Calcium and Parathyroid Study Sheet

in terms of calcium homeostasis, calcium is typically bound to what protein

albumin

besides bound calcium, there is also not bound calcium (free calcium): what is this known as and is it active or inactive?

ionized calcium- it is biologically active; bound is inactive

how does pH values affect calcium level

presence of H+ ions displace calcium from albumin, leading to elevated ionized calcium levels

—> acidemia elevates ionized calcium (free)

what are normal total serum levels for calcium

8.5-10.2 mg/dl

of the total serum calcium levels, about what % is bound to protein

40% bound to albumin

if albumin levels are low, what happens to total calcium? what about free calcium?

total calcium will be low, but free levels may still be normal

describe calcium balance in terms of how much is ingested/absorbed/excreted on daily basis

typical adult ingests 1g of elemental calcium per day; 200 mg absorbed and 800 mg excreted

calcium balance: how much calcium is generally stored in bone

1 kg of Ca is stored in bone (500 mg/day is released by resorption or deposited during bone formation)

calcium balance: how much calcium is filtered thru the kidneys and excreted

10 kg of calcium filtered thru; 200 mg excreted

calcium balance: what are the 3 main sources of calcium

bone, kidneys, and dietary calcium

describe intestinal absorption of calcium

1) calcium is not well absorbed

2) absorbed in duodenum (most) and jejunum (least)

what are the 2 different mechanisms of intestinal absorption

1) active/transcellular (saturable) transport which is controlled by vitamin D (this is the most important route)

2) passive/paracellular (non-saturable) transport

what is key for calcium absorption?

diet! you can only absorb calcium if you eat foods that contain it

what can we not control that might affect calcium absorption?

age affects absorptive power of the gut and the sensitivity to vitamin d

describe renal absorption of calcium in the PCT (note that diff segments of the nephron are tasked w calcium reabsorption)

1) 60% reabsorbed

2) absorption is passive

3) calcium follows sodium

4) Ca/H exchanger is bicarbonate dependent

describe renal absorption of calcium in thick ascending LOH

1) mostly passive reabsorption

2) Na/Cl/K triporter promotes luminal positive charge (electrochemical gradient that leads to passive reabsorption)

2) CaSR (calcium sensing receptor) on the basolateral membrane —> when activated (by high serum calcium) —> decreases Ca permeability —> decreases Ca reabsorption therefore helps remove calcium

describe renal absorption of calcium in the DCT

1) parathyroid hormone acts here

2) active transport (against chemical/electrical gradient)

3) PTH increases expression of Ca transport proteins

describe the role of bone modeling in calcium homeostasis

1) bone serves as important storage point for calcium

2) bone is remodeled to release calcium into the circulation: osteoclasts resorb bone and osteoblasts form bone

3) hormonal impact: PTH indirectly increases osteoclast activity —> calcium release from bone

4) hormonal impact: estrogen, calcitonin, growth hormone, glucocorticoids, and thyroid hormone also impact bone resorption (release of calcium from bone)

what is the role of parathyroid hormone in calcium homeostasis?

PTH controls minute to minute serum ionized calcium (free)

as calcium levels drop, PTH production ____________ and what is its action

increases, which acts to increase calcium release

therefore, as calcium levels increase, PTH levels ?

PTH production decreases

PTH also increases renal _____________ of phosphate, which does what?

excretion; decreases phosphate levels

PTH also increases 1-alpha hydroxylase activity, which does what

increases activation of 25 vitamin D to 1,25 vitamin D

what is 1,25 vitamin D and what is one of its roles

known as calcitriol which inhibits parathyroid cell proliferation to prevent excessive PTH production (negative feedback action)

what does calcitriol do to calcium levels (its other role)

increases calcium reabsorption in order to help raise serum calcium levels (this will in turn inhibit PTH secretion via negative feedback)

secretion of PTH is regulated by what 4 factors

1) extracellular calcium levels: if low, PTH secretion increases

2) extracellular phosphate levels: if high, PTH secretion increases

3) PTH increases 1-alpha hydroxylase activity, so with high enough 1,25 vit D levels —> PTH cell proliferation is inhibited

4) FGF23: this causes phosphate excretion which will inhibit PTH synthesis and secretion

what are the general actions of PTH release from parathyroid glands

1) increases osteoclast activity —> increases bone resorption

2) increases intestinal calcium reabsorption/increases 1-OH activation —> 1,25 vit D increases calcium absorption from the gut

what is the clinical presentation of hypercalcemia?

