T6 Disorders of Parathyroid Hormone Secretion

calcium - roles

hormone secretion, muscle contraction, nerve conduction, exocytosis, enzyme regulation, intracellular secondary messenger

phosphate - roles

ATP and cellular energy metabolism, enzyme activation/inactivation

calcium and phosphate - regulated by

parathyroid hormone, calcitriol (active vitamin D), calcitonin

calcium homeostasis - processes

intestinal absorption, bone turnover, kidney filtration and excretion

calcium absorption

UV-B > skin > convert to vitamin D2 and D3 > kidney convert 25(OH)D using 1alpha-hydroxylase into 1,25(OH)2D active form > enhance intestinal calcium absorption

what does PTH stimulate

osteoclast, 1alpha-hydroxylase (conversion into active form)

PTH - effect on calcium and phosphate in kidney

increase calcium, decrease phosphate

PTH - effect on calcium and phosphate in bone

increase calcium and phosphate

PTH - effect on calcium and phosphate in intestine

increase calcium and phosphate

what triggers PTH release

decreased calcium, increased phosphate

what inhibits PTH release

hypercalcemia, active vitamin D (1,25)

vitamin D - PTH gene regulation

vitamin D receptor binds active vitamin D > forms dimer with RXR > binds to DNA to inhibit transcription

PTH synthesis

pre-pro PTH synthesized in RER > cleaved into pro PTH in ER > cleaved into active PTH in golgi

PTH synthesis - calcium regulated

calcium bind to calcium sensing receptor > activate G protein > increase IP3 > open intestinal calcium channel to further increase calcium > PLA2 > inhibit PTH gene expression > less PTH mRNA

PTH synthesis - active vitamin D regulated

lipid soluble, enter cell > inhibit PTH gene, stimulate CaSR gene to translocate calcium sensing receptor back into membrane

PTH - acts where

intestine, kidney, bone

PTH - action mechanism

PTH bind to PTH/PTHrP receptor > second messenger cAMP > activate PKA > increase calcium reabsorption at distal convoluted tubule, increase phosphate and bicarbonate excretion in urine, inhibit NPT2a to prevent phosphate reabsorption, increase bone resorption

TRPV6

calcium ion channel in kidney and intestine

what binds calcium once it is inside the cell, and what is needed for it to function

calbindin D, active vitamin D

what pumps calcium into the blood

PMCA (with active vitamin D), sodium calcium exchanger

active vitamin D relation to calcium

increases calcium levels

PTH action in bone

inhibit collagen synthesis in osteoblast to reduce bone formation, stimulate RANKL production from osteoblasts to activate osteoclasts

hypocalcemia - clinical features

hypocalcemic tetany (trousseau’s sign), chvostek’ sign (tap face and spasm),

hypoparathyroidism - clinical features

paresthesia around mouth, prolonged QT interval, soft-tissue calcification, muscle cramps, tetany, spasms (laryngeal spasm can cause respiratory obstruction and death), seizures, elevated urinary calcium but no hypercalciuria

primary hyperparathyroidism

most common cause of hypercalcemia, due to parathyroid adenoma/hyperplasia

primary hyperparathyroidism - clinical signs

fatigue, kidney stones, bone pain

secondary hyperparathyroidism - cause

chronic renal disease or vitamin D deficiency

elevated PTH, elevated calcium, low phosphate, increased active vitamin D - condition

primary hyperparathyroidism

elevated PTH, low/normal calcium - condition

secondary hyperparathyroidism

low PTH, low calcium, high phosphate - condition

primary hypoparathyroidism (surgical resection, autoimmune)

high PTH, low calcium - condition

secondary hyperparathyroidism (vitamin D deficiency, chronic renal failure, vitamin D resistant rickets, decreased calcium intake)

low PTH, high calcium - condition

PTH-independent hypercalcemia (excessive dietary intake of calcium or vitamin D)

hypoparathyroidism - lab results

hypocalcemia (but bone remain strong), hyperphosphatemia

hypoparathyroidism - treatment

PTH, high dose vitamin D, calcium supplement, active vitamin D (fast but beware of overdose)

hyperparathyroidism - clinical features

renal stones, painful bones, abdominal groans, psychic moans, fatigue overtones

primary hyperparathyroidism - clinical features

lethargy, confusion, depression, muscle weakness, nausea, constipation, anorexia, if severe, decreased bone mass, osteitis fibrosa cystica (punched out lesions), kidney stones, high urinary calcium

parathyroid crisis/poisoning

emergency, presents with metastatic calcification, CaHPO4 deposit in lungs, kidneys, stomach, thyroid, arteries, hyperphosphatemia

primary hyperparathyroidism - treatment

acidic diet/drugs

secondary hyperparathyroidism - mechanism

compensatory increase in PTH due to hypocalcemia

secondary hyperparathyroidism - clinical features

osteomalacia in adults, rickets in children

how does PTH induce bone loss

PTH increase osteoblast release of RANKL to bind to osteoclast, activating bone resorption

DXA < -2.5

osteoporosis

lab tests done in bone health assessment

kidney function (GFR, BUN, creatinine, albumin), parathyroid activity, decreased estrogen

estrogen - relation to bone

decreased estrogen (menopause) > increased osteoclast activity > decreased bone density > increased PTH

bone resorption markers

collagen degradation products (NTX, CTX), enzymes (TARCP)

bone formation markers

matrix proteins (osteocalcin, PICP, PINP), enzyme (total alkaline phosphatase)

changes in bone turnover markers after parathyroidectomy

decreased bone turnover markers, increased bone density

severe osteoporosis - management

calcium and vitamin D supplement, antiresorptive drugs (bisphosphonates)

osteoporosis - common causes

decreased mechanical stress > decreased bone formation, decreased protein intake, vitamin C deficiency > impaired collagen synthesis, postmenopausal estrogen deficiency (estrogen inhibit osteoclast), decreased GH at old age, cushing’s syndrome

recommended calcium and vitamin D intake

1000, 600