Lecture 4 Endo Module - Parathyroid Glands
What ishypocalcemia?
Low extracellular Ca2+ increases membrane permeability for sodium Spontaneous Action Potentials occur Increased excitability of excitable cells Skeletal muscle: Muscle weakness, fatigue, Sensory nerves: Paresthesia CNS: Anxiety, depression, memory loss, changes the excitability of the nerves
What is hypercalcemia?
*symptoms:* Stones, Bones Groans Thrones --> polyuria - sits on throne Overtones --> depression, anxiety Often asymptomatic early
What is ionized Ca2+?
- albumins(proteins) low > ionized Ca measurement can be low, need to adjust measured Ca level -Almost always see in low protein diseases Changes in anion concentrations alter the ionized Ca2+ concentration by changing the fraction of Ca2+ complexed with anions phosphate PO4 -3 plasma phosphate concentration increases, the fraction of Ca2+ that is complexed increases (Ca3(PO4)2) thereby decreasing the ionized Ca2+ concentration. plasma phosphate concentration decreases, the complexed Ca2+ decreases and the ionized Ca2+ increases. Clinical importance Chronic renal failure > hi PO4 (phosphate) >so low Ca+2 >so hi PTH > so osteoporosis & increased renal damage -see later
Why isn't ionized Ca2+ measured directly?
--Need unusual tubes, handling of the sample A PAIN! Standard tube colors Sample type Serum, heparinized plasma (sodium heparin, lithium heparin) Anticoagulant EDTA or citrate cannot be used for ionized calcium measurement (these anticoagulants chelate calcium). Heparin can be used, but it is a polyanion (negatively charged) and will bind ionized calcium. careful! Erroneously low ionized calcium can also occur in vitro from under filled tubes, or tubes left uncapped before measurement, because the loss of carbon dioxide increases sample pH and increases protein-bound calcium. ionized Ca +2 Reference range is 4.5 - 5.3 mg/dL. Critical values are <3.5 mg/dL and >6.5 mg/dL. Specimen requirement is one SST tube of blood. Tourniquet time should not exceed one minute. The tube must remain capped and should be transported in wet ice. Hemolysis will falsely lower ionized calcium values. Once collected, the pH of a blood sample may decrease from cell metabolism or increase due to loss of carbon dioxide if the specimen is exposed to air. Ionized calcium values change inversely to pH. The magnitude of change is 0.05 mmol/L per 0.1 pH change
Pathophysyology of the PTH system can involve what 3 conditions?
-an excess of PTH -a deficiency of PTH -target tissue resistance to PTH
What are the parathyroid glands?
-gland that are embedded in posterior surface of thyroid gland -four total glands --> ectopic tissues of the neck/chest possible (a) chief cells- produce and secrete parathyroid hormone (PTH), regulation of blood calcium levels (b) function of one type of parathyroid cells, the oxyphil cells, unknown -appears in puberty, age? Dz?
What is primary hyperparathyroidism?
1o Primary hyperparathyroidism is most commonly caused by parathyroid adenomas (tumors), -secrete excessive amounts of PTH. Clinically see hypercalcemia, and hypophosphatemia. Hypercalcemia results from increased bone resorption, increased renal Ca2+ reabsorption, increased intestinal Ca2+ absorption Hypophosphatemia results from decreased renal phosphate reabsorption and phosphaturia
Explain why someone with a parathyroid gland tumor might develop kidney stones.
A parathyroid gland tumor can prompt hypersecretion of PTH. This can raise blood calcium levels so excessively that calcium deposits begin to accumulate throughout the body, including in the kidney tubules, where they are referred to as kidney stones
What is Vitamin D?
AKA 1,25-dihydroxycholecalciferol Vitamin D Vitamin D, in conjunction with PTH, is the second major regulatory hormone for Ca2+ and phosphate The role of PTH is to maintain Ca levels --role of vitamin D is to promote mineralization of new bone, and its actions are coordinated to increase both Ca2+ and phosphate concentrations in plasma so that these elements can be deposited in new bone Synthesis of Vitamin D Vitamin D (cholecalciferol) is provided in the diet produced in the skin from cholesterol Regulation of Vitamin D Synthesis Renal cells produce 1,25-dihydroxycholecalciferol (the active metabolite) or 24,25-dihydroxycholecalciferol (the inactive metabolite) depends on the "status" of Ca2+ in the body. CRF?
