Hyperparathyroidism

1
Hyperparathyroidism

• Sarah Rodriguez, MD
• Shawn Newlands, MD, PhD
• University of Texas Medical Branch
• Grand Rounds Presentation
• February 2006

2
PTH/Calcium Homeostasis

• Low circulating serum calcium concentrations
  stimulate the parathyroid glands to secrete PTH,
  which mobilizes calcium from bones by
  osteoclastic stimulation. PTH also stimulates the
  kidneys to reabsorb calcium and to convert
  25-hydroxyvitamin D3 (produced in the liver) to
  the active form, 1,25-dihydroxyvitamin D3, which
  stimulates GI calcium absorption. High serum
  calcium concentrations have a negative feedback
  effect on PTH secretion.

3
PTH

• Renal effects (steady state maintenance)
• Inhibition of phosphate transport
• Increased reabsorption of calcium
• Stimulation of 25(OH)D-1alpha-hydroxylase
• Bone effects (immediate control of blood Ca)
• Causes calcium bone release within minutes
• Chronic elevation increases bone remodeling and
  increased osteoclast-mediated bone resorption
• However, PTH administered intermittently has been
  shown to increase bone formation and this is a
  potential new therapy for osteoporosis

4
Hypercalcemia

• I.Parathyroid-related-Primary hyperparathyroidism
  -Lithium therapy-Familial hypocalciuric
  hypercalcemia
• II. Malignancy-related-Solid tumor with
  metastases (breast)-Solid tumor with humoral
  mediation of hypercalcemia (lung,
  kidney)-Hematologic malignancies (multiple
  myeloma, lymphoma, leukemia)
• III. Vitamin D-related-Vitamin D intoxication-?
  1,25(OH)2D sarcoidosis and other granulomatous
  diseases-Idiopathic hypercalcemia of infancy
• IV. Associated with high bone turnover-Hyperthyro
  idism-Immobilization-Thiazides-Vitamin A
  intoxication
• V. Associated with renal failure-Severe
  secondary hyperparathyroidism-Aluminum
  intoxication-Milk-alkali syndrome

Primary hyperparathyroidism and cancer account
for 90 of cases of hypercalcemia
5
Primary Hyperparathyroidism

• Estimated incidence is 1 case per 1000 men and
  2-3 cases per 1000 women
• Incidence increases above age 40
• Most patients with sporadic primary
  hyperparathyroidism are postmenopausal women with
  an average age of 55 years
• gt80 of cases are caused by a solitary
  parathyroid adenoma
• Approximately 10 are caused by double adenoma

6
Primary HPT Clinical Features

• Symptomatic
• Osteitis fibrosa cystica
• Nephrolithiasis
• Pathologic fractures
• Neuromuscular disease
• Life-threatening hypercalcemia
• ?Peptic Ulcer Disease
• ?Asymptomatic
• Fatigue
• Subjective muscle weakness
• Depression
• Increased thirst
• Polyuria
• Constipation
• Musculoskeletal aches and pains

7
Work-Up
CA/CRT ratio (24 hr urine calciumXserum crt)/(24
hr urine crtXserum calcium)

• Intact PTH and chemistry panel
• PTH elevated despite elevated serum calcium
• Serum phosphate in the low-normal to mildly
  decreased range
• Look at the serum creatinine to evaluate for
  CRI/CRF
• Rule out lithium or thiazide use
• 24-hour urine calcium excretion
• Used to rule out familial hypocalciuric
  hypercalcemia
• Values below 100mg/24 hours or a calcium
  creatinine clearance ratio of lt0.01 are
  suggestive of FHH
• Wrist, spine and hip DEXA
• Consider KUB, IVP or CT to evaluate for kidney
  stones
• Ionized calcium versus serum calciumthe debate
  rages on.
• CORRECTED SERUM CALCIUM
• Serum calcium (mg/dL)(0.8X4-albumin (g/dL))

8
Surgical Candidacy

• Symptomatic primary HPT
• NIH Consensus Development Panel 2002 Revised
  Guidelines if any of the following are met
• Serum calcium greater than 1mg/dL above the upper
  limit of the reference range
• 24 hour urine calcium greater than 400 mg
• Creatinine clearance reduced by more than 30
  compared with age-matched subjects
• Bone density at the lumbar spine, hip, or distal
  radius more than 2.5 SD below peak bone mass
• Age under 50
• Patients for whom medical surveillance is not
  desirable or possible

creatinine clearance (mL/min) ((urine
creatinine in mg/dL) (urine volume in mL)) /
((plasma creatinine in mg/dL) (time period in
minutes))
9
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

10
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

11
Scintigraphy Images
Traditional Sestamibi
Sestamibi-SPECT
12
Medical Management

• Asymptomatic patients may elect to be closely
  followed and managed medically
• A recent study of pts with asymptomatic primary
  HPT showed that the majority of pts followed for
  ten years did not demonstrate an increase in
  serum calcium or PTH levels25 of patients had
  progressive disease including worsening
  hypercalcemia, hypercalciuria and reduction in
  bone massyounger patients more likely to have
  progression of disease
• Patients opting not to have surgery should have a
  serum calcium level drawn every 6 months and
  should have annual bone densiometry at all three
  sites

13
Medical Management Primary HPT

• Estrogen
• Dose required is high
• SERMs
• Reduction in serum calcium and markers of bone
  turnover after 4 weeks
• Bisphosphonates
• Studies have shown increase in lumbar spine and
  femoral neck mineral density
• Calcium/Vitamin D
• Calcimimetic agents (Cinacalcet)
• Under investigation for primary HPT

