Transcript Plasma Calcium

Calcium and Phosphate Regulation
Functions of Calcium:
1.
Structural: bone and teeth.
2.
Neuromuscular: control of excitability, release of neurotransmitters and initiation of
muscle contraction.
3.
Enzymatic: coenzyme in coagulation factors.
4.
Signaling: intracellular second messenger.

Calcium is the most abundant mineral in the
human body, 99% is bound in the skeleton.

Bone is not metabolically inert most of the
calcium in bone is stable but some of it
moves between bone and the ECF to support
calcium homoeostasis
Plasma Calcium
 In the plasma, calcium is present in these forms:
Only the ionized form is the physiologically active and it is the concentration of ionized
calcium which is maintained by homeostastatic mechanisms.
Serum Calcium

A healthy person has a total serum calcium of around 2.4 mmol/L

About half is bound to protein, mostly albumin (non-diffusible)

Binding is pH dependent and is decreased in acidosis, because the
amino acids side chains on albumin become more positively charged.

The unbound calcium (diffusible) is the biologically active fraction

The unbound calcium concentration is recognized by PTH

Changes in serum albumin concentration in patients cause changes in
total calcium concentration. So:
Adjusted calcium (mmol/L)= Total measured calcium + 0.02 (47-albumin)

The measured calcium is ‘adjusted’ by 0.1 mmol/L for every 5 g/L
that the albumin is less than 47
Calcium-regulating Hormones
 Calcium concentration in the ECF is normally maintained within narrow limits by
a control system involving two hormones: Parathyroid hormone (PTH) and
calcitirol (1,25-dihydroxycholccalciferol).
 These hormones control calcium and the inorganic phosphate concentration in the
ECF
 Calcitonin has only a minor role in Ca homeostasis
Parathyroid hormone (PTH)
 This hormone is a polypeptide, comprising 84 amino acids
 PTH is secreted from the parathyroid glands in response to a low unbound
plasma calcium.
 Higher normal ECF calcium levels inhibit PTH secretion
Actions of parathyroid hormone (PTH):
1. Bone: rapid release of calcium, increase osteoclastic
resorption which leads to increase in plasma
calcium concentration.
2. Kidney: increase calcium reabsorption, decrease
phosphate reabsorption and decrease bicarbonate
reabsorption (leads to acidosis). Activation of
vitamin D which increases the calcium and
phosphate absorption from the GIT.
Calcitirol (1,25-dihydroxycholccalciferol)
 This hormone is derived from vitamin D by successive hydroxylation in the liver
(25-hydroxylation) and kidney (1 α-hydroxylarion).
Hydroxylation in the liver is not subject to feedback control, but that in the kidney
is closely regulated.
In the gut it stimulates absorption of dietary calcium and phosphate
 In the bone it stimulates the resorption of the bone and increase the release of
phosphate and Ca
It increases gastrointestinal calcium absorption, facilitates the effect parathyroid
hormone (PTH) on bone resorption, and increases (to little extent) renal tubular
absorption of calcium.
 Production of calcitriol by the cells of the proximal tubule of the nephron in the
kidney is stimulated by hypocalcemia and hypophosphatemia as well as
parathyroid hormone
Calcitirol (1,25-dihydroxycholecalciferol)
Calcium and phosphate homoeostasis
 Hypocalcaemia stimulates the secretion of PTH and this activates the
production of calcitirol  increase ECF of Ca and Pi (increase gut uptake
and bone release)
 PTH has phosphaturic effect excess Pi will be excreted by the kidney
 In hypophosphataemia, calcitriol secretion is increased but PTH is not,
the increase of the plasma calcium concentration inhibit PTH secretion.
 Calcium and phosphate absorption from the gut are stimulated.
 Calcitriol has a much smaller effect on renal calcium reabsorption than
PTH with the result that, in the absence of PTH, the excess calcium
absorbed from the gut is excreted in the urine.
The net outcome is the re-establishment of the phosphate concentration
towards normal, independently of that of calcium.
- PTH and calcitriol are essential for the maintenance of the plasma Ca2+
concentration, since their absence is associated with progressive
hypocalcemia due to decreases in bone resorption and intestinal
absorption and an increase in urinary Ca2+ excretion . In addition to
their individual effects, both hormones are able to interact so that Ca2+
and phosphate balance can be independently regulated.
Hypocalcemia
 Causes:
1. Hypoparathyroidism: Congenital or Acquired
2. Magnesium deficiency: Mg is required for PTH secretion and its
