SECTION VIII THE ENDOCRINE SYSTEM Adrenocortical Adenoma-Hyperaldosteronign A 45-year-old mn has a 10-year history of hypertension treated primarily with a thiazide diuretic.The patient had noted occasional bouts of muscle weakness and tingling sensations in his extremities.He denied vomiting.There was no history of pulmoeary disease.Physical examination showed blood pressure (BP)of 158/102, pulse of 70 beats/nin,and respirations of 6/ain.Except for slightly decreased muscle strength,the examination was normal.There was no edema.Laboratory studies showed sodiun of 146 nEq/L,bicarbonate of 35 mEq/L,chloride of 98 rEq/L,potassiun of 2 mEq/L.creatinine of 0.9 ng/dl,blood urea nitrogen of 8 ng/dl,and fasting plasma glucose of 134 mg/dl.The diuretic was stopped,large doses of potassiun vere given orally.and an angiotensin converting enzyne inhibitor was prescribed for hypertension.One week later,BP was 154/98.Repeat laboratory studies showed sodium of 145 mEq/L bicarbonate of 33 mEq/L,chloride of 98 nEq/L,and potassiun of 2.6 Eq/L After additional laboratory studies were performed,the angiotensin converting emzyre inhibitor was replaced with another drug.and potassium supplementation vas continued.BP decreased to 130/82,and potassfum increased to 4 rEq/L.The patient's symptons disappeared. 1.What is the most likely acid-base disorder in this patiemt?What directional changes in pll and PC02 might you find in his arterial blood? 2.What are the possible causes of his acid-base disorder? 3.What evidence favors or casts doubt on each cause you have listed? 4.What urinary measurerents would help define the cause of his problen? 5.What hormonal measurements would be helpful and in what physiologic state of the patient would you perform them? 6.Bow would increased secretion of a particular hormone have produced his hypokalemia？
SECTION VIII THE ENDOCRINE SYSTEM Adrenocortical Adenoma—Hyperaldosteronism A 45-year-old man has a 10-year history of hypertension treated primarily with a thiazide diuretic. The patient had noted occasional bouts of muscle weakness and tingling sensations in his extremities. He denied vomiting. There was no history of pulmonary disease. Physical examination showed blood pressure (BP) of 158/102, pulse of 70 beats/min, and respirations of 6/min. Except for slightly decreased muscle strength, the examination was normal. There was no edema. Laboratory studies showed sodium of 146 mEq/L, bicarbonate of 35 mEq/L, chloride of 98 mEq/L, potassium of 2 mEq/L, creatinine of 0.9 mg/dl, blood urea nitrogen of 8 mg/dl, and fasting plasma glucose of 134 mg/dl. The diuretic was stopped, large doses of potassium were given orally, and an angiotensin converting enzyme inhibitor was prescribed for hypertension. One week later, BP was 154/98. Repeat laboratory studies showed sodium of 145 mEq/L, bicarbonate of 33 mEq/L, chloride of 98 mEq/L, and potassium of 2.6 mEq/L. After additional laboratory studies were performed, the angiotensin converting enzyme inhibitor was replaced with another drug, and potassium supplementation was continued. BP decreased to 130/82, and potassium increased to 4 mEq/L. The patient's symptoms disappeared. 1. What is the most likely acid-base disorder in this patient? What directional changes in pH and PCO2 might you find in his arterial blood? 2. What are the possible causes of his acid-base disorder? 3. What evidence favors or casts doubt on each cause you have listed? 4. What urinary measurements would help define the cause of his problem? 5. What hormonal measurements would be helpful and in what physiologic state of the patient would you perform them? 6. How would increased secretion of a particular hormone have produced his hypokalemia?
