Adrenocortical Insufficiency: Addison's Disease

Transcription

1 280 PHYSIOLOGY CASES AND PROBLEMS Case 49 Adrenocortical Insufficiency: Addison's Disease Susan Oglesby is a 41-year-old divorced mother of two teenagers. She has always been in excellent health. She recently saw her physician because of several unexplained symptoms, including weight loss of 15 lb, extreme fatigue, and decreased body hair in the axillary and pubic regions. In addition, her skin was very tanned, even though she had not been in the sun. Susan hadn't had a menstrual period in 3 months; she knew she wasn't pregnant and wondered whether she was experiencing early menopause. In her physician's office, Susan appeared very thin, with sunken eyes and decreased skin turgor. When she was supine (lying), her blood pressure was 90/60 and her pulse rate was 95 beats/min. When she was standing, her blood pressure was 70/35 and her pulse rate was 120 beats/min. Her skin was deeply pigmented, especially her nipples and the creases in the palms of her hands. Susan's physician ordered laboratory tests (Table 6-5). TABLE 6-5 Susan aboratary Values Venous blood Na K* Osmolarity Glucose (fasting) Cortisol Aldosterone ACTH Arterial blood ph HCO3 126 meq/l (normal, 140 meq/l) 5.7 meq/l (normal, 4.5 meq/l) 265 rriosm/l (normal, 290 mosm/l) 50 mg/dl (normal, mg/dl) Decreased Decreased Increased 7.32 (normal, 7.4) 18 meq/l (normal, 24 meq/l) ACTH, adrenocorticotropic hormone. Results of an adrenocorticotropic hormone (ACTH) stimulation test were negative (i.e., there was no increase in the serum level of cortisol or aldosterone). Based on the symptoms, physical examination, laboratory values, and results of the ACTH stimulation test, Susan was diagnosed with primary adrenal insufficiency (Addison's disease). Susan's physician prescribed daily treatment with hydrocortisone (a synthetic glucocorticoid) and fludrocortisone (a synthetic mineralocorticoid). Susan was instructed to take hydrocortisone in two divided doses, with a larger dose at 8 A.M. and a smaller dose at 1 P.M. At a follow-up visit 2 weeks later, Susan's circulating ACTH level was normal. She had gained 5 lb, her blood pressure was normal (both supine and standing), her tan had started to fade, and she had much more energy. POI QUESTIONS 1. Why were Susan's serum cortisol, aldosterone, and ACTH levels consistent with primary adrenocortical insufficiency? How did her negative response to the ACTH stimulation test confirm this diagnosis? 2. How did adrenocortical insufficiency cause Susan's decreased arterial pressure? Why did her blood pressure decrease further when she moved from a supine position to a standing position?

2 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY Why was her pulse rate increased? Why was her pulse rate higher when she was standing than when she was supine? 4. Why was Susan's fasting blood glucose level lower than normal? 5. Why was her serum I(' concentration elevated (hyperkalemia)? 6. Why was her serum Na' concentration decreased (hyponatremia)? 7. What acid base abnormality did Susan have, and what was its cause? If her Pco 2 had been measured, would you expect it to be normal, increased, or decreased? Why? 8. Why did Susan's skin appear tanned (hyperpigmentation)? 9. Why did she have decreased pubic and axillary hair? 10. Why did Susan's ACTH level return to normal within 2 weeks of starting treatment? 11. Why was Susan instructed to take the hydrocortisone in two divided doses, with a larger dose at 8 A.M.?

