RAAS

Adrenal Cortex;

The adrenal cortex maintains 

1. electrolyte balance, 

2. glucose homeostasis, and 

3. sexual development

• Main regulator for Zona glomerulosa (ZG) =  RAAS (Angiotensin II) + serum K⁺ (the potent stimulus for aldosterone). ACTH has only a minor stimulatory effect on ZG, not the main driver

  • • High serum K⁺ directly depolarises zona glomerulosa cells → opens voltage-gated Ca²⁺ channels → Ca²⁺ influx drives aldosterone synthesis and secretion → K⁺ excretion → homeostasis

    • ZG is designed to protect against hyperkalemia. The body doesn’t wait for the pituitary! Even if ACTH = zero (secondary adrenal insufficiency or long-term steroid use), Aldosterone rises if K⁺ rises

    • ZG is shut down by low K ! (hyperpolarises the ZG membrane → Ca²⁺ channels stay closed)   --> aldosterone drops when K⁺ is low

    • Clinically, the dominant axis is K⁺ → Aldosterone, NOT Na⁺ → Aldosterone.

    • Aldosterone secretion is mainly driven by serum K⁺ and Angiotensin II, not sodium levels. Because the body cares more about protecting the heart from hyperkalemia than about small variations in sodium. A slight rise in K⁺ kills fast → arrhythmias → death. A rise in Na⁺ does not directly kill → the body tolerates it and can compensate later. So evolution designed aldosterone to respond primarily to K⁺, not Na⁺.

• Zona fasciculata (ZF) = strongly stimulated by ACTH → cortisol secretion. 

• So ACTH strongly stimulates ZF > ZG.

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• Primary adrenal insufficiency (Addison’s): ↓Cortisol + ↓Aldosterone (ZG and ZF both damaged)

• Secondary adrenal insufficiency (pituitary ACTH failure): ↓Cortisol but Aldosterone normal → because RAAS still works

• Long-term steroid use (like Cushing's): Suppresses ACTH → ZF atrophy, but ZG is preserved

• In Conn's disease, ↑ Aldosterone → RAAS suppressed, but ACTH unchanged

Acid-Base and Electrolytes: (Sodium and water follow aldosterone; potassium and hydrogen pay the price). 

RAAS, Aldosterone, and Cortisol form the Na–K–H axis, which preserves circulation (Na⁺, water) at the expense of K⁺ and H⁺.

• Aldosterone excess → H⁺ secretion → metabolic alkalosis + hypokalaemia

• Aldosterone deficiency / RTA 4 → H⁺ retention → metabolic acidosis + hyperkalaemia

Cortisol

1. METABOLIC

   • ↑ Gluconeogenesis (liver)

   • ↑ Protein catabolism → muscle wasting

   • ↑ Lipolysis, but central fat redistribution

   • ↑ Insulin resistance → hyperglycemia

2. CARDIOVASCULAR

   • ↑ α1 receptors → ↑ BP

   • Required for catecholamine action

   • Deficiency → refractory hypotension

3. IMMUNE

   • Anti-inflammatory: ↓ NF-κB, ↓ PLA2, ↓ PG/LT

   • Immunosuppression: ↓ T cells, ↓ cytokines

   • ↑ Neutrophils (demargination), ↓ eosinophils

4. ELECTROLYTES

   • At high doses: mineralocorticoid effect → ↑ Na, ↓ K

   • Deficiency → hyponatremia, hyperkalemia (via ↑ ADH)

5. BONES & TISSUE

   • ↓ Osteoblasts → osteoporosis

   • ↓ Collagen → thin skin, striae, poor wound healing

6. CNS

   • Mood, arousal, memory

   • Excess → euphoria/psychosis

   • Deficiency → fatigue, apathy

7. STRESS RESPONSE

   • Essential for survival

   • Maintains BP, glucose, and vascular tone

8. ENDOCRINE FEEDBACK

   • Hypothalamus: CRH → ACTH → Cortisol

   • Diurnal rhythm: peak AM, low at midnight

Cortisol at high levels → binds mineralocorticoid receptors, mimicking aldosterone (mild effect)

Cushing (Zona fasciculata overactive or exogenous steroids): ↑ Cortisol → powerful negative feedback → ↓ CRH + ↓ ACTH. The effects are

• Hypertension; Cortisol ↑ α₁ receptors + mild mineralocorticoid effect

• Diabetes; ↑ Gluconeogenesis + insulin resistance

• Weight: Central obesity, moon face, buffalo hump

• Protein catabolism; Muscle wasting / thin limbs

• Metabolic alkalosis + (mild hypokalemia) = > from mild mineralocorticoid effect

In Conn's disease, ↑ Aldosterone → RAAS suppressed, but ACTH unchanged

Stress dose steroid

“Stress-dose steroids” = physiologic replacement of cortisol during major stress (illness, surgery, trauma) when the patient’s own HPA axis cannot mount the required cortisol surge. Patients on chronic steroids/adrenal insufficiency cannot make this surge → they crash.

HPA axis likely supressed if; Patients on steroids ≥3 weeks at ≥5 mg prednisolone/day 

Under stress, cortisol is needed to maintain:

1. Vascular tone (α1 receptor expression)

2. BP response to catecholamines

3. Blood glucose (anti-insulin)

4. Anti-inflammatory balance

Adrenal Crisis Management:

1. 100 mg IV hydrocortisone STAT

2. Then 50 mg IV q6h (or 200 mg/day infusion)

3. 2–3 L isotonic saline first 24 h

4. Add Dextrose (D5 / D10) if hypoglycemic

5. Watch for rapid fall in K⁺ after fluids + steroids.

6. Maintain 200 mg/day hydrocortisone until shock resolves

7. Taper to maintenance (15–25 mg/day in divided doses) over 2–3 days

Conn's disease V/S Liddle

In Conn’s → ENaC needs aldosterone.

In Liddle → ENaC ignores aldosterone.

ENaC sits on the apical membrane of principal cells in the collecting duct.

1. 1. • When ENaC is overactive → 

        1. • ↑ Na⁺ reabsorption

           • The lumen becomes more negative

           • ↑ K⁺ secretion (ROMK)

           • ↑ H⁺ secretion (intercalated cells)

           • So clinically, we get HTN + hypokalemia + metabolic alkalosis + low renin.

Conn’s (Primary Hyperaldosteronism) -> Aldosterone binds the mineralocorticoid receptor (MR). Increases transcription of ENaC + Na⁺/K⁺-ATPase. -> Net effect → ENaC overactivity secondary to high aldosterone. Labs: increased Aldosterone, low Renin (suppressed because BP rises)

Liddle Syndrome -> The ENaC channel itself is mutated → the channel becomes hyperactive and cannot be degraded, working at full speed regardless of aldosterone. Result: Body senses ↑ BP → suppresses renin → suppresses aldosterone. So aldosterone becomes low, even though ENaC is still overactive. Labs: low Aldosterone, low Renin. Hypertension, hypokalemia, and alkalosis are identical to Conn’s.

ADH & Aldosterone; 

• ADH retains water only

• Aldosterone retains Na+ & water

In a patient with hypokalemia + metabolic alkalosis + hypertension:

• If renin is low → Primary hyperaldosteronism (Conn)

• If renin is high → Secondary hyperaldosteronism (renal artery stenosis, diuretic use, pregnancy, HF)

The root cause is always the K⁺–ZG–aldosterone axis.