Parathyroid Gland and Calcium Homeostasis
Extracellular Calcium Sensing Receptor (CaSR)
*Senses changes in the extracellular concentration of calcium ions *Member of the GPCR family *Expressed primarily in the parathyroid gland and kidney (basolateral TAL) *Activation of the CASR in the parathyroid gland leads to a decrease in PTH production *Activation of the CASR in the kidney leads to a decrease in calcium reabsorption
Lab findings of Primary Hyperparathyroidism
- increased serum PTH - increased serum calcium - decreased serum phosphate - increased urinary cAMP - increased serum alkaline phosphatase - chloride/phosphorus ratio > 33
Lab findings of Secondary Hyperparathyroidism
-increased serum PTH -decreased/normal serum calcium (never high) - increased serum alkaline phosphatase -usually decreased levels of Vitamin D -*decreased serum phosphate (Except in Secondary hyperparathyroidism due to CKD; impaired phosphate excretion => increased serum phosphate)*
What are the three situations that can cause an increase in PTH production seen in Secondary Hyperparathyroidism
1) Decreased calcium levels 2) Increased phosphate levels (complexes with free serum Ca) 3) Decreased Vitamin D levels
A 65-year-old female with chronic renal failure presents with recent onset of bone pain. Serum analysis reveals decreased levels of calcium and elevated levels of parathyroid hormone. One of the mechanisms driving the elevated PTH is most similar to that seen in: 1. End stage liver failure 2. Insufficient Ca intake 3. Parathyroid adenoma 4. Decreased functioning of the calcium-sensing receptor (CASR) 5. Sarcoidosis
1. End stage liver failure The patient, suffering from chronic renal failure, has hyperparathyroidism secondary to decreased production of active vitamin D (loss of renal 1-alpha-hydroxylase activity). 1-alpha hydroxylase activity as well as 25-hydroxylase are required to make the active form of vitamin D, 1,25 dihydrocholecalciferol. 25-hydroxylase is produced in the liver and in end stage liver disease you would be unable to produce active 1,25 vitamin D.
pseudohypoparathyroidism
AD Due to defective Gs protein α-subunit causing end-organ resistance to PTH. Defect must be inherited from mother due to imprinting. Albright Hereditary Osteodystrophy KNUCKLE KNUCKLE DYMPLE SIGN
Most common cause of hypoparathyroidism?
Accidental removal or damage during thyroid surgery
nephrocalcinosis
An accumulation of calcium within the renal parenechyma. A form of metastatic calcification => polyuria, polydipsia
What kind of kidney stone is associated with primary hyperparathyroidism (hypercalcemia)
Ca2+ -phosphate or Ca 2+ -oxalate stones
How does an increase in blood pH affect free calcium levels?
Decreases Free Calcium Levels *Albumin and other calcium-binding proteins have negatively charged binding sites for positively charged ions, such as Ca2+ and H+. *A decrease of H+ ions in the blood (increased pH) leads to increased protein binding of ionized calcium and decreased free calcium levels.
Where are the parathyroid glands located?
Embedded in the posterior surface of the thyroid gland
Causes of Secondary Hypoparathyroidism
Excess Vitamin D?
Usually high levels of calcium in the blood correlate with high levels of calcium in the urine. Which condition is an exception?
Familial hypocalciuric hypercalcemia
What two electrolyte disturbances can cause Nephrogenic Diabetes Insipidus?
Hypercalcemia, hypokalemia Due to decreased expression of aquaporin-2 channels
Hypocalcemia _________________ (increases/decreases) neuromuscular excitability Hypercalcemia _________________ (increases/decreases) neuromuscular excitability
Hypo: increases (tetany, paresthesias) Hyper: decreases (weakness/lethargy)
Why is serum alkaline phosphatase increased in Primary and Secondary Hyperparathyroidism?
In Hyperparathyroidism, increased PTH levels act on osteoblasts to increase expression of RANKL which stimulates osteoclast differentiation. Disorders of the bone that increase osteoblastic activity may cause ALP levels to increase
Inactivating mutations of the CaSR cause _______________ (hypo/hyper) calcemia. An example is: ________________ Activating mutations of the CaSR cause _______________ (hypo/hyper) calcemia. An example is: ________________
Inactivating: hypercalcemia: familial hypocalciuric hypercalcemia Activating: hypocalcemia; AD Hypocalcemia
Trousseau's sign
Inflation of the sphygmomanometer cuff on the upper arm to more than the systolic blood pressure is followed by carpal spasm within 3 minutes indication of LATENT tetany
Describe the "Salt and Pepper" appearance of the skull in Osteitis Fibrosa Cystica
Multiple, small areas of resorption of skull in hyperparathyroidism results in mottled appearance like salt and pepper FIND A PICTURE
Are PTH receptors are located on osteoclasts or osteoblasts?
Osteoblasts
How does PTH action cause an increase in urinary cAMP?
PTH binds to its receptor on the basolateral membrane in the PCT. The receptor is coupled, via a Gs protein, to adenylyl cyclase. Activated adenylyl cyclase increases the conversion of ATP to cAMP which activates a series of protein kinases. Activated protein kinases phosphorylate intracellular proteins which leads to the inhibition of luminal Na+ -phosphate cotransport The cAMP generated is excreted and is seen as an increase in urinary cAMP
PTH ___________ (increases/decreases) calcium reabsorption from ____________ (PCT/DCT) PTH ___________ (increases/decreases) phosphate reabsorption from ____________ (PCT/DCT)
PTH increases calcium reabsorption from DCT PTH decreases phosphate reabsorption from PCT
Compare the effects of PTH, Calcitonin, and Calcitriol on Renal excretion of Calcium and Phosphate
PTH: Inhibits excretion of Calcium, Increases excretion of Phosphate Calcitriol: Inhibits excretion of both Calcitionin: Increases excretion of both
How does hypocalcemia cause twitching and cramping of muscles if Calcium is required for the cross bridge cycling during muscle contractions?
