Hypokalemia is a pathophysiological state in which the serum potassium concentration is <3.5 mmol/L, and potassium deficiency is the loss of total potassium in the body. The latter is the main cause of hypokalemia. Clinically, the total potassium in the body is not deficient, but it can also be diluted or transferred to intracellular and lead to lower serum potassium; conversely, although potassium is deficient, the transfer of potassium from intracellular to extracellular or blood concentration can maintain normal blood potassium concentration or even increase it.
I. Etiology and pathogenesis
(A) Physiological metabolism and function of potassium
Potassium is distributed in 98% of the body’s cells, while plasma potassium accounts for only 0.3% of the total, with a concentration of 3.5~5.5 mmol/L. Adults need about 3~4 g (75~100 mmol) of potassium per day. 5% of potassium is excreted through sweat and saliva, 10% through feces, and 85% through urine. Almost all of the potassium in glomerular filtrate is reabsorbed in the proximal tubule, and the potassium excreted in the urine is mainly re-secreted by the distal tubule under the regulation of aldosterone. The kidney has a good sodium retention function but lacks effective potassium retention capacity; even without potassium intake, it still excretes 30-50 mmol of potassium daily. therefore, potassium intake, distal tubular sodium concentration, plasma aldosterone, and cortisol levels can affect the excretion of potassium by the kidney. Dependence on the sodium pump in the cell membrane allows intracellular potassium to reach 30 to 50 times that of the extracellular fluid. The main physiological roles of potassium include maintenance of normal cellular metabolism, maintenance of intracellular volume, ions, osmotic pressure and acid-base balance, maintenance of cell membrane stress and normal myocardial function. Disorders of potassium metabolism, especially hypokalemia, are very common in clinical practice. Understanding the factors that physiologically regulate potassium metabolism can help us to find the cause of hypokalemia.
(B) Etiology and pathogenesis
1. Potassium deficiency hyperkalemia
Characterized by a decrease in total body potassium, intracellular potassium and serum potassium concentration, it is essentially a potassium deficiency.
(1) Inadequate potassium intake: Long-term fasting, coma, digestive tract obstruction, anorexia nervosa and partial diet can lead to inadequate potassium intake. Potassium is commonly found in all kinds of foods and, except in special cases such as fasting, hypokalemia due to inadequate intake is generally rare. The role of the kidneys in the cationization of potassium is mainly sodium-preserving, and the mechanism of potassium preservation is much less well developed than that of sodium preservation. In the absence of potassium intake, urinary potassium must still be excreted, but only after several days of urinary potassium excretion to the lowest value, about 5-10 mmol per day. if the daily potassium intake is less than 3 grams, and continues for more than 2 weeks, hypokalemia can occur.
(2) Increased potassium excretion from the gastrointestinal tract: Since digestive juices are rich in potassium, gastric juices contain 14mmol/L and intestinal juices contain 6.2~7.2mmol/L. Long-term massive vomiting, diarrhea, gastrointestinal drainage, fistula, etc. can cause potassium loss from the gastrointestinal tract. Some rare diseases such as pancreatic schwannoma, which is caused by excessive secretion of vasoactive intestinal peptide from tumor cells, and choroidal adenoma, which is a tumor with a large area in the colon and rectum and manifests as chronic diarrhea, can cause potassium loss due to loss of digestive fluid. Potassium loss via the gastrointestinal tract is one of the common causes in clinical diseases.
(3) Increased renal excretion of potassium: including renal disease, abnormal adrenocortical hormone action and increased urinary potassium excretion due to drugs.
1) Renal diseases: Acute renal failure with polyuria, tubular acidosis, familial primary potassium loss nephritis, diuresis after release of urinary tract obstruction, Liddle’s syndrome and Fanconi’s syndrome, etc. Increased urinary potassium excretion due to renal tubular lesions leading to impaired reabsorption of potassium.
2) Increased adrenocorticotropic hormones
(1) Increased aldosterone: In primary or secondary aldosteronism, such as proaldosteronism, Bartter syndrome, reninoma, and renal artery stenosis, aldosterone acts on salt corticosteroid receptors in the renal tubular epithelium, promoting sodium reabsorption and reducing potassium reabsorption, resulting in increased urinary potassium excretion.
(2) Increased production or intake of aldosterone-like substances, such as increased production of deoxycorticosterone due to 17-alpha hydroxylase deficiency and increased intake of licorice, can produce manifestations of aldosteronism.
