A case report of a young boy with low renin and high aldosterone levels induced by Liddle syndrome who was previously misdiagnosed with primary aldosteronism.

OBJECTIVES: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalemia. CASE PRESENTATION: This report describes a 17-year-old male with hypertension and hypokalemia. We performed Captopril inhibition and postural stimulation test to diagnose and type primary aldosteronism. The plasma renin activity was consistently low, and aldosterone levels were high, hence the patient was initially diagnosed with primary aldosteronism. After genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of a p. Pro617Ser mutation in the SCNN1B gene. After diagnosis, the patient was prescribed one tablet of amiloride twice a day. The patient's blood pressure (average in 120-135/70-80 mmHg) and serum potassium levels (3.6-4.0 mmol/L) returned to normal and was well-controlled after treatment. CONCLUSIONS: Adolescent hypertension may be secondary to underlying medical conditions affecting the heart, kidneys, or endocrine system or primary with no known underlying disease process. Although in an adolescent with hypertension, hyperaldosteronism, and low plasma renin activity, the initial diagnosis suggested primary hyperaldosteronism, the failure of aldosterone receptor antagonist's therapy led to the diagnosis of Liddle syndrome. Increased aldosterone levels should always be evaluated with caution before a definitive diagnosis to prevent misdiagnosis. Genetic testing is the gold standard for the diagnosis of Liddle syndrome. Early diagnosis and early precise treatment can restore normal blood pressure and prevent severe sequelae of chronic hypertension in patients.

Premature Stroke Secondary to Severe Hypertension Results from Liddle Syndrome Caused by a Novel SCNN1B Mutation.

INTRODUCTION: Liddle syndrome (LS), an autosomal dominant and inherited monogenic hypertension syndrome caused by pathogenic mutations in the epithelial sodium channel (ENaC) genes SCNN1A, SCNN1B, and SCNN1G. OBJECTIVE: This study was designed to identify a novel SCNN1B missense mutation in a Chinese family with a history of stroke, and to confirm that the identified mutation is responsible for LS in this family. METHODS: DNA samples were collected from the proband and 11 additional relatives. Next-generation sequencing was performed in the proband to find candidate variants. In order to exclude genetic polymorphism, the candidate variantin SCNN1B was verified in other family members, 100 hypertensives, and 100 healthy controls by Sanger sequencing. RESULTS: Genetic testing revealeda novel and rare heterozygous variant in SCNN1B in the proband. This variant resulted in a substitution of threonine instead of proline at codon 617, altering the PY motif of ß-ENaC. The identified mutation was only verified in 5 relatives. In silico analyses indicated that this variant was highly pathogenic. In this family, phenotypic heterogeneity was present among 6 LS patients. Tailored medicine with amiloride was effective in controlling hypertension and improving the serum potassium concentration in patients with LS. CONCLUSIONS: We identified a novel SCNN1B mutation (c.1849C>A) in a family affected by LS. Patients with LS, especially those with severe hypertension, should be alert for the occurrence of premature stroke. Timely diagnosis using genetic testing and tailored treatment with amiloride can help LS patients to avoid severe complications.

Low-Renin Hypertension.

Low-renin hypertension affects 30% of hypertensive patients. Primary hyperaldosteronism presents with low renin and aldosterone excess. Low-renin, low-aldosterone hypertension represents a wide spectrum of disorders that includes essential low-renin hypertension, hereditary forms of hypertension, and hypertension secondary to endogenous or exogenous factors. This review addresses the different conditions that present with low-renin hypertension, discussing an appropriate diagnostic approach and highlighting the genetic subtypes within familial forms.

Monogenic Forms of Hypertension.

Essential hypertension is a highly prevalent disease in the general population. Secondary hypertension is characterized by a specific and potentially reversible cause of increased blood pressure levels. Some secondary endocrine forms of hypertension are common (caused by uncontrolled cortisol, aldosterone, or catecholamines production). This article describes rare monogenic forms of hypertension, characterized by electrolyte disorders and suppressed renin-aldosterone axis. They represent simple models for the physiology of renal control of sodium levels and plasma volume, thus reaching a high scientific interest. Furthermore, they could explain some features closer to the essential phenotype of hypertension, suggesting a mechanistically driven personalized treatment.

Resistant Hypertension: A Clinical Perspective.

Resistant hypertension is a common clinical entity, defined as suboptimal blood pressure response to multiple therapies after excluding medication nonadherence and secondary forms of hypertension. Patients with resistant hypertension generally share several comorbidities. Resistant hypertension is more common in individuals of African descent. Blood pressure should be optimized using multiple strategies, including lifestyle changes and single-pill combination therapies, with the aim of reducing cardiovascular events while reducing side effects from using antihypertensive therapy. A renin/aldosterone-based diagnostic and treatment approach will help tailor therapy. The use of mineralocorticoid receptor antagonists or amiloride as appropriate is favored.

A Novel Association of Martorell Ulcer With Liddle Syndrome.