The Ca 2+ that initiates the cross-bridge cycle in skeletal muscle contraction is INTRACELLULAR Ca 2+ hypocalcemia refers to low EXTRACELLULAR Ca2+ Decreased extracellular Ca lowers the threshold potential => increased excitability of nerves and muscle
What is the normal total Ca2+ concentration in the blood? What is the normal free ionized calcium concentration?
Total: 10 mg/dL Free Ionized: 5 mg/dL
excess sun exposure and ?
Ultravio let (UV) light also evokes skin tanning, decreasing the penetration of UV light, and thus decreases the subseq uent formation of D 3 . This mechanism may prevent overproduction of D3 in individuals exposed to large amounts of sunlight.?? may be eXtra
Chvostek's sign
abnormal spasm of the facial muscles elicited by light taps on the facial nerve in patients who are hypocalcemic
http://www.usmleforum.com/files/forum/2012/1/681559.php
compare the enzymes that are rich in osteoblasts vs osteoclasts Osteoblasts: ALP Osteolclasts: Acid phosphatase and collagenase
Albright Hereditary Osteodystrophy
consists of a constellation of features that occur in pseudohypoparathyroidism type 1a patients have short stature round facies obesity shortened fourth and fifth metacarpals
http://patient.info/doctor/hypoparathyroidism-pro
http://patient.info/doctor/hypoparathyroidism-pro
http://www.prep4usmle.com/forum/thread/99906/
http://www.prep4usmle.com/forum/thread/99906/ GOOD SUMMARY ON Primary secondary and tertiary
http://www.usmleforum.com/files/forum/2008/5/305579.php
http://www.usmleforum.com/files/forum/2008/5/305579.php
Vitamin D and bone resorption?
kaplan says that at high amounts it causes resorption (requirs PTH to be present) costanzo says it just increases resorption as a part of remodeilng to incrase phosphate and calcium
compare action of PTH and Vitamin D on kidney
note that vitamin d acts in parallel to increase phosphate and calcium in both places
pseudopseudohypoparathyroidism
physical exam features of Albright hereditary osteodystrophy but without end-organ PTH resistance. no manifestations of hypoparathyroidism Occurs when defective Gs protein α-subunit is inherited from father
hypercalcemia and acute pancreatitis
primary hyperparathyroidism causes HYPERCALCEMIA, and the increased calcium may stimulate proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, phospholipase) to cause acute pancreatitis *calcium is an enzyme activator ************
How does parathyroid hormone affect intestinal Ca2+ absorption? What is the mechanism of action?
PTH indirectly increases intestinal absorption of Ca2+ PTH stimulates 1α-hydroxylase in the kidney, which increases 1,25-(OH)2 vitamin D production. Vitamin D increases intestinal absorption of Ca2+.
Name 4 other causes other of Hypovitaminosis D other than Renal Failure
copy from p.609 of goljans -lack of sunlight -malabsorption -cirrhosis -drugs enhancing cytochrome system
A 12-year-old boy has had slowly progressive renal failure for the past 2 years. He is short and pale. Blood pressure is 150/92 mm Hg. Serum Ca++ concentration is decreased, and serum phosphate, BUN and creatinine concentrations are increased. X-rays of the bones show subperiosteal erosions of the phalanges, osteopenia, and coarsening trabeculae. Which of the following sets of laboratory findings in serum is most likely in this patient? 25-hydroxycholecalciferol 1,25-dihydroxycholecalciferol PTH A) Decreased, Normal, Decreased B) Normal, Decreased, Normal C) Increased, Increased, Increased D) Decreased, Normal, Increased E) Normal, Decreased, Increased
E) Normal, Decreased, Increased
A 74-year-old woman with type II diabetes mellitus, hypertension, and end-stage renal failure has been dialysis-dependent for several years. She develops a fracture of the left femoral head. Tissue taken from the fracture at the time of internal fixation is noted to have increased osteoclastic activity, with notable tunnel-like dissection by osteoclasts into the bony trabeculae. Increased levels of which of the following hormones is most likely to be responsible for this lesion? A. Calcitonin B. Cortisol C. Erythropoietin D. Glucagon E. Parathyroid hormone
E. Parathyroid hormone The patient has developed hyperparathyroidism, a well-recognized sequela of chronic renal failure. This condition is caused by high levels of serum phosphate and low serum calcium, which stimulate the release of parathyroid hormone (PTH) in an effort to normalize the calcium/phosphate ratio. PTH stimulates osteoblasts to become osteoclasts, which dissolve the bone reservoir of calcium and release it into the blood. This condition, known as renal osteodystrophy, may lead to osteomalacia and osteitis fibrosa cystica, which is classically associated with dissecting osteitis, as described in this question. *Tunnel-like dissection by osteoclasts into the bony trabeculae describes Dissecting Osteitis*
An investigator is studying the effect of parathyroid hormone (PTH) in experimental animals. During an 8-hour period, Animal X is infused with PTH and Animal Y is infused with 5% dextrose in water. Which of the following sets of findings best describes the most likely serum concentrations in Animal X compared with Animal Y at the end of the infusion? ______Calcium_________Phosphorus ______1,25-Dihydroxyvitamin D (A) Increased ______ increased ______ increased (B) Increased ______increased ______decreased (C) Increased ______decreased ______increased (D) Increased ______decreased ______decreased (E) Decreased ______increased ______increased (F) Decreased ______increased ______decreased (G) Decreased ______decreased ______increased (H) Decreased ______decreased ______decreased
(C) Increased ______decreased ______increased
Management of Hypercalcemia
* * * * * *
Cinacalcet
* * * * * * *
Describe the Clinical Presentation of Primary Hyperparathyroidism