(iii) Increased production of glucocorticoids, such as Cushing’s syndrome or ectopic adrenocorticotropic hormone (ACTH) secretion syndrome, because glucocorticoids also have weak salt corticosteroid activity. In addition, trauma, surgery, infection, and hypoxia can also promote increased urinary potassium excretion due to stress stimulation of adrenal glucocorticoid hypersecretion.
3) Drugs Potassium-discharging diuretics: such as furosemide, bumetanide, hydrochlorothiazide, acetazolamide, etc.; osmotic diuretics: such as mannitol, sorbitol, hypertonic sugar solution, etc.; hyperglycemic state; excessive sodium supplementation, resulting in increased potassium excretion due to renal tubular potassium-sodium exchange; certain antibiotics, such as penicillin, gentamicin, carbenicillin, polymyxin B, etc., may be due to changing the potential difference within the renal tubular epithelium, which facilitates potassium excretion. facilitates the excretion of potassium. Renal potassium loss is the most common cause of hypokalemia.
(4) Others: large burns, discharge of ascites, abdominal drainage, peritoneal dialysis, inappropriate hemodialysis, etc., because body fluids also contain large amounts of potassium ions.
2. Metastatic hypokalemia
Due to the transfer of extracellular potassium to intracellular cells, it is characterized by a normal amount of total potassium in the body, but an increase in intracellular potassium and a decrease in serum potassium concentration.
(1) Metabolic or respiratory alkalosis and recovery from acidosis: Generally, for every 0.1 increase in pH, blood potassium decreases by about 0.7 mmol/L. Respiratory alkalosis has less effect on blood potassium, while in metabolic alkalosis, the H+ concentration of extracellular fluid decreases, intracellular H+ is released, and K+ in extracellular fluid enters the cells, resulting in abnormal potassium distribution. In addition, the renal tubular epithelial cells excrete less H+ in alkalosis, so the exchange of H+ and Na+ is reduced while the exchange of Na+ and K+ is enhanced, resulting in increased urinary potassium excretion.
(2) Use of large amount of glucose solution: Large amount of glucose solution infusion, especially when insulin is applied at the same time, may lead to hypokalemia. Insulin promotes cellular glycogen synthesis, which requires potassium, and plasma potassium enters cells with glucose for glycogen synthesis. Insulin may also directly stimulate the Na+-K+-ATPase on the skeletal muscle cell membrane, thus increasing Na+ discharge from the muscle cell and increasing extracellular K+ entry into the muscle cell.
(3) Periodic paralysis: e.g. familial periodic paralysis, hyperthyroidism with periodic paralysis, idiopathic periodic paralysis. The pathogenesis is unclear and is generally believed to be related to fluctuations in potassium ion concentration inside and outside the cell, possibly due to excessive β-sympathetic excitation or an inherited mutation causing abnormal potassium channel activity.
(4) Acute stress state: such as cranial trauma, after cardiopulmonary resuscitation, increased secretion of adrenaline due to delirium tremens, acute ischemic heart disease, etc., which can promote the entry of potassium into the cells.
(5) Cottonseed oil and barium chloride poisoning: In barium poisoning, the Na+-K+-ATPase on the cell membrane is continuously activated, and potassium in the extracellular fluid continuously enters the cell, while the pore of potassium outflow from the cell is specifically blocked, thus hypokalemia occurs. Cottonseed oil contains cotton phenol which is associated with the development of hypokalemia.
(6) Treatment of anemia with folic acid and vitamin B12: hypokalemia can result from increased potassium utilization by newborn red blood cells.
(7) Repeated input of cold-stored and washed red blood cells and hypothermia: Because red blood cells can lose about 50% of potassium during cold storage, extracellular potassium rapidly enters the cells after input into the body causing extracellular hypokalemia. Hypothermia can make potassium enter the cell.
3.Dilutive hypokalemia
Characterized by a relative decrease in blood potassium concentration due to extracellular fluid retention and a normal amount of total body potassium and intracellular potassium. It is seen in cases of excessive water and water toxicity, or excessive and rapid rehydration without timely potassium replacement.
II. Diagnostic ideas
Hypokalemia is diagnosed mainly by biochemical tests. Hypokalemia should be noted if limb paralysis is present in a conscious condition. In the absence of these symptoms but the presence of a cause of potassium loss, the blood potassium level needs to be measured promptly. An electrocardiogram will help in the diagnosis before the results of blood potassium measurement are available.
(a) Take medical history
1. Any cause of potassium loss
Find out if there is any history of inadequate intake, vomiting, diarrhea, medication, endocrine diseases such as Graves’ disease, and any related family history.
2. Symptoms of hypokalemia
Such as limb paralysis, palpitations, abdominal distension and increased nocturia.
3.What are the concomitant symptoms of the disease?
