Hyper- and Hypoparathyroidism

Question 1

What is the calcium sensing receptor and where are these receptors located

Answer 1

• The calcium sensing receptor is responsible for monitoring and regulating calcium homeostasis
• They are located within the parathyroid gland, kidney and bone (and cartilage)
• The calcium sensing receptor interacts with the parathyroid gland to regulate the release of PTH

Question 2

What is iCa?

What is the difference between total calcium and iCa?

Discuss the relevance in clinical testing

Answer 2

• iCa is the biologically active form of calcium in the serum
• The total calcium is the combination of ionised or free calcium (~50% of total), calcium bound to albumin (~40%) and the calcium bound to other anions such as bicarbonate or citrate (~ 10%)
• The ratio between total calcium and ionised calcium is generally maintained, so testing of either can be appropriate for diagnosing a calcium abnormality
• Total calcium can be lowered by haemolysis, lipemia and hypoalbuminaemia
• Ionised calcium concentration can be altered by sample pH, either in disease or due to storage/handling
  
  • A reduced pH will cause increase in the iCa
  • An increase in pH will cause a reduction in iCa

Question 3

Describe the synthesis and secretion pattern of parathyroid hormone.

By what mechanisms does high or low serum calcium affect the release PTH

Answer 3

• PTH is continuously synthesised within the chief cells of the parathyroid gland. PTH is then stored in secretory granules within the cytoplasm
• PTH is metabolised quickly and continuously
• When the calcium levels are low, the rate of granule degradation is low
• When calcium levels are high, degradation is accellerated
• Vitamin D also influences PTH gene transcription
  
  • High Vitamin D slows PTH transcription
• Elevated phosphorus slows PTH degradation and enhances secretion
• High calcium is sensed by the calcium sensing receptor causing activation. The CaSR is G-protein coupled to gene expression
  
  • Activation of the CaSR causes a decrease in PTH production
• Low calcium causes inactivation of the calcium sensing receptor
  
  • Increased PTH gene expression, and parathyroid gland proliferation

Question 4

Briefly describe the pathway of vitamin D synthesis.

Answer 4

• Cholecalciferol is synthesised in the skin during UVB exposured
• Cholecalciferol is hydroxylated to 25-hydroxycholecalciferol by 25-hydroxylase witrhin the liver
  
  • This step is not regulated and 25-OH-vitamin D3 levels largely reflect the production of cholecalciferol
• 25-OH-cholecalciferol is further hydroxylated to active calcitriol (1,25-OH-cholecalciferol) by alpha-1-hydroxylase.
  
  • This conversion occurs within the kidney and is regulated by PTH (increased) and phosphate (supressed)

Question 5

How does vitamin D help to regulate PTH secretion and calcium metabolism?

Answer 5

• The active form of vitamin D, calcitriol, exerts the majority of its effect by enhancing the absorption of calcium from the GIT. Increased calcium due to increased GIT uptake is only one of 3 major components of calcium homeostasis and PTH function
• PTH mediates:
  
  • Production of calcitriol within the kidney
  • Enhances or suppresses the activity of osteoclasts
  • The resoption of calcium in the distal convoluted tubule and thick ascending loop of Henle

Question 6

Calcitonin helps to regulate calcium levels.

Briefly describe the production, release and role of calcitonin in calcium homeostasis

Answer 6

• Calcitonin is produced by the C cells in the thyroid gland
• Calcitonin has a role in limiting GIT calcium absorption in the post-prandial period, enhance calciuresis and decrease osteoclast activity
• Calcitonin can counteract the effects of PTH and can reduce calcium levels

Note:

• Medullary thyroid tumours of the C cells, producing excessive calcitonin does not disrupt calcium homeostasis.
• The role of calcitonin is relatively minor

Question 7

What are the three major mechanisms of action of parathyroid hormone that work synergistically to increase serum calcium concentration?

Answer 7

1. Increase calcium reabsorption in the distal convoluted tubule and ascending loop of Henle
2. Enhance the hydroxylation of 25,OH,vitamin D to calcitriol in the kidney
   
   • Calcitriol then enhances calcium absorption in the gut
3. Enchance the number of osteoclasts on bone surfaces, thus increasing bone resorption.

Question 8

What is the mechanism of polyuria and polydipsia with primary hyperparathyroidism?

Answer 8

• Hyperparathyroidism leads to hypercalcaemia
• High calcium antagonizes the effects of ADH on the collecting ducts
• HyperCa inhibits tubular uptake of sodium and chloride, inhibiting urinary concentrating mechanisms
• Polyuria is the primary process, with secondary polydipsia

Question 9

Describe the reasons why urinary calculi are common in dogs with primary hyperparathyroidism.

