PTH and Calcium Homeostasis

The active form of Vitamin D is

1,25-dihydroxycholecalciferol

A patient has the following test results: Increased serum calcium levels Decreased serum phosphate levels Increased levels of parathyroid hormone This patient most likely has: a) hyperparathyroidism b) hypoparathyroidism c) nephrosis d) steatorrhea

A HypERparathyroidism

Hormone: Parathyroid hormone

Gland of origin: Parathyroid gland Major action: ↑Serum [Ca2+] ↓Serum [phosphate]

Which of the following conditions involving electrolytes is described correctly? a) Pseudohyponatremia occurs only when undiluted samples are measured b) Potassium levels are slightly higher in heparinized plasma than in serum c) Hypoalbuminemia causes low total calcium but does not affect Ca(i) d) Hypercalcemia may be induced by low serum magnesium

c) Hypoalbuminemia causes low total calcium but does not affect Ca(i) When serum albumin is low, the equilibrium between bound and Ca(i) is shifted, producing increased Ca(i). This inhibits release of PTH by negative feedback until the Ca(i) level returns to normal... Magnesium is needed for release of PTH, and PTH causes release of calcium and magnesium from bone. Therefore hypocalcemia can be associated with either magnesium deficiency or magnesium excess.

Hypocalcemia is associated with: a. Acidosis b. Shortened QT interval c. Hypomagnesemia d. Myocardial irritability d. Hyperproteinemia

c. Hypomagnesemia Hypocalcemia is associated with a prolonged QT interval and may be aggravated by both hypomagnesemia and alkalosis. Serum calcium levels below 7.0mg/dL are encountered most frequently following parathyroid or thyroid surgery or in patients with acute pancreatitis. Hypocalcemia often occurs with hypoproteinemia even though the ionized serum calcium fraction remains normal.

Primary hyperparathyroidism is characterized by

↓ serum [phosphate] (hypophosphatemia) ↑ serum [Ca2+] (hypercalcemia) ↑ urinary phosphate excretion (phosphaturic effect of PTH) ↑ urinary Ca2+ excretion (caused by increased filtered load of Ca2+) ↑ urinary cAMP ↑ bone resorption

Free Calcium!

Ionized Calcium!

"Rickety Cricket"

Keep Children away from Rickety Cricket

Primary Hyperparathyroidism

Lab findings: Calcium ↑ phosphate ↓ mild acidosis. -Ionized calcium is increased -PTH level increase: confirm diagnosis

Causes of Hypercalcemia

-Hyperparathyroidism -Neoplastic disease of the bone -HypervitaminosisD- -Familial HypocalciuricHypercalcemia

Causes of Hypocalcemia

-Hypoparathyroidism -Steatorrhea(decreased absorption) -Nephrosis(increased loss) -Nephritis (increased P retention)

A hormone that inhibits osteoclasts which can lead to hypocalcemia. Synthesized by C cells

Calcitonin

Osteomalacia

Occurs in bone in adults (after closure of epiphyseal plates) • No bony deformities Old people

Rickets

Occurs in growing bone (in Children) -Bony deformities from bending of long bones due to gravity Rachitis "Rickety Cricket"

What is the mechanism of pseudohypoparathyroidism?

PTH levels are usually elevated, but the ability of target tissues (particularly kidney) to respond to the hormone is subnormal In pseudohypoparathyroidism type 1, the ability of PTH to generate an increase in the second-messenger cAMP is reduced — Type 1a: deficiency of the a subunit of the stimulatory G protein (Gs-a) — Type 1b, normal Gs-a, but altered regulation of the Gs-a gene transcription In patients with pseudohypoparathyroidism type 2, urinary cAMP is normal but the phosphaturic response to infused PTH is reduced

What are the mechanisms by which a tumor may cause hypercalcemia?

