Pathology Title of Lecture

AY 2018-2019 Instructor’s Name (Name, MD, other-post-nominals)

1st Shifting Exam MM/DD/YYYY

OUTLINE

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LEARNING OBJECTIVES

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VI. ADRENAL CORTEX

 Has three zones: zona glomerulosa (mineralocorticoids), zona

fasciculata (glucocorticoids), zona reticularis (sex steroids).

Figure X. Endogenous causes of Cushing syndrome

Figure X. Adrenal Glands
A. ADRENOCORTICAL HYPERFUNCTION
 May arise from 3 different conditions:
 Cushing syndrome: excessive cortisol
 Hyperaldosteronism: excessive aldosterone
 Virilizing syndromes or adrenogenital:
androgens
1. HYPERCORTISOLISM
 Morphology:
 Depending on the cause of the hypercortisolism, the
adrenals show one of the following abnormalities: (1) cortical
atrophy, (2) diffuse hyperplasia, (3) macronodular or
micronodular hyperplasia, and (4) an adenoma or carcinoma.
 Hyperplasia is always bilateral and adenoma is unilateral
 Crooke’s hyaline change
 Seen in Pituitary Hypercorticolism; most common
alteration in pituitary gland
 ACTH producing cells’ basophilic cytoplasm in the anterior
excess of pituitary becomes homogeneous and pale due to the
accumulation of intermediate keratin filaments in the
cytoplasm.

 “Cushing’s Syndrome”
 Causes:
 Exogenous
 The most common cause is exogenous administration of
exogenous glucocorticoids (“iatrogenic” Cushing
syndrome).
 Ex. Treatment of allergies or asthma

 Endogenous
 1. ACTH dependent
 70% of cases of endogenous hypercortisolism Figure X. Crooke’s hyaline change
 Pituitary neoplasms are the most common underlying  Abnormalities of adrenal gland:
causes (70% of all endogenous cases)  Cortical atrophy
 Cushing Disease, Corticotropin syndrome  Iatrogenic Cushing syndrome
 2. ACTH independent  Suppression of endogenous ACTH  lack of
 Uncommon stimulation of the zona fasciculata and reticularis 
 Ex. Macronodular hyperplasia where cortisol cortical atrophy
production is regulated by non- ACTH circulating  Diffuse hyperplasia
hormones, due to ectopic overexpression of their  ACTH-dependent Cushing syndrome
corresponding receptors in the adrenocortical cells  Both glands are enlarged