7.What is the intracellular mechanisn of action of this hormone? 8.What might explain the patient's ruscle weakness and sensory disturbance? What electro-cardiographic effect night have been seen? 9.Why did the patient not have edema? 10.How could you explain the elevated fasting plasma glucose? 11.Why did the angiotensin converting enzyme inhibitor not lower the blood pressure very much? 12.What class of drug do you think the patient was given,and how did it work? ANSVER I.Given the elevated bicarbonate and reduced chloride and potassiun levels, chronic petabolie alkalosis vith respiratory compensation is the most likely acid-base disturbance in this patient.Arterial blood pH would be slightly increased: PC02 would also be increased.A much less likely diagosis vould be chronic respiratory acidosis with netabolic compensation.In that case,however,arterial blood pH would he decreased,and PC02would be increased. 2.a.Vomiting with loss of hydrogen ions (as hydrochloric acid)in gastric juice and return of the simaltaneously generated bicarbonate to the extracellular fluid cause metabolic alkalosis.This is aggravated by emhanced renal tubular bicarbomate reabsorption secondary to contraction of the extracellular fluid.Renal potassium losses and hypokalemia are secoedary to the metabolic alkalosis. b.Ingestion of a diuretic that inhibits proximal tubular sodium reabsorption increases sodiun and water delivery to the distal tubular regions.This in turn enhances both potassium and hydrogen ion seeretion.which results in hypokalemia and netabolic alkalosis. c.Excess secretion of a nineralocorticoid hormone causes hypokaleaia and metabolic alkalosis. 3.a.Loss of gastric juices is an unlikely cause in this patient because of the absence of voiting.In addition,there were no signs of hyporolemia (low blood
7. What is the intracellular mechanism of action of this hormone? 8. What might explain the patient's muscle weakness and sensory disturbance? What electro-cardiographic effect might have been seen? 9. Why did the patient not have edema? 10. How could you explain the elevated fasting plasma glucose? 11. Why did the angiotensin converting enzyme inhibitor not lower the blood pressure very much? 12. What class of drug do you think the patient was given, and how did it work? ANSWER 1. Given the elevated bicarbonate and reduced chloride and potassium levels, chronic metabolic alkalosis with respiratory compensation is the most likely acid-base disturbance in this patient. Arterial blood pH would be slightly increased; PCO2 would also be increased. A much less likely diagnosis would be chronic respiratory acidosis with metabolic compensation. In that case, however, arterial blood pH would be decreased, and PCO2would be increased. 2. a. Vomiting with loss of hydrogen ions (as hydrochloric acid) in gastric juice and return of the simultaneously generated bicarbonate to the extracellular fluid cause metabolic alkalosis. This is aggravated by enhanced renal tubular bicarbonate reabsorption secondary to contraction of the extracellular fluid. Renal potassium losses and hypokalemia are secondary to the metabolic alkalosis. b. Ingestion of a diuretic that inhibits proximal tubular sodium reabsorption increases sodium and water delivery to the distal tubular regions. This in turn enhances both potassium and hydrogen ion secretion, which results in hypokalemia and metabolic alkalosis. c. Excess secretion of a mineralocorticoid hormone causes hypokalemia and metabolic alkalosis. 3. a. Loss of gastric juices is an unlikely cause in this patient because of the absence of vomiting. In addition, there were no signs of hypovolemia (low blood
pressure,rapid heart rate)nor of a decrease in glomerular filtration rate (elevated plasma creatinine and blood urea nitrogen levels). b.Lack of signs of hypowolemia and a failure to correct the acid-base and electrolyte abnoralities on cessation of the diuretie are evidence that the drug did not cause the problem c.An excess of a mineralocorticoid hormone is strongly suggested by the presence of hypertension and by the persistence of hypokalenia.despite adninistration of large amounts of potassium to the patient. d.Lack of any history of pulmonary dysfunction and a deereased,rather than increased,respiratory rate is strong evidence against chronic respiratory acidosis. In addition,serun potassiun would be expected to be high rather than low. 4.Measurement of potassium in the urine would be helpful.The presence of substantial amounts,greater than 40 mEq/day in the face of hypokalenia.would point to a renal tubular disturbance.Very small anounts of potassiun in the urine would suggest that hypokalemia was caused by potassium loss in intestinal secretions. 5.The adrenal mineralocorticoid hormone,aldosterone,and cortisol should be measured.Aldosterone should be measured when the patient is hypokalemic,in a sodiun replete state.and in a recumbent position.These physiologic circumstances should normally inhibit aldosterone secretion.Therefore a high plasma level of aldosterone found in such circunstances suggests hyperaldosteronisn Plasna renin should then be measured to determine if the renin-angiotensin system is driving the pathologic aldosterone excess.A high renin level suggests that umsppreciated hypowolemia or constriction of a remal artery is the cause of the metabolic disturhance.A low renin level,particularly obtained when the patient is upright and in the sodiun depleted condition (which should stimulate renin release).would argue for automomous hypersecretion of aldosterone as the cause of the hypokalemia and netabolic alkalosis. 6.An aldosterone excess stimulates sodiun reabsorption and potassium secretion in the distal nephron.This causes expansion of extracellular fluid volume. hypertension.and hypokalemia