Solid tumors usually produce hypercalcemia by secreting PTHrP, a 141-amino-acid peptide that is homologous with PTH at its amino terminal PTHrP has effects on bone and kidney similar to those of PTH; it increases bone resorption, increases phosphate excretion, and decreases renal calcium excretion, mimicking primary hyperparathyroidism Multiple myeloma produces hypercalcemia by a different mechanism: myeloma cells induce local bone resorption or osteolysis in the bone marrow, probably by releasing cytokines with bone-resorbing activity, such as interleukin-1 and tumor necrosis factor Rarely, lymphomas produce hypercalcemia by secreting 1,25-(OH)2D

PTH summary regulation of Ca2+

Stimulus for secretion ↓ Serum [Ca2+] Action on: Bone: ↑ Resorption Kidney: ↓ P reabsorption (↑urinary cAMP) ↑ Ca2+ reabsorption Intestine ↑ Ca2+ absorption (via activation of Vitamin D) Overall effect on Serum [Ca2+]: ↑ Serum [phosphate]: ↓

A 43-year-old male is admitted to the emergency room for severe pain in his left flank, radiating to the groin. The pain is intermittent and initiated after running a marathon on a hot summer day. The patient is asked for a urine specimen and blood is detected in the urine. He is hydrated, and additional diagnostic procedures are done. Laboratory values show serum Ca2+ of 12 mg/dL, and PTH values of 130 pg/mL. Which of the following findings would be predictable in this patient? A)Increased serum Pi B)Increased serum alkaline phosphatase C)Increased intestinal Ca loss D)Decreased urinary Ca excretion

The correct answer is B. Explanation: The precipitating factor in this young otherwise healthy patient is dehydration. He has high parathyroid hormone (PTH) levels (probably a problem that had been ongoing). High PTH is associated with increased bone resorption resulting in increased serum calcium (and consequently filtered calcium), which with dehydration, precipitated and formed kidney stones (reason for the pain and the blood in the urine when he passed them). You would expect low serum inorganic phosphate (Pi) because PTH promotes Pi excretion. High PTH would stimulate vitamin D synthesis and thus intestinal calcium absorption. The urinary calcium excretion likely reflects a reabsorption process that has been overwhelmed by the excess calcium filtered. The increase in bone resorption and turnover would be expected to be associated with increased serum alkaline phosphatase.

Vitamin D synthesis and activation.

Vitamin D is synthesized in the skin in response to ultraviolet radiation and also is absorbed from the diet. It is then transported to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating form of vitamin D. The final step in hormone activation, 1α-hydroxylation, occurs in the kidney.

A serum level of >60 ug/L of which of the following metals interrupts normal calcium exchage in bone and leads to osteomalacia? a. Antimony b. Aluminium c. Copper d. Arsenic

b

Vitamin D provides Ca2+ and phosphate to ECF for _________ mineralization

bone

long-term steroid usage (arthritic patients)

causes elevated serum [Ca2+]

Which electrolyte measurement is LEAST affected by hemolysis? a) Potassium b) Calcium c) Pi d) Magnesium

B Potassium, phosphorous, and magnesium are the major intracellular ions, and even slight hemolysis will cause falsely elevated results. Serum samples with visible hemolysis (20mg/dL free Hgb) should be redrawn.

What 3 actions are caused by PTH?

1) increased tubular reabsorption of calcium by the kidney 2) resorption of calcium from bone 3) stimulates renal 1,25(OH)2D production

Serum Ca and Phosphate are regulated by 2 hormones and a vitamin:

-parathyroid hormone (PTH) -calcitonin -vitamin D

Which of the following associations is correct? A) Hypokalemia: shortened Q-T interval B) Hypercalcemia: long Q-T interval C) Hypercalcemia: flattened T waves D) Hypocalcemia: U waves E) Hyperkalemia: Peaked T waves

E) Hyperkalemia: Peaked T waves Electrolyte abnormalities affect various portions of the service ECG. Both hypercalcemia and hypocalcemia affect ventricular repolarization and are thus represented by changes in the QT interval. Hypercalcemia results in a shortened QT interval, whereas hypocalcemia results in a prolonged QT interval. Calcium does not affect the T wave; it specifically changes the ST portion of the QT interval. Hyperkalemia may be represented by very tall Peaked T waves as potassium affects ventricular repolarization. Hypokalemia may be represented by U waves, which are small deflections following the T wave.

