Chapter 24: Calcium Homeostasis and Hormonal Regulation - PowerPoint Presentation

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Chapter 24: Calcium Homeostasis and Hormonal Regulation

By Josephine Abraham, Dev Abraham

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Calcium Homeostasis

Serum calcium maintained at a constant level

Cellular & tissue effects of calcium depend on blood calcium maintenance within a specific range.

Adult human body contains 1,000 g of calcium

99% as hydroxyapatite salt (bone)

1% in extra-cellular fluids (blood) – which regulates various biochemical events.

Diet is only source of calcium

Urine is only significant “way out”

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Calcium

Calcium critical for heart/muscle contractions, blood clotting, bone density, and other functions.

Of the 1% of body calcium in extra-cellular fluids (blood)

50% is ionized calcium

40% pound to protein

10% complexed form

(small ions - citrate and phosphate)

Vitamin D and Parathyroid hormone (PTH) – are the two most important hormones that regulate calcium homeostasis.

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Calcium Homeostasis (cont’d)

Calcium homeostasis

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Hormonal Control of

Calcium Metabolism

Vitamin D

Steroid hormone, not actually a vitamin –

synthesized by skin from cholesterol following UVB rays from sun.

Serum 25-hydroxyl Vitamin D is best indicator of body stores therefore, low 25-hydroxyl Vitamin D in blood = deficiency

Tissues involved in synthesis:

skin, liver, kidneys

Tissues it affects:

gut, bone, parathyroids

Can also be obtained from dietary sources: fortified milk, multivitamins, cod liver oil

Key point – Vitamin D is steroid hormone derived from cholesterol

.

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Hormonal Control of Calcium Metabolism

Vitamin D synthesis

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Hormonal Control of Calcium Metabolism

Parathyroid Hormone (PTH)

Secreted from 4 parathyroid glands

in region of

thyroid gland

Parathyroid glands have calcium-sensing receptors that respond to calcium levels by increasing or decreasing PTH secretion

.

Functions

Stimulates bone resorption and release of calcium into blood

Acts on kidney to increase fractional reabsorption

of renal tubular calcium & drive production of active metabolite

Promotes intestinal absorption of calcium by activating 1,25(OH)

2

D (Said another way – Vitamin D is enhanced by PTH, which promotes meal-related intestinal absorption of calcium.)

All functions raise blood calcium & are mediated via a specific PTH receptor.

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Parathyroid Hormone and Calcium Levels

When

Blood

Calcium decreases

PTH is secreted

by parathyroid glands

This

stimulates Osteoclasts

(cells that promote breakdown of bone for Calcium release) and

inhibits Osteoblasts

(bone building)

When

Blood

Calcium increases

PTH is suppressed

(Negative Feedback Mechanism)

Calcitonin is secreted by thyroid

This

stimulates Osteoblasts

(bone building cell) and

inhibits Osteoclasts

(bone breakdown cell)

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Organ Physiology and Calcium Metabolism

Gastrointestinal (GI) tract Regulation of Calcium

Factors required for calcium absorption

Normal intestinal function (short bowel syndrome & genetic or physiologic defects may have negative effect)

Adequate dietary calcium intake

Normal vitamin D availability

& metabolism

1,25 (OH)

2

D controls calcium absorption from the small bowel.

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Organ Physiology and Calcium Metabolism

Role of Kidneys in Calcium Metabolism

Diseased kidney impairs calcium

and phosphate metabolism.

Impaired hydroxylation of 25-hydroxyl Vitamin D to form the active 1,25 (OH)

2

D result in poor calcium absorption in the gut.

Serum PTH levels can be elevated (up to 1000x) in chronic renal failure – leading to hypercalcemia.

Once a critical calcium/phosphate level is reached, they precipitate into tissues with devastating consequences.

Primary hyperparathyroidism (PHPT) – over production of PTH causing hypercalcemia

PHPT patients form calcium kidney stones

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Organ Physiology and Calcium Metabolism

Bone Physiology

(Bone contains about 1kg of calcium)

Bone turnover (remodeling):

coupled process of simultaneous bone formation & breakdown occurring throughout life

Bone formation is mediated by osteoblasts

.

Alkaline Phosphatase = marker for bone formation

Bone breakdown (resorption) is mediated by osteoclasts

.

When resorption exceeds formation, bone mass decreases (increased risk of fracture).

Two main types of bone in skeleton

Cortical:

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

Trabecular:

axial skeleton (vertebrae); has many cross-hair type connections (trabeculae), providing strength & elasticity

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Calcium Reference Ranges

Total Calcium - Serum

8.6 to 10.0 mg/dL

Ionized Calcium – Serum

4.6 to 5.3 mg/dL

Ionized Calcium – Plasma

4.1 to 4.9 mg/dL

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Hypercalcemia

Blood calcium levels above expected normal range

Binding of calcium to other substances must be taken into account when considering total calcium levels.

Patient with low serum albumin would be expected to have low total calcium & normal ionized calcium.

Opposite is true for patients with high serum albumin.

PHPT most common cause of

hypercalcemia

in outpatient setting.

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Causes of Hypercalcemia

PHPT—most common

Secondary and tertiary hyperparathyroidism

Chronic Renal Failure – low stimuli causes high PTH which causes high calcium

CSR (calcium sensing receptor) abnormalities

Other endocrine disorders

Adrenal insufficiency, hyperthyroidism, etc.

Cancer-mediated

hypercalcemia

Granulomatous diseases

Tuburculosis

, leprosy, fungal infections, Crohn disease

Medications

HCTZ, lithium, Vitamin A or D toxicity,

etx

.

