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HYPERPARATHYROIDISM
Hasan Aydın M.D.Endocrinology and Metabolism
Yeditepe University Medical Faculty
Hyperparathyroidism
A clinical syndrome characterized by
– ↑ PTH,
– PTH induced bone resorption
– Hypercalcemia
Types of Hyperparathyroidism
- Primary
- Secondary
- Tertiary
Primary Hyperparathyroidism
Primary Hyperparathyroidism
• Excessive, relatively uncontrolled secretion of PTH
• One or more hyperfunctioning parathyroid glands.
• Hypercalcemia, the biochemical hallmark
• Most patients today are relatively asymptomatic.
• Symptoms remarkably varied and vague.
Epidemiology
• Overall incidence is 42 in 100,000
• Incidence increases with age
• Most patients with sporadic primary
hyperparathyroidism are postmenopausal
women with an average age of 55 years
• Female to male ratio is 2-3:1
Etiology and Pathogenesis• Primary hyperparathyroidism is caused by
…..Parathyroid adenoma – 80%
…..Parathyroid hyperplasia – 15%
…..Parathyroid carcinoma – 1-2%
…..Approximately 10% are caused by “double adenoma”
• It can occur as part of at least three familial endocrinopathies
…..MEN 1
…..MEN 2A
…..Isolated familial hyperparathyroidism
Manifestations
• Renal
• Skeletal
• Gastrointestinal
• Neurologic-Neuromuscular
• Other
Symptoms and Signs
• Renal – hypercalciuria– nephrolithiasis– nephrocalcinosis– polyuria and polydipsia– renal insufficiency
• Neuromuscular – weakness– myalgia
Symptoms and Signs
Neurologic and psychiatric
- Memory loss - Confusion
- Depression - Lethargy
- Psychosis - Fatigue
- Paresthesias
Skeletal- Bone pain- Osteoporosis- Pathologic fractures- Bone cysts/brown tumors- Arthralgias- Chondrocalcinosis - Pseudogout and gout- Subperiosteal skeletal
resorption
Symptoms and Signs
• Peptic ulcer
– Zollinger-Ellison Syndrome ( MEN 1)
• Chronic pancreatitis
Other Manifestations
• Polyuria, polydipsia, constipation
• ECG changes (shortened Q-T )
• Band keratopathy, subconjunctival deposits
• Pruritus
• Ectopic calcifications (lungs, kidneys, skin, arteries)
• Hypertension
Hyperparathyroid Bone Disease
• Elevation of the alkaline phosphatase level
• Osteitis fibrosa cystica
• Subperiosteal resorption of cortical bone (phalanges)
• A salt-and-pepper appearance (in the skull)
• Bone cyst or brown tumors (jaw)
• Loss of the lamina dura of the teeth
• Osteoporosis (predominant loss of cortical bone)
Osteitis Fibrosa Cystica
Classical Phrase
Laboratory Findings
• Hypercalcemia is universal (>10.6 mg/dL)
• Serum phosphorus is low normal (<3.5 mg/dl) or
low (<2.5 mg/dl)
• Mild hyperchloremic metabolic acidosis
• PTH is elevated or high normal
• Alkaline phosphatase may be increased
Work-Up
• Rule out lithium or thiazide use
• Wrist, spine and hip DEXA
• Consider IVP or CT to evaluate for kidney stones
• Ionized calcium versus serum calcium—the debate rages on….
Differential Diagnosis• Due to increased serum PTH
– Primary and ''tertiary'' hyperparathyroidism– Nonhematologic malignant neoplasms
• Not due to increased serum PTH – Drug-induced (thiazide, furosemide, vitamin D, calcium,
vitamin A, lithium) – Granulomatous (sarcoidosis, tuberculosis, berylliosis)– Genetic (familial hypocalciuric hypercalcemia) – Immobilization – Idiopathic– Nonhematologic malignant neoplasms – Malignant hematologic diseases – Nonparathyroid endocrine disease (Addison's disease,
hyper and hypothyroidism)
Differential Diagnosis of Osteitis Fibrosa Cystica
• Paget’s disease of bone• Osteoporosis• Osteomalacia• Malignant diseases• Polyostotic fibrous dysplasia• Secondary hyperparathyrodism• Pseudohypoparathyroidism
Differential Diagnosis of Nephrolithiasis/Nephrocalcinosis
• Gout
• Hyperoxaluria
• Renal tubular acidosis
• Pyelonephritis
Treatment
• Definitive treatment is surgical parathyroidectomy
• Cure rate for adenomas >95% (less for hyperplasia)
• No value in pre-op studies to localize parathyroid tumors
• The only localization study needed is to locate an experienced
parathyroid surgeon
• No definitive medical therapy for hyperparathyroidism
In the asymptomatic patient, who should undergo
surgery?
