S3: Disorders of Calcium and Phosphate Metabolism

Question 1

What are the causes of hypercalcaemia?

Answer 1

When looking at the causes of hypercalcaemia, we can divide the causes by the PTH level. There are causes associated with high PTH and there are causes associated with low PTH.
High PTH:
- Hyperparathyroidism
- Cancer
Low PTH:
- Cancer
- Hypervitaminosis D (exogenous and granulomatous disease)
- Increased bone turnover (acromegaly and thyrotoxicosis by causing parathyroids to stop producing PTH)

Question 2

Describe synthesis of vitamin D

Answer 2

7-dehydrocholesterol in the skin, under the influence of sunlight is converted to cholecalciferol. This travels to the liver where it is converted into 25 OH vitamin D (said 25 hydroxy vitamin D). This then passes through the kidney and is converted to its active form, 1,25 Di OH Vitamin D.
This final bit is the regulatory step in vitamin D production!

Question 3

Actions of PTH affecting Ca2+

Answer 3

• PTH increase vitamin D, which acts on the gut increasing Ca2+ absorption.
• PTH acts on bone stimulating osteoblasts to express RANK ligand to cause osteoclasts to reabsorb bone and increase plasma calcium.
• PTH increases Ca2+ reabsorption in the kidneys and decreases phosphate reabsorption (i.e. increases phosphate excretion) which means there is more free Ca2+ in the plasma.

Question 4

How does hypercalcaemia affect vitamin D, PTH and calcitonin?

Answer 4

• There is inhibition of the 1-alpha hydroxylation of vitamin D (the regulatory step in the kidney) and the production of PTH to compensate for the high calcium.
• There is also the production of calcitonin. This hormone is made from C cells of the thyroid medulla. Its action on bone is to inhibit the action of PTH (switches off the osteoblasts) so it reduces calcium levels. However, it isn’t that effective.

Question 5

What are three classifications of hyperparathyroidism?

Answer 5

Primary, Secondary and Tertiary.

Question 6

What is primary hyperparathyroidism?

Answer 6

In primary hyperparathyroidism, serum calcium is raised and there is a tumour in the parathyroid gland which produces too much PTH so PTH is also high.

Question 7

What is secondary hyperparathyroidism?

Answer 7

In secondary parathyroidism, the serum calcium is actually low. This is classically seen in renal disease (because vitamin D isn’t activated) or liver disease (both causing vitamin D deficiency) or Ca2+ malabsorption. Here PTH level is high but this is a normal physiological response to low calcium.
It can also be resistance to PTH.

Question 8

What is tertiary hyperparathyroidism?

Answer 8

Tertiary always follows secondary, the patient must have had a reason for having low Ca2+ in the past, e.g. they had renal disease but have now had a kidney transplant, or were vitamin D deficient but now taking supplements.
In this situation, the PTH is high and the Ca2+ starts to rise too high, this is because the gland has become autonomous and can’t turn itself off, even though it isn’t required because Ca2+ levels have normalised.

Question 9

What are some hormonal causes of hypercalcaemia of malignancy?

Answer 9

Some cancers cause hypercalcaemia and hyperparathyroidism by releasing hormones.

• PTH is generally only produced by small cell lung cancers.
• PTH-RP (embryonic PTH) can be produced by lung cancers, lymphoma and multiple myeloma.
• Osteoclast activating factor can be produced by lymphoma and multiple myeloma which directly stimulates the osteoclasts which is why bone scanning does not work for lymphoma. The other cause are metastatic solid tumours that tend to go to bone and cause hypercalcaemia are: lung, breast, kidney, prostate.

Question 10

Describe hormonal control of bone remodelling in malignancy

Answer 10

Bone resorption signalling is heavily based on immune regulators (inflammatory cytokines) from the osteoblast to activate the osteoclast. When a cancer cell comes along and starts invading the bone, it sets up an inflammatory response which produces these cytokines and immune mediators and activates the osteoclasts to resorb bone and calcium is released.

