Lecture 9 and 10: Calcium Metabolism I and II

Question 1

ECF ca2+ levels are _____

Answer 1

Tightly controlled, which suggests that it’s an important physiolgoical phenomenon

Question 2

What form of Ca2+ regulates PTH?

Answer 2

Ionised/free form

In the ECF, ECF, about 50% of calcium is in the free/ionised/bioactive form

Question 3

What organs are closely related to Ca2+ and phosphate?

Answer 3

Bone acts as a major reservoir for calcium and phosphate

The kidney regulates the excretion of calcium. It is an important contributor for regulation of rapid response and serum calcium

Question 4

How does the PTH stimulate release of Ca2+?

Answer 4

1. Stimulates osteoclastic bone resorption
2. Stimulates renal tubular reabsorption of Ca++
3. Stimulates _renal 1-hydroxylation of 25(OH)D (_long loop effect)- form bioactive form of vitamin D. This stimulate intestine Ca2 and K absorption

So directly or indirectly Restores serum Ca++ by acting on all effector organs

Question 5

_____ is the main regulator of serum calcium

Answer 5

Parathyroid hormone is the main defender of serum calcium

So directly or indirectly Restores serum Ca++ by acting on all effector organs

Question 6

Describe the effect of plasma Ca2+ on PTH

Answer 6

1) Decrease in plasma Ca2+
2) Calcium sensing receptor in the Parathyroids (chief cells) increase production of Parathyroid
3a) Increases Bone reabsorption of Ca2+ and Phosphate
3b) Increases renal tubular reabsorption of Ca2+. This decreases reabsorption of phosphate
3c) Stimulates renal 1-hydroxylation of 25(OH)D (long loop effect)- form bioactive form of vitamin D. This s_timulate intestine Ca2 and K absorption_

Question 7

What are parathyroid hormones?

Answer 7

Hormone secreted by the parathyroid glands that is important in bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time.

PTH is secreted in response to low blood serum calcium(Ca2+) levels.

Question 8

What is Parathyroid hormone release regulated by? (3)

Answer 8

1) Release is most importantly regulated by Serum ionized calcium level. (negative regulator)
2) Also regulated in some extent by serum phosphate, so that high levels of serum phosphate as a pharmacologic agent can stimulate PTH production (not major)
3) Also 1,25 dihydroxyvitamin D (negative regulator)

Question 9

Describe the composition of ECF calcium

Answer 9

45-50% ionized, bioactive

5-10% complexed with anions eg HCO3

45-50% protein-bound, albumin and globulins

Question 10

What happens if the Ca2+ levels are high

Answer 10

Schematic to reinforce the idea that there are specific cell membrane-bound receptor for ionised-calcium at the membrane of PTH chief cells.

In such a way that if the level of cA2+ is high, the receptor conformation changes and signals to the cells to switch off parathyroid hormone production and secretion.

Subsequent reduction in PTH

If the receptor function is disordered, (constantly switched off or switch off), will result in perdubation of Ca2+/PTH axis.

Question 11

Describe the DIRECT renal-handling of Ca2+

Answer 11

Another place (independent of PTH). CaR is expressed is the renal tubule

Basolateral membrane of renal tubular cells

ECF Ca2+ levels can module the reabsorption of Ca2+ from the urine back into the body

The receptor will signal to reduce further reabsorption of CA2+ into the ECF

Question 12

Describe Vit D and Ca2+

Answer 12

Vit D is technically a hormone (we produce it due to UVB exposure)

Through a series of steps, you produce calidiol (25OD H) then hydroxylation to 1,25(OH2)D (1,25 vitamin D)

Vitamin D then i_ncreases absorption of Ca2+ and Pi (fractionally)_

Question 13

Is Calcitonin is a physiological regulator of serum calcium?

Answer 13

NO

Question 14

Is the Parathyroid hormone-related peptide a regulator of serum calcium?

Answer 14

No, it is NOT a physiological regulator of serum calcium

It is an important paracrine regulator of breast, skin and bone development

Question 15

What is PTHrP?

