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The disorder of water and electrolyte and metabolism Body fluid distribution: Intracellular fluid (ICF): consists of all liquid inside the cells, the largest fluid compartment in the body. Extracellular fluid (ECF): existing in the spaces outside the cells. Divided into the interstitial fluid (inclu...

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1. The disorder of water and electrolyte and metabolism Body fluid distribution: Intracellular fluid (ICF): consists of all liquid inside the cells, the largest fluid compartment in the body. Extracellular fluid (ECF): existing in the spaces outside the cells. Divided into the interstitial fluid (including lymph), plasma and the transcellular fluid, or secreted fluid. It is also called internal environment. Interstitial fluid: comprising all fluid bathing the cells. Body fluid in a number of cavities is called the third space, including cerebrospinal, pericardial, pleural, synovial and gastrointestinal fluids. Fluid which are predominantly the product of epithelial cell secretion, separated from blood by capillary endothelium or interstitial fluid by epithelium is called transcellular fluid. Body fluid composition ECF contains large quantities of sodium, chloride and bicarbonate ions, whereas potassium, calcium, magnesium are in relatively low concentration. The major anions in the ICF are phosphate and protein. Plasma contains a large amount of protein. Capillary wall is permeable to water, electrolytes, glucose, oxygen and carbon dioxide. Osmosis: the cell membrane is permeable to water but not to some solutes, water moves toward the side with greater concentration of solutes through the cell membrane. Osmoles: the ability of solutes to generate osmosis and osmotic pressure Osmolality: when the concentration is expressed in osmoles per kilogram of water, the osmolar concentration of a solution is referred to as its osmolality. Intracellular osmolality is determined by potassium whereas plasma and interstitial fluid are determined by sodium and chloride AQPs: a family of small, hydrophobic proteins forming water-selective channels. AQP 1 is in the renal proximal tubule and descending thin limb of henle. AQP 2 is associated with AVP-induced an increased permeability of collecting duct cells. AQP 4 is highly expressed in the perivascular membrane of astroglial cells. Thirst: rise in ECF osmolality, fall in perfusion or angiotensin can stimulate the neuronal cells in the anteroventral wall of the third ventricle and the anterolateral preoptic hypothalamus called the thirst center to trigger thirst ADH: also called AVP. Osmolality in ECF↑, ADH secretion, ADH bind to V2 receptor, activates the adenylate cyclase/cAMP and protein kinase A system, induces reversible translocation of stored AQP2, to promote the reabsorption of water. The renin-angiotensin-aldosterone system ECF volume↓, renal arterial pressure↓, stimulation of sympathetic nervous system, secretion of renin (enzyme), renin acts on angiotensinⅡ , angⅡ stimulates zona glomerulosa cells to secret aldosterone. Plasma sodium concentration↓or plasma potassium↑ directly stimulates the aldosterone secretion. Aldosterone act on renal tubule cells to promote the reabsorption of sodium and water in exchange for hydrogen or potassium secretion.

