Parathyroid Adenoma

Chou Chien-Wen M.D.Endocrine & Metabolism Section

Chi-Mei Medical Center10 Jan 2003

Case Report 病歷號碼 : 14347945 姓名 : 黃 X 芷 出生日期 : 29-10-16 性別 : 女

Present Illness & Past History 62-year-old female, general twitching, painful sen

sation bothered her for months. Gout (+), HTN (+) Operation history:

• (1)R't renal stone s/p ESWL (1993 Sep)

• (2)Fail back surgery syndrome with HIVD with stenosis of L4-5 s/p disectomy of L5-S1 & laminectomy of L4-5 & L5-S1 (91-07-17)

• (3)HIVD with lumbar stenosis of L4-5, left s/p disectomy with laminectomy of L4-5 (91-08-28)

Laboratory Data: BUN/Cr: 22.8/1.17 (91-12-12) Na/K: 138.1/4.72 (91-12-12) Serum Ca:

• 13.7 (91-11-18) • 11.6 (91-12-14)• 12.3 (91-12-30) • 8.8 (92-01-02) postoperation

Free-Ca: 5.6 (91-12-18) P: 2.7 (91-12-3) Alk P-tase: 216 (91-12-3) i-PTH 223.7 pg/ml (91-12-2)

Operation & Pathology

Operation• Parathyroidectomy, right

• Partial central LNs dissection

Pathology• Parathyroid adenoma, right lower parathyroid

gl &, parathyroidectomy

• Nodular goiter, bilateral thyroid, bilateral subtotal thyroidectomy

Introduction The estimated incidence is 1 case per 1000 men & 2 to 3

cases per 1000 women. The severe complications of hyperparathyroidism, osteitis

fibrosa cystica & nephrocalcinosis, are rarely seen today. Distinguishing primary hyperparathyroidism from maligna

ncy, the next most common cause of hypercalcemia, Minimally invasive surgery is now available, in addition to

standard bilateral neck exploration, as curative therapy for primary hyperparathyroidism.

(Mayo Clinic Proceedings Volume 77(1) January 2002 pp 87-91)

Etiologic Factors & Pathogenesis (1) Sporadic, benign parathyroid adenomas 80%-85%

• Postmenopausal women, average age of 55 years External neck irradiation Lithium therapy 5%

• Multiple parathyroid glands may be abnormal, & hyperparathyroidism may persist after discontinuation of the drug.

Hereditary disorders 10%, including familial hyperparathyroidism or MEN type 1 & 2A & hyperparathyroidism-jaw tumor syndrome.

MEN 1 95% • present at a younger age, more severe disease

• Associated tumors include pancreatic (30%-80%) & pituitary (15%-50%) adenomas.

• The gene responsible for MEN 1, menin (chromosome 11), has been identified & cloned with tumor suppressor function.

Etiologic Factors & Pathogenesis (2) MEN 2A

• A milder form, resection of only enlarged glands compared to subtotal resections in patients with other forms of multigland disease.

• MCT is a universal component of this syndrome.• Pheochromocytoma 50% & primary hyperparathyroidism 10%. • Mutations of the ret proto-oncogene.

Hyperparathyroidism-jaw tumor syndrome• Early, relatively severe hypercalcemia in teenagers or young adult

s is the common presentation.• The pathologic finding is usually a single adenoma. Bone lesions o

f the jaw appear as cystic punched-out regions on x-ray films. • Frequent association with Wilms tumors or renal cysts.• A familial disorders

Etiologic Factors & Pathogenesis (3) Parathyroid carcinoma < 0.5% of cases

• Severe hypercalcemia, extremely high PTH levels, a palpable neck mass. Benign familial hypocalciuric hypercalcemia (FHH)

• an autosomal dominant disorder, hypercalcemia & relative hypocalciuria.

• The degree of hypercalcemia is generally mild. Normal PTH levels but in 5% to 10% of patients, modestly elevated.

• Most kindreds have an inactivating mutation of Ca sensing receptor, resulting in a mild increase in the set point for Ca suppression of PTH secretion.

• The Ca clearance-Cr clearance ratio with a cutoff of .01 distinguishing from primary hyperparathyroidism.

