L5 Flashcards
Where is calcium important
· Exocytosis
• Neurotransmitter secretion
• Hormone secretion
How does hypocalcaemia destabilise neurones
- The reason hypocalcemia causes neuron excitation (contrary to the above logic) is because a decrease in extracellular calcium concentration increases the neuron membrane’s permeability to sodium and allows sodium to easily depolarize the neuron’s membrane and cause an action potential
Physical signs of hypocalcaemia
Trousseau sign of latent tetany (aka carpopedal spasm)
Chvostek’s sign
What is a carpopedal spasm
In a patient with hypocalcemia, carpal spasm may be elicited by occluding the brachial artery.
To perform the maneuver, a blood pressure cuff is placed around the arm and inflated to a pressure greater than the systolic blood pressure and held in place for 3 minutes. If carpal spasm occurs, manifested as flexion at the wrist and metacarpophalangeal joints, extension of the distal interphalangeal and proximal interphalangeal joints, and adduction of the thumb and fingers, the sign is said to be positive and the patient likely has hypocalcemia.
How does neuromuscular inability present in hypocalcemia
Chvostek's sign Trousseau's sign Paresthesias Tetany Seizures (focal, petit mal, grand mal) Fatigue Anxiety Muscle cramps Polymyositis Laryngeal spasms Bronchial spasms
Neurological signs and symptoms associated with hypocalcemia
Extrapyramidal signs due to calcification of basal ganglia Calcification of cerebral cortex or cerebellum Personality disturbances Irritability Impaired intellectual ability Nonspecific EEG changes Increased intracranial pressure Parkinsonism Choreoathetosis Dystonic spasms
Mental status of a person with hypocalcemia
Confusion
Disorientation
Psychosis
Psychoneurosis
Ectodermal changes in a person with hypocalcemia
Dry skin Coarse hair Brittle nails Alopecia Enamel hypoplasia Shortened premolar roots Thickened lamina dura Delayed tooth eruption Increased dental caries Atopic eczema Exfoliative dermatitis Psoriasis Impetigo herpetiformis
Smooth muscle involvement in an individual with hypocalcemia
Dysphagia Abdominal pain Biliary colic Dyspnea Wheezing
Opthalmologic manifestations of hypocalcemia
- Subcapsular cataracts
- Papilledema
Cardiac effects of hypocalcemia
- Prolonged QT interval in EKG
- Congestive heart failure
- Cardiomyopathy
What is the hallmark of acute hypocalcemia
- Neuromuscular irritability
- Patients often complain of numbness and tingling in their fingertips, toes, and the perioral region. Paresthesias of the extremities may occur, along with fatigue and anxiety
How can neuromuscular irritability be demonstrated clinically
By eliciting chvostek’s or trousseau’s signs
In what percentage of normal individuals is chvostek’s sign present
- In 10% of normal individuals
How can chvostek’s sign be elicited
- Tapping the skin over the facial nerve anterior to the external auditory meatus produces this sign
What causes chvostek’s sign
Low plasma calcium increases the permeability of neuronal membranes to sodium ions, causing a progressive depolarization.
This increases the ease with which action potentials can be initiated. If the plasma Ca2+ decreases to less than 50% of the normal value action potentials may be spontaneously generated, causing contraction of peripheral skeletal muscle.
The reverse is true in hypercalcemia. High Calcium causing decreased permeability and thence muscle weakness.
What is chvostek sign a sign of
- Tetany seen in hypocalcemia
What is chvostek sign also seen in
- Respiratory alkalosis, such as that seen in hyperventilation
Acute consequences of hypercalcemia
- Thirst and polyuria
- Abdominal pain
Chronic consequences of hypercalcemia
- Constipation
- Musculoskeletal aches / weakness
- Neurobehavioral symptoms
- Renal calculi
- Osteoporosis
What is albumin
Albumin is a globular, water-soluble, un-glycosylated serum protein of approximate molecular weight of 65,000 Daltons.
