Chemistry, toxicology & urinalysis

General chemistry

Metabolism

Electrolytes


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Olajumoke Oladipo, M.D.

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PubMed Search: Electrolytes

Olajumoke Oladipo, M.D.
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Cite this page: Oladipo O. Electrolytes. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/chemistryelectrolytes.html. Accessed May 19th, 2024.
Definition / general
  • Sodium is the principal extracellular cation, while potassium is the principal intracellular cation
  • Principal extracellular anions are chloride and bicarbonate, while principal intracellular anions are proteins and phosphate
Essential features
  • Hyponatremia is dependent on plasma osmolality and volume status of the patient
  • Kidneys play an important role in electrolyte balance
  • Chloride concentrations in plasma usually parallels those of sodium
  • Most common method of analysis of electrolytes is by ion selective electrodes
Sodium
  • Sodium plays a central role in water balance and maintenance of extracellular fluid (ECF) osmotic pressure
  • Sodium balance is controlled by renal blood flow and aldosterone
  • Sodium and its associated anions (mainly chloride) contribute 90% or more to the measured plasma osmolality
  • Serum osmolality can be measured directly or calculated from serum sodium, urea and glucose
  • Urine sodium excretion is dependent on diet; urine sodium exhibits diurnal variation with lower sodium excretion occurring at night
  • Preanalytical factors affecting sodium measurements
    • Exercise
    • Prolonged tourniquet application
    • Sample collection: order of collection, needle size, mixing techniques, collection tubes
    • Posture
    • Postprandial
    • Stress
    • Medications
    • Weather / seasons
    • Transportation of samples
  • Reference: Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018

Hyponatremia
  • Defined as plasma serum sodium concentration of < 135 mmol/L
  • Affects ~5% of adults and 35% of hospitalized patients (JAMA 2022;328:280)
  • Clinical features include weakness, nausea, headache, vomiting, somnolence, seizures, cardiorespiratory distress
  • Cause: depends on the measurement of plasma osmolality
  • Hypo-osmotic hyponatremia: most common form; due to excess water loss or increased extracellular fluid volume and is also dependent on volume status
    • Hypervolemia: renal failure, congestive heart failure, liver cirrhosis with ascites, nephrotic syndrome
    • Hypovolemia
      • With increased renal loss (> 20 mmol/L urine sodium): diuretics, renal diseases, metabolic alkalosis, mineralocorticoid deficiency, carbonic anhydrase inhibitors
      • With decreased renal loss (< 10 mmol/L urine sodium): vomiting, diarrhea, burns
    • Euvolemia: diuretics, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypothyroidism, secondary hypoadrenalism
  • Hyperosmotic hyponatremia
    • Severe hyperglycemia
    • Uremia
    • Mannitol diuresis
  • Iso-osmotic hyponatremia: plasma osmolality is normal with decreased sodium concentration
    • Pseudohyponatremia: electrolyte exclusion effect due to hyperlipidemia or hyperproteinemia
      • Proteins and lipids decrease water content and can alter ion concentrations measured
      • Usually occurs in patients with hyperlipidemia or hyperproteinemia
      • Occurs in indirect ion selective electrode (ISE) measurements; most automated analyzers use the indirect ion selective electrode method
      • Results in underestimation of sodium
  • References: Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018, Nephrol Dial Transplant 2014;29:i1, JAMA 2022;328:280