Pseudohyperaldosteronism, or Liddle syndrome, is a rare, autosomal dominant condition characterized by early-onset hypertension, often associated with hypokalemia and metabolic alkalosis. Martorell hypertensive ischemic leg ulcer is a rare, underdiagnosed ulcer characterized by subcutaneous arteriolosclerosis, classically appearing over the dorsolateral lower extremity or Achilles tendon in patients with hypertension and diabetes. It presents an important diagnostic challenge because it can appear grossly similar to other entities such as pyoderma gangrenosum or venous stasis ulcers, but requires surgical intervention. This article presents a case study of surgical management of a Martorell ulcer in a 69-year-old woman with Liddle syndrome. To the authors' knowledge, this is the first case reported in the literature of this rare ulcer occurring secondary to this rare cause of hypertension.

Risk factors associated with pseudoaldosteronism in patients with chronic hepatitis: A retrospective cohort study.

Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin.

A case of Liddle's syndrome; unusual presentation with hypertensive encephalopathy.

Liddle's syndrome is a rare cause of secondary hypertension. Identification of this disorder is important because treatment differs from other forms of hypertension. We report an interesting case of a 35-year-old lady, a known diabetic and hypertensive patient, who presented with features of hypertensive encephalopathy. The family history was unremarkable. Past treatment with various combinations of antihypertensive medications including spironolactone, all at high doses, failed to control her blood pressure. Upon evaluation, the patient had hypokalemic alkalosis, low 24-h urine potassium and suppressed plasma renin activity. Although these findings were similar to hyperaldosteronism, plasma aldosterone was lower than the normal range. Blood pressure decreased markedly after administration of amiloride. Along with hyporeninemic hypo-aldosteronism, the non-responsiveness to spironolactone and good response to amiloride established the diagnosis of Liddle's syndrome.

Cerebrovascular consequences of pseudohyperaldosteronism.

The study of mechanistically defined forms of hypertension may provide insight into the relationship between hypertension and stroke. The author retrospectively studied a cohort of 23 individuals with pseudohyperaldosteronism (PHA), a condition associated with pathologic activation of the distal nephron epithelial sodium channel but low renin and aldosterone levels. During a median follow-up of 11 years (range: 1-30), 4 of 23 (17.4%) patients had a cerebrovascular event recorded. Intracranial hemorrhage was not observed in any patient. Cerebrovascular events tended to occur in older patients, minorities, and patients with a later diagnosis of PHA and additional vascular risk factors. In addition to strict blood pressure control, patients with PHA should have early evaluation and treatment of other vascular risk factors to reduce the risk of stroke.

Liddle syndrome in a Serbian family and literature review of underlying mutations.

UNLABELLED: Severe and reproducible low-renin hypertension responsive to salt restriction and amiloride-thiazide therapy in a 13-year-old otherwise asymptomatic boy suggested Liddle syndrome. This assumption was strengthened by a positive family history of hypertension poorly responsive to conventional treatment or sudden deaths under 40 years of age in four generations. DNA analysis of the beta and gamma subunits of the epithelial sodium channel revealed a heterozygous mutation c.C1852T (p.Pro618Ser) in the SCNN1B gene in the patient and in both his hypertensive mother and uncle. A PubMed search revealed 21 different disease-causing mutations reported to date, all but two clustering in the cytoplasmic C-terminal regions of either beta (16 mutations) or gamma (5) subunit, leading to a three- to eightfold increase in the amiloride-sensitive sodium current. Inter- and intrafamilial variability in both hypertension and hypokalemia were disclosed, which may not be obligatory among the subjects carrying a Liddle mutation. CONCLUSION: Liddle syndrome should be considered as a cause of hypertension in children or adolescents particularly with suppressed renin activity. Early diagnosis and appropriately tailored treatment avoid complications of long-term unrecognized or inappropriately managed hypertension.

High prevalence of liddle syndrome phenotype among hypertensive US Veterans in Northwest Louisiana.

Liddle syndrome (LS) is an autosomal dominant disorder due to a gain-of-function mutation in the epithelial Na(+) channel and is perceived to be a rare condition. A cross-sectional study of 149 hypertensive patients with hypokalemia (<4 mmol/dL) or elevated serum bicarbonate (>25 mmol/dL) was conducted at a Veterans' Administration Medical Center Hypertension Clinic in Shreveport, LA. Data on demographics, blood pressure, and select blood tests were collected and expressed as percentages for categoric variables and as mean ± standard deviation (SD) for continuous variables. Patients were diagnosed with likely LS when the plasma renin activity (PRA) was <0.35 µU/mL/h and the aldosterone was <15 ng/dL and likely primary hyperaldosteronism (PHA) with PRA <0.35 µU/mL/h and aldosterone level >15 ng/dL. The cohort included predominantly elderly (67.1±13.4 years), male (96%), and Caucasian (57%) patients. The average blood pressure was 143.8/79.8 mm Hg±27.11/15.20 with 3.03±1.63 antihypertensive drugs. Based on the above criteria, 9 patients (6%) satisfied the criteria for likely LS and 10 patients (6.7%) were diagnosed with likely PHA. In this hypothesis-generating study, the authors detected an unusually high prevalence of biochemical abnormalities compatible with likely LS syndrome from Northwestern Louisiana, approaching that of likely PHA.