Question 11

What would we do if we suspect a person has cancer and they have high PTH and high Ca2+ as well as known cancer history?

Answer 11

Bone scan

Question 12

How does a bone scan work?

Answer 12

The bone scan works by picking up osteoblastic activity, so when the cancers invade the bone there is increased bone turnover as osteoblast activity increases and we can see this.

Question 13

Why doesn’t a bone scan work for myeloma?

Answer 13

The one situation where the bone scan doesn’t help is myeloma because it bypasses the osteoblasts and stimulates osteoclasts directly. So the bone scan will not pick up abnormal osteoblastic activity.
Multiple myeloma produces osteoclast activating factor directly so it bypasses the step.

Question 14

List diagnostic factors to identify myeloma

Answer 14

• X rays for lesions
  Others (2/3 needed:
• Antibody fragment in urine (bent-jones protein).
• Plasma has a single monochromal antibody.
• X ray.

Question 15

What are granulomatous diseases and why can they cause hypercalcaemia?

Answer 15

Granulomatous diseases are characterised by immune responses. Granulomas contain macrophages and the one other tissue that isn’t the kidney that contains 1-alpha hydroxylase (enzyme to activate vitamin D) is macrophages. So granulomatous diseases can cause hypercalcaemia.

Question 16

Give examples of granulomatous diseases

Answer 16

• Sarcodiosis
• Tuberculosis
• Berylliosis (heavy metal problem)
• Coccidioidomycosis (fungal)
  Histoplasmosis

Question 17

What is the function of granuloma in our bodies?

Answer 17

The function of the granuloma is to deal with big parasites/fungal infection/bacterial infection/heavy metal poisoning, so if you have a thing too big in your body that can’t be consumed by macrophage. What the granulomas do is they surround the invader and isolate it from the rest of the body.

Question 18

List other miscellanoeous causes of hypercalaemia

Answer 18

• Immobilisation (bone is stimulated when you walk by electrical signal, if you don’t move then the osteoblasts slow down their activity and osteoclasts will remain working normally, so overall you’re breaking bone down faster than filling it in so overall Ca2+ increases).
• Recovery from renal transplant (tertiary hyperparathyroidism)
• Familial hypocalciuric hypercalcaemia (autosomal dominant) is a defect in the calcium receptor on parathyroid cells so there is high PTH and high calcium. There is low calcium in the urine.
• Milk-alkali syndrome.
  Thiazide diuretics (increase the reabsorption of Ca2+ in the proximal convoluted tubule).

Question 19

Describe familial hypercalcaemia

Answer 19

In familial hypocalciuric hypercalcaemia PTH and Ca2+ is raised, but if you look in the urine there is very little Ca2+ getting into the urine. In all other causes of hypercalcaemia we would see a lot of Ca2+ in the urine as the kidneys try kick all of it out.

• This is because in this case, there is a defect in the calcium sensing gene (CaSR gene) which encodes a calcium sensing receptor.
• This means even though calcium in the blood is raised, it doesn’t affect their physiology and this condition is asymptomatic despite having hypercalcaemia and hypocalciuria and high PTH.
• They may also have hypermagnesemia.

Question 20

Signs and symptoms of hypercalcaemia

Answer 20

‘Stones, Bones and Psychic Moans’ - Abdominal pain, renal stones, depression (affects CNS).

• Renal impairment (Ca2+ is excreted in DCT, hypercalcaemia is toxic to DCT so as calcium goes up, it reduces the ability for calcium to be excreted).
• Coma
• Fitting
• Shortening QT interval leading the arrhythmia
• Cloudiness of cornea due to calcium deposition in the eye
• Sub articular erosion of bone on radial side of phalanges
• Calcium causes release of gastrin so increases release of HCl

Question 21

Describe the initial investigations for hypercalcaemia

Answer 21

• Look at the calcium, phosphate, vitamin D, PTH and urinary calcium excretion.
• To look at the causes we would do a chest x ray and measure ACE levels and myeloma screen.

