RESUMEN
Multiple diagnostic entities are included among the causes of secondary arterial hypertension, so an appropriate screening is essential to diagnose potentially treatable pathologies. Genetic syndromes occupy a small percentage of these causes. The latter group includes Liddle syndrome, a rare genetic disease with autosomal dominant inheritance, caused by gain-of-function mutations in the genes that code for the epithelial sodium channel (ENaC), involved in sodium reabsorption in the distal renal tubules. The presence of a family history of arterial hypertension with onset at an early age and hypokalemia in some of them should lead to the suspicion of this genetic disorder, which must be confirmed with genetic tests. We describe a case, genetically confirmed, in which hypertension refractory to conventional treatment is the only manifestation of said syndrome, making diagnosis difficult and delayed until adulthood.
Asunto(s)
Hipertensión , Hipopotasemia , Síndrome de Liddle , Adulto , Canales Epiteliales de Sodio/genética , Humanos , Hipertensión/etiología , Hipopotasemia/etiología , Síndrome de Liddle/etiología , Síndrome de Liddle/genéticaRESUMEN
Licorice-induced pseudoaldosteronism is a common adverse effect in traditional Japanese Kampo medicine, and 3-monoglucuronyl glycyrrhetinic acid (3MGA) was considered as a causative agent of it. Previously, we found 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1), one of the metabolites of glycyrrhizin (GL) in the urine of Eisai hyperbilirubinuria rats (EHBRs) treated with glycyrrhetinic acid (GA), and suggested that it is also a possible causative agent of pseudoaldosteronism. The discovery of 1 also suggested that there might be other metabolites of GA as causal candidates. In this study, we found 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate (2) and 18ß-glycyrrhetyl-3-O-sulfate (3) in EHBRs' urine. 2 and 3 more strongly inhibited rat type 2 11ß-hydroxysteroid dehydrogenase than 1 did in vitro. When EHBRs were orally treated with GA, GA and 1-3 in plasma and 1-3 in urine were detected; the levels of 3MGA were quite low. 2 and 3 were shown to be the substrates of organic anion transporter (OAT) 1 and OAT3. In the plasma of a patient suffering from pseudoaldosteronism with rhabdomyolysis due to licorice, we found 8.6 µM of 3, 1.3 µM of GA, and 87 nM of 2, but 1, GL, and 3MGA were not detected. These findings suggest that 18ß-glycyrrhetyl-3-O-sulfate (3) is an alternative causative agent of pseudoaldosteronism, rather than 3MGA and 1.
Asunto(s)
Glycyrrhiza/efectos adversos , Ácido Glicirrínico/efectos adversos , Síndrome de Liddle/etiología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Femenino , Glycyrrhiza/química , Ácido Glicirrínico/química , Ácido Glicirrínico/aislamiento & purificación , Ácido Glicirrínico/orina , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Síndrome de Liddle/diagnóstico , Espectroscopía de Resonancia Magnética , Estructura Molecular , RatasRESUMEN
Pseudoaldosteronism is a common adverse effect associated with traditional Japanese Kampo medicines. The pathogenesis is mainly caused by 3-monoglucuronyl glycyrrhetinic acid (3MGA), one of the metabolites of glycyrrhizin (GL) contained in licorice. We developed an anti-3MGA monoclonal antibody (MAb) and an ELISA system to easily detect 3MGA in the plasma and urine of the patients. However, we found that some metabolites of GL cross-reacted with this MAb. Mrp2-deficient Eisai Hyperbilirubinemia rats (EHBRs) were administered glycyrrhetinic acid (GA), and we isolated 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide (1) from the pooled urine with the guidance of positive immunostaining of eastern blot as the new metabolite of GL. The IC50 of 1 for type 2 11ß-hydroxysteroid dehydrogenase (11ß-HSD2) was 2.0 µM. Similar plasma concentrations of 1 and GA were observed 12 h after oral administration of GA to EHBR. Compound 1 was eliminated via urine, whereas GA was not. In Sprague-Dawley (SD) rats orally treated with GA, compound 1 was absent from both the plasma and the urine. Compound 1 was actively transported into cells via OAT1 and OAT3, whereas GA was not. Compound 1, when produced in Mrp2-deficiency, represents a potential causative agent of pseudoaldosteronism, and might be used as a biomarker to prevent the adverse effect.