action on target tissues
3. Vitamin D deficiency: may be due to malabsorption, or an
inadequate diet with little exposure to sunlight decrease
absorption of Ca and phosphate from the gut. It causes
osteomalacia in adults and rickets in children.
4. Renal disease: the diseased kidneys fail to synthesize 1,25
DHCC. Increased PTH secretion in response to the
hypocalcaemia may lead to bone disease if untreated.
5. Pseudohypoparathyroidism: PTH is secreted but there is failure
of target tissue receptors to respond to the hormone.
 Clinical features
1. Neurological features: tingling, tetany and mental
changes
2. Cardiovascular signs: abnormal ECG
3. Cataracts
4. High levels of ALP (alkaline phosphatase)
 Treatment
1. Treatment of the cause
2. Oral calcium supplements are commonly prescribed in
mild disorders.
3. Intravenous Ca gluconate can be given
4. 1,25DHCC, or the synthetic vitamin D can be given
Trousseau’s sign is the most reliable
indication of latent tetany
Trousseau sign is a medical sign observed
in patients with low calcium.
This sign may become positive before
other gross manifestations of
hypocalcemia
To elicit the sign, 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.
This will occlude the brachial artery. In the
absence of blood flow, the patient's
hypocalcemia and subsequent
neuromuscular irritability will induce
spasm of the muscles of the hand and
forearm.
A diagnostic decision chart
Low Ca, Low Pi  low vit D
Low Ca, High Pi  low PTH
PTH
Corrected serum
calcium
Phosphate
Hypoparathyroidism
Low
Low
Elevated
Activating mutation
calcium sensing
receptor
Normal or
low
low
Elevated
Hypomagnesemia
Normal or
low
Low
Normal
PTH resistance
(pseudohypoparathyroi
dism)
Elevated
Low
Elevated
Vitamin D deficiency
Elevated
Low or normal
Low or normal
Chronic kidney disease
Elevated
Low
Elevated
Hypercalcemia
Two causes of hypercalcaemia account for up to 90% of cases:
1. Primary hyperparathyroidism: adenoma
2. Hypercalcemia associated with malignancy: this is a very common
cause of hypercalcaemia.
There may or may not be obvious metastases in bone.
Non-metastatic hypercalcaemia is due to the secretion by the tumor of
PTH-related peptides (PTHrP). This is a peptide having some Nterminal amino acid sequence homology with PTH.
Rarer causes of hypercalcaemia include
1. Large doses of f vitamin D or its metabolites e.g. in the treatment of
hypoparathyroidism or renal disease or due to self-medication.
2. Certain tumors (such as lymphomas) because of the increase in synthesis of
1,25 dihydroxycholecalciferol.
3. Thyrotoxicosis very occasionally leads to increased bone turnover and
hypercalcaemia.
4. Diuretic (thiazide) therapy: it decrease Ca excretion but the hypercalcaemia
is usually mild.
5. Renal disease: Long-standing secondary hyperparathyoidism may lead to
PTH secretion becoming independent of calcium feedback..
6. Calcium therapy: Patients are routinely given calcium containing solutions
during cardiac surgery, and may have transient hypercalcaemia afterwards.
7. Milk alkali syndrome: the combination of an increased calcium intake
together with bicarbonate, as in a patient self medicating with proprietary
antacid, may cause severe hypercalcaemia, but the condition is very rare
 Clinical features
Hypercalcaemia is usually discovered during the
investigation of an illness hypercalcaemia is often
clinically silent and is discovered in accidentally.
1. Neurological and psychiatric features: lethargy,
confusion, irritability and depression
2. GIT problems: anorexia, abdominal pain, nausea and
vomiting and constipation
3. Renal features: thirst and polyuria and renal calculi
4. Cardiac arrhythmias
 Treatment
• Treatment is urgent if the adjusted calcium is greater than 3.5
mmol/L and the priority is to reduce it to a safe level.
 Intravenous saline is administered first to restore the
glomerular filtration rate and promote a diuresis.
 Drugs that lower Ca level can be used like bisphosphonates,
steroids, calcitonin and intravenous phosphate.
Bisphosphonates such as pamidronate have become the
treatment of choice in patients with hypercalcaemia, it acts by
inhibiting bone resorption.
• The cause of the hypercalcaemia should be treated if possible.
 Surgical removal of a parathyroid adenoma usually provides a
complete cure for a patient with primary hyperparathyoidism.
 Immediately after successful surgery, transient hypocalcaemia
may have to be treated with vitamin D metabolites, until the
remaining parathyroids begin to operate normally.
A diagnostic decision chart
Phosphate
