Primary hyperaldosteronism

　　The etiology of primary hyperaldosteronism is not yet clear. According to the pathophysiological changes and biochemical characteristics, primary hyperaldosteronism has five types:

　　1. Adrenal aldosterone adenoma

　　A benign tumor occurring in the adrenal cortex glomerular zone and secreting aldosterone, known as the classic Conn syndrome. It is the main cause of primary aldosteronism, the most common clinical type, accounting for 65% to 80%, with solitary adenoma being the most common, with more on the left side than on the right; bilateral or multiple adenomas account for only 10%; some patients may have an adenoma on one side and hyperplasia on the other. The tumor diameter is between 1 to 2 cm, with an average of 1.8 cm. The weight is usually between 3 to 6 g, with tumors over 10 g being rare. The tumor is mostly round or oval, with a complete capsule and a clear boundary with surrounding tissues, with a golden yellow cut surface. Adenomas are mainly composed of large clear cells, which are 2 to 3 times larger than normal fascicular zone cells. Under the light microscope, the adrenal cortex glomerular zone cells, reticular zone, or dense cells, as well as cells of different sizes, are displayed as 'hybrid cells'. 'Hybrid cells' show the characteristics of both glomerular zone and fascicular zone cells, and some adenoma cells may coexist with diffuse hyperplasia of glomerular zone cells. Under the electron microscope, the mitochondria cristae of tumor cells are plate-like, showing the characteristics of glomerular zone cells. The cause of aldosterone adenoma is unknown, and the concentration of aldosterone in the patient's plasma is parallel to the diurnal rhythm of plasma ACTH, but there is no obvious response to changes in plasma renin. This type of patient has more obvious and typical biochemical abnormalities and clinical symptoms than other types of primary aldosteronism.

　　2. Idiopathic hyperaldosteronism

　　Abbreviated asaldosterone syndrome, it refers to idiopathic adrenal cortical hyperplasia, accounting for 10% to 30% of adult primary aldosteronism and taking the lead in pediatric primary aldosteronism. In recent years, there has been a trend of increasing incidence. The pathological changes are the hyperplasia of cells in the glomerular zone of bilateral adrenal glands, which can be diffuse or focal. The hyperplastic cortex can be seen with micro-nodules and large nodules. The hyperplastic adrenal glands are larger in size, with increased thickness and weight. Large nodules that grow on the surface of the adrenal glands can be seen with golden nodular protuberances, small as sesame seeds and large as soybeans, all without capsules. This is the fundamental difference in pathology and adenomas. Under light microscopy, lipid-filled cells can be seen, similar to normal fascicular zone cells. The nodules are mostly scattered, but can also be clustered. The etiology of aldosterone syndrome is still unclear. Histologically, aldosterone syndrome shows signs of stimulation of the adrenal glands, while the aldosterone synthase gene does not have mutations, but its expression increases and enzyme activity increases. Some scholars believe that the glomerular zone of patients with aldosterone syndrome is excessively sensitive to ATⅡ, and ACEI drugs can reduce aldosterone secretion. Some scholars also propose a hypothetical pathogenesis of aldosterone syndrome: the activity of certain serotoninergic neurons in the central nervous system is abnormally increased, stimulating the pituitary to produce aldosterone stimulating factor (aldosteronestimulating factor, ASF), β-endorphin (β-END), and α-melanocyte stimulating hormone (α-MSH) in excess, leading to hyperplasia of the adrenal cortical glomerular zone and the secretion of a large amount of aldosterone. Research also found that the serotonin antagonist cimetidine can significantly reduce the level of aldosterone in the blood of such patients, suggesting that serotonin activity is enhanced and may be related to the onset of the disease. However, there is no evidence to show that any of the aforementioned pro-opiomelanocortin (POMC) products, which are known to stimulate the function of glomerular zone cells, reach a concentration in the blood circulation of patients with aldosterone syndrome that can stimulate the function of glomerular zone cells. The biochemical abnormalities and clinical symptoms of patients with aldosterone syndrome are not as obvious as those with APA, and the concentration of blood aldosterone is not parallel to the diurnal rhythm of ACTH.

