Calcium, magnesium and phosphate

Question 1

Answer 1

Question 2

What are the serum concentration for calcium, phosphate and magnesium?

What organ system plays importal role in their metabolism?

Which organ pllays a major regulator of all 3 metabolism?

What receptors are importat for Ca/Mg regulation?

What hormones are important for regulation factor?

Answer 2

Serum concentration

 Calcium (Ca2+); 2.2-2.6 mmol/L (total)  Phosphate (HPO4 2- ); 0.8 – 1.5 mmol/L  Magnesium (Mg2+); 0.70 – 1.00 mmol/L

Organ systems that play an import role in their metabolism

 Kidney  Skeleton  GI tract  Parathyroid gland

Regulatory factors that play an import role in their metabolism

 Parathyroid hormone (PTH)  Vitamin D (1,25 dihydroxycholecalciferol)  FGF-23  Parathyroid hormone related protein (PTHrP)  Calcitonin (CT)

Kidney is the major regulator of the three mineral homeostasis - can decrease excretion to 0.5% filtered load and increase to up to 80% depending on magnesium levels

The Ca/Mg sensing receptor (CaSR), a member of the G coupled receptor family is an important regulator of calcium and magnesium homeostasis

Question 3

How is calcium, phosphorous and magnesium absorbed in skeleteral muscle for calcium and magnesium and phosphates in enterocytes?

Question 4

How is calcium and magnesium absorbed in the thick ascending limb of henle?

How is calcium and magnesium absorped in the distal convoluted tubule?

How is phosphate absorbed in the renal proximal tubule?

Where is most of the calcium, phosphorous and magnesium absorbed?

Answer 4

Calcium -> PCT absorbed

Phosphorous -> PCT absorbed

Magnesium - loop of henle

Question 5

Feedback mechanism of calcium is regulated by what type of calcium?

What does calcium levels depend on?

How to calculate corrected calcium?

When the pH decreases what happens to the calcium levels?

What happens to the calcium levels when the pH increases?

Answer 5

Feedback mechanisms are regulated by the FREE (ionised) fraction- physiologically important/

 [Calcium] depends on [protein]- “correction” Assumption of ‘Normality’ = 40 g/L Albumin For each g albumin ‘binds’ 0.02 mmol/L Calcium

For every g albumin <40 g/L multiply by 0.02 and add result to measured calcium. e.g. Calcium 2.10 mmol/L; Albumin 30 g/L 10 x 0.02 = 0.2; 0.2 + 2.10 = 2.30 mmol/L

 Decreased pH increases Ca++  Increased pH decreases Ca++

(Acidosis, on the other hand, decreases protein binding, resulting in increased free calcium levels.)

Question 6

What are common causes of hypocalcemia

What are the clinical problems that occur due to hypocalcemia?

Answer 6

 Chronic and acute renal failure

 Vitamin D deficiency

 Hypoparathyroidism (Usually surgical)

 Acute pancreatitis

 Magnesium deficiency

 Artefact -  ‘Wrong’ collection tube

Question 7

How is calcium controlled?

What is the function of PTH?

Whhat does PTH activate?

What does FGF23 do to PO4 reabsorption

What does activated vitamin D to do the bone?

What does calcitonin do to calcium?

Answer 7

Question 8

Describe the Vitamin D pathway - What does it activate and which organs?

Answer 8

Question 9

What do these people have in common?

What is it called in children and what it called in adults?

Why does it occur?

Answer 9

Deficiency of active vitamin D

Rickets when affects growing skeleton - osteomalacia when affects adult skeleton. Bone unduly soft in both situations.

Lack of mineralization of collagen component of bone (osteoid). Failure to absorb sufficient calcium from the GI tract.

Dietary/lack of sunlight, rarely inherited (vitamin D receptor, 1alphahydroxylase defects, X-linked hypophosphataemic rickets).

Rickets - osteoid at growth plate is weak (bow legs) growth plate expands to compensate (swollen joints)

Osteomalacia - bone pain, pseudofractures

Treatment = vitamin D replacement (dietary or through sunlight)

Question 10

What is the difference between hypothyroidism and pseudophypothyroidism?

Are the disorders usually autosomal dominant, recessive or sporadic?

Answer 10

Question 11

What level of calcium is hypocalcemia in?

What are the biochemical test you would order for someone with hypocalcemia first line and second line?

What causes would a high PTH and low PO4 indicate?

What cause would a high PTH and a hight PO4 indicate?

What does a low PTH and a high PO4 indicate?

What treatment is offered for hypocalcemia in an acutely ill and mildly symptomatic patient?