How to approach

First look at Ca: low or high Then look at PTH: low or high Same direction: abnormal PTH secretion Different directions: normal response to calcium imbalances- think renal failure/renal losses

What tumors commonly result in hypercalcemia?

Hypercalcemia occurs in approximately 10% of all malignancies Hypercalcemia is commonly seen with solid tumors, particularly squamous cell carcinomas (ie, lung, esophagus), renal carcinoma, and breast carcinoma Hypercalcemia occurs in more than one third of patients with multiple myeloma It is rarely seen in lymphomas and leukemias

Specimen Requirements

Serum or heparinized plasma

A 52-year-old man is taking an aminoglycoside for an infection. He develops tetany. A serum magnesium level is decreased. Which of the following are other likely laboratory findings on this patient? a) decreased serum PTH, decreased serum calcium b) increased serum PTH, decreased serum calcium c) increased serum PTH, increased serum calcium d) decreased serum PTH, increased serum calcium

A (decreased serum PTH, decreased serum calcium) Aminoglycosides are magnesium wasters and commonly lead to hypomagnesemia. Magnesium is a cofactor for adenylate cyclase. cAMP is required for PTH activation. Therefore, hypomagnesemia leads to hypOparathyoridism and a corresponding decrease in serum PTH and calcium, the latter resulting in tetany.

A biochemical profile routinely performed bimonthly on a renal dialysis patient showed a decreased serum calcium and decreased PTH level. Such a lab result may be explained by which of the following circumstances? a. Malignancy b. Aluminum toxicity c. Hypervitaminosis D d. Acidosis

b. Aluminum toxicity Aluminum present in meds and dialysis bath fluid can cause aluminum toxicity in patients recieving dialysis. Renal failure patients often display high PTH level owing to poor retention of calcium, and are at risk of developing osteitis fibrosa (soft bones). Excess aluminum causes osteomalacia by inhibiting release of parathyroid hormone.

Which of the following results from the action of parathyroid hormone (PTH) on the renal tubule? a. Inhibition of 1α-hydrolase b. Stimulation of Ca2+ reabsorption in the distal tubule c. Stimulation of phosphate reabsorption in the proximal tubule d. Interaction with receptors on the luminal membrane of the proximal tubular cells e. Decreased urinary excretion of cyclic adenosine monophosphate (CAMP)

b. Stimulation of Ca2+ reabsorption in the distal tubule PTH stimulates both renal Ca2+ reabsorption in the renal distal tubule and the 1α-hydrolase enzyme. PTH inhibits (not stimulates) phosphate reabsorption in the proximal tubule, which is associated with an increase in urinary cAMP. The receptors for PTH are located on the basolateral membranes, not the luminal membranes

Which of the following is most often elevated in hypercalcemia associated with malignancy? a) Parathyroid-derived PTH b) Ectopic PTH c) Parathyroid hormone-related protein (PTHRP) d) Calcitonin

c) Parathyroid hormone-related protein (PTHRP) PTHRP is a peptide produced by many tissues and normally present in the blood at a very low level. The peptide has an N-terminal sequence of eight amino acids that are the same as found in PTH and that will stimulate the PTH receptors of bone. Some malignancies (e.g., squamous, renal, bladder, and ovarian cancers) secrete PTHRP, causing hypercalcemia-associated malignancy. Because the region shared with PTH is small and poorly immunoreactive, the peptide does not cross-react in most assays for PTH. For this reason, and because tumors producing ectopic PTH are rare, almost all patients who have an elevated Ca(i) and elevated PTH have primary hyperparathyroidism. The immunoassay for PTHRP will frequently be elevated in patients who have not yet been diagnosed with malignancy but have an elevated Ca(i), without an elevated serum PTH Calcitonin is a hormone produced in the medulla of the thyroid that opposes the action of PTH.

HypERparathyroidism is most consistently associated with which of the following? a. Hypocalcemia b. Hypercalciuria c. Hypophosphatemia d. Metabolic alkalosis

c. HyPOphosphatemia Parathyroid hormone (PTH) is responsible for maintaining calcium levels by acting on bone and the kidneys and by activating vitamin D. PTH acts on the bone to release calcium and phosphorus through osteoclastic activity. Once released from bone, PTH acts on the kidneys to allow absorption of calcium and excretion of phosphorous. High levels of PTH would most likely manifest with hypercalcemia and hypophosphatemia.