Albumin (when ionized in water at pH 7.4, as found in the body) is negatively charged
Why might the corrected Ca2+ be inaccurate in a lab report
- Albumin concentration may be below 20 g/l
- In severe acute illness (in these cases measure ionised Ca2+ directly)
Effect of pH on protein binding with calcium
- An increase in pH, alkalosis, promotes increased protein binding, which decreases free calcium levels
- Acidosis, on the other hand, decreases protein binding, resulting in increased free calcium levels
Reference range of ionised calcium
1.1-1.35 mmol/L
Normal range of calcium levels in the blood
2.15-2.55 mmoles/L
What are parathyroid chief cells
- Are cells in the parathyroid glands which produce parathyroid hormone
What does increased secretion by the chief cells of a parathyroid gland cause
- An increase in the serum level of calcium
- Parathyroid chief cells constitute one of the few cell types of the body that regulate intracellular calcium levels as a consequence of extracellular(or serum) changes in calcium concentration
What stimulates the uptake of calcium by the parathyroid chief cell
- The calcium-sensing receptor(CaSR) is sensitive to an increase in serum calcium, and stimulates the uptake of calcium by the parathyroid chief cell
- This mechanism is critically important, as it describes a physiological feed-back loop by which parathyroid hormone secretion is down-regulated in response to a restoration of serum calcium
What is parathyroid hormone released in response to
- Low extracellular concentrations of free calcium
Link between blood phosphate concentrations and parathyroid hormone secretion
Changes in blood phosphate concentration can be associated with changes in parathyroid hormone secretion, but this appears to be an indirect effect and phosphate per se is not a significant regulator of this hormone.
Link between calcium concentration and secretion of parathyroid hormone
When calcium concentrations fall below the normal range, there is a steep increase in secretion of parathyroid hormone. Low levels of the hormone are secreted even when blood calcium levels are high.
What type of receptor is the calcium-sensing receptor
G-protein coupled receptor
Features of the calcium-sensing receptor
Like other family members, it contains seven hydrophobic helices that anchor it in the plasma membrane.
The large (~600 amino acids) extracellular domain is known to be critical to interactions with extracellular calcium.
The receptor also has a rather large (~200 amino acids) cytosolic tail
Effects of activation of the calcium sensor
- Activation of phospholipase C, which leads to generation of the second messengers diacylglycerol and inositol trisphosphate.
- Inhibition of adenylate cyclase, which suppresses intracellular concentration of cyclic AMP.
The sensor can also activate the mitogen-activated protein kinase pathway, suggesting an ability to influence nuclear function.
Expression of calcium sensors
The calcium sensor is expressed in a broad range of cells, including parathyroid cells and C cells in the thyroid gland, indicating its involvement in controlling the synthesis and secretion of parathyroid hormone and calcitonin.
The calcium sensor is also expressed in several cell types in the kidney, osteoblasts, a variety of hematopoietic cells in bone marrow, and in the gastrointestinal mucosa. Strangely, it is also present in the squamous epithelial cells of the esophagus. Such a broad distribution of expression supports that concept that calcium, acting as a hormone, has direct effects on the function of many cell types.
Link between the calcium sensor and the synthesis and secretion of parathyroid hormone and calcitonin
Functional studies and investigation of animals with mutations in the calcium sensor gene have confirmed that the calcium sensor directly affects secretion of these two hormones.
In which group of patients were a large number of different mutations in the calcium sensor gene identified
- Patients affected by a type of calcium resistance known as familial hypocalciuric hypercalcemia
- The different mutations result in a spectrum of calcium sensor dynfunctions, ranging from total inactivation to a moderate decrease in affinity of the receptor for calcium
A prominent clinical consequence of inactivating mutations in the calcium sensor gene
- A prominent clinical consequence of such mutations is an abnormal set point or sensitivity of the parathyroid gland to blood calcium concentration.
- Abnormalities in renal excretion of calcium are also observed.
What is the clinical consequence of activating mutations
- Certain types of mutations lead to a calcium sensor with an elevated sensitivity to calcium.
- The clinical consequence of such mutations is familial hypercalciuric hypocalcemia - basically the opposite of what is seen with inactivating mutations in the sensor gene.
High blood calcium affects the normal calcium sensor to suppress parathyroid hormone secretion. If the calcium sensor is constitutively more active than, a type of hypoparathyroidism results.
Effect of low magnesium levels on PTH release
- Low magnesium prevents PTH release
Which hormones are critical controllers of calcium and phosphorus balance
- Parathyroid hormone and its cousin parathyroid hormone-related protein (PTHrP) are critical controllers of calcium and phosphorus balance
Function of type 1 parathyroid hormone receptor
Binds both parathyroid hormone and amino-terminal peptides of PTHrP
Effect of binding of ligand to a type 1 parathyroid hormone receptor
Binding of ligand to this receptor activates both adenylyl cyclase and phospholipase C systems, generating protein kinase A and protein kinase C signals, respectively.
