Hyperparathyroidis

Hyperparathyroidis

m

m

Sarah Rodriguez, MD

Sarah Rodriguez, MD

Shawn Newlands, MD, PhD

Shawn Newlands, MD, PhD

University of Texas Medical Branch

University of Texas Medical Branch

Grand Rounds Presentation

Grand Rounds Presentation

February 2006

February 2006

PTH/Calcium Homeostasis

PTH/Calcium Homeostasis

Low circulating serum

Low circulating serum

calcium

calcium

concentrations

concentrations

stimulate the

stimulate the

parathyroid glands to

parathyroid glands to

secrete PTH, which

secrete PTH, which

mobilizes calcium

mobilizes calcium

from bones by

from bones by

osteoclastic

osteoclastic

stimulation. PTH also

stimulation. PTH also

stimulates the

stimulates the

kidneys to reabsorb

kidneys to reabsorb

calcium and to

calcium and to

convert 25-

convert 25-

hydroxyvitamin D3

hydroxyvitamin D3

(produced in the

(produced in the

liver) to the active

liver) to the active

form,

form,

1,25-

1,25-

dihydroxyvitamin D3,

dihydroxyvitamin D3,

which stimulates GI

which stimulates GI

calcium absorption.

calcium absorption.

High serum calcium

High serum calcium

concentrations have a

concentrations have a

negative feedback

negative feedback

effect on PTH

effect on PTH

secretion.

secretion.

PTH

PTH



Renal effects (steady state maintenance)

Renal effects (steady state maintenance)

–

Inhibition of phosphate transport

Inhibition of phosphate transport

–

Increased reabsorption of calcium

Increased reabsorption of calcium

–

Stimulation of 25(OH)D-1alpha-hydroxylase

Stimulation of 25(OH)D-1alpha-hydroxylase



Bone effects (immediate control of blood Ca)

Bone effects (immediate control of blood Ca)

–

Causes calcium bone release within minutes

Causes calcium bone release within minutes

–

Chronic elevation increases bone remodeling and

Chronic elevation increases bone remodeling and

increased osteoclast-mediated bone resorption

increased osteoclast-mediated bone resorption

–

However, PTH administered intermittently

However, PTH administered intermittently

has been shown to increase bone formation

has been shown to increase bone formation

and this is a potential new therapy for

and this is a potential new therapy for

osteoporosis

osteoporosis

Hypercalcemia

Hypercalcemia

I.Parathyroid-related

I.Parathyroid-related

-Primary hyperparathyroidism

-Primary hyperparathyroidism

-Lithium therapy

-Lithium therapy

-Familial hypocalciuric hypercalcemia

-Familial hypocalciuric hypercalcemia

II. Malignancy-related

II. Malignancy-related

-Solid tumor with metastases (breast)

-Solid tumor with metastases (breast)

-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)

-Solid tumor with humoral mediation of hypercalcemia (lung, kidney)

-Hematologic malignancies (multiple myeloma, lymphoma, leukemia)

-Hematologic malignancies (multiple myeloma, lymphoma, leukemia)

III. Vitamin D-related

III. Vitamin D-related

-Vitamin D intoxication

-Vitamin D intoxication

-↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases

-↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases

-Idiopathic hypercalcemia of infancy

-Idiopathic hypercalcemia of infancy

IV. Associated with high bone turnover

IV. Associated with high bone turnover

-Hyperthyroidism

-Hyperthyroidism

-Immobilization

-Immobilization

-Thiazides

-Thiazides

-Vitamin A intoxication

-Vitamin A intoxication

V. Associated with renal failure

V. Associated with renal failure

-Severe secondary hyperparathyroidism

-Severe secondary hyperparathyroidism

-Aluminum intoxication

-Aluminum intoxication

-Milk-alkali syndrome

-Milk-alkali syndrome

**Primary
hyperparathyroidis
m and cancer
account for 90% of
cases of
hypercalcemia

Primary

Primary

Hyperparathyroidism

Hyperparathyroidism



Estimated incidence is 1 case per 1000 men and 2-

Estimated incidence is 1 case per 1000 men and 2-

3 cases per 1000 women

3 cases per 1000 women

–

Incidence increases above age 40

Incidence increases above age 40

–

Most patients with sporadic primary

Most patients with sporadic primary

hyperparathyroidism are postmenopausal

hyperparathyroidism are postmenopausal

women with an average age of 55 years

women with an average age of 55 years



>80% of cases are caused by a solitary parathyroid

>80% of cases are caused by a solitary parathyroid

adenoma

adenoma



Approximately 10% are caused by “double

Approximately 10% are caused by “double

adenoma”

adenoma”

