Ca , Ph Homeostasis Flashcards
____ per cent of body calcium is found in the skeleton
Ninety-eight
The extraosseous fraction,
although amounting to only 1 per cent of the total, is essential because of its effect on neuromuscular excitability and cardiac muscle
An important mediator of intracellular calcium is _____, a calciumbinding regulatory protein.
calmodulin
What’s the Role of Vitamin D in ca absorption?
Active Metabolite: The body needs the active form of vitamin D, called 1,25-dihydroxycholecalciferol or calcitriol, for efficient calcium absorption.
Vitamin D Activation: Calcitriol is produced in the kidneys from vitamin D obtained through sunlight exposure or dietary sources. It enhances the absorption of calcium from the intestine.
The mean plasma calcium concentration in healthy
subjects is tightly controlled, at around ____ to–
____ mmol/L,
2.15 to 2.55
The plasma concentration of ca is present in two main forms which are?
Which is the active form?
Calcium bound to proteins, mainly albumin: this
accounts for a little less than half the total calcium
concentration as measured by routine analytical
methods and is the physiologically inactive form.
● Free ionized calcium (Ca2+), which comprises most
of the rest. This is the physiologically active fraction
What’s the formula for calculating the free ca?
Ca+ = plasma measured calcium + (40 – plasma[albumin]) (g/L) × 0.02
Impact of Albumin Level Changes
High Albumin Levels:
When albumin levels are high, more calcium binds to albumin. This increases the measured total calcium concentration.
Effect on Free Ionized Calcium: The concentration of free ionized calcium remains unchanged because the body tightly regulates this active form to maintain physiological function.
And VISE VERSA
Effect of Posture: Total plasma calcium is lower when lying down (supine) compared to standing up (erect). This is due to posture affecting fluid distribution and, consequently, plasma protein concentration.
Explain the Impact of Hydrogen Ion Concentration on Calcium Binding
Competition Between H+ and Ca2+
Binding Sites: Plasma proteins, primarily albumin, have specific binding sites for calcium (Ca2+).
Competition: Hydrogen ions (H+) compete with calcium ions (Ca2+) for these binding sites on proteins.
Short-Term Effects: Acidosis and alkalosis can cause immediate changes in the proportion of calcium that is free versus bound.
Acidosis: Increases free ionized calcium temporarily.
Alkalosis: Decreases free ionized calcium temporarily
What are the effects of acidosis and alkalosis on Ca
Acidosis (Increased [H+]):
Decreased Calcium Binding: More H+ ions are available to compete with Ca2+ for binding sites on plasma proteins. This results in fewer Ca2+ ions being bound to proteins.
Increased Free Ionized Calcium: With fewer Ca2+ ions bound to proteins, more calcium remains in the free ionized form (Ca2+), which is the physiologically active form.
Increased Solubility and Bone Release: Acidosis also increases the solubility of calcium, leading to more calcium being released from bones into the extracellular fluid (ECF).
Increased Renal Loss: The increased load of free calcium in the blood reaches the kidneys, where more calcium is excreted, leading to increased renal calcium loss.
Potential for Osteomalacia: Prolonged acidosis can lead to osteomalacia (softening of the bones) as bone acts as a buffer to neutralize excess acid, releasing calcium and weakening bone structure
Alkalosis (Decreased [H+]):
Increased Calcium Binding: With fewer H+ ions to compete with Ca2+, more calcium ions bind to plasma proteins.
Decreased Free Ionized Calcium: More calcium being bound to proteins means less is available in the free ionized form.
Tetany Risk: Even if the total plasma calcium concentration remains normal, the reduction in free ionized calcium can lead to tetany, a condition characterized by muscle cramps and spasms due to increased neuromuscular excitability.
A 45-year-old man was in the intensive care unit for
multiple trauma following a road traffic accident.
Some of his biochemistry results were as follows:
Plasma
Calcium 1.98 mmol/L (2.15–2.55)
Albumin 30 g/L (35–45)
Phosphate 0.92 mmol/L (0.80–1.35)
What is the albumin-adjusted calcium?