Question 22

Describe further investigations of hypercalcaemia if a patient has high PTH

Answer 22

If high PTH we assume this is going to be someone with primary hyperparathyroidism so we start localizing where the tumour is in order to remove it. We also want to look at the kidneys to see if there are any stones and also do a DEXA scan (measures calcium in bone, as high PTH can cause osteoporosis).

• SestaMIBI scan
• Ultrasound of neck
• USS renal tract
• DEXA

Question 23

Describe further investigations of hypercalcaemia if a patient has low PTH

Answer 23

For decreased PTH:

• Bone scan
• Localisation of primary

Question 24

Why is SestMIBI scanning useful?

Answer 24

The problem with scanning the parathyroids is all the markers both go into the thyroid and parathyroid so we can’t distinguish. However it is retained in parathyroids longer, so we can identify the parathyroids.
This type of scanning is called SestaMIBI scanning.

Question 25

Describe treatment for hypercalcaemia

Answer 25

- When treating hypercalcaemia the most important thing is to rehydrate the patient with saline, this allows the Na+/Ca2+ exchanger to work in the distal convoluted tubule again. If they aren’t peeing enough we give them a loop diuretic like furosemide to flush the calcium out of the body.  - We stop osteoclasts working by giving bisphosphonates. - We can give the hormone calcitonin. - We can give prednisolone, as the osteoclast is an imunno-stimulated cell, giving the steroid will suppress the immune responses/activity.  - A calcium of over 3 can kill you, so if it’s very high we will dialyse the patient. It an also cause arrhythmias.

Question 26

Describe treatment of hyperparathyroidism

Answer 26

- Often we will use surgery, if we can identify the tumour we cut it out and this helps. If the patient doesn’t want surgery or too ill for surgery we keep them under observation. If they have developed osteoporosis we can give bisphosphonates to try maintain existing bone mineralisation.  - If calcium levels get too high, we can give them calcimimetics e.g. cinacalcet. These are drugs that active the calcium sensing receptor, so induce the processes to bring calcium levels down.

Question 27

How does hypocalcaemia affect PTH and vitamin D?

Answer 27

  When there is low calcium, PTH release is stimulated and also increased activation of 1-alpha hydroxylase to activate vitamin D.

Question 28

What are the causes of hypocalcaemia?

