy parathyroidectomy and total parathyroidectomy with autotransplantation are appropriate, and with autotransplantation are appropriate, and parathyroid tissue should also be cryopreserved. parathyroid tissue should also be cryopreserved.

Special SituationsSpecial SituationsNEONATAL HPTNEONATAL HPT

Infants with neonatal HPT present with Infants with neonatal HPT present with severe hypercalcemia, lethargy, severe hypercalcemia, lethargy, hypotonia, and mental retardationhypotonia, and mental retardation. .

associated with homozygous mutations in associated with homozygous mutations in the CASR gene. the CASR gene.

Urgent total parathyroidectomy (with Urgent total parathyroidectomy (with autotransplantation and cryopreservation) autotransplantation and cryopreservation) and thymectomy is indicatedand thymectomy is indicated

Subtotal resection is associated with high Subtotal resection is associated with high recurrence rates.recurrence rates.

Special SituationsSpecial SituationsParathyromatosisParathyromatosis

rare condition characterized by the finding rare condition characterized by the finding of of multiple nodules of hyperfunctioning multiple nodules of hyperfunctioning parathyroid tissue throughout the neck parathyroid tissue throughout the neck and mediastinumand mediastinum, usually following a , usually following a previous parathyroidectomy. previous parathyroidectomy.

true etiology not known. true etiology not known. postulated to arise either from overgrowth of postulated to arise either from overgrowth of

congenital parathyroid rests (ontogenous congenital parathyroid rests (ontogenous parathyromatosis) or seeding at surgery from parathyromatosis) or seeding at surgery from rupture of parathyroid tumors or subtotal rupture of parathyroid tumors or subtotal resection of hyperplastic glands. resection of hyperplastic glands.

Postoperative Care and Postoperative Care and Follow-Up Follow-Up

Patients are reexamined Patients are reexamined 2 weeks 2 weeks postoperativelypostoperatively, at which time the wound is , at which time the wound is checked and blood work (calcium, phosphate, checked and blood work (calcium, phosphate, and PTH levels) is obtained. and PTH levels) is obtained.

Patients who have undergone Patients who have undergone parathyroidectomy are advised to undergo parathyroidectomy are advised to undergo calcium level checks annuallycalcium level checks annually. .

Recurrence rates are rare (less than 1%), except Recurrence rates are rare (less than 1%), except in patients with familial hyperparathyroidism. in patients with familial hyperparathyroidism.

Recurrence rates of 15% at 2 years and 67% at Recurrence rates of 15% at 2 years and 67% at 8 years have been reported for MEN1 patients.8 years have been reported for MEN1 patients.

PERSISTENT and PERSISTENT and RECURRENT RECURRENT

Hyperparathyroidism Hyperparathyroidism Persistence Persistence is defined as hypercalcemia is defined as hypercalcemia

that fails to resolve after that fails to resolve after parathyroidectomy parathyroidectomy and is more common and is more common than than recurrencerecurrence, which refers to HPT , which refers to HPT occurring after an intervening period of occurring after an intervening period of at least 6 months of biochemically at least 6 months of biochemically documented normocalcemiadocumented normocalcemia. .

Most common causes for both these states:Most common causes for both these states: ectopic parathyroidsectopic parathyroids unrecognized hyperplasiaunrecognized hyperplasia supernumerary glandssupernumerary glands subtotal resection of a parathyroid tumorsubtotal resection of a parathyroid tumor parathyroid cancerparathyroid cancer parathyromatosis. parathyromatosis.

PERSISTENT and PERSISTENT and RECURRENT RECURRENT

Hyperparathyroidism Hyperparathyroidism More rare causes include More rare causes include

parathyroid carcinoma, parathyroid carcinoma, missed adenoma in a normal positionmissed adenoma in a normal position incomplete resection of an abnormal glandincomplete resection of an abnormal gland an inexperienced surgeon. an inexperienced surgeon.

