Body Fluid Compartments & Electrolyte Balance
A Step 1 walkthrough of body fluid compartments (60-40-20 rule, dilution tracers, effective osmoles) and the two independent control systems that defend osmolality (ADH/thirst) versus effective circulating volume (RAAS/ANP), anchored by Darrow-Yannet fluid shifts and the classic sodium/potassium clinical correlations (SIADH, diabetes insipidus, hyperkalemia).
The compartments and the two variables the boards separate
Body water is partitioned into compartments divided by membranes that water crosses freely but most solutes do not. Total body water (TBW) ≈ 60% of body weight — roughly 42 L in a 70-kg man — and follows the 60-40-20 rule: two-thirds is intracellular (ICF = 40% BW, ~28 L) and one-third is extracellular (ECF = 20% BW, ~14 L). The ECF splits 3:1 into interstitial fluid (~10.5 L) and plasma (~3.5 L); add red-cell volume and total blood volume is ~5 L. Because adipose tissue holds little water, TBW falls to ~50% in women and the obese, and is highest in neonates.
At steady state the compartments are in osmotic equilibrium: water shifts across cell membranes until ICF and ECF osmolality are equal (normal 275–295 mOsm/kg). The single most tested concept is that two variables are regulated by two different systems: total-body Na⁺ sets ECF volume, whereas water balance sets plasma [Na⁺] and osmolality. Na⁺ (kept out of cells by the Na⁺/K⁺-ATPase) is the dominant ECF osmole and K⁺ the dominant ICF osmole; these effective osmoles decide how water distributes across cell membranes. Glucose is also an effective osmole — in insulin deficiency (DKA/HHS) it accumulates in the ECF and pulls water out of cells, producing translocational (dilutional) hyponatremia — whereas urea and alcohol are ineffective: they cross membranes freely and pull no sustained water shift (why urea is dropped from the tonicity equation).
- 60-40-20: TBW ≈ 60% BW (~42 L); ICF = 40% (2/3 of TBW); ECF = 20% (1/3 of TBW). ECF = 3/4 interstitial + 1/4 plasma. Fat is water-poor → women & obese ≈ 50%.
- Volume of distribution (indicator dilution): TBW = ³H₂O / D₂O / antipyrine; ECF = inulin, mannitol, sulfate; plasma = Evans blue, radioiodinated albumin (RISA). ICF and interstitial volumes are calculated by subtraction, not measured directly.
- Plasma osmolality 275–295 mOsm/kg; estimate Posm = 2[Na⁺] + glucose/18 + BUN/2.8. Effective osmolality (tonicity) = 2[Na⁺] + glucose/18 (urea excluded — it is ineffective).
- Na⁺ = ECF osmole that sets ECF volume; total-body Na⁺ (not its concentration) determines ECF volume, while water balance sets [Na⁺]/osmolality.
- Na⁺/K⁺-ATPase = 3 Na⁺ out : 2 K⁺ in per ATP — electrogenic; maintains the steep gradients (high-K⁺ ICF, high-Na⁺ ECF) underlying the resting membrane potential and secondary active transport.
- Renal Na⁺ handling: PCT ~65% (Na/H exchanger, Na-glucose/AA), thick ascending limb ~25% (NKCC2, loop-diuretic target, water-impermeable → dilutes urine), DCT ~5% (NCC, thiazide target), collecting duct ~3–5% (ENaC, aldosterone/amiloride-sensitive).
- Two control systems: osmolality → defended by ADH + thirst; effective circulating volume → defended by RAAS, sympathetics, and ANP/BNP.
Darrow-Yannet: how each disturbance moves ECF, ICF, and osmolarity
| Disturbance | Classic cause | ECF volume | ICF volume | ECF osmolarity |
|---|---|---|---|---|
| Isotonic gain | Isotonic saline infusion | ↑ | ↔ | ↔ |
| Isotonic loss | Diarrhea, acute hemorrhage | ↓ | ↔ | ↔ |
| Hypertonic gain | Hypertonic saline, high-salt load | ↑ | ↓ | ↑ |
| Hypertonic loss | Sweating, fever, diabetes insipidus | ↓ | ↓ | ↑ |
| Hypotonic gain | SIADH, water intoxication | ↑ | ↑ | ↓ |
| Hypotonic loss | Adrenal insufficiency (Addison) | ↓ | ↑ | ↓ |
The four regulatory hormones — trigger, target, effect
| Hormone | Main trigger | Target (receptor) | Net effect |
|---|---|---|---|
| ADH (vasopressin) | ↑ plasma osmolality (sensitive); large ↓ blood volume/BP | Collecting duct V2 → cAMP → AQP2; vessels V1 | Inserts aquaporins → free-water reabsorption, concentrates urine; V1 vasoconstriction |
| Aldosterone | Angiotensin II; hyperkalemia | CD principal cells (ENaC, Na⁺/K⁺-ATPase); α-intercalated cells | Na⁺ reabsorption + K⁺ secretion (principal cells); H⁺ secretion (α-intercalated cells) |
| Angiotensin II | ↓ renal perfusion → renin (macula densa low NaCl, β1-sympathetic, low pressure) | Efferent arteriole, PCT, adrenal, brain | Efferent constriction (preserves GFR), ↑ PCT Na/H exchange, stimulates aldosterone + ADH + thirst, systemic vasoconstriction |
| ANP / BNP | Atrial/ventricular stretch (volume overload) | Afferent arteriole, CD (cGMP) | Afferent dilation → ↑ GFR + natriuresis; inhibits renin, aldosterone, and ADH |
Mechanism: Non-osmotic ADH release drives collecting-duct AQP2 → free water retained → dilutional (euvolemic) hyponatremia with inappropriately concentrated urine. Volume stays near-normal because retained water spreads across all of TBW and mild expansion triggers natriuresis.
