What are the differences between Bartter (Bartter syndrome), Gitelman (Gitelman syndrome), and Liddle (Liddle syndrome) syndromes?

From the Guidelines

Bartter, Gitelman, and Liddle syndromes are distinct genetic disorders that require different treatment approaches to manage their respective symptoms and prevent long-term complications, with the primary goal of minimizing morbidity, mortality, and improving quality of life. Bartter syndrome presents in infancy or early childhood with severe symptoms including polyuria, polydipsia, growth retardation, and metabolic alkalosis with hypokalemia, hypochloremia, and normal to low blood pressure, as described in the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders consensus and recommendations 1. It results from mutations in genes encoding transporters in the thick ascending limb of the loop of Henle, with five different forms (BS1–5) identified to date, each with distinct clinical characteristics, such as polyuria, dehydration, failure to thrive, growth retardation, and a medical history of polyhydramnios with premature birth 1. Gitelman syndrome typically appears in late childhood or adulthood with milder symptoms including fatigue, muscle cramps, and salt craving, along with hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis, stemming from mutations in the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule 1. Liddle syndrome differs significantly as it causes hypertension, hypokalemia, metabolic alkalosis, and low renin and aldosterone levels due to gain-of-function mutations in epithelial sodium channels, leading to excessive sodium reabsorption, and has been associated with specific genetic variants, such as those affecting the epithelial sodium channel (ENaC) subunits 1. Treatment approaches vary:

• Bartter and Gitelman syndromes require potassium and magnesium supplementation, NSAIDs, and sometimes potassium-sparing diuretics,
• while Liddle syndrome requires sodium restriction and amiloride or triamterene to block the overactive sodium channels. Accurate diagnosis through clinical presentation, electrolyte patterns, and genetic testing is essential for proper management of these conditions, with genetic testing panels including genes underlying BS, as well as Gitelman syndrome, and other hypertensive disorders that can mimic BS, such as pseudohypoaldosteronism type 1 (PHA1) and familial hyperaldosteronism (HALD) 1. In addition, prenatal intervention, such as maternal treatment with NSAIDs, may be considered in cases of polyhydramnios secondary to BS, but carries significant risks for the fetus and requires close monitoring with fetal echocardiography 1. Overall, a comprehensive understanding of the clinical characteristics, genetic basis, and treatment options for Bartter, Gitelman, and Liddle syndromes is crucial for providing optimal care and improving outcomes for patients with these rare genetic disorders.

From the Research

Comparison of Bartter, Gitelman, and Liddle Syndromes

• Bartter and Gitelman syndromes are rare inherited autosomal recessive salt-losing tubulopathies characterized by severe and chronic hypokalemia associated with metabolic alkalosis and secondary hyperaldosteronism 2.
• Bartter syndrome results from a furosemide-like defect in sodium reabsorption in the Henle's loop leading to hypercalciuria and defect in urinary concentration capacity, whereas Gitelman syndrome is a thiazide-like salt-losing tubulopathy associated with hypomagnesemia and hypocalciuria without defect in urinary concentration capacity 2.
• Liddle syndrome is not discussed in the provided studies, however, Bartter and Gitelman syndromes share similar clinical symptoms and therapeutic approaches 3.
• The main clinical features of Bartter and Gitelman syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism 3.
• Patients with Bartter syndrome types 1,2, and 4 present at a younger age than classic Bartter syndrome type 3, and may have severe symptoms in the neonatal period, whereas patients with Gitelman syndrome often present later in life with symptoms such as tetany, delay in height-weight growth curves, chronic tiredness, muscle weakness, myalgia, and vertigo 2, 4.

Diagnostic Challenges and Therapeutic Approaches

• The diagnosis of Bartter and Gitelman syndromes is often made in adolescents or adults, and requires a combination of clinical evaluation, laboratory tests, and genetic analysis 3, 5.
• The treatment of Bartter and Gitelman syndromes consists of lifelong oral supplementations of potassium, salt (Bartter), and magnesium (Gitelman), as well as dietary changes and the use of non-steroidal anti-inflammatory drugs in Bartter syndrome 2, 3.
• Potassium-sparing diuretics may be helpful in severe hypokalemia in Gitelman syndrome, but may reinforce hypovolemia 2.
• Early identification and management of these disorders are essential to prevent long-term complications such as nephrocalcinosis and chronic kidney disease in Bartter syndrome, and chondrocalcinosis in Gitelman syndrome 2, 5.