Electrolytes

Introduction

Body fluids and electrolytes

• Total body mass: 45%–60% water
  • Intracellular fluid (ICF)
  • Extracellular fluid (ECF):
    • Interstitial compartment (majority of ECF)
    • Intravascular compartment
• Electrolytes:
  • Minerals with an electric charge
  • Electrolytes dissociate into cations (positively charged) and anions (negatively charged) when dissolved in water.

Electrolyte balance

The ICF and ECF compartments have different and unequal electrolyte distribution to maintain physiological function.

Intracellular fluid:

• K⁺: main intracellular cation
• Mg²⁺
• Phosphates (HPO₄²^–/H₂PO₄^–) electrically balance the intracellular cations along with the negatively charged proteins.

Extracellular fluid:

• Na⁺: 
  • Main extracellular cation
  • Important in determining serum osmolarity (solutes/L)
  • Controls ECF volume and water distribution in the body
• Calcium (Ca²⁺)
• Chloride and HCO₃^–: 
  • Chloride is the most abundant anion in the ECF.
  • Anions balance the extracellular cations.

Sodium

Overview

• Normal range: 135–145 mEq/L
• 95% of the ingested Na⁺ is absorbed by the gut.
• Excretion: 
  • 90%–95% excreted by the kidneys
  • Remainder through feces and sweat
• Functions:
  • Establishes osmotic pressure
  • Na⁺ transcellular gradient:
    • Regulated by ATP-dependent cell membrane channels: Na⁺-K⁺ ATPase
    • Essential in maintaining the resting membrane potential
  • Transient influx of Na⁺ generates action potential that leads to:
    • Nerve conduction
    • Muscle contraction
    • Cardiac conduction
    • Activation of intracellular signaling pathways

Regulation

• Na⁺ homeostasis: 
  • Regulated through the kidneys (majority in the proximal tubules)
  • Occurs by sensing changes in the effective circulating volume (ECV):
    • ↑ Na⁺ causes ↑ ECV
    • ↓ Na⁺ causes ↓ ECV
• RAAS:
  • Juxtaglomerular apparatus and carotid sinus/aortic arch baroreceptors trigger renin release from kidneys when ECV ↓
  • If Na⁺ is low: ↓ ECV → renin → angiotensin (causing vasoconstriction) → aldosterone is secreted: 
    • Na⁺ reabsorption from the renal tubules
    • Promotes K⁺ secretion in urine
• Natriuretic peptides:
  • Includes atrial natriuretic peptide and BNP
  • If Na⁺ is high: ↑ ECV → cardiac baroreceptors sense an ↑ in ECV → natriuretic peptide is secreted 
    • Stimulates urinary Na⁺ excretion (natriuresis)
    • Also promotes excretion of water
    • Inhibits angiotensin II production

Related disorders

• Hypernatremia: Na⁺ > 145 meq/L
• Hyponatremia: Na⁺ < 135 meq/L

Potassium

Overview

• Normal range: 3.5–5.2 mEq/L
• Excretion: 90% is excreted in the urine, 10% in feces
• Functions: 
  • ٌResting cellular membrane potential and the propagation of action potentials
  • Hormone secretion and action
  • Vascular tone
  • Systemic BP control
  • GI motility
  • Glucose and insulin metabolism
  • Concentrating ability of kidneys and pH regulation

Regulation

• Kidneys are responsible for 90%–95% of the overall K⁺ regulation.
  • ↑ ECF K⁺ level triggers mechanisms for renal K+ excretion
  • Aldosterone:
    • Stimulates Na+-K⁺ ATPase
    • Increases K+ excretion into distal tubules and collecting ducts 
• Transcellular shifting (mediated by insulin and sympathetic nervous system) prevents the excessive increase in ECF K⁺ levels.
  • β2 receptor activation:
    • Stimulates K⁺ uptake into cells (primarily into muscle and liver cells)
    • β2 antagonists block K⁺ uptake and cause hyperkalemia.
    • α1 receptor activation causes a shift of K⁺ out of the cells. 
  • Insulin:
    • Stimulates Na⁺-K⁺ ATPase
    • Increases K⁺ uptake into cells
    • Responsible for dietary uptake of K⁺ into cells after a meal
• Other factors:
  • Acid-base status:
    • Acidosis causes K⁺ to move out of cells.
    • Alkalosis causes K⁺ to move into cells.
  • Exercise: moves K⁺ out of muscle cells