Answer 15

Parathyroid hormone-related peptide (PTHrP)

• Important paracrine regulator of breast, skin and bone development
• NOT a physiological regulator of serum calcium
  
  • PTH is usually suppressed due to elevated serum calcium concentrations.
  • A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include:
    
    • -Impaired renal function due to a tumor or its treatment
    • -Osteolytic activity within bony metastases
    • -Release of calcemic cytokines by non-osteolytic bony metastases
    • -Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases)
    • -Other as yet unknown factors
• Produced in excess by some cancers, esp epithelial cell tumours → humoral hypercalcemia of malignancy (HHM)
  
  • Most c_ommon cause of cancer-associated hypercalcemia_
  • Acts v similarly to PTH, signals via PTHR1
  • Hypercalcemia can be severe and life-threatening

Question 16

What is produced in excess by some cancers, esp epithelial cell tumours?

Answer 16

Parathyroid hormone-related peptide (PTHrP)

Question 17

What are the causes of hypercalcemia?

Answer 17

PTH-dependent, ↑sCa++, ↑/N PTH (due to excess of PTH)

• Primary hyperparathyroidism
• Bengin Familial Hypercalcemia: FHH/inactivating CaSR mutations (tricked into thinking Ca2+ concentration is lower than it is)
  
  • High Ca2+, High PTH, Low Ca2+ excreted in urine

PTH-independent, ↑sCa++, ↓ PTH

• a_. Cancer_
  
  • • almost always releated to increased PTHrP (parathyroid hormone-related peptide)
  • • increased bone reabsorption: extensive lytic bone disease (myeloma)
  • • 1,25 dihydroxyvitamin D dependent hypercalcemia (v rare)
• b. Vitamin D-dependent
  
  • • Sarcoidosis
  • • Vitamin D intoxication

Question 18

If someone comes in with hypercalcemia, what should you do?

Answer 18

Do a PTH test to determine whether the cause is PTH-dependent or PTH-independent

Raised PTH= PTH-dependent diseases

Decreased PTH = PTH-independent diseases

Question 19

How does PThRP cause hypercalcemia?

Answer 19

NOT a physiological regulator of serum calcium

Hypercalcemia of malignancy is typically not due to excess parathyroid hormone (PTH). In these disorders, PTH is usually suppressed due to elevated serum calcium concentrations. A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include:

• Impaired renal function due to a tumor or its treatment
• Osteolytic activity within bony metastases
• Release of calcemic cytokines by non-osteolytic bony metastases
• Ectopic 1-alpha hydroxylase activity in tumor tissues
• Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases)
• Other as yet unknown factors

Question 20

What are the causes of hypocalcemia?

Answer 20

1) Hypoparathyroidsim

• due to postsurgical, post neck irradiation
• autoimmune disease
• genetic, including activating CaSR mutations (even though serum calcium levels are low, it mimics )
• severe hypomagnesaemia

2) Parathyroid hormone resistance

-High parathyroid, but the receptors are resistant.

3) Abnormaltieis of vitamin D metabolism

• Vitamin D deficiency (deficient 1a-hydroxylation)
• Renal failure (vit D resistance)

Question 21

Describe 3 things that regulate the level of phosphate in our body

Answer 21

• lots of overlap with Ca2+ metabolism
  1) Vitamin D plays an important role in absorption of Potassium from diet
  2) PTH modulates fluctuation of P from within bone to ECF. Also at a kidney level, stimualtes the excretion of P

**3) Phosphatonins (group of proteins) which importantly regulate the renal excretion- to stimulate phosphoturia (serum phosphate levels fall)

Question 22

What organs are related to phophate metabolism

Answer 22

1) Intestine (absorbed)
2) Kidney (excretion)
3) Bone (depositied in bone)

Question 23

Describe the important contributers to determine the level of phosphate in our plasma

Answer 23

1) Diet (some level)
2) Fluxes between intracellular and extracellular fluid (more important)
3) Kidney (source of tissue responsible for hyperphosphatemia)

Question 24

What are the causes of hyperphosphatemia?

Answer 24

1) Increased input
- IV phosphate,
- cell death
2) Decreased excretion-
- renal failure**
- PTH deficiency
- PTH resistance

Question 25

What are some causes of hypophosphatemia?

