CLINICAL CHEMISTRY 2 MIDTERMS: ELECTROLYTES (Na+, K+, Cl-, Ca2+)

Water = consists 60% of total body weight.

Water in the body is divided into 2: Intracellular Fluid (ICF) or Extracellular Fluid (ECF)

ICF = 40% of body weight.

ECF = 20% of body weight. (Divided into two: Interstitial Fluid and Plasma)

Interstitial fluid = 80% of ECF while Plasma = 20% of ECF.

Electrolytes – are ions that carry electrical charges. (IT IS VERY IMPORTANT TO WRITE
ELECTROLYTES WITH THEIR CORRESPONDING CHARGE: Na+, K+, Ca2+, Cl-)

- They are solutes kept inside various body fluid compartments (in ICF or ECF).
- They can be classified as anions or cations (depending on their charge) and as free ions or
tissue-bound ions (depending on their location).
- 8 Major Electrolytes in the body: Sodium, Potassium, Calcium, Chloride, Magnesium,
Lactate, Phosphate and Bicarbonate.

Function of Electrolytes: (Familiarize!)

- Volume and osmotic regulation (WATER BALANCE) = Sodium, Chloride and Potassium.
- Myocardial rhythm and contractility = Potassium, Magnesium and Calcium.
- Cofactors in enzyme activation = Calcium, Magnesium and Zinc (Clue: all of them are
cofactors we already used in enzymes)
- Regulation of ATPase ion pumps = Magnesium.
- Acid-Base Balance = Bicarbonate, Potassium and Chloride.
- Blood Coagulation = Calcium and Magnesium.
- Neuromuscular Excitability = Potassium, Calcium and Magnesium.
- Production and use of ATP from Glucose = Magnesium and Phosphate.

***Bolded functions represent functions that are related to what we have already discussed in enzymes
or in the first four electrolytes. But also familiarize other functions for finals.

Laboratory Aspects of Electrolytes:

Laboratory Assays:

1. Chemical Methods – uses a sample which is first converted to a protein free filtrate (PFF)
and is made to react with certain chemicals to produce a color reaction.
- PFF = precipitate the proteins out from the sample first and remove them as proteins carry
charges which may interfere with electrolyte testing.
2. Flame Emission Spectrophotometry – uses a flame which is capable of exciting Group 1
metals (such as sodium, potassium and lithium) leading to their emission of color.
- Sodium = Yellow, Potassium = Purple, Lithium = Red.
- AKA Atomic Emission Spectrophotometry.
3. Atomic Absorption Spectrophotometry – uses a hollow cathode lamp which gives off energy
capable of exciting Group 2 metals (such as calcium).
4. Ion-Selective Electrode – uses a glass ion exchange membrane. (MOST COMMONLY USED
METHOD IN ALL ELECTROLYTE DETERMINATIONS)
Sodium

- Serum or Plasma can be used.

- When using plasma, always make sure that the anticoagulant of choice will not inhibit nor falsely
increase sodium levels in the body. (Lithium heparin, ammonium heparin and lithium oxalate
may be used as suitable anticoagulants)
- Anticoagulants which act to chelate metallic ions = False Decrease in Sodium levels.
- Use of Sodium Citrate, Sodium Heparin and Sodium EDTA = False Increase in Sodium
levels.
- Theoretically, sodium is not predominant intracellularly which is why sodium should not be
affected by hemolysis. But in reality or lab setting, hemolysis triggers the dilutional effect to occur.
- Dilutional effect happens because as RBCs lyse, they release water from their cells. This
causes sodium and chloride in the ECF to become falsely lower (diluted) due to water from the
lysed cells diluting the ECF where sodium and chloride are found predominantly.
- Slight hemolysis does not cause a significant change in Sodium levels but marked hemolysis
may falsely decrease Sodium levels.
- Whole blood may be used but only for STAT procedures. It is suitable for STAT since there is
no need to centrifuge whole blood specimens thus conserving time. It is only rarely used to test
for sodium levels.
- 24-hour timed Urine Specimen stored at refrigerator temperature (2nd morning urine of the 1st
day up to the 1st morning urine of the 2nd day)
- Sweat
- Pseudohyponatremia occurs when using an indirect ion-selective electrode method in a patient
who is hyperproteinemic or hyperlipidemic. The indirect ISE dilutes the sample prior to
analysis causing falsely decreased sodium levels. (Just a laboratory interference)

