Calcium Flashcards
What are functions of Calcium?
- Structure
- Protection
- Huge repository of calcium
- Muscle function/contraction
- Cell signalling
- Blood coagulation cascade
What is involved in Calcium Homeostasis?
- Achieved through interaction between calciotropic hormones and their effector tissues in the kidney, intestine and bone. Key to this is the calcium-PTH axis
- Vitamin D and vitamin D receptors expressed within nucleus of parathyroid cells, play important role in calcium homeostasis
What are the forms of Calcium distributed through the body?
- Calcium Hydroxyapatite
- Calcium Phosphate
- Intracellular Calcium
- Plasma Calcium - bound calcium to Proteins and Anions, Ionised Calcium
What are reference ranges for calcium?
- Ionised calcium = 1.13-1.32 mmol/L
- Adjusted calcium = 2.20-2.60 mmol/L
What is Hypocalcaemia and Hypercalcaemia?
- Hypocalcaemia = Adjusted calcium <2.20 mmol/L
- Hypercalcaemia = Adjusted calcium >2.60 mmol/L
What is the equation for Adjusted Calcium?
Measured [Ca] + (40 - [albumin]) x 0.02) = Adjusted [Ca]
What are some drawbacks to Adjusted Calcium?
- Relationship poor at extremes of relationship
- Population specific – based on ‘healthy’ population
- ?Use in ITU – ionised more useful.
- Ionised calcium clinically more useful but impractical
- Method specific – BCP/BCG (albumin); calcium (NM-BAPTA/AZ-III/CPC)
Where is Parathyroid Hormone secreted from?
- PTH is synthesised, stored and secreted by chief cells which are in parathyroid glands.
- Concentration of PTH in plasma determined by its synthesis and secretion by parathyroid glands
- Magnesium is essential for secretion of PTH parathyroid gland
- PTH acts directly on bone and kidney
- Indirectly on intestine to regulate [Ca2+] and [PO4]
Which organs metabolise and clear PTH?
Metabolism and clearance determined by liver and kidneys
Which are features of the calcium sensing receptors?
- G-protein coupled receptor
- Expressed in parathyroid and renal tubules of kidney
Which intracellular signalling pathways are triggered by Calcium Sensing Receptors?
There are 2 major pathways depending on the ionised [calcium]
- Hypo – AC/cAMP pathway
- Hyper – PLC/IP3/DAG pathway
Describe the process of calcium regulation from detection by the calcium sensing receptor?
- CaSR in the parathyroids detects reductions in extracellular Ca2+ and leads to the release of PTH
- PTH acts on the PTH1 receptor (PTH1R) to increase resorption of Ca2+ from bone, promote urinary Ca2+ reabsorption and increase expression of the renal 1-α-hydroxylase (1αOHase) enzyme, which converts the 25-hydroxyvitamin D (25D) precursor metabolite to biologically active 1,25-dihydroxyvitamin D (1,25(OH)2D).
- The elevated levels of 1,25(OH)2D increase absorption of dietary calcium by acting on the intestinal vitamin D receptor (VDR).
- CaSR in the renal cortical thick ascending limb also acts independently of PTH to regulate urinary Ca2+ reabsorption
- Increases in Ca2+ and 1,25(OH)2D concentrations lead to negative feedback on the parathyroid glands, thereby inhibiting further PTH release.
How is Calcium transported through the body?
- Calbindin-D is vital in transport of calcium from lumen to lamina propria (ileum and duodenum are main sights for absorption)
Where is the Calcium Sensing Receptor expressed in the kidneys?
CaSR is expressed in the following portions of the nephron:
- Apical membrane of the proximal tubule (60-70 % Ca2+ reabsorbed here), where it regulates 1,25(OH)2D synthesis and inorganic phosphate (Pi) excretion
- Basolateral membrane of the cortical thick ascending limb of the loop of Henle
- Apical membrane of the distal convoluted tubule, where it regulates Ca2+ reabsorption
What is the action of Calcium Sensing Receptor in the mammary glands?
