Calcium metabolism

Question 1

what is the daily intake of calcium required for females, males, “growing skeleton”, someone with osteoporosis and the maximum intake you can have?

Answer 1

350mg minimum (Female)
450mg minimum (Male)
750mg “Growing Skeleton”
1500mg Osteoporosis
3000mg maximum

Controversies over if excessive Ca has a role in MI and Cardiac arrythmias

• 1kg of calcium in the bone
• Osteoblast puts calcium in the bone
• ECF contains 10mg/L of calcium

Question 2

what is calcium stored in the bone as?

Answer 2

HYDROXYAPETITE

Note PO4 bound in bone with Ca and will also be released when bone is broken down)

Hydroxyappeptie contains magnesium and sodium, PO4 as long as Ca

Question 3

what is adjusted calcium?

Answer 3

The measured total calcium (CaPr + Ca2+) can be adjusted for the prevailing Albumin concentration and this ACa is a better reflection of the “ionised calcium”.

This is of particular value in chronic disease states e.g. cancer where the decrease in albumin may mask hypercalcaemia

Question 4

what is the formula used to adjust for albumin?

Answer 4

The formula used to adjust for albumin is-
Adjusted Ca (Aca)= Total Ca + 0.02 x (40-[Albumin])

40 is the mean albumin concentration in population

Example- A patient with lung cancer has a total calcium of 2.52 mmol/L and an albumin of 25g/L
ACa = 2.52 + 0.02 x (40-25)
ACa = 2.52 + 0.02 x 15
ACa = 2.82 mmol/L

Question 5

how is plasma calcium regulated?

Answer 5

Binding to proteins/PO4

Parathyroid Hormone (PTH)
o	Interrelates with Vitamin D

Vitamin D

(Calcitonin)

Question 6

where is PTH released from

Answer 6

parathyroid glands and some in the thymus too

Question 7

what does PTH do as a response to decreased circulating calcium?

Answer 7

Calcium sensing receptor responds increasing PTH synthesis and release from parathyroid gland Chief Cells
PTH acts in 3 ways-

Promotes Ca Reabsorption via kidney

Stimulates Osteoclast Resorption of bone releasing Ca

Drives 1,25 (OH)2 D (Active) vitamin D( production in Kidney which results in increased Ca Absorption via the gut

Calcitonin will decrease, removing the inhibitory effect on osteoclasts allowing PTH stimulation to result.

negative feedback loop to turn off PTH

Question 8

What is a common calcium sensing receptor defect?

Answer 8

Genetic defects can occur where the calcium sensing receptor “resets” the prevailing circulating ionised (adjusted) calcium.

The commonest and most important of these is where the circulating calcium is elevated in the condition Familial Benign Hypercalcaemic Hypocalciuria (FBHH)

Calcium in blood is higher= calcium in urine is lower

WILL BE IN QUESTIONS IN THE FUTURE!

Have to exclude this benign condition- no need for surgery

Question 9

what is RANKL?

Answer 9

• Receptor Activator for Nuclear Kappa Beta
• Tumour Necrosis Family
• Decoy Receptor Osteoprotegrin
• Regulates Skeletal Remodeling and
• Immune Function
• MCSF + RANKL = Osteoclastogenesis

RANKL- major stimulator of osteoclast production

Involved in skeletal turnover and calcium release from the bone

Question 10

what is the role of RANKL and OPG during bone resorption?

Answer 10

PTH acts on osteoblasts–> causes them to retract

Osteoblast produces RANKL–>RANKL binds to RANK (Receptor) on osteoclast–> bone resorption

Balance between RANKL and OPG determines how active the osteoclast is

• PTH stimulates osteoblast to produce more RANKL
• PTH regulates osteoclast formation and calcium release from bone through this

Question 11

what is the main producer of OPG and how does OPG counteract bone resorption

Answer 11

estrogen

• E2 causes the production of OPG–> OPG binds to RANKL–> RANK can’t bind to RANKL–> osteoclast reduces
• E2 is a major regulator of OPG
• Lack of estrogen: excess of reabsorption over formation