　　3. Dexamethasone suppressible hyperaldosteronism

　　Also known as dexamethasone suppressible hyperaldosteronism (DSH). Since the first case reported by Sutherland DJA et al. in 1966, more than 50 cases have been reported in foreign literature by 1990, and there have also been individual cases and pedigrees reported in China. It is a special type of primary aldosteronism, accounting for about 1%. It mostly manifests in adolescents, and can be familial or sporadic, with familial cases being inherited in an autosomal dominant manner. The adrenal glands show nodular hyperplasia, and the plasma aldosterone concentration is parallel to the diurnal rhythm of ACTH. The characteristic of this disease is that exogenous ACTH can continuously stimulate aldosterone secretion, while low-dose dexamethasone can inhibit excessive aldosterone secretion and restore the patient's blood pressure, blood potassium, and renin activity to normal. The study of the molecular biological mechanism of its onset has found that non-equivalent exchange occurs between the gene encoding aldosterone synthase and the gene encoding 11β-hydroxylase, resulting in a new chimeric gene. The 5′ end of the chimeric gene contains sequences regulated by ACTH for 11β-hydroxylase, while the 3′ end is the coding sequence for aldosterone synthase. The transcription and translation products of the chimeric gene have the activity of aldosterone synthase, but due to the presence of sequences regulated by ACTH at the 5′ end, the synthesis and secretion of aldosterone can be regulated by ACTH and are mainly expressed in the fasciculate band. When exogenous corticosteroids are used, the expression level of the chimeric gene decreases due to feedback inhibition of pituitary ACTH secretion, and the secretion of aldosterone also decreases, hence the administration of exogenous dexamethasone to the patient can control the condition satisfactorily.

　　4. Primary adrenal cortical hyperplasia

　　It accounts for about 1% of primary aldosteronism. Kater et al. found 4 cases between APA and IHA in 1982, with a pathological morphology similar to IHA, which can be unilateral or bilateral adrenal glomerular zone hyperplasia, but its biochemical changes are similar to APA. This condition has a good response to spironolactone treatment, and unilateral or subtotal adrenalectomy can correct the symptoms and biochemical abnormalities of excessive aldosterone.

　　5. Aldosterone-producing adenocarcinoma

　　It is a type of adrenal cortical adenocarcinoma (adrenalcorticalcarcinoma), accounting for 1% to 2% of primary aldosteronism. It can occur at any age, but it is most common between 30 and 50 years old.

　　Patients with primary aldosteronism may develop a relatively benign hypertension due to the suppression of renin secretion. If hypertension persists for a long time, it can lead to damage to the heart, brain, and kidneys. Long-term hypokalemia can also affect the heart, with severe cases leading to ventricular fibrillation. It has been reported that among 58 patients with primary aldosteronism, 34% had cardiovascular complications, 15.5% had strokes, including 6.9% with cerebral infarction and 8.6% with cerebral hemorrhage. 9.4% had hypertensive heart disease, 1.9% had uremia, and 13.2% had strokes (5.79% cerebral infarction, 9.4% cerebral hemorrhage).

　　Regardless of the etiology or type of primary aldosteronism, the clinical manifestations are caused by excessive secretion of aldosterone. The following is a specific introduction to the common symptoms of this disease:

　　1. Hypertension

　　It is the most common initial symptom of primary aldosteronism, with clinical manifestations resembling essential hypertension, including headache, dizziness, fatigue, tinnitus, and weak vision, among other symptoms seen in the outpatient department of internal medicine. It can appear 2 to 7 years earlier than hypokalemia, with most cases presenting as a slowly progressing benign hypertension process, presenting with mild to moderate hypertension (150-170/90-109 mmHg). With the progression of the disease course and condition, most patients have diastolic hypertension and headaches, with some patients' diastolic blood pressure reaching as high as 120-150 mmHg. A few cases may show malignant progression. Severe cases can reach as high as 210/130 mmHg, with降压 drugs often showing no significant efficacy. Retinal changes are often not proportional to the degree of hypertension, but they can still cause damage to target organs such as the heart, brain, and kidneys, such as left ventricular hypertrophy, angina, left ventricular insufficiency, coronary aneurysms, and aortic dissection; transient ischemic attack or stroke, retinal hemorrhage; renal insufficiency, etc.

