Transcript Hyperparathyroidism - London Health Sciences Centre

Primary
Hyperparathyroidism
Megha Poddar, PGY5
January 2015
Objectives
• To Review:
• Differential diagnosis of hypercalcemia
• Pathophysiology of hyperparathyroidism
• Clinical Presentation
• Diagnosis
• Treatments
Hypercalcemia is a common metabolic abnormality seen in
approximately 5% of hospitalized individuals.
The Canadian Journal of Diagnosis / February 2006/Aliya Khan
Primary Hyperparathyoidism –
Epidemiology
• PHPT - most common cause of hypercalcemia in the outpatient
clinical setting
• Prevalence ranges from 1 to 4 per 1000 people
• Female-to-Male ratio: 2:1 to 3:1
• Incidence increases with age
• Postmenopausal women have an incidence 5x higher than the general
population
Canadian Family Physician February 2011 vol. 57 no. 2 184-189
The Parathyroid Glands
• History:
• The parathyroid glands were first discovered in the
Indian Rhinoceros by Richard Owen in 1850.
• The glands were first discovered in humans by Ivar
Viktor Sandström, a Swedish medical student, in 1880.
• It was the last major organ to be recognized in humans.
Parathyroid Gland:
Ectopic locations are seen in 4- 16% - the parathyroid glands might also be
found in the carotid sheath, anterior mediastinum, and intrathyroidal tissue.
Atlas of Microscopic Anatomy: Section 15 - Endocrine Glands
115-AAC
trypsin-like protease
90-AAC
84-AAC
Packaged
PTH is an 84-amino acid polypeptide (chain) derived from a prohormone
The biosynthetic process is estimated to take less than one hour.
BASIC BIOLOGY OF MINERAL METABOLISM, F. Richard Bringhurst
Parathyroid hormone:
 84 amino acid peptide
 Recognized by PTH-1 receptor and then acts on target organs to
effect calcium homeostasis
 70% metabolized by the liver and 20% by kidneys; Half life of 2
minutes
Functions of PTH
• Chief cells – produce PTH
• PTH = Main regulator of calcium homeostasis in the body
• Ionised calcium – tightly regulated for optimum function of
cell signalling, neural function, muscular function, and bone
metabolism
• PTH responds to changes in circulating ionised calcium via
the calcium-sensing receptor (CaSR) located on the surface of
the chief cells
Parathyroid Hormone
Receptors
• PTH acts by binding to its receptor(PTH1R and
PTH2R)
• Both are members of the G Protein coupled receptor family of
transmembrane proteins
• PTH-1R receptor binds PTH and PTHrP with equal affinity.
• Regulates calcium homeostasis through activation
of adenylate cyclase and phospholipase C
• mostly expressed in bone and kidney
• PTH2R selectively binds PTH only.
• PTH2R expressed heavily in the brain, pancreas,
endothelium
Uptodate: Parathyroid Hormone and Action
Calcium sensing receptors
• CaSR expressed in parathyroid, thyroid C cells and kidney.
• Activation of the CaSR by increased extracellular Ca2+ inhibits
parathyroid hormone (PTH) secretion, stimulates calcitonin secretion,
and promotes urinary Ca2+ excretion, and thereby maintains the
extracellular Ca2+ at the normal level
PTH/Calcium Homeostasis
Causes of Hyperparathyroidism
Primary
Secondary- In
response to
hypocalcemia
Tertiary
•Parathyroid Adenoma,
Hyperplasia, Carcinoma
•Renal Failure
-Impaired calcitriol
production
-Hyperphosphatemia
•Autonomous hypersecretion
of parathyroid hormone
-chronic secondary
hyperparathyroidism
-After renal transplantation
•MEN 1 or MEN 2a
•Familial hypocalciuric
hypercalcemia
•Hyperparathyroid-jaw
tumor (HPT-JT) syndrome
•Decreased calcium
-Low oral intake
-Vit D deficiency
-Malabsoption
-renal calcium loss – lasix
•Familial isolated
hyperparathyroidism
(FIHPT)
•Inhibition of bone resorption
-Bisphophonates
-Hungry Bone Syndrome
Primary Hyperparathyroidism (PHPT)
• Etiology:
• Single gland adenoma: 75-85%
• Multigland adenoma
• 2 glands: 2-12%
• 3 glands: <1-2%
• 4 or > glands: 1-15%
• Parathyroid carcinoma: 1%
Lancet 2009; 374: 145–58
Lower pole adenomas are
more common than are
upper pole adenomas; sizes
range from 1 cm to 3 cm
and weights from 0·3 g to
5 g; may be more than 25g.
