Parathyroid Flashcards
What are the effects of parathyroid hormone on the body?
PTH = Increase serum calcium, decrease serum phosphates
A. BONE:
- Increase osteoclasts
B. KIDNEY:
- Increase calcium reabsorption
- Decrease phosphate reabsorption
- Increase 1,25-dihydroxyvitamin-D (calcitriol or D3) synthesis (increases efficiency of calcium reabsorption)
C. GUT:
- Increase calcium absorption via stimulation by Vitamin D (from kidney)
What are the effects of calcitonin on the body?
CALCITONIN = Decrease serum calcium
A. BONE:
- Inhibits osteoclasts
B. KIDNEY:
- Increase excretion of calcium and phosphate
C. GUT:
- Inhibits calcium absorption
What is the blood supply to the superior and inferior parathyroid glands?
Superior and inferior parathyroid arteries
- Originate from inferior thyroid artery (86% of the time)
- Some contribution from superior thyroid artery (10-20%)
How much do each parathyroid weigh?
30-40g
What are the most common number of parathyroids? What percentage have a different number?
- 85% have 4 parathyroids
- 10% have < 4
- 5% have >4
What are the different types of hyperthyroidism? What are their laboratory findings?
Normal kidney = excretes phosphate, absorbs calcium
A. PRIMARY HYPERPARATHYROIDISM
- Elevated calcium, decreased phosphate, high urine Calcium
- FHH: Urine Ca low
- Normocalcemic primary hyperpara: Normal Ca2+, high PTH
- Significantly elevated PTH
- If PTH is mildly elevated or normal but calcium is inappropriately high, most likely diagnosis is still primary hyperparathyroidism, but have to exclude familial hypocalciuric hypercalcemia
B. SECONDARY HYPERPARATHYROIDISM
- Due to malfunction of another organ system (makes serum calcium look low, so parathyroid glands compensating)
- Low or normal calcium, high phosphate, high PTH
- PO4 supresses calcitonin, decreases Ca2+ absorption, therefore elevating PTH
- PO4 high = renal problem (normal kidney excretes excess PO4 and absorbs calcium, but if problematic then they can’t excrete and absorb)
- Prevent with phosphate binders and Vitamin D replacement
C. TERTIARY HYPERPARATHYROIDISM
- Autonomous production (e.g. gland abnormal now) after the cause of secondary hyperpara has been corrected (like an “induced” primary hyperpara because of secondary issues) - parathyroid gland more commonly becomes hyperplastic rather than creates another adenoma (similarly in secondary hyperpara, starting to become hyperplastic)
- Normal or high Ca2+, elevated PTH, low vitamin D, variable PO4 (usually high if Ca2+ high, but dependent on kidney function)
List 4 causes of primary hyperparathyroidism
- Benign adenoma (most common)
- Parathyroid hyperplasia (syndromic MEN1/2a, or sporadic)
- Familial hypocalciuric hypercalcemia
- Normocalcemic primary hyperparathyroidism
List 7 causes of secondary hyperparathyroidism
- Chronic renal failure
- Vitamin D deficiency
- Multiple myeloma
- Osteogenesis imperfecta
- Paget’s disease
- Bone metastasis (PTBLK - prostate, thyroid, breast, kidney, lung)
- PItuitary basophilism
What are 4 different ways to differentiate between parathyroid adenoma vs. hyperplasia?
- 4-gland exploration (one gland enlarged, or all glands enlarged)
- Permanent section (frozen can’t tell)
- Decreased or no fat in hyperplastic glands, vs. fat in adenoma
- Adenoma will have a rim of normal tissue surrounding it whereas hyperplastic glands won’t - Intraoperative PTH measurement
- Thyroid ultrasound (As part of work-up for hyperparathyroidism)
What is the incidence of the following parathyroid pathologies in primary hyperparathyroidism?