What is a unique trait regarding bone?
Bone turnover continues lifelong, regardless of plasma Ca2+ - turnover in adults about 18% per year, - in infants 100% per year Pb exposure!
What is calcitonin?
Calcitonin: is synthesized and secreted by the parafollicular or C ("C" for calcitonin) cells of the thyroid gland. Stimulus for calcitonin secretion is increased plasma Ca2+ concentration (stimulus for PTH secretion, decreased plasma Ca2+ concentration) The major action of calcitonin is to inhibit osteoclastic bone resorption, which decreases the plasma Ca2+ concentration. Calcitonin salmon injection is used to treat osteoporosis in postmenopausal women. Calcitonin does not participate in the minute-to-minute regulation of the plasma Ca2+ concentration in humans. A physiologic role for calcitonin in humans is uncertain
How does secondary hyperparathyroidism affect the kidneys in CRF?
Changes in anion concentration alter the ionized Ca2+ concentration by changing the fraction of Ca2+ complexed with anions. plasma phosphate concentration increases, the fraction of Ca2+ that is complexed increases, thereby decreasing the ionized Ca2+ concentration. If plasma phosphate concentration decreases, complexed Ca2+ decreases and ionized Ca2+ increases Chronic renal failure hi PO4 phosphate ? so low ion Ca+2 > so hi PTH hi phosphate toxic to renal cells!?
What is chronic dysfuction of the parathyroid hormone?
Chronic (long-term) changes in plasma Ca2+ concentration alter synthesis and storage of PTH, and growth of the parathyroid glands. Chronic hypocalcemia (decreased plasma Ca2+ concentration) causes secondary hyperparathyroidism, increased synthesis and storage of PTH and hyperplasia of the parathyroid glands chronic hypercalcemia (increased plasma Ca2+ concentration) causes hypoparathyroidism, decreased synthesis and storage of PTH, increased breakdown of stored PTH, and release of inactive PTH fragments into the circulation.
What is the pathophysiology of PTH cancer?
Humoral hypercalcemia of malignancy Some malignant tumors (e.g., lung, breast) secrete PTH related peptide (PTH-rp) PTH-rp - structurally similar has all the physiologic actions of PTH including increased bone resorption, inhibition of renal phosphate reabsorption, and increased renal Ca2+ reabsorption. -effects of PTH-rp cause hypercalcemia and hypophosphatemia, blood chemistry profile similar to that seen in Primary hyperparathyroidism Circulating levels of PTH are low, (as would occur in primary hyperparathyroidism); PTH secretion by the parathyroid glands is suppressed by the hypercalcemia. Humoral hypercalcemia of malignancy - treated with furosemide, inhibits renal Ca2+ reabsorption increases Ca2+ excretion, inhibitors of bone resorption such as etidronate High Ca+2 think cancer as a Ddx!
What is osteomalacia?
In adults, vitamin D deficiency/resistance results in osteomalacia, in which new bone fails to mineralize, resulting in bending and softening of the weight-bearing bones. Vitamin D resistance occurs when the kidney is unable to produce the active metabolite, 1,25-dihydroxycholecalciferol -condition is called "resistant" because no matter how much vitamin D is supplemented in the diet, it will be inactive because the C1 hydroxylation step in the kidney is absent or is inhibited. Vitamin D resistance causes = chronic renal failure common rare = congenital absence of 1α-hydroxylase
How does PTh affect bone?