Hypernatremia
  • Plasma sodium concentration > 145 mmol/L
  • Always hyperosmolar in nature
  • Can present as acute or chronic hypernatremia; clinical features include weakness, malaise, delirium, tremors, irritability, confusion, coma, ataxia (Diagnosis (Berl) 2022;9:403)
  • Cause depends on volume status (Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018)
  • Hypovolemic hypernatremia: decreased extracellular fluid caused by renal (osmotic diuretics) or extrarenal (diarrhea, fever, burns, excessive sweating and respiratory losses, poor water intake) loss of hypo-osmotic fluid leading to dehydration
  • Hypervolemic hypernatremia: net gain of water and sodium with a higher sodium gain compared to water; occurs in hospitalized patients on hypertonic saline or bicarbonate infusion, Conn syndrome or Cushing syndrome with excess mineralocorticoid, accidental salt ingestion
  • Normovolemic / euvolemic hypernatremia: normal extracellular fluid volume; can be renal (glycosuria, increased urea load, diabetes insipidus) or extrarenal (hyperventilation)
  • Artifactual or pseudohypernatremia: can occur following the use of collection tubes with sodium heparin as anticoagulant
Potassium
  • Major intracellular cation
  • 2% present in extracellular fluid; ~90% of the daily K+ intake is excreted in the urine and ~10% is excreted by the gastrointestinal tract
  • Intracellular potassium is maintained by energy dependent sodium - potassium ATPase pump
  • Extracellular H+ ions affect the entry of potassium into all cells
  • Kidney is the major organ responsible for K+ homeostasis (major site is the distal convoluted tubule) (Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018)
  • Preanalytical factors affecting potassium measurements
    • Hemolysis falsely elevates K+ value (intracellular release)
    • Serum K+ is higher than plasma potassium due to release during clot formation
    • Thrombocytosis / leukocytosis
    • Refrigeration of whole blood specimens
    • In unspun specimens at 37 °C
    • Prolonged tourniquet application
    • Exercise

Hypokalemia
  • Plasma potassium < 3.5 mmol/L
  • Clinical features include muscle weakness, paralysis, irritability, tachycardia, cardiac conduction defects, cardiac arrest
  • Redistribution
    • Alkalosis
    • Insulin response
    • Hypothermia
    • Familial hypokalemic periodic paralysis
    • Pseudohypokalemia in thrombocytosis or leukocytosis
    • Beta adrenergic excess
  • True potassium deficit
    • Renal (if renal potassium loss is > 30 mmol/day)
      • Renal tubular acidosis
      • Fanconi syndrome (disorder of renal proximal tubules leading to excessive excretion of certain electrolytes and amino acids)
      • Diuretic phase of acute tubular necrosis (ATN)
      • Medications: diuretics, penicillins, amphotericin B toxicity
      • Glucocorticoid excess
      • Mineralocorticoid excess
    • Nonrenal (renal potassium loss is < 30 mmol/day)
      • Diarrhea, vomiting, GI fistula
      • Starvation
      • Excessive sweating
  • Reference: Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018

Hyperkalemia
  • Plasma potassium > 5.0 mmol/L
  • Clinical features include mental confusion, weakness, tingling, flaccid paralysis of extremities, bradycardia and respiratory muscle weakness
  • Severe hyperkalemia (> 7 mmol/L) can lead to cardiac arrest
  • Causes
    • Redistribution
      • Acidemia transfer of intracellular K to extracellular fluid
      • Tissue hypoxia
      • Diabetic ketoacidosis
      • Severe burns
      • Massive intravascular hemolysis
      • Status epilepticus (sustained muscular activity)
      • Tumor lysis syndrome
      • Rhabdomyolysis
    • Potassium retention
    • Pseudohyperkalemia
      • Hemolysis
      • Thrombocytosis
      • Leukocytosis
Chloride