1. Chemical or Colorimetric Methods

a. Albanese-Lein – sodium (in PFF) + zinc uranyl acetate (actual reagent) + polyvinyl alcohol
(precipitate out the product) = sodium uranyl acetate precipitate.
- Sodium Uranyl Acetate precipitate + Water = YELLOW SOLUTION.
- Protein precipitant to form PFF = Trichloroacetic acid.

b. Magnesium-Uranyl – sodium (in PFF) + magnesium uranyl acetate = release of uranyl

ions.
- Uranyl ions + Thioglycolic = YELLOW-BROWN complex.
- Protein precipitant to form PFF = Uranyl Acetate and Magnesium Acetate.

2. Flame Emission Spectrophotometry – Sodium releases a yellow flame which is measured

spectrophotometrically.

3. Atomic Absorption Spectrophotometry

4. Ion-Selective Electrode – has no end color and uses a Sodium glass as membrane for
sodium level quantitations.

Reference Range: Plasma/Serum = 136-145 mmol/L

***Include the reference range for electrolytes!!! (No need for enzymes)
Potassium

- Higher levels in serum than in plasma. (This is because when blood coagulates, platelets
rupture and potassium is excreted out to the serum)
- Both serum and plasma may be used as sample but plasma is more preferred. (Due to above)
- Only electrolyte which differs significantly in its plasma and serum levels.
- Increased Platelet count (Thrombocytosis) = Increased Potassium levels. (Due to above)
- Prolong tourniquet application and fist clenching = False Increased Potassium levels
(Due to increased muscle exertion which leads to leaking of potassium from the cells)
- It is still, however, okay to tourniquet for potassium assays as long as it is not for too long.
- In vitro hemolysis = False Increase in Potassium levels. (Significantly and Greatly Elevated
since Potassium is higher in concentration intracellularly)
- Whole blood samples may be used but must be stored at room temp. and analysed
immediately.
- Use of Potassium EDTA (K2EDTA) and Potassium Oxalate Anticoagulants = False
Increase.
- ANTICOAGULANT OF CHOICE FOR POTASSIUM DETERMINATION = HEPARIN.
1. Chemical or Colorimetric Method
a. Lockhead and Purcell Method – Potassium + Sodium Cobaltinitrite (reagent) = Sodium
Potassium Cobaltinitrite.
- Sodium Potassium Cobaltinitrite + Phenol = BLUE COLOR.
2. Ion-Selective Electrode
- Uses a Valinomycin Membrane (antibiotic type of membrane) and KCl (Potassium
Chloride) as inner electrolyte solution.

Reference Range: Serum only = 3.5-5.1 mmol/L, Plasma only = 3.5-4.5 mmol/L or 3.4 to 4.4 mmol/L

Chloride

- Serum or Plasma may both be used as samples.

- Anticoagulant of choice = LITHIUM HEPARIN.
- Everything that happens to sodium, happens to chloride.
- Also subject to dilutional effect in cases of hemolysis similar with sodium.
- Slight hemolysis = No significant effect.
- Marked hemolysis = False Decrease (due to dilutional effect).
- Whole Blood, 24-hour timed Urine Specimen and Sweat may also be used as samples.
1. Mercurimetric Titration (Schales and Schales) – Chloride (in PFF) titrated with mercuric ions
(from mercuric nitrate) = mercuric chloride (does not dissociate to mercuric ions).
- Excess mercuric ions from the reaction (those that did not participate in the reaction) + s-
diphenylcarbazone = BLUE-VIOLET COLOR.
- Protein precipitant used to form PFF = Tungstic acid.
- Traditional Method for Chloride Determination.
2. Colorimetric Method: Mercuric Thiocyanate (Whitehorn Titration) – Sample + Mercuric
Thiocyanate = Mercuric Chloride.
- Free thiocyanate (those that did not participate in the reaction) + ferric ions (ferric nitrate) =
REDDISH-BROWN COLOR (Ferric thiocyanate).
 3. Amperometric-Coulometric Titration – Silver Ions (Ag2+) + Chloride ions = AgCl2.
- Excess or Free Silver from the reaction is used to indicate endpoint of the titration.
4. Ion-Selective Electrode – uses an ion-exchange membrane which selectively binds to
Chloride ions.