Hyperparathyroidism is most consistently associated with: a. Hypocalcemia b. Hypocalciuria c. Hypophosphatemia d. Metabolic alkalosis

c. Hypophosphatemia Hyperparathyroidism causes increased resorption of calcium and decreased renal retention of phosphate. Increase serum calcium leads to increased urinary excretion. The distal collecting tubule of the nephron reabsorbs less bicarbonate as well as phosphate, resulting in acidosis

Which statement regarding the use of PTH is true? a. Determination of serum PTH level is the best screening test for disorders of calcium metabolism b. PTH levels differentiate primary and secondary causes of hypoparathyroidism c. PTH levels differentiate primary and secondary causes of hypocalcemia d. PTH levels are low in patients with pseudohypoparathyroidism

c. PTH levels differentiate primary and secondary causes of hypocalcemia Serum Ca(i) is the best screening test to determine if a disorder of calcium metabolism is present, and will distinguish primary hyperparathyroidism (high Ca(i)) and secondary hyperparathyroidism (low Ca(i)). PTH levels are used to distinguish primary and secondary causes of HYPOcalcemia. Serum PTH is low in primary hypocalcemia (which results from parathyroid gland disease), but is high in secondary hypocalcemia (e.g., renal failure)... Serum PTH is also used to help distinguish primary hyperparathryoidism (high PTH) and hypercalcemia of malignancy (usually low PTH).

Which of the following best describes the action of parathyroid hormone? a. PTH increases calcium and phosphorus reabsorption in the kidney b. PTH decreases calcium and phosphorus release from bone c. PTH decreases calcium and increases phosphorus reabsorption in the liver d. PTH increases calcium reabsorption and decreases phosphorus reabsorption in the kidney

d. PTH increases calcium reabsorption and decreases phosphorus reabsorption in the kidney Parathyroid hormone (PTH) is responsible for maintaining calcium levels by acting on bone and the kidneys and by activating vitamin D. PTH acts on the bone to release calcium and phosphorus through osteoclastic activity. Once released from bone, PTH acts on the kidneys to cause the kidneys to absorb calcium and excrete the phosphorous.

Fill in The Blank A decrease in extracellular (ECF) calcium (Ca2 ) triggers an increase in ______________ secretion.

parathyroid hormone (PTH) secretion

Cortical:

primary type in long bones (femur); strong, rigid

Chief cells

secrete parathyroid hormone)

↓ ionized calcium

stimulates PTH synthesis & release

Calcitonin

•Secreted by the THYROID gland, specifically specialized C-cells. •Elevated in medullary cancer of the thyroid. lowers serum Ca

1alpha-hydroxylase activity is increased by the following

↑ PTH levels Decreased serum [Ca2+] Decreased serum [phosphate]

↑Ca2+ and ↑Calcitonin

↑Osteoblasts

↓ Ca2+ and ↑PTH

↑Osteoclasts

What is the net effect of PTH?

↑SerumCa ↓SerumPO4

Fill in The Blank A decrease in extracellular (ECF) calcium (Ca2 ) triggers an ____________ in parathyroid hormone (PTH) secretion.

increase

Free Calcium Measurement uses what?

- Ion selective electrode (ISE)

Nterference

-hemolysis -lipemia -Mg2+ in photometric methods

PTH has 3 effects

1. Promotes reabsorption (dissolution i.e. dissolving) of bone. -----PTH action leads to dissolution which in turn leads to increased serum PO4and serum Ca. 2. Action on kidney: PTH promotes reabsorption of Ca in tubular fluid. -----Ca saved in tubular fluid and returned to serum. ----Excretion of Phosphate is increased (decreased reabsorption of PO4). 1+2 net effect: SerumCa↑; SerumPO4↓ 3. GI Tract: Regulates synthesis of active form of Vit. D in kidney. -Vitamin D is necessary for proper absorption of Ca in GI tract-PTH acts in concert with Vit. D to promote Ca absorption from diet (indirectly increase Ca). Note that all of the actions of PTH promote/elevate levels of serum Ca.