Hypochloremia
Hyperchloremia
Bicarbonate
  • Bicarbonate makes up the second largest fraction (behind Cl-) of plasma anions
  • Includes (1) plasma bicarbonate ion (HCO3-), (2) carbonate ion (CO32-) and (3) CO2 bound in plasma carbamino compounds (RCNHCOOH)
  • Actual bicarbonate ion concentration is not measured in clinical laboratories
  • Analyte usually measured in plasma is total CO2, which includes bicarbonate and dissolved CO2 (dCO2) but is often referred to as serum bicarb
  • The most important buffer of plasma is the bicarbonate / carbonic acid pair
  • Because HCO3- and CO2 are the major buffers of the body, pH is typically expressed as a function of their ratio
  • Disorders of CO2 are usually referred to as respiratory disorders and disorders of HCO3- are referred to as metabolic disorders
  • Kidneys have the predominant role of regulating the systemic HCO3- concentration
  • Methods for total CO2 measurement with today’s automated instruments may be electrode based or enzymatic
  • Reference: Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018
Calcium
  • Calcium has a major structural role in the formation of bone and is important in blood coagulation, neurological and neuromuscular function and intracellular signaling
  • Majority of calcium in the body is localized to bone (~99%)
  • ~1% of calcium that is not associated with bone makes up the slowly exchangeable pool and the rapidly exchangeable pool
    • Slowly exchangeable pool encompasses calcium in dystrophic sites (such as atheromas and damaged cartilage) and in subcellular organelles (such as the mitochondria and the endoplasmic reticulum)
    • Rapidly exchangeable pool includes calcium in systemic circulation, interstitial fluid and cellular cytoplasm as well as calcium that has recently been deposited on bone surfaces
  • Plasma total calcium exists as free calcium (40 - 50%); protein bound calcium to mostly albumin (~40%) or complexed (~10%) to anions such as citrate, lactate and phosphate
  • Causes of hypercalcemia include hyperparathyroidism, malignancy, endocrine disorders, granulomatous diseases, drugs, immobilization and other miscellaneous causes
  • Causes of hypocalcemia include decreased parathyroid hormone action, deficient vitamin D action, extreme dietary calcium deficiency, healing phase of various forms of bone disease and calcium saponification (e.g., acute pancreatitis)
  • References: McPherson: Henry's Clinical Diagnosis and Management by Laboratory Methods, 22nd Edition, 2011, Crook: Clinical Biochemistry and Metabolic Medicine, 8th Edition, 2012, Clarke: Contemporary Practice in Clinical Chemistry, 4th Edition, 2020
Phosphate
  • Phosphate is involved in many critically important biochemical processes, including energy metabolism (e.g., adenosine triphosphate [ATP]), nucleic acid metabolism, cell signaling, bone formation and maintenance of acid / base balance (especially related to urinary phosphate buffering)
  • The majority of total body phosphate resides as organic phosphate complexed with proteins, lipids and carbohydrates
  • In blood, organic phosphate is located primarily in erythrocytes, with the plasma containing mostly inorganic phosphate
  • Inorganic phosphate (noncomplexed phosphate) in plasma is a very small proportion of total body phosphate
  • ~10% of the serum phosphate is bound to proteins; 35% is complexed with sodium, calcium and magnesium; the remaining 55% is free
  • Only inorganic phosphorus is measured in routine clinical settings
  • Causes of hyperphosphatemia include hypoparathyroidism, pseudohypoparathyroidism, renal failure, hypervitaminosis D, cell lysis (tumor lysis, burns, shock, etc.), increased bone turnover or release from bone (thyrotoxicosis, prolonged immobilization, glucocorticoid withdrawal or deficiency)
  • Causes of hypophosphatemia include inadequate intake (e.g., inadequate dietary intake or malabsorption of intestinal phosphate), phosphate redistribution into cells (e.g., acute respiratory alkalosis, insulin administration), excessive loss (e.g., renal phosphate wasting, rickets with secondary hyperparathyroidism, heavy metal poisoning, drug induced renal phosphate wasting)
  • References: McPherson: Henry's Clinical Diagnosis and Management by Laboratory Methods, 22nd Edition, 2011, Crook: Clinical Biochemistry and Metabolic Medicine, 8th Edition, 2012, Clarke: Contemporary Practice in Clinical Chemistry, 4th Edition, 2020
Magnesium
  • Magnesium is the fourth most abundant cation in the body (following sodium, potassium and calcium)
  • Total body magnesium is ~50 - 60% in bone and 40 - 50% in soft tissue
  • It is the second most abundant intracellular cation (following potassium)
  • Only 1% of the total body magnesium (TBMg) is in extracellular fluid
  • No primary hormone controls circulating magnesium concentrations
  • In serum, ~55% of magnesium is ionized or free magnesium (Mg++), 30% is associated with proteins (primarily albumin) and 15% is complexed with phosphate, citrate and other anions
  • Hypermagnesemia is mostly iatrogenic (e.g., infusion of magnesium sulfate in the treatment of preeclampsia or eclampsia in pregnant women)
  • Other causes of hypermagnesemia include excessive oral intake, increased gastrointestinal tract absorption (e.g., hypomotility and milk alkali syndrome), cellular release (e.g., tumor lysis syndrome and rhabdomyolysis) and contraction of the circulating blood volume
  • Causes of hypomagnesemia include malabsorption, malnutrition and renal magnesium wasting from drugs (e.g., loop or thiazide diuretics, cisplatin, cyclosporine or tacrolimus), endocrine disorders (e.g., primary hyperaldosteronism, hypoparathyroidism and hyperthyroidism) or osmotic diuresis
  • References: McPherson: Henry's Clinical Diagnosis and Management by Laboratory Methods, 22nd Edition, 2011, Crook: Clinical Biochemistry and Metabolic Medicine, 8th Edition, 2012, Clarke: Contemporary Practice in Clinical Chemistry, 4th Edition, 2020
Laboratory investigations for electrolytes
  • Specimen is usually serum, plasma or urine; others include capillary blood, heparinized whole blood (for blood gas and pH determinations), body fluid aspirates, feces and sweat (chloride)
  • Anion gap
    • ([Na+] + [K+]) − ([Cl-] + [HCO-3])
    • Potassium is commonly omitted from the calculation
    • Elevated anion gap (> 12 mEq/L) = metabolic acidosis
    • Reduced anion gap (< 3 mEq/L) may be due to hypoalbuminemia as albumin is the primary unmeasured anion
  • Laboratory methods used to determine electrolyte concentrations include (Rifai: Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics, 8th Edition, 2018)
    • Atomic absorption spectrophotometry
    • Flame emission spectrophotometry
    • Ion selective electrodes (direct using undiluted sample or indirect using diluted sample)
    • Enzymatic spectrophotometry
    • Coulometric - amperometric titration (sweat chloride)
  • Ion selective electrodes is the most common method used
  • Typical reference intervals
    • Serum sodium: 136 - 145 mmol/L
    • Serum potassium: 3.5 - 5.1 mmol/L
    • Serum chloride: 98 - 107 mmol/L
Board review style question #1
A patient is found to have plasma potassium of 6.9 mmol/L during his annual health check. The analysis was done a few hours after collection. He does not have any known health issues and is not on any medications. His complete blood count was normal. His renal functions are normal and his last potassium check was normal a few months ago. What is the most likely cause of the high potassium result?