*>50% of patients are asymptomatic *Skeletal: (due to PTH related increased osteoclast activity) -affects cortical bone more than medullary bone => cortical thinning -decreased bone density and osteoporosis (prone to fractures) -Osteitis Fibrosa Cystica in advanced cases; causes bone and joint pain -Chondrocalcinosis (pseudogout) is rarely seen *Renal: -Hypercalciuria predisposes to Calcium stone formation -Nephrocalcinosis (metastatic calcification of the renal tubules) is rare and can result in polyuria and polydipsia (Also possibly due to ADH resistance as hypercalcemia is one of the causes of nephrogenic diabetes insipidus) GI: -Abdominal pain -*Peptic ulcer disease: Increased calcium stimulates gastrin* -Constipation -*Acute pancreatitis: Calcium activates phospholipase* Neuro: -Depression -Confusion, Psychosis -Seizures, stupor and coma seen with severe hypercalcemia Neuromuscular: Weakness and Fatigue Cardiac: -*ECG shows shortening of QR interval* Other general symptoms of hypercalcemia include: loss of appetite, decreased reflexes, vomiting (CHECK THESE) *Because serum calcium levels are frequently checked, Renal stones and Osteitis Fibrosa Cystica and are rarely encountered in clinical practice nowadays
Secondary and Tertiary Hyperparathyroidism
*A compensatory hyperplasia caused by any condition that gives rise to a chronic hypocalcemia *Most Common cause is Chronic Renal Failure *Other causes include : Vitamin D deficiency due to malabsorption or liver Failure *Clinical presentation: Tends to be milder or less prolonged than Primary Hyperparathyroidism and the clinical features are usually dominated by the Renal failure or Vitamin D Deficiency *Secondary hyperparathyroidism is the leading cause of renal osteodystrophy *Virtually all patients with renal failure have secondary hyperparathyroidism to some degree and it begins early in the course of CKD *Long standing Secondary Hyperparathyroidism can result in autonomous secretion of PTH by parathyroid glands regardless of Ca levels => Hypercalcemia *Tertiary hyperparathyroidism commonly occurs in the setting of post-renal transplant patients, following chronic renal failure. *Tx:
Familial Hypocalciuric Hypercalcemia (FHH)
*AKA Familial Benign Hypercalcemic hypocalciuria *Due to loss-of-function mutations in CaSR *Perceived lack of calcium levels by CaSR => constitutively high levels of PTH and hypercalcemia *High PTH levels increase calcium reabsorption from DCT and prevent hypercalciuria *Generally asymptomatic and does not require treatment *Important to distinguish between FHH and mild hyperparathyroidism to prevent unnecessary and ineffective parathyroidectomies *History of failed parathyroid surgery in relatives is sometimes present *Summary: High PTH, High serum calcium, Low urinary calcium
Renal Osteodystrophy
*Broad term used to describe all of the pathologic features of bone due to renal failure *Pathophysiology: Due to Increased PTH levels as a result of hypovitaminosis D and hyperphosphatemia *Features include -Adynamic bone disease (low turnover) : due to overly aggressive suppression of PTH -Osteitis fibrosa cystica (high turnover) -Osteomalacia (low turnover: due to decreased bone mineralization) -Osteoporosis (due to increased H+ ions) *Adynamic bone disease is currently the most common type of osteodystrophy
Osteitis Fibrosa Cystica
*Classical skeletal manifestation of advanced Primary Hyperparathyroidism *Very rare now in the US *Due to PTH related increased osteoclast activity *Histologic findings include: -Dissecting Osteitis: tunnel-like dissection by osteoclasts into the bony trabeculae -Marrow spaces replaced by fibrosis -Brown tumors: Cystic spaces with hemosiderin deposition, fibrosis, and giant cells *Radiographic findings include: -"Salt and Pepper" appearance of the skull -Subperiosteal bone resorption of phalanges -Resorption of distal phalanges (acro-osteolysis) -Resorption around tooth sockets => disappearance of lamina dura of teeth -The first bones to show X-ray features are the fingers
Describe the Clinical Presentation of Hypoparathyroidism
*Clinical findings depend on the severity and duration of hypocalcemia * * * * *
Name three factors that increase the activity of the renal 1α-hydroxylase enzyme
*Decreased Ca *Decreased Phosphate *Increased PTH
Primary Hyperparathyroidism
*Excess PTH due to disorder of Parathyroid gland itself *Most common cause is parathyroid adenoma (>80% of cases) *Remaining 10% from parathyroid hyperplasia; parathyroid carcinoma accounts for less than 1% of all cases *More common in females 3:1 *Primary hyperparathyroidism can occur as a part of MEN *About 50% of patients are asymptomatic *Diagnosis is made based on lab findings of Increased PTH, increased Calcium, decreased Phosphate *Hypercalciuria is usually present but may be absent in 1/3 of patients *Tx: Asymptomatic mild increases in calcium do not need to be treated. Medical treatment includes bisphosphonates and cinacalcet. Parathyroidectomy is indicated as treatment when hypercalcemia is symptomatic (elevated creatinine level, Presence of kidney stones, Osteoporosis)
Hypoparathyroidism
*Hypofunction of the parathyroid glands leading to hypocalcemia and hyperphosphatemia *Can be Primary or Secondary (PTH levels low in response to a hypercalcemia) *Most common cause is * * * * *Tx: Administering Calcium and Vitamin D
Actions of PTH
*Increased bone resorption releasing Calcium and Phosphate in blood *Increased reabsorption of Calcium in DCT *Decreased reabsorption of Phosphate in PCT *Stimulates kidney 1α-hydroxylase in PCT: => Increased 1,25-(OH)2D3 (calcitriol) production (increased calcium and phosphate absorption in the gut) *Summary: PTH acts directly on bones, kidneys, and indirectly on intestines to raise Calcium levels back to normal FIND A PIC!
Brown Tumors of Osteitis Fibrosa Cystica
*Increased osteoclastic activity creates cystic spaces *Characterized by numerous giant cells, hemosiderin, fibrosis, and hemorrhage *The brown color is a result of hemosiderin deposition *Histologically similar to Giant Cell Tumors (both have ) *Classically found in phalanges or mandible *Appear radiopaque (black) on radiographs
Name three different causes of Primary Hyperparathyroidism. Which is the most common?