Miscellaneous – Wilson’s Syndrome

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Hypercalcemia

Endocrine Causes of Hypercalcemia

Primary hyperparathyroidism (PHPT)

Most common cause of hypercalcemia in outpatient setting

Hallmark of PHPT is overproduction of PTH

caused by a single adenoma(s) in one of the parathyroid glands

Parathyroid carcinoma occurs more commonly in a familial syndrome called hyperparathyroidism-jaw tumor syndrome.

Hypervitaminosis D

Caused by excessive intake of vitamin D or aberrant production of 1,25(OH)

2

D

Cancers (PTHrP), tumors

Cause release of hormones or hormone-like substances

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Hypercalcemia

Signs and Symptoms

CNS:

lethargy, decreased alertness, depression, confusion, forgetfulness,

obtundation

, coma

GI:

anorexia, constipation, nausea & vomiting

Renal:

impairs kidney’s ability to concentrate urine, leading to dehydration, increased risk of kidney stones

Skeletal:

increased bone resorption, increased bone demineralization & risk of fracture

Cardiovascular:

causes or exacerbates hypertension

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Hypercalcemia

Familial

Hypocalciuric Hypercalcemia

Benign condition

Germline mutation of CSR

(Calcium Sensing Receptors)

Stable, mild hypercalcemia from birth

Hypocalciuria

is the hallmark

of the disease, along with mild

hypercalcemia

, mild PTH elevation, and mild elevation of Magnesium.

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Hypercalcemia

Other causes of

hypercalcemia

:

Hyperthyroidism – increased resorption (low PTH)

Addison’s disease,

Addisonian

crisis

Milk-alkali syndrome (Burnett’s syndrome)

Results from ingestion of large amounts of calcium together with an absorbable alkali

PTH level is low.

Renal failure

Renal excretion of both calcium & phosphate is severely impaired.

Production of active form of vitamin D is limited.

PTH secretion is stimulated.

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Hypercalcemia

Medications That Can Cause Hypercalcemia

Thiazide diuretics

Used to treat hypertension

Cause retention of glomerularly filtered calcium

Lithium

Used to treat bipolar affective disorder

Appears to shift “set point” at calcium-sensing receptor

Vitamin A

Believed to activate osteoclasts & enhance bone resorption, elevating blood calcium; PTH & 1,25(OH)

2

D are suppressed

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Hypocalcemia

State of blood calcium levels below expected range

Best measured by ionized calcium

Signs and symptoms

Neuromuscular:

tetany

in hands, feet, legs, back; Chvostek’s sign (twitching at corner of mouth(; numbness & tingling in face, hands, & feet

CNS:

irritability, seizures, personality changes, impaired intellectual functioning

Cardiovascular:

QT prolongation, electromechanical dissociation

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Hypocalcemia

Causes

Parathyroid glands, when functioning properly, will not only correct falling blood calcium but also prevent it by increasing PTH secretion.

Compensatory rise in PTH secretion is known as secondary hyperparathyroidism.

Features that distinguish secondary hyperparathyroidism from primary:

Parathyroids are functioning properly; increased PTH is appropriate mechanism.

Treatment involves identifying & correcting process threatening hypocalcemia,

not

removal of parathyroid(s).

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Hypocalcemia

Endocrine Causes of Hypocalcemia

Hypoparathyroidism

(lack of PTH)

as a result of:

Neck surgery (removal of or damage to parathyroid glands)

Autoimmune destruction of parathyroid tissue

Mutations in PTH gene

Abnormal deposition of copper/aluminum in

parathyroids

Magnesium deficiency

Pseudohypoparathyroidism

(

lack of responsiveness to PTH

)

(Decreased calcium, elevated phosphorous, elevated PTH)

Vitamin D deficiency

(malnutrition, malabsorption,

etc

)

Tertiary hyperparathyroidism

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Hypocalcemia

Organ System Causes of Hypocalcemia

Intestinal disorders

resulting in

inadequate calcium or vitamin D absorption

Short bowel syndrome, dumping syndrome, celiac sprue

Threaten hypocalcemia, increased PTH secretion

Renal insufficiency/failure

As a result of hyperphosphatemia & defective metabolism of vitamin D

Genetic defects resulting in impaired ability to recover filtered calcium from tubular fluid

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Hypocalcemia

Medications That Affect Calcium Metabolism

Antiresorptive agents

Medications that stimulate bone resorption

Lithium

Thiazide diuretics

Recombinant human parathyroid hormone

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Metabolic Bone Diseases

Rickets and Osteomalacia

Caused by

abnormal bone mineralization & vitamin D deficiency

Rickets

Occurs in

growing bone (in

children

)

Bony deformities

from bending of long bones due to gravity

Osteomalacia

Occurs in

bone in

adults

(after closure of epiphyseal plates)

No bony deformities

Alkaline Phosphatase levels are increased

– due to increased osteoblastic activity.

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Osteoporosis

Most prevalent metabolic bone disease in adults

Affects estimated 20–25 million Americans

4:1

female

:male

predominance

Believed to cause 1-1/2 million fractures annually in U.S.

Diagnosis

Based on clinical characteristics and/or a DEXA scan

Fragility fracture

: fracture occurring at an inappropriate degree of trauma

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Magnesium

Neuromuscular excitability

Decreases in Mg produces neuromuscular excitability

Increased Mg levels (hypermagnesia)

Excessive antacid intake

Enemas

Administration of mg in the presence of renal disease

Intracellular levels are higher than extracellular

Impacted by hemolysis

Hemolysis = falsely elevated Mg results

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More, more, moreOf the following, which has the least influence on serum calcium concentrations when present in physiological amounts?

PTH

Serum phosphorous

Calcitonin

Vitamin D