Related disorders

• Hyperkalemia: K⁺ > 5.2 mEq/L
• Hypokalemia: K⁺ < 3.5 mEq/L

Chloride

Overview

• Normal range: 96–106 mEq/L

• Rapidly and almost totally absorbed by the GI tract
• Excretion: through GI tract, urinary tract, and skin
• Functions:
  • Follows Na⁺ across cellular membranes to maintain charge neutrality
  • Maintenance of cell homeostasis 
  • Transmission of action potentials in neurons
  • Maintenance of ECF osmolarity (together with Na⁺), thus regulating:
    • Blood volume
    • BP 
  • Acid-base balance
  • Synthesis of gastric hydrochloric acid 
  • Control of epithelial fluid transport

Regulation

Chloride homeostasis:

• Mainly by the kidneys (through reabsorption in the tubules)
• Affected by acid-base disorders:
  • ↑ Chloride: associated with acidosis
  • ↓ Chloride: associated with alkalosis 
• Affected by changes in Na⁺ levels. Reabsorption is mediated by cation cotransporters in combination with Na⁺.

Related disorders

• Hyperchloremia (chloride > 106 mEq/L): 
  • From pure water loss (electrolyte-free fluid), such as hypotonic dehydration 
  • Administration of NaCl-containing fluids or hypertonic feeding
  • Acidosis:
    • Renal tubular acidosis
    • Small bowel diarrhea 
    • Pancreatic fistula
  • Drugs (acetazolamide)
• Hypochloremia (< 96 mEq/L):
  • Inadequate NaCl intake
  • Loss of chloride:
    • Vomiting: loss of hydrochloric acid in the stomach, leading to hypochloremic hypokalemic metabolic alkalosis
    • Gastric lavage
    • Burns
    • Excessive use of diuretics or osmotic diuresis
    • In combination with hyponatremia

Calcium

Overview

• Normal range: 8.5–10.5 mg/dL
• Ca²⁺: metabolically active form (normal range 4.65–5.25 mg/dL)
• Most abundant mineral in the human body with 99% found in the skeleton
• Functions: 
  • Enzyme activity
  • Cellular functions related to cell division, exocytosis, communication
  • Muscle contraction
  • Cardiac contractility
  • Nerve conduction
  • Blood coagulation
  • Bone mineralization

Regulation

• Bone, intestine, and kidneys are involved in homeostasis.
• Key elements of Ca²⁺ regulation:
  • Parathyroid hormone (PTH) from parathyroid glands:
    • ↑ Vitamin D production in the kidneys 
    • ↑ Ca²⁺ reabsorption in the distal tubules and ↑ Ca²⁺ absorption in the intestines
    • ↑ Bone resorption (release of Ca²⁺ and HPO₄²^–/H₂PO₄^– from bones)
  • Vitamin D:
    • Activates osteoclasts to release Ca²⁺ and phosphorus
    • ↑ Intestinal Ca²⁺ and HPO₄²^–/H₂PO₄^– absorption
  • pH: 
    • ↑ pH (alkalosis) → ↑ binding to albumin = ↓ ionized Ca²⁺
    • ↓ pH (acidosis) → ↓ binding to albumin = ↑ ionized Ca²⁺
  • Albumin:
    • Every 1 g/dL ↓ in albumin → ↓ in Ca²⁺ by 0.8 mg/dL
    • Corrected Ca²⁺ (mg/dL) = measured total Ca²⁺ (mg/dL) + [0.8 x (4.0 – albumin concentration (g/dL))]
  • Other factors:
    • Calcitonin from the thyroid gland (opposes PTH →↓ Ca²⁺)
    • Hyperphosphatemia (↑ HPO₄²^–/H₂PO₄^– binding, ↓ Ca²⁺)
    • Hypomagnesemia (↓ PTH release → ↓ Ca²⁺)

Related disorders

• Hypercalcemia: Ca²⁺ > 10.5 mg/dL
• Hypocalcemia: Ca²⁺ < 8.5 mg/dL

Magnesium

Overview

• Normal range: 1.5–2.2 mg/dL

• 4th most abundant cation in the body
• Mg²⁺ distribution in the body:
  • Skeleton: 55%
  • Soft tissue: 45%
  • ECF: 1% (about 55% free, with the remainder complexed with anions or protein)
• Functions:
  • Cofactor for enzymatic reactions involved in ATP and/or DNA and RNA synthesis
  • Cellular replication and biochemical processes (i.e., glycolysis)
  • Linked with Ca²⁺ and K⁺ homeostasis
  • Neuromuscular excitability:
    • Smooth muscle contraction and relaxation
    • Stabilization of cardiac muscle
  • Coagulation

