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424 Disorders of the Parathyroid Gland and Calcium

Homeostasis

Parathyroid gland
o Four glands; located posterior to the thyroid gland
o Produce parathyroid hormone
Parathyroid hormone
o Acts directly on the bone to induce calcium release
o Acts on the kidney to enhance calcium reabsorption and
increase synthesis of 1,25-dihydoxyvitamin D
1,25-dihydroxyvitamin D
o Increase gastrointestinal calcium absorption
PARATHYROID HORMONE

I. PHYSIOLOGY

Primary function is to maintain ECF calcium concentration

Production is regulated by concentration of serum ionized calcium

Overall effects:
o Increase rate of dissolution of bone mineral
o Reduce renal clearance of calcium
o Increase efficiency of intestinal calcium absorption by
stimulating production of 1,25 (OH)2D

Renal effects:
o Proximal tubule Inhibition of phosphate transport
o Distal tubule Augmentation of calcium reabsorption
o Stimulation of renal 25(OH)D-1a-hydroxylase

Bone effects:
o increase osteoblasts and osteoclasts; increase bone
remodeling
o Continuous exposure increased osteoclast-mediated
bone resorption
o Intermittent exposure net stimulation of bone
formation
o Osteoblasts have PTH receptors, crucial to boneforming effect
o Osteoclasts lack PTH receptors, activated by
osteoblast-derived cytokines

PARATHYROID HORMONE-RELATED PROTEIN (PTHrP)

I. PTH AND PTHrP HORMONE ACTION

Both PTH and PTHrP bind to and activate the PTH/PTHrP receptor
o PTH1R respond equivalently to both
o PTH2R (human) respond efficiently to PTH (but not to
PTHrP)
CALCITONIN

2. Regulation of PTH Secretion

Ionized fraction of blood calcium the important determinant of


hormone secretion

Intracellular magnesium deficiency impairs PTH secretion

Calcium-sensing Receptor (CaSR)


o Stimulation by high calcium levels suppress PTH
secretion
o FHH - heterozygous loss-of-function mutations in CaSR
3. Metabolism

Peripheral metabolism does not appear to be regulated by


physiologic states (high versus low calcium, etc.)

Indirect antagonist to the calcemic actions of PTH


Limited physiologic response in humans
Medically significant
o As a tumor marker in medullary thyroid carcinoma
o Adjunctive treatment in sever hypercalcemia and
Pagets disease of the bone
Physiologic effects:
o Inhibition of osteoclast-mediated bone resorption
o Stimulation of renal calcium clearance
Thyroid major source of the horome
Salmon calcitonin 10-100 times more potent than mammalian
forms in lowering serum calcium
HYPERCALCEMIA

II. BIOSYNTHESIS, SECRETION AND METABOLISM


1. Synthesis

Multiple responses to hypocalcemia


o Secretion of preformed hormones (within minutes)
o Induced PTH mRNA expression (within hours)
o Cellular replication to increase parathyroid gland mass
(within days)

PTH gene regulation


o Physiologic calcium levels transcription is nearly
maximally suppressed
o Hypocalcemia increases transcriptional activity within
hour
o 1,25 (OH)2D strongly suppresses transcription

Responsible for humoral hypercalcemia of malignancy


Produced normally by brain, pancreas, heart, lung, mammary
tissue, placenta, smooth muscles
Directs transplacental calcium transfer
Plays an essential role in endochondral bone formation
Little influence on calcium homeostasis in adults except in large
tumors (squamous cell carcinomas)

Hyperparathyroidism
o A frequent cause of asymptomatic hypercalcemia
Malignancy
o Second most common cause of hypercalcemia in the
adult
o Symptoms bring the patient to the physician
o Interval between detection of hypercalcemia and death is
often <6 months
Other causes
o Excessive vitamin D action
o Impaired metabolism of 1,25 (OH)2D
o High bone turnover
o Renal failure
Clinical manifestations
o Fatigue, depression
o Mental confusion
o Anorexia, nausea, vomiting
o Increased urine output
o Short QT interval and cardiac arrhythmias
Severe hypercalcemia ( 3.7-4.5 mmol/L)
o Coma and cardiac arrest can occur

I. PRIMARY HYPERPARATHYROIDISM
1. Natural History and Incidence

Hypercalcemia and hypophosphatemia

Recurrent nephrolithiasis, peptic ulcers, mental changes and


extensive bone resorption

Minimal or no symptoms

Hypercalcemic parathyroid crisis worsening


hyperparathyroidism causing dehydration and coma

2. Etiology
SOLITARY ADENOMAS

The cause in ~80% of patients

Usually a benign neoplasm or adenoma, rarely a parathyroid


carcinoma

In ~15% of patients, all glands are hyperfunctioning


HEREDITARY SYNDROMES AND MULTIPLE PARATHYROUD TUMORS

Multiple endocrine neoplasia (MEN) 1


o Wermers syndrome
o Parathyroid, pancreas and pituitary tumors (PaPa Pi)