Primary HPT: Clinical

Primary HPT: Clinical

Features

Features



Symptomatic:

Symptomatic:

–

Osteitis fibrosa cystica

Osteitis fibrosa cystica

–

Nephrolithiasis

Nephrolithiasis

–

Pathologic fractures

Pathologic fractures

–

Neuromuscular disease

Neuromuscular disease

–

Life-threatening

Life-threatening

hypercalcemia

hypercalcemia

–

?Peptic Ulcer Disease

?Peptic Ulcer Disease



?Asymptomatic:

?Asymptomatic:

–

Fatigue

Fatigue

–

Subjective muscle weakness

Subjective muscle weakness

–

Depression

Depression

–

Increased thirst

Increased thirst

–

Polyuria

Polyuria

–

Constipation

Constipation

–

Musculoskeletal aches and

Musculoskeletal aches and

pains

pains

Work-Up

Work-Up



Intact PTH and chemistry panel

Intact PTH and chemistry panel

–

PTH elevated despite elevated serum calcium

PTH elevated despite elevated serum calcium

–

Serum phosphate in the low-normal to mildly decreased range

Serum phosphate in the low-normal to mildly decreased range

–

Look at the serum creatinine to evaluate for CRI/CRF

Look at the serum creatinine to evaluate for CRI/CRF



Rule out lithium or thiazide use

Rule out lithium or thiazide use



24-hour urine calcium excretion

24-hour urine calcium excretion

–

Used to rule out familial hypocalciuric hypercalcemia

Used to rule out familial hypocalciuric hypercalcemia

–

Values below 100mg/24 hours or a calcium creatinine

Values below 100mg/24 hours or a calcium creatinine

clearance ratio of <0.01 are suggestive of FHH

clearance ratio of <0.01 are suggestive of FHH



Wrist, spine and hip DEXA

Wrist, spine and hip DEXA



Consider KUB, IVP or CT to evaluate for kidney stones

Consider KUB, IVP or CT to evaluate for kidney stones



Ionized calcium versus serum calcium—the debate rages

Ionized calcium versus serum calcium—the debate rages

on….

on….

–

CORRECTED SERUM CALCIUM

CORRECTED SERUM CALCIUM



Serum calcium (mg/dL)+(0.8X[4-albumin (g/dL)])

Serum calcium (mg/dL)+(0.8X[4-albumin (g/dL)])

CA/CRT ratio: (24 hr
urine calciumXserum
crt)/(24 hr urine
crtXserum calcium)

Surgical Candidacy

Surgical Candidacy



Symptomatic primary HPT

Symptomatic primary HPT



NIH Consensus Development Panel 2002 Revised

NIH Consensus Development Panel 2002 Revised

Guidelines [if any of the following are met]

Guidelines [if any of the following are met]

–

Serum calcium greater than 1mg/dL above the upper

Serum calcium greater than 1mg/dL above the upper

limit of the reference range

limit of the reference range

–

24 hour urine calcium greater than 400 mg

24 hour urine calcium greater than 400 mg

–

Creatinine clearance reduced by more than 30%

Creatinine clearance reduced by more than 30%

compared with age-matched subjects

compared with age-matched subjects

–

Bone density at the lumbar spine, hip, or distal radius

Bone density at the lumbar spine, hip, or distal radius

more than 2.5 SD below peak bone mass

more than 2.5 SD below peak bone mass

–

Age under 50

Age under 50

–

Patients for whom medical surveillance is not desirable

Patients for whom medical surveillance is not desirable

or possible

or possible

creatinine clearance (mL/min) =

creatinine clearance (mL/min) =

((urine creatinine in mg/dL) * (urine

((urine creatinine in mg/dL) * (urine

volume in mL)) / ((plasma creatinine

volume in mL)) / ((plasma creatinine

in mg/dL) * (time period in minutes))

in mg/dL) * (time period in minutes))