• This disorder results in hypercalcemia at birth

• Surgery or further medical evaluation is not indicated because it is a benign condition without progressive complications.

Etiologic Factors & Pathogenesis (4) Insufficient Vit D &/or insufficient Ca intake

• Mild secondary hyperparathyroidism

• Normal serum Ca level & an elevated PTH level

• Measurement of 25-hydroxyvitamin D & 24-hour urinary Ca level is helpful

• Such patients often have intermittent elevations of ionized Ca levels with documented stone disease &/or osteoporosis.

ESRD • most common cause of secondary hyperparathyroidism.

• PTH secretion is stimulated by hypocalcemia, which results from low concentrations of 1,25-dihydroxy-vitamin D due to decreased renal production, & by hyperphosphatemia.

• Prevention with supplementation with 1,25-dihydroxyvitamin D & Ca & control of hyperphosphatemia

Tertiary hyperparathyroidism• Prolonged abnormalities can evolve into a state of autonomous PTH secr

etion & hypercalcemia,

Evaluation The total Ca level can be "corrected" by adding 0.8 mg/dL for every 1.0 g/dL

by which the serum albumin concentration is lower than 4.0 g/dL. All patients will have increased ionized Ca levels. Hypercalcemia, an elevated or inappropriately high-normal PTH level is diag

nostic Malignancy is associated with suppressed levels of PTH. Modern intact PTH assays have no cross-reactivity with PTH-related protein. FHH: in young patients with mild hypercalcemia & normal or slightly elevated

PTH levels. The urinary Ca clearance-Cr clearance ratio, previous Ca levels, & family his

tory are helpful. Evaluation for other endocrine disorders associated with one of the MEN syn

dromes Appropriate genetic testing for MEN BMD is usually measured, cortical sites such as the distal one-third radius. A 24-hour urinary Ca measurement & radiological evaluation for the presenc

e of kidney stones

Radiographic manifestations of PHP.

A=subperiosteal resorption of radial side of middle phalanges & distal turfs; B="Brown tumour" (arrow) in the proximal tibia; C=resorption & tapering of distal clavicleD=cystic changes in head of humerus

Technetium-99m sestamibi/iodine scans in planar (A), coronal (B), & sagittal (C) views.

A=increased uptake of the radiotracer in right lower parathyroid adenoma & thyroid in early image (after 20 min)B=after 2 h, concentration of radiotracer in parathyroid adenoma with disappearance of thyroid uptakeC=confirms concentrations in parathyroid adenoma

Management (1) Institution of therapy for hypercalcemia depends on the degree of hype

rcalcemia & the presence or absence of clinical symptoms. Mild hypercalcemia usually have no symptoms, require no Ca-lowering

agents Moderate hypercalcemia & symptoms probably benefit from hypocalce

mic agents. Severe hypercalcemia require hospitalization & therapy. The combination of altered mental status, anorexia, nausea, & defectiv

e urine-concentrating ability results in dehydration. Iv fluids are the initial therapy for severe hypercalcemia.

Diuretic therapy with furosemide (20 mg) should not be instituted until euvolemia is achieved.

Correction of fluid deficits alone can produce a decrease in the Ca level but rarely restores normocalcemia

Management (2) Hypocalcemic agents, calcitonin (4-8 IU/kg im or sc q 6-8 hrs) has the

most rapid onset of action. Resistance to its hypocalcemic effects develops & limits its use to 24 t

o 48 hrs of therapy. Calcitonin alone rarely normalizes serum Ca levels but is useful in addi

tion to bisphosphonates. Iv bisphosphonate therapy with pamidronate (60-90 mg) The onset of action for pamidronate is 24 to 48 hours after infusion, wit

h nadir Ca at about 7 days. Duration of treatment effect varies from weeks to months. Plicamycin, gallium nitrate, & etidronate, used in the past to treat sever

e hypercalcemia are rarely used today. H/D in severe hypercalcemia with impaired renal function.

Management (3) Glucocorticoids: hypercalcemia due to lymphoma or granulomat

ous diseases but have no role in managing hypercalcemia due to hyperparathyroidism.

