Pathology of Parathyroid and Metabolic Bone Disease Flashcards
What is the key cell within the parathyroid gland and its role?
- chief cell= regulates serum FREE (ionized) calcium via PTH secretion.
*** What does PTH do in response to low FREE (ionized) calcium in the blood?
- increases bone osteoCLAST activity (by activating the osteoBLAST which uses RANKL to activate the osteoCLAST), increasing calcium and phosphate.
- increases small bowel absorption of calcium and phosphate (indirectly by activating vitamin D).
- increases renal calcium reabsorption (distal convoluted tubule) and decreases phosphate reabsorption (proximal convoluted tubule; important bc this is what allows the increase in FREE calcium, unbound to phosphate).
** What is PRIMARY HYPERparathyroidism?
- excess PTH due to disorder of the parathyroid gland.
What are the 3 possible ways by which you can get PRIMARY HYPERparathyroidism?
- parathyroid adenoma (MOST COMMON)
- sporadic parathyroid hyperplasia
- parathyroid carcinoma
What is parathyroid adenoma (primary hyperparathyroidism)?
- benign neoplasm (usually involving one gland).
- results in ASYMPTOMATIC HYPERcalcemia, however it can present with consequences of increased PTH and hypercalcemia.
Even though parathyroid adenoma (primary hyperparathyroidism) is most often asymptomatic, what are some consequences that can occur due to increased PTH and hypercalcemia?
- NEPHROLITHIASIS (calcium oxalate stones)
- NEPHROCALCINOSIS= metastatic calcification of renal tubules, leading to renal insufficiency and polyuria.
- CNS disturbances (depression and seizures)
- CONSTIPATION, PUD, and ACUTE PANCREATITIS (bc calcium can activate pancreatic enzymes).
- OSTEITIS FIBROSA CYSTICA= resorption of bone leading to fibrosis and cystic spaces.
What lab findings will you see with parathyroid adenoma (primary hyperparathyroidism)?
- increased serum PTH
- increased serum calcium
- decreased serum phosphate
- increased urinary cAMP
- increased serum ALK phos (bc remember PTH receptors are actually on the osteoBLAST, causing it to increase alk phos).
How do you treat parathyroid adenoma (primary hyperparathyroidism)?
- surgical removal of the affected gland.
** What is SECONDARY HYPERparathyroidism?
- excess production of PTH due to disease process EXTRINSIC to the parathyroid gland.
*** What is the most common cause of secondary hyperparathyroidism?
- CHRONIC RENAL FAILURE
*** Why does chronic renal failure lead to secondary hyperparathyroidism?
- renal insufficiency leads to decreased phosphate excretion.
- increased serum phosphate then binds FREE calcium in the blood.
- decreased FREE calcium stimulates all 4 parathyroid glands.
- increased PTH leads to bone resorption (contributing to renal osteodystrophy).
What lab findings will you see with secondary hyperparathyroidism?
- increased PTH
- decreased serum calcium
- increased serum phosphate
- increased alk phos (again bc PTH is stimulating the osteoBLASTS to increase alk phos).
** What is HYPOparathyroidism?
- LOW PTH caused by autoimmune damage, surgical excision, or DIGEORGE syndrome (failure to develop 3rd and 4th pharyngeal pouches bc the parathyroid is a derivative of these)
How does HYPOparathyroidism present?
symptoms of low serum calcium:
- numbness and tingling (perioral)
- muscle spasms (tetany)= elicited by filling of blood pressure cuff (TROUSSEAU sign) or tapping on the facial nerve (CHVOSTEK sign)
What labs will you see with HYPOparathyroidism?
- decreased PTH
- decreased serum calcium
** What is PSEUDOHYPOparathyroidism?
- signs and symptoms of hypoparathyroidism, but due to END-ORGAN RESISTANCE (due to Gs protein) to PTH.
What will you see with pseudohypoparathyroidism?
- HYPOcalcemia with INCREASED PTH.
With what is the autosomal dominant form of pseudohypoparathyroidism associated?
- SHORT stature
- SHORT 4th and 5th DIGITS
*** What is Achondroplasia? (PICMONIC)
- AUTOSOMAL DOMINANT ACTIVATING mutation in fibroblast growth factor 3 (FGFR-3) leading to impaired cartilage proliferation in the growth plate
- common cause of DWARFISM
What does over-expression of FGFR-3 lead to in achondroplasia?
- inhibition of cartilage growth.
* most mutations are sporadic and related to increased paternal age.
*** What are the clinical features of achondroplasia?
- SHORT EXTREMITIES with normal-sized head and chest, due to poor ENDOCHONDRAL BONE formation.