Regulation

• Maintaining Mg²⁺ levels in the serum varies and depends on:
  • Intake
  • GI absorption
  • Renal reabsorption and excretion
• Kidneys will conserve Mg²⁺ when the levels are low and excrete the excess when the intake is high.
• Key elements:
  • Increased Mg²⁺ absorption in the presence of:
    • PTH
    • Vitamin D
    • Na⁺ in the diet
    • Thyroid hormone
  • Decreased Mg²⁺ absorption in the presence of:
    • Ca²⁺
    • Aldosterone (promotes excretion of Mg²⁺ with K⁺, and retention of Na⁺)

Related disorders

• Hypermagnesemia (Mg²⁺ > 2.2 mg/dL):
  • Overuse of Mg²⁺-containing laxatives or antacids
  • Renal failure
  • Features: 
    • Generalized muscle weakness, nausea
    • Hypotension 
    • Cardiac rhythm abnormalities (especially if Mg²⁺ > 6 mg/dL): prolonged PR, wide QRS, peaked T waves
  • Management includes calcium gluconate, diuresis, and dialysis.
• Hypomagnesemia (Mg²⁺ < 1.5 mg/dL): 
  • Alcoholism (most common electrolyte change is ↓ Mg²⁺)
  • Diarrhea and GI disease
  • Diuretic use
  • Proton pump inhibitor therapy
  • Common cause of refractory hypokalemia

Phosphate

Overview

• Normal range: 2.5–4.5 mg/dL (higher in children)
• 2 forms in the serum (depending on the acid-base status):
  •  Dihydrogen phosphate (H₂PO₄^–) 
  • Monohydrogen phosphate (HPO₄²^–)
• 85% of the total body phosphate is in the bones and teeth in the form of hydroxyapatite.
• Only 1% in the ECF
• Functions:
  • Required for cellular function and skeletal mineralization
  • Component of many metabolic intermediates (ATP) and nucleotides
  • Aerobic and anaerobic energy metabolism
  • O₂ delivery to tissues

Regulation

• Maintained by dietary intake, mobilization from the bone, and renal excretion
• Key elements:
  • Vitamin D: 
    • Increases HPO₄²^–/H₂PO₄^– reabsorption and release from bones
    • Renal tubular reabsorption: in proximal tubules through Na⁺-dependent phosphate (Na/Pi) cotransporter
  • PTH: increased HPO₄²^–/H₂PO₄^– excretion by the kidneys
  • Fibroblast growth factor (FGF)-23: 
    • Produced by osteocytes
    • Inhibits renal production of vitamin D →↓ HPO₄²^–/H₂PO₄^– reabsorption
    • Inhibits GI HPO₄²^–/H₂PO₄^– absorption

Related disorders

• Hyperphosphatemia (HPO₄²^–/H₂PO₄^– > 4.5 mg/dL):
  • Renal failure
  • Hypoparathyroidism
  • Tumor lysis syndrome
  • Rhabdomyolysis
  • Vitamin D toxicity
• Hypophosphatemia (HPO₄²^–/H₂PO₄^– < 2.5 mg/dL):
  • Decreased intake (malabsorption, alcoholism)
  • Hyperparathyroidism
  • Refeeding syndrome (patients who are malnourished experience sudden insulin release with parenteral nutrition, shifting HPO₄²^–/H₂PO₄^– intracellularly)

Bicarbonate

Overview

• Normal range: 22–28 mEq/L
• Functions:
  • Indirect indicator of total CO₂ level in serum
  • Vital component of pH regulation
  • HCO₃^– buffer system: the balance between carbonic acid (H₂CO₃), HCO₃^–, and CO₂, which maintains blood pH:

                                      CO₂ + H₂O ⇆ H₂CO₃ ⇆ H⁺ + HCO₃^–

Regulation

To maintain homeostasis, the following mechanisms are triggered to keep the pH in the physiological range (7.35–7.45):

• Respiratory compensation: 
  • Changes in ventilation compensate for changes in the blood HCO₃^– levels.
  • Lungs respond to metabolic acidosis by ↑ ventilation
  • Lungs respond to metabolic alkalosis by ↓ ventilation
• Renal compensation: 
  • Kidneys regulate the secretion of H⁺ into the urine, and, at the same time, reabsorb HCO₃^– (normally 100% is absorbed).
  • Kidneys respond to respiratory acidosis by increasing serum HCO₃^– levels through ↑ secretion of H⁺
  • Kidneys respond to respiratory alkalosis by decreasing serum HCO₃^– through ↓ secretion of H⁺ and urinary excretion of HCO₃^–

Related disorders

• Metabolic disorders: primarily caused by abnormal HCO₃^– levels
  • Metabolic acidosis
  • Metabolic alkalosis
• Respiratory disorders: primarily caused by abnormal CO₂ levels
  • Respiratory acidosis
  • Respiratory alkalosis