• Phosphate is abundant in the body
and is an important intracellular and
extracellular anion
• Much of the phosphate inside cells
is covalently attached to lipids and
proteins, phosphorylation of proteins.
• Most of the body’s phosphate is in bone
• Phosphate changes accompany calcium deposition or resorption of
bone
• Control of ECF phosphate concentration is achieved by the kidney,
where tubular reabsorption is reduced by PTH.
• The phosphate which is not reabsorbed in the renal tubule acts as
an important urinary buffer
Plasma inorganic phosphate
• At physiological hydrogen ion concentrations,
phosphate exists in the ECF both as monohydrogen
phosphate and as dihydrogen phosphate. Both forms
are together termed 'phosphate‘, and the total is
normally maintained within the limits of 0.8-1.40
mmol/L
• Approximately 20% of plasma phosphate is attached to
protein
• In plasma, calcium and phosphate often have a
reciprocal relationship. In particular, if phosphate rises,
calcium falls
Hyperphosphatemia
• Persistent hyperphosphataemia may result in calcium
phosphate deposition in soft tissues
• Causes of a high serum phosphate concentration include:
1. Renal failure. Phosphate excretion is impaired. This is
the commonest cause of hyperphosphataemia.
2. Hypoparathyroidism. The effect of a low circulating PTH
decreases phosphate excretion by the kidneys
3. Hemolysis. This may occur intravascularly in the patient,
or may be a consequence of an improper sampling
procedure
4. Psuedohypoparathyroidism. There is tissue resistance to
PTH
5. Neonatal causes. Increased intake of phosphate in milk
(cow’s milk)
 Signs and symptoms:
• Signs of hyperphosphatemia include an elevated blood phosphate level. Other
electrolyte values are likely to be affected, depending on the disease.
• There are no symptoms of hyperphosphatemia. Patient may not know that his blood
phosphate levels are elevated. The symptoms that he have are due to the underlying
disease.
 Diagnosis:
- The diagnosis of hyperphosphatemia is most often made only by the laboratory finding
serum phosphate > 1.6 mmol/L.
- The specific cause of hyperphosphatemia can usually be determined from the clinical
history, but serum creatinine and electrolytes should be obtained.
- In patient who have hyperphosphatemia from administration of phosphate salts,
metabolic acidosis with large anion gap can be found.
 Treatment:
- High phosphate levels can be avoided with phosphate binders
and dietary restriction of phosphate.
- Phosphate binders: are a group of medications used to reduce the
absorption of phosphate and taken with meals and snacks. They
are typically used in patients with chronic renal failure (CRF) as
they cannot get rid of the phosphate that gets into their blood.
- Common phosphate binders:
Aluminium hydroxide, Calcium carbonate, Calcium acetate.
Hypophosphatemia
Is an electrolyte disturbance in which there is an abnormally low level of phosphate in the
blood.
An increase in phosphate in the urine is called phosphaturia.
Severe hypophosphataemia (<0.3 mmol/L) is rare and causes muscle weakness which
may lead to respiratory impairment. The symptomatic disorder requires immediate
intravenous infusion of phosphate
Modest hypophosphataemia is much more common
 Causes:
.
Refeeding syndrome: is a syndrome consisting of metabolic disturbances that occur as
a result of reinstitution of nutrition to patients who are starved or severely
malnourished . Refeeding syndrome usually occurs within four days of starting to feed.
Most effects result from a sudden shift from fat to carbohydrate metabolism and a
sudden increase in insulin levels after refeeding which leads to increased cellular uptake
of phosphate.
2. Alkalosis: Hypophosphatemia secondary to phosphorus redistribution is
commonly caused by alkalosis and refeeding of malnourished patients.
Acute respiratory alkalosis and metabolic alkalosis decrease serum
phosphorus concentration
3. Alcohol abuse: Alcohol impairs phosphate absorption. Alcoholics are usually
also malnourished with regard to minerals. Patients (specially chronic
alcoholics) are given large amounts of carbohydrates, which creates a
high phosphorus demand by cells, removing phosphate from the blood
and the stress of alcohol withdrawal may create respiratory alkalosis,
which exacerbates hypophosphatemia.
4. Malabsorption: This includes GI damage, and also failure to absorb phosphate
due to lack of vitamin D, or chronic use of phosphate binders such as
sucralfate, aluminum-containing antacids, and (more rarely) calciumcontaining antacids.
Hypophosphatemia