The most common sites of ectopic The most common sites of ectopic parathyroid glands in patients with parathyroid glands in patients with persistent or recurrent HPT are persistent or recurrent HPT are paraesophageal (28%), mediastinal (26%), paraesophageal (28%), mediastinal (26%), intrathymic (24%), intrathyroidal (11%), intrathymic (24%), intrathyroidal (11%), carotid sheath (9%), and high cervical or carotid sheath (9%), and high cervical or undescended (2%) undescended (2%)

Once the diagnosis of persistent or recurrent Once the diagnosis of persistent or recurrent HPT is suspected, it should be confirmed by HPT is suspected, it should be confirmed by the necessary biochemical tests. the necessary biochemical tests.

In particular, a In particular, a 24-hour urine collection24-hour urine collection should be performed to rule out BFHH. If this should be performed to rule out BFHH. If this is not helpful, a is not helpful, a urine calcium to urine calcium to creatinine ratio of less than 0.01 is creatinine ratio of less than 0.01 is confirmatory for BFHHconfirmatory for BFHH. .

In redo parathyroid surgery, the glands are In redo parathyroid surgery, the glands are more likely to be in ectopic locations and more likely to be in ectopic locations and postoperative scarring tends to make the postoperative scarring tends to make the procedure more technically demanding. procedure more technically demanding.

Management of recurrent and persistent HPTManagement of recurrent and persistent HPT

HYPERCALCEMIC HYPERCALCEMIC STATESSTATES

Patients with primary HPT may occasionally present Patients with primary HPT may occasionally present acutely with nausea, vomiting, fatigue, muscle acutely with nausea, vomiting, fatigue, muscle weakness, confusion and a decreased level of weakness, confusion and a decreased level of consciousness; a complex referred to as consciousness; a complex referred to as hypercalcemic crisishypercalcemic crisis. . result from severe hypercalcemia from uncontrolled PTH result from severe hypercalcemia from uncontrolled PTH

secretion, secretion, worsened by polyuria, dehydration, and reduced kidney worsened by polyuria, dehydration, and reduced kidney

function, function, may occur with other conditions causing hypercalcemia. may occur with other conditions causing hypercalcemia.

Calcium levels are markedly elevated and may be as Calcium levels are markedly elevated and may be as high as 16 to 20 mg/dL. high as 16 to 20 mg/dL.

Parathyroid glands tend to be large or multiple, and Parathyroid glands tend to be large or multiple, and the tumor may be palpable. the tumor may be palpable.

Patients with parathyroid cancer or familial HPT are Patients with parathyroid cancer or familial HPT are more likely to present with hyperparathyroid crisis.more likely to present with hyperparathyroid crisis.

HYPERCALCEMIC HYPERCALCEMIC STATESSTATES

Treatment consists of therapies to Treatment consists of therapies to lower lower serum calcium levels followed by surgery to serum calcium levels followed by surgery to correct hyperparathyroidismcorrect hyperparathyroidism..

The mainstay of therapy involves The mainstay of therapy involves rehydration with a 0.9% saline solution to rehydration with a 0.9% saline solution to keep urine output greater than 100 mL/hkeep urine output greater than 100 mL/h..

Once urine output is established, diuresis Once urine output is established, diuresis with furosemide is begun. with furosemide is begun. Furosemide works by increasing renal calcium Furosemide works by increasing renal calcium

clearance, but should not be used without clearance, but should not be used without adequate rehydration and salt loading. adequate rehydration and salt loading.

SECONDARY SECONDARY HYPERPARATHYROIDISMHYPERPARATHYROIDISM

Secondary HPT commonly occurs in patients Secondary HPT commonly occurs in patients with chronic renal failure but may also occur in with chronic renal failure but may also occur in those with hypocalcemia secondary to those with hypocalcemia secondary to inadequate calcium or vitamin D intake, or inadequate calcium or vitamin D intake, or malabsorption. malabsorption.

The pathophysiology of HPT in chronic renal The pathophysiology of HPT in chronic renal failure is complex failure is complex related to hyperphosphatemia (and resultant related to hyperphosphatemia (and resultant

hypocalcemia), deficiency of 1,25-dihydroxy vitamin hypocalcemia), deficiency of 1,25-dihydroxy vitamin D as a result of loss of renal tissue, low calcium D as a result of loss of renal tissue, low calcium intake, decreased calcium absorption, and abnormal intake, decreased calcium absorption, and abnormal parathyroid cell response to extracellular calcium or parathyroid cell response to extracellular calcium or vitamin D in vitro and in vivovitamin D in vitro and in vivo

Patients are generally hypocalcemic or Patients are generally hypocalcemic or normocalcemic. normocalcemic.