Hypercalcemia Critical value

>15 mg/dL: coma and cardiac arrest

A 42-year-old man develops acute renal failure. Laboratory studies also reveal hypocalcemia. What is the most likely mechanism underlying this electrolyte disturbance? A) Hyperphosphatemia B) Hyponatremia c) Increased sensitivity to 1,25-dihydryoxyvitamin D d) Increased sensitivity to parathyroid hormone (PTH)

A Hyperphosphatemia associated with renal failure is the likely cause for this patient's hypocalcemic state. Phosphate excretion is impaired, and metabolic phosphate production is often increased. High serum levels of phosphate can lead to the deposition of calcium phosphate in tissues, decreasing the plasma calcium concentration. Hyponatremia (choice B) in acute renal failure (ARF) is generally due to ingestion of water or inappropriate adminstartion of hypotonic IV solutions. It does not directly affect the levels of calcium in the plasma Decreased, rather than increased, sensitivity to 1,25-dihydroxyvitamin D (choice C) is typical of ARF. Again, increased sensitivity to 1,25-dihydroxyvitamin D could result in hypERcalcemia, not in hypocalcemia. Decreased, rather than incresed, sensitivity to PTH (choice D) is typical of ARF. Regardless, since PTH acts to increase serum calcium, increased sensitivity to PTH could result in hypERcalcemia, not hypocalcemia

Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range (8.9-10.1 mg/dL [2.2-2.5 mM]).

A decrease in extracellular (ECF) calcium (Ca2 ) triggers an increase in parathyroid hormone (PTH) secretion (1) via the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2D production (3). 1,25(OH)2D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.

Schematic representation of the hormonal control loop for vitamin D metabolism and function.

A reduction in the serum calcium below ~2.2 mmol/L (8.8 mg/dL) prompts a proportional increase in the secretion of parathyroid hormone (PTH) and so mobilizes additional calcium from the bone. PTH promotes the synthesis of 1,25(OH)2D in the kidney, which in turn stimulates the mobilization of calcium from bone and intestine and regulates the synthesis of PTH by negative feedback.

What are the risk factors for osteoporosis?

Age, particularly post-menopausal state for women Female gender, Caucasian and Asian ethnicity Gonadal steroid deficiency, either estrogen (women) or androgens (men) Medications: corticosteroids or endogenous cortisol excess, excessive thyroid hormone, anticonvulsants, and chronic heparin therapy, alcohol abuse, smoking Immobilization Inadequate intake of calcium and vitamin D, high dietary protein and sodium chloride intake leading to urinary calcium losses Malabsorption Connective tissue diseases or certain malignancies such as multiple myeloma

Test methodology for monitoring parathyroid glandular function in diagnosis of hypo- or hyperparathyroidism should be focused on assessing: a) intact PTHrP molecule b) the C-terminal PTH c) intact PTH amino acids 1-84 d) N-terminal PTH amino acids 1-7

C Intact parathyroid hormone (84 amino acids with C and N terminal ends) relates best to secretory function of the parathyroid gland. PTHrP is a tumor marker and fragments of PTH often correlate with renal failure. [Bishop 2018, p494]

PTH is major hormone for regulation of serum calcium and is secreted by the ______________ cells of the PTH glands.

Chief cells

Schematic diagram to illustrate similarities and differences in structure of human parathyroid hormone (PTH) and human PTH-related peptide (PTHrP).

Close structural (and functional) homology exists between the first 30 amino acids of hPTH and hPTHrP (red area). The PTHrP sequence may be ≥139 amino acid residues in length. PTH is only 84 residues long; after residue 30, there is little structural homology between the two. Dashed lines in the PTHrP sequence indicate identity; underlined residues, although different from those of PTH, still represent conservative changes (charge or polarity preserved). Ten amino acids are identical, and a total of 20 of 30 are homologues.

What are the causes of hypoparathyroidism?