ANP: atrial natriuretic peptide. Provides a negative feedback against AVP by inhibit V2 receptor-mediated action of AVP, increase GFR, decease plasma renin activity, aldosterone and endothelin release. Produce cGMP-dependent inhibition of sodium reabsorption. The guanylin family: guanylin and uroguanylin regulate the intestinal fluid and electrolyte secretion by a paracrine mechanism. In the kidney, uroguanylin stimulates urine flow, increase sodium, chloride and potassium excretion. Hyponatremia: serum concentration below 135mmol/L with or without changes in ECF volume. Hypovolemic hyponatremia: hyponatremia with deceased ECF, also called hypotonic dehydration, serum sodium concentration falls below 135mmol/L, plasma osmotic pressure is less than 280mmol/L. Etiology and pathogenesis: 1. Renal losses of sodium (1) inappropriate long-term use of diuretics: furosemide, thiazides (2) adrenocortical insufficiency: lack of aldosterone. (3) Renal disease, particularly tubulointerstitial diseases: dysfunction of diluting segment (4) Renal tubular acidosis: dysfunction of H+-Na+ exchange (5) Cerebral salt-wasting syndrome: sodium wasting, hyponatremia and ECF volume depletion 2. extrarenal losses of sodium (1) excessive amounts of sodium may be lost through gastrointestinal tract: diarrhea, vomiting (2) heavy perspiration and burns (3) body fluid accumulation in the “third space” Alterations of metabolism and function ECF volume↓, osmolality of ECF↓, inhibition of ADH, water diuresis ECF volume↓:Decreased skin turgor(肿胀), postural hypotension, tachycardia(心动过 速) and even shock Cellular swelling Prevention and treatment Identify and correct causes of sodium loss, isotonic salt solutions (0.9% sodium chloride solution or 5% glucose normal saline) must be administered to restore ECF volume and blood pressure. Hypovolemic hyponatremia: hyponatremia with increased ECF volume, always associated with increased total body sodium and water, an increased total body water is greater than that in total body sodium. Water intoxication would occur. Etiology and pathogenesis 1. excessive water intake: hypotonic intravenous infusion or tap water enema administration. The rate of water intake exceeds the normal renal ability to

produce free water. 2. Decreased water output: congestive heart failure (decreased cardiac output or renal blood flow, renal perfusion), hepatic cirrhosis and nephrotic syndrome (intravenous volume contraction and decreased effective circulating plasma volume, kidney retain sodium and water). Alterations of metabolism and function Cellular swelling Water intoxication by swelling of brain cells. Elevated blood pressure, weight gain, edema and lower serum protein concentration Prevention and treatment Restriction of water intake, correction of the causative diseases. In severe case, it is necessary for treatment with diuretics. Normovolemic hyponatremia: hyponatremia with almost normal ECF volume, most commonly caused by syndrome of inappropriate ADH secretion (SIADH) and reset osmostat syndrome. Etiology and pathogenesis SIADH is triggered by a wide spectrum of diseases, including malignant tumors, cerebral disorders and pulmonary diseases. An increased ADH level result in expanded ECF volume and diluted serum concentration, increase GFR and decrease reabsorption of sodium, reduces aldosterone release and stimulate ANP to induce natriuresis. Reset osmostat syndrome in psychosis, pregnancy, quadriplegia 四肢麻痹, and other chronic debilitating 虚弱 diseases. Mechanism: reduced threshold of ADH release with normal osmoreceptor response to changes in serum osmolality. Alterations of metabolism and function ADH-induced water conservation, volume expansion, increased GFR, natriuresis, urinary sodium concentration is elevated. CNS dysfunction due to brain edema. Prevention and treatment Treatment of SIADH: causative factors. Block the action of ADH by lithium carbonate or demeclocycline 地美环素. Reset osmostat syndrome improve with correction of debilitating disorders. Restrict free water intake. Administrate diuretics and hypertonic salt solution if neurologic symptom exhibit. Hypernatremia: serum sodium concentration more than 150 mmol/L. Resulting from increase in the ratio of sodium to water in ECF. Hypovolemic hypernatremia: hypernatremia with decreased ECF volume, the water loss is greater than sodium loss. Etiology and pathogenesis: 1. Inadequate water intake: decreased water intake with impaired consciousness, impaired thirst and difficulty in swallowing or environmental water deficit