Multiple endocrine neoplasa (MEN) 2A


o Parathyroid, pheochromocytoma, medullary thyroid
carcinoma
3. Pathology

Adenomas are most often located in the inferior parathyroid


glands

Chief cells are predominant in both hyperplasia and adenoma

Parathyroid carcinoma
o Often not aggressive
o Usually more severe clinically
o Associated with serum calcium values of 3.5-3.7 mmol/L
4. Signs and Symptoms

Many patients are asymptomatic

Kidney manifestations
o Calcium deposition in the renal parenchyma
o Recurrent nephrolithiasis

Bone manifestations
o Osteitis fibrosa cystica

Distinct bone manifestation of


hyperparathyroidism

Giant multinucleated osteoclasts

Fibrous replacement of marrow elements


o Bone density

Cortical bone density is reduced

Cancellous bone density is relatively


preserved

CNS manifestations
o Proximal muscle weakness
o Atrophy of muscles
o Complete regression of neuromuscular disease after
surgery (distinguishing feature)

GI manifestations
o Duodenal ulcers secondary to Zollinger-Ellison
syndrome in MEN1

Asymptomatic primary hyperparathyroidism


o Most prevalent form
5. Diagnosis

Elevated PTH with asymptomatic hypercalcemia

Serum phosphate usually low but may be normal in renal failure


6. Treatment

Surgical excision of abnormal parathyroid tissue


o Definitive therapy
o Conservative approach

If an enlarged gland is found, a normal gland


should be sought

If biopsy of normal gland is normal, no further


exploration or excision is needed
o Alternative approach

All four glands should be sought

Most of the total parathyroid tissue mass must


be removed

Pre-operative 99m Tc sestamibi scan


o Predict location of abnormal gland

Intraoperative PTH sampling before and after removal of


adenoma

Confirm a rapid fall (>50%) to normal PTH


levels
Multiple-gland hyperplasia
o Two approaches

Remove three glands with partial excision of


the fourth gland

Total parathyroidectomy with


transplantation of minced parathyroid gland
into the forearm muscles
Serum calcium response
o Decline occurs within 24 hours
o Falls to low-normal values for 3-5 days until remaining
parathyroid tissue resumes full activity
o Iatrogenic hypoparathyroidism

If serum calcium falls to <2 mmol/L AND

Serum phosphate rises simultaneously


Hypocalcemia
o Muscle twitching
o General sense of anxiety
o Positive Chvosteks and Trousseaus signs
o Treatment

Parenteral calcium

When hypocalcemia is
symptomatic

0.5 2 mg/kg/hr

Calcitriol and/or oral calcium

If symptoms worsen or parenteral


calcium is needed for >2-3 days
o

TABLE 424-2 GUIDELINES FOR SURGERY IN ASYMPTOMATIC PRIMARY


HYPERPARATHYROIDISM
Parameter
Guideline
Serum calcium (above normal)
> 1 mg/dL
24-h urinary calcium
No indication
Creatinine clearance
If <60 mL/min
T score < -2.5 at any of 3 sites
Bone denisty
(spine, hip, distal radius)
Age
< 50
TABLE 424-3 GUIDELINES FOR MONITORING IN ASYMPTOMATIC
PRIMARY HYPERPARATHYROIDISM
Parameter
Guideline
24-h urinary calcium
Recommended
Creatinine clearance
Recommended
Serum calcium
Annually
Annually 3 sites
Bone denisty
(spine, hip, distal radius)
Serum creatinine
Annually
II. MALIGNANCY-RELATED HYPERCALCEMIA
1. Clinical Syndromes and Mechanisms of Hypercalcemia

PTHrP humoral agent responsible for hypercalcemia

Histologic character of tumor is more important than extent of


skeletal metastases
o Squamous cell CA develop hypercalcemia

Mechanisms of hypercalcemia
o Humoral hypercalcemia of malignancy

PTHrP-mediated bone resorption (solid


tumors)
o Osteoclast activation factor

Several cytokines produced by myeloma and


lymphoma cells
2. Diagnostic Issues

Undetectable PTH

Tumor symptoms are prominent with incidental finding of


hypercalcemia
Squamous cell tumors most frequently associated with
hypercalcemia
o Lung
o Kidney
o Head and neck
o Urogenital tract