Other Considerations in

Other Considerations in

Surgical Referral

Surgical Referral



Neuropsychological abnormalities

Neuropsychological abnormalities

–

Several studies document improvement in HRQL after

Several studies document improvement in HRQL after

parathroidectomy

parathroidectomy

–

Studies on neurobehavioral abnormalities have reported less

Studies on neurobehavioral abnormalities have reported less

consistent results with parathyroidectomy

consistent results with parathyroidectomy



Cardiovascular abnormalities

Cardiovascular abnormalities

–

Symptomatic patients suffer from increased cardiovascular

Symptomatic patients suffer from increased cardiovascular

mortality before and after treatment

mortality before and after treatment

–

Asymptomatic primary HPT is associated with LVH; some

Asymptomatic primary HPT is associated with LVH; some

studies suggest this is reversible with parathyroidectomy

studies suggest this is reversible with parathyroidectomy

–

Primary HPT patients have increased calcifications of mitral

Primary HPT patients have increased calcifications of mitral

and aortic valve

and aortic valve



Perimenopausal women

Perimenopausal women

–

Asymptomatic primary HPT associated with increased bone

Asymptomatic primary HPT associated with increased bone

turnover, reduced bone mineral density and higher risk for

turnover, reduced bone mineral density and higher risk for

fractures

fractures

Pre-Operative Imaging

Pre-Operative Imaging



High-resolution ultrasound

High-resolution ultrasound

–

Sensitivity 65-85% for adenoma; 30-90% for enlarged gland

Sensitivity 65-85% for adenoma; 30-90% for enlarged gland

–

Results suboptimal in pts with multinodular thyroid disease,

Results suboptimal in pts with multinodular thyroid disease,

pts with short thick neck, ectopic glands (15-20%)

pts with short thick neck, ectopic glands (15-20%)

–

May be useful in detecting sestamibi scan negative adenomas

May be useful in detecting sestamibi scan negative adenomas



CT with contrast/thin section

CT with contrast/thin section

–

Sensitivity of 46-87%

Sensitivity of 46-87%

–

Good for ectopic glands in the chest

Good for ectopic glands in the chest



MRI

MRI

–

Sensitivity of 65-80%

Sensitivity of 65-80%

–

Good for ectopic glands

Good for ectopic glands



Sestamibi

Sestamibi

–

85-95% accurate in localizing adenoma in primary HPT

85-95% accurate in localizing adenoma in primary HPT



Sestamibi-SPECT

Sestamibi-SPECT

–

Sensitivity 60% for enlarged gland and 98% for solitary

Sensitivity 60% for enlarged gland and 98% for solitary

adenomas

adenomas

Scintigraphy Images

Traditional Sestamibi

Sestamibi-SPECT

Medical Management

Medical Management



Asymptomatic patients may elect to be

Asymptomatic patients may elect to be

closely followed and managed medically

closely followed and managed medically

–

A recent study of pts with asymptomatic primary

A recent study of pts with asymptomatic primary

HPT showed that the majority of pts followed for

HPT showed that the majority of pts followed for

ten years did not demonstrate an increase in

ten years did not demonstrate an increase in

serum calcium or PTH levels—25% of patients

serum calcium or PTH levels—25% of patients

had progressive disease including worsening

had progressive disease including worsening

hypercalcemia, hypercalciuria and reduction in

hypercalcemia, hypercalciuria and reduction in

bone mass—younger patients more likely to have

bone mass—younger patients more likely to have

progression of disease

progression of disease



Patients opting not to have surgery should

Patients opting not to have surgery should

have a serum calcium level drawn every 6

have a serum calcium level drawn every 6

months and should have annual bone

months and should have annual bone

densiometry at all three sites

densiometry at all three sites

Medical Management Primary

Medical Management Primary

HPT

HPT



Estrogen

Estrogen

–

Dose required is high

Dose required is high



SERMs

SERMs

–

Reduction in serum calcium and markers of

Reduction in serum calcium and markers of

bone turnover after 4 weeks

bone turnover after 4 weeks



Bisphosphonates

Bisphosphonates

–

Studies have shown increase in lumbar spine

Studies have shown increase in lumbar spine

and femoral neck mineral density

and femoral neck mineral density



Calcium/Vitamin D

Calcium/Vitamin D



Calcimimetic agents (Cinacalcet)

