SECTION VIIL THE ENDOCRINE SYSTEM Diabetes Insipidus A30-year-old woman sustained mltiple injuries.including a skull fracture. in an auobile accident.Although initially in a com,she gradually regained consciousness.Five days later she abruptdeveloped freqrintiodthir with a subsequent neasured fluid intake and output of 8 L/day.Physical examination rerkble except forsligh Koutine urinalysis was normal:no red blood cells were present.Urine osmolality as75/gAfter8 hours of water deprivtion.during which she lostof her body weight,she continued to excrete 150 ml/hr,and urine osmolality stabilized at 125/gAt this tine,serun osmolalitywas/kg and serm sodiu was 155 E/L.Serun creatinine was 0.8n/d1,and blood urea nitrogen was 10ng/d1. There was no glucose in her urine. 1.that is the significance of this patient's urine osmlality being persistently less than plasm osolality? 2.What is the sigificance of the elevated serun sodim level? 3.What portions of the nephron are critical to preventing excessive loss of 4.What regulates the process of conserving free water,and how does the chief regulatory substance act on its target cells? 5.How and where is this regulatory substance synthesized and stored? 6.What modulates secretion of this substance? 7.What vere the possible causes of this patient's polyuria and polydipsia? 8.What as thispatient's plasm AD level at the end of her vater deprivation? 9.What is likely to happen when ADH is administered to the patient?
SECTION VIII THE ENDOCRINE SYSTEM Diabetes Insipidus A 30-year-old woman sustained multiple injuries, including a skull fracture, in an automobile accident. Although initially in a coma, she gradually regained consciousness. Five days later she abruptly developed frequent urination and thirst, with a subsequent measured fluid intake and output of 8 L/day. Physical examination was unremarkable except for slightly dry mucous membranes. Vital signs were normal. Routine urinalysis was normal; no red blood cells were present. Urine osmolality was 75 mOsm/kg. After 8 hours of water deprivation, during which she lost 4% of her body weight, she continued to excrete 150 ml/hr, and urine osmolality stabilized at 125 mOsm/kg. At this time, serum osmolality was 310 mOsm/kg, and serum sodium was 155 mEq/L. Serum creatinine was 0.8 mg/dl, and blood urea nitrogen was 10 mg/dl. There was no glucose in her urine. 1. What is the significance of this patient's urine osmolality being persistently less than plasma osmolality? 2. What is the significance of the elevated serum sodium level? 3. What portions of the nephron are critical to preventing excessive loss of free water, and what processes are involved? 4. What regulates the process of conserving free water, and how does the chief regulatory substance act on its target cells? 5. How and where is this regulatory substance synthesized and stored? 6. What modulates secretion of this substance? 7. What were the possible causes of this patient's polyuria and polydipsia? 8. What was this patient's plasma ADH level at the end of her water deprivation? Why? 9. What is likely to happen when ADH is administered to the patient?
10.What does the plasna ADll and the patient's response to ADil indicate about 11.Assuming this patient's condition of polyuria and polydipsia is permanent when would she need another dose ofD? 13.If the patient became stuporous again,what new dangers could arise despite continued treatment with ADH? rate of clearance of free,osmotically unencumbered vater.It could be a normal compensation for an excessive voluntary intake of vater,or it could indicate an inabilityof the paikidneyseater and conentrate the urine.The necessary signal(s)to the kidneys to conserve vater. water.An elevated concentration of sodiun generally indicates a deficit of total body vater,because extracellular fluid and intracellular fluid are in osmotic equilibriun.Because sodium cannot enter cells to any great extent,the absolute plasma sodi level is also an excellent quantitative indicator of the mgnitude of the hody water deficit.The percentage increase in serun sodiun above norml is equivalent to the percentage decrease in total bodyater,providing there hasbeen no significant loss of sodium itself from the body. 3.Tuhular urine is isosnotic until it reaches the loop of Henle.The operation of syst(passive rapid reabsorption of in the thin and active of sodiun in the thickascending limb)produces a hyperosuotic medullary interstitial fluid.When the resultant hypoosmoticdistal tubular fluid reaches the coinductswater is reabsorbed because of the between the tubular luen and the interstitia