1. Adenoma
2. Hyperplasia
3. Multiple adenoma
4. Carcinoma
- Adenoma - 85%
- Hyperplasia - 10%
- Multiple adenoma - 5%
- Carcinoma - < 1%
Regarding familial hypocalciuric hypercalcemia, discuss:
1. Genetics and inheritence
2. Investigations and findings 4
3. Managememnt
GENETICS:
- CaSR (mutation in the calcium-sensing receptor gene, expressed in kidney and parathyroid) on chromosome 3q13
- Autosomal dominant
INVESTIGATIONS: Parathyroids can’t tell that calcium is elevated because of problem in the sensing-receptor gene so the PTH is normal/elevated; kidney’s can’t tell there is calcium, so they increase absorption
- Urine calcium < 100ng/24 hours
- Calcium-to-creatinine ratio < 0.01
- Mildly elevated to normal PTH
- High calcium, low phosphate
Management:
Not excreting appropriately –> not a surgical disease
Regarding primary normocalcemic hyperparathyroidism, discuss:
1. Hallmark laboratory findings
2. Diagnostic criteria
3. Management
pnHPT was discovered due to overzealous endocrinologists checking PTH in patients with low bone mineral density, despite having normal calcium
HALLMARK (labs look like secondary Hyperpara):
- Normal calcium
- Elevated PTH
- Usually in the setting of osteoporosis (tissue resistance to PTH; normally elevated PTH should have HIGH calcium)
DIAGNOSIS requires exclusion of secondary causes of elevated PTH:
1. Vitamin D deficiency (< 20µg/L)
2. Renal abnormalities - reduced creatinine clearance (< 60mL/min)
3. Medications (HCTZ, loop diuretics, lithium)
4. Hypercalciuria (CKD)
5. Gastrointestinal disorders associated with calcium malabsorption (e.g. Gluten enteropathy, IBD, gastric bypass surgery, CF, celiac)
6. PTHrp (“related protein” - to identify paraneoplastic secretion)
MANAGEMENT (controversial)
- Most follow guidelines for primary hyperparathyroidism
- Localization study - most will have a negative study
- Four gland exploration
What are the normal anatomic locations of the parathyroid glands?
SUPERIOR PAIR:
- Usually on deep surface of the thyroid, within 1cm of RLN entry at cricothyroid joint; OR 1cm above intersection of RLN and inferior thyroid artery (within 2cm of this point)
INFERIOR PAIR:
- Usually within 1-2cm of inferior thyroid artery entry into the thyroid gland
SUPERIOR PARATHYROID = deep to plane of the RLN and lateral to the nerve
INFERIOR PARATHYROID = Superficial to the plane of the RLN and medial to the nerve
Vancouver Pg 157
What are 4 non-invasive localization studies that can be used for a parathyroid adenoma diagnosis?
A. ULTRASOUND
- Poor if < 5mm
B. SESTAMIBI SCINTIGRAPHY (measurements at 10min & 2 hours)
- Tracer accumulates in mitochondria - adenomas have high oxyphilic cells, rich in mitochondria. Initial uptake of tracer in the parotids, submandibular glands and thyroid. However after 2 hours, tracer washes out of the thyroid except for the parathyroid adenoma
- 99mTc-sestamibi by itself: 89% sensitive for single adenomas, poor for multiple adenomas/hypertrophy
- SPECT - Sestamibi-single photon emission computer tomography - improved visualization but uses same transfer, sensitivity 98%
- SPECT-CT - SPECT fused with CT scanning
- Subtraction scans - Technetium-thallium. Technetium accumulates in parathyroid, thallium accumulates in thyroid and parathyroid. Final image = thallium - technetium (poor for multigland disease)
C. 4D-CT
- Images rapid contrast uptake and washout from parathyroid adenomas
- High dose of radiation (do not use in young people)
- Needs to be more than 1cm, poor for intrathyroidal
D. OTHERS:
- MRI
- Choline 11 - Methionine PET
What are 6 alternative sites for parathyroid gland location and their relative % incidences?