SECONDARY SECONDARY HYPERPARATHYROIDISMHYPERPARATHYROIDISM

Aluminum hydroxide, which was often used Aluminum hydroxide, which was often used as a phosphate binder, contributes to the as a phosphate binder, contributes to the osteomalacia observed in this disease.osteomalacia observed in this disease. generally treated medicallygenerally treated medically

low-phosphate diet low-phosphate diet phosphate bindersphosphate binders adequate intake of calcium and 1,25-dihydroxyvitamin adequate intake of calcium and 1,25-dihydroxyvitamin

DD high-calcium, low-aluminum dialysis bath. high-calcium, low-aluminum dialysis bath.

Calcimimetics control parathyroid Calcimimetics control parathyroid hyperplasia and osteitis fibrosa cystica hyperplasia and osteitis fibrosa cystica associated with secondary HPT in animal associated with secondary HPT in animal studies, and decrease plasma PTH and total studies, and decrease plasma PTH and total and ionized calcium levels in humans.and ionized calcium levels in humans.

Secondary Secondary HyperparathyroidismHyperparathyroidism

Surgical treatment is indicated and Surgical treatment is indicated and recommended for patients with bone pain, recommended for patients with bone pain, pruritus, andpruritus, and (1) a calcium-phosphate product (1) a calcium-phosphate product (2) Ca greater than 11 mg/dL with markedly elevated (2) Ca greater than 11 mg/dL with markedly elevated

PTH, PTH, (3) calciphylaxis(3) calciphylaxis

a rare, limb- and life-threatening complication of secondary a rare, limb- and life-threatening complication of secondary HPT HPT

characterized by painful (sometimes throbbing), violaceous characterized by painful (sometimes throbbing), violaceous and mottled lesions, usually on the extremities, which often and mottled lesions, usually on the extremities, which often become necrotic and progress to nonhealing ulcers, gangrene, become necrotic and progress to nonhealing ulcers, gangrene, sepsis, and death.sepsis, and death.

(4) progressive renal osteodystrophy(4) progressive renal osteodystrophy (5) soft-tissue calcification and tumoral calcinosis. (5) soft-tissue calcification and tumoral calcinosis.

Secondary Secondary HyperparathyroidismHyperparathyroidism

Patients should undergo routine dialysis the day prior to Patients should undergo routine dialysis the day prior to surgery to correct electrolyte abnormalities, especially in surgery to correct electrolyte abnormalities, especially in serum potassium levels. serum potassium levels.

Localizations studies are unnecessary but can identify Localizations studies are unnecessary but can identify ectopic parathyroid glands. ectopic parathyroid glands.

A bilateral neck exploration is indicated. A bilateral neck exploration is indicated. The parathyroid glands in secondary HPT are The parathyroid glands in secondary HPT are

characterized by characterized by asymmetric enlargement and nodular asymmetric enlargement and nodular hyperplasiahyperplasia. .

These patients may be treated by subtotal resection, These patients may be treated by subtotal resection, leaving about 50 mg of the most normal parathyroid gland leaving about 50 mg of the most normal parathyroid gland or total parathyroidectomy and autotransplantation of or total parathyroidectomy and autotransplantation of parathyroid tissue into the brachioradialis muscle of the parathyroid tissue into the brachioradialis muscle of the nondominant forearm. nondominant forearm.

Upper thymectomy is usually performed because 15 to Upper thymectomy is usually performed because 15 to 20% of patients have one or more parathyroid glands 20% of patients have one or more parathyroid glands situated in the thymus or perithymic fat.situated in the thymus or perithymic fat.

Bone and joint pain improve in Bone and joint pain improve in approximately 75% of patients who approximately 75% of patients who undergo parathyroidectomy. undergo parathyroidectomy.

Pruritus and malaise also improve in Pruritus and malaise also improve in most, but not all, patients. most, but not all, patients.

Parathyroidectomy also improves Parathyroidectomy also improves bone mineral density, sexual bone mineral density, sexual function, and survival in patients function, and survival in patients with secondary HPT.with secondary HPT.