Reference Range: Plasma/Serum = 98-107 mmol/L

Calcium

- Total Calcium Levels = Serum or Lithium Heparinized Plasma collected without venous stasis.
- EDTA and Oxalate INHIBITS calcium levels and therefore must not be used.
- Ionized Calcium Levels (Free Calcium) = Heparinized Whole Blood; Serum may be used if
centrifugation is done in less than 30 minutes at room temperature.
- For ionized calcium levels, dried heparin products must be used since it has an inert “puff” that
eliminates interferences by heparin. (DO NOT USE LIQUID HEPARIN PRODUCTS as they
partially bind to calcium and lower its concentration)
- Samples must be collected anaerobically as loss of CO2 will increase the pH of the sample.
- Timed Urine Specimens may be used but needs to be acidified with 6M HCl. (1mL of acid per
100 mL of urine or 1:100)
1. Ortho-cresolphthalein Complexone – forms a complex with calcium ions and uses 8-
hydroxyquinoline to eliminate/prevent Magnesium interference.
2. Arsenazo III Dye – forms a complex with calcium ions.
3. Atomic Absorption Spectrophotometry – reference method for Total Calcium levels.
4. Ion-Selective Electrode – use membranes with special molecules that selectively but
reversibly bind to calcium ions.

***Flame Emission or Atomic Emission Spectrophotometry is not used for Calcium as it is not easily
excited by flame so it does not emit any color.

Reference Range: Do not memorize for calcium since there are too many.

***NOTE THAT FOR THE REFERENCE RANGE, A GREAT CLUE WILL BE TO IDENTIFY IF THE
ELECTROLYTE IS INTRACELLULAR OR EXTRACELLULAR. Extracellular electrolytes have greater
values in serum while intracellular electrolytes have very low values in serum.

For example: Sodium and Chloride (Extracellular) = 100+ in serum

Potassium and Calcium (Intracellular) = Only 3-5 (K+) or 1-2 (Ca2+) in serum.
SODIUM

- A monovalent cation bearing the charge of 1+ (Na+).

- Most abundant EXTRACELLULAR CATION representing 90% of all extracellular cations. (The
most abundant extracellular cation is a frequent question in quizzes and exams)
- Large determinant of plasma osmolality.
- Present in the ECF much larger than inside the cell. (Always remember PISO: Potassium
inside, Sodium outside)
- Sodium is important to the ECF because where sodium goes, water follows. If sodium is
increased inside the cell, then water will also go inside the cell which causes swelling and
eventual cell lysis.
- The continual removal of sodium from the cell prevents osmotic rupture of the cell since it also
draws out water from the cell whenever sodium is expelled out.

Sodium-Potassium Leak Channels

- Even though sodium is supposed to be only predominant outside the cell while potassium should
be inside, the high concentration of sodium outside will cause them to follow the principle of
simple diffusion (movement of molecules from an area of higher concentration to lower
concentration) which is why they may also leak into the cell. To correct this, we have the Na-K
Pump.

Sodium-Potassium ATPase Pump

- Follows the principle of PISO, DOS, TRES meaning that potassium should be inside while
sodium should be outside. The pump works by importing 2 potassium ions into the cell while
excreting 3 sodium ions outside the cell. (This fulfils the PISO principle of sodium in, potassium
out)

Regulation of Sodium: (Understand and do not memorize. This will go a long way if mastered although
really confusing so always read questions carefully and imagine what your body must do to correct
imbalances) (IN RELATION TO DISEASES NA PUD NI SYA NA PART)

Plasma Sodium Concentration – depends greatly on intake and excretion of water and, to a
lesser extent, on the renal regulation of Sodium.

1. Intake of Water in response to Thirst

- When you are thirsty, it suggests that your body is in need of water to balance the growing high
concentrations of sodium (hypernatremia and hyperosmolality) in the plasma. This is why the
brain stimulates you to drink water as this will balance the sodium concentration in the plasma
by diluting it.