If the symptoms are accompanied by fear of heat and sweating, hyperphagia, diarrhea, lethargy, irritability and palpitations, thyroid function tests should be performed to determine whether the disease is hyperthyroidism. If accompanied by hypertension, aldosteronism should be considered.
(ii) Physical examination
In addition to muscle weakness and arrhythmias caused by hypokalemia itself, some special clinical signs should be noted. For example, centripetal obesity, purple skin stripes and hypertension suggest cortisolism. Rapid heart rate, enlarged thyroid and protruding eyes suggest Graves’ disease. Adrenal hydroxylase deficiency should be considered in the absence of secondary sex characteristics.
(C) Auxiliary examination
Detailed history and physical examination will help to arrange the necessary tests in a targeted manner.
1.Serum potassium sodium chloride measurement
Serum potassium <3.5 mmol/L in patients with hypokalemia, and may not be low in patients with acidosis or dehydration with potassium deficiency in the body. Aldosteronism and Cushing's syndrome are often associated with hypernatremia or high blood sodium. Renal tubular acidosis may show hyperchloremia.
2. Urinary potassium measurement
There are three methods of measurement as follows. The last method of evaluation is simple, easy to perform, and is important for identifying the cause of hypokalemia.
(1) 24-hour urinary potassium excretion: When the blood potassium is below 3.5 mmol/L, urinary potassium is still above 25 mmol/24h, suggesting renal potassium loss.
(2) Urinary potassium concentration: when blood potassium is below 3.5 mmol/L, if urinary potassium is still >20 mmol/L, it is mostly a renal potassium loss, but <20 mmol/L does not completely exclude renal potassium loss, especially for patients with low sodium uptake and those who have just used potassium-eliminating diuretics.
(3) Urinary potassium/urinary myohepatic ratio (K/C) in a random urine: if the ratio of the two is <1.5 (mmol/mmol) or <15mmol/g, it suggests a non-renal source of potassium loss and a high possibility of reduced potassium intake, gastrointestinal loss of potassium or intracellular transfer of potassium.
3. Routine urine examination
Urine pH is often alkaline or neutral in distal renal tubular acidosis and aldosteronism. In severe proximal tubular acidosis, urine pH may drop below 5.5 and may also be positive for urinary sugars and amino acids. In potassium loss nephropathy, proteinuria and tubular urine may be seen.
4. Blood pH measurement
Blood pH is often elevated or normal in patients with simple hypokalemia. Metabolic alkalosis is often present in states such as aldosteronism, increased production or intake of aldosterone-like substances or glucocorticoids, and violent vomiting. However, metabolic acidosis is often present in states such as renal tubular acidosis, severe diarrhea, and diabetic ketoacidosis with hypokalemia. Blood pH decreases and urine pH often increases in distal renal tubular acidosis.
5.Blood calcium, phosphorus and magnesium measurement
Fanconi syndrome is often accompanied by obvious hypophosphatemia and can be accompanied by hypercalcemia.
6, plasma renin activity and aldosterone measurement
Primary aldosteronism should be considered in patients with elevated plasma aldosterone levels and decreased renin activity. Patients with both elevated levels should be considered with secondary aldosteronism, such as renal artery stenosis and reninoma. A decrease in both may be due to 17-alpha hydroxylase deficiency or increased glycogen intake. An increased plasma aldosterone (ng/dl)/plasma renin activity (ng/ml/h) ratio is now considered to be usually the earliest indicator of autonomic aldosterone secretion. As a screening indicator for primary aldosteronism, when its ratio is greater than 20 and plasma aldosterone level is greater than 15ng/dl, it is highly suggestive of the possibility of primary aldosteronism and requires further examination.
7.Blood thyrotropin (TSH), T3 and T4 measurement
Increased blood T3 and T4 levels and decreased TSH can diagnose primary hyperthyroidism.
8.Blood ACTH and cortisol measurement
An elevated blood cortisol level indicates Cushing’s syndrome. Further analysis of the cause of increased cortisol based on blood ACTH level.
9.Electrocardiogram
In severe hypokalemia, the T wave is inverted and the ST segment decreases. In severe hypokalemia, the T-wave is inverted and the ST-segment decreases. ECG changes often appear earlier and more reliably than clinical symptoms. The ECG changes can be used as one of the supporting evidence for hypokalemia.