Answer 25

1) Inadequate GI absorption (e.g. vitamin D deficiency) 2) most common: Intracellular shift - respiratory alkalosis, usually self-limiting - prolongued intense exercise - refeeding of malnourished patients 3) Renal loss - ↑PTH - ↑phosphatonins - alcoholism

Question 26

Where are the phosphatonins from and what does it cause?

Answer 26

1) FGF23 is Derived from bone 2) Inhibitor of 1a-hydroxylase enzme, which leads to the reduction of production of 1,25(OH2)D 2) Decrease NaPi 3) Both decrease phosphate reabsorption 4) Hypophosphatemia

Question 27

What is the NPT2 transporter at the renal regualted by?

Answer 27

1) PTH 2) \*\*\* FGF-23 (phosphatonins)

Question 28

What is ONE _major_ player in phosphate-losing conditions Explain how it works

Answer 28

1) _FGF-23 (phospahtonin)_ normally comes out of bone (made from oestoclasts), _inhibts 1a-OHase_ which leads to _reduction in vitD production_ and therefore intestinal _Ca and Pi absorptio_n = Phosphate Loss 2) FGF-23 also inhibits phosphate transporters, which increases renal phosphate exrection, which leads to hypophosphatemia.

Question 29

What is FGF23 regulated by?

Answer 29

Phex- regulated by osteoblast. Phex inactivates FGF23

Question 30

What is FGF23 and what is it produced by?

Answer 30

Type of Phosphatonin Produced by osteocytes

Question 31

How might high levels of FGF23 be achieved? What does this result in?

Answer 31

1) Tumours (derived from mesenchymal cell origin) 2) Abnormal PHEX

Question 32

Diagnose * 60 year old man with 2 year history of tiredness * One previous episode of haematuria * Investigations * I_ncreased plasma calcium_ * Normal Plasma albumin * _Increased ionized calcium_ * Lowish-but normal- Plasma phosphate * _Decreased TmP/GFR_ * _Increased 24 hour urine calcium_ * Normal ALP * _Increased PTH level_

Answer 32

**_Hypercalcemia_** Low GFR= _low ability to reabsorb calcium_ **_Primary hyperparathyoidism (_**many have no symptoms and are common in older patients) (Increased PTH levels) Treatment: -Neck expoloration, and the inferior parathyroid adenoma was removed.

Question 33

What are the 4 main causes of hypercalcaemia?

Answer 33

1) Primary hyperparathyoidism 2) Cancer-associated 3) Vitamin D toxicity (endogenous, exogenous) 4) Familial Benign Hypercalcaemia (FHH/FBH) 95% fall into one of these categories

Question 34

Diagnose * 68 year old man * L sided chest pain * Cigarette smoker * History * Gout * Hypertension * Chronic bronchitis * Xray * Pleural mass- squamous cell cancer * 12 months later * Pyloric ulceration * Weight loss * Polyuria * _Increased calcium levels_ * _Decreased albumin_ * _Decreased Phosphate levels_ * _Decreased creatinine_ * _Low PTH_

Answer 34

**-Hypercalcemia** **-low PTH levels suggest this is PTH-independent Hypercalcemia** caused by -Cancer (solid tumours secreting PTHrP) (or multiple skeletal metastases or bone marrow malignancy) **Parathyroid Hormone-related pepitide**

Question 35

What dos PTHrP do?

Answer 35

-bone _1) Stimulate calcium release in bone_ -kidney _2) Raise plasma calcium_ _3) Lower plasma phosphate_

Question 36

Diagnose * A 74 year old woman presents with a 3/12 history of bone pain and decreasing mobility * She gives two year history of diarrhoea and weight loss * Diagnosed with anaemia secondary to folate and iron deficiency * Physical examination * V. thin * Muscle wasting * Bone pain\* * Biochemistry * _Low plasma calcium_ * _Low plasma phosphate_ * _High ALP_ * _Low GGT_ * _Low Creatinine_ * _Increased PTH_ * _Serum 25 OH vit D is undectable_ * _Increased Faecal fat assessment_

Answer 36

_Hypocalcemia_ This combination of biochemistry suggests- _osteomalacia_ (softening of bone) _Malabsorbing_ (faecal fat assessment) **_Diagnonsis: Coeliac disease_**

Question 37

What is osteomalacia?