pressure, rapid heart rate) nor of a decrease in glomerular filtration rate (elevated plasma creatinine and blood urea nitrogen levels). b. Lack of signs of hypovolemia and a failure to correct the acid-base and electrolyte abnormalities on cessation of the diuretic are evidence that the drug did not cause the problem. c. An excess of a mineralocorticoid hormone is strongly suggested by the presence of hypertension and by the persistence of hypokalemia, despite administration of large amounts of potassium to the patient. d. Lack of any history of pulmonary dysfunction and a decreased, rather than increased, respiratory rate is strong evidence against chronic respiratory acidosis. In addition, serum potassium would be expected to be high rather than low. 4. Measurement of potassium in the urine would be helpful. The presence of substantial amounts, greater than 40 mEq/day in the face of hypokalemia, would point to a renal tubular disturbance. Very small amounts of potassium in the urine would suggest that hypokalemia was caused by potassium loss in intestinal secretions. 5. The adrenal mineralocorticoid hormone, aldosterone, and cortisol should be measured. Aldosterone should be measured when the patient is hypokalemic, in a sodium replete state, and in a recumbent position. These physiologic circumstances should normally inhibit aldosterone secretion. Therefore a high plasma level of aldosterone found in such circumstances suggests hyperaldosteronism. Plasma renin should then be measured to determine if the renin-angiotensin system is driving the pathologic aldosterone excess. A high renin level suggests that unappreciated hypovolemia or constriction of a renal artery is the cause of the metabolic disturbance. A low renin level, particularly obtained when the patient is upright and in the sodium depleted condition (which should stimulate renin release), would argue for autonomous hypersecretion of aldosterone as the cause of the hypokalemia and metabolic alkalosis. 6. An aldosterone excess stimulates sodium reabsorption and potassium secretion in the distal nephron. This causes expansion of extracellular fluid volume, hypertension, and hypokalemia
7.Aldosterone binds to a nuclear receptor,and the complex induces expression of the Nat,K+-ATPase gene.This increases enzyme concentration in the basal merbrane of the renal tubular cell.The action of Na+,K+-ATPase stimulates reentry of Nat into the plasma and secretion of K+into the tubular luren.Hydrogen ion secretion is also directly stinulated.In addition.Ht is transferred into the tubular lumen in response to the electronegative gradient created by Na+reabsorption. 8.Hpokalenia prevents gemeration of normal neuronal action potentials,and thus impairs neuro-muscular function.In the heart.repolarization is primarily affected,so that on the electrocardiogran,T-waves are flat or disappear entirely. and a late U-wave is generated. 9.Although extracellular fluid volune is expanded modestly by an excess of aldosterone,escape from a comtinuous positive sodium balance with gross edema occurs by two nechanisms.Glonerular filtration rate is increased,and with it the filtered load of sodium,so that a greater percentage of filtered sodium escapes reabsorption.The expanded extracellular fluid volune also stimlates secretion of atrial natriuretic hormone,which offsets the effect of aldosterone by direetly inhibiting sodium reabsorption in the collecting ducts. 10.Normal secretion of insulin in response to glucose depends on normal extracellular potassium concentrations.Hypokalemia decreases pancreatic islet beta cell function and therefore fasting plasma glucose may increase. 11.The patient probably has primary hyperaldosteronisn,that is.autononous hypersecretion from an adenom of the adrenal zona glomerulosa.Therefore levels of renin and generation of angiotensin I will be reduced.The patient's hypertension will not be very dependent on conversion of angiotensin I to angiotensin II.which is the powerful vasocomstrictor.Therefore converting enzyme inhibitor therapy was not very effective. 12.The logical treatment was the administration of an aldosterone antagonist. By binding to and blocking the aldosterone receptor,renal tubular sodium
7. Aldosterone binds to a nuclear receptor, and the complex induces expression of the Na+, K+-ATPase gene. This increases enzyme concentration in the basal membrane of the renal tubular cell. The action of Na+, K+-ATPase stimulates reentry of Na+ into the plasma and secretion of K+ into the tubular lumen. Hydrogen ion secretion is also directly stimulated. In addition, H+ is transferred into the tubular lumen in response to the electronegative gradient created by Na+ reabsorption. 8. Hypokalemia prevents generation of normal neuronal action potentials, and thus impairs neuro-muscular function. In the heart, repolarization is primarily affected, so that on the electrocardiogram, T-waves are flat or disappear entirely, and a late U-wave is generated. 9. Although extracellular fluid volume is expanded modestly by an excess of aldosterone, escape from a continuous positive sodium balance with gross edema occurs by two mechanisms. Glomerular filtration rate is increased, and with it the filtered load of sodium, so that a greater percentage of filtered sodium escapes reabsorption. The expanded extracellular fluid volume also stimulates secretion of atrial natriuretic hormone, which offsets the effect of aldosterone by directly inhibiting sodium reabsorption in the collecting ducts. 10. Normal secretion of insulin in response to glucose depends on normal extracellular potassium concentrations. Hypokalemia decreases pancreatic islet beta cell function and therefore fasting plasma glucose may increase. 11. The patient probably has primary hyperaldosteronism, that is, autonomous hypersecretion from an adenoma of the adrenal zona glomerulosa. Therefore levels of renin and generation of angiotensin I will be reduced. The patient's hypertension will not be very dependent on conversion of angiotensin I to angiotensin II, which is the powerful vasoconstrictor. Therefore converting enzyme inhibitor therapy was not very effective. 12. The logical treatment was the administration of an aldosterone antagonist. By binding to and blocking the aldosterone receptor, renal tubular sodium
reabsorption and potassiun secretion would be decreased.which would allow plasma potassium to rise to normal and blood pressure to fall to normal
reabsorption and potassium secretion would be decreased, which would allow plasma potassium to rise to normal and blood pressure to fall to normal