Differential diagnosis
(A) Primary aldosteronism
This disease is caused by excessive secretion of aldosterone from adrenal cortical hyperplasia, adenoma or adenocarcinoma, which is an excessive secretion of salt corticosteroids not dependent on renin-angiotensin, causing sodium and potassium retention and expansion of body fluid volume and suppressing the renin-angiotensin system. The main clinical manifestations are polyuria, nocturia, thirst, excessive drinking, muscle weakness or periodic paralysis, hypertension, detectable hypokalemia, hypernatremia, alkalemia, alkalinuria, elevated plasma aldosterone concentration, decreased plasma renin activity, and a plasma aldosterone (ng/dl)/plasma renin activity (ng/ml/h) ratio often greater than 20. Imaging of the adrenal glands may reveal an occupying lesion or bilateral Diffuse enlargement.
(ii) Secondary aldosteronism
1. Reninoma
This disease is usually seen in young people, manifesting as severe hypertension, hypokalemia, and elevated plasma renin activity and aldosterone levels.
2, various causes of renal ischemia
Malignant hypertension, renal artery stenosis and renal atrophy can lead to inadequate blood supply to the kidneys and elevated plasma renin activity and aldosterone levels. Patients often have severe hypertension, and some exhibit hypokalemia, often with azotemia or uremia.
(iii) Cushing’s syndrome
Cushing syndrome is caused by excessive secretion of glucocorticoids by the adrenal glands due to various etiologies, including Cushing’s disease and ectopic ACTH syndrome. The main manifestations are centripetal obesity, full-moon face, polycythemia, purple striae, acne, masculinization, and may be examined for hypertension, hypokalemic alkalosis, elevated blood cortisol concentration without circadian rhythm, unsuppressed by low-dose dexamethasone suppression test, and elevated (ACTH-dependent) or decreased (non-ACTH-dependent) blood ACTH levels. On imaging, an occupying lesion or bilateral diffuse enlargement of the adrenal site is seen.
(iv) Congenital adrenal hyperplasia
It is one of the more common autosomal recessive disorders due to congenital defects in the enzymes required in the synthesis of corticosteroids. Among them, both 11-β-hydroxylase and 17α-hydroxylase defects can cause excessive production of salt corticosteroids such as 11-deoxycorticosterone. Although aldosterone production is not increased at this time, patients often show hypertension, hypernatremia and hypokalemia because the former also has a sodium retention and potassium excretion effect. At the same time, patients with increased or decreased production of adrenal androgens exhibit female masculinization, male pseudoprecocious puberty, or male feminization and female primary amenorrhea. The abnormal sexual differentiation in such patients has an important etiologic suggestive role.
(v) Liddle syndrome
Autosomal dominant hereditary renal tubular epithelial cell dysfunction with abnormal sodium channels, resulting from increased sodium reabsorption in the distal renal tubules. It manifests as hypertension, hypokalemia, renin suppression, low blood aldosterone, and ineffective treatment with spironolactone. Drugs that prevent sodium reabsorption and excrete potassium from the renal tubular epithelium, such as amiloride and aminopterin, can correct hypokalemia and lower blood pressure.
(F) Epiphenomenal salt corticosteroid excess syndrome
It is a congenital 11β-hydroxysteroid dehydrogenase defect that prevents the conversion of cortisol into corticotropin and slows down its clearance, which can activate the salt corticosteroid receptor, manifesting as severe hypertension, hypokalemic alkalosis, reduced urinary 17-hydroxy and free cortisol excretion, and reduced urinary corticotropin metabolite/cortisol metabolite ratio. However, plasma cortisol is normal because daily secretion is also reduced. Most commonly seen in children and young adults. Treatment with spironolactone or dexamethasone may be effective.
(vii) Bartter syndrome
Congenital cases are associated with heredity, while acquired cases are mostly seen in chronic kidney disease. Granulocyte hyperplasia is seen in the glomerular parietal organ in patients with this disease. Gitelman syndrome is a variant of Bartter syndrome, also known as Bartter syndrome with low urinary calcium and low blood magnesium. The former is an autosomal recessive renal tubular disease, which is mostly characterized clinically by low blood potassium, low blood magnesium, low urinary calcium, metabolic alkalosis, high renin, and high aldosterone with normal blood pressure. Urinary calcium to urinary creatinine ratio (urinary calcium / urinary creatinine) ≤ 0.2, while patients with Bartter syndrome urinary calcium / creatinine > 0.2. 100% of patients with Gitelman syndrome have low blood magnesium and increased urinary magnesium.
(ix) renal tubular acidosis
Divided into 4 types, of which ? type (distal tubular acidosis) and Π type (proximal tubular acidosis) patients often show hypokalemia, metabolic acidosis, alkaline urine (the latter may have acid urine in severe cases), while the renal function is normal, plasma renin activity and aldosterone levels are normal.