Is his calcium levels normal?
= 1.98 + 0.20 = 2.18 mmol/L
Note that the plasma calcium now adjusted falls within the reference range and does not require specific treatment. Remember this if the patient has hypoalbuminaemia.
Calcium homeostasis follows the general rule that extracellular
concentrations are controlled rather than the total
body content. The effectiveness of this control depends
upon:
● an adequate supply of:
– calcium,
– vitamin D,
● normal functioning of the:
– intestine,
– parathyroid glands,
– kidneys.
What are the Biological Actions of PTH
Bone Resorption:
Mechanism: PTH stimulates osteoclasts, leading to bone resorption.
Outcome: This releases free ionized calcium and phosphate into the extracellular fluid (ECF), increasing their plasma concentrations.
Renal Actions:
Phosphate Reabsorption: PTH decreases renal tubular reabsorption of phosphate, leading to phosphaturia (increased phosphate excretion in urine).
Calcium Reabsorption: PTH increases renal tubular reabsorption of calcium, contributing to higher plasma calcium levels.
What regulates the secretion of PTH?
Calcium Concentration: The secretion of PTH is primarily regulated by the concentration of free ionized calcium in the blood:
Low Calcium Levels: A decrease in free ionized calcium stimulates PTH secretion.
High Calcium Levels: Once calcium levels return to normal, PTH secretion decreases.
Magnesium Concentration: Severe, chronic hypomagnesemia can decrease PTH secretion.
What’s the function of Parathyroid Hormone-related Protein (PTHRP)
Function: The exact role of PTHRP is not well understood, but it is believed to Mimic PTH activity and may play a role in fetal calcium metabolism. Its gene can be activated in tumors, causing hypercalcemia.
Calcitonin is produced by _____ & what’s it’s function?
the C cells (parafollicular cells) of the thyroid gland.
Calcitonin primarily acts to decrease osteoclastic activity, which slows the release of calcium from bones into the bloodstream.
Despite its effects, calcitonin is considered less crucial than PTH in maintaining calcium homeostasis under normal physiological conditions.
Paget’s Disease of Bone: Calcitonin is also used in the treatment of Paget’s disease, a disorder characterized by abnormal bone remodeling.
What are the Sources of Vitamin D
Ergocalciferol (Vitamin D2): Obtained from plants through the diet.
Cholecalciferol (Vitamin D3): Formed in the skin via the action of ultraviolet light (wavelength 270–310 nm) on 7-dehydrocholesterol. It is also found in animal tissues, especially the liver.
In adults, most cholecalciferol is derived from sunlight exposure rather than food. Dietary sources become critical when sunlight exposure is limited, such as during growth, pregnancy, or in the elderly and chronically sick who are often indoors.
Explain the Activation of Vit D
Liver Hydroxylation: Cholecalciferol is hydroxylated in the liver by the enzyme 25-hydroxylase to form 25-hydroxycholecalciferol, the main circulating form and store of the vitamin. inactive
Kidney Hydroxylation: In the kidney’s proximal tubular cells, 25-OHD3 undergoes a second hydroxylation by the enzyme 1-α-hydroxylase to form the active metabolite 1,25-dihydroxycholecalciferol (1,25-(OH)2D3), also known as calcitriol.
What are the Biological Actions of Active Vitamin D (1,25-(OH)2D3)?
Calcium Absorption:
Increases calcium absorption from the intestinal mucosal cells.
Bone Resorption:
Stimulates osteoclastic activity, releasing calcium from bones into the circulation. This action works synergistically with PTH.
Role in PTH Function:
Essential for the full action of PTH on bones. PTH secretion is stimulated by a fall in plasma free ionized calcium concentration.
PTH enhances 1-α-hydroxylase activity, increasing the synthesis of 1,25-(OH)2D3.
Synergistic Effects:
PTH and 1,25-(OH)2D3 together increase calcium release from bones and calcium absorption from the intestines.