2. Excessive water loss: through the extrarenal avenues, including gastrointestinal tract, skin and lung, diarrhea and vomiting, evaporation 蒸发 and perspiration. Renal pathway: diabetes insipidus, defect in ADH generation or secretion or renal insensitivity to ADH. 3. Increased blood protein or glucose levels Alterations of metabolism and function Thirst sensation, ingestion of water Osmotic pressure ↑ and volume↓ stimulate ADH secretion. Reduced blood pressure and elevation in body temperature. Cellular dehydration and shrinkage, particularly in brain cells, twitching and somnolence to coma, respiratory paralysis and even death. Dry tongue and mucous membrane. Prevention and treatment Normal saline, hypotonic solution. Idiogenic osmoles, it will cause brain cell swelling if serum osmolality reduces too quickly. Treat primary diseases, replacement with potassium. Hypervolemic hypernatremia: hypernatremia with ECF volume expansion. Caused by increased sodium and water intake and primary sodium retention. Infusion of hypertonic salt solution Hyperaldosteronism and Cushing’s syndrome, more aldosterone and cortisone secretion, sodium and water reabsorption Stimulates thirst and ADH release. Circulating overload, hypertension, edema and weight gain. Severe causes brain shrinkage and CNS dysfunction. Therapeutic approach: diuretics plus 5% dextrose and water. Normovolemic hypernatremia: essential hypernatremia. Serum sodium concentration is slightly elevated. Insensitivity of thirst center and osmoreceptor to stimulate ADH release. Hypothalamus dysfunction. To administer 5% dextrose and water.

Isotonic dehydration: water loss is identical to salt loss, both the serum sodium concentration and plasma osmotic pressure are normal, ECF is isotonic. Vomiting, diarrhea, hemorrhage, and loss of body fluid can cause. Reduced ECF, thirst, ADH and aldosterone release. Low blood pressure, postural hypertension and even shock. To correct causative factors and administrate isotonic salt solution Edema: presence of excessive fluid in the tissue of the body, mainly the accumulation of excess fluid in the extracellular compartment, which is a pathologic process. It may be local (local edema) or generalized (anasarca). Etiology and pathogenesis 1. Imbalance of fluid interchange between plasma and interstitial compartment. (1) Increased capillary hydrostatic pressure Heart failure, thrombosis, failure of venous pumps

(2) Decreased plasma colloid osmotic pressure Nephrosis, burns, hepatic disease (3) Obstruction of lymphatic flow (4) Increased capillary permeability Infection, allergic response, trauma 2. The renal retention of sodium and water (1) Decreased GFR, reduces sodium and water excretion, retention. In glomerulonephritis, congestive heart failure and nephrotic syndrome Decrease in effective circulating blood volume, SNS, activation of reninangiotensin system, reduce blood flow to kidney (2) Increase in filtration fraction. Increase reabsorption of sodium and water. (3) Increase ADH and aldosterone secretion. Renal water and sodium retention Alterations of metabolism and function Transudates result from imbalance of fluid interchange between plasma and interstitial compartment under normal capillary permeability. Exudates result from increase in capillary permeability. Containing plentiful cells and a large amount of proteins. Usually seen in inflammation. Pitting edema: when the interstitial fluid is too increased, most of extra fluid forms large free fluid spaces in the tissue, pressed by thumb, the free fluid is pushed out of that area into other. When the thumb is removed, a pit is left in the skin by thumb for a few seconds. In cardiac edema, ambulant patients with congestive heart failure, the swelling of the ankles. Increased capillary hydrostatic pressure, ADH and aldosterone-induced, decreased GFR. In renal edema induced by glomerulonephritis, swelling of eyelids and face. Decreased in GFR and retention of water and sodium In hepatic edema, ascites 腹水. Increased portal venous pressure, overflow of hepatic lymph, decreased effective circulating blood volume and hypoalbuminemia. Edema impedes nutritional supply for widens the distance between capillary and cells. Intracranial pressure increases and advance to brain herniation. Potassium balance 1. Transfer between intracellular and extracellular compartment Membrane-bound sodium-potassium ATPase (Na+-K+ pump): sodium outwards and potassium inwards, energy dependent. Insulin increases pump, independent of cellular glucose uptake, increase in serum potassium concentration stimulates insulin secretion. β-adrenergic agents elevate pump via cAMP-mediated. α-adrenergic agents enhance potassium out of cells Aldosterone activates pump, from peritubular interstitial into cells, enhance the membrane permeability to K+ in renal tubular cell Rise in extracellular potassium concentration increase pump.