10. What does the plasma ADH and the patient's response to ADH indicate about the diagnostic cause of her condition? 11. Assuming this patient's condition of polyuria and polydipsia is permanent, when would she need another dose of ADH? 12. What dietary components would influence the patient's urine output and how? 13. If the patient became stuporous again, what new dangers could arise despite continued treatment with ADH? ANSWER 1. A urine osmolality consistently lower than plasma osmolality indicates a high rate of clearance of free, osmotically unencumbered water. It could be a normal compensation for an excessive voluntary intake of water, or it could indicate an inability of the patient's kidneys to reabsorb water and concentrate the urine. The latter defect could be caused by an intrinsic renal abnormality or a lack of the necessary signal(s) to the kidneys to conserve water. 2. Sodium and its associated anions constitute the predominant solute in plasma water. An elevated concentration of sodium generally indicates a deficit of total body water, because extracellular fluid and intracellular fluid are in osmotic equilibrium. Because sodium cannot enter cells to any great extent, the absolute plasma sodium level is also an excellent quantitative indicator of the magnitude of the body water deficit. The percentage increase in serum sodium above normal is equivalent to the percentage decrease in total body water, providing there has been no significant loss of sodium itself from the body. 3. Tubular urine is isosmotic until it reaches the loop of Henle. The operation of the countercurrent multiplication system (passive rapid reabsorption of water in the thin descending limb and active reabsorption of sodium in the thick ascending limb) produces a hyperosmotic medullary interstitial fluid. When the resultant hypoosmotic distal tubular fluid reaches the collecting ducts, water is reabsorbed because of the large osmotic gradient between the tubular lumen and the interstitial
fluid.Reahsorption occurs through cell meabranes whose permeability to water is physiologically modulated to increase flow froa tuhular lumen into the cell when water conservation is necessary. 4.A single hormone,ADH,stimulates the process of water conservation,and the product is a final urine that is hyperosaotic to plasm.ADl acts on the thick ascending limb of the loop of Henle to stimulate sodiun reabsorption.Most important, however,ADH increases the perneability of the collecting duct cell to water.ADH acts through cyelic AllP as a second messenger.Merbrane proteins are phosphorylated, and subsequently water-comveying cytoplasmic organelles move to and fuse with the luminal side of the plasma menbrane.Once water has entered the cell,it is drawn into the nedullary interstitiun by the high osmolarity gemerated by the countercurrent multiplication system.The urine/plasma osmolality ratio can reach a maxinun of 4:I. 5.AD is synthesized fron a large precursor molecule in hypothalanic neurons in the supraoptic and paraventricular nuclei.ADl travels domn the axons and is stored in granules in the posterior pituitary gland.From there,ADH is released by exocytosis after a nerve impulse causes calciun influx into the granules. 6.ADH is released in response to an increase in plasma osrolality caused by any substance,such as sodiun,which cannot readily enter cells.Thus,plasma hyperosmolality.resulting from the loss of free water.stimulates osmoreceptor cells in the hypothalamus:these in turn stimulate ADH secretory neurons.A decrease in blood volune and pressure also stimulates ADH release via baroreceptor and other stretch reflexes.Other nonspecific stimuli of AD release inelude pain,nausea, and psychic stress. 7.a.The skull fracture could have disrupted the patient's thirst nechanisa and caused primary polydipsia.However,in that case,the patient's plasm sodium and osnolality would have been decreased rather than increased.Furthermore,when she was subjected to water deprivation,her urine volume would have decreased normlly to 30 to 50 ml/hr
fluid. Reabsorption occurs through cell membranes whose permeability to water is physiologically modulated to increase flow from tubular lumen into the cell when water conservation is necessary. 4. A single hormone, ADH, stimulates the process of water conservation, and the product is a final urine that is hyperosmotic to plasma. ADH acts on the thick ascending limb of the loop of Henle to stimulate sodium reabsorption. Most important, however, ADH increases the permeability of the collecting duct cell to water. ADH acts through cyclic AMP as a second messenger. Membrane proteins are phosphorylated, and subsequently water-conveying cytoplasmic organelles move to and fuse with the luminal side of the plasma membrane. Once water has entered the cell, it is drawn into the medullary interstitium by the high osmolarity generated by the countercurrent multiplication system. The urine/plasma osmolality ratio can reach a maximum of 4: 1. 5. ADH is synthesized from a large precursor molecule in hypothalamic neurons in the supraoptic and paraventricular nuclei. ADH travels down the axons and is stored in granules in the posterior pituitary gland. From there, ADH is released by exocytosis after a nerve impulse causes calcium influx into the granules. 6. ADH is released in response to an increase in plasma osmolality caused by any substance, such as sodium, which cannot readily enter cells. Thus, plasma hyperosmolality, resulting from the loss of free water, stimulates osmoreceptor cells in the hypothalamus; these in turn stimulate ADH secretory neurons. A decrease in blood volume and pressure also stimulates ADH release via baroreceptor and other stretch reflexes. Other nonspecific stimuli of ADH release include pain, nausea, and psychic stress. 7. a. The skull fracture could have disrupted the patient's thirst mechanism and caused primary polydipsia. However, in that case, the patient's plasma sodium and osmolality would have been decreased rather than increased. Furthermore, when she was subjected to water deprivation, her urine volume would have decreased normally to 30 to 50 ml/hr
