Case Files Biochemistry, 3rd Edition (2015)

CASE 46

A 32-year-old man was seen in the emergency department yesterday after experiencing a concussion and head trauma from a motor vehicle accident. The patient was stabilized in the emergency department and transferred to the intensive care unit (ICU) for observation. The patient had computed tomography (CT) scan of the head that revealed a small amount of cerebral edema but was otherwise normal. During the second day in the ICU, the nurse informs you that the patient has had a large amount of urine output in the last 24 hours. The nursing records report his urine output during the last 24 hours was 6400 cc. He has been given no diuretic medications. A urine osmolality was ordered and was found to be low. His physician remarks that the kidneys are not concentrating urine normally.

What is the most likely diagnosis for the increasing dilute urine output?

What is the biochemical mediator that is responsible for this disorder?

ANSWERS TO CASE 46:

Diabetes Insipidus

Summary: A 32-year-old man with head trauma is in stable condition in the ICU with increasing dilute urine output.

• Diagnosis: Diabetes insipidus (DI).

• Biochemical mechanism: Absence of vasopressin leading to inability to retain free water.

CLINICAL CORRELATION

Vasopressin is a hormone produced in the hypothalamus and stored in the posterior pituitary gland. It is also called antidiuretic hormone, because its presence stimulates water resorption in the distal renal tubule. Excess antidiuretic hormone can lead to “water intoxication” and hyponatremia. By contrast, lack of vasopressin leads to excess loss of free water and hypernatremia. The clinical presentation is that of a patient who is excessively thirsty, having to drink large amounts of water, and urinating large amounts of dilute urine. Head trauma is one of the most common causes, particularly if the posterior pituitary stalk is disrupted. Excessive water (psychogenic water drinking) may present similarly, but these individuals will have normal decreased urine response to water restriction, and during sleep. By contrast, patients with DI will have excessive urinary loss even with water restriction and even during the night. The treatment is administration of desmopressin acetate (DDAVP), a synthetic analogue of arginine vasopressin (AVP).

APPROACH TO:

Vasopressin and Water Balance

OBJECTIVES

1. Explain the role of vasopressin in the control of water metabolism.

2. Describe the role of aldosterone in regulating salt and water balance.

3. Describe the role of the hormones renin and angiotensins I, II, and III in the regulation of salt and water balance.

DEFINITIONS

ALDOSTERONE: A mineralocorticoid hormone that is synthesized from cholesterol in the adrenal cortex and released in response to angiotensin II or III. It increases the ability of the kidney to absorb Na⁺, Cl^–, and water from the glomerular filtrate.

ANGIOTENSIN-CONVERTING ENZYME: An enzyme found primarily in the lung (as well as the vascular epithelium and other tissues) that removes 2 amino acids from angiotensin I to form angiotensin II.

ANGIOTENSINOGEN: α₂-Globulin; a 14-amino acid peptide that circulates in the plasma. It is cleaved by the protease renin to give the inactive decapeptide angiotensin I. Angiotensin converting enzyme hydrolyzes 2 amino acids from the C-terminus of angiotensin I to give the active angiotensin II, which gives rise to angiotensin III by the action of an aminopeptidase.

DIABETES INSIPIDUS (DI): The chronic excretion of large quantities of very pale urine of low specific gravity resulting in dehydration and extreme thirst.

NEUROPHYSIN: A protein that is secreted with oxytocin and vasopressin from the posterior pituitary gland. Neurophysin binds to these 2 hormones and stabilizes them.

RENIN: A protease that is synthesized by the juxtaglomerular cells of the kidney and secreted into the bloodstream in response to conditions of hypovolemia and hyponatremia. It hydrolyzes circulating angiotensinogen to angiotensin I.

VASOPRESSIN: Antidiuretic hormone; a nine-amino acid peptide that is synthesized by the hypothalamus and controls resorption of water by distal tubules of the kidney. It stimulates the insertion of water channels (aquaporins) into the apical membranes of kidney tubules.

DISCUSSION

Vasopressin (antidiuretic hormone) is a nonapeptide that controls resorption of water by distal tubules of the kidney to regulate the osmotic pressure of blood. It functions to conserve body water by reducing the output of urine, and thus it is known as an antidiuretic. Vasopressin is synthesized in the supraoptic nucleus of the hypothalamus where it is bound to a neurophysin protein carrier, packaged in granules, and delivered by intracellular transport to nerve terminals in the posterior pituitary. Vasopressin bound to neurophysin is released from the granules in response to increased extracellular osmolarity sensed by hypothalamic osmoreceptors, signaling by atrial stretch receptors or after a rise in angiotensin II levels. Its secretion is increased by dehydration or stress and decreased after alcohol consumption.

Vasopressin promotes increased resorption of water in the renal distal tubule by stimulating insertion of water channels or aquaporins into the apical membranes of kidney tubules. Water is resorbed across the renal epithelium into the blood leading to a decrease in plasma osmolarity and an increase in the osmolarity of urine. In DI, this process is impaired, leading to excessive urine production. In the absence of vasopressin, the kidney cannot resorb water and it flows out as urine. This condition can arise from a deficiency in vasopressin secretion from the posterior pituitary as a result of hypothalamic tumors, injury (as in the case of this patient) or infection. Alternately, the condition may result from mutations in the vasopressin receptor or aquaporin genes or other diseases impairing renal response to vasopressin. When injected in pharmacologic doses, vasopressin acts as a vasoconstrictor.