Parathyroid adenoma
Largest reported weighted 120g
Largest number was 8
Lancet 2009; 374: 145–58
Causes
• Exact cause of primary hyperparathyroidism is unknown
• Ionizing radiation maybe associated
• Irradiation for acne -?2·3-fold increase
• Survivors of an atomic bomb - 4-fold increase
• A dose response was recorded in people receiving
external-beam radiotherapy for benign disease
before their 16th birthday
• Present doses of radioactive iodine for thyrotoxicosis do not
increase the incidence of primary hyperparathyroidism
Lancet 2009; 374: 145–58
Rare Familial Disorders
• Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene mutation
(Parathyroid, pituitary, pancreatic)
• MEN type 2A syndromes –RET gene mutation (Parathyroid, Pheo,
MTC)
• Familial hypocalciuric hypercalcemia (FHH)- autosomal dominantinactivating mutation of the CaSR gene
• Familial hyperparathyroidism–jaw tumour syndrome- HRPT2 gene;
Autosomal dominant
• Familial isolated hyperparathyroidism
FHH
PHPT
Mechanism
(CaSR gene on Chr 3) –
PTH Adenoma, Hyperplasia,
makes PTHR less sensitive to carcinoma
calcium - higher serum
calcium level is required to
reduce PTH secretion
Fhx
+ Autosomial Dominant
+ rare syndromes
PTH
Mildly high in 15-20%
High normal – high
Urine Calcium /Magnesium
Low
Normal – high
FECa ; sensitivity 85%,
specificity 88%, PPV 85%
<1%
>1%
Symptoms
-
+/-
Management
Conservation
Parathyroidectomy
Plasma albumin-adjusted
calcium (mmol/L)
2.55-3.5
2.55-4.5
Age/sex
<40; women = male
>50; mainly women
Clinical Presentation of PHPT
• Possible presentations:
• Asymptomatic Incidental hypercalcemia – 70-80%
• In most patients, mean serum calcium < 0.25 mmol/L above the
ULN range
• Normocalcemic hyperparathyroidism
• Usually present for evaluation of low BMD, osteoporosis, or fragility
fractures
• Symptomatic hypercalcemia
Symptoms of Hypercalcemia
• Stones
• Bones
• Groans
• Psychiatric
Moans
Renal Manifestations
• Nephrolithiasis 15-20%
• Nephrocalcinosis
• Polyuria
• Renal insufficiency
• Acute hypercalcaemic
crisis with nephrogenic
diabetes insipidus and
dehydration seen when
calcium greater than 3·0
mmol/L
Psychic Moans:
• Neuropsychiatric: lethargy,
decreased cognitive and social
function, depressed mood,
psychosis, and coma in those
with severe hypercalcemia.
• Neuromuscular: weakness and
myalgia
• Prolonged HPTH causes direct
neuropathy with abnormal
nerve conduction velocities
Gastrointestinal Manifestations
Commonly constipation, nausea, vomiting, anorexia
• Uncommon, but serious: PUD or Acute pancreatitis
• Mechanism:
•
• PTH stimulates gastrin secretion (PUD), decreases peristalsis, and
increases the calcium- phosphate product with calcium-phosphate
deposition and obstruction in pancreatic ducts
Uptodate: Clinical manifestations of primary
hyperparathyroidism
Bone Manifestations
•
•
•
•
Bony pain
Low bone mineral density – most at cortical sites
Fragility fractures
Rarely PHPT bone disease – osteitis fibrosa cystica- <5 percent of
patients
• Proximal muscle weakness due to type II muscle fibre atrophy can be
seen in association with severe bone disease (osteitis fibrosa cystica).