Exercise promotes potassium shift out of cells through opening ATP dependent K channels and decreases pump Acidosis induces potassium out of cells with hydrogen ions into cells. Alkalosis, potassium moves into cells with hydrogen efflux from cells. Osmolality increase in ECF, potassium from ICF to ECF. 2. Regulation of renal potassium excretion Aldosterone: increase potassium excretion by activating pump in principle cells and increase luminal membrane permeability EC potassium concentration: increase pump and luminal membrane permeability, decrease potassium outflow into the interstitial fluid, increase potassium excretion Urinary flow rate increase: decrease potassium concentration in tubular lumen, enhance potassium excretion Acid-base status: increased hydrogen inhibits pump, reduces potassium excretion. Increase PH tends to potassium secretion, due to hydrogen-potassium exchange Distal delivery of sodium: increase sodium concentration promotes potassium secretion Impermeable anions: increased impermeable anions make the tubular lumen more electronegative, attract potassium into tubular lumen. Hypokalemia It is defined as a decrease in serum potassium concentration below 3.5 mmol/L. implying potassium deficit (deletion). Etiology and pathogenesis Induced by inadequate potassium intake and increased loss of potassium or potassium shift into cells 1. Inadequate potassium intake: fasting, starvation, malnutrition. 2. Potassium redistribution: (1) alkalosis: hydrogen moves out of cells, potassium enters into cells. Alkalosis in renal tubule causes potassium excretion. (2) Insulin and β-adrenergic agonists. VB12 and folate (rapid production of red cells, potassium enters into the new red blood cells). (3) Barium and crude cottonseed oil poisoning: block potassium channels in skeletal muscle cell membrane, decrease potassium move from ICF to ECF. (4) Familial hypokalemic periodic paralysis: 3. Excessive gastrointestinal losses of potassium: alkalosis, aldosterone. 4. Excessive renal losses of potassium: (1) diuretic agents (2) renal tubular acidosis (3) aldosterone and Cushing’s disease (4) magnesium deficit Alteration of metabolism and function 1. Changes in the neuromuscular irritability: RMP becomes more negative, threshold increase, cell membrane becomes less sensitive, causing muscle flabbiness, weakness and even paralysis. 2. Effects of hypokalemia on the heart: (1) reduces permeability of cardiac cell membrane to potassium. Nernst potential is decreased, RMP value induces and become near to the threshold, irritability of cardiac muscle cells is increased. (2) velocity and amplitude fall and the conductivity of the cardiac cells decreases. (3)

potassium in ECF inhibit calcium inward flow. So hypokalemia enhances the contractility of cardiac muscle cells. (4) automaticity of cardiac cells increases. In ECG: prolonged P-R interval, widened QRS complex, depressed S-T segment, flatted T wave, prominent U wave. Hyperkalemia Serum potassium concentration of greater than 5.5 mmol/L. Etiology and pathogenesis: 1. Increased potassium intake: renal function for potassium excretion is impaired. 2. Potassium shift from ICF to ECF: (1) β-adrenergic antagonists reduce potassium shift into cells. Insulin deficiency, acidosis. (2) cell injury by potassium redistribution. (3) hyperkalemic periodic paralysis. 3. Decreased renal excretion of potassium: renal failure, hypoaldosteronism. Diuretics inhibit aldosterone action. Alterations of metabolism and function 1. Neuromuscular effects: in mild, reducing RMP value, more sensitive to stimulus. In severe, sodium-channels inactivated. Irritability of nerve and muscle cells is decreased. 2. Effects on the heart: conductivity of cardiac cells is decreased. Automaticity of cardiac cells is decreased. Permeability of cardiac cell membrane to potassium increases. In ECG: peaking of T waves, loss of P waves, widening of QRS complex and prolongation of the P-R interval. Prevention and treatment Hypokalemia: oral potassium replacement, intravenous potassium supplements (avoid hyperkalemia) Hyperkalemia: firstly, use of sodium salts and calcium salts for cardiac electrophysiologic events, infusion of sodium salts enhances cardiac cell conductivity. Secondly, administration of insulin and glucose or an alkalinizing solution. Finally, remove potassium from body. Correcting the underlying disorders. Hypomagnesemia Etiology and pathogenesis 1. Inadequate magnesium intake: combined with increased loss or requirement 2. Increased magnesium loss: use of diuretics, hyperparathyroidism, extracellular volume expansion, diabetic ketoacidosis and hypercalcemia reduce magnesium reabsorption, antibiotics generate renal magnesium wasting. 3. Redistribution of magnesium: hyperthyroidism or during treatment of diabetic ketoacidosis with insulin Alterations of metabolism and function 1. Central and neuromuscular effects: hyperexcitability and increase tetany, act as calcium antagonist. 2. Cardiovascular effects: cardiac arrhythmias, increased blood pressure. 3. Metabolic effects: hypocalcemia and hypokalemia.