- Retroesophageal (most common location for ectopic superior glands) - 25%
- Superior mediastinal (most common location for ectopic inferior glands) - 25%
- Intrathymic (20%)
- Intrathyroidal (10%)
- Carotid sheath
- Tracheoesophageal
What are 5 invasive localization studies for parathyroid adenoma?
A. ARTERIOGRAPHY
- Thyrocervical trunk, internal mammary and carotids
B. DIGITAL SUBTRACTION ANGIOGRAPHY
- For multiple gland disease in revision cases
- 60-70% sensitive
C. SELECTIVE VENOUS CATHETERIZATION
- 80% sensitive
- Two-fold rise in PTH
- Expensive, high skill required
- 3-5 hours to complete
- Difficult if post-op with ligation of vessels
D. U/S GUIDED FNA
E. INTRAOPERATIVE LOCALIZATION METHODS
1. Intraoperative ultrasound
2. Injection of methylene or toluidine blue
3. Gamma probes (after Tc99m injection 2 hours pre-op, radiation > 20% than surgical bed is positive)
4. Intraop PTH & frozen section
5. Urinary adenosine monophosphate (historic)
Why and how is intraoperative PTH monitoring done? 2 indications that surgery is complete
- Mainly done for primary hyperparathyroidism
- PTH intraop monitoring has replaced bilateral exploration
- Bilateral exploration used to be routine for primary hyperparathyroidism (to exclude 4 gland hyperplasia - 10% risk; and multiple adenomas - 5% risk)
Several protocols for monitoring exist.
The most widely accepted protocol = “dual criteria”
1. PTH half life is 3-5 minutes
2. Two samples: (1) before skin incision, (2) 10 minutes post-gland excision
Surgery finished when:
1. Decrease PTH by 50%; AND
2. PTH level normalized
What are the indications for surgery for primary hyperparathyroidism?
A. SYMPTOMATIC PATIENTS (Essentially all symptomatic patients)
1. Muscle weakness
2. Osteitis fibrosa cystica (Brown’s tumor - giant cell focal lesion arises in result of abnormal bone metabolism)
3. Renal calculi ± radiograph
4. Life threatening hypercalcemic crisis
5. Psychiatric problems
6. GI symptoms
7. Fibromyalgia symptoms
B. ASYMPTOMATIC PATIENTS, if:
1. Serum calcium > 1mg/dL (0.25mmol/L)
2. Skeletal scan:
- BMD by DEXA: T-score < -2.5 at the tested site (more negative)
- Vertebral fracture by radiograph (CT/MRI) or vertebral fracture assessment
3. Renal:
- Creatinine clearance/GFR < 60mL/min
- 24-hour urine for calciu, > 400mg/day and increased stone risk by biochemical analysis
- Nephrolithiasis or nephrocalcinosis by radiograph (US or CT)
4. Age < 50
C. CHRONIC RENAL FAILURE INDICATIONS (50% effective)
1. Calciphylaxis (tissue calcification) unresponsive to hemodialysis or meds
2. Refractory bone pain/pruritus
3. Renal osteodystrophy
4. Pathologic fractures
5. Anemia non-responsive to EPO
What is one medication that can be used in patients with primary hyperparathyroidism that are poor surgical candidates, and for patients with secondary hyperparathyroidism?
CINACALCET
- Calcimimetic (activates the calcium-sensing receptor in the parathyroid gland)
- Decreases PTH
- Decreases calcium
Indications:
1. Secondary hyperparathyroidism
2. PTH carcinoma
Regarding parathyroid carcinoma, discuss:
1. Lab findings
2. Management
3. Pathology findings
RARE
Lab findings:
1. Severe hypercalcemia
2. Elevated PTH
Pathology findings:
1. Angioinvasion seen on histology
Management:
1. Resection and neck dissection prophylactically
2. IMRT for palliative cases
What are 3 surgical options for parathyroid hyperplasia?