• Other causes of a low serum phosphate include:
1. Hyperparathyroidism. The effect of a high PTH is to increase
phosphate excretion by the kidneys and this contributes to a low
serum concentration
2. Congenital defects of tubular phosphate reabsorption. In these
conditions phosphate is lost from the body
3. Ingestion of non-absorbable antacids, such as aluminum hydroxide.
These prevent phosphate absorption
4. Treatment of diabetic ketoacidosis. The effect of insulin in causing
the shift of glucose into cells may cause similar shifts of phosphate
5. Severe dietary deficiency.
6. Oncogenic hypophosphatemia. This is a rare cause of severe
hypophosphataemia, and the causative factor produced by the tumor
remains to be identified
 Sings and symptoms:
• Except for the effects on mineral metabolism, the symptoms of
hypophosphatemia are due to two consequences of intracellular phosphate
depletion which impact virtually all organ systems :
1.
Red cell 2,3-DPG (diphosphoglycerate) levels fall, thereby increasing the
affinity of hemoglobin for oxygen and reducing oxygen release at the
tissue level.
2.
Intracellular ATP levels fall with severe hypophosphatemia and those cell
functions dependent upon energy-rich phosphate compounds begin to fail.
• Weak muscles
• Muscle dysfunction
• Respiratory depression
• Low cardiac output
• Respiratory muscle weakness
 Management
•
Parenteral phosphate supplementation is generally reserved for patients who have
life-threatening hypophosphatemia or nonfunctional gastrointestinal syndromes.
•
Vitamin D supplementation is appropriate for patients with vitamin D deficiency.
•
The management of patients with hypophosphatemia can be divided into various
subgroups based on the severity of the hypophosphatemia and the need for
ventilation:
1.
Severe hypophosphatemia (< 0.3 mmol/L) in critically ill, should be managed with
intravenous replacement therapy (0.08–0.16 mmol/kg) over 2-6 hours.
2.
Moderate hypophosphatemia (0.3–0.8 mmol/L) in patients on a ventilator should be
managed with intravenous replacement therapy (0.08–0.16 mmol/L) over 2-6 hours.
3.
Moderate hypophosphatemia (0.3–0.8 mmol/L) in non-ventilated patients should be
managed with oral replacement therapy (1000 mg/d).
4.
Mild hypophosphatemia should be managed with oral replacement therapy (1000
mg/dl)
Magnesium
-
Magnesium is an essential element in biological systems, occurs
typically as the Mg2+ ion.
- Magnesium is the fourth most abundant mineral in the body and is the
second-most abundant intracellular cation, it is essential to good health.
- Approximately 50% of total body magnesium is found in bone. The other
half is found predominantly inside cells of body tissues and organs.
- Only 1% of magnesium is found in blood, but the body works very hard
to keep blood levels of magnesium constant.
- Green vegetables such as spinach are good
sources of magnesium , Some legumes
(beans and peas), nuts and seeds, and
whole, unrefined grains are also good
sources of magnesium and Tap water ”
hard water “ can be a source of
magnesium.
Magnesium
 Magnesium ions are the second
most abundant intracellular cations
Some 300 enzyme systems are
magnesium activated.
Most aspects of intracellular
biochemistry are magnesium
dependent, including glycolysis,
oxidative metabolism and
transmembrane transport of
potassium and calcium.
The electrical properties of cell
membranes are affected by any
reduction in the intracellular
magnesium concentration.
Functions
-
It is an essential mineral nutrient for life and is present in every cell type in every
organism. For example, ATP must be bound to a magnesium ion in order to be
biologically active. ATP is often actually Mg-ATP.
- Similarly, magnesium plays a role in the stability of all polyphosphate compounds in
the cells, including those associated with DNA and RNA synthesis.
-
It helps maintain normal muscle and nerve function, keeps heart rhythm steady,
supports a healthy immune system, and keeps bones strong.
-
Magnesium also helps regulate blood sugar levels, promotes normal blood pressure,
and is known to be involved in energy metabolism and protein synthesis.
-
Magnesium influences the secretion of PTH by the parathyroid glands and severe
hypomagnesaemia may cause hypoparathyroidism.
 Magnesium influences the secretion of PTH by the parathyroid
glands and severe hypomagnesaemia may cause hypoparathyroidism.
Magnesium homeostasis
Since magnesium is an integral part of chlorophyll green vegetables
are an important dietary source, as are cereals and animal meats. An