Uptodate: Clinical manifestations of primary
hyperparathyroidism
subperiosteal resorption
Osteitis fibrosa cystica
• Very rare; occurs only in severe cases – carcinoma
• Characterized clinically by bone pain
• Radiographically by subperiosteal bone resorption on the radial
aspect of the middle phalanges, tapering of the distal clavicles, a
"salt and pepper" appearance of the skull, bone cysts, and brown
tumors of the long bones
Uptodate: Clinical manifestations of primary hyperparathyroidism
Cardiovascular:
-
Shortened QT interval
HTN – hypercalcemia causes vasoconstriction
Arrhythmias in severe hypercalcemia
Deposition of calcium on valves, in coronaries, and
myocardium
Other Manifestations
• Arthralgia, synovitis, arthritis
• HPT associated with increased crystal deposition from calcium
phosphate, calcium pyrophosphate (pseudogout), and uric acid
(gout)
• Band Keratopathy – Calcium phosphate precipitation in medial
and limbic margins of cornea
Symptoms
• The classic features of hypercalcemia are very
uncommon initial complaints in the Western world
• Most patients in developed countries have
asymptosymatic forms of PHPT or nonspecific
symptoms such as fatigue, mild depression, or
cognitive impairment.
Diagnosis
• Repeat calcium to confirm, correct for low Albumin
• Ionized Calcium: adds little if you have a normal albumin and
no acid base problems
• ?Useful if normocalcemic primary hyperparathyroidism – in one
series 16/60 patients had a raised ionized calcium, but normal serum
calcium
• Check PTH – rule in PHPT if frankly elevated PTH
concentration or normal PTH level with hypercalcemia
• Supporting findings: low P04,high Cl, high urine pH (>6),
high ALP
• Address DDX hyperparathyroidism and hypercalcemia
• Multiple endocrine neoplasia (MEN) type 1 –MEN1 gene
mutation
• -MEN type 2A syndromes –RET gene mutation
• -Familial hypocalciuric hypercalcemia (FHH)
• Familial hyperparathyroidism–jaw tumour syndrome- HRPT2
gene; Autosomal dominant
• -Familial isolated hyperparathyroidism
• Teritiary HPT
• Medications
• Two most common causes are Primary HPT and Cancer- related
hypercalcemia (PTH related protein mediated, or directly via
bony lesions)
How do PTHrP and PTH differ?
• PTHrP has 3 protein forms: 139, 141, 173 amino acids
• First 139 AA are the most common among all 3 forms
• 8 of first 13N-terminal AA are same as intact PTH (1-84),
therefore PTHrP and PTH can stimulate the same receptors
• But, different effects on 1,25(OH)2D
• Continuous secretion of PTHrP by tumors downregulates
receptors that stimulate 1 alpha hydroxylase  decreased
enzyme decreased 1,25(OH)2D
• Higher levels of Calcium may also decrease 1,25(OH)2D
Differences between PTHrP and PTH
Intact
PTH
Primary
High
HPT
PTHrP
Low
malignancy
PTHrP
1,25 VitD Calcium
Low
High
High
High
Low
High
Two drugs deserve special consideration when
evaluating a patient for hyperparathyroidism:
• Thiazide:
• Reduce urinary calcium excretion and cause mild hypercalcemia
[upto 2.9 mmol/L]) – therefore may unmask the HPT
• Lithium
• Decreases parathyroid gland sensitivity to calcium, shifting the
calcium-PTH curve to the right; has an action downstream of the
calcium-sensing receptor, but the exact locus is still unknown.
• If possible; trial of discontinuation: calcium more likely to
normalize if the duration of lithium use short, eg, less than a few
years, but less likely if it had been longer, eg, more than 10 years.
Uptodate: Diagnosis and differential diagnosis of
primary hyperparathyroidism
Approach
• PHPT: elevated intact PTH or at the high end of the normal
range in the setting of elevated total calcium
• Repeat measurements (usually 2- 3), check PO4 (low-normal),
ALP (high)
• Further laboratory testing is to rule out other causes of
hypercalcemia.
• Distinguish FHH from PHTP– 24h urine and FECa
• Correct levels of 25(OH)D if present may cause a false positive
• Renal function tests r/o secondary causes
• Consider genetic testing if Fhx of MEN syndrome
Localize
• Localization: technetium 99m–labeled sestamibi scanning,
ultrasound, CT, MRI, and PET. Used to aid surgery.