Is intramembranous bone formation affected in achondroplasia?
- NO, just endochondral.
What is endochondral bone formation?
- formation of a CARTILAGE MATRIX, which is then REPLACED by BONE.
- how LONG BONES form.
What is intramembranous bone formation?
- formation of bone without a preexisting cartilage matrix.
- how FLAT BONES (skull and ribcage) develop.
Will mental function, life span, and fertility be affected in achondroplasia?
- NO :)
** What is Osteogenesis Imperfecta? (PICMONIC)
- congenital defect of bone formation resulting in WEAK BONE.
- most commonly due to AUTOSOMAL DOMINANT defect in COLLAGEN TYPE I synthesis.
- remember bONE has the word ONE in it for type 1 collagen.
What are the clinical features of Osteogenesis Imperfecta?
- MULTIPLE FRACTURES (can mimic child abuse, but bruising is absent).
- BLUE SCLERA= thinning of scleral collagen reveals underlying CHOROIDAL VEINS.
- hearing loss= bones of the middle ear easily fracture.
** What is Osteopetrosis?
- inherited defect of bone RESORPTION resulting in abnormally THICK, HEAVY BONE that FRACTURES easily.
- due to poor osteoCLAST function.
- multiple genetic variants exist
*** What mutation is most common in osteopetrosis?
- CARBONIC ANHYDRASE II mutation, which leads to LOSS of the ACIDIC microenvironment required for bone resorption.
- think of carbonic anhydrase like dumping a can of coke down calcified water pipes to clear them.
*** What are the clinical features of osteopetrosis?
- bone fractures
- anemia, thrombocytopenia, and leukopenia with extramedullary hematopoiesis due to bony replacement of the marrow (myelophthisic process).
- vision and hearing impairment (due to impingement on cranial nerves).
- hydrocephalus (due to narrowing of the foramen magnum).
- renal tubular acidosis (seen with carbonic anhydrase II mutation= lack of carbonic anhydrase results in decreased tubular reabsorption of HCO3-, leading to metabolic acidosis.
*** How do you treat osteopetrosis?
- BONE MARROW TRANSPLANT bc osteoclasts are derived from monocytes.
** What is Rickets/Osteomalacia?
- defective mineralization of osteoid due to LOW levels of VITAMIN D, which results in low serum calcium and phosphate.
- osteoblasts normally produce osteoid, which is then mineralized with calcium and phosphate to form bone
How can vitamin D deficiency occur?
- decreased sun exposure (vitamin D is normally derived from the skin upon exposure to sunlight; 85% and from the diet; 15%).
- poor diet
- malabsorption
- liver failure and renal failure
How is vitamin D activated?
- via 25-hydroxylation by the liver followed by 1-alpha-hydroxylation by the proximal tubule cells of the kidney.
How does active vitamin D raise serum calcium and phosphate?
by acting on:
- intestine= increases absorption of calcium and phosphate.
- kidney= increases reabsorption of calcium and phosphate.
- bone= increases resorption of calcium and phosphate.
*** What is Rickets?
- LOW vitamin D in CHILDREN (usually less than 1 y/o), resulting in abnormal bone mineralization.
How does Rickets present?
- PIGEON-BREAST deformity
- FRONTAL BOSSING (enlarged forehead) due to osteoid deposition on the skull.
- RACHITIC ROSARY due to osteoid deposition at the costochondral junction.
- BOWING of the LEGS in ambulating children.
*** What is Osteomalacia?
- LOW vitamin D in ADULTS.
- inadequate mineralization (aka osteoid being laid down, but no calcium and phosphate to mineralize it) results in weak bone with an increased risk for fracture.
What lab findings will you see with Osteomalacia?
- decreased serum calcium
- decreased serum phosphate
- increased PTH
- increased ALK PHOS
- remember, whenever osteoBLASTS are activated, you will see an increase in alk phos (bc an alkaline environment is needed to mineralize bone).
** What is osteoporosis?
- REDUCTION in TRABECULAR BONE mass.
- results in POROUS bone with an increased risk for fracture.
*** On what is risk for osteoporosis based?
- PEAK BONE MASS (attained at early adulthood) and RATE of BONE LOSS that follows thereafter.
When is your peak bone mass reached, and on what is it based?
- by 30 years of age
- based on genetics (vitamin D receptor variants), diet, and exercise.
- thereafter slightly less than 1% of bone mass is lost each year.
What would cause bone mass to be lost more quickly, leading to osteoporosis?
- lack of weight-bearing exercise (e.g. space travel)
- poor diet
- decreased estrogen (e.g. menopause).
What are the 2 most common forms of osteoporosis?