Complication of thyroid, parathyroid, or laryngeal surgery Autoimmune destruction of the parathyroid glands— Autoimmune polyendocrine failure syndrome type 1 (APS-1)— Isolated Secondary to magnesium depletion or excess Post-131I therapy for Graves disease or thyroid cancer Accumulation of iron (thalassemia, hemochromatosis) or copper (Wilson disease) Genetic forms of hypoparathyroidism (several rare causes) Acquired activating mutations of the calcium-sensing receptor (CaSR) Autoimmune syndrome caused by autoantibodies to CaSR Tumor invasion (very rare)

Parathyroid Hormone-Related Protein (PTHrP)

Expressed in most normal tissues • autocrine and paracrine factor •skeletal development and calcium homeostasis •Principle mediator of HHM, secreted by tumors •Increases bone resorption (osteolysis), decreases bone formation, resulting hypercalcemia

How can primary hyperparathyroidism be distinguished from familial hypocalciuric hypercalcemia?

Familial hypocalciuric hypercalcemia is inherited in an autosomal dominant manner and is typically due to point mutations in one allele of the calcium-sensing receptor (CaSR) gene Individuals with this condition typically have a mildly elevated serum calcium and magnesium, normal or mildly elevated PTH levels, and hypocalciuria Urinary calcium levels are typically low and almost always less than 100 mg/24 hr Genetic testing for CaSR gene mutations is commercially available in several reference laboratories and is the best approach to achieving a definitive diagnosis

Fill in the Blank: A 32-year-old woman presents to the emergency department with complaints of involuntary hand spasms. She states that as she worked folding the laundry, she had a sudden severe spasm of her right hand such that her fingers flexed. The spasm was quite painful and lasted several minutes, resolving spontaneously. She is 6 months pregnant. Her medical history is otherwise notable for a thyroid tumor, status post-thyroidectomy 3 years ago. She is taking synthetic thyroid hormone and a prenatal multivitamin. Family history is unremarkable. On physical examination, she has positive Chvostek and Trousseau signs. Examination is otherwise unremarkable. Serum calcium level is low. ________________________ as a complication of the thyroid surgery is suspected.

Hypoparathyroidism

What is/are the biologically active parts of PTH?

Intact PTH molecule amino-terminal fragment

Solid tumor with humoral hypercalcemia (lung, kidney) caused by increase in...

PTH-related Peptide (PTHrP)

Vitamin D metabolism and physiologic effects at target organs.

Provitamin D (7-dehydrocholesterol) in the skin is converted to cholecalciferol by ultraviolet (UV) light. Cholecalciferol and ergocalciferol (from diet) are transported to the liver, where they undergo hydroxylation at C-25 to 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. The second hydroxylation step occurs in the kidney and results in the hormonally active vitamin D [1,25(OH)2D], also known as calcitriol. This activation step, mediated by 1α-hydroxylase, is under tight regulation by parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Ca2+ levels, and vitamin D [1,25(OH)2D]. The activity of 1α-hydroxylase is stimulated by PTH and inhibited by Ca2+, FGF23, and 1,25(OH)2D. Decreased activity of 1α-hydroxylase favors formation of the inactive form of vitamin D by C-24 hydroxylation. Vitamin D increases bone resorption and formation (turnover), increases dietary Ca2+ absorption, facilitates renal Ca2+ reabsorption, and decreases PTH synthesis by the parathyroid glands. The overall effect of vitamin D is to increase plasma Ca2+ concentrations.

Vitamin D regulation of Ca2+

Stimulus for secretion ↓ Serum [Ca2+] ↓ Serum [phosphate] ↑ PTH Action on: Bone: ↑ Resorption Kidney: ↑ P reabsorption ↑ Ca2+ reabsorption Intestine ↑ Ca2+ absorption (calbindin D-28K) ↑ P absorption Overall effect on Serum [Ca2+]: ↑ Serum [phosphate]: ↑

What are the common symptoms and signs of primary hyperparathyroidism?