　　Although patients with primary hyperaldosteronism have increased blood volume due to water and sodium retention, the benign course of hypertension and the absence of edema are due to the occurrence of the 'escape' phenomenon. APA patients have a 'spoon-shaped' drop in blood pressure at night, which seems to still exist a diurnal rhythm. GRA patients often have a family history of maternal hypertension.

　　2. Hypokalemia

　　In patients with hypertension accompanied by spontaneous hypokalemia and abnormal increased urinary potassium of unknown cause, primary hyperaldosteronism should be considered first. Blood potassium can be normal or persist at the lower limit of normal in the early stage of the disease, with no clinical symptoms of hypokalemia. As the condition progresses and the course lengthens, blood potassium continues to decrease, and 80% to 90% of patients have spontaneous hypokalemia, which is more prominent in APA patients, while it may be不明显 even absent in IHA and dexamethasone-suppressible primary hyperaldosteronism patients. Some patients have normal blood potassium levels, but rarely >4.0 mmol/L. High sodium diet or diuretic-containing antihypertensive drugs can induce hypokalemia.

　　Primary hyperaldosteronism refers to the excessive secretion of aldosterone by the adrenal cortex, causing hypertension and hypokalemia. The cause is mostly unilateral adrenal adenoma, a few are bilateral adrenal cortical hyperplasia, and occasionally adrenal carcinoma.

　　1. Do not stay outdoors for a long time or sweat repeatedly to prevent fainting. Pay attention to appropriate salt supplementation when drinking beverages.

　　2. Cardiovascular patients should take medication under the guidance of a doctor and should not change the dosage or combination arbitrarily. Pay attention to re-examination of blood electrolytes in daily life.

　　3. When occasional symptoms such as palpitations, dizziness, limb weakness, convulsions, and arrhythmias occur, one should go to the hospital as soon as possible with the accompaniment of family members.

　　4. Cardiovascular patients are mostly elderly and need a long-term low-salt and low-fat diet. Therefore, more potassium-rich foods should be eaten in the diet, such as lean meat, green leafy vegetables, bananas, and soy products, etc.

　　Primary hyperaldosteronism is a disease of abnormal adrenal cortical secretion, and it generally requires the following examinations:

　　1. General examination

　　(1) Most patients with hypokalemia have blood potassium levels below normal, usually between 2 to 3 mmol/L, and can be below 1 mmol/L. Hypokalemia is persistent.

　　(2) Mild increase in blood sodium.

　　(3) Alkalosis causes a decrease in intracellular pH and an increase in extracellular pH, with blood pH and carbon dioxide binding capacity at the normal high limit or slightly elevated.

　　(4) Elevated urinary potassium is not proportional to hypokalemia, and daily urinary potassium excretion remains greater than 25 mmol in cases of hypokalemia. In cases of hypokalemia caused by gastrointestinal potassium loss, urinary potassium is always below 15 mmol/24h.

　　(5) Decreased urine specific gravity and urine osmolality: Reduced renal concentrating function, with nocturnal urine volume greater than 750 ml.

　　2. Plasma aldosterone (PAC), renin activity (PRA) measurement, and supine/erect position test

　　The method for measuring plasma aldosterone and renin activity at Peking Union Medical College Hospital is as follows: After an overnight fast in a supine position, blood is drawn immediately after an empty stomach at 8 a.m. the next day, followed by an intramuscular injection of Furosemide 40 mg, then the patient is in an upright position for 2 hours in the morning, and blood is drawn at 10 a.m. The concentrations of plasma aldosterone and renin activity are measured by radioimmunoassay. The normal values of plasma aldosterone are 58.2 to 376.7 pmol/L in the supine position and 91.4 to 972.3 pmol/L in the upright position, and the normal values of plasma renin activity are 0.2 to 1.9 ng/(ml·h) in the supine position and 1.5 to 6.9 ng/(ml·h) in the upright position. In patients with primary aldosteronism, the plasma aldosterone level in the supine position is elevated, and the renin activity is suppressed. After exercise and the stimulation of diuretics, the renin activity in the upright position does not increase significantly.