Indications for Surgery
• Overt clinical manifastations of primary hyperparathyroidism
– Radiographic nephrolithiasis or documented renal stones
– Reduced creatinine clearance (not otherwise explained)
– Radiographically evident hyperparathyroid bone disease
– Classical hyperparathyroid neuromuscular disease
– Symptoms attributable to hypercalcemia per se
– Previous episode of life threatening hypercalcemia
• Serum Ca concentration >12 mg/dL
• Low or declining bone mineral density
– >2 SD below age/sex matched controls (any site) or
– Vertebral osteopenia or– Declining vertebral bone mineral
density• Age younger than 50 years• Uncertain prospect for successful
monitoring
– Patient requests surgery– Consistent followup seems unikely– Coexistent illness that may contribute
to or confound detection of, disease progression
Other Considerations in Surgical Referral
• Neuropsychological abnormalities
– Several studies document improvement in HRQL after parathroidectomy
– Studies on neurobehavioral abnormalities have reported less consistent results with parathyroidectomy
• Cardiovascular abnormalities
– Symptomatic patients suffer from increased cardiovascular mortality before and after treatment
– Asymptomatic primary HPT is associated with LVH; some studies suggest this is reversible with parathyroidectomy
– Primary HPT patients have increased calcifications of mitral and aortic valve
• Perimenopausal women
– Asymptomatic primary HPT associated with increased bone turnover, reduced bone mineral density and higher risk for fractures
Pre-Operative Imaging
• High-resolution ultrasound– Sensitivity 65-85% for
adenoma; 30-90% for enlarged gland
– Results suboptimal in pts with multinodular thyroid disease, pts with short thick neck, ectopic glands (15-20%)
– May be useful in detecting sestamibi scan negative adenomas
• CT with contrast/thin section– Sensitivity of 46-87%– Good for ectopic glands in the
chest
• MRI– Sensitivity of 65-80%
– Good for ectopic glands
• Sestamibi
– 85-95% accurate in localizing adenoma in primary HPT
• Sestamibi-SPECT– Sensitivity 60% for enlarged gland
and 98% for solitary adenomas
Ultrasonographic Localization
Traditional Sestamibi Sestamibi-SPECT
Scintigraphy Images
MRI Localization
Medical Management Primary HPT
• Bisphosphonates
– Studies have shown increase in lumbar spine and femoral neck
mineral density
• Calcimimetic agents (Cinacalcet)
– For intractable case of primary HPT
• Estrogen
– Dose required is high
• SERMs
– Reduction in serum calcium and markers of bone turnover after 4
weeks
Medical Treatment
Chronic moderate (12-15 mg/dL) hypercalcemia
– The drug of first choice for most patients is pamidronate
disodium. This is a biphosphanate drug that acts by
inhibiting osteoclastic bone resorption. The initial dose is
60-90 mg by intravenous infusion over 4-24 hours.
– Glucocorticoids-(hypercalcemia associated with
hematologic malignancies)
Medical Treatment
• Mithramycin- inhibition of bone resorption, (hematologic and
solid malignant disorders).
• Phosphate- lncreases in serum phosphorus above 5 mg/dL
should be avoided because of the danger of inducing
extraskeletal calcifications.