*MCC: Parathyroid adenoma; usually a single adenoma (>80% of cases) *Parathyroid hyperplasia; all four glands involved (10%) *Parathyroid carcinoma (<1%)
Describe the mechanism by which PTH induces bone resorption
*PTH binds to PTH receptors on osteoblasts *Stimulates osteoblasts to produce RANK-L (Receptor activator of nuclear-factor kappa-B ligand and G-CSF *G-CSF stimulates hematopoietic stem cells to give rise to osteoclasts that express RANK receptor *RANK ligand binds to RANK receptor on osteoclasts *Cause osteoclast proliferation and
What is the mechanism by which Thiazides decrease calcium excretion?
*Thiazides block the Na/Cl cotransporter on the apical side of the DCT *Results in decreased Na concentration intracellularly *Ca/Na exchanger on the basolateral side is activated to increase intracellular Na. Results decreased intracellular Ca *Calcium is reabsorbed via channels on the apical side of the DCT down its gradient (TRPV5) Thiazides work on the DCT at the same site where PTH increases calcium reabsorption. (PTH binds to PTH receptor on the basolateral side of DCT which activates adenylate cyclase and upregulates TRPV5)
Name the radiographic changes of Osteitis Fibrosa Cystica that are being shown by the following -Dashed white line -Solid white line -Solid black line
-Dashed white line: Resorption of distal phalanges (acro-osteolysis) -Solid white line: Subperiosteal bone resorption -Solid black line: Brown tumor
How does End Stage Liver Disease cause Vitamin D Deficiency?
25-hydroxylase is produced in the liver and in end stage liver disease you would be unable to produce active 1,25 vitamin D
Symptoms of Hypoparathyroidism
-low blood calcium levels Most symptoms are the same as those for hypocalcemia -cramping -twitching of muscles/tetany -prolonged QT interval Adults: tingling in the hands, feet and around the mouth Children: carpopedal spasm, stridor, convulsions Hyperirritability Fatigue/Lethargy Anxiety Seizures (especially in patients with epilepsy) Hoarseness (due to laryngospasm) Wheezing and dyspnea (due to bronchospasm) biliary colic Hypomagnesemia, hypokalemia, and alkalosis (eg, hyperventilation), which worsen signs and symptoms of hypocalcemia
List Seven Causes of Primary Hypoparathyroidism
1) Accidental removal or damage during thyroid surgery (MCC) 2) Autoimmune destruction; Associated with APS1 syndrome due to mutation in AIRE gene (associated with recurrent candidiasis) 3) Excessive radiation to the face, neck, or mediastinum 4) Congenital causes include DiGeorge's syndrome (abnormal development of the parathyroid glands) as well as a few other rare diseases 5)Infiltrative causes: Hemochromatosis and thalassemia, both of which are associated with iron overload, may result in primary hypoparathyroidism. Wilson disease, with copper overload, may also cause primary hypoparathyroidism. http://patient.info/doctor/hypoparathyroidism-pro
Which of the following series of lab values is most consistent with a diagnosis of high turnover renal osteodystrophy? 1) Decreased calcium, increased serum phosphate, increased alkaline phosphatase, increased parathyroid hormone 2) Decreased calcium, decreased serum phosphate, increased alkaline phosphatase, increased parathyroid hormone 3) Increased calcium, normal serum phosphate, increased alkaline phosphatase, normal parathyroid hormone 4) Decreased calcium, increased serum phosphate, normal alkaline phosphatase, decreased parathyroid hormone 5) Increased calcium, normal serum phosphate, normal or high alkaline phosphatase, increased parathyroid hormone
1) Decreased calcium, increased serum phosphate, increased alkaline phosphatase, increased parathyroid hormone High turnover renal osteodystrophy is classically associated with significantly increased phosphate and parathyroid hormone (PTH) levels. Chronic renal disease leads to a decrease in renal phosphorus excretion, which leads to phosphate retention and a significant increase in PTH levels. This ultimately can lead to secondary hyperparathyroidism.
What are the three classifications of Hyperparathyroidism?
1) Primary Hyperparathyroidism 2) Secondary Hyperparathyroidism 3) Tertiary Hyperparathyroidism
How does Renal Insufficiency cause Secondary Hyperparathyroidism?
1) Renal insufficiency leads to decreased phosphate excretion. Increased serum phosphate binds free calcium. This decreases the serum free calcium levels and stimulates all 4 parathyroid glands to increase PTH production. Increased phosphate concentration can also directly stimulate PTH 2) Renal insufficiency leads to decreased renal 1-alpha-hydroxylase activity => Vitamin D Deficiency (reduced calcium absorption by the intestine leading to hypocalcemia)
A 46-year-old Caucasian man presents with a history of fatigue and poor concentration for the last few months. Past medical history is significant for kidney stones and a treated peptic ulcer years ago. He has smoked 1 pack of cigarettes each day for the last 15 years. Review of systems was positive for bilateral hand pain for the past several months, which was not alleviated by ibuprofen. The patient denies taking any other medications. Physical examination is unremarkable. Thyroid function tests and blood glucose are normaI. The serum calcium is 11 mg/dL and serum phosphorus is 2.6 mg/dL. Parathyroid hormone (PTH) is 800 pg/mL. Urine calcium is 425 mg/24 hr. Question 1 of 5 Which of the following is the most likely diagnosis? A. Primary hyperparathyroidism B. Sarcoidosis C. Secondary hyperparathyroidism due to ectopic secretion of a PTH-Iike substance D. Secondary hyperparathyroidism due to renal failure E. Vitamin D excess Question 2 of 5 Bilateral hand x-ray films are obtained. They show subperiosteal bone resorption and some cyst formation. What do these x-ray findings suggest? A. Hungry bone syndrome B. Osteogenesis imperfecta C. Osteitis fibrosa cystica D. Osteomalacia E. Paget disease of bone Question 3 of 5 Which of the following would be the most appropriate management for this patient? A. Bisphosphonates B. Calcitonin C. FIuid hydration with diuretics D. Observation with yearly measurement of serum calcium and creatinine E. Parathyroidectomy Question 4 of 5 If this patient had decreased serum PTH Ievels, which of the following would be the most likely diagnosis? A. Graves Disease B. Lithium use C. Malignancy D. Sarcoidosis E. Thiazide diuretics Question 5 of 5 If this patient also stated that his mother had thyroid cancer surgery and his brother had uncontrolled hypertension, which of the following diagnoses would be most likely? A. Familial benign hypercalcemic hypocalciuria B. MEN Type l C. MEN Type lI/IIa D. MEN Type llI/IIb E. Pseudohypoparathyroidism
1. A. Primary hyperparathyroidism 2. C. Osteitis fibrosa cystica 3. E. Parathyroidectomy 4. C. Malignancy 5 C. MEN Type lI/IIa Parathyroidectomy is indicated as treatment when hypercalcemia is symptomatic (elevated creatinine level, Presence of kidney stones, Osteoporosis)
Receptor activator of nuclear-factor kappa-B ligand (RANKL) is an important regulator of bone resorption. Which of the following cells is the MAJOR source of RANKL in bone remodelling? 1) Osteoclasts 2) Osteoblasts 3) Integrins 4) T cells 5) Macrophages
2) Osteoblasts RANKL, a key osteoclastogenic protein, is expressed by osteoblasts and binds to the RANK receptor on osteoclast precursor cells.