　　Because there is an overlap in plasma aldosterone levels between patients with primary aldosteronism and primary hypertension, most scholars currently propose using the ratio of plasma aldosterone to renin activity (PAC/PRA) to distinguish between primary aldosteronism and primary hypertension. If PAC (ng/dl)/PRA (ng/ml·h) > 25, it strongly suggests the possibility of primary aldosteronism, and PAC/PRA ≥ 50 can be diagnosed as primary aldosteronism.

　　3. Urinary aldosterone level measurement

　　Under normal dietary conditions, the urinary aldosterone excretion of normal individuals is 9.4 to 35.2 nmol/24h, which is significantly higher in patients with primary aldosteronism.

　　4. Normal saline infusion test

　　Patients are in a supine position, and 0.9% normal saline is administered intravenously at a rate of 300 to 500 ml/h for a continuous period of 4 hours. In normal individuals and patients with primary hypertension, after 4 hours of saline infusion, the plasma aldosterone level is suppressed to below 277 pmol/L (10 ng/dl), and the plasma renin activity is also suppressed. In patients with primary aldosteronism, especially those with adrenal cortical aldosterone adenomas, the plasma aldosterone level remains above 277 pmol/L (10 ng/dl) and is not suppressed. However, patients with adrenal cortical glomerulosa hyperplasia may show a false-negative reaction, that is, the secretion of aldosterone is suppressed. However, it should be noted that this test should be contraindicated in patients with high blood pressure, older age, and heart failure.

　　5. Captopril (Capoten) test

　　In normal individuals or patients with primary hypertension, after taking Captopril, the plasma aldosterone level is suppressed to below 416 pmol/L (15 ng/dl), while the plasma aldosterone in patients with primary aldosteronism is not suppressed.

　　6. Spironolactone test

　　Patients with hyperaldosteronism generally experience an increase in blood potassium and a decrease in blood sodium, a reduction in urinary potassium, and symptom improvement after taking medication for 1 week. After continuing medication for 2 to 3 weeks, the blood pressure of most patients can decrease, blood potassium levels can be restored to normal, and alkalosis can be corrected. This test can only be used to distinguish between hyperaldosteronism and primary or secondary hyperaldosteronism.

　　7. Sodium loading test

　　In patients with primary hyperaldosteronism, the urinary excretion of potassium is significantly reduced, and hypokalemia and hypertension are alleviated. The rapid decrease in urinary sodium is balanced with intake, and renin activity remains suppressed; in the high sodium test, there is no significant change in blood potassium in normal people and hypertensive patients, while in patients with primary hyperaldosteronism, blood potassium can drop below 3.5 mmol/L, symptoms and biochemical changes worsen, and plasma aldosterone remains higher than normal.

　　8. Plasma 18-hydroxycorticosterone (18-OH-B) measurement

　　The plasma 18-OH-B (precursor of aldosterone) level in patients with adrenal cortical aldosterone secretion adenoma is significantly increased, often >2.7 mmol/L (100 ng/dl), while those with idiopathic hyperaldosteronism and primary hypertension are lower than this level.

　　For patients, a reasonable diet is the key to disease recovery, therefore, it is recommended that patients with primary hyperaldosteronism should pay attention to the following dietary principles:

　　1. Consume a normal potassium and sodium fixed diet for 2 weeks or longer (3 to 5 weeks).

　　2. After 2 to 3 days of potassium and sodium fixed diet adaptation, on the 3rd to 4th day, collect 24-hour urine to measure potassium and sodium, and at the same time, measure blood potassium, blood sodium, and carbon dioxide binding power.

　　3. First, according to the specific situation of the patient, formulate the daily intake of staple food (avoid using flour made from wheat added with alkali or leavening powder in the main sugar), calculate the amount of K+ and Na+ provided by the staple food daily according to the 'Food Composition Table', and then subtract the amount of K+ and Na+ provided by the staple food from the total amount of K+ and Na+ specified in the diet check. The remaining K+ and Na+ mg amount should be supplemented from side dishes and salt (NaCl).

