Disorders of the Parathyroid Gland Flashcards
MOA of chief cells
have secretory granules containing parathyroid hormone (PTH)
MOA of oxyphil cells
found throughout the normal parathyroid either singly or in small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm, and
are tightly packed with mitochondria
third pharyngeal pouch forms the
inferior parathyroid gland
fourth pharyngeal pouch forms the
superior PTH gland
pathogenesis of CASR gene calcium in homeostasis
Decrease in extracellular calcium concentration
extracellular fluids (ECF) ——>
diminishes the activity CaSR parathyroid
Release of PTH——–>
PTH acts on kidney and bone to increase renal and
bone Ca2+ resorption + favors vitamin D synthesis
in kidney.——–>
Vitamin D promotes Ca2+ absorption in small
intestine.———->
These effects contribute altogether to return
extracellular Ca2+ levels to the normal level, thus
activating the CaSR and inhibiting release of PTH.
list 4 effects of PTH
- Increased renal tubular reabsorption of calcium
- Increased urinary phosphate excretion,
- Increased conversion of vitamin D to its active
dihydroxy form in the kidneys, - Enhanced osteoclastic activity
what is the role of fibroblastic growth factor 23 (FGF 23)
FGF 23
* Phosphaturic hormone
* Reduces expression of sodium phosphate
cotransporters in kidney PCT
* reducing 1,25 dihydroxy Vit D levels
what is the role of fibroblastic growth factor 23 (FGF 23)
FGF 23
* Phosphaturic hormone
* Reduces expression of sodium phosphate
cotransporters in kidney PCT
* reducing 1,25 dihydroxy Vit D levels
what is the function of RANKL (receptor activator of nuclear factor κB ligand)
Membrane-bound protein of osteoblasts that stimulates osteoclasts by interacting with RANK
Ensures fusion and differentiation into activated osteoclasts and prevents their apoptosis
what is the function of RANK
receptor on osteoclasts and osteoclast precursors, for interaction with osteoblasts
what is the function of Osteoprotegerin (OPG)
A regulatory protein secreted by osteoblasts that binds RANKL
Inhibits RANK-RANKL interaction, leading to decreased osteoclast activity.
__________ :
-Secreted by osteoblasts
-Promotes the proliferation of osteoclast precursor cells
-Simultaneous binding and fusion of ______and RANKL on the surface of precursor osteoclasts on the synovium→ differentiation of precursor osteoclasts into osteoclasts
M-CSF(macrophage colony-stimulating factor)
Interaction of membrane bound or soluble _______with RANK ____________ cells induces their differentiation and activation into mature osteoclasts.
RANKL , RANK-expressing osteoclast precursor cells
vitamin D3, prostaglandin E2 (PGE2), parathyroid hormone (PTH) and several cytokines - (TNFα) and
interleukin (IL)-1, -11 and -17. induced ___________ expression
RANKL expression by osteocytes and osteoblasts
Expression of the decoy receptor osteoprotegerin (OPG) is induced by :
17-β oestradiol,
IL-4
TGF-β
OPG ___________ with RANK/RANKL interaction thereby _________bone degradation
interferes, inhibition
list 3 inducers of RANKL expression
progesterone
PTH
calcitriol (vit. D3)
estrogen, induces the expression of the _______
decoy receptor OPG
____________ important cause of hypercalcemia.
Primary hyperparathyroidism
- Adults, more common in women than men 4 : 1.
!Adenoma: 85% to 95%:
primary or secondary hyperPTH
1º hyper-PTH
pathogenesis of PRIMARY HYPERPARATHYROIDISM
Excess production of PTH → Hypercalcemia
Clinically silent – cause of hypercalcemia
Primary hyperparathyroidism
Clinically apparent – causes of hypercalcemia
Cancer – PTH like polypeptide + Osteolytic bone metastasis
Persistent hyperplasia in long standing secondary
hyperparathyroidism even with correction
Calcium and phosphate increased
Requires parathyroidectomy
teritary hyper-PTH
Compensatory hyperplasia of all parathyroids because
of prolonged hypocalcemia - CKD or Vit D def
Calcium levels low / normal
secondary hyperparathyroidism
Primary Hyperparathyroidism is most common in adults or children
women or men
4:1 ratio
adenoma 85-95%
ADULTS , WOMEN
list 3 genetic abnormalities in primary hyperparathyroidism
- Cyclin D1 gene rearrangements – overexpressed in 40% parathyroid adenoma
Cyclin D1 – normal cell cycle regulator, gene
located at 11q Inversion Chr 11 repositions this
gene adjacent to PTH gene located at 11p drives
abnormal expression of Cyclin D1 in PTH
producing cells - MEN mutations: MEN-1,MEN-2a ( parathyroid tumors)
- Familial hypocalciuric hypercalcemia (CASR inactivating mutations)
determine diiagnosis:
-rare autosomal dominant condition.
-(CASR inactivating mutations) decreasing sensitivity
to extracellular calcium leading high PTH levels.
Familial hypocalciuric hypercalcemia (FHH)
diagnosis of FHH
- asymptomatic hypercalcemic patient with a family history of hypercalcemia,
- asymptomatic hypercalcemia before the age of 40 years
- serum calcium values from first-degree relatives in the absence of family history.
FHH patient typically have electrolyte imbalances of:
- mild hypercalcemia
- hypocalciuria
- hypermagnesemia
- hypophosphatemia.
FHH patient typically have electrolyte imbalances of:
- mild hypercalcemia
- hypocalciuria
- hypermagnesemia
- hypophosphatemia.