b.Umsuspected renal traums could have caused a tubular insensitivity to the action of ADH:this is called nephrogenic diabetes insipidus.However,this is unlikely,given that there were no red blood cells in the urine and the patient's serun creatinine and blood urea nitrogen levels were normal. c.The skull fracture could have caused structural or functional damage to the mechanisn for releasing ADH.This is called central diabetes insipidus.AD deficiency is the most likely explanation for the patient's polyuria and thirst. 8.The patient's plasma level of ADH was almost certainly low.This could reflect destruction or darage to the ADE secretory neurons or danage to osnoreceptor cells. with an upsard resetting of the osmostat for ADl release.The plasm ADl level would also have been low after danage to the thirst mechanism,because the excess water intake would have suppressed ADH secretion by negative feedback from a decrease in plasna osmolality and an increase in circulating volume.In the case of renal tubular danage,the plasma ADH level would be elevated by the constant state of water deficiency. 9.Administration of AD to the patient would sharply reduce the rate of urine flow by reducing free water clearance.As plasma osnolality declines to norml, thirst would diminish.This response would help to confirm the diagnosis of central diabetes insipidus.If renal tubular insensitivity to AD were the fundarental problem,the administration of ADH would have little or no effect on the rate of urine flow. 10.The patient had ADH deficfency,which is referred to as central diabetes insipidus. 11.The patient should be taught to administer ADH when she notes the return of a high urine flow rate.If she waits for a return of thirst as a signal,she will always be slightly water deprived because thirst would indicate a significant rise in plasma osmolality. 12.A higher dietary intake of sodiun or a higher intake of protein (which generates urea)would increase the osmolar load.This would create a higher rate of delivery of fluid to the distal nephron.In turn,this would decrease the osnolar
b. Unsuspected renal trauma could have caused a tubular insensitivity to the action of ADH; this is called nephrogenic diabetes insipidus. However, this is unlikely, given that there were no red blood cells in the urine and the patient's serum creatinine and blood urea nitrogen levels were normal. c. The skull fracture could have caused structural or functional damage to the mechanism for releasing ADH. This is called central diabetes insipidus. ADH deficiency is the most likely explanation for the patient's polyuria and thirst. 8.The patient's plasma level of ADH was almost certainly low. This could reflect destruction or damage to the ADH secretory neurons or damage to osmoreceptor cells, with an upward resetting of the osmostat for ADH release. The plasma ADH level would also have been low after damage to the thirst mechanism, because the excess water intake would have suppressed ADH secretion by negative feedback from a decrease in plasma osmolality and an increase in circulating volume. In the case of renal tubular damage, the plasma ADH level would be elevated by the constant state of water deficiency. 9. Administration of ADH to the patient would sharply reduce the rate of urine flow by reducing free water clearance. As plasma osmolality declines to normal, thirst would diminish. This response would help to confirm the diagnosis of central diabetes insipidus. If renal tubular insensitivity to ADH were the fundamental problem, the administration of ADH would have little or no effect on the rate of urine flow. 10. The patient had ADH deficiency, which is referred to as central diabetes insipidus. 11. The patient should be taught to administer ADH when she notes the return of a high urine flow rate. If she waits for a return of thirst as a signal, she will always be slightly water deprived because thirst would indicate a significant rise in plasma osmolality. 12. A higher dietary intake of sodium or a higher intake of protein (which generates urea) would increase the osmolar load. This would create a higher rate of delivery of fluid to the distal nephron. In turn, this would decrease the osmolar
gradient between the distal tubular urine and the medullary interstitium.Thus,less water would be reabsorbed even in the presence of ADH,and urine volume would increase. 13.When a patient with central diabetes insipidus is stuporous,thirst is inoperative.This coedition places both water intake and water output in the hands of the physiciam.If too much fluid is given intravenously along with effective doses of ADH.vater retention may becone excessive and serious hypoosnolality may result. This state of water intorication can lead to further central nervous system dysfunction and even convulsions
gradient between the distal tubular urine and the medullary interstitium. Thus, less water would be reabsorbed even in the presence of ADH, and urine volume would increase. 13. When a patient with central diabetes insipidus is stuporous, thirst is inoperative. This condition places both water intake and water output in the hands of the physician. If too much fluid is given intravenously along with effective doses of ADH, water retention may become excessive and serious hypoosmolality may result. This state of water intoxication can lead to further central nervous system dysfunction and even convulsions