1) bones: osteoporosis

2) groans: bone pain, abdominal pain, constipation

3) stones: renal stones, hypercalciuria

4) psychiatric overtones: anxiety, depression, mild cognitive dysfunction

what are the 2 general categories of hypercalcemia

1) PTH-mediated- due to elevated PTH

2) non-PTH mediated- due to problems with bone, kidney, or gut regulation of calcium

describe the etiology of PTH-mediated hypercalcemia (what are some causes of PTH elevation)

1) parathyroid adenoma (most common): benign functional tumor of PTH glands; excess PTH —> hypercalcemia from increased Ca absorption from gut, increased bone turnover, increased Ca resorption at kidney

2) parathyroid hyperplasia

3) inactivation of CaSR mutation

describe the CaSR mutation and how its inactivation causes hypercalcemia

1) mutation of CaSR: the receptor "thinks" there is too much calcium even when levels are normal or low; it suppresses PTH secretion inappropriately

2) mutation leads to inappropriately low PTH; we would actually see hypocalcemia

3) inactivation of the mutation, however, changes things. the receptor will now be less sensitive to calcium levels (it wont freak out at normal or low levels); it will take even higher levels of calcium to trigger the suppression of PTH release

4) inactivation leads to inappropriately high PTH; we see hypercalcemia and low calcium in urine

the CaSR mutation is related to what inherited disease

familial hypocalciuric hypercalcemia: autosomal dominant inherited disease; heterozygous loss of function of CaSR gene; mutation makes pt less sensitive to calcium levels—> low calcium in urine and hypercalcemia

etiology of non-PTH mediated hypercalcemia can be from what 3 things?

1) increased bone resorption

2) impaired renal excretion

3) increased gut absorption

describe 3 things that might cause increased bone resorption which leads to hypercalcemia

1) malignancy

2) thyrotoxicosis

3) immobility (increased bone resorption bc no forces/use but this is uncommon)

describe how bone malignancy can lead to hypercalcemia

mechanism of increase bone resorption depends on the cancer but:

1) metastases: local osteolysis increases serum calcium

2) cytokines stimulate differentiation of osteoclasts, increasing resorption

3) PTHrP: hormone secreted by tumor that mimics action of PTH (paraneoplastic)

4) lymphoma: increased 1 alpha hydroxylase

describe how thyrotoxicosis can lead to hypercalcemia

mild hypercalcemia occurs in up to 15-20% of thyrotoxic pts due to a thyroid hormone mediated increase in bone resorption

describe what might cause impaired renal excretion which leads to hypercalcemia

milk-alkali syndrome:

1) very high intake of calcium w absorbable alkali (like milk + sodium bicarbonate) can lead to hypercalcemia despite suppression of calcitriol

2) hypercalcemia decreases GFR, causes diuresis, volume depletion —> leads to absorption of bicarbonate —> hypercalcemia, alkalosis, volume depletion

describe 2 things that might cause increased gut absorption which leads to hypercalcemia

1) high calcium intake combined with CKD —> hypercalcemia

2) excessive vit D intake —> high 1,25 dihydroxyvitamin D (calcitriol) —> increased gut calcium absorption

why does high calcium intake alone rarely cause hypercalcemia in terms of gut absorption

• high Ca suppresses PTH

• decreases activation of calcitriol

• inhibits absorption of Ca from the gut

describe which factors are involved in decreased calcium absorption

high calcium intake —> suppresses PTH —> decreases activation of calcitriol —> inhibits gut absorption of Ca

what role does renal and extra-renal 1-alpha-hydroxylase play in calcium homeostasis (4)

1) renal and extra-renal calcitriol production = increased 1-hydroxylase activity

2) leads to activated macrophages in lungs and lymph nodes

3) described w lymphoma, sarcoidosis, TB

4) leads to increased calcium absorption —> increase in bone resorption

what is the clinical presentation of hypocalcemia (8)

1) paresthesia

2) muscle spasm

3) cramps

4) perioral numbness

5) EKG changes

6) personality changes

7) neuromuscular irritability

8) seizures

what are notable signs of physical exam findings of hypocalcemia

1) chvostek sign: twitching of upper lip when tapped on cheek 2 cm anterior to earlobe, below zygomatic process overlying facial nerve

2) trousseau sign: more reliable; carpopedal spasm observed following application of an inflated BP cuff over systolic pressure for 3 minutes in hypocalcemic pts

what might you see in terms of PTH levels in PTH-mediated hypocalcemia; what is PTH mediated hypocalcemia

low PTH levels —> primary hypoparathyroidism (PTH mediated: problem with PTH glands and inadequate stimulation for calcium release from bones, inadequate absorption from diet, or inadequate kidney resorption)

what are 4 etiologies of PTH-mediated hypocalcemia

1) congenital

2) post-surgical

3) autoimmune

4) infiltrative disease

what might you see in terms of PTH levels in non-PTH mediated hypocalcemia; what is non-PTH mediated hypocalcemia

high PTH levels —> secondary hyperparathyroidism (non-PTH mediated: high PTH is an appropriate response to low calcium; suggest that problem is at level of bone, kidney, or gut)

what are 5 etiologies of non-PTH mediated hypocalcemia

1) decreased bone modeling

2) renal Ca loss

3) vit D/Ca deficiency (includes vit D resistance)

4) malabsorption

5) PTH resistance, cinacalcet, critical illness

describe how decreased bone modeling leads to non-PTH mediated hypocalcemia

1) drugs that decrease bone turnover: bisphosphonates, denusomab

2) osteoblastic metastasis

example of how renal Ca loss leads to non-PTH mediated hypocalcemia

chronic kidney disease —> high PO4, low 1,25 (OH)2 vit D

example of how PTH resistance leads to non-PTH mediated hypocalcemia

PTH resistance —> pseudohypoparathyroidism (end organ resistance to PTH, presents in childhood)

how does critical illness lead to non-PTH mediated hypocalcemia

impairs PTH excretion

what is cinacalcet and how does it lead to non-PTH mediated hypocalcemia

Hypocalcemia as a result of acute inhibition of PTH release

bone remodeling process is _________ and can be affected by what 3 things

dynamic!