2. Excretion of Water in response to ADH. (Other name for ADH is AVP = Arginine
Vasopressin)
- Also in response to thirst (hypernatremia or hyperosmolality), the brain will release ADH which
will act on the collecting duct of the kidneys to stimulate water reabsorption. This will cause a
low urine volume because the water is conserved so that the body can balance the high sodium
concentration.
 3. Blood Volume Status through Aldosterone, Angiotensin II and ANP (Atrial Natriuretic
Peptide)
- Kidneys have the ability to conserve or excrete large amounts of Sodium as normally 60-75%
of filtered sodium is reabsorbed back in the PCT.
- Some sodium is also reabsorbed by the Loop of Henle and DCT and exchanged for Potassium
ions in the collecting duct. (Work of Aldosterone if reabsorption while ANP prevents this from
occuring)
- When there is hypovolemia (low blood volume) or low blood pressure, the kidneys will detect
the stimulus and activate the Renin-Angiotensin-Aldosterone System (RAAS). Angiotensin II is
the final product of the RAAS which will increase the blood pressure of the body and also
stimulate release of aldosterone by the zona glomerulosa of the adrenal cortex.
- Aldosterone functions for Sodium Retention in the kidneys and with it Water Retention
(since where sodium goes, water follows) which corrects the hypovolemia experienced by the
body.

***Imagine that if you only reabsorb sodium, the body will have too much positive charge on one side.
In order to combat the excess positive charge, aldosterone must also excrete potassium ions out
of the body. You gain positive but you also lose positive = BALANCE.

- ANP has the opposite function with aldosterone and is stimulated in cases of hypervolemia
and high blood pressure. ANP will facilitate Sodium Excretion and therefore also Water
Excretion. By excreting sodium and water, this will correct the hypervolemic state of the body.

***If you are wondering why aldosterone and ANP affects blood pressure, this is because that increased
blood volume = higher blood pressure while low blood volume = lower blood pressure. (The effects of
these hormones in maintaining blood volume also corrects blood pressure changes)

***In summary, hypernatremia and hyperosmolality triggers WATER TO BE INSIDE THE BODY by
eliciting thirst (if you drink water, the problem is corrected) and secretion of ADH (by conserving water
the problem is corrected).

Additionally in cases of hypernatremia, ANP is released by the heart in order to regulate sodium levels
in the body (by facilitating sodium excretion and potassium reabsorption).

In cases of hyponatremia and subsequent hypovolemia (since low sodium = low water retention),
Angiotensin II and Aldosterone work hand in hand by increasing sodium and water reabsorption in the
kidneys while excreting potassium (to maintain electrical charge balance).

Diseases:

Hyponatremia – less than 136 mEq/L.

- One of the most common electrolytes disorders.

- Caused by: Increased Sodium Loss, Increased Water Retention and Water Imbalance.

Hypernatremia – greater than 145 mEq/L.

- Less common
- Caused by: Increased Sodium Intake, Increased Water Loss, Decreased Water Intake.

Clinical Significance: FAMILIARIZE HOW THE DISEASE CAUSE THE CONDITION

HYPONATREMIA (More water retention will cause the serum to be diluted thus causing low sodium)

1. Increased Water Retention

- Renal Failure, Hepatic Cirrhosis and Nephrotic Syndrome = Decreased Plasma Proteins (due to
damage in kidneys or damage to liver) = Water Migration from Blood vessels to Tissues =
Stimulation of ADH = Increased Water Retention = Diluted Sodium (Hyponatremia)
2. Water Imbalance
- Excess Water Intake (Polydipsia) = More water = more diluted sodium = Low Sodium
Levels.
- SIADH (Syndrome of Inappropriate ADH) = More ADH = More water retention = Diluted
Sodium.
- Pseudohyponatremia = Sodium is measured using indirect ion-selective electrodes in a
patient who is hyperproteinemic or hyperlipidemic. The indirect ISE dilutes the sample prior
to analysis causing falsely decreased sodium levels. (Pseudo = not a pathologic type of
hyponatremia)
3. Increased Sodium Loss
- Hypoaldosteronism = Low Aldosterone = Low Sodium Retention = Low Sodium in Body.
- K+ Deficiency = Low Potassium = Kidneys conserve Potassium = Excrete Sodium (to
maintain balance)
- Diuretic Use = More urination = More Sodium Excreted = Low Sodium Levels.
- Use of ACE inhibitors (CAPTOPRIL) = No Angiotensin II = No Aldosterone Stimulation =
Low Sodium Retention (Hyponatremia)
- Prolonged vomiting = self-explanatory (stimulate ADH) = diluted sodium.
- Diarrhea = self-explanatory (stimulate ADH) = diluted sodium.
- Severe Burns = self-explanatory (stimulate ADH) = diluted sodium.