Treating the underlying cause of hypercalcemia is necessary. Ca sensing receptor agonists (calcimimetics) have been studied

in a small number of patients but are not available clinically. Estrogen replacement therapy for postmenopausal women can

attenuate bone resorption & results in modest reduction in serum Ca levels.

Older bisphosphonates did not sustain reductions in serum Ca levels.

Surgery is the only curative therapy for primary hyperparathyroidism

Management (4) Up to 25% of patients develop an indication for surgery during medica

l observation. Increases in BMD of both the hip & the spine after surgical cure of hyp

erparathyroidism Avoidance of drugs that could worsen hypercalcemia, especially thiazi

des. Modest Ca intake is generally recommended because low Ca intake c

ould theoretically stimulate more PTH production. Estrogen therapy can be considered in postmenopausal women. Yearly measurement of bone density, 24-hour urinary Ca values, & se

rum Ca levels is advised, as is monitoring for nephrolithiasis. Preventing tertiary hyperparathyroidism by controlling serum phospha

te levels, replacing 1,25-dihydroxyvitamin D, & maintaining Ca levels to decrease stimulation of PTH secretion & parathyroid gland growth.

Management (5) The doses of calcitriol needed to suppress serum PTH levels can lead to

hypercalcemia or hyperphosphatemia. New vitamin D analogues, 22-oxacalcitriol, 19-nor-1,25-dihydroxyvitamin

D2 (paricalcitol), & 1-alpha-hydroxyvitamin D2 (doxercalciferol), have the advantages of suppressing PTH & a reduced tendency to increase serum Ca & phosphate levels

After tertiary hyperparathyroidism has developed, calcitriol must be used carefully because it can worsen hypercalcemia.

Sevelamer is a polymer-based phosphate binder that can be used in place of Ca-based phosphate binders to decrease hyperphosphatemia in patients with hypercalcemia.

Surgery is often necessary to control hypercalcemia in patients with tertiary hyperparathyroidism.

Indications for surgery in secondary hyperparathyroidism due to renal failure include severe metabolic bone disease (renal osteodystrophy, fractures), intractable bone pain & pruritis, & rarely necrotizing skin ulcers (calciphylaxis) not responding to dialysis & medical therapy.

Surgery (1) An experienced endocrine surgeon cures > 95% undergoing initial bi

lateral neck exploration & incurs < 1% perioperative morbidity. Reoperations for persistent or recurrent primary hyperparathyroidism

are less successful (about 80% cure) & much higher incidence of complications.

25% of patients remained either hypercalcemic (13%) or permanently hypocalcemic (12%), a reflection of previously failed procedures.

Preoperative localization of the abnormal parathyroid gland(s) is unnecessary for initial bilateral neck exploration.

In patients who have had prior neck surgery, preoperative localization is essential because scar tissue & altered anatomy make surgical exploration more challenging.

Sestamibi imaging of the parathyroid gland has the best specificity & sensitivity (90%-95% & 80%-85%, respectively)

In sporadic cases of primary hyperparathyroidism, a single adenomatous gl & is usually found & removed.

A New, Practical Intraoperative Parathyroid Hormone Assay (1)

PTH measurement by immuno-chemiluminometric assay (ICMA) is a nonradioisotopic technique that is more practical for use during parathyroidectomy.

Sixteen patients had multiple samples taken during parathyroidectomy.

PTH levels measured 5 minutes after excision of a suspected abnormal gland were compared with pre-operative or preexcision samples & either confirmed complete excision or indicated the need for more exploration in each patient.

Correlation of 88 ICMA samples with standard 24-hour IRMA controls was excellent (r equals 0.9218, P <0.0001).

The sensitivity of the test in predicting postoperative Ca levels was 94 percent.

(American Journal of Surgery Volume 168(5) November 1994 pp 466-468)

Intraoperative monitoring (with immunochemiluminometric assay ICMA) identified 11 patients with single-gland involvement by a marked decrease in intraoperative (QPTH) levels after excision.

Four patients who had minimal decreases in (PTH) required excision of a second hyperfunctioning gland before an adequate decrease in PTH predicted a return to normocalcemia. One patient with an unusual tumor had a delayed (20 min) fall in QPTH.

