Liddle syndrome

　　The pathogenesis of Liddle syndrome is due to gene mutations in the beta, gamma subunits of the amiloride-sensitive sodium channel (ENaC) in renal tubular epithelial cells, which prevents regulatory proteins from binding to the carboxyl-terminal proline-rich region of the beta, gamma subunits, causing a large number of active ENaC to flip and expose to the apical side of the lumen membrane, leading to an increase in the number and activity of this channel on the lumen membrane, an increase in sodium reabsorption, and an increase in potassium secretion.

　　ENaC is located on the apical side of the epithelial cell membrane of the distal tubules, collecting tubules, cortex, and medullary collecting tubules, which are tightly connected. It can absorb sodium ions (Na+) from the lumen into the epithelial cells along the electrochemical gradient, and then pump them into the intercellular space by the basolateral Na+-K+-ATPase pump, and reabsorb them into the blood. ENaC is the rate-limiting step for sodium reabsorption and an important factor for maintaining the sodium homeostasis and blood pressure stability outside the cells. This channel is specific to sodium and lithium and can be specifically blocked by triamterene or amiloride. The activity of ENaC can be regulated by ubiquitination and endocytosis of the cytoplasmic C-terminus, and its activity can be regulated by aldosterone, vasopressin, insulin, and regulatory pathways including the cytoskeleton and protein kinase A, C.

 

　　Like hypertension caused by any other cause, Liddle's syndrome can cause various complications. The risk of stroke, myocardial infarction, arrhythmia (especially in the presence of coronary artery disease), and heart failure in family members of Liddle's syndrome is increased; renal progressive sclerosis and renal failure may also occur, but it is not clear whether this is due to hypertension or the inherent characteristics of the disease. Long-term hypokalemic alkalosis can lead to Kaliopenic nephropathy, accompanied by cloudy swelling of the proximal tubules and functional changes in the distal tubules, reducing the kidney's ability to acidify urine, eliminate acid load, and concentrate urine.

　　The clinical manifestations of Liddle's syndrome are mainly reflected in the following three aspects.
　　1. Hypertension
　　It is the earliest and most common symptom, occurring frequently in adolescents and being relatively severe. Patients often come to seek medical attention with this symptom.
　　2. Electrolyte disturbance
　　Hypokalemia is a common symptom, but about 50% of patients have high blood pressure while blood potassium is normal, with blood potassium levels generally at 2.4～2.8mmol/L; sometimes only slightly low potassium, at 3.0～3.6mmol/L; very low blood potassium (1.8～2.2mmol/L) is rare. Other manifestations include metabolic alkalosis with elevated plasma HCO3- levels, increased arterial blood pH, increased blood sodium, low plasma renin and aldosterone levels, decreased urinary sodium, increased urinary potassium, and low urinary aldosterone levels.
　　3. Hypokalemia manifestations
　　Symptoms may include muscle weakness, periodic paralysis, cramps in the hands and feet, and even rhabdomyolysis (with elevated plasma creatine kinase), sensory abnormalities, polyuria, and thirst.

　　Liddle's syndrome is a rare autosomal dominant genetic disease, and there is currently no effective preventive method. In the diagnosis and treatment of hypertension, be vigilant about the existence of the disease, and further investigate when suspicious signs are found, in order to detect and treat early, and prevent the occurrence of complications. Pay attention to comprehensive prevention when combining the issues of hypertension heredity and family medical history with autosomal dominant genetic diseases.

　　Liddle's syndrome can be considered for diagnosis based on clinical symptoms, laboratory tests, combined with family medical history, and excluding other hypokalemic nephropathies.

　　Laboratory examination:Laboratory tests show severe renal hypokalemia, with blood potassium levels decreasing to 2.4-3.5mmol/L, urinary sodium significantly increased, up to 80mmol/24h, Na+/K+ ratio in saliva and sweat normal or increased, and fecal potassium normal. Hormonal tests show decreased blood aldosterone, no abnormalities in urinary 17-hydroxysteroids and 17-ketosteroids, and no abnormalities in ACTH tests. Taking su9055 (i.e., 3-1,2,3,4-tetrahydro-1-OXO-2-haphthyl)-pyridine can further reduce blood aldosterone levels without affecting blood and urine electrolyte levels; spironolactone also has no effect; taking triamterene can cause significant natriuresis and potassium retention, restoring normal blood potassium levels.

　　Other auxiliary examinations:Routine X-ray and ultrasound examinations can detect and assist in excluding other similar diseases.

　　Liddle's syndrome patients are more sensitive to salt content in the blood, therefore, strictly limiting the intake of salt in the diet is the key to dietary attention for Liddle's syndrome patients, with a maximum of 2g of salt allowed in the daily diet. At the same time, patients need to pay attention to a reasonable dietary balance and a balanced diet.

　　Liddle's syndrome is sensitive to salt restriction and sodium channel blockers (potassium-sparing diuretics), and potassium-sparing diuretics such as triamterene andamiloride are effective. They can directly inhibit the luminal membrane ENaC of the distal tubule and collecting duct, inhibit Na+ reabsorption, increase urinary sodium, and decrease urinary potassium. Strict salt restriction or moderate salt restriction with potassium-sparing diuretics can normalize blood pressure and restore plasma renin and aldosterone levels. Dosage of diuretics: triamterene 100-300mg/d or amiloride 5-20mg/d.

　　The main symptoms of Liddle's syndrome are caused by hypertension and chronic hypokalemia. With positive and correct treatment, complications can be prevented, and the condition can be as normal as a healthy person. If not treated, the disease has no self-healing possibility and can lead to early death due to the disease itself or complications. Because Liddle's syndrome is a familial disease, all blood relatives of the patient should have their blood pressure and blood potassium levels checked.