PHAR: Bone & Calcium Metabolism I/II

Question 1

• What are the systems affected by hypercalcemia?
  
  • What are the symptoms associated with each symptom?

Answer 1

• Neurological.
  
  • Lethargy.
  • Confusion.
  • Headache.
  • Depression.
  • Paranoia.
  • Muscle weakness.
• Renal.
  
  • Polyuria.
  • Polydipsia (excessive thirst).
  • Nephrocalcinosis (Ca deposition in the kidneys).
• Gastrointestinal.
  
  • Constipation.
  • Anorexia.
  • Nausea.
  • Vomiting.
• Cardiovascular.
  
  • Bradycardia.
  • Short QT.
    
    • Short QT interval on an EKG.
• Other.
  
  • Soft tissue calcification.
  • Pruritus (itch).

Question 2

Fill in the gaps using the following conditions:

• Hypoparathyroidism.
• FHH.
• Malignancy.
• Vitamin D deficiency.
• Ca deficiency.
• Primary or tertiary hyperparathyroidism.
• Sarcoidosis.
• Renal failure.
• Lithium-induced hyperparathyroidism.
• Secondary hyperparathyroidism.
• Thyrotoxicosis, thiazide duretics, immobilisation, Addison’s disease.

Answer 2

Question 3

From the graph in slides, what are the reference ranges for:

• Ionised calcium (mmol/L).
• PTH levels (pmol/L).

Answer 3

• Ionised calcium.
  
  • 1.12-1.32.
• PTH.
  
  • 1.6-6.9.

Question 4

• What is the most common cause of primary hyperparathyroidism (PHPT)?
• What is the most common cause of secondary hyperparathyroidism (SHPT)?
• What can SHPT lead to?

Answer 4

• Tumour of the parathyroid gland.
  
  • Excess production of Ca.
• Renal failure.
  
  • Excess secretion of PTH in response to hypocalcemia.
• Tertiary hyperparathyroidism.
  
  • Patient becomes hypercalcemic, much like in PHPT.

Question 5

• How does increased PTH levels elevate Ca release from bone?
• How does increased PTH levels elevate Ca absorption in the kidney?
• How does increased PTH levels elevate Ca absorption in the gut?

Answer 5

• PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL.
  
  • Stimulate osteoclast formation and activity.
  • Increased calcium release from bone.
• PTH inhibits phosphate ion reabsorption, leading to a decrease in phosphate ion concentration, leading to a decrease in the formation of water-insoluble salts phosphate forms with calcium. Thus, a decrease in the phosphate concentration of the blood plasma increases the amount of calcium that is ionized.
• Conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.

Question 6

Describe FHH.

• What are its causes?
• How is it similar to primary hyperparathyroidism? How is it different?
• Is it malignant or benign?
• How is it best treated?

Answer 6

• Familial hypocalciuric hypercalcemia.
• Mutation in gene that encodes for CaSR (calcium sensing receptor).
  
  • Perceived lack of calcium → increased production of PTH.
  • Calcium resorption in the kidney is higher i.e. decreased calcium excretion via urine (hypocalciuria).
• FHH mimics PHPT but degree of renal Ca conservation is higher.
• Benign.
• DON’T treat with surgery.
  
  • Genetic mutation → removing one gland won’t have any effect.
  • Can take cinacalcet alters the function of the receptor

Question 7

Where is CaSR primarily found?

Answer 7

Renal tubules of the kidney and the parathyroid gland.

Question 8

• What does cinacalcet do? (mechanism of action)
• What does it treat?
• What are the side effects?
• Their is no clinical evidence linking cinacalcet and what observed phenomenon?

Answer 8

• Allosteric activation of CaSR.
  
  • Alters how CaSR interprets calcium.
  • Reduces PTH secretion
• Primary hyperparathyroidism.
• Nausea and muscle spasms.
• Cinacalcet and bone density.

Question 9

• How can a malignancy lead to hypercalcemia? (2 ways).
• How is malignant hypercalcemia treated?

Answer 9

1. Breast cancer and squamous cell carcinoma of the lungs produces PTHrP (parathyroid hormone related protein), which looks like PTH, and activates the receptors for PTH, causing hypercalcemia.
2. Cancer may directly invade bone, causing release of local factors that lead to hypercalcemia.

• Rehydration, zoledronic acid IV (bisphosphonates), denosumab (RANKL inhibitor).

Question 10

• Describe the underlying pathology of sarcoidosis.
• How is it treated?
• What tests can be run?

Answer 10

• Condition produces granulomas → macrophage accumulation → increased hydroxylation of vitamin D (outside the kidneys) → excess vitamin D activation → increased calcium resorption (hypercalcemia).
• Glucocorticoids eg prednisolone.
• Ca levels, PTH levels, urinary Ca excretion.
  
  • Sarcoidosis leads to hypercalciuria.

Question 11

• What are the systemic symptoms of hypocalcemia?
• What are the two signs?
• What are the possible causes?
  
  • What are the treatments for the different causes?

Answer 11

Neuro:

• Irritability, depression, paranoia, muscle cramps, spasms.

CV:

• Prolonged QT, peaked or inverted T.
• Chvostek’s sign and Trousseau’s sign.
• Autoimmune (AI).
  
  • Oral or IV calcium.
    
    • IV if symptomatic for hypocalcemia.
  • Note: Patients with AI hypoparathyroidism are likely to never revert to normal function.
  • Calcitriol.
    
    • The active metabolite of vitamin D.
    • Patient will have low PTH, so vitamin D won’t be activated, and regular vitamin D WON’T be effective.
• Post-parathyroidectomy.
  
  • Same as autoimmune.
• Vitamin D deficiency.
  
  • Give Ca and normal vitamin D.
    
    • Calcitriol required if patient can’t synthesize PTH.

Question 12

• Prevalence of primary hyperparathyroidism (PHPT).
• Two risk groups.
• Common presentations of PHPT.
• What are three treatment plans for PHPT?

Answer 12

• ~1:800.
• More common in the elderly (>50) and in women.
• Many patients have vague or no symptoms.
  
  • Patients may present with symptoms of:
    
    • Hypercalcemia.
    • Osteopenia.
    • Osteoporosis.

1. Surgical excision of parathyroid adenoma.
2. Bisphosphonates.
3. Cinacalcet.