Vignette: A 63-year-old smoker with small-cell lung cancer is confused. Na⁺ 118, serum osm 248, urine osm 560, urine Na⁺ 65, euvolemic, normal thyroid/cortisol → SIADH (ectopic ADH). Diagnostic triad: low serum osm + inappropriately high urine osm (>100) + urine Na⁺ >40. Other causes: CNS lesions, pulmonary disease, drugs (carbamazepine, SSRIs).
Treatment & trap: Fluid restriction (± hypertonic saline if seizing; ± vaptan). Raise Na⁺ < 8 mEq/L per 24 h — over-rapid correction causes osmotic demyelination syndrome (central pontine myelinolysis): dysarthria, dysphagia, and spastic quadriparesis appearing days later.
Mechanism: Excess free-water loss from ADH deficiency (central) or renal ADH resistance (nephrogenic) → large-volume dilute urine → hypernatremia/hyperosmolality when thirst or water access is impaired.
Vignette: Polyuria >3 L/day, polydipsia, Na⁺ 149, urine osm 180 (dilute). Water-deprivation test: urine stays dilute despite dehydration. Then give desmopressin (dDAVP): central DI → urine osm rises >50%; nephrogenic → little/no change.
Causes/treatment:
- Central — pituitary surgery, trauma, tumor, ischemia → treat with desmopressin.
- Nephrogenic — lithium, hypercalcemia, hypokalemia, X-linked V2-receptor mutation → remove the offender, low-solute diet, and a thiazide (paradoxically antidiuretic via mild volume contraction → ↑ proximal reabsorption).
- ~98% of body K⁺ is intracellular; the tiny ECF pool means transcellular shifts alone can be lethal. Always ask: shift or total-body problem?
- Shifts K⁺ INTO cells → hypokalemia: insulin, β2-agonists (albuterol), alkalosis, hypothermia.
- Shifts K⁺ OUT of cells → hyperkalemia: acidosis, insulin deficiency/hyperosmolality, β-blockers, digoxin (Na⁺/K⁺-ATPase block), cell lysis (rhabdomyolysis, tumor lysis, hemolysis), succinylcholine.
- Renal K⁺ secretion by CD principal cells is driven by aldosterone, high distal Na⁺ delivery/flow, and alkalosis — the main excretory route.
- DKA pearl: measured serum K⁺ is often normal/high despite total-body depletion (insulin lack + hyperosmolality push K⁺ out); it drops sharply once insulin is given — replace K⁺.
- ECG: hypokalemia → flattened T, U waves, ST depression; hyperkalemia → peaked T, widened QRS.
Mechanism: Raising ECF K⁺ raises (depolarizes) the resting membrane potential. Mild elevation is initially hyperexcitable, but sustained depolarization inactivates voltage-gated Na⁺ channels, leaving myocytes inexcitable → conduction block and arrest.
ECG progression: peaked T waves → PR prolongation → P-wave flattening/loss → QRS widening → sine wave → VF/asystole.
Vignette: A hemodialysis patient misses a session; K⁺ 7.3 with peaked T waves. Treatment order:
- IV calcium gluconate — stabilizes the myocardial membrane (does NOT lower K⁺).
- Insulin + glucose (fastest shift), β2-agonist, or bicarbonate — drive K⁺ into cells.
- Remove K⁺ — dialysis, K⁺-binders, loop diuretics.
- 60-40-20 rule — TBW 60% BW → ICF 40% → ECF 20%; within ECF, 3/4 interstitial : 1/4 plasma (≈ 15% and 5% of body weight).
- "From low to high, the pons will die; from high to low, the brain will blow." — Correct hyponatremia too fast (Na low→high) → osmotic demyelination / central pontine myelinolysis; correct hypernatremia too fast (Na high→low) → cerebral edema.
- "C BIG K Drop" — hyperkalemia treatment: Calcium → Bicarbonate → Insulin + Glucose (± β-agonist) → K-binder (Kayexalate/patiromer) → Drop via Diuresis/Dialysis.
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