There are 2 major types of vasopressin receptors, V1 and V2. The V1 receptor occurs in vascular smooth muscle and is coupled via G_q to activation of the phosphoinositide cascade-signaling system and generation of the second messenger inositol trisphosphate (IP₃) and diacylglycerol. V2 receptors are found in kidney and are coupled via G_s to activation of adenylate cyclase and production of the second messenger cyclic AMP.

The steroid hormone aldosterone, synthesized in the zona glomerulosa of the adrenal cortex, also plays an important role in maintaining blood osmolarity. It binds its receptors in the cytoplasm of epithelial cells of the distal colon and the renal nephron, followed by translocation of the hormone-receptor complex to the nucleus and activation of transcription of ion transport genes to increase Na⁺ reabsorption and K⁺ secretion. Water follows Na⁺ movement by osmosis. These transporters include the luminal amiloride-sensitive epithelial Na⁺ channel, the luminal K⁺ channel, the serosal Na⁺, K⁺-ATPase, the Na⁺/H⁺ exchanger, and the Na⁺/Cl^– cotransporter.

Vasopressin and aldosterone each act on the kidney to increase fluid retention and both are in turn regulated by angiotensin II. Renin is a proteolytic enzyme that is released from the kidney in response to sympathetic neuron stimulation, renal artery hypotension, or decreased Na⁺ delivery to renal distal tubules. Renin cleaves circulating angiotensinogen to form the decapeptide angiotensin I. Then angiotensin-converting enzyme found primarily in lung removes 2 amino acids from angiotensin I to form the octapeptide angiotensin II. In addition to other important targets in regulating blood volume, arterial pressure and cardiac and vascular function, angiotensin II stimulates aldosterone release from the adrenal cortex and vasopressin release from the posterior pituitary. The actions of angiotensin II are mediated by plasma membrane seven-helix receptors coupled via G_q signaling by the phosphoinositide pathway.

COMPREHENSION QUESTIONS

For questions 46.1 to 46.3 refer to the following case scenario:

Following brain surgery involving trans-sphenoidal removal of a pituitary adenoma, a patient experienced polyuria, polydipsia, and nocturia. These symptoms appeared shortly after the surgery and had never been previously observed. Osmolarity of the urine was below normal, even if liquid consumption was restricted. Administration of desmopressin alleviated these symptoms.

46.1 Which of the following possibilities is the most likely hypothesis to explain these symptoms?

A. Damage to the thirst mechanism from surgical trauma, leading to excessive consumption of liquids

B. Damage to the pituitary or hypothalamus from surgical trauma, leading to decreased secretion of vasopressin

C. Onset of diabetes mellitus following surgery

D. Renal injury

E. Oversecretion of angiotensin II following surgery

46.2 Desmopressin acts mainly by which of the following mechanisms?

A. Stimulating aldosterone secretion by the adrenal gland

B. Increasing synthesis of Na⁺ transporters in kidney distal tubule

C. Increasing aquaporin insertion into renal distal tubule apical membranes

D. Acting as an insulin sensitizer

E. Stimulation of angiotensin II release

46.3 Which of the following would be least likely to stimulate vasopressin release from the posterior pituitary?

A. Dehydration

B. Stress

C. Angiotensin II

D. Atrial stretch receptors

E. Aldosterone

ANSWERS

46.1 B. Desmopressin is a vasopressin analog. Symptoms are consistent with DI arising from surgical trauma to the pituitary or hypothalamus and impairment of vasopressin release. The other possibilities would not be alleviated by desmopressin.

46.2 C. Vasopressin, and its analog desmopressin, acts by increasing insertion of aquaporin (water channels) into the renal distal tubule membrane, permitting increased resorption of water from the urinary filtrate.

46.3 E. Aldosterone acts independent of vasopressin to increase water resorption by the kidney, by stimulating the insertion of ion transporters into the membrane of distal colon and kidney distal tubule.

BIOCHEMISTRY PEARLS

Vasopressin (antidiuretic hormone) is a nonapeptide that controls resorption of water by distal tubules of the kidney to regulate the osmotic pressure of blood.

Vasopressin is synthesized in the hypothalamus and stored in the posterior pituitary.

Vasopressin is released in response to increased extracellular osmolarity sensed by hypothalamic osmoreceptors, signaling by atrial stretch receptors or after a rise in angiotensin II levels. Its secretion is increased by dehydration or stress.

Vasopressin promotes increased resorption of water in the renal distal tubule by stimulating insertion of water channels or aquaporins into the apical membranes of kidney tubules.

REFERENCES

Booth RE, Johnson JP, Stockand JD. Aldosterone. Adv Physiol Educ. 2002;26(1-4):8-20.

de Gasparo M, Catt KJ, Inagami T, et al. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000;52(3):415-472.

Litwack G, Schmidt TJ. Biochemistry of hormones I: polypeptide hormones. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. 7th ed. New York: Wiley-Liss; 2010.

Colorado State University. Pathophysiology of the Endocrine System. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/.