- CaSR in the mammary gland detects reductions in Ca2+, which leads to increased PTH-related peptide (PTHrP) secretion from mammary epithelial cells into the circulation.
- PTHrP acts on the PTH1R to increase bone resorption, which in turn releases Ca2+ for milk production.
What are the parathyroid hormone actions?
Bone
- Osteolysis
- Differentiation of osteoclasts
- Regulation of osteoblasts (bone remodelling)
- Bone resorption or formation (depends on duration of exposure and concentration
Kidneys
- Reabsorption of Ca2+
- Inhibition of phosphate reabsorption
- Hydroxylation of 25(OH) vitamin D
- Bicarbonate excretion (inhibits Na+-H+ anti-porter activity
How can PTH Mobilisation be described?
PTH mobilisation of calcium is biphasic
- A rapid phase involving existing cells
- Long term response dependent on proliferation of osteoclasts
What happens to Serum and Urinary Calcium in the event of increased PTH?
- Increase in serum total and free calcium
- Urinary calcium is increased when larger filtered load of calcium from bone resorption and intestinal reabsorption overrides increased tubular reabsorption of calcium
- In absence of disease the increase in serum calcium reduces PTH secretion through negative feedback loop maintaining homeostasis.
What is PTH related peptide?
- Synthesized in various tissues including keratinocytes, lactating mammary tissue, placenta and foetal parathyroid glands
- Actions similar to PTH and binds to PTH receptors
- Important in regulating Ca2+ fluxes between foetal and maternal circulations, Ca2+ concentrations in breast milk and a role in foetal development
- Tumour marker
- RR <1.8 pmol/L
How does PTHrP differ to PTH?
- PTHrp does not increase renal 1α-hydroxylase enzyme activity
What is Calcitonin?
- Produced by parafollicular C-cells of thyroid gland. It is a 32 amino acid peptide
- Inhibits bone resorption by acting on the osteoclast
- Not significant in the regulation of normal calcium homeostasis
What can Calcitonin be used for in management?
Its potent anti-resorptive effect has led to its use in treating
- Paget’s bone disease
- Osteoporosis
- Hypercalcaemia
- Osteogenesis imperfecta
What can lead to deviations in Calcium Homeostasis?
Hypercalcaemia
- Increased GI absorption
- Increased bone resorption
- Decreased bone mineralisation
- Decreased urinary excretion
Hypocalcaemia
- Decreased GI absorption
- Decreased bone resorption
- Increased bone mineralisation
- Increased urinary excretion
What are reference ranges for Hypocalcaemia?
- Mild adjusted calcium: >2.0-<2.2 mmol/L
- Moderate adjusted calcium: 1.8-2.0 mmol/L
- Severe adjusted calcium: <1.80 mmol/L
What are causes of Hypocalcaemia?
- Hypothyroidism: Magnesium deficiency, Post-surgical damage or neck irradiation, Infiltrative (e.g haemachromatosis,wilson’s disease and metastases), Genetic (DiGeorge syndrome)
- Parathyroid hormone resistance: Pseudohypoparathyroidism
- Abnormalities of vitamin D metabolism: Vitamin D deficiency
- Deficient A1-hydroxylase enzyme activity: Chronic Kindey disease, Acidosis, Vitamin D-dependant rickets type 1
- Vitamin D resisitance: Vitamin D-dependant rickets type 1
- Others: Spurios, Acute Pancreatitis, Sepsis, Blood trnasfusion, Rhabdomyolysis, Bisphosphonate therapy, Hungry bone syndrome
How does CKD affect calcium metabolism?
- Fall in calcium: Decreased conversion 25(OH)D to 1,25(OH)2D
- Increase in phosphate: Kidneys not excreting excess. FGF-23 has role in monitoring phsopahate
- Increase in PTH: Stimulated by low calcium. Continual stimulation of parathyroid glands leads to secondary hyperparathyroidism
- Patients with end stage renal failure can become hypercalcaemic. Probably due to development of autonomous PTH secretion from prolonged hypocalcaemic stimulus
- Such hypercalcaemia may manifest for the first time in a renal transplant patient who becomes able to metabolise vitamin D normally leading to Tertiary hyperparathyroidism
What is Pseudohypoparathyroidism (PHP)?