- SUBTOTAL PARATHYROIDECTOMY
- Preferred if patient doesn’t have MEN or renal failure (ie. use in sporadic 4-gland hyperplasia)
- Involves removal of 3 glands and removal of 1/3 to 2/3 of the fourth gland
- Can use PTH titration - TOTAL PARATHYROIDECTOMY W/ AUTO-TRANSPLANTATION
- For chronic renal failure, 50% effective
- Implant into SCM, brachioradialis or infraclavicular
- Can cryopreserve parathyroid up to 18 months - TOTAL PARATHYROIDECTOMY W/ CRYOPRESERVATION OF 1 GLAND
- Chronic renal failure or MEN
What is the 6 differential diagnosis of persistent hypercalcemia post-surgical exploration and excision (>6 months post-op)?
- Supranumerary gland
- Second adenoma
- Residual gland
- Failure to recognize diseased gland
- 4-gland hyperplasia (wrong diagnosis)
- Malignancy
Discuss the management of hypercalcemia crisis. Name 6 things
- Saline hydration and electrolyte correction
- Furosemide diuresis
- Glucocorticoids
- Calcitonin (inhibits osteoclasts) - 5 IU/Kg IM
- Bisphosphonates (inhibits osteoclasts) - Pamidronate 60mg IV over 4 hours
- Organic phosphates - 8mg IV, PO, or PR
- Mithramycin (MOA poorly understood but works well) - 25 mcg/kg IV over 4 hours
- Gallium nitrate (inhibits osteoclasts)
- Hemodialysis for life threatening situations
- Cinacalcet
Describe the symptoms of hypercalcemia
BONES: Osteoporosis
STONES: Renal lithiasis
GROANS:
- N/V
- Constipation
- Cramps
- Gallstones
- Pancreatitis
- Peptic ulcers
MOANS:
- Depression
- Fatigue
- Confusion
- Stupor
- Coma
TONES:
- Shortened QT
Describe the ECG findings of hypercalcemia
- Shortening QTc interval
- Osborn waves (J-waves)
- Ventricular irritability and VF arrest (if severe)
Vancouver pg 160
Describe the ECG findings of Hypocalcemia
Q-Tc prolongation –> Torsade’s –> Ventricular arrhythmia
What are the causes of hypercalcemia?
CHIMPANZEES
C: Calcium supplementation
H: Hyperparathyroidism
I: Iatrogenic (drugs such as thiazides, or immobility after surgery)
M: MIlk-alkali syndrome (caused by taking too much calcium, usually in the form of dietary supplements taken to prevent osteoporosis, and absorbable alkali (found in antacid drugs))
P: Paget’s disease of the bone, also osteogenesis imperfecta
A: Acromegaly and Addison’s disease
N: Neoplasia (common cause) - Multiple myeloma, bone metastasis
Z: Zollinger-Ellison Syndrome (MEN Type 1)
E: Excessive Vitamin D
E: Excessive Vitamin A
S: Sarcoidosis
Describe hungry bone syndrome. What are the risk factors for this?
- Rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, and exacerbated by suppressed PTH levels
- Follows parathyroidectomy in patients with severe primary hyperparathyroidism (pHPT) and pre-operative high bone turnover
- Believed to be due to increase influx of calcium into bone, due to sudden removal of the effect of high circulating levels of PTH on osteoclastic reabsorption
- Elevated alkaline phosphatase (high bone turover) pre-op suggests patient will need Ca2+/Mg+ post-op
What enzyme stimulated by PTH activates Vitamin D?
1-alpha hydroxylase
What investigations should be ordered (other than calcium and PTH) could be performed with diagnosis of hyperparathyroidism?
