Hypertension Case 2

Hypertension Case 2

A 41-year-old woman comes to the physician's office complaining of fatigue, muscle weakness, cramping, headaches, polydipsia, and
polyuria. She has been treated for hypertension for 6 years, and her doctors have told her that she has renal problems. Beta-blockers, calcium channel blockers, and diuretics have been used to control her hypertension. There is a family history of renal disease and hypertension. Her blood pressure is 240/140 mm Hg and her pulse is 85/min. The remainder of her examination is normaI. A routine chemical panel shows hypokalemia, hypernatremia, and metabolic alkalosis.


Q1
Pathologic examination of this patient would most likely reveal which of the following findings?
/ A. Adrenal adenoma
/ B. Adrenal carcinoma
/ C. Bilateral nodular hyperplasia
/ D. Multiple adrenal adenomas
/ E. Unilateral nodular adrenal hyperplasia


Q2
This patient is found to have an excessive amount of an adrenal hormone in her plasma. Which of the following factors is a major regulator of
the synthesis of this hormone?
/ A. ACTH
/ B. Atrial natriuretic peptide
/ C. Dopamine
/ D. Renin-angiotensin system
/ E. Sodium


Q3
Spironolactone is used in the treatment of patients with this disease. Which of the following is the most important adverse reaction of
spironolactone therapy?
/ A. Anti-androgen
/ B. Cardiac arrhythmia
/ C. Dehydration
/ D. Hyperkalemia
/ E. Skin reaction


Q4
The serum potassium level in this patient is found to be 2.5 mEq/L. Which of the following EKG changes would most likely be expected?
/ A. Prolonged QT interval
/ B. Prominent U waves, flattened T waves
/ C. Shortened QT interval
/ D. ST segment elevation, convex upwards
/ E. TalI, peaked T waves


Q5
The mineralocorticoid receptor (MR) displays the same affinity for glucocorticoid hormones as it does for the hormone that is in excess in this patient. The sensitivity of the MR to this hormone depends on which of the following enzymes?
/ A. AIdosterone synthase
/ B. C17,20-Iyase
/ C. 11-beta hydroxysteroid dehydrogenase type 2 (HSD2)
/ D. Na+/K+-ATPase
/ E. 17-alpha hydroxylase


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Hypertension Case 2 Answers

A1
The correct answer is A. 50% of patients with Conn syndrome present with a solitary adenoma of the adrenal cortex zona glomerulosa, which secretes aldosterone (aldosteronoma). Aldosterone-secreting adenomas are usually less than 2 cm in diameter with a bright yellow appearance. 60% of these lesions are found in the left adrenal gland. Histologically, these tumors are composed of lipid-laden zona glomerulosa cells in cords, although compact cells can also be seen. The unaffected cortex is not atrophic, since aldosterone does not feedback on the production of ACTH.
Rarely, aldosterone can be secreted by adrenocortical carcinoma (choice B).
Approximately 40% of patients with Conn syndrome have bilateral hyperplasia (choice C) of the zona glomerulosa. The hyperplasia may be micronodular, macronodular, or a mixture of both.
10% of the patients have multiple benign tumors (choice D), with the same appearance as a solitary adenoma.
A few patients have unilateral nodular adrenal hyperplasia (choice E) that is similar in function to adenoma.

A2
The correct answer is D. The major factors stimulating aldosterone production and release by the zona glomerulosa are angiotensin II and the serum potassium concentration. Angiotensinogen, the precursor of angiotensin peptides, is synthesized by the liver. In the circulation, renin, secreted by juxtaglomerular cells, cleaves four amino acids from angiotensinogen, forming the decapeptide angiotensin I (AI). AI is cleaved by angiotensin-converting enzyme (ACE) to form an octapeptide, angiotensin II (AII). In the zona glomerulosa of the adrenal cortex, AII stimulates the production of aldosterone. The mechanism of AII action involves an increase in activity of aldosterone synthase, the key enzyme in the biosynthesis of aldosterone. AII is the principal stimulator of aldosterone production when intravascular volume is reduced. Also found in the circulation, the des-ASP heptapeptide (angiotensin III) is as active as angiotensin II in stimulating aldosterone release but has much less pressor activity. Potassium is also a major physiologic regulator of aldosterone secretion; hyperkalemia also increases the activity of aldosterone synthase. The mechanism of potassium effect may involve depolarization and activation of voltage-gated calcium channels. AII produces quantitatively the most significant increase in aldosterone production, but the hormone secretion is most sensitive to small changes in serum potassium ion concentrations.
ACTH (choice A) stimulates aldosterone secretion, but does not appear to play a significant role in the physiological regulation of mineralocorticoid homeostasis.
Atrial natriuretic peptide (choice B) antagonizes the AII-stimulated release of aldosterone.
Dopamine (choice C), acting locally as a paracrine agent, inhibits secretion of aldosterone.
The extent of sodium (choice E) reduction that is necessary to alter aldosterone secretion is rarely seen in pathologic, let alone physiologic situations.