A 56-year-old woman is in the ER after a seizure. Although suffering from some continued confusion, she keeps pointing at the area around her mouth and saying that it feels "funny." Her husband states that she has a history of osteoarthritis and thyroid cancer, for which she underwent a total thyroidectomy one month ago. As far as he knows, she has no family history of epilepsy. Her exam is notable for 3+ reflexes in her upper and lower extremities. After applying a blood pressure cuff to her arm for 3 minutes, her hand looks like Figure A. Which laboratory abnormality is her blood work most likely to reveal? 1. Low phosphorous 2. Low ionized calcium 3. Low magnesium 4. High 25-hydroxyvitamin D 5. High PTH
2. Low ionized calcium A post-thyroidectomy patient presenting with seizure, circumoral paresthesias, hyperreflexia, and carpopedal spasm (Trousseau's sign) most likely has hypoparathyroidism, which causes low ionized calcium.
which is the main circulating form of vitamin D
25 oh vitamin D?
A 1-year-old boy presents to pediatrics clinic for a well-child visit. He has no complaints. He has a cleft palate and an abnormal facial appearance. He has been riddled with recurrent infections and is followed by cardiology for a ventricular septal defect (VSD). Vital signs are stable, and the patient's physical exam is benign. If this patient's medical history is part of a larger syndrome, what might one also discover that is consistent with the manifestations of this syndrome? 1. Kidney stones 2. B-cell deficiency 3. A positive Chvostek's sign 4. A shortened QT Interval 5. Hypoactive deep tendon reflexes
3. A positive Chvostek's sign Severe hypocalcemia is a serious concern in infants born with DiGeorge Syndrome. Patients with hypocalcemia may exhibit Chvostek's sign where tapping of the facial nerve elicits contraction of the facial muscles. DiGeorge syndrome is one of the 22q11 microdeletion syndromes. Presentation may be variable and include cleft palate, abnormal facies, thymic aplasia leading to T-cell deficiency and recurrent infections, cardiac defects, and hypocalcemia secondary to absence of the parathyroid glands. Patients with hypocalcemia may complain of numbness and tingling around the mouth and in the fingers and toes. Furthermore, tetany may be manifested by hyperactive deep tendon reflexes and positive Chvostek's sign and Trousseau's sign on physical exam. Trousseau's sign refers to the elicitation of carpal spasms when a blood pressure cuff is inflated to a pressure higher than the patient's systolic blood pressure for 3 minutes. On EKG, patients may have a prolonged QT interval.
A 54-year-old female presents to her primary care physician with complaints of fatigue, constipation, and what the patient describes as "aching in her bones." Her medical history is significant for hypertension, well-controlled on lisinopril, and two prior kidney stones that both passed spontaneously without need for surgery. Vital signs are within normal limits, and physical exam is not significant for any notable findings. Preliminary lab work is ordered and reveals: calcium 11.6 mg/dL (normal range 8.5 - 10.9 mg/dL), phosphorus 2.1 mg/dL (normal range 2.4 - 4.1 mg/dL), and an elevated parathyroid hormone (PTH) level. Which of the following findings would most likely be expected on radiographic evaluation of this patient's hands? 1. Joint space narrowing at the proximal and distal interphalangeal joints 2. Osteoid matrix accumulation around bony trabeculae 3. Subperiosteal cortical thinning 4. Ulnar deviation of the metacarpophalangeal joints 5. Dense bone filling the medullary cavity of the phalanges and metacarpals
3. Subperiosteal cortical thinning This patient's presentation is consistent with primary hyperparathyroidism. Resorption of subperiosteal cortical bone is an early pathognomonic sign of hyperparathyroidsm
An 8-year-old white boy presents to the pediatrician with a nontender mass on his right lower jaw. His mother had first noticed the lump a few months earlier, and it had slowly increased in size during this time. The patient also complained of some minor "bone pain," which his mother attributed to a recent growth spurt. On examination, the patient's vital signs were as follows: T 37.1°C, BP 110/68 mm Hg, pulse 72 beats per minute, and RR 16. There was a firm, nontender, smooth 5- × 4-cm mass on the left mandible but there was no lymphadenopathy or thyromegaly appreciated. The rest of the boy's physical exam was normal. Initial laboratory testing revealed serum calcium of 12.46 mg/dL and a parathyroid hormone (PTH) level of 124 pg/dL. Based on these findings, which of the following is the most likely diagnosis? A. Brown tumor B. Burkitt's lymphoma C. Giant cell granuloma D. Salivary gland inclusion E. Traumatic bone cyst
A. Brown tumor Increased PTH and serum Calcium suggest that the mass is due to a Brown tumor resulting from Hyperparathyroidism
Alkalosis ________________ (increases/decreases) free plasma Ca Acidosis ________________ (increases/decreases) free plasma Ca
Alkalosis decreases free plasma Ca (by increasing protein binding) Acidosis increases free plasma Ca (by decreasing protein binding)
In parathyroid cells, calcium regulates expression and release of parathyroid hormone (PTH) by binding to: A. A nuclear receptor in the supergene family that includes steroid hormone receptors, the thyroid hormone receptor, and a number of "orphan" receptors. B. A transmembrane protein receptor that activates a G-protein-mediated signal cascade. C. The golgi bodies where PTH is stored, and stimulating their fusion with exocytotic vesicles. D. A calcium-binding domain in the extracellular matrix, inducing a structural change in the matrix. E. A glycoprotein in the gap junction between parathyroid cells, mediating transcytotic calcium flux.