Homeostatic Mechanisms
When plasma free ionized calcium concentration drops:
PTH secretion increases, enhancing 1-α-hydroxylase activity and boosting 1,25-(OH)2D3 production.
These hormones act on osteoclasts and intestines to restore calcium levels.
Once calcium levels normalize, PTH and 1,25-(OH)2D3 secretion are suppressed.
Increased plasma free Ca ion = high ph as well
But low plasma free Ca ion = phosphaturia; the loss of urinary phosphate over-rides the tendency to hyperphosphataemia due to the action of PTH on bone.
Low Plasma Calcium: Stimulates PTH secretion, leading to increased calcium levels and decreased phosphate levels due to phosphaturia.
High Plasma Calcium: Inhibits PTH secretion, resulting in decreased calcium levels and increased phosphate levels.
Renal Dysfunction: Can disrupt the normal relationship by impairing phosphate excretion.
What are the primary clinical consequences of hypercalcemia.
Bones, Moans, Groans, and Stones”
Bone and Joint Pain: Hypercalcemia is associated with pain in the bones and joints
Neuromuscular Excitability: High extracellular calcium levels depress neuromuscular excitability, leading to muscular weakness and hypotonia (decreased muscle tone)
Gastric Secretion: Calcium stimulates the secretion of gastrin, which increases gastric acid production. This can lead to peptic ulceration. Patients might also experience constipation and abdominal pain, and in severe cases, hypercalcemia can present as an acute abdomen.
Renal Calculi: Kidney stones (renal calculi) can form due to the precipitation of calcium salts in the urine when the free ionized calcium concentration in the glomerular filtrate is high.
Polyuria: Chronic hypercalcemia often leads to excessive urination. This happens due to calcification of the renal tubular cells, which impairs their ability to concentrate urine. Acute hypercalcemia can inhibit the tubular response to antidiuretic hormone (ADH), causing reversible polyuria and potential dehydration.
What are the Electrocardiogram (ECG) Changes in hypercalcaemia
shortening of the QT interval
Broadening of the T waves.
Plasma calcium levels above 3.5 mmol/L pose a risk of sudden cardiac arrest or ventricular arrhythmias, requiring urgent treatment.
True free ionized or albumin-adjusted hypercalcaemia with hypophosphataemia is usually caused by inappropriate secretion of PTH or PTHRP. The term
‘inappropriate secretion’ is used in this book to indicate that the release of hormone into the circulation is not adequately inhibited by negative feedback control.
Inappropriate PTH secretion occurs in the following clinical situations:
● production of PTH by the parathyroid glands due to:
– primary hyperparathyroidism,
– tertiary hyperparathyroidism.
Intestinal Absorption: PTH indirectly increases calcium absorption from the intestines by stimulating the production of active vitamin D (1,25-dihydroxyvitamin D)
What’s the most likely cause of true free ionized or albumin-adjusted hypercalcemia coupled with hypophosphatemia?
Inappropriate Secretion Explained:
Normally, hormone secretion is regulated by negative feedback mechanisms. For PTH, high levels of blood calcium should inhibit further secretion.
Inappropriate secretion means this feedback control fails, and PTH or PTHRP continues to be released even when calcium levels are high
Primary Hyperparathyroidism:
Definition: Overproduction of PTH by one or more of the parathyroid glands.
Causes: Often due to a benign tumor (adenoma) on a parathyroid gland, hyperplasia (enlargement) of the glands, or rarely, parathyroid cancer.
Tertiary Hyperparathyroidism:
Definition: Autonomous (independent) overproduction of PTH after long-standing secondary hyperparathyroidism, often associated with chronic kidney disease.
Causes: Prolonged stimulation of the parathyroid glands in response to low calcium levels due to kidney dysfunction, eventually leading the glands to function independently of calcium regulation.
Effects: Persistent high levels of PTH, causing hypercalcemia and hypophosphatemia despite high calcium levels
Absorption: Magnesium is absorbed in the gastrointestinal tract (GIT), primarily in the small intestine. Unlike calcium, its absorption is not dependent on Vitamin D.
Elimination: Approximately ____ of dietary intake is eliminated in feces without being absorbed.