14
Familial Syndromes

• MEN I
• MEN IIA
• Familial Hypocalciuric Hypercalcemia
• Hyperparathyroidism-jaw tumor syndrome
• Fibro-osseous jaw tumors
• Renal cysts
• Solid renal tumors
• Familial isolated hyperparathyroidism

15
MEN I

• MEN I
• 1 in 30,000 persons
• Features
• Hyperparathyroidism (95)
• Most common and earliest endocrine manifestation
• Gastrinoma (45)
• Pituitary tumor (25)
• Facial angiofibroma (85)
• Collagenoma (70)
• HPT in MEN I
• Early onset
• Multiple glands affected
• Post-op hypoparathyroidism more common (more
  extensive surgery)
• Successful subtotal parathyroidectomy followed by
  recurrent HPT in 10 years in 50 of cases

16
STIGMATA OF MEN I
Lipomas
Collagenomas
Angiofibromas
17
MEN IIA (Sipples Syndrome)

• Features
• MTC(95)
• Pheochromocytoma(50)
• HPT(20)
• RET mutation (98)
• 1 in 30,000-50,000 people
• Usually single adenoma but may have multi-gland
  hyperplasia

18
Familial Hypocalciuric Hypercalcemia

• This benign condition can be easily mistaken
  for mild hyperparathyroidism. It is an autosomal
  dominant inherited disorder characterized by
  hypocalciuria (usually lt 50 mg/24 h), variable
  hypermagnesemia, and normal or minimally elevated
  levels of PTH. These patients do not normalize
  their hypercalcemia after subtotal parathyroid
  removal and should not be subjected to surgery.
  The condition has an excellent prognosis and is
  easily diagnosed with family history and urinary
  calcium clearance determination.

19
Secondary Hyperparathyroidism

• Decreased GFR leads to reduced inorganic
  phosphate excretion and consequent phosphate
  retention
• Retained phosphate has a direct stimulatory
  effect on PTH synthesis and on cellular mass of
  the parathyroid glands
• Retained phosphate also causes excessive
  production and secretion of PTH through lowering
  of ionized Ca2 and by suppression of calcitriol
  production
• Reduced calcitriol production results both from
  decreased synthesis due to reduced kidney mass
  and from hyperphosphatemia.
• Low calcitriol levels, in turn, lead to
  hyperparathyroidism via both direct and indirect
  mechanisms. Calcitriol is known to have a direct
  suppressive effect on PTH transcription and
  therefore reduced calcitriol in CRD causes
  elevated levels of PTH
• Reduced calcitriol leads to impaired Ca2
  absorption from the GI tract, thereby leading to
  hypocalcemia, which then increases PTH secretion
  and production.

20
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 Sevelamer
• Treatment
• Medical
• Calcimimetic agents
• Surgical
• Considered in cases of refractory
• severe hypercalcemia, severe
• bone disease, severe pruritis,
• calciphylaxis, severe myopathy

21
Tertiary Hyperparathyroidism

• 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 gt 70
• - severe bone disease and pain
• -intractable pruritus
• - extensive soft tissue calcification with
  tumoral calcinosis
• -calciphylaxis

22
Lab Abnormalities

• Primary HPT
• Increased serum calcium
• Phosphorus in low normal range
• Urinary calcium elevated
• Secondary HPT (renal etiology)
• Low or normal serum calcium
• High phosphorus
• Tertiary HPT (renal etiology)
• High calcium and phosphorus

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Quiz 1

• A 45 year old woman is referred to you for
  evaluation of elevated calcium and PTH found on
  routine lab work. The PCP ordered a 24 hour urine
  collection and the urinary calcium is less than
  50 mg for 24 hrs. Next step?
• A. Order the mibi/schedule the surgery
• B. Consider estrogen replacement in this
  perimenopausal woman
• C. Take a careful family history
• D. Look for stigmata of MEN I

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Quiz 2

• You receive a hospital consult for
  parathyroidectomy. You look at the pts labs and
  note elevated PTH, calcium and phosphorus.
• A. Have primary team order a mibi before you see
  the patient
• B. Suspect MEN IIA and have the primary team
  order ret-proto oncogene screening
• C. Evaluate the pt in the dialysis unit with
  careful questioning as to symptoms of pruritis,
  skin calcifications or necrosis

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Quiz 3

• Primary HPT
• Is more common in post-menopausal women
• Is most likely due to a parathyroid adenoma
• Usually is discovered when the pt is
  asymptomatic
• All of the above

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Quiz 4

• Surgical candidacy for primary HPT includes
• 24 hour urine calcium greater than 400 mg
• Age under 50
• Creatinine clearance decreased 30 when compared
  to age matched norms
• All of the above

27
Quiz 5

• You are in endocrine multidisciplinary clinic
  presenting a patient. You are asked What is the
  calcium-creatinine clearance ratio?
• You reply ask an endorinologist
• You ask the calcium creatinine what?
• You say Let me just answer this page, Ill be
  right back and you consult Dr. Quinns online
  textbook

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Quiz 6

• You have a patient with asymptomatic primary
  HPT. You discuss surgery with her but she is very
  reluctant. You tell her that patients with
  primary HPT can be followed medically and
• Her chance of dying from complications of primary
  HPT in the next year are 50
• She will need monthly serum calcium and 24 hour
  urine collections to monitor her disease
• Most patients with asymptomatic primary HPT do
  not demonstrate progression of their disease over
  a ten year period