HYPERNATREMIA (When there is no water reabsorption, all the water filtered by the glomerulus will
be excreted in the urine causing a low water volume in the body which concentrates the serum)

1. Increased Water Loss

- Diabetes Insipidus = No ADH = No water reabsorption = Concentrated serum = High
Sodium.
- Renal Tubular Disorder = No water reabsorption = Concentrated serum = High Sodium.
- Prolonged Sweating = Lose water = Concentrated serum = High Sodium.
- Diarrhea = Lose water = Concentrated serum = High Sodium.
- Severe Burns = Lose water = Concentrated serum = High Sodium.
2. Decreased Water Intake
- Geriatric patients (Old people) = Impaired water reabsorption = Concentrated serum = High
Sodium.
- Infants = Cannot get water to drink = Forgetful parents = Concentrated serum = High Sodium.
- Mental Impairment = Some people are insensitive to thirst = Concentrated serum = High
Sodium.
3. Increased Sodium Intake/Retention
- Hyperaldosteronism = More sodium retention = High Sodium.
- Excess Sodium Bicarbonate or Hypertonic Dialysis Solutions = used for a certain medical
procedure (which I do not know) but since more sodium intake = High Sodium. (USUALLY
NEONATES ARE SUSCEPTIBLE TO THIS)
***The bolded ones are the very prominent factors which may most likely come out of the exam. Please
familiarize and understand how they cause hyper or hyponatremia.

POTASSIUM

- MAJOR INTRACELLULAR CATION. (Frequent question in exams or quizzes)

- It is 20x greater inside the cell than outside which is why it is termed as “housed within the
cell”.
- Follows the principle of PISO and PISO, DOS, TRES : 2 molecules of Potassium goes inside
the cell in exchange for 3 molecules of Sodium to go outside.
- Regulated by the Sodium-Potassium ATPase Pump.

Functions:

1. Neuromuscular Excitability and Heart Contraction (Memorize table!)

Hyperkalemia (Increased) Hypokalemia (Decreased)
Low Intracellular Potassium High Intracellular Potassium
Muscles Decreased Contraction Increased Contraction
Heart Bradycardia (Slow Heart Rate) Tachycardia (Fast Heart Rate)
Paralysis Flaccid Paralysis Rigid Paralysis

2. Maintenance of Intracellular Fluid Volume – since potassium is the one being imported inside
the cell, it prevents too much sodium and water to go inside the cell thus controlling ICF volume.
3. Maintenance of H+ Concentration
- Increased H+ in plasma will cause an acidic pH. When blood is too acidic, H+ in the ECF is
exchanged with the K+ inside the cells in order to decrease plasma hydrogen
concentration and thus regulating the pH. However, this will also cause an increased potassium
level in the plasma due to the exchange leading to hyperkalemia.
- Exchange can happen since potassium ions have 1 positive charge while hydrogen also has 1
positive charge. They balance out each other.
- The opposite happens when there is alkalosis. Decreased H+ in plasma will cause H+ inside
the cells to be secreted out to the plasma with subsequent exchange of potassium going
inside the cell. This mechanism regulates the pH but also causes a decreased potassium level
in the plasma causing hypokalemia.
Regulation:

- In normal conditions, almost 100% of potassium ions are reabsorbed by the PCT.
- However when aldosterone is present, additional K+ is excreted into the urine in exchange for
Na+ to be reabsorbed. (When sodium is reabsorbed, potassium must also be excreted in order
to maintain electrical charge balance)
- More aldosterone (Hyperaldosteronism) = More sodium (Hypernatremia) and also Less
potassium (Hypokalemia).
- Hypoxia = inhibits the Na+/K+ ATPase Pump since the pump requires oxygen to perform its
function. (This causes sodium and potassium imbalance in the body: most likely hyponatremia
and hyperkalemia but may also be the other way around)
- Insulin = promotes cellular entry of potassium ions by increasing the activity of the Sodium-
Potassium Pump. (Insulin overdose = Hypokalemia)
- Catecholamines (Beta-stimulator) = promotes cellular entry of potassium ions. (Leading to
Hypokalemia)
- Propanolol (Beta-blocker) = impairs cellular entry of potassium ions. (Leading to
Hyperkalemia)
- Dietary intake of potassium is not usually a primary cause of hypo or hyperkalemia. But dietary
deficiency and excess of potassium enhances the degree of already existing hypo or
hyperkalemia in a patient.