- senile
2. postmenopausal
What are the clinical features of osteoporosis?
- bone pain and fractures in weight-bearing areas such as the vertebrae (leads to loss of height and kyphosis), hip, and distal radius.
How is bone density measured?
- DEXA scan
What will labs show with osteoporosis?
- serum calcium, phosphate, PTH, and ALK PHOS are NORMAL.
* labs help to exclude osteoMALACIA, which has a similar clinical presentation.
How do we treat osteoporosis?
- exercise, vitamin D, and calcium to limit bone loss.
- BISPHOSPHONATES= induce apoptosis of osteoCLASTS.
- estrogen replacement therapy is debated.
Are glucocorticoids contraindicated for use in osteoporosis?
- YES bc they worsen it.
** What is Paget Disease of bone?
- imbalance between osteoCLAST and osteoBLAST function.
- usually seen in late adulthood (over age 60).
- remember: the osteoclast cannot work, without the permission of the osteoBLAST (which receives its signals from PTH).
What causes Paget Disease of bone?
- unknown, but possibly viral.
Does Paget disease involve the entire skeleton?
- NO! It is localized to one or more bones.
** What are the 3 distinct stage of Paget disease?
- osteoCLASTIC (goes crazy)
- MIXED osteoBLASTIC-osteoCLASTIC (until osteoclasts burn out).
- osteoBLASTIC (lays down as much bone as possible).
* end result is thick sclerotic bone that fractures easily.
What will a biopsy of bone reveal in Paget disease?
- MOSAIC pattern of lamellar bone.
* looks like a puzzle piece.
*** What are the clinical features of Paget disease?
- bone pain (due to microfractures).
- increasing hat size (skull is commonly affected).
- hearing loss (impingement on cranial nerve).
- lion-like facies (involvement of craniofacial bones).
- isolated ELEVATED ALK PHOS (most common cause of isolated elevated alk phos in patients over 40).
How do we treat Paget disease of bone?
- CALCITONIN= inhibits osteoCLAST function.
- BISPHOSPHONATES= induces apoptosis of osteoCLASTS.
** What are the complications of Paget disease?
- high-output cardiac failure= due to formation of AV shunts in bone.
- osteosarcoma (malignant tumor of osteoBLASTS).
** What is Osteomyelitis?
- infection of marrow and bone, usually in CHILDREN.
What is the most common cause of osteomyelitis?
- bacterial infection arising due to hematogenous spread.
How does seeding of Osteomyelitis differ between CHILDREN and ADULTS?
- CHILDREN= seeds METAPHYSIS.
- ADULTS= seeds EPIPHYSIS
*** What bacteria most often cause Osteomyelitis?
- Staph aureus (MOST COMMON)
- Neisseria gonorrhoeae= sexually active young adults.
- Salmonella= sickle cell disease
- Pseudomonas= diabetics or IV drug abusers.
- Pasteurella= associated with cat or dog bites/scratches.
- Mycobacterium tuberculosis= usually involves the VERTEBRAE (POTT DISEASE).
*** What are the clinical features of osteomyelitis?
- BONE PAIN with systemic signs of infection (fever and leukocytosis).
- lytic focus (abscess) surrounded by sclerosis of bone on x-ray; lytic focus is called SEQUESTRUM, and sclerosis is called INVOLUCRUM.
How do you make the diagnosis of Osteomyelitis?
- blood culture
What is Avascular (aseptic) necrosis?
- ischemic necrosis of bone and bone marrow.
What causes Avascular (aseptic) necrosis of bone?
- trauma or fracture (MOST COMMON)
- steroids
- sickle cell anemia
- Caisson disease= development of gas emboli (nitrogen) which can precipitate out of the blood and lodge in the blood.
What are the major complications of avascular (aseptic) necrosis?
- osteoarthritis (wear and tear) and fracture
What is osteoprotegrin?
- a decoy receptor of RANKL which removes excess ligand and prevents unbalanced bone resorption.
What causes familial primary hyperparathyroidism?
- inactivated MEN-1 gene on chromosome 11q13, which occurs in parathyroid adenomas and parathyroid hyperplasia.
- MEN-2 syndrome caused by activating mutation in the tyrosine kinase receptor RET; associated with parathyroid hyperplasia.
What is parathyroid carcinoma?
- rare circumscribed tumor affecting one parathyroid with an irregular mass, which is larger than 10 gm.
Can nonparathyroid tumors secrete PTHrP?
- YES, which inhibits osteoprotegerin (a decoy RANKL receptor) secretion by osteoblastic cells, altering the RANKL/osteoprotegerin ratio to favor osteoCLASTOGENESIS.