B. A transmembrane protein receptor that activates a G-protein-mediated signal cascade.
A 35-year-old woman having an anxiety attack collapses. The EMT who arrives on the scene notes that she is hyperventilating and suspects that she is suffering from tetany, a continuous contraction of skeletal muscle fibers caused by an increase in the excitability of nerves and muscle membranes. The increased membrane excitability is caused by which of the following? A. Decreased release of inhibitory neurotransmitter from nerve terminals B. Depolarization of the nerve and muscle membranes C. Spontaneous release of calcium from the sarcoplasmic reticulum D. Activation of sodium channels at more negative membrane potentials E. Increased magnitude of the action potentials invading nerve terminals
B. Depolarization of the nerve and muscle membranes Hyperventilation => Alkalosis Alkalosis decreases free plasma Ca (by increasing protein binding) => Hypocalcemia Hypocalcemia => increased neuromuscular excitability by increasing the permeability to sodium => depolarization
Following a thyroidectomy, a patient develops severe hypocalcemia and hyperphosphatemia, resulting in carpopedal spasms, muscle and abdominal cramps, and tingling of his lips and hands. Tapping the man's face in front of the ear elicits tetany of his facial muscles. Which of the following drugs would most likely ameliorate the patient's signs and symptoms? A. Bumetanide B. Ergocalciferol C. Levothyroxine D. Niacin E. Pamidronate
B. Ergocalciferol The patient is presenting with signs and symptoms highly suggestive of hypoparathyroidism. This condition occurs most frequently after thyroidectomy or the removal of a parathyroid adenoma. Hypoparathyroidism is characterized by severe hypocalcemia and hyperphosphatemia, resulting in tetany, carpopedal spasms, muscle and abdominal cramps, and tingling of the lips and hands. A positive Chvostek sign (tapping the face in front of the ear elicits tetany) and Trousseau sign (abnormal muscular contractions elicited by applying a blood pressure cuff) will often be noted. Since the blood calcium levels are often very low, either calcium gluconate or vitamin D preparations should be administered to correct the condition. Vitamin D preparations, such as ergocalciferol (Vitamin D2), elevate calcium levels, and decrease phosphate levels.
A 60-year-old woman has a serum calcium concentration of 7.0 mg/dL and a serum potassium concentration of 2.8 mEq/L. Her serum parathyroid hormone (PTH) concentration is decreased. The decreased PTH is most likely related to a severe depletion of which of the following? A ) Iodine B ) Iron C ) Magnesium D ) Selenium E ) Zinc
C ) Magnesium
A 63 year old man with chronic renal failure and type 2 diabetes presented to the surgery with generalised aching. He was taking twice daily mixed insulin for his diabetes and ramipril for vascular risk modification. On examination his blood pressure was 155/92 mm Hg; his pulse was 75 beats/min and regular. Physical examination was otherwise unremarkable. The following laboratory results were obtained: Haemoglobin 109 g/l (normal range 135-180) White cell count 6.1×109/l (4-10) Platelets 191×109/l (150-400) Sodium 140 mmol/l (134-143) Potassium 5.3 mmol/l (3.5-5) Creatinine 320 μmol/l (60-120) Calcium 2.05 mmol/l (2.2-2.67) Urine protein + Which one of the following is the most likely underlying diagnosis? A Hypoparathyroidism B Primary hyperparathyroidism C Secondary hyperparathyroidism D Tertiary hyperparathyroidism E Vitamin D intoxication
C Secondary hyperparathyroidism Chronic renal failure leads to low concentrations of hydroxylated vitamin D, and hence to hypocalcaemia. This leads to a secondary increase in parathyroid hormone values. Primary hyperparathyroidism (B), tertiary hyperparathyroidism (D), and vitamin D intoxication (E) would cause hypercalcaemia. Standard treatment of choice is alfacalcidol three times a week. Once calcium concentrations approach the normal range, parathyroid concentrations often fall. Cinacalcet may be used in patients with endstage renal disease receiving maintenance haemodialysis, with frequent monitoring of parathyroid hormone and calcium.