70%
How is magnesium regulated?
Parathyroid Hormone (PTH): Regulates magnesium levels by enhancing renal reabsorption.
Insulin: Facilitates magnesium uptake into cells, thereby lowering serum levels.
Calcitonin: Involved in magnesium homeostasis, although its specific role is less clear compared to calcium.
Hypermagnesemia (> ___ mmol/l)
1.2 mmol/l
Clinical signs that f Hypermagnesemia
Clinical Signs and Symptoms
ECG Changes:
Prolonged PR interval
Widening QRS complex
Increased T-wave amplitude
Other Symptoms:
Hypotension due to vasodilation
Respiratory depression
Causes of Hypermagnesemia
Increased Intake:
Magnesium-containing antacids
Milk-alkali syndrome (excessive intake of calcium and antacids)
Purgatives containing magnesium
Parenteral nutrition with high magnesium content
- Impaired Renal Excretion:
Acute and chronic renal failure impair magnesium excretion.
Familial hypocalciuric hypercalcemia affects renal handling of multiple electrolytes, including magnesium.
Lithium treatment can disrupt magnesium balance.
- Miscellaneous Causes:
Hypothyroidism may alter magnesium metabolism.
Adrenal insufficiency can affect electrolyte regulation.
Treatment of hypermagnesemia
Treatment
Severe Cases:
IV calcium gluconate (10 ml of 10%) administered slowly to antagonize the effects of magnesium on cardiac function.
Insulin and Glucose Infusion: Promotes intracellular shift of magnesium.
Dialysis: Reserved for severe cases or when other measures fail to correct hypermagnesemia.
Hypomagnesemia ____ mmol/l)
(< 0.80
Clinical Signs and Symptoms Hypomagnesemia
General Symptoms:
Anorexia, vomiting, nausea
Lethargy, muscle weakness
Personality changes
Cardiac Manifestations:
Cardiac arrhythmias, potentially life-threatening
Causes of Hypomagnesemia
- Redistribution of Magnesium Between Cells:
Excess catecholamines in stress conditions shift magnesium into cells.
Re-feeding syndrome and hungry bone syndrome can lead to intracellular uptake of magnesium.
- Reduced Intake of Magnesium:
Parenteral nutrition lacking magnesium
Starvation or malnutrition with inadequate dietary intake
- Poor Magnesium Absorption:
Intestinal resection, gastrointestinal fistulae, and malabsorption syndromes impair magnesium absorption.
Increased Renal Loss of Magnesium:
Post-renal transplantation and dialysis increase magnesium excretion.
Bartter’s and Gitelman’s syndromes disrupt renal tubular reabsorption of magnesium.
Drug-Induced:
Diuretics, cytotoxic drugs, aminoglycosides, beta-2-adrenergic agonists, cyclosporine, tacrolimus, pamidronate, pentamidine, amphotericin B, and foscarnet can all cause magnesium loss.
- Miscellaneous Causes:
Alcoholism, hypercalcemia, hyperthyroidism, hyperaldosteronism, and poorly controlled diabetes mellitus affect magnesium homeostasis.
Treatment of Hypomagnesemia
Treatment
Severe Hypomagnesemia (< 0.5 mmol/L):
Oral magnesium salts (e.g., magnesium gluconate) up to 48 mmol/day in divided doses, but may cause gastrointestinal upset.
IV magnesium sulfate is used for rapid correction in severe cases.
Correction of hypomagnesemia may aid in managing refractory hypokalemia and hypocalcemia.
___ is a a divalent anion.
& is the major intracellular anion, with approximately 80% stored in bones and 20% in soft tissues and muscles.
Ph
____ of Ph is absorbed in the ___ . Sources include protein-rich foods, cereals, and nuts.
Excretion: Over 90% of phosphate is excreted via the kidneys, with gastrointestinal losses accounting for the remaining 10%.
80% in jejunum
FEPi% (Fractional Phosphate Excretion)
A value > 10% indicates renal phosphate loss.