3 282 PHYSIOLOGY CASES AND PROBLEMS F11 ANSWERS AND EXPLANATIONS Ai 1. Susan's decreased serum levels of cortisol and aldosterone and increased serum level of ACTH were consistent with primary adrenocortical insufficiency (Addison's disease). In this disease, the adrenal cortex is destroyed (usually secondary to an autoimmune process). As a result, the adrenal cortex can no longer secrete its steroid hormones cortisol, aldosterone, and the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione. The circulating ACTH level can be used to distinguish primary adrenocortical insufficiency from secondary adrenocortical insufficiency (refer back to Figure 6-5 in Case 48). In the primary form, the defect is in the adrenal cortex itself; the serum ACTH level is increased because the low level of cortisol reduces negative feedback inhibition of ACTH secretion by the anterior pituitary, thereby increasing ACTH levels. In the secondary form (hypothalamic or anterior pituitary failure), serum ACTH levels are decreased (which leads to decreased cortisol secretion). The ACTH stimulation test evaluates the responsiveness of cortisol secretion to an injection of exogenous ACTH. The test confirmed that Susan's disease was caused by primary adrenal failure. Even the large amount of ACTH in the injection couldn't stimulate her adrenal cortex to secrete cortisol! 2. Decreased circulating levels of cortisol and aldosterone were responsible for Susan's decreased arterial pressure (90/60 supine), as follows. (1) One action of cortisol is up-regulation of al-adrenergic receptors on vascular smooth muscle, resulting in increased responsiveness of blood vessels to catecholamines. In the absence of cortisol, the responsiveness of blood vessels to catecholamines is decreased. As a result, there is a decrease in total peripheral resistance and arterial pressure. (2) A major action of aldosterone is increased Na- reabsorption by the renal principal cells, leading to increases in extracellular fluid volume and blood volume, venous return, cardiac output, and arterial pressure. In the absence of aldosterone, there is decreased Na' reabsorption, decreased extracellular fluid volume and blood volume, and decreased arterial pressure. The further decrease in Susan's arterial pressure when she was upright (orthostatic hypotension) is characteristic of hypovolemia (decreased blood volume). When Susan stood up, blood pooled in the veins of the legs, further compromising venous return, cardiac output, and arterial pressure. 3. Susan's pulse rate was elevated (95 beats/min) because decreases in arterial pressure activate the baroreceptor reflex. This reflex directs an increase in sympathetic outflow to the heart and blood vessels. One of these sympathetic responses is an increase in heart rate mediated by I3 1-adrenergic receptors in the sinoatrial node. When Susan stood up, her pulse rate increased because her blood pressure had decreased further. The even lower arterial pressure triggered an even stronger response of the baroreceptor reflex. 4. Susan was hypoglycemic (fasting blood glucose level, 50 mg/dl) as a result of her decreased cortisol level. One action of cortisol is to increase the blood glucose concentration by promoting gluconeogenesis and decreasing glucose uptake by the tissues. Thus, in cortisol deficiency, gluconeogenesis decreases, glucose uptake by the tissues increases, and as a result, the blood glucose concentration decreases. 5. Susan's serum K* concentration was elevated (hyperkalemia) secondary to her decreased aldosterone level. In addition to stimulating Na- reabsorption, aldosterone stimulates IQ- secretion by the renal principal cells. Thus, in aldosterone deficiency, 1<-' secretion is decreased, which leads to positive K* balance and hyperkalemia. 6. You may have proposed that Susan was hyponatremic because aldosterone deficiency caused her to excrete too much Na* in urine. While this explanation seems logical, it is not complete.