• Calcitonin-4-8 IU/kg
• Estrogen
• Other agents-- and -adrenergic blockers and cimetidine
Medical Treatment
Acute severe (> 15 mg/dL) hypercalcemia-.
a. Hospitalization-(immobilization may increase serum calcium
in some patients)
b. Calcium restriction
c. Reduction of digitalis
d. Hydration and diuretics- 4-6 L of isotonic saline IV+
furosemide 20-100 mg every 1-2 hours or ethacrynic acid 10-
40 mg every 1-2 hours
Maintenance Regimen
• Furosemide ( 40-160 mg/d orally) or ethacrynic acid (50-200
mg/d orally),
• Sodium chloride tab (400-600 mEq/d orally)
• At least 3 L of fluid per day
• Other drugs-
(1) Indomethacin-
(2) Mithramycin-
Treatment Categories
Criteria Preferred Treatment
1. One or more of the following: Surgical removal of
• Serum calcium > 11 mg/dl. parathyroid lesion
• Osteitis fibrosa cystica.
• Metabolically active nephrolithiasis
• Decreased renal function.
• Intractable peptic ulcer.
• Pancreatitis.
• Serious psychiatric disease.
• Severe hypertension.
Treatment Categories
• Unsuccessful surgery , or recurrence with manifestations; noted in category 1
• Serum calcium < 11 mg/dl.• Abnormal serum iPTH• Absence of manifestations noted in
category 1
• Surgery contraindicated.
• Surgical removal of parathyroid lesion; preoperative localization may be indicated
• Surgical removal of parathyroid lesion or medical management
• Medical management for hypercalcemia and nephrolithiasis prevention
Extent of Parathyroidectomy
Number of Glands Involved Procedure
All 4 Removal of 3 glands and all but 35-
50 mg of the fourth gland
Two or 3 Removal of all but half of a normal
gland; suture tagging of
remaining half.
One Removal of involved gland;
identification of remaining glands
(often by biopsy)
Ectopic Parathyroids
• In several studies the abnormal parathyroid glands were found
in the following sites.
– 30 to 54 percent were in the neck.
– 16 to 34 percent were in the mediastinum.
– 14 to 39 percent were retro-esophageal.
– 5 percent were in the aortic arch area.
– 8 percent were in the upper cervical area.
– A few were in the carotid sheath.
Secondary HPT
• Clinical presentation– Usually asymptomatic
• Diagnosis– Elevated PTH in the
setting of low or normal serum calcium is diagnostic
– If phosphorous is elevated, cause is renal
– If phosphorous is low, other causes of vit D deficiency should be sought
• Prevention
– Vit D replacement
– Phosphorus binders
• Treatment
– Medical
• Calcimimetic agents
– Surgical
• Considered in cases of refractory severe hypercalcemia, severe bone disease, severe pruritis, calciphylaxis, severe myopathy
Secondary Hyperparathyroidism of Chronic Renal Failure
• Associated with prolonged stimulation of the parathyroid
glands by chronic decreases in the concentration of ionic
calcium in the blood.
• Serum iPTH progressively increases as glomerular filtration
rate decreases below 40 ml/min.
• Increases in serum phosphorus concentrations at this same
level of GFR (40 mU/min)
Secondary Hyperparathyroidism of Chronic Renal Failure
Major Causes of Chronic Hypocalcemia in Renal Failure
• Dietary deficiency of vitamin D or calcium.
• Decreased intestinal absorption of vitamin D or calcium due to primary small bowel disease, short bowel syndrome, and postgastrectomy syndrome.
• Drugs that cause rickets or osteomalacia such as phenytoin, phenobarbital, cholestyramine, and laxatives.
• States of tissue resistance to vitamin D.
• Excessive intake of inorganic phosphate compounds.
• Pseudohypoparathyroidism .
• Severe hypomagnesemia.
• Chronic renal failure.
Tertiary Hyperparathyroidism
– Develops in patients with long-standing secondary hyperparathyroidism, which stimulates the growth of an autonomous adenoma.
– A clue to the diagnosis of tertiary hyperparathyroidism is intractable hypercalcemia and/or an inability to control osteomalacia despite vitamin D therapy.
Surgical Referral- calcium- phosphate product > 70- severe bone disease and pain -intractable pruritus- extensive soft tissue calcification
with tumoral calcinosis -calciphylaxis
In Conclusion
• Primary hyperparathyroidism is mostly caused by an
adenoma
• Most of the patient asymptomatic
• Definitive treatment with surgery
• Differentiated from secondary and tertiary
hyperparathyroidism
T h a n k Y o u