A 28-year-old woman is evaluated for a serum calcium level of 11.0 mg/dL (2.74 mmol/L) obtained during a routine physical examination. All other laboratory values are normal. The parathyroid hormone (PTH) level was subsequently checked and is 40 pg/mL (40 ng/L). The patient is healthy and has no symptoms of polyuria, constipation, or fatigue. Her mother and maternal grandfather have a history of hyperparathyroidism, and they both underwent parathyroidectomy but remained mildly hypercalcemic. The patient had a recent renal ultrasound that showed no evidence of nephrolithiasis. Her diet is rich in dairy products, and she has no history of gastrointestinal illness. Which of the following tests would be most likely to confirm the diagnosis? A 25-hydroxyvitamin D B 1,25-dihydroxyvitamin D 3 C Urine calcium/creatinine clearance ratio D Parathyroid hormone related peptide E Prolactin
C Urine calcium/creatinine clearance ratio In an asymptomatic patient with mild hypercalcemia and an inappropriately normal parathyroid hormone level, the main differential includes primary hyperparathyroidism versus benign familial hypocalciuric hypercalcemia.' FHH is easily confused with milder cases of the more common primary hyperparathyroidism (HPT), which is generally treated by parathyroidectomy. In the case of FHH, parathyroidectomy is not only unnecessary but also inappropriate, since it does not cure FHH-associated hypercalcemia. It is therefore important to identify patients with FHH to prevent unnecessary parathyroidectom
A 20-year-old woman is referred because of an elevated serum calcium level (11 .3 mg/dL) obtained during a routine preoperative evaluation before minor gynecologic surgery. All other laboratory values are normal. The parathyroid hormone level was subsequently checked and is slightly elevated (67 pg/mL). The patient is healthy except for recent metrorrhagia. Her mother and maternal grandfather both had hyperparathyroidism and underwent neck surgery but remained mildly hypercalcemic. The patient underwent a bone density study, which was normal, and renal ultrasonography, which shows no evidence of nephrolithiasis. Her 24-hour urine calcium level is 63 mg. Her diet is rich in dairy products, and she has no history of digestive illness. What is the most likely diagnosis? A. Primary hyperparathyroidism B. Secondary hyperparathyroidism C. Familial benign hypocalciuric hypercalcemia D. Multiple endocrine neoplasia type 1 E. Milk-alkali syndrome
C. Familial benign hypocalciuric hypercalcemia Mild primary hyperparathyroidism is frequently asymptomatic, and affected patients may not have osteopenia or renal tract stones. However, a low urine calcium level in an asymptomatic patient with mild hypercalcemia should raise suspicion of familial benign hypocalciuric hypercalcemia. This autosomal dominant condition results from a partial inactivating mutation of the calcium-sensing receptor, resulting in a decreased set-point for parathyroid hormone release by the parathyroids and increased renal tubular reabsorption of calcium. A history of failed parathyroid surgery in relatives is sometimes present. Surgical therapy is neither necessary nor effective because the condition is not associated with any of the sequelae of primary hyperparathyroidism. Primary hyperparathyroidism is possible but is usually associated with hypercalciuria (>4 mg/kg of body weight). A more precise method to assess urine calcium excretion is to calculate the calcium-to-creatinine clearance ratio from a spot urine sample, which is typically less than 0.01 in familial benign hypocalciuric hypercalcemia and greater than 0.02 in primary hyperparathyroidism. Examination of the calcium-sensing receptor gene by a research laboratory confirms the diagnosis of familial benign hypocalciuric hypercalcemia. Consultation with a specialist in mineral metabolism is helpful. Secondary hyperparathyroidism should be considered whenever the parathyroid hormone concentration is high, but the serum calcium is usually low or low-normal in this condition, usually in association with chronic renal insufficiency. Multiple endocrine neoplasia syndromes are familial conditions associated with primary hyperparathyroidism, but patients are also usually hypercalciuric and other endocrine features are usually encountered.
A 45-year-old woman with chronic renal disease has bone disease with features of both osteomalacia and osteitis fibrosa cystica. Which of the following laboratory result profiles would be expected from the serum of this patient? Calcium Phosphate PTH A. dec dec inc B. dec inc dec C. dec inc inc D. inc dec inc E. inc inc inc
C. dec inc inc
What regulates parathyroid hormone release?
Calcium and Magnesium Levels *Free ionized calcium is the primary regulator *Decrease in Mg causes an increase in PTH secretion *Decrease in Free Ca causes an increase in PTH (Severe decrease in Mg causes a decrease in PTH)
The parathyroid gland contains which two types of cells? Which cells secrete parathyroid hormone?
Chief Cells and Oxyphil Cells Chief Cells: secrete PTH Oxyphil Cells: function unknown
Role of Parathyroid
Chief cells regulate serum FREE IONIZED calcium via PTH Secretion what is FREE IONIZED calcium?
What is the most common cause of Secondary Hyperparathyroidism?
Chronic Renal Failure
What is the effect of cinacalcet on parathyroid hormone secretion?
Cinacalcet increases the sensitivity of the Ca2+-sensing receptor (CaSR) in the parathyroid gland to circulating Ca2+. This decreases the secretion of parathyroid hormone
A 42-year-old man presents with a 1-day history of increasing nausea, vomiting, and lethargy. He has an extensive smoking history and was recently diagnosed with lung cancer. He is not taking any medications and has not yet initiated chemotherapy. On physical examination, he is afebrile and somnolent. His lungs are clear to auscultation, and his heart is regular in rate and rhythm. His skin shows eroding calcium deposits. Laboratory results indicate a serum calcium level of 13.4 mg/dL. Which of the following is the most appropriate initial step in management? A. Calcitonin B. Etidronate C. Hydrochlorothiazide D. IV saline E. Prednisone
D. IV saline This patient has lung cancer and is probably exhibiting a paraneoplastic secretion of parathyroid-related hormone, which is making him hypercalcemic. Hypercalcemia can be treated with IV saline and furosemide. Fluid replacement with IV saline and forced diuresis with saline and a loop diuretic, such as furosemide, is a rapid and safe way to lower serum calcium and should be the initial approach to therapy. Etidronate (choice B) is a bisphosphonate that prevents bone resorption by inhibiting osteolytic activity. It is often used in preventive therapy for osteoporosis. However, it would be of limited value in this acute setting (Usually takes 2-3 days for effects to occur) Hydrochlorothiazide (choice C) is a thiazide diuretic that decreases urinary calcium excretion and can cause hypercalcemia and is contraindicated in this setting Calcitonin (choice A), a hormone secreted by the parafollicular cells of the thyroid, inhibits osteoclast activity and decreases the rate of bone loss and fractures in osteoporosis. It may be added after IV hydration and diuresis with furosemide.
What is the mechanism by which Hypercalcemia causes Weakness, Constipation, and CNS symptoms such as confusion?
Excess calcium blocks sodium channels and raises the threshold for depolarization of skeletal and neural tissue => Decreased excitability Results in Weakness/fatigue, Constipation, Confusion
What form of plasma calcium is biologically active?
