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