Clinical Significance:

HYPOKALEMIA – less than 3 mmol/L.

- Caused by Gastointestinal Loss, Renal Loss, Cellular Shift and only rarely Decreased Intake.

1. Gastointestinal Loss (All are self-explanatory. One loses potassium by excreting a lot of it or by
not absorbing it in the body)
- Vomiting
- Diarrhea
- Gastric Suction
- Intestinal Tumor
- Malabsorption
- Cancer therapy (chemotherapy or radiation)
- Large Doses of Laxatives

2. Renal Loss (Mostly self-explanatory)

- Diuretics = Increased urination = Increased Potassium Loss in Urine = Hypokalemia.
- Nephritis = Damage to the Kidneys = General Low Ion Retention = Hypokalemia.
- Renal Tubular Acidosis = Inability to release ammonia by the renal epithelial cell =
Decreased H+ excretion = Increased K+ excretion. (Remember H+ and K+ relationship and
balance)
- Hyperaldosteronism = High Aldosterone Secretion = High Na+ Retention = High
Potassium Excretion (Hypokalemia).
- Cushing’s Syndrome = High Cortisol = High Adrenal Gland Stimulation = High
Aldosterone = High Sodium Retention = High Potassium Excretion (Hypokalemia).
- Hypomagnesemia = Decreased Mg2+ = Decreased Na+/K+ ATPase Pump and Increased
Aldosterone Secretion = Low Plasma Potassium = Hypokalemia.
 3. Cellular Shift

- Alkalosis = Decreased H+ in Plasma = H+ inside cell will go out to regulate pH = K+ in

ECF will go inside the cell (to maintain balance) = Low Plasma Potassium (Hypokalemia).
- Insulin Overdose = High Insulin = Increased Na+/K+ ATPase Pump Activity = Low Plasma
Potassium = Hypokalemia.

HYPERKALEMIA – panic value is > 8 mmol/L.

- Caused by Decreased Renal Excretion, Cellular Shift, Increased Intake, Artifactual

1. Decreased Renal Excretion

- Acute or Chronic Renal Failure
- Hypoaldosteronism = Low aldosterone = Low Sodium Retention = High Potassium
Retention (Hyperkalemia).
- Addison’s Disease = Low cortisol = Low stimulation of adrenal glands = Low aldosterone

= Low Sodium Retention = High Potassium Retention (Hyperkalemia).

2. Cellular Shift
- Acidosis = Increased H+ in blood = H+ goes inside cell to regulate pH = K+ goes outside
the cell (to maintain electroneutrality balance) = High Plasma Potassium (Hyperkalemia).
- Muscle/Cellular Injury (Crush Injury) = Cellular Damage = Release of Intracellular
Potassium to ECF = High Plasma Potassium (Hyperkalemia).
- Chemotherapy (especially Captopril) = Inhibition of ACE = No Angiotensin II = No
Aldosterone = Low Sodium Retention = High Potassium Retention.
- Hemolysis = Lysis of RBCs = Release of Intracellular Potassium = High Plasma Potassium
(Hyperkalemia).
- Leukemia

3. Increased Intake
- Oral or Intravenous Potassium Therapy = Greatest Risk and Most Common Cause of
Hyperkalemia.
4. Artifactual (Sources of Error for Lab Assays; discussed already in lab methods)
- Sample Hemolysis = self-explanatory.
- Prolonged tourniquet Use or Excessive Fist Clenching = leaking of potassium from cells.
- Serum = Platelets must rupture in order to form clot. Since serum is coagulated blood, platelets
rupture which leads to release of potassium.
- Thrombocytosis = Increased Platelets = Increased Coagulation = Increased Rupture =
Increased Potassium.

***DIABETES MELLITUS is also capable of causing hyperkalemia. This is because in DM, insulin is
deficient. Insulin deficiency promotes cellular loss of K+ (opposite to effect of insulin overdose stated
in hypokalemia).