How would you treat underlying issues such as hypoparathyroidism and vitamin D

Answer 11

state of the patient symptoms - acutely ill with neuro-muscular symptoms- IV calcium - mildly symptomatic/asymptomatic- oral calcium

 Level and duration of calcium level - slightly low/ long standing duration

Underlying cause of hypocalcaemia

• if VD deficient replace VD
• if Hypoparathyroidism – add 1,25 D3 products

Question 12

A 45 year-old woman attended the outpatient clinic with a history of progressive muscle cramps, pins and needles in her hand. As she spoke very little English, no further history was available. In the clinic she was noted having a carpopedal spasm. Shad had large anterior surgical neck scar and a positive Trousseau’s sign. The following biochemical investigations were performed:

Serum

Creatinine 86 mmol/L 59 – 104

Sodium 138 mmol/L 133 – 146

Potassium 4.1 mmol/L 3.5 – 5.3

Calcium 1.59 mmol/L 2.2 – 2.6

Albumin 29 g/L 35 – 50

Phosphate 2.40 mmol/L 0.8 – 1.5

Which (if any) of the above findings may explain her presenting symptoms and signs?

Is her level of calcium proportionate to her symptoms? Why?

What is the probable diagnosis and how would you confirm it?

How would you manage this patient?

Answer 12

Symptoms - cramps pins and needle and trousseau’s sign - positive means that calcium is low

proportionate calcium loss with albumin - she is not in a coma state so it was not a quick loss of calcium

the diagnosis - phophate high and calcium low so there is hyperparathyroidism

management - you need to do surgery and active form of vitamin D (alphacalcidon) because kidneys arent able to convert the vit D

Question 13

What causes increase in calcium levels physiologically?

What are causes of hypercalcemia?

Answer 13

 Primary Hyperparathyroidism (Increased PTH)

 Malignancy (Low PTH)

RARE

 Familial hypocalcuric hypercalcaemia (Low /normal PTH)

 Sarcoid (Low PTH)

 Drugs - Vitamin D toxicity /Thiazide/Lithium

 Prolonged immobilisation (Low PTH)

 Adrenal failure (Low PTH)

 Milk alkali (very rare)

Question 14

What are the different causes of hyperparathyroidism?

Primary, secondary and tertiary

Answer 14

 Primary

 Increased secretion of PTH  Single or multiple adenoma (common)  Parathyroid hyperplasia (less common)  Parathyroid carcinoma (rare)

 Secondary  Renal failure  (Failure of 1-hydroxylation)  Vitamin D deficiency  (Failure to absorb Ca2+ )

 Tertiary  As a result of prolonged secondary hyperparathyroidism  Renal transplantation

Question 15

What are clinical features of primary hyperparathyroidism?

Answer 15

 Most patients are asymptomatic and may not develop symptoms throughout their life time

 Younger patient may develop the following Clinical Features:

 Osmotic symptoms - thirst/polyuria/constipation

 Aches and pain

 Neuropsychiatric - Lethargy/depression - Confusion/coma

 Renal stone/osteoporosis/pancreatitis

Question 16

Whata are malignant associated hypercalcemia?

What is the malignancy-associated hypercalcemia?

Answer 16

complicates the course of 10%–30% of all patients with malignancies

 can be a sign of very poor prognosis and advanced malignancy

 Prompt recognition of the nonspecific signs and symptoms of hypercalcemia and institution of therapy can be life saving

Question 17

What is the treatment for malignancy associated hypercalcemia?

Answer 17

Question 18

A 76 year-old man was referred for investigation of haematuria and recurrent urinary tract infections. He also complained of constipation and had lost 5kg in weight during the past three months. His only medication was trimethoprim as prophylaxis against recurrent urinary tract infections. The laboratory telephones you with the following results:

Serum Ref range

Calcium 3.00 mmol/L 2.2 – 2.6

Albumin 31 g/L 35 – 50

What is your initial differential diagnosis?

What routine biochemistry results would you wish to know?

Answer 18

Initial differential: malignancy associated hypercalcemia

Serum Ref range

Urea 7.5 mmol/L 2.5 – 7.8

Creatinine 115 mmol/L 59 – 104

Sodium 144 mmol/L 133 – 146

Potassium 3.2 mmol/L 3.5 – 5.3

Phosphate 0.65 mmol/L 0.8 – 1.5

ALP 88 U/L 30 – 150

eGFR 57 ml/min/1.73m2

PTH 0.7 pmol/L 1.6 – 6.9

ACE 38 U/L 23 – 85

TSH 0.5 mIU/L 0.27 – 4.2

PSA 7.6 ng/ml < 5.0, age-related

Serum and urine protein electrophoresis – normal pattern

Question 19

What are cauises of hypophosphatemia?

Answer 19

Question 20

How does phosphate get regulates?

What does PTH do to the phosphate levels.

What does FGF23 do to PTH level?

Answer 20

Question 21

Clinical consequences of hypophosphatemia?

Answer 21

Question 22

If phosphate level is less than 0.5mmol/L what would you consider

what are phosphate dosage orally and IV?