List the functions of Ph
Functions of Phosphate
Intracellular Buffer: Acts as an important intracellular buffer, balancing hydrogen ions.
Structural Components: Essential component of phospholipids, nucleoproteins, and nucleic acids.
Metabolic Role: Crucial in cellular metabolic pathways like glycolysis and oxidative phosphorylation.
Neurological Function: Facilitates excitation-stimulus response coupling and nervous system conduction.
Immune Function: Supports optimal function of leukocytes and platelets.
What’s Ph reference range?
Reference Range: 0.87 – 1.45 mmol/l.
Factors regulating Ph
Vitamin D: Influences phosphate absorption in the gut.
Parathyroid Hormone (PTH): Increases urinary phosphate excretion and mobilizes calcium and phosphate from bones.
Growth Hormone: Enhances plasma phosphate levels by reducing renal excretion.
Kidney Function: Determines the physiological state of phosphate regulation.
Ionized Calcium Levels: Reciprocal variation with phosphate ions in plasma due to their complex interplay in bone metabolism.
Causes of Hyperphosphatemia
In-vitro hemolysis or old blood samples can falsely elevate phosphate levels.
Increased Phosphate Intake:
Inappropriate intravenous phosphate administration.
Increased Tissue Breakdown:
Seen in conditions like tumor lysis syndrome, malignant hyperpyrexia, and crush injuries.
Renal Conditions:
Acute or chronic renal failure leads to impaired phosphate excretion.
Acid-Base Disorders:
Acidaemia, whether metabolic or respiratory acidosis.
Diabetic ketoacidosis can also cause hyperphosphatemia.
Hormonal Disorders:
Hypoparathyroidism and acromegaly.
Excess intake of vitamin D can disrupt phosphate balance.
Treatment of Hyperphosphatemia
Treatment:
Oral phosphate binding agents like magnesium hydroxide or calcium carbonate.
In severe or persistent cases, hemodialysis or peritoneal dialysis may be necessary
Clinical signs of Hypophosphatemia
General Symptoms:
Anorexia, muscle weakness, neuromuscular disturbances.
Osteomalacia, potentially leading to coma or death in severe cases.
Causes of Hypophosphatemia
Cellular Redistribution:
Intravenous glucose administration.
Alkalosis, whether metabolic or respiratory.
Medical Interventions:
Administration of insulin or re-feeding syndrome.
Poor intake in conditions like total parenteral nutrition or malabsorption states.
Specific Disorders:
Renal tubular losses as seen in isolated phosphate disorders.
X-linked hypophosphatemia or conditions associated with oncogenic or Fanconi syndrome.
Miscellaneous Causes:
Liver disease, septicemia, hyperparathyroidism, or parathyroid hormone-related peptide release.
Treatment of Hypophosphatemia
General Management:
Usually unnecessary unless phosphate levels fall below 0.30 mmol/L or if symptomatic.
Oral phosphate salts are used, though they may cause diarrhea.
In severe cases, IV phosphate replacement with caution regarding risks in patients with hypercalcemia to avoid metastatic calcification.
Causes of Hypercalcemia
Primary hyperparathyroidism (adenoma, hyperplasia, or associated with multiple endocrine neoplasias).
Tertiary hyperparathyroidism.
Lithium-induced
hyperparathyroidism
High Bone Turnover:
Thyrotoxicosis.
Immobilization, as seen in Paget’s disease
Vitamin D toxicity.
Granulomatous diseases like sarcoidosis, tuberculosis
What are the rear cases & endocrine causes of hypercalemia
Other Endocrine Causes:
Adrenal insufficiency.
Acromegaly.
Rare Causes:
Human immunodeficiency virus (HIV) infection.
Leprosy.
Histoplasmosis.
Berylliosis (beryllium poisoning).
What are the drugs that can cause hypercalsemia
Drugs:
Thiazide diuretics (reduce renal calcium excretion).
Vitamin A toxicity.
Milk-alkali syndrome (excessive calcium and alkali intake).
Effects of Hypercalcemia
Gastrointestinal Effects:
Peptic ulceration due to increased gastrin production.