III. HYPERCALCEMIA ASSOCIATED WITH RENAL FAILURE


1. Severe Secondary Hyperparathyroidism

PTH resistance
o Major factor in developing hypocalcemia
o Leads to parathyroid gland enlargement

FGF23
o Potent inhibitor of renal 1-a hydroxylase

Adaptive response of parathyroid glands (reversible) vs.


autonomous growth (irreversible) in primary hyperparathyroidism

Renal osteodystrophy
o Bone disease seen in secondary hyperparathyroidism
and CKD

Adynamic bone disease


o Low-turnover bone disease
o Due to excessive PTH suppression
2. Treatment

Reduction of excessive blood phosphate


o Dietary restriction
o Use of phosphate binders

Calcium carbonate

Preferable over aluminumcontaining antacids

Sevelamer

Synthetic gel that avoids excess


calcium loading
o Selective addition of calcitriol

Tertiary hyperparathyroidism
o Severe hyperparathyroidism no longer responsive to
medical therapy
o Surgery necessary to control this condition
TREATMENT OF HYPERCALCEMIC STATES
I. HYDRATION, INCREASED SALT INTAKE, MILD AND FORCED
DIURESIS

Restore normal hydration first principle of treatment

Increase urinary sodium excretion (400-500 mmol/d)


o Further increase in urinary calcium excretion

Furosemide / ethacrynic acid


o After rehydration has been achieved
o Decrease tubular reabsorption of calcium
II. BISPHOSPHONATES

Powerful inhibitors of bone resorption

Concentrated in areas of high bone turnover

Inhibit osteoclast action

Increasing order of potency


o Etidronate < Tiludronate < Pamidronate < Alendronate <
Risedronate < Zoledronate

Pamidronate
o Single IV bolus (30 90 mg)
o Normalize calcium within 24-48 h
o Effect lasts for weeks

Zoledronate
o 4 or 8 mg / 5 min infusion
o More rapid and sustained effect than pamidronate

III. CALCITONIN

Acts within a few hours of administration

Act through calcitonin receptors on osteoclasts

Tachyphylaxis
o No longer effective after 24 hours
IV. OTHER THERAPIES

Denosumab antibody that blocks the RANK ligand

Plicamycin inhibits bone resorption

Gallium nitrate inhibits bone resorption

Glucocorticoids
o Effective in multiple myeloma, Hodgkins lymphoma,
leukemia
o Also effective in sarcoidosis and vitamin D
intoxication

Dialysis
o Treatment of choice for severe hypercalcemia in renal
failure

Phosphate therapy
o Limited role in certain circumstances
o IV phosphate one of the most dramatically effective
treatments but is toxic
HYPOCALCEMIA

Chronic hypocalcemia
o Muscle spasms, carpopedal spasms, facial grimacing
o Respiratory arrest may occur
o Increased intracranial pressure and papilledema
o Mental changes

Irritability, depression and psychosis


o Prolonged QT interval
o Positive Chvosteks or Trosseaus sign

I. PTH ABSENT

Hereditary hypoparathyroidism
o Basal ganglia calcification and extrapyramidal
syndromes are more common and earlier in onset

Hypocalcemia associated with hypomagnesemia


o Deficient PTH release
o Impaired responsiveness to PTH
1. Genetic abnormalities and Hereditary Hypoparathyroidism

Typically occur with other abnormalities

DiGeorge syndrome
o Defective development of both thymus and parathyroid
gland
o Severe infections, hypocalcemia and seizures

Kenney-Caffey syndrome
o Short stature, osteosclerosis and thick cortical bones

Sanjad-Sakati syndrome
o Growth failure seen in Middle Eastern patients

Kearns-Sayre syndrome
o Ophthalmoplegia and pigment retinopathy

MELAS syndrome
o Mitochondrial encephalopathy, lactic acidosis, stroke-like
syndrome

Autosomal dominant hypocalcemic hypercalciuria (ADHH)


o Gain-of-function mutation in CaSR
2. Acquired Hypoparathyroidism

Usually the result of inadvertent surgical removal of parathyroid


glands

Thyroid surgery most frequent cause in the past

Parathyroid surgery now the most frequent cause

Acquired chronic hypoparathyroidism


o Radioiodine therapy

o Hemochromatosis
o Infection usually does not cause hypoparathyroidism
Transient hypoparathyroidism
o Frequent following parathyroid surgery

3. Treatment

Replacement with Vitamin D or calcitriol


o 40,000-120,000 U/d

High oral calcium intake


o 1 g elemental calcium

Thiazide diuretics
o Lower urine calcium
o Prevent nephrocalcinosis and nephrolithiasis

PTH therapy
o Not approved as of yet

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