average dietary intake is around 15mmol per day which generally
meets the recommended dietary intake.
Children and pregnant or lactating women have higher equirements.
About 30% of the dietary magnesium is absorbed from the small
intestine and widely distributed to all metabolically active tissue.
Hypermagnesaemia is uncommon but is occasionally seen in renal
failure.
The symptoms of hypomagnesaemia are very similar to those of
hypocalcacmia: impaired neuromuscular function such as tetany,
hyperirritability, tremor, convulsions and muscle weakness.
Magnesium Deficiency
 Since magnesium is present in most common foodstuffs,
low dietary intakes of magnesium is associated with
general nutritional insufficiency.
 Magnesium deficiency can be expected as a result of:
1. dietary insufficiency accompanied by intestinal
malabsorption, severe vomiting, diarrhnea or other causes
of intestinal loss.
2. osmotic diuresis such as occurs in diabetes mellitus.
3. prolonged use of diuretic therapy especially when dietary
intake has been marginal prolonged.
4. nasogastric suction.
5. cytotoxic drug therapy such as cisplatinum which impairs
renal tubular reabsorption of magnesium
6. treatment with the immunosuppressant drug; cyclosporin.
Laboratory diagnosis
Magnesium concentration of less than 0.7 mmo1/L in a
serum specimen is evidence of marked intracellular
depletion. However, intracellular magnesium depletion may
exist where the serum magnesium concentration is within
the reference range.
Management
Oral, IM and IV regimens have been proposed.
Administration of magnesium salts, by whatever route is
contraindicated when there is a significant degree of renal
impairment. In these circumstances any supplementation
must be monitored carefully to avoid toxic effects associated
with hypermagnesaemia.
Bone metabolism:
Bone is constantly being broken down and reformed in
the process of bone remodeling
Osteoblasts or osteocytes: bone forming cells
Osteoclasts: resorption
•
1.
2.
3.
4.
Biochemical markers
Biochemical markers of bone resorption and bone formation can be useful in
assessing the extent of disease, as well as monitoring treatment:
Hydroxyproline, from the breakdown of collagen
Deoxypyridinoline, collagen degradation product
Alkaline phosphatase, the osteoblasts (bone forming cells) have high activity of
this enzyme
Osteocalcin, noncollagenous constituent of bone
Common bone disorders
• Osteoporosis
• Osteomalacia and rickets
• Paget’s disease: increased
osteoclastic activity which leads
to increased bone resorption.
Increased osteoblastic activity
repairs resorbed bone, but the
new bone is laid down in a
disorganized way
Osteoporosis
Osteomalacia
 Osteomalacia term for the softening of the bones due to defective bone mineralization.
 Osteomalacia in children is known as rickets, and because of this, use of the term
osteomalacia is often restricted to the milder, adult form of the disease.
 It may show signs as diffuse body pains, muscle weakness, and fragility of the bones.
 A common cause of the disease is a deficiency in vitamin D, which is normally obtained
from the diet and/or sunlight exposure
Osteoporosis
 The underlying mechanism in all cases of osteoporosis is an imbalance between bone
resorption and bone formation.
 In normal bone, there is constant matrix remodeling of bone;
 Bone is resorbed by osteoclast cells (which derive from the bone marrow), after which
new bone is deposited by osteoblast cells.
 Osteoporosis is most common in women after menopause, when it is called
postmenopausal osteoporosis,
 It may also develop in men, and may occur in anyone in the presence of particular
hormonal disorders

It may also develop in chronic diseases or as a result of medications, specifically
glucocorticoids, when the disease is called steroid- or glucocorticoid-induced
osteoporosis.
 Given its influence in the risk of fragility fracture, osteoporosis may significantly affect
life expectancy and quality of life.
Paget’s disease
 In this disease there will be an increased
osteoclastic activity which leads to increased
bone resorption. Increased osteoblastic activity
repairs resorbed bone, but the new bone is laid
down in a disorganized way
 It is a chronic disorder that typically results in
enlarged and deformed bones
 This causes bone to weaken, resulting in bone
pain, arthritis, deformities, and fractures.
 Men are more commonly affected than women
Causes
 Paget disease may be caused by a slow virus
infection (i.e., paramyxoviruses) present for
many years before symptoms appear
 There is also a hereditary factor
Paget’s
disease