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  Hyperplastic cortex shows expanded lipid-poor zona
reticularis with compact eosinophilic cells surrounded
by outer zone of vacuolated “lipid-rich” cells
 Macronodular hyperplasia
 The adrenals are almost entrirely replaced by
prominent nodules of varying sizes, which contain an
admixture of lipid-poor and lipid-rich cells
Figure X. Macronodular hyperplasia. The nodules are filled with
lipid rich areas because the precursors of the hormones are
cholesterol, thus, they need more lipid.
 Micronodular hyperplasia
 Darkly pigmented (pigments composed of brown to
black- lipofuscin) micronodules, with atrophic intervening
areas.
 Not much of a change when it comes to size
Figure X. Micronodular hyperplasia. (Right) you can observe the
accumulation of lipofuscin on the far left.
 Primary Adrenocortical neoplasms
 Malignant/ benign
 More common in women in 30s – 50s
 Adrenocortical adenomas: yellow tumors surrounded by
capsule; cells are similar to normal zona fasciculata
 To differentiate it from carcinoma, one of the basis is
the SIZE, most of the time 30 grams is an adenoma
and more than 300 grams it becomes a carcinoma.
 Resemble the cells found in zona fasciculate
 Contain numerous vacuolated cells because due to the
lipids present
 Carcinoma: unencapsulated masses that have all of the
anaplastic characteristics of cancer
 Tend to be larger than the adenomas; poorly
demarcated lesions containing areas of necrosis,
hemorrhage, and cystic change.
Figure X. Gross picture of adrenal cortical adenoma. Is is
distinguished from nodular hyperplasia by its solitary, well-
circumscibed nature. Basis is the size!
Patho Title of Lecture
Figure X. Adrenocortical carcinoma. Shows marked
degree of anaplasia and pleomorphism in the nucleus.
 Clinical Manifesations:
 Central pattern of adipose tissue deposition which becomes
apparent in the form of truncal obesity, moon facies, and
buffalo hump. (most common)
 Decrease in muscle mass and proximal limb weakness
 Hyperglycemia, glucosuria, and polydipsia (secondary
diabetes)
 Clinical Course
 Develops slowly; early stages: hypertension and weight gain
 Pattern of adipose deposition is distinct: truncal obesity,
moon facies, and accumulation of fat in the posterior neck
and back (buffalo hump)
 Selective atrophy of fast-twitch (type 2) myofibers → ↓muscle
mass and proximal limb weakness
 Glucocorticoids induce gluconeogenesis → inhibit uptake of
glucose → hyperglycemia, glucosuria and polydipsia
(secondary diabetes)
 Catabolic effects: loss of collagen, resorption of bones
 Skin: thin, fragile, easily bruised, poor wound healing,
cutaneous striae in abdominal area
 Bone resorption → osteoporosis, backache, ↑susceptibility
to fracture
 Mental disturbances: mood swings, depression, and frank
psychosis
 Hirsutism & menstrual abnormalities in women
 Laboratory Diagnosis:
 Inc. 24 hour urine free cortisol concentration
 Loss of normal diurnal pattern of cortisol secretion
 Normally the cortisol is expected to be increasing as the
day goes on and goes down at the end of the day but in
Cushing’s syndrome it is persistently elevated.
 Determining the cause of Cushing’s syndrome depends on
ACTH secretion and measurement of urinary steroids after
Dexamethasone administration (Dexamethasone Test)
 By performing Dexamethasone suppression test you can
localize where the problem is
Dexamethose Suppression Test is used to suppress the release of
ACTH from your anterior pituitary. With this, the only syndrome
here wherein there’s an increase release of ACTH is the Cushing’s
Syndrome. The rest is due to ectopic releases or adrenal tumors
that are outside the brain so they are not affected. Thus, this is a
test to detect Cushing’s Syndrome.
 General Pattern of Tests:
1. Pituitary Hypercorticolism
 Low dose dexamethasone: ↑ACTH and can’t be suppressed,
no reduction in urinary excretion of 17-hydroxycorticosteroids
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  High dose of dexamethasone: ↓ACTH secretion,
suppression of urinary steroid secretion

2. Ectopic ACTH
 ↑ACTH, but its secretion is completely insensitive to low or
high doses of exogenous dexamethasone
 Seen in some of the paraneoplastic syndromes (certain form
of cancers)
 Not related to adrenal or pituitary but rather to the tumor that
is producing the ACTH
 Insensitive to low or high doses of Dexamethasone

3. Adrenal tumor
 Low or high doses of Dexamethasone cannot suppress Figure X. Gross: Conn’s Syndrome. Almost always
cortisol excretions; Insensitive to high and low doses of solitary, small, well-circumscribed lesions that are bright yellow on
dexamethasone cut section composed of lipid-laden cortical cells.
 In general, ACTH levels are low due to feedback inhibition
Aldosterone-producing adenoma
Table X. Pattern of results for different diseases with the  Almost always solitary, small (<2cm), well circumscribed lesions
Dexamethasone suppression test
 More often found on the left than on right adrenal gland
Disease Low-dose High-dose ACTH
 Bright yellow in cut section, composed of lipid laden cortical
Dexamethasone Dexamethasone
cells
Cushing’s Non-responsive Responsive High
 Presence of eosinophilic, laminated cytoplasmic inclusions
Disease
known as spironolactone bodies upon treatment with
Ectopic ACTH Non-responsive Non-responsive High
spironolactone
secretion
 Does not usually express ACTH secretion
Adrenal Non-responsive Non-responsive Low
Tumor
 Glucocorticoid-remediable hyperaldosteronism
 Uncommon cause of primary familial hyperaldosteronism
2. HYPERALDOSTERONISM
 Involves chromosome 8, CYP11B2 (encoding aldosterone
synthase) under control of ACTH responsive CYP11B1 gene
 Generic term for a group of closely related conditions promoter
characterized by chronic excess aldosterone secretion.  Unusual circumstance – aldosterone production under
 It may be primary or secondary (extra-adrenal cause). control of ACTH – thus, dexamethasone suppressible
 Endpoint: HYPERTENSION