Principle of treatment Identifying and treating the cause of magnesium depletion and oral, intramuscular or intravenous magnesium supplement. Hypermagnesemia Etiology and pathogenesis Administration of large dose of magnesium salt, acute or chronic renal failure, hypothyroidism and renal insufficiency. Severe trauma and burns, magnesium releases from cell. Alterations of metabolism and function Antagonizes the calcium action, decrease neuromuscular excitability, muscle weakness, nausea, vomiting, depressed deep tendon reflexes, respiratory paralysis and central nervous system depression. ECG: prolonged P-R and Q-T intervals, widening of QRS complex. Prevention and treatment Severe needs emergent treatment, intravenous administration of calcium, hemodialysis for decreasing serum magnesium. Increasing magnesium excretion. Hypocalcemia Serum calcium ion concentration is less than 1 mmol/L or total plasma calcium less than 2.2 mmol/L at the normal plasma protein concentration. Etiology and pathogenesis: 1. Vitamin D deficiency: hepatic disease, obstruction of biliary ducts, pancreatic disorder influence VD absorption, increasing urine calcium excretion and reduce intestinal calcium absorption. 2. Deficit or absence of parathyroid hormone: PTH deficit or absence enhance bone calcium deposition, and urinary calcium excretion. 3. Resistance to parathyroid hormone: in renal failure and pseudoparathyroidism. 4. Chronic renal failure: defective intestinal absorption and hyperphosphatemia 5. Hypomagnesemia: severe hypomagnesemia reduces parathyroid hormone release, induce hormone on the skeleton 6. Other: acute pancreatitis, rhabdomyolysis, sepsis 脓毒病, use of calcitonin and plicamycin Alterations of metabolism and function 1. Neuromuscular effects: irritability increases. 2. Cardiovascular effects: reduction in myocardial contractility and cardiac index, even congestive heart failure. In ECG: lengthening of Q-T interval, ventricular dysrhythmia. 3. Effects on bone: bone deformity or fracture, osteitis fibrosa cystica osteomalacia, ricket. Prevention and treatment Severe with intravenous calcium infusion. Associated hypomagnesemia and hyperphosphatemia should be treated. Administration of vitamin D and oral calcium. Hypercalcemia

Etiology and pathogenesis 1. Hyperparathyroidism: excessive PTH promotes bone reabsorption and renal absorption 2. Malignant tumors: impaired renal calcium excretion. 3. VD intoxication, hyperthyroidism, use of thiazide diuretics, acidosis. Alterations of metabolism and function 1. Neuromuscular effects: inhibition 2. Cardiovascular effects: enhance myocardial contractility and reduces conductivity. Shortening Q-T interval. Digitalis-induced arrhythmias, hypertension 3. Renal effects: chronic antagonize ADH action, impair urinary concentrating and dilut...