Benefits of Benefits of Parathyroidectomy in Parathyroidectomy in

Secondary Secondary Hyperparathyroidism Hyperparathyroidism

Tertiary hyperparathyroidism is seen most Tertiary hyperparathyroidism is seen most commonly in patients with long-standing renal commonly in patients with long-standing renal dysfunction who undergo successful renal dysfunction who undergo successful renal transplantation. transplantation.

Generally, renal transplantation is an excellent Generally, renal transplantation is an excellent method of treating secondary HPT, but some method of treating secondary HPT, but some patients develop autonomous parathyroid gland patients develop autonomous parathyroid gland function and tertiary HPT. function and tertiary HPT.

Tertiary HPT can cause problems similar to Tertiary HPT can cause problems similar to PHPT, such as pathologic fractures, bone pain, PHPT, such as pathologic fractures, bone pain, renal stones, peptic ulcer disease, pancreatitis, renal stones, peptic ulcer disease, pancreatitis, and mental status changes. The transplanted and mental status changes. The transplanted kidney is also at risk.kidney is also at risk.

TERTIARY TERTIARY HYPERPARATHYROIDISMHYPERPARATHYROIDISM

Operative intervention is indicated for Operative intervention is indicated for symptomatic symptomatic disease or if autonomous PTH secretion persists for disease or if autonomous PTH secretion persists for more than 1 year after a successful transplantmore than 1 year after a successful transplant. .

All parathyroid glands should be identified. The traditional All parathyroid glands should be identified. The traditional surgical management of these patients consisted of surgical management of these patients consisted of subtotal or total parathyroidectomy with subtotal or total parathyroidectomy with autotransplantation. However, more recent studies 79 autotransplantation. However, more recent studies 79 suggest that these patients derive similar benefit from suggest that these patients derive similar benefit from excision of only obviously enlarged glands, while avoiding excision of only obviously enlarged glands, while avoiding the higher risks of hypocalcemia associated with the the higher risks of hypocalcemia associated with the former approach. former approach.

It is recommended that all parathyroid glands be It is recommended that all parathyroid glands be identified. If one gland is distinctly abnormal and others identified. If one gland is distinctly abnormal and others minimally abnormal, the abnormal gland and the more-minimally abnormal, the abnormal gland and the more-normal gland on the same side should be resected with the normal gland on the same side should be resected with the remaining parathyroids marked. If all the glands are remaining parathyroids marked. If all the glands are abnormal, a subtotal parathyroidectomy should be abnormal, a subtotal parathyroidectomy should be performed with upper thymectomy.performed with upper thymectomy.

Tertiary Tertiary HyperparathyroidismHyperparathyroidism

General complications includeGeneral complications include bleeding bleeding wound complications such as wound complications such as

seromas seromas Infection - rare Infection - rare

Specific complications include Specific complications include transient and permanent vocal cord palsy transient and permanent vocal cord palsy hypoparathyroidism. hypoparathyroidism.

more likely to occur in patients who undergo four-gland more likely to occur in patients who undergo four-gland exploration with biopsies, subtotal resection with an inadequate exploration with biopsies, subtotal resection with an inadequate remnant, or total parathyroidectomy with a failure of remnant, or total parathyroidectomy with a failure of autotransplanted tissue. autotransplanted tissue.

more likely to occur in patients with high turnover bone disease as more likely to occur in patients with high turnover bone disease as evidenced by elevated preoperative alkaline phosphatase levels. evidenced by elevated preoperative alkaline phosphatase levels.

Vocal cord paralysis and hypoparathyroidism are Vocal cord paralysis and hypoparathyroidism are considered considered permanent if they persist for more than 6 permanent if they persist for more than 6 monthsmonths. . rare, ~ 1%rare, ~ 1%

COMPLICATIONS OF COMPLICATIONS OF PARATHYROID SURGERYPARATHYROID SURGERY

Patients with symptomatic hypocalcemia or those Patients with symptomatic hypocalcemia or those with calcium levels less than 8 mg/dL are treated with calcium levels less than 8 mg/dL are treated with with oral calcium supplementation (up to 1 to oral calcium supplementation (up to 1 to 2 g every 4 hours). 2 g every 4 hours). 1,25-1,25-

Dihydroxy vitamin D (Rocaltrol 0.25 to 0.5 g bid) Dihydroxy vitamin D (Rocaltrol 0.25 to 0.5 g bid) may also be required, particularly in patients with may also be required, particularly in patients with severe hypercalcemia and elevated serum alkaline severe hypercalcemia and elevated serum alkaline phosphatase levels preoperatively and with osteitis phosphatase levels preoperatively and with osteitis fibrosa cystica. fibrosa cystica.