- Resistance to PTH and various other glycoprotein hormones.
- PTH resistance at the kidney so patients so hyperparathyroid bone disease
What is Ellsworth-Howard test?
Involves measurement of serum and urinary phosphate and cAMP after intravenous administration of parathyroid extract; used in the diagnosis of pseudohypoparathyroidism. 6-30min urine collections and corresponding serum samples
- Normally 10-12 fold increase in cAMP, fall in TmP/GFR of 20%
- Pseudo type I: <5-fold increase in cAMP, <10% fall in TmP/GFR
- Pseudo type II: normal response to cAMP, <10% fall in TmP/GFR
What are symptoms of Hypocalcaemia?
- Paraesthesia
- Circumoral numbness
- Cramps
- Anxiety
- Tetany are followed by convulsions
- Laryngeal stridor
- Dystonia
- Psychosis
What are clinical signs of Hypocalcaemia?
- Chvostek’s sign: Gentle tapping over the facial nerve causes twitching of the ipsilateral facial muscles
- Trousseau’s sign: Inflation of the sphygmomanometer cuff above systolic pressure for 3 minutes induces tetanic spasm of the fingers and wrist
What are ECG changes of Hypocalcaemia?
- Prolongation of the QT-interval
- Narrowing of the QRS complex
- Reduced PR interval
- T wave flattening and inversion
- Prominent U-wave
How is Hypocalcaemia treated?
Treat underlying condition
- Acute symptomatic patient (10-20 mL 10 % calcium gluconate over 5 mins, Follow with continuous infusion of 9-18mmol/2L/24 h)
- Magnesium replacement
- Cholecalciferol (Vitamin D3)
- Alfacalcidol (1-α hydroxylated vitamin D3) - Given when 1-αhydroxylation defective (1-4 µg/day) e.g. hypoparathyroidism, VDDR I
- Calcitriol (1,25(OH)2 vitamin D3) - 0.75-2.25 µg/day
What are reference ranges for Hypercalcaemia?
- Mild adjusted calcium >2.60-<3.0 mmol/L
- Moderate adjusted calcium 3.0-3.5 mmol/L
- Severe adjusted calcium >3.5 mmol/L
What are causes of Hypercalcaemia?
- Parathyroid hormone mediated: Sporadic (adenoma, hyperplasia or carcinoma) , familial , Ectopic parathyroid hormone in malignancy, tertiary hyperparathyroidism
- Malignancy: Humoral hypercalcaemia of malignancy, Local osteolysis, Ectopic parathyroid hormone in maignancy, calcitriol related hypercalcaemia
- Vitamin D related: Granulomatous disease, Vitamin D intoxication
- Endocrine Disorders: Thyrotoxicosis, Adrenal insufficiency, Pheochromacytoma, VIPoma (Verner-Morison) syndrome
- Drugs: Thiazide diuretics, Lithium, Milk-Alkali syndrome, Vitmain A, Parathyroid Hormone
- Others: Coexisting malignancy and primary hyperparathyroidism, immobilisation, Acute renal failure, Chronic renal failure treaed with calcium and calcitriol or vitamin D analogues, Renal Transplant
What are types of Hyperparathyroidism?
- Primary: One or more parathyroid glands secrete excess parathyroid hormone
- Secondary: Increased secretion of this hormone is a response to lowered ionised calcium as a result of kidney, liver, or bowel disease
- Tertiary: State of autonomous secretion of parathyroid hormone usually occurs as a result of longstanding chronic kidney disease
What is Primary Hyperparathyroidism?
One or more of the four parathyroid glands secrete excess PTH, resulting in hypercalcaemia
- Parathyroid gland adenoma
- 1 gland: 80 %
- 2-3 glands: 10-11 %
- ≥4 glands <10 %
- Parathyroid carcinoma is rare (~1 %).
What are typical biochemical features of Primary Hyperparathyroidism?