Systemic: weakness, fatigue, weight loss, anemia, anorexia, pruritis Ocular: band keratopathy Cardiac: shortened QT interval, hypertension Skeletal: osteopenia, pathologic fractures, brown tumors of bone, bone pain, gout, pseudo-gout, chondrocalcinosis, osteitis fibrosa cystica Neurologic/psychiatric: depression, poor concentration, poor memory, neuropathy, muscle weakness Renal: stones, polyuria, polydipsia, metabolic acidosis, urine concentrating defects, nephrocalcinosis Gastrointestinal: peptic ulcer disease, pancreatitis, constipation, nausea, vomiting

What are the symptoms and signs of hypocalcemia?

Tetany, spontaneous tonic muscular contractions, can result in painful carpal spasms and laryngeal stridor Latent tetany may be demonstrated by testing for Chvostek and Trousseau signs — Chvostek sign is elicited by tapping on the facial nerve anterior to the ear: twitching of the ipsilateral facial muscles indicates a positive test — A positive Trousseau sign is shown by painful carpal muscle contractions and spasms stimulated by an inflated blood pressure cuff If hypocalcemia is severe and unrecognized, airway compromise, altered mental status, generalized seizures, and even death may occur Chronic hypocalcemia can produce intracranial calcifications (with a predilection for the basal ganglia) and calcification of the lens and cataracts

Synthesis and activation of vitamin D (cholecalciferol).

Vitamin D is supplied from the diet and by synthesis from cholesterol-based precursors in the skin. Activation of vitamin D occurs in two stages: 25-hydroxylation in the liver (not regulated) and 1-hydroxylation in the kidney (stimulated by parathyroid hormone and hypophosphatemia).

Calcitonin acts primarily to _________ bone resorption

inhibit

↑ ionized calcium

inhibits PTH synthesis & release

The best method of analysis for serum PTH involves using antibodies that detect: a. The amino terminal fragment of PTH b. The carboxy-terminal end of PTH c. Both the amino-terminal fragment and intact PTH d. All fragments of PTH as well as intact hormone

c. Both the amino-terminal fragment and intact PTH PTH is a polypeptide comprised of 84 amino acids. The biological activity of the hormone resides in the N-terminal portion of the polypeptide, but the hormone is rapidly degraded and produces N-terminal, middle, and C-terminal fragments. Fragments lacking the N-terminal are inactive... The assay of choice is a two-site double-antibody sandwich method that measures only intact PTH and active fragments.

1,25(OH)2D, in turn, acts principally on the intestine to increase

calcium absorption

Phosphate homeostasis

is maintained by the coordinated actions of FGF-23 and 1,25(OH)2D. Low serum phosphate (PO43−) levels suppress FGF-23 production, which increases 1,25(OH)2D production and the expression of renal and intestinal phosphate transporters (NaPi 2a, 2c). As a result, intestinal and renal phosphate reabsorption rises to restore serum phosphate back to normal. When serum phosphate levels increase, FGF-23 levels rise, thereby suppressing these same biochemical pathways and restoring the serum phosphate balance.

PTH deficiency gives ______ calcium and generally________ serum phosphate

low calcium and generally high serum phosphate

Bone "Builiding"/formation is mediated by?

osteoBlasts

Secretion of PTH

-controlled by serum Calcium bind to to Ca2+ sensing receptors in the parathyroid cell membrane. -decreased serum calcium increases PTH secretion -Mild decreases in serum [Mg2+] stimulate PTH secretion -Severe decreases in serum [Mg2+] inhibit PTH secretion and produce symptoms of hypoparathyroidism (e.g., hypocalcemia)

Total calcium Photometric

-metallochromic indicators 1. Metal-complexing dye CPC (o-cresopphthalein) form a red chromophorewith Ca2+, measured between 570 and 580 nm 2. ArsenazoIII -Ca++ complex; pH6 purple, 650 nm

Primary hyperparathyroidism (non-malignant parathyroid gland tumors)

1. Calcium- Increased (98 %) 2. Alkaline Phosphatase- Increased (41 %) (increased osteoblastic activity). In serum, isoenzymes from liver, bone, intestinal, placental sources: bone fraction increased ('Bone Burns'). 3. Phosphate - Decreased (33 %) 4. Urine Calcium-Increased (> 300 mg/24hr) •Confirm diagnosis by measuring PTH