The cyclic AMP/protein kinase A pathway is predominant.
As might be expected from the actions of parathyroid hormone, the mRNA encoding the type 1 receptor is most abundant in bone (especially in chondrocytes at growth plates) and kidney.
The mRNA is also expressed at lower levels in many other tissues, probably reflecting its use as a receptor for PTHrP.
Function of type 2 parathyroid hormone receptor
- Binds parathyroid hormone, but shows very low affinity for PTHrP
- This molecule is expressed in only a few tissues, and its structure and physiologic significance are poorly characterised
What is the type 2 parathyroid hormone receptor coupled to
- Like the type 1 receptor, it is coupled to adenylyl cyclase and ligand binding induces a rise in intracellular concentration of cyclic AMP
What are mutations in the type 1 receptor associated with
Mutations in the type 1 receptor have been associated with rare human diseases.
Jansen’s metaphyseal chondroplasia
Blomstrand’s chondroplasia results
What is jansen’s metaphyseal chondroplasia
Jansen’s metaphyseal chondroplasia is a syndrome of short limbed dwarfism resulting from a mutation that constitutively activates the receptor
What is blomstrand’s chondroplasia
Blomstrand’s chondroplasia results from an inactivating mutation in the receptor gene, leading to a disease of early death with defective bone maturation, very similar to mice with targeted deletions of the PTHrP gene.
How does PTH activate the PTH/PTHrP receptor
- PTH activates the pTH/PTHrP receptor by changing its shape
What is PTH
PTH is a peptide containing 84 amino acids that is secreted by the parathyroid glands after cleavage from preproparathyroid hormone (115 amino acids) to proparathyroid hormone (90 amino acids) to the mature hormone.
1st major action of PTH
The first action is to increase renal calcium resorption and phosphate excretion. In the kidney, PTH blocks reabsorption of phosphate in the proximal tubule while promoting calcium reabsorption in the ascending loop of Henle, distal tubule, and collecting tubule. Calcium also may exert a direct effect on renal resorption.
How does PTH promote absorption of calcium from bone
a. The rapid phase brings about a rise in serum calcium within minutes and appears to occur at the level of the osteoblasts and osteocytes. Although it may seem counterintuitive that the cells that promote deposition of bone are involved in resorption, these cells form an interconnected network known as the osteocytic membrane overlying the bone matrix, but with a small layer of interposed fluid termed bone fluid. When PTH binds to receptors on these cells, the osteocytic membrane pumps calcium ions from the bone fluid into the extracellular fluid.
b. The slow phase of bone resorption occurs over several days and has 2 components. First, osteoclasts are activated to digest formed bone, and second, proliferation of osteoclasts occurs. Interestingly, mature osteoclasts lack PTH membrane receptors; activation and proliferation appear to be stimulated by cytokines released by activated osteoblasts and osteocytes or by differentiation of immature osteoclast precursors that possess PTH and vitamin D receptors.