**Imaging should not be used to establish the
diagnosis of PHPT or to screen patients for
surgical referral**
• Gold standard: a four gland parathyroid exploration
• However, a more focused, minimally invasive approach to
parathyroid surgery is being adopted at many centers to facilitate
unilateral exploration and minimally invasive surgery in those
with probable single gland disease
Sestamibi scintigraphy
• Sestamibi scintigraphy — Technetium-99mmethoxyisobutylisonitrile (99mTc-sestamibi or MIBI)
• 99mTc-sestamibi is taken up by the mitochondria in thyroid and
parathyroid tissue; however, the radiotracer is retained by the
mitochondria-rich oxyphil cells in parathyroid glands longer
than in thyroid tissue
• Planar images obtained after injection of 99mTc-sestamibi and
again at 2hours to identify foci of retained radiotracer activity
consistent with hyperfunctioning parathyroid tissue.
Uptodate: Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism
Imaging StudiesIt has an accuracy rate of 50% to 70%
• High false negative rate: parathyroid hyperplasia, multiple
parathyroid adenomas, by CCB that interfere with the take up
of the isotope by parathyroid cells
• Other gland characteristics that can increase the likelihood of
a negative scan include small size, superior position, and a
paucity of oxyphil cells
• a single-focus positive imaging result does not reliably
exclude the presence of multiglandular parathyroid disease
• Thyroid disease requiring surgery significantly increases both
the false positive and false negative rate
Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism
PHPT Localization
• Biochemically confirmed PHPT and non-localizing imaging
studies – need bilateral exploration by ENT surgeon.
• In such patients: a single adenoma more common(62 to 77%);
however, multiglandular disease is also common (20 to 38 %).
• For re-operation (5-10% of patients): negative sestamibi and
ultrasound results usually lead to use of CT and/or MRI. If these
studies are also non-localizing, then invasive studies such as
arteriography or selective venous sampling can be performed.
• Reoperation with negative imaging: high failure rate (up to 50
%) and nonoperative medical management should be considered
Uptodate: Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism
Management
Acute Management of Hypercalcemia
• Avoid thiazides, lithium, volume depletion, prolonged bed rest,
or inactivity, and high calcium diet (>1g/day)
• Rehydration!!!
• Calcitonin +/- cinacalcet can also be of value in the short
term to maintain a reduction of calcium
• If surgery planned within a few days, AVOID IV
bisphosphonates because post op hypocalcemia risk
Parathyroidectomy
• Definitive therapy
• Surgical techniques: total open parathyroidectomy or a
minimally invasive procedure with or without the use
of intraoperative PTH assays
• Only a subgroup of people with asymptomatic PHTP
benefit from surgery
Guidelines for parathyroid surgery in patients with
asymptomatic PHPT
Results after Surgery
• Calcium, phosphate, and urine calcium return to normal quickly
• PTH levels fall by 50% within the first 10-15 min
• Indicators of bone resorption (c-telo) normalise quicker than
formation (ALP). Bone turnover returns to normal within 6 –
12 months
• Osteoblast > osteoclast activity, resulting in a substantial
improvement in bone mineral density – greatest at hip and spine
A 10-Year Prospective Study of Primary Hyperparathyroidism
with or without Parathyroid Surgery
Shonni J. Silverberg, N Engl J Med 1999; 341:1249-1255
Methods: 10 year prospective study in 121 patietns with PHPT 30 men and
91 women (age range, 20 to 79 years).
121 patients
83% asymptomatic
17% symptomatic
Surgery (50%)
49 Asymptomatic
12 symptomatic
Normalization of markers
& increased BMD in 100%
No surgery 50%
52 Aysmptomatic
8 symptomatic
Disease progression
Stable Disease
100% in Symptomatic 73% Aysmptomatic
8% after
1yr
(P=0.05)
12%
after 10
years
(P=0.03)
6% after
1 year
(P=0.00
2)
14 %
after 10
years
(P=0.00
2)
Silverberg, NEJM 1999
Will surgery decrease future fractures?
• Retrospective cohort study of 1569 patients with
PHPT(452 of whom had had a parathyroidectomy):
• Reported a significant increase in 10-year fracture-free survival, mainly
hip fractures after parathyroidectomy (59% vs 73%)
• Parathyroidectomy decreased the 10-year hip fracture rate by 8% (P =
.001) and the upper extremity fracture rate by 3%
(P = .02)
VanderWalde LH. The effect of parathyroidectomy on bone fracture
risk in patients with primary hyperparathyroidism. Arch Surg 2006; 141: 885–89.
Mollerup CL. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid
surgery: controlled retrospective follow up study. Bmj, 325: 807, 2002.