Calcimimetic agents (Cinacalcet)

–

Under investigation for primary HPT

Under investigation for primary HPT

Familial Syndromes

Familial Syndromes



MEN I

MEN I



MEN IIA

MEN IIA



Familial Hypocalciuric Hypercalcemia

Familial Hypocalciuric Hypercalcemia



Hyperparathyroidism-jaw tumor

Hyperparathyroidism-jaw tumor

syndrome

syndrome

–

Fibro-osseous jaw tumors

Fibro-osseous jaw tumors

–

Renal cysts

Renal cysts

–

Solid renal tumors

Solid renal tumors



Familial isolated hyperparathyroidism

Familial isolated hyperparathyroidism

MEN I

MEN I



MEN I

MEN I

–

1 in 30,000 persons

1 in 30,000 persons

–

Features:

Features:



Hyperparathyroidism (95%)

Hyperparathyroidism (95%)

–

Most common and earliest endocrine manifestation

Most common and earliest endocrine manifestation



Gastrinoma (45%)

Gastrinoma (45%)



Pituitary tumor (25%)

Pituitary tumor (25%)



Facial angiofibroma (85%)

Facial angiofibroma (85%)



Collagenoma (70%)

Collagenoma (70%)



HPT in MEN I

HPT in MEN I

–

Early onset

Early onset

–

Multiple glands affected

Multiple glands affected

–

Post-op hypoparathyroidism more common (more

Post-op hypoparathyroidism more common (more

extensive surgery)

extensive surgery)

–

Successful subtotal parathyroidectomy followed by

Successful subtotal parathyroidectomy followed by

recurrent HPT in 10 years in 50% of cases

recurrent HPT in 10 years in 50% of cases

STIGMATA OF MEN I

Lipoma
s

Collagenomas

Angiofibromas

MEN IIA (Sipple’s Syndrome)

MEN IIA (Sipple’s Syndrome)



Features:

Features:

–

MTC(95%)

MTC(95%)

–

Pheochromocytoma(50%)

Pheochromocytoma(50%)

–

HPT(20%)

HPT(20%)



RET mutation (98%)

RET mutation (98%)



1 in 30,000-50,000 people

1 in 30,000-50,000 people



Usually single adenoma but may

Usually single adenoma but may

have multi-gland hyperplasia

have multi-gland hyperplasia

Familial Hypocalciuric

Familial Hypocalciuric

Hypercalcemia

Hypercalcemia

This benign condition can be easily mistaken for mild

This benign condition can be easily mistaken for mild

hyperparathyroidism. It is an autosomal dominant

hyperparathyroidism. It is an autosomal dominant

inherited disorder characterized by hypocalciuria

inherited disorder characterized by hypocalciuria

(usually < 50 mg/24 h), variable hypermagnesemia,

(usually < 50 mg/24 h), variable hypermagnesemia,

and normal or minimally elevated levels of PTH.

and normal or minimally elevated levels of PTH.

These patients do not normalize their hypercalcemia

These patients do not normalize their hypercalcemia

after subtotal parathyroid removal and should not be

after subtotal parathyroid removal and should not be

subjected to surgery. The condition has an excellent

subjected to surgery. The condition has an excellent

prognosis and is easily diagnosed with family history

prognosis and is easily diagnosed with family history

and urinary calcium clearance determination.

and urinary calcium clearance determination.

