Liddle Syndrome

Liddle syndrome was initially characterized by hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin and aldosterone, resulting from gain-of-function variants in the epithelial Na+ channel (ENaC). Efficient treatment with ENaC inhibitors is available, but the phenotypic spectrum of genetically confirmed Liddle syndrome is unknown, and some patients may remain undiagnosed and risk inefficient treatment. Here, we used a reverse-phenotyping approach to investigate the Liddle syndrome phenotypic spectrum and genotype-phenotype correlations.

Pubmed, Embase, Scopus, and the Human Gene Mutation Database were searched for articles reporting Liddle syndrome variants. The genetic variants were systematically classified to identify genetically confirmed Liddle syndrome patients. We identified 62 articles describing 45 unique variants within 86 LS families, and phenotypic data were pooled for 268 confirmed Liddle syndrome patients.

The Liddle syndrome variants localized to exon 13 of SCNN1B and SCNN1G, disrupting the PY motif critical for downregulating ENaC activity. Hypertension sensitive to ENaC inhibition was present in 97% of adults carrying Liddle syndrome variants, while hypokalemia, metabolic alkalosis, plasma renin and aldosterone suppression showed incomplete penetrance. Additionally, 95% and 55% of patients had a family history of hypertension or cerebrovascular events. The genotype had minor phenotypic effects; however, probands compared to relatives showed significant phenotypic discrepancies consistent with selection bias for initial genetic screening.

Patients with genetically confirmed Liddle syndrome displayed a phenotypic spectrum with ENaC-sensitive hypertension and family history of hypertension being the most common features. The phenotype appeared independent of the specific gene or variant type involved.

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0-25.9], 8.1 [5.4-12.0], and 5.5 [1.4-21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2-2.6]; P = 0.006), older age (≥70, 5.0 [3.2-7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5-3.2]; P < 0.001), diuretics usage (2.1 [1.3-4.8]; P = 0.004), hypertension (1.6 [1.1-2.4]; P = 0.014), and dementia (7.0 [4.2-11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9-2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7-4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.

Liddle syndrome is an autosomal dominant disorder characterized by hypertension, hypokalemia, low aldosterone levels, and reduced renin activity. Atypical Liddle syndrome can be easily misdiagnosed due to its clinical phenotypes resembling hyperaldosteronism.

The patient was diagnosed with primary aldosteronism due to hypertension and hypokalemia, and underwent left adrenalectomy. After the operation, the patient still had hypertension and hypokalemia that were not easy to control and correct, and had acute cerebral infarction.

The genetic test showed that the base duplication in the coding region of SCN1B gene caused a frameshift mutation:c.1789dupC (p.Arg597fs), Liddle syndrome was diagnosed.

The patient was treated with a low-sodium diet and oral triamterene. The serum potassium level returned to normal and the blood pressure was controlled.

Some Liddle syndrome may present with normal aldosterone levels, genetic testing is necessary for the diagnosis. If the diagnostic test of primary aldosteronism is positive, but the treatment with spironolactone is ineffective, we should actively search for other causes.