4 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY 283 Susan was hyponatremic because she had excess water in her body relative to Na'; the excess water diluted her serum Na H concentration. Now we are faced with a more difficult question: Why did Susan retain excess water? There are two major reasons why an increase in body water occurs: (1) the person drinks more water than the kidneys can excrete or (2) there is increased water reabsorption by the kidneys. The first mechanism (primary polydipsia) is a rare cause of hyponatremia. It is much more likely that Susan's kidneys reabsorbed too much water because of a high circulating level of antidiuretic hormone (ADH). Recall that ADH secretion is stimulated by both hyperosmolarity and hypovolemia, and that the hypovolemic stimulus will "override" the osmotic stimulus. Thus, Susan's hyponatremia was caused by the following sequence of events: decreased Na* reabsorption (as a result of aldosterone deficiency), decreased extracellular fluid volume, decreased blood volume, increased ADH secretion (secondary to hypovolemia), and increased reabsorption of water by the renal collecting ducts. You may ask whether this high ADH secretion was appropriate given Susan's low serum osmolarity. Shouldn't her low serum osmolarity have turned off ADH secretion? Yes, it should have! Again, the hypovolemic stimulus for ADH secretion overrides the osmotic stimulus. 7. With an arterial ph of 7.32 and an HCO 3- concentration of 18 meq/l, Susan had metabolic acidosis. (Recall from acid base physiology that metabolic acidosis begins with a decrease in HCO 3- concentration, which decreases ph.) If her arterial Pc02 had been measured, it would have been decreased secondary to respiratory compensation for metabolic acidosis (i.e., hyperventilation). The likely cause of Susan's metabolic acidosis is aldosterone deficiency. In addition to increasing Isla' reabsorption and K.' secretion in the renal principal cells, aldosterone increases H" secretion and "new" HCO 3- reabsorption in the renal intercalated cells. Thus, aldosterone deficiency leads to decreased Na" reabsorption (leading to decreased extracellular fluid volume), decreased K H secretion (leading to hyperkalemia), and decreased secretion and new HCO3- reabsorption (leading to metabolic acidosis). This form of metabolic acidosis (secondary to aldosterone deficiency) is called type IV renal tubular acidosis. Specifically, aldosterone deficiency causes hyperkalemia, which inhibits renal NH 3 synthesis, the decreased supply of NH 3, combined with decreased It- secretion, leads to a decrease in NH 4+ excretion and metabolic acidosis. 8. Susan's hyperpigmentation was a consequence of the negative feedback regulation of ACTH secretion. Susan had primary adrenocortical failure, which led to decreased serum levels of cortisol. Decreased levels of cortisol led to decreased negative feedback inhibition of proopiomelanocortin (POMC) synthesis by the anterior pituitary. POMC, the precursor for ACTH, is a complex molecule that contains melanocyte-stimulating hormone (MSH) fragments (in addition to ACTH). Thus, when POMC levels are increased, so are the levels of MSH, which pigments the skin. 9. Susan had decreased pubic and axillary hair because, in addition to deficiencies of cortisol and aldosterone, she had a deficiency of adrenal androgens. In women, the adrenal cortex is the major source of androgens (DHEA and androstenedione), which are responsible for body hair and libido. 10. Susan's ACTH level returned to normal within 2 weeks of the initiation of hormone replacement treatment with hydrocortisone (a glucocorticoid) and fludrocortisone (a mineralocorticold). Like endogenous cortisol, exogenous glucocorticoid has a negative feedback effect on the secretion of ACTH from the anterior pituitary. 11. Susan was instructed to take hydrocortisone (glucocorticoid) in two divided doses, with a larger dose at 8 A.M. and a smaller dose at 1 P.M. to replicate the body's diurnal pattern of cortisol secretion. Endogenous cortisol secretion is pulsatile (occurs in bursts), with the largest burst occurring just before awakening (e.g., at 8 A.M.). Several smaller bursts occur in the afternoon, and the lowest rates of cortisol secretion occur in the evening and just after falling asleep.

5 284 PHYSIOLOGY CASES AND PROBLEMS Key topics Addison's disease Adrenocortical insufficiency Adrenocorticotropic hormone (ACTH} Aldosterone Antidiuretic hormone (ADH) Arterial pressure Baroreceptor reflex Cortisol Diurnal pattern (of cortisol secretion) Hyperkatemia Hyperpigmentation Hypoglycemia Hyponatremia Melanocyte-stimulating hormone (MSH) Metabolic acidosis Orthostatic hypotension Pro-opiomelanocortin (POMCI Type IV renal tubular acidosis

6 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY 285 Case 50 Congenital Adrenal Hyperplasia: 21p-Hydroxylase Deficiency Lauren and Tim Anderson recently had their second child, a girl whom they named Anne Carter. A day after the delivery, the pediatrician told the Andersons that Anne Carter's clitoris was enlarged. The pediatrician ordered a chromosomal evaluation, which confirmed an XX (female) genotype. Other tests showed that she has ovaries, a uterus, and no testes. Table 6-6 gives the results of laboratory tests. TABLE 6-6 A nue Carter's Laboratory Values Blood glucose Serum cortisol Serum ACTH 17-Ketosteroid excretion 70 mg/dl (normal fasting, mg/dl) Low-normal Increased Increased ACTH, adrenocorticotropic hormone. The consulting pediatric endocrinologist made a diagnosis of congenital adrenal hyperplasia secondary to 2113-hydroxylase deficiency. It was recommended that Anne Carter receive hormone replacement therapy and that she undergo surgery to reduce the size of her clitoris. QUESTIONS 1. Using your knowledge of the biosynthetic pathways of the adrenal cortex, predict the consequences of 2 1I3-hydroxylase deficiency. Which adrenocortical hormones will be deficient? Which hormones will be produced i n excess? 2. What are the expected physiologic consequences of the hormonal deficiencies you predicted in Question 1? 3. Why was Anne Carter's serum adrenocorticotropic hormone (ACTH) level increased? 4. Anne Carter's blood glucose and serum cortisol levels were both low-normal. Why weren't these values more obviously abnormal? 5. What was the significance of her increased urinary excretion of 17-ketosteroids? 6. Why was Anne Carter's clitoris enlarged at birth? 7. Did she have partial or complete deficiency of 2113-hydroxylase? 8. What hormone replacement therapy did she receive? 9. In terms of later development, what might have happened if Anne Carter's condition had not been diagnosed (and she did not receive hormone replacement therapy)?