Asunto(s)
Ácido Glicirretínico/análogos & derivados , Ácido Glicirrínico/análogos & derivados , Síndrome de Liddle/etiología , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Perros , Femenino , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/toxicidad , Humanos , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos BALB C , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Eliminación RenalRESUMEN
BACKGROUND: Liddle's syndrome is a rare monogenic form of hypertension caused by truncating or missense mutations in the C termini of the epithelial sodium channel (ENaC) ß or γ subunits. Patients with this syndrome present with early onset of hypertension, hypokalemia, metabolic alkalosis, hyporeninemia and hypoaldosteronism, and a potassium-sparing diuretics (triamterene or amiloride) can drastically improves the disease condition. Although elderly patients having these characteristics were considered to have Liddle's syndrome or Liddle's-like syndrome, no previous report has indicated that Liddle's-like syndrome could be caused by nephrotic syndrome of primary glomerular disease, which is characterized by urinary excretion of > 3 g of protein/day plus edema and hypoalbuminemia, or has explained how the activity function of ENaC could be affected in the setting of high proteinuria. CASE PRESENTATION: A 65-year-old Japanese man presented with nephrotic syndrome. He had no remarkable family history, but had a medical history of hypertension and hyperlipidemia. On admission, hypertension, spironolactone-resistant hypokalemia (2.43 mEq/l), hyporeninemic hypoaldosteronism, and metabolic alkalosis, which suggested Liddle's syndrome, were observed. Treatment with triamterene together with a steroid for nephrotic syndrome resulted in rapid and remarkable effective on improvements of hypertension, hypokalemia, and edema of the lower extremities. Renal biopsy revealed membranous nephropathy (MN) as the cause of nephrotic syndrome, and advanced gastric cancer was identified on screening examination for cancers that could be associated with the development of MN. After total gastrectomy, triamterene was not required and proteinuria decreased. A mutation in the ß or γ subunits of the ENaC gene was not identified. CONCLUSION: We reported for the first time a case of Liddle's-like syndrome associated with nephrotic syndrome secondary to MN. Aberrant activation of ENaC was suggested transient during the period of high proteinuria, and the activation was reversible with a decrease in proteinuria.
Asunto(s)
Glomerulonefritis Membranosa/diagnóstico , Síndrome de Liddle/diagnóstico , Síndrome Nefrótico/diagnóstico , Anciano , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/genética , Humanos , Síndrome de Liddle/etiología , Síndrome de Liddle/genética , Masculino , Síndrome Nefrótico/etiología , Síndrome Nefrótico/genéticaRESUMEN
The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human ß/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of ßENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of ß/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.
Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte/deficiencia , Hipertensión/etiología , Túbulos Renales/fisiopatología , Receptores de Droga/metabolismo , Simportadores/metabolismo , Ubiquitina-Proteína Ligasas/deficiencia , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Canales Epiteliales de Sodio/metabolismo , Humanos , Hipertensión/genética , Hipertensión/fisiopatología , Síndrome de Liddle/etiología , Síndrome de Liddle/genética , Síndrome de Liddle/fisiopatología , Ratones , Ratones Noqueados , Ubiquitina-Proteína Ligasas Nedd4 , Potasio/sangre , Potasio/orina , Canales de Potasio de Rectificación Interna/metabolismo , Sodio/sangre , Sodio/orina , Sodio en la Dieta/administración & dosificación , Sodio en la Dieta/efectos adversos , Miembro 3 de la Familia de Transportadores de Soluto 12 , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoAsunto(s)
Síndrome de Liddle , Canales Epiteliales de Sodio/química , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/fisiología , Humanos , Proteínas Inmediatas-Precoces/fisiología , Túbulos Renales Colectores/metabolismo , Síndrome de Liddle/etiología , Mutación , Polimorfismo Genético , Potasio/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/fisiologíaRESUMEN
We describe here the interesting case of a 73-year-old hypertensive man with pseudoaldosteronism. He had been taking glycyrrhizin at a dose of 75 mg/day for 12 years because of mild liver damage, but had never experienced any previous symptoms associated with hypokalemia. He was referred to our hospital because of hypokalemic tetraparesis and rhabdomyolysis. At that time, we noted mineralocorticoid excess characterized by hypokalemia due to urinary K loss, exacerbation of hypertension due to increased tubular Na reabsorption, metabolic alkalosis, and suppression of both plasma renin activity and plasma aldosterone concentration. His urinary free cortisol excretion rate and the urinary ratio of free cortisol to free cortisone were markedly elevated. Thus we diagnosed pseudoaldosteronism that was related to the long-term use of glycyrrhizin. When he developed pseudoaldosteronism, he also contracted pneumonia, and exhibited elevated levels of serum cortisol and creatinine clearance (CCr) as well as hypouricemia, hypocalcemia, and hypophosphatemia. All normalized after the recovery from pneumonia and the administration of spironolactone. The extracellular volume expansion associated with increased tubular Na reabsorption by the aldosterone-sensitive distal nephron and the resulting increase in CCr caused an inhibition of proximal tubular reabsorption of uric acid, Ca, and inorganic phosphate, leading to their renal loss and therefore hypouricemia, hypocalcemia, and hypophosphatemia, respectively. In this patient, the increased circulating cortisol associated with the stress of inflammation caused by pneumonia triggered the development of pseudoaldosteronism.