Secondary

Secondary

Hyperparathyroidism

Hyperparathyroidism



Decreased GFR leads to reduced inorganic phosphate

Decreased GFR leads to reduced inorganic phosphate

excretion and consequent phosphate retention

excretion and consequent phosphate retention



Retained phosphate has a direct stimulatory effect on PTH

Retained phosphate has a direct stimulatory effect on PTH

synthesis and on cellular mass of the parathyroid glands

synthesis and on cellular mass of the parathyroid glands



Retained phosphate also causes excessive production and

Retained phosphate also causes excessive production and

secretion of PTH through lowering of ionized Ca2+ and by

secretion of PTH through lowering of ionized Ca2+ and by

suppression of calcitriol production

suppression of calcitriol production



Reduced calcitriol production results both from decreased

Reduced calcitriol production results both from decreased

synthesis due to reduced kidney mass and from

synthesis due to reduced kidney mass and from

hyperphosphatemia.

hyperphosphatemia.

–

Low calcitriol levels, in turn, lead to hyperparathyroidism via

Low calcitriol levels, in turn, lead to hyperparathyroidism via

both direct and indirect mechanisms. Calcitriol is known to have

both direct and indirect mechanisms. Calcitriol is known to have

a direct suppressive effect on PTH transcription and therefore

a direct suppressive effect on PTH transcription and therefore

reduced calcitriol in CRD causes elevated levels of PTH

reduced calcitriol in CRD causes elevated levels of PTH

–

Reduced calcitriol leads to impaired Ca2+ absorption from the

Reduced calcitriol leads to impaired Ca2+ absorption from the

GI tract, thereby leading to hypocalcemia, which then increases

GI tract, thereby leading to hypocalcemia, which then increases

PTH secretion and production.

PTH secretion and production.

Secondary HPT

Secondary HPT



Clinical presentation

Clinical presentation

–

Usually asymptomatic

Usually asymptomatic



Diagnosis

Diagnosis

–

Elevated PTH in the setting of low or normal serum calcium is diagnostic

Elevated PTH in the setting of low or normal serum calcium is diagnostic

–

If phosphorous is elevated, cause is renal

If phosphorous is elevated, cause is renal

–

If phosphorous is low, other causes of vit D deficiency should be sought

If phosphorous is low, other causes of vit D deficiency should be sought



Prevention

Prevention

–

Vit D replacement

Vit D replacement

–

Phosphorus binders [Sevelamer]

Phosphorus binders [Sevelamer]



Treatment

Treatment

–

Medical

Medical



Calcimimetic agents

Calcimimetic agents

–

Surgical

Surgical



Considered in cases of refractory

Considered in cases of refractory

severe hypercalcemia, severe

severe hypercalcemia, severe

bone disease, severe pruritis,

bone disease, severe pruritis,

calciphylaxis, severe myopathy

calciphylaxis, severe myopathy

Tertiary

Tertiary

Hyperparathyroidism

Hyperparathyroidism

Tertiary hyperparathyroidism develops in patients with

Tertiary hyperparathyroidism develops in patients with

long-standing secondary hyperparathyroidism, which

long-standing secondary hyperparathyroidism, which

stimulates the growth of an autonomous adenoma. A

stimulates the growth of an autonomous adenoma. A

clue to the diagnosis of tertiary hyperparathyroidism is

clue to the diagnosis of tertiary hyperparathyroidism is

intractable hypercalcemia and/or an inability to control

intractable hypercalcemia and/or an inability to control

osteomalacia despite vitamin D therapy.

osteomalacia despite vitamin D therapy.

Surgical Referral

Surgical Referral

- calcium- phosphate product > 70

- calcium- phosphate product > 70

- severe bone disease and pain

- severe bone disease and pain

-intractable pruritus

-intractable pruritus

- extensive soft tissue calcification with tumoral calcinosis

- extensive soft tissue calcification with tumoral calcinosis

-calciphylaxis

-calciphylaxis

Lab Abnormalities

Lab Abnormalities



Primary HPT

Primary HPT

–

Increased serum calcium

Increased serum calcium

–

Phosphorus in low normal range

Phosphorus in low normal range

–

Urinary calcium elevated

Urinary calcium elevated



Secondary HPT (renal etiology)

Secondary HPT (renal etiology)

–

Low or normal serum calcium

Low or normal serum calcium

–

High phosphorus

High phosphorus



Tertiary HPT (renal etiology)

Tertiary HPT (renal etiology)

–

High calcium and phosphorus

High calcium and phosphorus

Quiz #1

Quiz #1



A 45 year old woman is referred to you for

A 45 year old woman is referred to you for

evaluation of elevated calcium and PTH

evaluation of elevated calcium and PTH

found on routine lab work. The PCP

found on routine lab work. The PCP

ordered a 24 hour urine collection and the

ordered a 24 hour urine collection and the

urinary calcium is less than 50 mg for 24

urinary calcium is less than 50 mg for 24

hrs. Next step?

hrs. Next step?