Clinical Relevance

Disorders related to sodium levels

• Hyponatremia: a condition defined as Na⁺ < 135 mmol/L. Severe hyponatremia is defined as Na⁺ < 120 mEq/L. Hyponatremia occurs in the case of severe diarrhea (with both Na⁺ and water losses) and SIADH (increased total body water). Symptoms can be absent, mild, or severe (confusion, seizures, coma). Acute severe hyponatremia and neurologic or hemodynamic compromise require an urgent supplementation of serum Na⁺, which is best accomplished using hypertonic (3%) NaCl. If untreated, the complications include acute cerebral edema and osmotic demyelination syndrome. In all other cases, the gradual correction of Na⁺ levels is preferred.
• Hypernatremia: a condition defined by serum Na⁺ > 145 mEq/L. The vast majority of cases are chronic where there is a slow rise in plasma tonicity. Increased Na⁺ levels are seen in diarrhea (hypovolemic) and diabetes insipidus (euvolemic). Neurologic (lethargy, altered mental status, irritability, and seizures) features are mainly observed. Hypernatremia can also cause muscle cramps and decreased deep tendon reflexes. The initial treatment for severe hypovolemic hypernatremia is isotonic 0.9% saline. Once the volume deficit has been restored, patients are switched to half-normal (0.45%) saline.

Disorders related to potassium levels

• Hyperkalemia: a condition defined by serum K⁺ > 5.2 mEq/L. Severe hyperkalemia is seen in acute renal failure and can be catastrophic as it causes respiratory paralysis, generalized muscle paralysis, and cardiac arrest. Drugs such as ACEi are a common cause of hyperkalemia.
• Hypokalemia: a condition defined by plasma K⁺ < 3.5 mEq/L. Features of hypokalemia include muscle weakness and general fatigue. Hyperpolarization affects excitability and delays the repolarization of cardiac muscles. The ECG findings include low T wave and presence of U wave. Diuretic use, thyrotoxicosis, and other conditions (Liddle’s syndrome, Bartter’s syndrome) lead to low K⁺.

Disorders related to chloride levels

• Cystic fibrosis: an autosomal recessive hereditary disease of the exocrine glands that primarily affects the lungs and digestive system. Cystic fibrosis is due to a spectrum of defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A mutation in this gene leads to an inability to properly transport chloride. Given the interlinking functions of chloride with Na⁺, there is a subsequent impairment in Na⁺ and water absorption. A characteristic feature is the abnormally high (> 60 mEq/L) chloride concentration in sweat. Hyperviscous mucus is found in the other glands.

Disorders related to calcium levels

• Hypocalcemia: Calcium levels are regulated by the PTH secreted by the parathyroid gland. Hypercalcemia or hypocalcemia result if the body fails to maintain Ca²⁺ levels within the normal range. The presentation of patients with hypocalcemia can vary from asymptomatic to life-threatening hemodynamic instability. Conditions related to low Ca²⁺ include hypoparathyroidism, CKD, and acute pancreatitis.
• Hypercalcemia: might be mild, moderate, or severe. Principal causes include hyperparathyroidism, thyrotoxicosis, and cancer. Clinical features include constipation, weakness, confusion, and coma.
• Osteoporosis: a chronic progressive metabolic bone disease characterized by decreased bone density and deterioration of bone strength and integrity. Osteoporosis is common in post-menopausal women and older men and is also associated with many chronic conditions.

Disorders related to magnesium levels

• Alcoholism: a chronic (> 12 months), problematic pattern of alcohol use causing significant distress. Hypomagnesemia is the most common electrolyte change in alcoholism (decrease intake, increased renal losses, and diarrhea).

Disorders related to phosphate levels

• Hyperparathyroidism: a condition resulting from elevated PTH levels. The most common cause is a parathyroid adenoma, and other causes include hyperplasia or carcinomas. The presenting features of hyperparathyroidism include nonspecific symptoms (fatigue, constipation), abdominal pain, renal stones, bone pain, and neuropsychiatric symptoms.
• Hypoparathyroidism: decreased secretion or activity of the PTH. The most common cause of hypoparathyroidism is the iatrogenic removal of the parathyroid glands during thyroid surgeries. Other causes include autoimmune conditions, congenital absence of the parathyroid glands, or defective Ca²⁺ sensing. Features include perioral tingling and numbness, muscle cramps, tetany, carpopedal spasms, and seizures.

Disorders related to bicarbonate levels

• Renal tubular acidosis (RTA) II: a condition characterized by impaired proximal tubular acidification mechanism in the kidneys caused by the reduced reabsorption of HCO₃^– in the proximal tubules. Renal tubular acidosis II is seen in multiple myeloma, where the excreted light chains produce proximal tubular dysfunction.