1) hormones (estrogen, vit D, PTH)

2) mechanical stress on skeleton

3) medications

briefly describe the bone remodeling cycle (4)

1) osteoblasts secrete RANKL

2) RANKL binds to RANK —> stimulates osteoclast maturation and activity

3) osteoblasts fight back by secreting OPG which inhibits RANK-RANKL interaction

4) RANK-RANKL-OPG interplay dictates if resorption or formation predominates

what are the 2 major bone composition disorders

1) osteoporosis

2) osteomalacia

describe osteoporosis (4)

1) abnormal structure, normal mineralization

2) chronic progressive dz characterized by low bone mass and deterioration of microarchitecture

3) bone fragility

4) increase fracture risk (highest risk found among white women)

describe osteomalacia (3)

1) normal structure, decreased mineralization

2) abnormal mineralization is most often due to vit D deficiency (malabsorption, poor diet, limited sun exposure)

3) clinically: bone pain, muscle weakness, fractures, abnormal gait

how is osteoporosis a statistical definition? (2)

1) osteoporosis is defined statistically based on the number of standard deviations a pt's bone density is below a normal peak bone mass

2) observational data has identified a significant increase in fracture risk at 2.5 standard deviations below average, so this has been set as definition of osteoporosis

what are the non-modifiable risk factors for osteoporosis

age, genetics

what are the medical risk factors for osteoporosis

renal dz, liver dz, hyperthyroidism, hyperparathyroidism, hypogonadism, malabsorption, chronic inflammation

what are the medication risk factors for osteoporosis

steroids, anti-epileptics, TZDs

what are the nutrition and lifestyle risk factors for osteoporosis

low vit D, low calcium, alcoholism, tobacco, caffeine, immobility, low body weight

what are the 5 general screening guidelines for osteoporosis (which pt populations should be screened most often based on sex hormone status)

1) all women (cis or trans) age 65+ and men (cis or trans) age 70+ regardless of risk factors

2) post-menopausal women and men 50-70 y/o when risk factors are present

3) adults w a fragility fracture

4) adults w a condition or taking a med assoc w low bone mass or bone loss

5) trans or gender non-conforming individuals w/o hormone therapy for >1 year

what is the difference between the 2 primary hyperparathyroid disorders (parathyroid adenoma and parathyroid hyperplasia)

1) parathyroid adenoma is the most common cause; it is the most common diagnosis for pts in whom hypercalcemia is incidentally discovered

2) parathyroid hyperplasia is a four gland hyperplasia that develops either sporadically or is found in genetic conditions such as multiple endocrine neoplasia (MEN) type 1 or 2A

what is secondary hyperparathyroidism and how does it develop

1. chronic kidney disease and

2. vit D deficiency can lead to elevated PTH levels

3. This is in an attempt to maintain normal calcium (in vit D deficiency) and normal serum phosphorus levels

4. These usually present w hypocalcemia, which leads to compensatory increase in PTH

what is tertiary hyperparathyroidism and how does it develop

long standing secondary hyperparathyroidism can result in autonomous parathyroid function (tertiary) which develops as the hyperplastic glands develop focal adenomatous regions

how is the distinction between secondary and tertiary hyperparathyroidism usually made?

by the presence of hypercalcemia in pts with longstanding CKD

what is the MOA of calcitonin in the regulation of bone mineral density

suppresses osteoclast activity; inhibits bone resorption

what is the MOA of PTH in the regulation of bone mineral density

leads to an increase in RANKL which stimualtes osteoclasts to increase bone resorption

what is the MOA of active vit D in the regulation of bone mineral density

low vit D causes decrease in bone mineralization, poor bone growth, and secondary hyperparathyroidism

what is the MOA of bisphosphonates in the regulation of bone mineral density

1) inhibit osteoclast mediated bone resorption, which slows bone loss

2) main side effect w oral bisphosphonates is esophagitis

3) has dental implications —> MRONJ

What is the MOA of denosumab in the regulation of bone mineral density

is a monoclonal antibody which inhibits RANKL, thus preventing osteoclast mediated resorption

What is the MOA of raloxifene in the regulation of bone mineral density

it is a selective estrogen receptor modulator (SERM) that has positive effects in the bone, slowing bone loss, but has antiestrogenic effects in uterus —> will not increase risk of endometrial cancer

What is the MOA of cinacalet in the regulation of bone mineral density

cinacalet is a CaSR agonist which helps control PTH levels in pt w secondary hyperparathyroidism due to CKD —> activates CaSR which downregulates PTH release