Lecture: calcium and phosphate

Question 1

When does hypercalcaemia remain asymptomatic?

Answer 1

Usually asymptomatic < total Ca = 3 mmol/l

Question 2

Gastrointestinal effects of hypercalcaemia?

Answer 2

• Anorexia, nausea, vomiting
• Constipation
• (Severe; peptic ulcer, pancreatitis)

Question 3

Renal effects of hypercalcaemia?

Answer 3

• Polyuria, polydipsia (osmotic diuresis)
• Prerenal failure (secondary to dehydration)
• Nephrocalcinosis

Question 4

Neuropsychiatric effects of hypercalcaemia?

Answer 4

• Depression

* ↓ consciousness

Question 5

Cardiovascular effect of hypercalcaemia?

Answer 5

• Arrhythmia (esp short QT)

* Hypertension

Question 6

Occular effects of hypercalcaemia?

Answer 6

– Band keratopathy

Question 7

Five indications for surgery in the setting of primary hyperparathyroidism.

Answer 7

1. Serum calcium >2.80 mmol/L
2. Skeletal T < -2.5 and/or previous vertebral fracture
3. Age (y) < 50
4. Renal eGFR<60 ml/min/1.73m2 and/or stones
5. 24 hour urine Ca >10 mmol/24 hours and high risk of stones

Question 8

Outline the three fractions of total calcium:

Answer 8

50% ionised and biologically active
40% protein bound
10% complexed with phosphate, bicarbonate, citrate

Question 9

Describe three steps involved in assessing true calcium status.

Answer 9

• Measure ionised calcium directly
– need anaerobic sample as for blood gas
– Calcium binding to albumin is pH dependent
• “Corrected” calcium to albumin 40g/L
– Calcium + [(40-albumin) x (0.02 x calcium)]
• SA Pathology calculates ionised calcium
– iterative calculation using albumin, globulins, bicarbonate and anion gap

Question 10

Where is calcitonin released from?

Answer 10

Thyroid clear cells

Question 11

What stimulates calcitonin release?

Answer 11

Secretion by clear cells in response to ↑ ionised Ca and gastrin

Question 12

Function of calcitonin?

Answer 12

• Inhibit osteoclast function
• Unclear role in long term calcium regulation:
– normal ICa in patients with no thyroid
– Normal ICa in medullary thyroid cancer

Question 13

PTH-related protein (PTHrP) physiological role:

Answer 13

– Cartilage differentiation/ growth plate
– Tooth eruption
– Smooth muscle (induced by mechanical stretch)
– Breast development and lactation

Question 14

Describe three major mechanisms by which hypercalcemia of malignancy can occur.

Answer 14

●Tumor secretion of parathyroid hormone-related protein (PTHrP)
●Osteolytic metastases with local release of cytokines (including osteoclast activating factors)
●Tumor production of 1,25-dihydroxyvitamin D (calcitriol)
Ectopic tumoral secretion of parathyroid hormone (PTH) can also cause hypercalcemia, but it is rare.

Question 15

Two artefact examples of hypercalcaemia?

Answer 15

Artefact (increased albumin)

– Prolonged tourniquet application, dehydration

Question 16

Medications that can cause hypercalcaemia?

Answer 16

– Drugs (lithium, thiazide diuretics)

Question 17

Genetic abnormality that can cause hypercalcaemia?

Answer 17

• Other

– Familial hypocalciuric hypercalcaemia (mutation in CaSR)

Question 18

Endocrine abnormalities that can cause hypercalcaemia?

Answer 18

– Endocrine (hyper/hypothyroidism, cortisol insufficiency)

Question 19

Really obvious cause of hypercalcaemia?

Answer 19

• Primary hyperparathyroidism

Question 20

Vitamin D mediated cause of hypercalcaemia?

Answer 20

• Vitamin D mediated
– Granulomatous disease (TB, sarcoid)
– Milk alkali syndrome

Question 21

Malignancy medicated cause of hypercalcaemia?

Answer 21

– Skeletal metastases
– Humoral hypercalcaemia of malignancy (PTHrP)
– Vitamin D mediated (esp lymphoma)

Question 22

Most common epidemiological presentation of primary hyperparathyroidism

Answer 22

Usually solitary adenoma (85%)
•75% women, average 55y at Dx
•Incidence ~8/100,000/y
•20%: somatic mutation in MEN-1 tumour suppressor gene
• Multiple gland disease: Multiple adenomas or Hyperplasia
•Rare: parathyroid carcinoma (<1%)

Question 23

Monitoring requirements for primary hyperparathyroidism if surgery is not performed

Answer 23

Serum calcium: Annual
BMD: Every 2 years
Serum creatinine: Annually
If at risk for stones 24-hour urine calcium and
Cr, renal US every 1-2y

Question 24

Hypercalcaemia treatment bedside, primary cause and medications?

Answer 24

Rehydration – Use saline: loop diuretics only after volume restored
• Treat the primary cause!
• Drugs
– Bisphosphonates
– Corticosteroids
– Calcitonin

Question 25

Two differentials for solitary adenoma in setting of primary hyperparathyroidism?