Answer 22

Question 23

A 17-year-old patient was involved in a motor vehicle accident. He was found to be hypotensive at the scene of the accident and had to be resuscitated. He suffered multiple injuries to his lower extremities and required numerous surgeries and prolonged mechanical ventilation. He was started on a high concentration of enteral glucose feeds on a 24-hour protocol. Four weeks later, he is still dependent on the mechanical ventilator, but his chest x-ray remains clear. He has profound respiratory muscle weakness and the MRI shows significant thinning of the diaphragm.

 What further biochemical investigations may be of use?

Serum Ref range

Creatinine 35 umol/L 45-84

eGFR > 90 ml/min/1.73m2

Urea 1.8 mmol/L 2.5-7.8

Sodium 131 mmol/L 133-146

Potassium 1.9 mmol/L 3.5-5.3

Bicarbonate 43 mmol/L 22-29

Calcium 1.88 mmol/L 2.2-2.6

Albumin 28 g/L 35-50

Phosphate 0.54 mmol/L 0.8-1.5

Magnesium 0.45 mmol/L 0.70-1.00

Comment on the result? What is the differential diagnosis?

Question 24

Causes of hyperphosphatemia?

Clinical features in acute and chronic setting?

Answer 24

 Most patients are asymptomatic 

Acute

 Tetany  Hypocalcaemia  seizures  Hypotension

 Chronic

 Secondary hyperparathyroidism  Soft tissue calcification: kidneys, cornea, skin

Question 25

Causes of Mg deficiency?#

Clinical manifestations?

ECG changes?

Answer 25

 [Mg] <0.74mmol/l(<1.8mg/dl)

 Early symptoms are non specific-lethargy and weakness

 More pronounced hypomagnesemia presents with symptoms of increased neuromuscular excitability such as tremors, carpopedal spasm, muscle cramps, tetany, generalized seizures

 can cause cardiac arrhythmias including atrial and ventricular tachycardia, prolong QT interval and torsades depointes

 frequently associated with other electrolyte abnormalities such as hypokalemia and hypocalcemia

Question 26

how is hypomagnesemia diagnosed?

Answer 26

results from negative magnesium balance in the setting of decreased oral intake, increased gastrointestinal or renal losses

 is an acquired disorder; only in rare instances does have underlying hereditary etiology

 urinary magnesium excretion help todifferentiate renal from extrarenal causes of magnesium wasting

 24 hour magnesium excretion in the urine is expected to be less than 1 mmol (<24 mg) per day.

Question 27

Hypomagnesmia and renal magneseium wasting are distinct features of what syndrome

Is this syndrome autosomal recessive or dominant?

What gene affects it?

Answer 27

 Hypomagnesemia and renal magnesium wasting are distinctive features of Gitelman syndrome

 Gitelman syndrome is AR caused by mutation in the SLC12A3 gene that encodes the sodium-chloride cotransporter ( NCCl), which is expressed in the DCT

Question 28

 37 y.o M presented to AE with severe muscle cramps/spasms Perioral twitches of five days duration. He was otherwise fit and well. He was haemodynamically stable and well hydrated. ECG and CXR were normal.

 What other information would you ask the patient? - Patient known to have hypomagnesemia for over 15 years and has been on magnesium supplements for several years.

 What biochemical test would you ask for?

Serum Ref range Creatinine

63 umol/L 45-84

Urea 5.8 mmol/L 2.5-7.8

Sodium 141 mmol/L 133-146

Potassium 3.9 mmol/L 3.5-5.3

Calcium 2.48 mmol/L 2.2-2.6

Phosphate 0.94 mmol/L 0.8-1.5

Magnesium 0.35 mmol/L 0.70-1.00

What is the explanation for patients hypomagnesemia?

 What is the underlying cause?

Answer 28

He is probably not compliant to his magnesium and it is probably.

He has gitterman syndrome

Question 29

If magnesium is <0.5mmol/L then consider what?

What are the dosage for oral and intravenous Magnesium

Answer 29

Question 30

What are causes of magnesium excess?

What clinically will be shown in hypermanesemia?

What ECG changes will you see?

what level of magnesium would lead to a problem with magnesium?

Answer 30

Causes

 Acute renal failure (not diuretic phase)  Severe diabetic ketoacidosis  Addison’s disease  Supplements

 Clinically  Loss of deep tendon reflexes  Increased PR interval (Cardiac arrest)  But only a problem when the Mg2+ >2.0 mmol/L

Question 31

How do you monitor patients with severe mineral imbalance(emergency)

Answer 31

Fluid balance  Fluid intake  Output  Daily weight (increase >0.25 kg/day or 1.5 kg/week consider fluid accumulation)

 ECG monitor (arrythmias)

 Renal function and electrolytes at least daily (U&E, LFT, Bone =Ca/Phos, Mg, Bicarbonate & Chloride)