Question 12

what is the level that defines hypercalcaemia and hypocalcaemia

Answer 12

Hypercalcaemia ACa>2.6 mmol/L

Hypocalcaemia ACa<2.2 mmol/L

Question 13

what are the signs and symptoms of hypercalcaemia

Answer 13

Nausea 
mental disturbances
peptic ulcers
depression
renal stones
renal failure
polyuria
constipation
soft tissue calcification

“bones, moans, Stones, abdominal groans”

Painful Bones – Painful bone condition (Classically osteitis fibrosa cystica)
Renal Stones – Kidney Stones (Can ultimately lead to renal failure)
Abdominal Groans -GI symptoms: Nausea, Vomiting, Constipation, Indigestion
Psychiatric Moans – Effects on nervous system: lethargy, fatigue, memory loss, psychosis, depression

Question 14

what are the causes of hypercalcaemia?

Answer 14

Hyperparathyroidism (1°HPT):

• BENIGN
• Elevated PTH (> 3pmol/L)

Hypercalcaemia of Malignancy (HCM, TIH):

• Associated with malignancy- tumour induced hypercalcaemia
• Any question will get so far will be about HPT, HCM or TIH (distinguishing between these two)
• MALIGNANT

IATROGENIC (Ca + vitamin D)–>
A lot more calcium and vitamin D being prescribed to patients e.g. those that have osteoporosis

Toxicosis, Sarcoid, GH excess, Vitamin A Excess, Li, Addisons

Idiopathic Infantile Hypercalcaemia

Question 15

how is hypercalcaemia initially investigated?

Answer 15

LOOK AT PAGE 7

• MALIGNANCY is the number 1 cause of PTH being low and calcium being high (i.e. a non-parathyroid cause)
• KNOW THIS WELL
• Focus on primary hyperparathyroidism or malignancy
• Myeloma is also common

Question 16

how is primary hyperparathyroidism?

Answer 16

Surgery

• Irrespective of age surgery is the only definitive treatment for 1°HPT.
• Surgery should be considered in all symptomatic patients or if complications have been documented
• Use a SPECT to localise the gland

Question 17

Lung cancer, breast cancer and haematological malignancies are the most common causes of hypercalcaemia

Might be a possible Q!

Answer 17

then:

head + neck
renal
prostate 
others 
unknown primary

Question 18

what are the recent changes in surgery for primary HPT?

Answer 18

Minimally Invasive Surgery
Local Anaesthesia
Intra-operative PTH Measurement
Localisation techniques

Radiology - Sestamibi, MRI, US, CT, Biochemical – Selective Venous Sampling

Question 19

what are the causes of HCM?

Answer 19

Many Tumours produce a factor that acts like PTH but is slightly different in structure to PTH:
Parathyroid Hormone Related Protein (PTHrP)

PTHrp Circulates in the blood–> stimulates RANKL production

More potent than PTH

Results in far worse hypercalcaemia than PTH

Question 20

what are the signs and symptoms of hypocalcaemia?

Answer 20

Paraesthesia (Numbness, Tingling)
Muscle Spasm
Tetany
Seizures/Fits
Coma
Chvostek’s Sign
Trousseau’s Sign

Cardiac:

• Arrythmias
• ECG
• Hypotension
• Failure

Cataracts

Extraskeletal Calcification (Basal Ganglia)

Question 21

what are the causes of hypocalcaemia?

Answer 21

Renal Failure
Hypoparathyroidism (likely to ask)
Vitamin D Deficiency/Malabsorption (likely to ask)
Osteomalacia and rickets can occur too
Factitious
Pancreatitis/Rhabdomyolysis
Phosphate
Prematurity/Genetic
Adrenal Insufficiency

Question 22

what are the causes of hypoparathyroidism?

Answer 22

Post-operative (Parathyroid,Thyroid, Cancer)
Idiopathic
Auto-immmune
Functional (Mg Deficiency, Ca Sensor)
Di George Syndrome (Tissue aplasia/dysgenesis)
Familial
Infiltrative (Fe, Cu, Al, Cancer, Amyloid, Sarcoid)
Resistance