Chapter 6 Metabolic alkalosis (& chloride homeostasis)

6.1 Causes of a metabolic alkalosis

The causes of a metabolic alkalosis can be classified as being either due to chloride depletion (and therefore chloride responsive) or due to other causes (chloride resistant) (Luke & Galla, 2012).

LOW ECF VOLUME = CHLORIDE-DEPLETION / CHLORIDE-RESPONSIVE	GI chloride loss	vomiting / NG losses
	GI chloride loss	colonic villous adenoma / congenital chloride diarrhoea / high-volume ileostomy (rare)
		loop / thiazide diuretics *
		Bartter / Gitelman *
NORMAL ECF VOLUME = CHLORIDE-RESISTANT	renal H + loss	true mineralocorticoid XS (low-renin / high-renin)
		apparent mineralocorticoid XS (and Liddle’s)
		Cushings
		post-hypercapnic alkalosis (UCl < 10 mM)
		milk-alkali syndrome
		hypokalaemia

* in chloride-responsive states UCl < 10 mM except where chloride is being lost in the urine (i.e. diuretics / Gitelman / Barrter syndrome).

Perhaps a more useful classification would be:

1. Pendrin-dependent with volume depletion = extra-renal chloride loss
   
2. ENaC-dependent with volume depletion = renal chloride loss (secondary aldosteronism)
   
3. ENaC-dependent with volume expansion = primary mineralocorticoid XS
   
4. base-loading

Initial diagnostic work-up includes checking volume status, blood pressure, serum chloride and urinary chloride. Checking renin and aldosterone levels then helpful if suspected mineralocorticoid XS.

As a general rule, extreme alkalosis (HCO₃ > 45 mM) can only be due to vomiting (and consider pyloric stenosis / Zollinger Ellison syndrome).

6.1.1 Specific syndromes and their mechanisms

Cystic fibrosis: loss of chloride in sweat and / or downregulation of renal pendrin (so uCl may be high or low).

Post-hypercapnic alkalosis: occuds when chronic hypercapnoea is abruptly corrected - usuall in the context of mechanical ventilation. Chronic increase in renal HCO₃ reabsorption and ammoniagenesis leads to loss of urinary NH₄Cl. Therefore induces a low-Cl state that requires Cl resuscitation to correct.

Pendred syndrome (AR): no acid-base disturbace at baseline but susceptible to alkalosis when provoked (e.g. by thiazides).

Calcium-alkali syndrome (formerly ‘milk-alkali’): triad of hypercalcaemia, alkalosis, AKI. Caused by ingestion of large quantities of calcium (+/- alkali); often exacerbated by thiazides. Inhibition of CaSR in TALH causes salt-wasting (and hence chloride depletion and secondary hyperaldosteronism) and alkalosis stimulates Ca²⁺ reabsorption through TRPV5 in DCT. So a vicious cycle; abort with IV NaCl.

Crack cocaine: sometimes made with drain cleaner.

Hypokalaemia: associated with alkalosis because of a common underlying cause (e.g. hyperaldosteronsim), cell shifts and / or hypokalaemia stimulating ammoniagenesis.

6.2 Chloride

U_Cl NR = 100 – 250 mmol / 24 hrs

In chloride-responsive alkalosis, UCl < 10 mM:

• vomiting
  
• villous adenoma
  
• congenital chloride diarrhoea
  
• recent diuretics (pause on clinic day in surruptitious use)

In chloride-resistant alkalosis UCl > 10 – 30 mM (and also if chloride loss is due to diuretics / tubulopathies).

UCl is persistently low after vomiting and is therefore a useful test for surreptitious vomiting.

6.2.1 Chloride-depletion alkalosis

In chloride depletion, reduced ECF volume leads to reduced GFR (less filtered NaHCO₃) and increased Na reabsorption. Thus NaHCO₃ reabsorption is increased. Increased distal Na reabsorption leads to increased acid excretion. Therefore, after vomiting, an acid urine is produced (paradoxically) in the face of a metabolic alkalosis. Treatment is volume expansion with NaCl and correction of hypoK.