Surgery (2) Hereditary & multigland disease, more aggressive initial surgery is performed, usu

ally a subtotal or a total parathyroidectomy with autotransplantation. Recurrence of primary hyperparathyroidism due to remnant gland or autotranspla

nted tissue is common in patients with MEN 1 & renal failure. Because of improvements in preoperative localization imaging of the parathyroid g

lands with sestamibi scintigraphy & high-resolution ultrasonography coupled with intraoperative rapid PTH assay, minimally invasive techniques are feasible.

Minimally invasive parathyroidectomy refers to one of several procedures, including video-assisted or endoscopic, radioguided, & unilateral image-guided explorations.

Abnormal parathyroid gland must be located preoperatively on imaging studies, usually sestamibi imaging.

Patients with known or suspected multigland disease or prior neck surgery are not generally candidates for this procedure.

Cure rates are no better than those with traditional bilateral neck exploration. Improved cosmetic appearance, less pain, & shorter operative time. Procedures performed with local anesthesia are associated with fewer GI adverse

effects.

Minimal InvasiveAdenectomy

(Ann of Surgery Volume 231(4) April 2000  pp 559-565)

Changes in the pattern of clinical presentation of primary hyperparathyroidism

Indications for surgery in asymptomatic patients with hyperparathyroidism

(1) serum Ca level > 1 mg/dL above reference range

(2) any complications such as nephrolithiasis or bone disease

(3) an episode of life-threatening hypercalcemia

(4) severe hypercalciuria (>400 mg/24 h)

(5) reduced bone mass, especially of distal radius (T score less than -2)

(6) age younger than 50 years

Role of surgery in mild primary hyperparathyroidism in the elderly The usual reasons for advising surgery in an 'asymptomat

ic' or minimally symptomatic patient are to prevent complications such as nephrolithiasis, deterioration in renal function, accelerated bone loss and fracture

Elderly patients with primary HPT present more often with indistinct psychiatric and musculoskeletal symptoms, and these are the symptoms most likely to be improved by operation

Morbidity and mortality rates related to neck exploration in the elderly are similar to those in younger age groups

(British Journal of Surgery Volume 87(12) December 2000 pp 1640-1649)

Success of Cervical Exploration for Patients with Asymptomatic

Primary Hyperparathyroidism 61 patients were identified. 19 (31%) had no symptoms, 21 (34%)

had subjective symptoms, & 21 had associated conditions Average preop & postop Ca levels were 11.5 mg% & 8.5 mg%, re

spectively. Average PTH levels fell from 142 pg/mL to 49 pg/mL after surgery.

Preop & postop Ca & PTH levels for the three groups showed no

significant differences. The success of surgery in identifying pathology ranged from 90.5

% to 95%, & again showed no difference among the three groups. Long-term morbidity (>6 months) in all groups was 0%. Cervical exploration & parathyroidectomy for asymptomatic primar

y hyperparathryoidism is safe & has similar success rates in identifying pathology & correcting biochemical abnormalities compared with patients with symptomatic disease.

( Am J Surg. 1999;177:69-74).( Am J Surg. 1999;177:69-74).

Ethanol Ablation

The abnormal parathyroid gland(s) must be detectable by ultrasonography & confirmed by fine-needle aspiration for cytology & PTH measurement before this approach.

Large parathyroid adenomas are difficult to cure by ethanol injection.

Patients who have undergone a subtotal parathyroidectomy for multigland disease & have recurrent hyperparathyroidism due to the remnant gland are c&idates for ethanol ablation.

Hypoparathyroidism & recurrent laryngeal nerve damage are rarely seen.

Cure rates are much lower than those with surgery.

Angiographic Ablation of Mediastinal Parathyroid Adenomas

3 patients with likely mediastinal parathyroid adenomas that had single feeding arteries underwent attempted arteriographic ablation with a slow continuous infusion of contrast medium.

All 3 patients were cured (follow-up 22 to 68 months) with no long-term complications.

(American of medicine Volume 97(6) December 1994 pp 529-534)