Constipation, abdominal pain, which can mimic acute abdomen.
Cardiovascular Effects:
Hypertension.
ECG changes: shortening of the QT interval and broadening of the T waves.
Risk of sudden cardiac arrest or ventricular arrhythmias if plasma calcium exceeds 3.5 mmol/L.
Musculoskeletal Effects:
Bone and joint pains.
How so you investigate for hypercalsemia?
Investigations of Hypercalcemia
Calcium Levels:
Establish plasma albumin concentration and correct for albumin to get the corrected calcium.
Ensure sample collection without venous stasis.
Medical History:
Review drug history, including vitamin D supplements and thiazide diuretics.
Consider milk-alkali syndrome and assess acid-base status if suspected.
Other Tests:
Check plasma phosphate concentration, as hypophosphatemia can suggest primary hyperparathyroidism.
Measure plasma PTH concentration.
Imaging studies to evaluate parathyroid glands.
Treatment of Hypercalcemia
Mild to Moderate Hypercalcemia (< 3.5 mmol/L):
No urgent treatment if no significant symptoms or ECG changes attributable to hypercalcemia.
Treat underlying cause once diagnosed.
Severe Hypercalcemia (≥ 3.5 mmol/L or with ECG changes):
Rehydration with saline to increase urinary calcium clearance and prevent fluid overload.
Loop diuretics (e.g., frusemide) may be used to enhance calcium excretion.
Bisphosphonates to inhibit bone resorption.
Steroids can be considered in certain cases.
Calcitonin for acute management to lower serum calcium levels.
Causes of Hypocalcemia
Exclude Hypoalbuminemic States:
Corrected calcium levels needed to account for albumin levels.
Drugs and Chemicals:
Furosemide.
Enzyme-inducing drugs like phenytoin.
Rarely, ethylene glycol overdose.
Hypocalsemia Causes with Hypophosphatemia & points to what dxs?
Vitamin D deficiency leading to rickets or osteomalacia.
Malabsorption states impairing calcium absorption
Hypocalsemia: Causes with Hyperphosphatemia:
Chronic renal failure.
Hypoparathyroidism (low PTH levels).
Surgical removal or congenital absence of parathyroid glands (e.g., DiGeorge syndrome).
Infiltration of parathyroid glands by tumors or conditions like hemochromatosis.
Pseudohypoparathyroidism (rare).
Miscellaneous Causes
:
Acute pancreatitis.
Sepsis.
High calcitonin levels.
Rhabdomyolysis.
Severe hypomagnesemia.
Autosomal dominant hypercalciuric hypocalcemia
What are the Effects of Hypocalcemia
Neuromuscular Effects:
Increased neuromuscular activity leading to tetany, carpopedal spasm, generalized seizures, laryngospasm, hyperreflexia, paraesthesia, and hypotension.
Prolonged hypocalcemia can lead to cataracts.
Other Effects:
Depression and other psychiatric symptoms.
Cardiac arrhythmias, prolonged QT interval on ECG.
How do you investigate for Hypocalcemia
Medical History:
Assess drug history and any history of neck surgery.
Laboratory Tests:
Measure plasma phosphate concentration, electrolytes (including calcium), urea, and creatinine.
PTH assay and plasma alkaline phosphatase activity.
Assess plasma 25-hydroxyvitamin D levels.
Imaging:
Perform relevant bone X-rays if indicated for conditions like rickets or osteomalacia.
Treatment of Hypocalcemia
Treat true hypocalcemia with mild symptoms using oral calcium supplements and vitamin D.
In renal disease, lower plasma phosphate concentration first to prevent calcium phosphate precipitation.
Symptomatic Hypocalcemia:
Life-threatening symptoms (cardiac arrhythmias, seizures, severe tetany) require urgent treatment.
Administer IV calcium gluconate (10 ml of 10% calcium gluconate over 5 minutes).
Postoperative Hypocalcemia:
Replace calcium during the first week post-op if tetany occurs.
Long-term vitamin D supplementation may be necessary.
