Present Illness & Past History
62-year-old female, general twitching, painful
sensation bothered her for months.
Gout (+), HTN (+)
• (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 &
• (3)HIVD with lumbar stenosis of L4-5, left s/p disectomy
with laminectomy of L4-5 (91-08-28)
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
malignancy, the next most common cause of
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%)
• The gene responsible for MEN 1, menin (chromosome 11), has been
identified & cloned with tumor suppressor function.
Etiologic Factors & Pathogenesis (2)
• A milder form, resection of only enlarged glands compared to
subtotal resections in patients with other forms of multigland
• 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
adults is the common presentation.
• The pathologic finding is usually a single adenoma. Bone lesions
of 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
• The Ca clearance-Cr clearance ratio with a cutoff of .01 distinguishing from
• 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.
• 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
• Prolonged abnormalities can evolve into a state of autonomous PTH
secretion & hypercalcemia,
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
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
The urinary Ca clearance-Cr clearance ratio, previous Ca levels, & family
history are helpful.
Evaluation for other endocrine disorders associated with one of the MEN
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
presence 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
C=resorption & tapering of distal clavicle
D=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 uptake
C=confirms concentrations in parathyroid adenoma
Institution of therapy for hypercalcemia depends on the degree of
hypercalcemia & the presence or absence of clinical symptoms.
Mild hypercalcemia usually have no symptoms, require no Ca-lowering
Moderate hypercalcemia & symptoms probably benefit from
Severe hypercalcemia require hospitalization & therapy.
The combination of altered mental status, anorexia, nausea, &
defective 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
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
to 48 hrs of therapy.
Calcitonin alone rarely normalizes serum Ca levels but is useful in
addition to bisphosphonates.
Iv bisphosphonate therapy with pamidronate (60-90 mg)
The onset of action for pamidronate is 24 to 48 hours after infusion,
with 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
severe hypercalcemia are rarely used today.
H/D in severe hypercalcemia with impaired renal function.
Glucocorticoids: hypercalcemia due to lymphoma or
granulomatous 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
Surgery is the only curative therapy for primary
Up to 25% of patients develop an indication for surgery during
Increases in BMD of both the hip & the spine after surgical cure of
Avoidance of drugs that could worsen hypercalcemia, especially
Modest Ca intake is generally recommended because low Ca intake
could theoretically stimulate more PTH production.
Estrogen therapy can be considered in postmenopausal women.
Yearly measurement of bone density, 24-hour urinary Ca values, &
serum Ca levels is advised, as is monitoring for nephrolithiasis.
Preventing tertiary hyperparathyroidism by controlling serum
phosphate levels, replacing 1,25-dihydroxyvitamin D, & maintaining
Ca levels to decrease stimulation of PTH secretion & parathyroid
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
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.
An experienced endocrine surgeon cures > 95% undergoing initial
bilateral neck exploration & incurs < 1% perioperative morbidity.
Reoperations for persistent or recurrent primary hyperparathyroidism
are less successful (about 80% cure) & much higher incidence of
25% of patients remained either hypercalcemic (13%) or
permanently hypocalcemic (12%), a reflection of previously failed
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
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
before an adequate
decrease in PTH
predicted a return to
patient with an unusual
tumor had a delayed (20
min) fall in QPTH.
Hereditary & multigland disease, more aggressive initial surgery is performed,
usually a subtotal or a total parathyroidectomy with autotransplantation.
Recurrence of primary hyperparathyroidism due to remnant gland or
autotransplanted tissue is common in patients with MEN 1 & renal failure.
Because of improvements in preoperative localization imaging of the
parathyroid glands 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
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
(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
(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
'asymptomatic' or minimally symptomatic patient are to
prevent complications such as nephrolithiasis,
deterioration in renal function, accelerated bone loss and
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
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
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%,
Average PTH levels fell from 142 pg/mL to 49 pg/mL after
Preop & postop Ca & PTH levels for the three groups showed no
The success of surgery in identifying pathology ranged from
90.5% to 95%, & again showed no difference among the three
Long-term morbidity (>6 months) in all groups was 0%.
Cervical exploration & parathyroidectomy for asymptomatic
primary 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).
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
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
3 patients with likely mediastinal parathyroid
adenomas that had single feeding arteries
underwent attempted arteriographic
ablation with a slow continuous infusion of
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)