Page 770 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster
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756 C H A P T E R 19 Endocrine System precursor steroids, which are then channeled into synthesis
drug of choice in primary hyperaldosteronism. In contrast of androgens with virilizing activity. Certain enzyme
with cortical adenomas associated with Cushing syndrome, defects also may impair aldosterone secretion, adding salt
those associated with hyperaldosteronism do not usually sup- loss to the virilizing syndrome. The most common enzymatic
press ACTH secretion. Therefore, the adjacent adrenal defect in CAH is 21-hydroxylase deficiency, which accounts for
cortex and that of the contralateral gland are not atrophic. more than 90% of cases. 21-Hydroxylase deficiency may
Bilateral idiopathic hyperplasia is marked by diffuse or range in degree from a total lack to a mild loss, depending
focal hyperplasia of cells resembling those of the normal zona on the nature of the underlying mutation involving the
glomerulosa. CYP21A2 gene, which encodes this enzyme.
Clinical Features MORPHOLOGY
The clinical hallmark of hyperaldosteronism is hypertension.
With an estimated prevalence rate of 5% to 10% among In all cases of CAH, the adrenals are hyperplastic bilater-
unselected hypertensive patients, primary hyperaldos ally, sometimes expanding to 10 to 15 times their normal
teronism may be the most common cause of secondary weights. The adrenal cortex is thickened and nodular, and on
hypertension (i.e., hypertension secondary to an identifi- cut section, the widened cortex appears brown as a result of
able cause). The long-term effects of hyperaldosteronism- depletion of all lipid. The proliferating cells mostly are
induced hypertension are cardiovascular compromise compact, eosinophilic, lipid-depleted cells, intermixed with
(e.g., left ventricular hypertrophy and reduced diastolic lipid-laden clear cells. In addition to cortical abnormalities,
volumes) and an increase in the prevalence of adverse adrenomedullary dysplasia also has recently been
events such as stroke and myocardial infarction. Hypokale- reported in patients with the salt-losing 21-hydroxylase defi-
mia results from renal potassium wasting and, when ciency. This is characterized by incomplete migration of the
present, can cause a variety of neuromuscular manifesta- chromaffin cells to the center of the gland, with pronounced
tions, including weakness, paresthesias, visual distur- intermingling of nests of chromaffin and cortical cells in the
bances, and occasionally frank tetany. In primary periphery. Hyperplasia of corticotroph (ACTH-producing)
hyperaldosteronism, the therapy varies according to cause. cells is present in the anterior pituitary in most patients.
Adenomas are amenable to surgical excision. By contrast,
surgical intervention is not very beneficial in patients Clinical Features
with primary hyperaldosteronism due to bilateral hyper- The clinical manifestations of CAH are determined by the
plasia, which often occurs in children and young adults. specific enzyme deficiency and include abnormalities
These patients are best managed medically with an related to androgen metabolism, sodium homeostasis, and
aldosterone antagonist such as spironolactone. The treatment (in severe cases) glucocorticoid deficiency. Depending on
of secondary hyperaldosteronism rests on correcting the nature and severity of the enzymatic defect, the onset
the underlying cause of the renin-angiotensin system of clinical symptoms may occur in the perinatal period,
hyperstimulation. later childhood, or (less commonly) adulthood.
Adrenogenital Syndromes In 21-hydroxylase deficiency, excessive androgenic activity
causes signs of masculinization in females, ranging from
Excess of androgens may be caused by a number of clitoral hypertrophy and pseudohermaphroditism in
diseases, including primary gonadal disorders and infants to oligomenorrhea, hirsutism, and acne in postpu-
several primary adrenal disorders. The adrenal cortex bertal girls. In males, androgen excess is associated with
secretes two compounds—dehydroepiandrosterone and enlargement of the external genitalia and other evidence of
androstenedione—which require conversion to testoster- precocious puberty in prepubertal patients and with oligo-
one in peripheral tissues for their androgenic effects. Unlike spermia in older patients. In some forms of CAH (e.g.,
gonadal androgens, adrenal androgen formation is regu- 11β-hydroxylase deficiency), the accumulated intermedi-
lated by ACTH; thus, excessive secretion can present as an ary steroids have mineralocorticoid activity, with resultant
isolated syndrome or in combination with features of sodium retention and hypertension. In other cases, however,
Cushing disease. The adrenal causes of androgen excess including about one third of persons with 21-hydroxylase
include adrenocortical neoplasms and an uncommon group deficiency, the enzymatic defect is severe enough to
of disorders collectively designated congenital adrenal hyper- produce mineralocorticoid deficiency, with resultant salt
plasia (CAH). Adrenocortical neoplasms associated with (sodium) wasting. Cortisol deficiency places persons with
symptoms of androgen excess (virilization) are more likely CAH at risk for acute adrenal insufficiency (discussed later).
to be carcinomas than adenomas. They are morphologi-
cally identical to other functional or nonfunctional cortical CAH should be suspected in any neonate with ambigu-
neoplasms. ous genitalia; severe enzyme deficiency in infancy can be
a life-threatening condition, with vomiting, dehydration,
CAH represents a group of autosomal recessive disor- and salt wasting. In the milder variants, women may
ders, each characterized by a hereditary defect in an enzyme present with delayed menarche, oligomenorrhea, or hirsut-
involved in adrenal steroid biosynthesis, particularly cor- ism. In all such cases, an androgen-producing ovarian neo-
tisol. In these conditions, decreased cortisol production plasm must be excluded. Treatment of CAH is with
results in a compensatory increase in ACTH secretion due exogenous glucocorticoids, which, in addition to providing
to absence of feedback inhibition. The resultant adrenal adequate levels of glucocorticoids, also suppress ACTH
hyperplasia causes increased production of cortisol levels, thereby decreasing the excessive synthesis of the