Cardiac/Renal Outcomes
• Cardiac Outcomes:
• Longterm hypertension control not improved
• Left ventricular hypertrophy decreases after surgery
in some
• slower the progression of aortic and mitral valve
calcification
• Renal Outcomes:
• Kidney stones are reduced in frequency amongst
those with a history of kidney stones
Neurological and neuropsychiatric
outcomes
• No consistent significant change in symptoms (fatigue,
weakness, lassitude, anxiety, depression)
• In an uncontrolled open prospective study of 74 patients, a
significant improvement in SF-36 scores was noted 1 year after
parathyroidectomy in five (asymptomatic) and seven
(symptomatic).
• A prospective study of 191 patients with mild asymptomatic
primary hyperparathyroidism who were randomised to medical
observation or surgical intervention has not shown any benefit of
operative treatment on SF-36 or psychological symptoms after 2
years
www.thelancet.com Vol 374 July 11, 2009
Medical Management for
those NOT candidates for
parathyroidectomy
Medical Management
• Focused on goals:
• Improving BMD as most are postmenopausal women – HRT,
SERMS, Bisphosphonates
HRT:
• significant reduction in calcium (0·1–0·3 mmol/L)
• 4–8% increase in BMD at trabecular and cortical
sites
Orr-Walker BJ. Effects of hormone replacement therapy on bone mineral density in
postmenopausal women with primary hyperparathyroidism: four-year follow-up and
comparison with healthy postmenopausal women. Arch Intern Med 2000;
160: 2161–66.
42 Postmenopausal
women with mild
PHPT, a 2-yr
randomized, placebocontrolled trial.
1.3% ± 0.4%; P = 0.004
3.6%
5.2% ± 1.4%; P = 0.002
6.6%
Grey AB. 1996 Effect of hormone replacement therapy on bone mineral density
in postmenopausal women with mild primary hyperparathyroidism.
A randomized, controlled trial. Ann Intern Med 125:360 –368
SERMS
• A small, placebo-controlled, randomized trial reported the effects of
raloxifene (60 mg/d) on serum calcium and phosphorus over 2
months in postmenopausal women with PHPT
• calcium declined significantly by 2 months in the raloxifene-treated
women. No changes in PTH, but a significant decline in the levels of
urinary NTX and serum osteocalcin
• Case series: BMD decline at both spine and hip sites in three subjects
were arrested by the introduction of treatment with raloxifene (60 or
120 mg/d).
J Clin Endocrinol Metab, February 2009, 94(2):373–381
Bisphosphonates
• Pamidronate in patients with mild PHPT- Infusions (30 mg) 10
patients in a randomized crossover study and were effective in
reducing serum calcium from 2.72 to 2.49 mmol/liter after 1
wk.
• Short-term treatment with risedronate was effective in lowering
serum calcium in individuals with mild PHPT; no long term
study
• Alendronate most extensively evaluated in individuals with
PHPT.
• Data from the RCT have consistently shown that alendronate
decreases bone turnover and increases BMD at the lumbar spine and
proximal femur in PHPT.
Effect of alendronate on lumbar spine (A), total hip (B), femoral neck (C), and one third distal
radius (D) BMD. *, Significantly higher than baseline (P < 0.001); †, significantly higher than
baseline (P < 0.05).
LUMBAR
4.92%
6.85%
TOTAL HIP
4.01%
FEMORAL
One third
distal radius
Khan A A et al. JCEM 2004;89:3319-3325
©2004 by Endocrine Society
Medical Treatment Points to Remember:
• Alendronate decreases bone turnover and increase BMD in PHPT
(level I evidence)
• Hormone replacement therapy (HRT) also improved BMD in
postmenopausal women with mild PHPT (level I evidence)
• It is not known whether these treatments also reduce fracture risk.
• Raloxifene, SERM, decreases bone turnover in postmenopausal
women with PHPT, but more research is needed to evaluate its effects
on BMD (level I evidence).
• Ensure Vit D is replete
• Do not limit calcium intake
Summary
• Primary hyperparathyroidism is the third most common
endocrine disorder
• Asymptomatic disease is common, and severe disease with renal
stones and metabolic bone disease arises less frequently.
• Primary hyperparathyroidism can be cured by
parathyroidectomy for those with symptomatic hypercalcemia
and a subgroup of asymptomatic patients
• Medical options for treating the skeletal complications of PHPT
include bisphosphonates, HRT, and raloxifene