In bone, PTH receptors are located on osteoblasts but not on osteoclasts. Initially and transiently, PTH causes an increase in bone formation by a direct action on osteoblasts. (This brief action is the basis for the usefulness of intermittent synthetic PTH administration in the treatment of osteoporosis.) In a second, long lasting action on osteoclasts, PTH causes an increase in bone resorption. This second action on osteoclasts is indirect and mediated by cytokines released from osteoblasts; these cytokines then increase the number and activity of the bone-resorbing osteoclasts. The bone-forming cells, osteoblasts, are required for the bone-resorbing action of PTH on osteoclasts. When PTH levels are chronically elevated, as in hyperparathyroidism, the rate of bone resorption is persistently elevated, which increases the serum Ca2+ concentration. The overall effect of PTH on bone is to promote bone resorption, delivering both Ca2+ and phosphate to ECF
What happens in Vitamin D deficiency?
In children, vitamin D deficiency causes rickets, a condition in which insufficient amounts of Ca2+ and phosphate are available to mineralize the growing bone This condition is rare in areas where vitamin D is supplemented (Milk) and when there is adequate exposure to sunlight.
How does the parathyroid hormone affect renal processes?
Kidney PTH - two actions on the kidney Increase Ca reabsorption PTH stimulates Ca2+ reabsorption -renal action on the distal convoluted tubule 2) PTH inhibits phosphate reabsorption PTH causes phosphaturia, an increased excretion of phosphate in urine. -phosphaturic action of PTH is critical because the phosphate that was resorbed from bone is excreted in the urine; this phosphate would have otherwise complexed Ca2+ in ECF Excreting phosphate in urine "allows" the plasma ionized Ca2+ concentration to increase
What occurs in the bones with age?
Lower dietary intake Lower activity (loss of weight-bearing stimuli) Decreased intestinal absorption Vitamin D deficiency due to lower sunlight Cellular and body Ca2+, PTH senile osteoporosis
What is the difference bewteen total blood Ca2+ and ionized Ca2+?
Measure TOTAL Ca on most chem panels Because changes in plasma protein concentration usually are chronic and develop slowly over time, they do not cause a parallel change in ionized Ca2+ concentration. Changes in plasma protein concentration(albumin) alter the total Ca2+ concentration in the same direction as the protein concentration; Can order or convert total Ca to ionized Ca on blood chemistry panel
What is osteoporosis?
Most common bone remodeling disorder --> pro-inflammatory cytokines Aggravated by loss of estrogen --> loss of OPG's bone protection Aggravated by lower weight-bearing mechanical stress (piezzo effect) senile osteoporosis see next slide Osteoporosis is defined as bone mineral density being 2.5 SD below the average If milder, it is called osteopenia Activates the pro-inflammatory cytokines and is aggravated by the loss of estrogen because estrogen acts on the same system immune system is influenced by estrogen bone is stimulated by mechanical bending (Wolff'sLaw). It is important to exercise because it stimulates bone growth!
What is involved in bone metabolism?
Osteoid organic matrix (95% type I collagen) Hydroxyproline is breakdown product (e.g. elevated in urine in Paget's disease) + Cells Osteoblasts are involved in bone deposition Osteoclasts, are bone-resorbing cells Osteocytes are mainly quiescent osteoblasts Bone remodeling always involves both, osteoclasts and osteoblasts basic multicellular unit (BMU)
What organs and hormones are involved in Ca2+ homeostasis?
Overall Calcium Homeostasis Ca +2 homeostasis involves the coordinated interaction of three organ systems (bone, kidney, and intestine) three hormones parathyroid hormone, calcitonin, vitamin D
What is secondary hyperparathyroidism?
PTH increased secondary hyperparathyroidism, -parathyroid glands are normal are stimulated to secrete excessive PTH secondary to hypocalcemia caused by -vitamin D deficiency -chronic renal failure secondary hyperparathyroidism, circulating levels of PTH are elevated blood levels of Ca2+ are low or normal but never high
How is parathyroid hormone regulated?
PTH secretion -regulated by the plasma Ca2+ -Stimulated by Ionized Ca levels only!!! if total Ca2+ concentration is in the normal range (10 mg/dL plus) PTH -secreted at a basal level If plasma Ca2+ concentration decreases to less than 10 mg/dL, > PTH secretion is stimulated response occurs within seconds! Magnesium (Mg2+) has parallel, although less important, effects on PTH secretion
What do you treat hyperphosphatemia with in chronic renal failure?