　　4. When arranging side dishes, it is advisable to choose foods that are available in the market at the time and preferred by the patient according to the 'Food Composition Table' (it is best to choose those with low K+ and Na+ content). First, ensure the required amount of K+. Then, add an appropriate amount of NaCl (1g NaCl = 393mg Na+) as a seasoning to make up for the total required amount of Na+.

　　The treatment of primary aldosteronism depends on the cause. APA should be treated with surgery as soon as possible, and most patients can be cured after surgery. Unilateral or subtotal resection of PAH is also effective, but some patients may experience recurrence of symptoms after surgery, so in recent years, there has been a trend towards more medication therapy. For patients with APC who are found early, with localized lesions and no metastasis, surgery can be expected to improve survival rates. IHA and GRA are best treated with medication. If it is difficult to determine whether it is an adenoma or hyperplasia clinically, exploratory surgery can be performed, and medication can also be used, followed by follow-up of the disease development and evolution, and the treatment plan is determined according to the final diagnosis.

　　1. Surgical treatment

　　To ensure the smooth progress of surgery, it is necessary to make preoperative preparations. Preoperative correction of electrolyte imbalance and alkalosis due to hypokalemia is necessary to prevent serious arrhythmias.

　　2. Medication therapy

　　Patients diagnosed with IHA, GRA, or those with poor treatment effects from surgery, or APA patients who do not want to undergo surgery or cannot tolerate surgery, can be treated with medication. The treatment of IHA can choose the following drugs:

　　(1) Spironolactone, an aldosterone antagonist, is the first-line drug for the treatment of primary aldosteronism. It binds to receptors in the cytoplasm and nucleus of renal tubular cells, competitively inhibits aldosterone, causing potassium retention and sodium excretion. When there is an excess of aldosterone in the body, the effect of spironolactone is particularly obvious, but the synthesis of aldosterone is not affected, and the content of aldosterone remains unchanged during the medication period.

　　(2) Calcium channel blockers can inhibit aldosterone secretion and can also inhibit the contraction of vascular smooth muscle, reduce vascular resistance, and at the same time lower blood pressure.

　　(3) Angiotensin-converting enzyme inhibitors can reduce aldosterone secretion, improve potassium balance, and lower blood pressure to normal. Commonly used in clinical practice include captopril, enalapril, cilazapril, benazepril, and so on, the specific usage is the same as that of hypertension treatment. Common adverse reactions include cough, rash, headache, gastrointestinal discomfort, and so on. When combined with potassium-sparing diuretics, this drug can cause hyperkalemia, and should be used with caution.

　　(4) Aminoglutethimide, a drug that inhibits aldosterone synthesis, can block the conversion of cholesterol to pregnenolone, thereby inhibiting the synthesis of adrenal cortical hormones. Ketoconazole, an imidazole derivative, can block the activity of cytochrome P450 enzymes at high doses, interfere with the activity of 11β-hydroxylase and cholesterol side-chain cleavage enzyme in the adrenal cortex, and significantly reduce aldosterone in primary aldosteronism patients, restore blood potassium and blood pressure to normal. However, it has significant adverse reactions, and long-term use requires observation.

　　(5) Cabergoline, a POMC derivative inhibitor, is a serotonin inhibitor that can inhibit the production of POMC derivatives in the pituitary gland, significantly reduce aldosterone levels in patients, and is used to treat hyperplastic primary aldosteronism. However, the effects on blood potassium, blood pressure, and long-term efficacy still need to be observed. Some authors have tried aldosterone stimulating factor (ASF) preparations or morphine antagonists to treat IHA.

　　(6) Dexamethasone, a glucocorticoid, is effective for GRA patients. The appropriate dose can be taken for a long time. Generally antihypertensive drugs can be added when necessary. After taking the medicine, blood pressure, blood potassium, renin, and aldosterone can be restored to normal, and patients can maintain a normal state for a long time. Regular measurement of blood electrolytes, attention to changes in blood potassium, and adverse drug reactions are required during the medication period.

　　(7) Most APC patients have extensive metastasis of cancer cells at the time of diagnosis, and consider using high-dose cisplatin treatment.