Intravenous calcium supplementation is rarely Intravenous calcium supplementation is rarely needed, except in cases of severe, symptomatic needed, except in cases of severe, symptomatic hypocalcemia. Caution should be exercised in its hypocalcemia. Caution should be exercised in its administration because extravasation from the vein administration because extravasation from the vein can cause extensive tissue necrosis.can cause extensive tissue necrosis.

Complications of Complications of Parathyroid SurgeryParathyroid Surgery

The parathyroid glands may be congenitally absent in the The parathyroid glands may be congenitally absent in the DiGeorge syndrome, which also is characterized by lack of thymic DiGeorge syndrome, which also is characterized by lack of thymic development, and, therefore, a thymus-dependent lymphoid development, and, therefore, a thymus-dependent lymphoid system. system.

Hyperparathyroidism in pregnant women can lead to Hyperparathyroidism in pregnant women can lead to hypoparathyroidism in neonates from suppression of fetal hypoparathyroidism in neonates from suppression of fetal parathyroid tissue. parathyroid tissue.

the most common cause of hypoparathyroidism is thyroid the most common cause of hypoparathyroidism is thyroid surgery, particularly total thyroidectomy with a surgery, particularly total thyroidectomy with a concomitant central neck dissection. concomitant central neck dissection.

Patients often develop transient hypocalcemia as a result of Patients often develop transient hypocalcemia as a result of bruising or damage to the vascular supply of the glands; bruising or damage to the vascular supply of the glands; permanent hypoparathyroidism is rare. permanent hypoparathyroidism is rare.

Hypoparathyroidism may also occur after parathyroid surgery, Hypoparathyroidism may also occur after parathyroid surgery, which is more likely if patients have parathyroid hyperplasia and which is more likely if patients have parathyroid hyperplasia and undergo a subtotal resection or total parathyroidectomy with undergo a subtotal resection or total parathyroidectomy with parathyroid autotransplantation. Parathyroid tissue should be parathyroid autotransplantation. Parathyroid tissue should be cryopreserved in any patient who could develop cryopreserved in any patient who could develop hypoparathyroidism, but is only needed in approximately 2% of hypoparathyroidism, but is only needed in approximately 2% of patients.patients.

HYPOPARATHYROIDISM HYPOPARATHYROIDISM

Acute hypocalcemia results in decreased ionized Acute hypocalcemia results in decreased ionized calcium and increased neuromuscular excitability. calcium and increased neuromuscular excitability. circumoral and fingertip numbness and tingling. circumoral and fingertip numbness and tingling. Mental symptoms include anxiety, confusion, and Mental symptoms include anxiety, confusion, and

depression. depression. Physical examination reveals Physical examination reveals

positive positive Chvostek's signChvostek's sign (contraction of facial muscles (contraction of facial muscles elicited by tapping on the facial nerve anterior to the ear) elicited by tapping on the facial nerve anterior to the ear)

Trousseau's sign Trousseau's sign (carpopedal spasm, which is elicited by (carpopedal spasm, which is elicited by occluding blood flow to the forearm with a blood pressure occluding blood flow to the forearm with a blood pressure cuff for 2 to 3 minutes). cuff for 2 to 3 minutes).

Tetany, which is characterized by tonic–clonic Tetany, which is characterized by tonic–clonic seizures, carpopedal spasm, and laryngeal stridor, seizures, carpopedal spasm, and laryngeal stridor, may prove fatal and should be avoided. may prove fatal and should be avoided.

Most patients with postoperative hypocalcemia can Most patients with postoperative hypocalcemia can be treated with oral calcium and vitamin D be treated with oral calcium and vitamin D supplements. supplements.

Intravenous calcium infusion is rarely required.Intravenous calcium infusion is rarely required.

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