Increased PTH secretion despite
increased Serum Calcium
= Hypercalcemia
is seen in?
in parathyroid ; reuced CASR function
Increased calcium reabsorption
despite increased Serum Calcium
= Hypercalcemia & Hypocalciuria
is seen in?
in kidney; reduced CASR function
Determine Diagnosis:
- 24 hours urinary calcium excretion is less than 100 mg/24 hours.
- Ca/Cr excretion ratio is low. (0.020 or less)- should be tested for CaSR gene mutations.
- Serum Magnesium is in the upper-normal range or mildly elevated
Morphologic findings in Primary hyperparathyroidism: parathyroid adenoma GROSS:
- solitary nodule confined to single gland;
- other glands normal/shrunken (feedback inhibition by calcium)
- well-circumscribed – delicate capsule
- soft, tan to reddish-brown
- 0.5-5g
Morphologic findings in Primary hyperparathyroidism: parathyroid adenoma Microscopically:
- fairly uniform, polygonal chief cells with small, centrally placed nuclei- endocrine
atypia - Absence of adipose tissue that is seen in normal parathyroid.
Morphologic findings in Primary hyperparathyroidism: parathyroid HYPERPLASIA:
All 4 glands involved - asymmetry (together not >1g)
Chief cell predominant- nodular / diffuse
Fat may be inconspicuous
Morphologic findings in Primary hyperparathyroidism: parathyroid CARCINOMAS:
involves one parathyroid
circumscribed lesions / clearly invasive neoplasms
Gross:
* gray-white, irregular masses weighing up to 10g
Microscopy
* dense, fibrous capsule
* cells usually are uniform and resemble normal parathyroid cells nodular or trabecular
patterns.
* Diagnosis of carcinoma based on cytologic detail is unreliable, invasion of surrounding
tissues and metastasis are the only definitive criteria
bones marrow contains fibrous tissue accompanied by foci of hemorrhage and cyst formation
(osteitis fibrosa cystica- Brown tumor of hyperparathroidism)
clinical features of 1º hyperPTH
-painful bones ( abnormal remodeling, osteolysis & fractures)
-renal stones ( renal colic)
-abdominal groans ( hypercalcemia induced ileus, constipation, pancreatitis, peptic ulcer)
-psychic moans ( malaise, fatigue, depression)
lab diagnosis for 1º hyper-PTH
- Elevated serum Calcium and PTH
D/D:
Paraneoplastic syndrome (e.g., squamous cell cancer of the lung) and Renal cell carcinoma
distinguishing factors: serum PTH levels will be low due to negative feedback
what is the renal pathogenesis for secondary hyper-PTH
renal insufficiency –> Reduced α 1 hydroxylase –>
Reduced synthesis of active Vit D–> Reduced Calcium absorption in GIT - chronic hypocalcemia —> Parathyroid stimulation —>PTH
describe the gross morphology of 2º hyperparathyroidism
glandular enlargement
describe the microscopic morphology of 2º hyperparathyroidism
hyperplastic glands with increased water clear chief cells, fat decreased
Metastatic calcification in various tissues.
Vascular calcification – ischemic damage to skin and other organs.
Bone: as seen in primary hyperparathyroidism
what are the 5 main lab dx. for 2º hyperparathyroidism
➢Hypocalcemia*
➢Hyperphosphatemia *
➢Increased PTH levels
➢Decreased Vit D
➢Increased ALP
Disorder : Primary hyperparathyroidism
Serum calcium
Serum PTH
Serum phosphorus
Serum 1,25(OH)2
Increased
Increased
Decreased
Increased
Disorder: secondary hyperparathyroidism (renal vit D. Def)
Serum calcium
Serum PTH
Serum phosphorus
Serum 1,25(OH)2
Decreased
Increased
Increased
Decreased
Disorder: malignancy induced hypercalemia
Serum calcium
Serum PTH
Serum phosphorus
Serum 1,25(OH)2
Increased
Decreased
Normal
Decreased
Disorder: hypoparathyroidism
Serum calcium
Serum PTH
Serum phosphorus
Serum 1,25(OH)2
decreased
decreased
increased
decreased
what are 4 main causes for hypoparathyroidism
- Acquired - inadvertent consequence of surgery of thyroid / neck dissection
Autoimmune hypoparathyroidism- assc. w/ APS1 - Autosomal-dominant hypoparathyroidism is caused by gain-of-function mutations in
the calcium-sensing receptor (CASR) gene. - Congenital absence of parathyroid glands: Associated malformations like thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome – DiGeorge Syndrome
- hypomagnesemia
determine dx:
* Defective response in renal tubule to PTH ( PTH resistance)
* Due to defects in G protein receptor
Type IA ( Albrights hereditary osteodystrophy)
* May be associated with end organ resistance to TSH/ FSH/LH
Pseudohypoparathyroidism
lab findings for pseudohypoparathyroidism
- Increased PTH
- Hypocalcemia
- Hyperphosphatemia
- increased Alkaline phosphatase
what are to signs for neuromuscular irrirabilty
- Chvostek sign: twitch of the facial muscles that occurs when gently tapping an
individual’s cheek, in front of the ear
Trousseau sign - carpopedal spasm
ACUTE clinical features for hypo-PTH
Acute- surgical ablation
* neuromuscular irritability : tingling, muscle spasms, facial grimacing and sustained
carpopedal spasm (tetany)
- chvostek sign
- trousseau sign
- cardiac arrythmas
- increased ICP & seixures
CHRONIC clinical features for hypo-PTH
Cataract, calcifications of the basal ganglia, dental abnormalities
* Mental status changes - emotional instability
Disorder: pseudohypoparathyroidism
Serum calcium
Serum PTH
Serum phosphorus
Serum 1,25(OH)2
dec
inc
inc
inc