***For hypokalemia (most likely case study in exam): Renal Tubular Acidosis, Hypomagnesemia,
Cushing’s Syndrome, Hyperaldosteronism

***For hyperkalemia: Hypoaldosteronism, Addison’s, Captopril, Crush Injury, Metabolic Acidosis, DM,
IV or Oral Potassium Therapy and all sources of laboratory errors.
Additional on Potassium not discussed in Lecture (Bishop):

Hypothermia – causes movement of K+ into cells (hypokalemia).

Hyperthermia (warming of body) – causes release of K+ from cells (hyperkalemia).

Increased Bicarbonate in Blood (Alkalosis) – causes hypokalemia due to H+/K+ relationship. (Likely to
come out in exam)

Digoxin – inhibits Na+/K+ Pump causing hyperkalemia and hyponatremia.

Banked Blood – RBC storage causes gradual release of potassium (hyperkalemia).

CHLORIDE

- MAJOR EXTRACELLULAR ANION. (Frequent question in exams and quizzes)

- It is very important to be partnered to Sodium for maintenance of ELECTRONEUTRALITY.
- If only Na+, then ECF gains too much positive charge. But with chloride, it evens out the positivity
of sodium.
- Amount of Sodium Reabsorbed = Depends on Chloride Levels.
- Sweat Chloride Levels are important for the diagnosis of cystic fibrosis. Cystic fibrosis is a
disease that occurs due to a defect in the cystic fibrosis transmembrance conductance
regulatory protein (CFTR). Presence of chloride in sweat is a positive test. Sweat chloride is a
very sensitive and specific test for cystic fibrosis.

Chloride Shift:

- Acts to Maintain Electroneutrality together with Na+/Cl- reabsorption relationship.

- Acts to regulate electroneutrality with Bicarbonate (HCO3-).
- HCO3 is abundant inside the cell while chloride is abundant outside the cell.
- In cases of acidic pH, HCO3 goes outside the cell to regulate the pH while chloride goes inside
the cell causing hypochloremia. (If bicarbonate goes out, chloride must go in)
- In cases of alkaline pH, HCO3 goes inside the cell to regulate pH while chloride goes outside
the cell causing hyperchloremia. (If bicarbonate goes in, chloride must go out)
- Similar in principle to K+ and H+ Relationship.

Regulation: May be affected by aldosterone since it functions for sodium retention which also requires
chloride retention to maintain electroneutrality.

- Excessive sweating also stimulates aldosterone secretion leading to sodium and chloride
reabsorption.

Clinical Significance:

ALL DISORDERS THAT DISTURB SODIUM LEVELS ALSO AFFECT CHLORIDE IN THE SAME WAY
AS CHLORIDE WILL ALWAYS FOLLOW SODIUM.

Only disorders that are exceptional for Chloride are the following:

- Excess Loss of HCO3- due to GI losses, Renal Tubular Acidosis or Metabolic Acidosis =
Loss of Plasma Bicarbonate = Negatively Charged Plasma = To restore balance, Chloride
goes out to the plasma = Hyperchloremia (restores balance to the electroneutrality).
 - Respiratory Acidosis = acidic pH = Bicarbonate goes out to plasma while chloride must
go in = Hypochloremia.

CALCIUM

- MOST ABUNDANT CATION IN THE BODY. (Frequently asked question in exam and quizzes)
- Unique since most abundant in ICF + ECF while potassium is most abundant only in the ICF.
- 99% of calcium in the body is stored in the bones as hydroxyapatite or hydroxyphosphate.
- 1% is found in the circulation where: 15% = bound to anions, 40% = bound to albumin,
45% = occurs as free/ionized calcium.

Functions:

- Structure and Function of Bones and Teeth.

- Stabilizes Cell Membrane and Reduces Cell Permeability to Sodium.
- Transmit Nerve Impulses.
- Muscle Contraction. (Very Important)

***Under the function of muscle contraction, Calcium has a very important role in myocardial
contraction. Both Calcium and Potassium are known as Chronotropic Chemicals. In the heart,
Potassium has a greater effect in myocardial contraction than Calcium but both of them exert the
same function.

***WHATEVER HEART INVOLVEMENT THAT HAPPENS IN HYPERKALEMIA ALSO OCCURS IN

HYPERCALCEMIA (with only a lower effect than that of potassium).