Free Ionized Calcium
In what three forms is calcium transported in the blood?
Free ionized (45%) Bound to albumin (40%) Bound to anions (e.g., phosphate, sulfate, citrate) (15%)
A 3-year-old boy has a mutation in the calcium receptors on cell surfaces of his parathyroid gland and on the basolateral (blood) side of the thick ascending limb of the loop of Henle. Which of the following patterns is expected with a mutation that leads to activation of this receptor in the absence of binding of its ligand, calcium? _____Serum Ca_____ serum PTH_____ Urine Ca A) Hypercalcemia_____ high__________ high B) Hypercalcemia_____high_______ ___ low C) Hypercalcemia_____low_______ ___ high D) Hypercalcemia_____low_______ ___ low E) Hypocalcemia_____high________ __ high F) Hypocalcemia_____ high________ __ low G) Hypocalcemia_____ low________ __ high H) Hypocalcemia_____ low_______ ___ low
G) Hypocalcemia_____ low__________ high Activating mutations of the CaSR makes the protein more sensitive to calcium, meaning even low levels of calcium can trigger it to stimulate it. Thus it continues to send signals to prevent calcium increases, even when levels in the blood are very low. As a result, calcium levels in the blood remain low, causing hypocalcemia. This condition is called AD Hypocalcemia (Thinking the body has high calcium when it actually doesn't => decrease in PTH production and decrease in renal calcium reabsorption)
Osteoporosis and Chronic Renal Failure
H+ ions?
What is the relationship between plasma phosphate concentration and parathyroid hormone?
High plasma phosphate concentration complexes with free calcium causing the free ionized calcium concentration to fall, which stimulates PTH secretion. High phosphate levels also directly stimulate PTH secretion. *Summary: Increase plasma phosphate concentrations causes an increase in PTH*
What metabolite detected in the urine reflects parathyroid hormone-mediated bone resorption?
Hydroxyproline Hydroxyproline that is released from bone matrix is excreted in the urine
What is the net effect of PTH on serum [Ca2+] and serum [phosphate]? Urine [phosphate]?
Increased serum [Ca2+] Decreased or Unchanged serum [phosphate] Increased urine [phosphate] *Serum phosphate may be unchanged as a result of increased bone resorption + increased GI absorption (due to Vit D) + increased renal excretion
What is the mechanism by which hypocalcemia causes increased neuromuscular excitability?
Low plasma calcium increases the permeability of neuronal membranes to sodium ions, causing a progressive depolarization. This increases the ease with which action potentials can be initiated. If the plasma Ca2+ decreases to less than 50% of the normal value action potentials may be spontaneously generated, causing contraction of peripheral skeletal muscle. The reverse is true in hypercalcemia. High Calcium causing decreased permeability and hence muscle weakness as the excess calcium blocks sodium channels and raises the threshold for depolarization of skeletal and neural tissue => Decreased excitability
How does Hypomagenesemia cause hypoparathyroidism
Mg2+ is a cofactor for the production of cAMP Mg2+ and Ca2+ both act on CaSR Mg2+ has less affinity for CaSR than calcium As serum [Mg2+] decreases, CaR activation decreases and PTH secretion increases. However, when serum [Mg2+] falls below 0.5mM, the inverse relationship no longer holds and PTH release decreases. Hypomagnesemia (less than 1 mg/dl) and hypermagnesemia (higher than 6 mg/dl) impairs PTH secretion from the parathyroid glands.
Primary Hyperparathyroidism and Hypercalcemia of Malignancy account for about 80% of all cases of hypercalcemia. How can you distinguish the two based on lab findings?
Primary Hyperparathyroidism: PTH is increased Hypercalcemia of Malignancy: PTH is decreased
Compare the lab findings of Primary vs Secondary Hypoparathyroidism
Primary: inadequate PTH activity Secondary: PTH levels are low in response to a primary process that causes hypercalcemia, hypophosphatemia *********
Name three factors that increase PTH release Name three factors that decrease PTH release
Stimulators of PTH *Decreased free serum Ca *Mild decreases in serum Mg *Increase in serum Phosphate (complexes with free serum Ca) Inhibitors of PTH *Increased free serum Ca *Severe decreases in serum Mg **Calcitriol/1,25-(OH)2 D3*
What mnemonic can be used to help remember the symptoms of Primary Hyperparathyroidism?
Stones, Bones, Groans, and Psychiatric Overtones Stones: Calcium stones Bones: Osteitis fibrosa cystica (bone pain) Groans: Psychiatric Overtones:
Primary Hyperparathyroidism is most commonly asymptomatic T/F?
T >50% of patients are asymptomatic and are diagnosed during
How does hyperparathyroidism cause hypercalciuria if PTH is supposed to increase renal absorption of Calcium?
The high plasma Ca 2+ concentration in primary hyperparathyroidism results in a high filtered load of Ca 2+, which overwhelms the reabsorptive capacity of the nephron—the Ca 2+ that is not reabsorbed is spilled into the urine.
fgf23 and phosphorus homeostasis
Until recently, it was thought that the phosphorus homeostasis was mainly achieved by PTH and vitamin D. Recent studies identified fibroblasts growth factor (FGF)-23 as a new protein with phosphaturic activity. It is mainly secreted by osteocytes and is now considered to be the most important factor for regulation of phosphorus homeostasis. Through the Klotho receptor it acts mainly on the kidney to increase phosphorus clearance.[8] FGF-23 also inhibits the 1-α hydoxylase activity, causing a low 1,25 dihydroxyvitamin D level. Hyperphosphatemia is the principal stimulator for FGF-23. It is not yet proven if there is any direct relation between PTH and FGF-23
metastatic calcification
Widespread [Diffuse, metastatic] deposition of calcium in NORMAL TISSUE
Describe the calcium and PTH levels as low or high in a) Primary hypoparathyroidism b) Secondary hypoparathyroidism c) Pseudohypoparathyroidism
a) low PTH, low calcium b) low PTH, high calcium c) high PTH, low calcium