A3
The corrects answer is A. Spironolactone is a competitive antagonist of the aldosterone receptor. Hypokalemia and hypertension in patients with primary aldosteronism can be controlled by spironolactone, 50-100 mg/d. Although spironolactone is an effective aldosterone receptor antagonist, it is not without side effects that can limit its use in the chronic treatment of this disease. The most important are anti-androgenic reactions. Spironolactone acts as an anti-androgen by decreasing the production of testosterone by the adrenal gland and by preventing DHT (dihydrotestosterone) from binding to its androgen receptor. As a result of this, in the long run, gynecomastia occurs in more than 10% of the treated men. Impotence, loss of libido, and menstrual irregularities are also common side effects of spironolactone therapy. On the other side, these spironolactone features are the basis for its usage in the treatment of hirsutism, acne, and alopecia. Spironolactone is also used by transsexuals in the feminizing regimen because of its anti-androgenic actions. Eplerenone is a new aldosterone antagonist that may overcome the limitations of spironolactone.
Cardiac arrhythmia (choice B) is not a frequent adverse reaction to spironolactone treatment, and it is seen only in the presence of significant hyperkalemia.
Dehydration (choice C) is usually very mild, and can be prevented with adequate water intake.
Hyperkalemia (choice D) develops in 5-10% of treated patients, especially if renal function is compromised, or the patient is diabetic, or elderly.
Skin reactions (choice E), mostly urticaria, are rare side effects of spironolactone therapy.

A4
The correct answer is B. In hypokalemia, the triad of prominent U waves, low amplitude T waves, and ST segment depression is a typical finding. High-amplitude positive U waves are the usual EKG features that can be expected in this patient. The origin of the U wave is still unclear, although most authors correlate the U wave with the phenomenon of after depolarizations in the ventricles. U waves become as tall as T waves at a serum level of about 3.0 mEq/L, and at about 2.0 mEq/L, become taller than T waves. T waves begin to flatten at a serum potassium level of about 3.0 mEq/L, and eventually may either fuse with the U waves or become inverted. Ventricular arrhythmias may occur with hypokalemia in the presence of digitalis.
The EKG in hypocalcemia typically shows prolongation of the QT interval (choice A). T wave peaking or inversion can also be seen.
Shortening of the QT interval (choice C) is seen in patients with hypercalcemia.
ST segment elevation, convex upwards (choice D) is pathognomonic for acute myocardial infarction.
A hyperkalemic state is characterized primarily by tall, peaked T waves (choice E). There may be also wide, flat P waves, lowering of the R wave, and increased depth of the S wave.

A5
The correct answer is C. Mineralocorticoid receptors (MR) are members of a superfamily of steroid/thyroid/retinoid/orphan (STRO) receptors. MR are intracellular and act as ligand-activated transcription factors to regulate gene expression. The human MR is a 984 amino acid protein, and the cDNA has been cloned and sequenced. The MR shows the same affinity for aldosterone and glucocorticoids. Since the plasma concentration of cortisol is much higher than that of aldosterone, a mechanism is necessary to protect MRs from constant occupancy by glucocorticoid hormones. This mechanism depends on the activity of 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), which converts cortisol (and corticosterone) into 11-dehydro metabolites in the endoplasmic reticulum. These are not ligands for MR. This permits the MR to be occupied by aldosterone as a function of its serum levels. In the absence of, or inhibition of HSD2, the MR will be occupied by glucocorticoids, and a permanent Na+ reabsorption will occur. This concept can be seen at work in patients with excessive ingestion of licorice. Glycyrrhizic acid, an active hypertensive component in licorice, and its derivative 18-beta-glycyrrhetinic acid, inhibit HSD2 activity. Cortisol activation of MR induces sodium retention, potassium excretion, and hydrogen ion excretion in the kidney, mimicking the symptoms of aldosteronism: hypertension, hypokalemia, and metabolic alkalosis.
Aldosterone synthase (choice A) converts a CH3 group at C18 of the steroid molecule to an aldehyde group, from whence comes the name aldosterone. This enzyme is expressed exclusively in zona glomerulosa of adrenal cortex. Aldosterone synthase is encoded by the gene CYP11B2 and has 11-beta-hydroxylase, 18-hydroxylase, and 18-hydroxy-dehydrogenase activity.
Activity of C17,20-lyase (choice B) is responsible for producing the androgens, dehydroepiandrosterone (DHEA) and androstenedione.
Na+/K+-ATPase (choice D) is located in basolateral membranes of the distal tubular cells and generates the electrochemical gradient that drives diffusion through the sodium and potassium channels. Aldosterone stimulates gene expression of mRNA for this enzyme.
The synthesis of cortisol requires 17-alpha hydroxylation of pregnenolone by 17-alpha hydroxylase (choice E), which is expressed only in the zona fasciculata.