A. Order the mibi/schedule the surgery

A. Order the mibi/schedule the surgery

B. Consider estrogen replacement in this

B. Consider estrogen replacement in this

perimenopausal woman

perimenopausal woman

C. Take a careful family history

C. Take a careful family history

D. Look for stigmata of MEN I

D. Look for stigmata of MEN I

Quiz #2

Quiz #2



You receive a hospital consult for

You receive a hospital consult for

“parathyroidectomy”. You look at the pts

“parathyroidectomy”. You look at the pts

labs and note elevated PTH, calcium and

labs and note elevated PTH, calcium and

phosphorus.

phosphorus.

A. Have primary team order a mibi before you

A. Have primary team order a mibi before you

see the patient

see the patient

B. Suspect MEN IIA and have the primary team

B. Suspect MEN IIA and have the primary team

order ret-proto oncogene screening

order ret-proto oncogene screening

C. Evaluate the pt in the dialysis unit with careful

C. Evaluate the pt in the dialysis unit with careful

questioning as to symptoms of pruritis, skin

questioning as to symptoms of pruritis, skin

calcifications or necrosis

calcifications or necrosis

Quiz #3

Quiz #3



Primary HPT:

Primary HPT:

A.

A.

Is more common in post-menopausal

Is more common in post-menopausal

women

women

B.

B.

Is most likely due to a parathyroid

Is most likely due to a parathyroid

adenoma

adenoma

C.

C.

Usually is discovered when the pt is

Usually is discovered when the pt is

“asymptomatic”

“asymptomatic”

D.

D.

All of the above

All of the above

Quiz #4

Quiz #4



Surgical candidacy for primary HPT

Surgical candidacy for primary HPT

includes:

includes:

A.

A.

24 hour urine calcium greater than 400

24 hour urine calcium greater than 400

mg

mg

B.

B.

Age under 50

Age under 50

C.

C.

Creatinine clearance decreased 30%

Creatinine clearance decreased 30%

when compared to age matched norms

when compared to age matched norms

D.

D.

All of the above

All of the above

Quiz #5

Quiz #5



You are in endocrine multidisciplinary

You are in endocrine multidisciplinary

clinic presenting a patient. You are

clinic presenting a patient. You are

asked “What is the calcium-

asked “What is the calcium-

creatinine clearance ratio?”

creatinine clearance ratio?”

–

You reply “ask an endorinologist”

You reply “ask an endorinologist”

–

You ask “the calcium creatinine what?”

You ask “the calcium creatinine what?”

–

You say “Let me just answer this page,

You say “Let me just answer this page,

I’ll be right back” and you consult Dr.

I’ll be right back” and you consult Dr.

Quinn’s online textbook

Quinn’s online textbook

Quiz #6

Quiz #6



You have a patient with “asymptomatic”

You have a patient with “asymptomatic”

primary HPT. You discuss surgery with her

primary HPT. You discuss surgery with her

but she is very reluctant. You tell her that

but she is very reluctant. You tell her that

patients with primary HPT can be

patients with primary HPT can be

followed medically and…

followed medically and…

A.

A.

Her chance of dying from complications of

Her chance of dying from complications of

primary HPT in the next year are 50%

primary HPT in the next year are 50%

B.

B.

She will need monthly serum calcium and 24

She will need monthly serum calcium and 24

hour urine collections to monitor her disease

hour urine collections to monitor her disease

C.

C.

Most patients with asymptomatic primary

Most patients with asymptomatic primary

HPT do not demonstrate progression of their

HPT do not demonstrate progression of their

disease over a ten year period

disease over a ten year period