Phosphate binders > excrete phosphorus intestinally
What are other receptors/enzymes that also affect PTH in bone metabolism?
Receptor activator of nuclear factor-kB ligand (RANKL), a protein that binds to receptor activator of nuclear factor-kB (RANK), is the primary mediator of osteoclast differentiation, activation, and survival (Figure 1). RANK ligand is the primary mediator of bone resorption. Osteoprotegerin (OPG) provides an alternative binding site for RANKL and acts as a decoy receptor by blocking RANK ligand binding to its cellular receptor RANK. Ligand binding activates cellular signalling. Ligand that is bound to a decoy receptor cannot activate cellular signalling. Denosumab is an osteoporosis treatment designed to target RANKL
Describe the role of negative feedback in the function of the parathyroid gland.
The production and secretion of PTH is regulated by a negative feedback loop. Low blood calcium levels initiate the production and secretion of PTH. PTH increases bone resorption, calcium absorption from the intestines, and calcium reabsorption by the kidneys. As a result, blood calcium levels begin to rise. This, in turn, inhibits the further production and secretion of PTH
How are Ca2+ levels and cancer related?
The types of cancers that are most commonly associated with high blood Calcium are: myeloma - nearly half of all people with myeloma have this at some stage breast cancer squamous cell lung cancer kidney cancer head and neck cancers prostate cancer Although less common, high blood calcium can happen in other types of cancer
What is important about body calcium?
Total Body Calcium 1000g Over 99% stored in skeleton Of this calcium, ~1% is in simple, non-hormonal equilibrium with the extracellular pool (labile bone)
What is important about total plasma calcium?
Total Plasma Calcium bound and ionized ! Between 8.8-10.4 (~10mg)mg/dL measured Value assumes normal albumin 40% bound to protein, primarily albumin 5-10% complexed to phosphate, citrate, bicarbonate and other ions 45-50% free or ionized form 4.5-5.6 mg/dL regulated hormonally if <3 mg/dl significant symptoms
Which of the following can result from hyperparathyroidism? A. Increased bone deposition B. Convulsions C. Fractures D. Hypocalcemia
fractures
What happens in excessive osteoblast activity?
have an increase in alkaline phosphatase increase normal ALP measurements > ALP from many sources The osteoblasts activate the osteoclasts (RANK-L is a positive regulator and OPG is a negative regulator) Bone alkaline phosphatase (BAP) is the bone-specific isoform of alkaline phosphatase. A glycoprotein that is found on the surface of osteoblasts, BAP reflects the biosynthetic activity of these bone-forming cells. BAP has been shown to be a sensitive and reliable indicator of bone metabolism. Males <2 years: 25-221 mcg/L 2-9 years: 27-148 mcg/L 10-13 years: 35-169 mcg/L 14-17 years: 13-111 mcg/L Adults: < or =20 mcg/L Females <2 years: 28-187 mcg/L 2-9 years: 31-152 mcg/L 10-13 years: 29-177 mcg/L 14-17 years: 7-41 mcg/L Adults Premenopausal: < or =14 mcg/L Postmenopausal: < or =22 mcg/L
What is the pathophysiology of PTH in hypoparathyroidism?
hypoparathyroidism Ca2+ are low or normal never high. Iatrogenic! Hypoparathyroidism relatively common, inadvertent consequence of thyroid surgery or parathyroid surgery Autoimmune and congenital hypoparathyroidism are less common give patients calcium pills for a few days after surgery See: low circulating levels of PTH, Hypocalcemia results from decreased bone resorption, decreased renal Ca2+ reabsorption decreased intestinal Ca2+ absorption Hyperphosphatemia results from increased phosphate reabsorption. -treated with the combination of an oral Ca2+ supplement -active form of vitamin D, 1,25-dihydroxycholecalciferol Check Ca+2 levels post op after thyroid Sx!!
When blood calcium levels are low, PTH stimulates ________. A. Urinary excretion of calcium B. A reduction in calcium absorption from the GI tract C. The activity of osteoblasts D. The activity of osteoclasts
the activity of osteoclasts