PRIMARY HYPERALDOSTERONISM
 Primary – autonomous overproduction of aldosterone, with
resultant suppression of the RAAS and ↓ renin activity
 High plasma aldosterone, LOW plasma renin
 Blood pressure elevation is the most common manifestation of
primary hyperaldosteronism secondary to increased
aldosterone production.
 Caused by 3 mechanisms:
 Bilateral Idiopathic hyperaldosteronism
 Older > younger population characterized by bilateral
nodular hyperplasia
 Most common underlying cause, accounting for 60% of
cases
 Less severe hypertension than with adrenal neoplasms
 Unclear pathogenesis but recently KCNJ5 mutation, a
potassium channel
 Diffuse, focal hyperplasia of cells resembling those of
normal zone glomerulosa
 Wedge-shaped, extending from the periphery towards the
center of the gland
 Adrenocortical neoplasm
 May be an aldosterone adenoma or rarely adrenocortical
carcinoma
 Adenoma – 2nd most common cause
 Glucocorticoid suppressible adenoma in the pituitary
causing excessive ACTH release
 35% by solitary aldosterone-secreting adenoma known
as Conn Syndrome
 Middle life, F > M (2:1); KCNJ5 mutation also present Figure X. Mechanisms of primary hyperaldosteronism

SECONDARY HYPERALDOSTERONISM
 Secondary – aldosterone release in response to the activation
of RAAS due to:
 Increased levels of renin