Answer 28

``` Low PTH: - Hypoparathyroidism - Pseudo-hypoparathyroidism - Pseudo-psuedo hypoparathyroidism - Activating mutation of Ca2+ receptor. High PTH: - Vitamin D deficiency (renal and liver disease) - Poor dietary Ca2+ - Malabsorption - Chelation (massive blood transfusion_ ```

Question 29

Describe different causes of impaired parathyroid secretion or action

Answer 29

- Primary hypoparathyroidism can be congenital, usually seen in Digeorges syndrome. It can also happen as an autoimmune conditions where antibodies attack the parathyroids and stop them working.  - For secondary hypoparathyroidism, it is usually to do with things in the neck. After surgery or trauma, damaging the parathyroids. Sometimes radioiodine may damage the parathyroids. - Can also have neonatal hypoparathyrodism if child is born too early before parathyroids develop. - Hypomagnesemia or hypermagnesemia can result in hypoparathyroidism as magnesium is a very important co-factor in PTH production.

Question 30

Causes of vitamin D deficiency

Answer 30

- Liver/kidney disease (synthesis) - Resistance to hormone (receptor) - Malabsorption - Dietary insufficiency - Poor exposure to sunlight (sun block, obesity, latitude, skin pigmentation by melanocytes)

Question 31

Describe calcium chelation or precipitation

Answer 31

Calcium is essential as a co-factor for many enzymes of the clotting cascade. - Citrate in blood stops calcium. - Ethylene glycol which is present in anti-freeze chelates calcium - Pancreatitis can cause chelation as well, this ends up happening by making a bar of soap in pancreas - Rhabdomyolysis, if you have a large amount of muscle damage, myoglobin gets out into the circulation and binds Ca2+, causing hypocalcaemia - Chemotherapy can also cause hypocalcaemia

Question 32

Symptoms of hypocalcaemia

Answer 32

- Paresthesias (pins and needles, esp. in hand) - Laryngospasm - Bronchospasm - Tetany - Seizures

Question 33

What is chvosteks sign?

Answer 33

Chvosteks sign – tap on facial nerve in front of ear and a patient with hypocalcaemia will twitch.

Question 34

What is trousseau's sign?

Answer 34

Blood pressure cuff put around arm and inflated to a pressure greater than systolic BP and held for 3min (blood goes acidotic), patients hand will go into a tetanic spasm if they have hypocalcaemia.

Question 35

SIgns of hypocalcaemia on ECG

Answer 35

Prolonged Q-T interval on ECG

Question 36

What is extra that we do in the investigations for hypocalcaemia (compared to hypercalcaemia?

Answer 36

The investigations for hypocalcaemia include the tests done for hypercalcaemia. However we also screen for malabsorption, this includes looking at : - B12 - Folate - Coeliac screen

Question 37

Signs and symptoms of vitamin D deficiency

Answer 37

- Aches and pains in bones. - Proximal myopathy. - Mild hypocalcaemia - secondary hyperparathyroidism. - Hypophosphataemia and hyperchloraemic acidosis. If you have vitamin D deficiency in childhood you have severe bone deformities, this is rickets. It can lead to bowlegs (varus) and knock-knees (valgus). This occurs in children and their bones are softer so can deform more.

Question 38

Treatment of hypocalcaemia

Answer 38

To treat hypocalcaemia we look for the underlying cause and try treat that, we could do that by discontinuing offending drugs and correcting other electrolyte disorders. We give calcium and give vitamin D supplementation. If the patient is unconscious or fitting we can administer the calcium IV.

Question 39

Treatment for severe hypocalcaemia

Answer 39

IV 10ml 10% calcium gluconate diluted in 200ml N saline over 10 minutes

Question 40

Treatment for vitamin D deficiency

Answer 40

For treatment of Vit D deficiency, we give somewhere between 800-1000 units daily of calcium and vitamin D tablets. In someone who has severe deficiency or can’t take that we give Vit D injection of 300,000 units intramuscularly every 6 months.  - If someone has kidney disease we can’t give Vit D as the Vit D won’t become active. In this case we give alpha calcidol.

Question 41

What is pseudo- hypoparathyroidism?

Answer 41

Here you can produce PTH but the PTH receptor doesn’t work. If you look at the biochemistry we see: - PTH levels are high - Ca2+ is low - PO4 is high - Active Vit D is low It is an autosomal recessive disorder that displays imprinting.

Question 42

Symptoms of hypoparathyroidism

Answer 42

``` There is a very classic body habitus (physique/build) that occurs with these children/adults. They have a short stature, are obese and have a round face. They also have reduced IQ, brachydactyly (shortening of fingers and toes due to short bones). Ectopic calcification (pathological deposition of calcium). - Such individuals also tend to have issues with the other pituitary hormones like LH/FSH etc. ```

Question 43

How do we classify pseudohypoparathyroidism?

Answer 43

Pseudohypoparathyroidism is classified into four types and the classification depends on whether they have cAMP in the urine. The test was to infuse patient with PTH and then look at the action of the PTH receptor in the kidney we would measure cAMP in the urine.

Question 44

Describe the types of pseudohypoparathyroidism

Answer 44

In type 1 disease we see there is a reduction in cAMP, which shows it doesn’t work. Type a patients had the clinical phenotype and reduced cAMP. Type b patients didn’t have the clinical phenotype but reduced cAMP. Type c is where the response to PTH seems to be normal, so not problem with receptor but a downstream problem is occurring. Type 2 cAMP is normal, urinary phosphate is normal, clinical phenotype is normal but they have the biochemistry with high PTH and high serum phosphate (pseudo pseudo).