Congenital Conditions Causing Potassium Shifts
Bartter syndrome and Gitelman syndrome are the primary congenital conditions that cause shifts in potassium levels, both presenting with hypokalemia due to renal potassium wasting from genetic defects in tubular ion transporters. 1, 2
Bartter Syndrome
Bartter syndrome is a group of congenital tubulopathies caused by mutations affecting the thick ascending limb of the loop of Henle, leading to severe renal potassium loss 1:
Type 1 (SLC12A1 gene): Defective Na+-K+-2Cl- cotransporter (NKCC2), presenting prenatally with severe polyhydramnios and severe hypokalemic metabolic alkalosis 1, 3
Type 2 (KCNJ1 gene): Defective ROMK potassium channel, also presenting prenatally with severe polyhydramnios 1
Type 3 (CLCNKB gene): Presents between 0-5 years with polyuria, hypochloremia, and hypokalemia 1
Type 4a and 4b (BSND gene): Present prenatally with very severe polyhydramnios, deafness, and risk for chronic kidney disease 1
Type 5 (MAGED2 gene): Presents with transient disease, with pregnancies complicated by polyhydramnios 1
The mechanism involves increased distal delivery of sodium and water, which enhances sodium reabsorption via ENaC in the collecting duct, coupled with increased potassium and hydrogen ion secretion, resulting in hypokalemia and metabolic alkalosis 4.
Gitelman Syndrome
Gitelman syndrome (SLC12A3 mutations) is distinguished from Bartter syndrome by later age of presentation (typically adolescence or adulthood, usually after age 6), hypocalciuria rather than hypercalciuria, and milder symptoms. 2
The diagnostic triad consists of hypokalemia, hypomagnesemia, and hypocalciuria, with hypocalciuria being the critical distinguishing feature from Bartter syndrome 2
Fractional excretion of chloride >0.5% indicates renal salt wasting in both conditions 1, 2
The defect in the Na+-Cl- cotransporter (NCC) in the distal convoluted tubule increases distal sodium delivery, leading to enhanced potassium secretion 4
Hypokalemic Periodic Paralysis
Hypokalemic periodic paralysis represents a distinct mechanism where potassium shifts from extracellular to intracellular compartments due to genetic defects in skeletal muscle ion channels 3, 5:
Caused by pathogenic variants in CACNA1S gene affecting membrane calcium ion channels in skeletal muscle 3
Results in transcellular potassium shifts rather than renal losses, causing episodic severe hypokalemia with muscle weakness or paralysis 6, 5
Serum potassium drops due to intracellular sequestration, not increased excretion 1
Key Diagnostic Distinctions
Polyhydramnios is virtually always caused by Bartter syndrome when due to excessive fetal polyuria, with no reports of other inherited tubular disorders causing severe polyhydramnios. 1
Urinary chloride excretion (fractional chloride excretion >0.5%) distinguishes renal from extrarenal potassium losses 1, 2
Age at presentation is critical: prenatal/early infancy suggests Bartter syndrome, while adolescence/adulthood suggests Gitelman syndrome 1, 2
Urinary calcium helps differentiate: high in Bartter syndrome, low in Gitelman syndrome 1, 2
Clinical Pitfalls
Avoid diuretic testing (loop diuretics or thiazides) in suspected cases, as these tests are obsolete and carry potential risk of severe volume depletion, especially in infancy. 1
Genetic testing has surpassed functional testing for diagnosis 1
Consider transcellular shift disorders when evaluating neonatal or childhood hypokalemia, as patients are at increased risk of rebound potassium disturbances 6, 3
Exclude diuretic abuse and laxative use before pursuing genetic diagnoses 1