Answer 25

Multiple endocrine neoplasia type I | Familial hypocalciuric hypercalcaemia

Question 26

Multiple endocrine neoplasia type I

Answer 26

* Autosomal dominant inheritance * Inactivating germ line mutation in MEN-1 gene * Parathyroid (85%), enteropancreatic (Zollinger Ellison in 35%), pituitary (prolactinoma in 25%) may be involved

Question 27

Familial hypocalciuric hypercalcaemia

Answer 27

* Inactivating germ line mutation in calcium sensing receptor * Parathyroid cells insensitive to inhibition by calcium * Surgery contraindicated

Question 28

Name five causes of inadequate phosphate intake?

Answer 28

``` • Dietary restriction – Alcoholism – Eating disorders – Also beware refeeding • Antacid abuse (bind P in gut) • Vitamin D deficiency • Diarrhoea – include PEG preparation for colonoscopy • Generalised malabsorption syndromes ```

Question 29

Seven clinical features of hypocalcaemia?

Answer 29

• Neuromuscular irritability (twitching) – Trousseau’s sign (BP cuff 20mm >SBP for 3 min) – Chvostek’s sign (tap facial nerve in front of ear) • Paraesthesiae (numbness/ tingling in digits) • Muscle cramps • Tetany • Laryngospasm • Seizures • Long QT interval

Question 30

Hypocalcaemia causes?

Answer 30

``` • Artefact (decreased albumin) – Sick hospital patient, protein losing states • Primary hypoparathyroidism – Surgery – Autoimmune (isolated or polyglandular) • Low vitamin D → secondary hyperparathyroidism – renal failure – Drugs (eg phenytoin) • Reduced parathyroid function – Hypomagnesaemia – Hungry bone syndrome • Parathyroid hormone resistance (Pseudohypoparathyroidism + osteodystrophy) • Other – Pancreatitis, rhabdomyolysis, tumour lysis Pseudohypoparathyroidism + osteodystrophy ```

Question 31

Primary hypoparathyroid calcium and PTH levels?

Answer 31

Low calcium | Low PTH

Question 32

Secondary hyperparathyroid calcium and PTH levels?

Answer 32

Low calcium | Elevated PTH

Question 33

Malignancy, Granuloma and Milk alkali etc. calcium and PTH levels?

Answer 33

Elevated calcium | Low PTH

Question 34

Primary hyperparathyroid calcium and PTH levels?

Answer 34

Elevated calcium | Elevated PTH

Question 35

Causes of hyperphosphataemia?

Answer 35

• Artefact (old/haemolysed specimen) • Renal failure – a factor in hypocalcaemia – independent risk factor for vascular disease • Catabolic states • Metabolic acidosis • Endocrine – hypoparathyroidism, Addisons, hyperthyroid, acromegaly • Iatrogenic – milk alkali syndrome, bisphosphonates, hyperalimentation, phosphate containing laxatives (eg “Fleet”)

Question 36

Hyperphosphataemia clinical features?

Answer 36

* Hypocalcaemia, tetany * Hypotension * Osteodystrophy * Soft tissue calcification – Especially kidney, conjunctiva, arteries, skin

Question 37

Clinical features of severe hypophosphataemia?

Answer 37

``` • Bone mineralisation defect – bone pain/ deformity – fractures • Reduced conscious state • Impaired cardiac and skeletal muscle function – muscle pain, weakness – heart failure ```

Question 38

Causes of hypophosphataemia?

Answer 38

``` Redistribution • Respiratory alkalosis • Insulin mediated – Refeeding – Treated ketoacidosis • Sepsis • Hungry bone syndrome ```

Question 39

Where are calcium sensing receptors located?

Answer 39

Parathyroid gland | Kidney

Question 40

PTH actions on bone

Answer 40

* Activate osteoblast PTH receptor *  cytokine expression (RANK, M-CSF) *  osteoclast formation and function * Decrease OPG production

Question 41

Outline four broad functions of vitamin D

Answer 41

 Increase plasma Ca, PO4. Bone mineralisation (deficiency: rickets in children, osteomalacia in adults) and Neuromuscular function  Increase calcium absorption  Increase osteoclast formation  Increase renal Ca reabsorption

Question 42

What factors affect vitamin D levels?

Answer 42

``` • How much UVB reaches dermis – Season – Hours of exposure – Skin pigmentation – Amount of skin exposed • Availability of 7-dehyrocholesterol – Falls with age • Intake – More important in low UV exposure – More efficient in fatty meal ```

Question 43

Functional role of PTrH?

Answer 43

• Structural homology with PTH • Physiological role: – Cartilage differentiation/ growth plate – Tooth eruption – Smooth muscle (induced by mechanical stretch) – Breast development and lactation

Question 44

Proportion and type of humoral malignancy accounting for hypercalcaemia?

Answer 44

• Humoral hypercalcaemia of malignancy: – Up to 80% of malignancy related hypercalcaemia – Breast ca, squamous ca (eg lung, head/neck), T cell lymphomas

Question 45

Four mechanisms by which hypercalcaemia can result from malignancy?

Answer 45

Hypercalcemia of malignancy can result from: 1. humoral hypercalcemia of malignancy (characterized by tumor secretion of parathyroid hormone-related peptide [PTHrP]); 2. local osteolytic hypercalcemia (characterized by local release of factors, including PTHrP, by bony metastases that promote osteoclast differentiation and function); 3. calcitriol (1,25-dihydroxyvitamin D)-mediated hypercalcemia (characterized by autonomous production of calcitriol [(1,25-dihydroxyvitamin D)] by lymphoma cells); 4. ectopic hyperparathyroidism (characterized by tumor production of parathyroid hormone), which is very rare.