The regulation of calcium and phosphorous metabolism is accomplished by which of the following glands? a) thyroid b) parathyroid c) adrenal glands d) pituitary

b Regulation of Ca2+ and PO43- metabolism [Bishop 2018, p356]

A 49-year-old woman with a previous history of a radical mastectomy 7 years ago complains of bone pain. A bone scan is reported as abnormal. The QT interval is shortened on an ECG. Which of the following are other likely laboratory findings on this patient? a) decreased serum PTH, decreased serum calcium b) increased serum PTH, decreased serum calcium c) increased serum PTH, increased serum calcium d) decreased serum PTH, increased serum calcium

D (Decreased serum PTH, increased serum calcium) The bone pain in this patient is likely due to breast cancer metastasis to the bone. In this case, it has produced hypercalcemia (short QT interval in an ECG) leading to suppression of PTH synthesis by the parathyroid glands. The metastatic lesions in the bone have activated osteoclasts leading to lytic lesions and an increase in serum calcium

A reciprocal relationship exists between: a) sodium and potassium b) Calcium and phosphate c) Chloride and CO2 d) Calcium and magnesium

b) Calcium and phosphate Reciprocal relationship between calcium and phosphate [Bishop 2018, p356]

A reciprocal relationship exists between: a) sodium and potassium b) calcium and phosphate c) chloride and CO2 d) calcium and magnesium

b Reciprocal relationship of Ca2+ and phosphate

What percent of serum calcium is in the ionized form? a. 30% b. 50% c. 60% d. 80%

b. 50% Calcium exists in three forms, 45% unbound (ionized), 45% bound to albumin, and 10% bound to other anions. Only the ionized (unbound form) is the physiologically active form.

Which of the following is most often elevated in hypercalcemia associated with malignancy? a. Parathyroid-derived PTH b. Ectopic PTH c. Parathyroid hormone-related protein (PTHRP) d. Calcitonin

c. Parathyroid hormone-related protein (PTHRP) PTHRP is a peptide produced by many tissues and normally present in the blood at very low levels. The peptide has an N-terminal sequence of eight amino acids that are the same as found in PTH and that will stimulate PTH receptors of bone. Some malignancies (squamous, renal, bladder, and ovarian cancers) secrete PTHRP causing hypercalcemia-associated malignancy.

In the atomic absorption method for calcium, lanthanum is used: a) as an internal standard b) to bind calcium c) to eliminate protein interference d) to prevent phosphate interference

d) to prevent phosphate interference In calcium analysis by AAS, lanthanum is added to bind with phosphate, thereby preventing interference by the formation of calcium phosphate

A 41-year-old woman has hypocalcemia, hyperphosphatemia, and decreased urinary phosphate excretion. Injection of parathyroid hormone (PTH) causes an increase in urinary cyclic adenosine monophosphate (cAMP). The most likely diagnosis is: a. Primary hyperparathyroidism b. Vitamin D intoxication c. Vitamin D deficiency d. Hypoparathyroidism after thyroid surgery e. Pseudohypoparathyroidism

d. Hypoparathyroidism after thyroid surgery Low blood [Ca2+] and high blood [phosphate] are consistent with HYPOparathyroidism. Lack of PTH decreases bone resorption, decreases renal reabsorption of Ca2+, and increases renal reabsorption of phosphate (causing low urinary phosphate). Because the patient responded to exogenous PTH with an increase in cAMP, the G protein coupling the PTH receptor to adenylate cyclase is apparently normal.Consequently, pseudohypoparathyroidism is ruled out. Vitamin D intoxication would cause hypercalcemia, not hypocalcemia. Vitamin D deficiency would cause hypocalcemia and hypophosphatemia.

Hypocalcemia symptoms:

muscle spasms, facial grimacing, prolonged QT interval; irritability, depression, psychoses - tetany

Bone breakdown (resorption) is mediated by?

osteoclasts

Calcitonin is synthesized and secreted by the _________________________ cells of the thyroid

parafollicular