***Hypokalemia and Hypocalcemia = tachycardia and increased muscle contraction.

***Hyperkalemia and Hypercalcemia = bradycardia and decreased muscle contraction.

- Blood Coagulation. (IMPORTANT COFACTOR IN THE CLOTTING PATHWAY WHICH IS

WHY MOST ANTICOAGULANTS FUNCTION TO INHIBIT CALCIUM)

Regulation:

1. Parathyroid Hormone – produced by the Parathyroid Gland and acts to increase Calcium
levels.
- PTH release is stimulated by a decrease in ionized Ca2+ levels.
- PTH acts to stimulate osteoclastic activity resulting to increased bone resorption and
subsequent release of calcium in the body. It acts on the kidneys to facilitate calcium
reabsorption in the tubules and also stimulates renal production of active Vitamin D.
2. Vitamin D3 – full name is 1,25-Dihydroxycholecalciferol and is the active form of Vitamin D.
- It is obtained from the diet or exposure of skin to sunlight.
- It functions to increase Calcium absorption in the intestines and enhances the effect of
PTH on bone resorption.
3. Calcitonin – produced by the medullary cells of the thyroid gland which acts to decrease
Calcium levels.
- Calcitonin release is stimulated by an increase in blood Calcium levels (hypercalcemic
state).
- It acts to inhibit the actions of both PTH and Vitamin D3.
Clinical Significance:

CAUSES OF HYPOCALCEMIA:

Primary Hypoparathyroidism (aplasia, destruction or removal) – Absence of PTH = Absence of

All Functions of PTH = Decreased Calcium Levels in Body = Hypocalcemia.

Pseudohypoparathyroidism – Hereditary Disorder where there is Decreased Cyclic Adenosine

Monophosphate (cAMP) = End Organ Resistance (bone and kidneys are insensitive to PTH) =
Low Calcium Levels (Hypocalcemia).

Hypomagnesemia and Hypermagnesemia – Low Magnesium or Too High Magnesium = Causes

Inhibition of PTH Secretion, Inhibits PTH Action in Bone and Causes Vitamin D Resistance =
Low Calcium Levels (Hypocalcemia).

Rhabdomyolysis (along with crush injury and muscle damage) – Causes Increased Phosphate
Release from Muscle Cells = Binds to Free Calcium Ions = Low Calcium Levels (Hypocalcemia).

Acute Pancreatitis – Causes Release of Amylase and Lipase = Both Utilize Calcium as Cofactor
= Low Calcium Levels (Hypocalcemia).

Hypoalbuminemia (due to chronic liver disease, nephrotic syndrome and malnutrition) = Decrease in
TOTAL CALCIUM LEVELS but NORMAL IONIZED CALCIUM LEVEL.

Vitamin D Deficiency and Malabsorption – self-explanatory.

Renal Disease (caused by Glomerular Failure) – Increased Loss of Calcium in Urine = Hypocalcemia.

CAUSES OF HYPERCALCEMIA:

Primary Hyperparathyroidism – Excess Secretion of PTH = Increased Calcium Levels =

Hypercalcemia. (MAIN CAUSE OF HYPERCALCEMIA)

Malignancies – Tumors Produce PTH-Related Peptide (PTH-rP) = Binds to PTH Receptors =

Increased Calcium Levels = Hypercalcemia. (SECOND MAIN CAUSE OF HYPERCALCEMIA)

Hyperthyroidism – Enlargement of Thyroid Gland = Due to Close Proximity of Thyroid and

Parathyroid, Parathyroid also Undergoes Enlargement = More Secretion of PTH = Increased
Calcium Levels (Hypercalcemia).

Increased Vitamin D – self-explanatory.

Benign Familial Calciuria

Thiazide Diuretics

Prolonged Immobilization = Increased Bone Resorption = Increased Calcium Levels (Hypercalcemia)

***Hypercalcemia can be an indicator of Multiple Myeloma. This is due to the breakdown of bone
which occurs in the disease which leads to leaking of calcium from the bone to the bloodstream.

***For Hypocalcemia: Primary Hypoparathyroidism, Pseudohypoparathyroidism, Hypomagnesemia,

Rhabdomyolysis and ACUTE PANCREATITIS (related with enzyme knowledge so case study is likely).

***For Hypercalcemia: Primary Hyperparathyroidism, Hyperthyroidism, Malignancies and Multiple

Myeloma.