Answer 37

Failure of bone to mineralise: Softening of the bones, typically through a deficiency of vitamin D or calcium. Characterised by lots of unmineralized osteoid (bone): It is a histological diagnosis Osteomalacia in childhood causes rickets

Question 38

What are the causes of vit D deficiency?

Answer 38

1) Inadequate exposure to sunlight (most common) 2) Enzyme induction 3) Impaired 1ahydorxlase (due to renal disfunction) 4) Poor diet/GI disease

Question 39

Diagnose * 30 year old man, presented with grand mal seizures * _Decreased serum Ca2+_ * _Slightly increased PO4_ * _Increased PTH_ * Normal serum creatinine * Normal 25(OH) vit D * Physical * Short stature * Short 4th metacarpal and metatarsal * fT4 11pmlol/L, TSH 7mlIU/ml

Answer 39

Hypocalcaemia PTH-dependent **Diagnosis: Pseudohypoparathyroidsim (PTH resistance)**

Question 40

What is this indicative of? Short 4th and 5th metacarpals

Answer 40

Pseudohypoparathyroidsim (PTH resistance)

Question 41

What is a common feature in Pseudohypoparathyroidsim (PTH resistance)?

Answer 41

Short 4th and 5th metacarpals

Question 42

What often causes Pseudohypoparathyroidsim (PTH resistance)?

Answer 42

Mutations in Gs-a

Question 43

Diagnose * Flu-like ilness + anorexia * Vomiting and nusea * Abdo pain-central costant * Severe muscle cramps * PMHx is unremarkable * Afrebrile * _Carpopedal spasm_ (often wiwth hypocalcemia) * _Hyperactive tendon reflexes_ * _Upper resp tract infection_ * Investigations * _Decreased calcium_ * _Decreased phosphate_ * _Undetectable PTH_ * Normal Albumin * No history of surgery * Normal magnesium level

Answer 43

**Hypocalcaemia** **(Hypoparathyroidism ?)** (no surgery, no hypomagnesaemia, no iron overload) = **Idiopathic/Genetic** (had family history)- _autosomal dominant hypercalciuric hypocalcaemia._

Question 44

What are the 2 types of Calcium Receptor mutations (found in bones and renal tubules)

Answer 44

Activating (green) mutations (**Autosomal Dominant hypocalcemia**) Inactivating (red) mutations (**Benign familial hypocalcemia**) - receptor is inactivated/less activated - lower level of calcium is present, but increased PTH is released - Low urinary Ca2+ secretion occurs Optimal management for both: do nothing if asymptoatic If recurrent symptoms: Small doses of vit D

Question 45

What is the management plan for Autosomal dominant hypocalcemia?

Answer 45

Optimal management for both: Do nothing if asymptoatic (if they're treated with vit D, they can get hypercalciuria with nephrocalcinosis) If recurrent symptoms: Small doses of vit D

Question 46

Describe ADHH features

Answer 46

autosomal dominant hypocalcaemia with hypercalciuria 1) Autosomal dominant inheritance 2) Hypocalcemia- usually asymptomatic 3) Mild hypomagnesaemia (sometimes) 4) Detectable/'high' levels of PTH 5) Higher uirnary calcium excretion

Question 47

When would you suspect that someone may have FHH?

Answer 47

Familial hypocalciuric hypercalcemia PTH is in the 'normal range' despite high Ca2+ Family history of hypercalcemia

Question 48

How do you diagnose FHH?

Answer 48

Familial hypocalciuric hypercalcemia Screening immediate relatives (Autosomal Dominant inheritance) Ratio of fasting urine calcium to creatinine clearance (Cit D replete, no thaizides) CaR genotyping (currently in research)

Question 49

Diagnose * 79 year old English tourist * In ED 3 days after a minor fall * Twisted her R leg, with increasing R hip pain and difficulty mobilising * Trochinteric fracture * 4kg weight loss in last year * Blood Tests * _Low serum phosphate_ * _Increased ALP_ * Other liver ezymes were normal (suggest has osteomalacia) * _PTH was high_ * Normal 25OHD * _substatial increase in Serum FGF23_

Answer 49

Hypophosphatemia Tumour - cause increase FGF23

Question 50

If someone has increased ALP but other liver enzymes are normal, what is this indicative of?

Answer 50

osteomalacia