- Increased PTH
- Long Hx of moderate hypercalcaemia
- Development of nephrolithiasis
- Plasma PO4 low in 50% cases
- Hyperchloraemic metabolic acidosis
- Normal ALP seen in 50% of cases
Need to confirm Dx with clinical and radiological evidence
What are indications for parathyroid surgery in PHPT?
- Serum calcium 0.24 mmol/L above the upper limit of the normal range, for patients younger than 50 years of age
- Men and peri-menopausal or postmenopausal women ≥50 years of age who have T scores of −2.5 or lower at a central bone densitometry site or in the distal third of the radius or who recently have had a fragility fracture
- GFR <60 mL/min/1.73 m2
- Renal stones, and a urine calcium level of >400 mg per day (10.0 mmol per day)
What causes Hypercalcaemia in Malignancy?
- Erosion of bone by secondaries
- Production of PTH like substance e.g. PTHrP
- Prostaglandin produced by tumour
- Production of osteoclast activating factor
- Coincidence of hyperparathyroidism
- Ectopic PTH
What is Familial Hypocalciuric Hypercalcaemia?
- Autosomal dominant
- Patients are heterozygous for inactivating mutations in the calcium sensing receptor (CaSR)
- Set point for PTH increased, mild PTH dependent hypercalcaemia develops with hypocalciuria
- In FHH inappropriate avid reabsorption of Ca2+
- Largely asymptomatic (accounts for 2 %)
What are symptoms and signs of FHH?
- Lethargy
- Polydipsia
- Pancreatitis
Neonates with two mutations present with severe life threatening hypercalcaemia
How is FHH differentiated from PHP?
UCa/Cr Cl ratio = (U[Ca] (mmol/L) x P[Creat] (µmol/L) / (P[Ca] (mmol/L) x U[Creat] (mmol/L)
Ca/Cr Cl ratio:
- <0.01 in FHH
- >0.015 in PHP
What are signs and symptoms of Hypercalcaemia?
- Tiredness
- Malaise
- Dehydration
- Depression
- Renal colic from stones
- Polyuria or nocturia
- Haematuria
- Hypertension occurs
- May have bone pain. Hyperparathyroidism mainly affects cortical bone
- Bone cysts and locally destructive ‘brown tumours’ occur but only in advanced disease
- Bone disease may be more apparent when there is coexisting vitamin D deficiency
- Abdominal pain
- Chondrocalcinosis and ectopic calcification (rare)
- Corneal calcification (long-standing hypercalcaemia)
What are ECG changes in Hypercalcaemia?
Hypercalcaemia speeds up repolarisation
- Mild: Broad based tall peaking T waves
- Severe: Extremely wide QRS, Low R wave, Disappearance of p waves, Tall peaking T waves.
What is the treatment of Hypercalcaemia?
Mandatory if the patient is seriously ill or if Ca2+ >3.0 mmol/L
- Rehydrate 4-6 L of 0.9 % saline on day 1, and 3-4 L for several days thereafter
- IV bisphosphonates: Treatment of choice in malignancy and of undiagnosed cause. Zolendronate (4 mg) in 0.9 % saline and Pamidronate (60-90 mg) in 0.9 % saline
- Prednisolone (30-60 mg daily): Used in granulomatous disease
- Calcitonin (200 units i.v. 6-hourly, maximum use 5 days): Has short-lived action
What are requirements for patients before the use of Bisphosphonates?
- Ensure eGFR >60 mL/min/1.73 m2
- [Ca2+] fall after 24-72 hours, lasting for approximately two weeks
What are imaging techniques for Hypercalcaemia?
- Abdominal X-rays may show renal calculi or nephrocalcinosis
- High-definition hand X-rays can show sub-periosteal erosions in the middle or terminal phalanges
- DEXA bone density scan is useful to detect bone effects in asymptomatic patients with HPT in whom conservative management is planned
- USS which, though insensitive for small tumours, is simple and safe
- High-resolution CT scan or MRI (more sensitive)
- Radioisotope scanning using technetium (99mTc)sestamibi: 90 % sensitive in detecting adenomas