What is the rank ligand
Receptor activator of nuclear factor kappa B ligand (RANKL) is the final common mediator that regulates bone remodeling
RANKL is the primary mediator of osteoclast formation, function and survival
What is RANKL produced by
- Osteoblasts and other cells
Effect of RANKL
- Causes osteoclast precursors to form and differentiate into active (mature) osteoclasts
- RANKL also has been implicated in altering the adherence of osteoclasts to the bone surface and suppresses apoptosis of mature osteoclasts
What is osteoprotegerin (OPG)
- A protein that the body naturally produces
- Neutralises the effects of RANKL, keeping the bone loss process in check
What does excess RANKL activity cause
- Drives bone destruction across a broad range of conditions
- In osteoporosis, RANKL has direct catabolic effects on cortical and trabecular bone including reductions in bone density, volume and strength
What is an osteoclast
- Is a type of bone cell that removes bone tissue by removing the bone’s mineralised matrix
- This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue. Osteoblasts form bone; osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line
What are osteoclasts characterised by
- high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K
Actions of PTH in the kidney
- rapid calcium reabsorption
2. Increase phosphate excretion
Where does PTH cause an increase in calcium reabsorption in the kidney
- Loop of henle
- Distal tubule
- Collecting ducts
Renal synthesis of active vitamin D - Sun
Sun/UVLb –> Skin –> Vitamin D Cholecalciferol –> Liver 25 OH vitamin D
Dietary sources of vitamin D
Cod liver oil
Oily fish (wild)
Mushrooms
Fortified foods
Renal actions of PTH
- Conversion of 25 OH vitamin D –> 1,25 OH vitamin D –> calcium transporters and binding protein (calbindin) in gut cells –> increase in calcium absorption
Effect of PTH and FGF23 on 1,25(OH)2D production in the kidney
- PTH stimulates
- FGF23 inhibits
Effect of 1,25(OH)2D on PTH production and FGF23 production from bone
1,25(OH)2D inhibits PTH production and secretion from the parathyroid glands and stimulates FGF23 production from bone
Phosphate excretion pathway
Osteocyte –> FGF23 –> Renal phosphate excretion
Biochemical diagnosis - Primary hyperparathyroidism
- Serum calcium increased
- Serum phosphate reduced
- PTH increased
Symptoms of primary hyperparathyroidism
Fatigue Fractures Decreased height Upper abdominal pain Loss of appetite Nausea Muscular weakness Muscle pain Depression Personality changes Stupor and possibly coma Kidney stones Increased urination
What is a rare cause of hyperparathyroidism
Parathyroid cancer
What causes primary hyperparathyroidism normally
- In primary hyperparathyroidism, enlargement of one or more of the parathyroid glands causes extra parathyroid hormone to be released
- This increases calcium levels
- The effects of increased calcium are seen in several body systems including
In which age group is primary hyperparathyroidism most common
- Most common in people over 60, but can also be seen in younger adults
What can increase the risk of hyperparathyroidism
- Radiation to the head and neck increases risk
Symptoms of hyperparathyroidism
Fatigue Fractures Decreased height Upper abdominal pain Loss of appetite Nausea Muscular weakness Muscle pain Depression Personality changes Stupor and possibly coma Kidney stones Increased urination
What is a radioimmunoassay
- A test which may show an increased level of PTH in hyperparathyroidism
Bone x-rays and ECG in hyperparathyroidism
- Bone x-ray may show bone reabsorption(the body breaks down the bone), or fractures
- ECG may show abnormalities
Iatrogenic causes of hypoparathyroidism
- Thyroidectomy
- Radical neck surgery
Causes of hypoparathyroidism
- Autoimmune
- Hypomagnesaemia
- Genetic mutations
Common causes of secondary hyperparathyroidism
· Low/low normal serum calcium + HIGH PTH
- Low serum 25 OH vitamin D
· Lack of sun exposure
· Gastrointestinal problems
- Malabsorption
- Extensive surgery (small bowel)
- Renal failure
Reduced vitamin D concentration –> rickets
What is rickets
- A softening of the bones in children potentially leading to fractures and deformity
Predominant cause of rickets
- Vitamin D deficiency, but lack of adequate calcium in the diet may also lead to rickets
What is osteomalacia
- Term used to describe a similar condition to rickets occurring in adults, generally due to a deficiency of vitamin D
Effects of parathyroid hormone release
- Efflux of calcium from bone
- Decreased loss of calcium in urine
- Enhanced absorption of calcium from intestine
–> maintains blood Ca2+ concentration + maintains bone mineral density
Physiologic effects of parathyroid hormone
- Mobilisation of calcium from bone
- Enhancing absorption of calcium from the small intestine
- Suppression of calcium loss of urine
How does PTH cause mobilisation of calcium from bone
Although the mechanisms remain obscure, a well-documented effect of parathyroid hormone is to stimulate osteoclasts to reabsorb bone mineral, liberating calcium into blood
How does PTH enhance absorption of calcium from the small intestine
Facilitating calcium absorption from the small intestine would clearly serve to elevate blood levels of calcium.
Parathyroid hormone clearly stimulates this process, but indirectly by stimulating production of the active form of vitamin D in the kidney.
Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into blood.
How does PTH cause suppression of calcium loss in urine
In addition to stimulating fluxes of calcium into blood from bone and intestine, parathyroid hormone puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by stimulating tubular reabsorption of calcium. Another effect of parathyroid hormone on the kidney is to stimulate loss of phosphate ions in urine.