  1. Diabetic ketoacidosis
  2. Diarrhea
  3. Hemolysis
  4. Thrombocytosis
  5. Tumor lysis syndrome
Board review style answer #1
C. Hemolysis. Hyperkalemia in a healthy person is most likely due to a preanalytic issue, the most common being hemolysis. Hemolysis falsely elevates potassium in plasma and can occur due to delayed processing of whole blood specimens or refrigeration of whole blood. A repeat assay should be requested. Answer D is incorrect because the complete blood count was normal and therefore rules out thrombocytosis as a cause. Answer A is incorrect because a patient with diabetic ketoacidosis will be critically ill. Answer E is incorrect because tumor lysis syndrome can cause hyperkalemia but in this patient, the patient had no history of malignancy or therapy. Answer B is incorrect because diarrhea would cause hypokalemia and not hyperkalemia.

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Reference: Electrolytes
Board review style question #2
What is pseudohyponatremia caused by?

  1. Hypoproteinemia
  2. Hyperlipidemia
  3. Liver cirrhosis
  4. Nephrotic syndrome
  5. Renal failure
Board review style answer #2
B. Hyperlipidemia. Pseudohyponatremia occurs as a result of how the blood sample is processed for serum sodium measurement. Using automated indirect ion selective electrode methods, proteins and lipids decrease the water content, which alters the ion concentrations measured and gives a falsely low sodium result. It is also called the electrolyte exclusion effect. Answer A is incorrect because hyperproteinemia (and not hypoproteinemia) gives the same electrolyte exclusion effect as hyperlipidemia. Answers C, D and E are incorrect because these are all causes of hypoproteinemia and not hyperproteinemia.

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Reference: Electrolytes
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