- Albumin
- Alkaline phosphatase (measure of bone turnover)
- Bone densitometry (DEXA)
- BUN and Creatinine
- Calcitonin (r/o MEN 2A)
- Thyroid function test (TSH)
- 24h urine calcium (r/o familial hypocalciuric hypercalcemia)
- Gastrin (r/o MEN 1)
- ACE (r/o sarcoid)
- Phosphorus
- Urine catecholamines (r/o MEN 2a)
- Prolactin (r/o MEN 1)
- Thyroid U/S - high rate of concurrent thyroid nodules (easiest to manage concurrently)
Discuss the follow up management of hyperparathyroidism 3
- Labs: Ca2+, Cr/GFR, Urinalysis, PTH q6 months
- Bone density yearly
- Restrict oral calcium intake < 1g/day
Discuss the management of hyperparathyroidism associated with renal failure 3
Renal failure - Phosphate high, calcium low/normal, PTH high
- Calcium salts (phosphate binder for hyperphosphatemia) - Sevelamer - binds to phosphate and prevents its absorption (increases excretion)
- Vitamin D (because hypovitamin D) - Calcitriol
- Cinecalcet
What is the danger of primary hyperparathyroidism in pregnancy?
- Neonatal tetany (involuntary muscle contractions and peripheral nerve stimulation)
- Calcium crosses placenta, PTH doesn’t
- Newborn PTH is suppressed and serum Ca2+ drops soon after delivery –> leading to hypocalcemia (tetany)
What are the causes of congenital hypoparathyroidism? 2
Due to agenesis of the parathyroids
- Deletion 22q11.2 spectrum (DiGeorge, Velocardiofacial syndrome)
- Mother hyperparathyroid - supresses fetal parathyroid function –> hypocalcemia after birth/withdrawal of PTH –> Possible neonatal tetany (due to hypocalcemia)
What does primary hyperparathyroidism in infancy present with? 3
- Respiratory distress
- Hypotonia
- Skeletal Demineralization
Regarding Hyperparathyroidism-Jaw tumor syndrome, discuss:
1. Genetics and inheritance
2. Clinical presentation -3
GENETICS/INHERITANCE:
1. Gene: CDC73 on chromosome 1q31
2. Inheritance: Autosomal dominant
3. Protein affected: Parafibromin (tumor suppressor gene)
CLINICAL PRESENTATION:
1. Hyperparathyroidism (solitary or multiple adenomas, 10% will present as parathyroid carcioma, severe hypercalcemia as a teenager)
2. Jaw: Cemento-ossifying fibromas
3. Renal: Cysts, hamartomas, Wilms’ tumor (nephroblastoma)
What is a Brown’s tumor?
Pathophysiology?
What should be ruled out when you see a patient with a Brown’s tumor?
Brown’s tumor = A type of Osteitis fibrosa cystica
OFC = Combination of cystic brown tumors, peritrabecular fibrosis and increased bone activity
PATHOPHYSIOLOGY:
- Giant cell focal lesions that arise from abnormal bone metabolism due to hyperparathyroidism
- Areas of extensive bone resorption, replaced by fibrovascular tissue and giant cells with abundant deposits of hemorrhage and hemosiderin (brown color)
Clinical presentation:
- Most common present in mandible or maxilla
RULE OUT:
1. Primary hyperparathyroidism
2. Renal osteodystrophies (renal disease causing skeletal abnormalities) - much more secondary than primary hyperparathyroidism, so more commonly seen in secondary HPT
3. MEN 1/2a
Regarding parathyroid cysts, discuss:
1. Presentation
2. Diagnosis 2
3. Differential 4
4. Management
PARATHYROID CYSTS:
- Rare presentation, most are non-functional
- Functional cysts are often secondary to degeneration of parathyroid adenomas
PRESENTATION:
- Majority located in neck (some in mediastinum)
- Can (rarely) present with parathyroid crisis
DIAGNOSIS:
1. Cystic mass with CLEAR fluid
2. Elevated PTH in the fluid
DIFFERENTIAL:
1. TGDC
2. Branchial cleft cyst
3. Thyroid cyst
4. Parathyroid carcinoma
MANAGEMENT:
1. Asymptomatic with normal calcium = observation
2. Symptomatic or increased Ca2+ = surgery
Recurrent hyperparathyroidism, post-4-gland - what else can you do?
Thymectomy (in case of intra-thymic parathyroid)