Answer 9

• PTH causes an increased uptake of calcium from the renal tubules, however, dogs with high PTH and hypercalcaemia still excrete increased amounts of calcium in the urine (calciuresis)
• Phosphate excretion is increased by PTH
• Supersaturation of the urine with calcium and phosphorus can lead to crystal and stone formation
  
  • calcium phosphate stones
• Increased calcium absorption from the gut lumen also enhances absorption of oxalate
  
  • Increased oxalate absorption leads to increased oxalate excretion in the urine
    
    • calcium oxalate stones

Question 10

List and discuss the various treatment options for management of hypercalcaemia (PHPT or hypercalcaemia of malignancy)

Answer 10

1. Fluid therapy
   
   • saline fluid therapy enhances calciuresis
   • sodium competes with calcium ions, reducing tubular reuptake
2. Frusemide
   
   • Use once hydrated
3. Glucocorticoids
   
   • No effect for PHPT
   • Reduce PTHrP by inducing tumour lysis or reduced sysnthesis and secretion
   • Increase renal calcium loss, decrease GIT absorption, decrease bone resorption
4. Bisphosphonates
   
   • Inhibit osteoclastic activity and induce osteoclast apoptosis
   • Primarily used for HOM or for bone pain associated with osteolytic bone lesions.
5. Calcitonin
   
   • inhibits osteoclastic activity and inhibits renal reabsorption of calcium
6. Surgery
   
   • Parathyroid tumour removal will reduced calcium levels rapidly

Question 11

What are the common aetiologies for hypoparathyroidism in dogs and cats?

Answer 11

• Post cervical trauma or surgery
• Immune mediated - majority of cases - presumed due to presence of lymphocytic +/- plasmacytic infiltrate on necropsy
• Idiopathic

Question 12

Describe the clinical signs expected with hypoparathyroidism

What is the typical time frame leading to clinical presentation?

Answer 12

• The clinical signs of hypoparathyroidism are primarily caused by persistently low calcium levels.
• Neuromuscular signs tend to predominate
• Signs can include:
  
  • muscle cramping, fasciculations and pain
    
    • may affect behaviour
  • Tremors / shaking
  • Stiff or stilted gait
  • Jaw champing
  • Facial pruritis
  • Seizures
• The clinical signs are often present for days to weeks prior to presentation. Median ~ 2 weeks. Clinical signs may be acute in onset and occasionally have been present for > 1 year prior to presentation

Question 13

What are the differentials for hypocalcaemia - common and rare?

Answer 13

1. Eclampsia
2. Hypoparathyroidism
   
   • post surgery, trauma or immune mediated/idiopathic
3. AKI
4. CKD
5. Pancreatitis
6. Diabetes mellitus
7. Malabsorption syndromes
8. Urinary tract obstruction
9. Phosphorus containing enemas

Question 14

Discuss the acute management of dogs with clinical signs and hypocalcaemia

Answer 14

• If signs are severe, then treatment with an IV calcium gluconate bolus is recommended (together with IV fluids)
  
  • Followed by a Ca Gluconate CRI
• Monitor the ECG during the initial bolus - over 10-15 minutes.
• Continue calcium infusion for 1-3 days with ~ q 12 hour calcium monitoring
• Oral calcium supplementation can be provided
• Oral calcitriol supplementation should be commenced
  
  • Calcitriol is then used medium to long term depending on the inciting cause for the hypocalcaemia and if the condition is permanent.

Question 15

What are the chronic treatment options for dogs or cats with hypoparathyroidism?

Briefly note the mechanism of action of treatment?

Answer 15

• Complete lack of PTH leads to hypocalcaemia due to the following mechanisms:
  
  • reduced bone resorption
  • reduced calcitriol formation in the kidney - reduced GIT absorption
  • Reduced Ca reabsorption fro, the kidney
• Supplementation with Vitamin D3 (calcitriol) increased the absorption of calcium from the GIT
  
  • Initially calcium may be supplemented, but generally this is not required longer term
  • For most dogs/cats, compounded calcitriol needs to be used to avoid inaccurate dosing
    
    • Consistent choice of experienced pharmacy is important
• Aim for calcium to be low normal or just below the reference range
  
  • Avoids hypocalcaemia clinical signs
  • Minimises the risk of vitamin D toxicosis (hyperCa, HyperPO4 and AKI)
  • Low phosphate diets would be recommended as lack of PTH causes increased PO4 resorption in the kidney

Question 16

What are the treatment goals for hypoparathyroidism and how are they monitored?

Answer 16

• Treatment is directed at maintaining calcium levels above the level that could result in clinical signs.
• A target in the low normal range or just below the normal range is ideal
• The target range aims to reduce calciuresis and the risk of calcium containing urolith formation
• Aiming for a low end calcium level also reduces the total supplementation of Vitamin D, limiting the risk of vitamin D toxicosis