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  Decreased renal perfusion (arteriolar nephrosclerosis, renal
artery stenosis)
 Arterial hypovolemia and edema (CHF, cirrhosis, nephrotic
syndrome); dehydration, hemorrhage,
 Pregnancy (estrogen-induced increase in plasma renin
substrate) – may increase levels of renin
 Related to any condition that could increase renin in the
blood as in cases of decreased renal perfusion (Severe renal
artery stenosis)
 High plasma aldosterone AND high plasma renin
 Morphology:
 Aldosterone-producing adenoma – Spironolactone bodies
 Lipid-laden cortical cells closely resembling the fasciculata
cells than the glomerulosa (source of aldosterone)
 Cells tends to be uniform in size and shape with some
nuclear and cellular pleomorphism
Figure X. Spirolactone bodies – eosinophilic, laminated
cytoplasmic inclusion in the cortex.
 Clinical course:
 Most important clinical consequences: Hypertension
 Long term effects are cardiovascular compromise, stroke, MI,
hypokalemia
 Hypertension – the most important clinical consequence of
hyperaldosteronism (most common cause of secondary
hypertension)
 Promotes Na+ reabsorption through its effects on the
mineralocorticoid receptor → ↑ Cardiac output
 Long term effects
 Cardiovascular compromise (LV hypertrophy, ↓diastolic
volumes)
 Increased risk of stroke and myocardial infarction
 Hypokalemia – renal potassium wasting as sodium is
reabsorbed
 Previously a mandatory feature but has changed due to
increasing numbers of normokalemic patients
 Hypokalemia is common but not pathognomonic
 Treatment
 Therapy varies according to cause
 Adenomas – surgical excision
 Bilateral hyperplasia – medical intervention (aldosterone
antagonist, e.g. spironolactone)
 Secondary hyperaldosteronism – correcting the underlying
cause stimulating the RAAS
 Diagnosis
 Primary hyperaldosteronism – elevated ratios of plasma
aldosterone concentration to plasma renin activity
Patho Title of Lecture
 If screening test is positive, confirmatory aldosterone
suppression test must be performed
3. ANDROGENITAL SYNDROMES
 There are 2 important enzymes: 21-alpha hydroxylase and 17-
hydroxyprogesterone. Blockage of the 21-alpha will result in
salt-wasting because there is no aldosterone. When the 2
enzymes are blocked, there will be an increase in sex hormone
production leading to a virilised male or female.
 Female will grow facial hairs, hair on extremities and menstrual
problem. In men, alopecia, sexual dysfunction.
 2 kinds: adrenocortical neoplasia or congenital adrenal
hyperplasia
 The adrenal cortex secretes two compounds –
dihydroepiandosterone and androstenedione which require
conversion to testosterone in peripheral tissues for androgenic
effects. Adrenal androgen formation is regulated by ACTH; thus,
excessive secretion can present as an isolated syndrome or in
combination with features of Cushing’s disease.
 Adrenocortical neoplasia associated with virilization are more
likely to be androgen-secreting adrenal carcinomas than
adenomas
a. CONGENITAL ADRENAL HYPERPLASIA
 Autosomal recessive inherited metabolic errors leading to a lack
of enzyme particularly cortisol synthesis
 Leads to a compensatory increases in ACTH secretion due to
absence of feedback inhibition
 21-hydroxylase deficiency – salt losing syndrome; simple
virilising adrenogenital syndrome without salt wasting; involves
mutation of the CYP21A2 gene
 Non-classic or late onset adrenal virilism – leading to increased
activity of 17-hydroxylase
 Morphology:
 The adrenals are hyperplastic bilaterally sometimes
expanding 10-15 times their normal weights
 Adrenal cortex is thickened and nodular, widened cortex on
cut section is brown due to lipid deposition
 Proliferating cells are compact, eosinophilic, lipid depleted
cells intermixed with lipid-laden cells
“Nonclassic” Or Late-Onset Adrenogenitalism
 More common than the classic patterns
 Partial deficiency in 21-hydroxylase function → later onset
 Virtually asymptomatic or have mild manifestations, such as
hirsutism, acne, and menstrual irregularities.
 Diagnosis: Demonstration of biosynthetic defects in
steroidogenesis.
Salt-Wasting (“Classic”) Adrenogenitalism
 Inability to convert progesterone into deoxycorticosterone
because of a total lack of 21-hydroxylase
 Virtually no synthesis of mineralocorticoids
 Blockage in the conversion of hydroxyprogesterone into
deoxycortisol resulting in cortisol deficiency
 Usually presents soon after birth, because in utero, the
electrolytes and fluids can be maintained by the maternal
kidneys.
 Males are generally unrecognized at birth but come to clinical
attention 5 - 15 days later because of some salt-losing crisis
 Salt wasting, hyponatremia, and hyperkalemia, which induce
acidosis, hypotension, cardiovascular collapse, and possibly
death
Simple Virilizing Adrenogenitalism
 Presenting as genital ambiguity, in ~1/3 patients with 21-
hydroxylase deficiency.
 Generate sufficient mineralocorticoid to prevent a salt-
wasting “crisis”
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 Lowered glucocorticoid level fails to cause feedback inhibition of
ACTH secretion
 Increased level of testosterone → progressive virilization

 Clinical Course:
 Determined by the specific enzyme deficiency and
abnormalities related to androgen excess, with or without
aldosterone and glucocorticoid deficiency
 21-hydroxylase deficiency causes excessive androgenic
activity
 Signs of masculinization in females
 Clitoral hypertrophy & pseudohermaphroditism in
infants,
 Oligomenorrhea, hirsutism, and acne in postpubertal
females.
 In males, androgen excess is associated with:
 Enlargement of the external genitalia (precocious
puberty) in prepubertal patients
 Oligospermia in older males.
 CAH should be suspected in any neonate with ambiguous
genitalia
 CAH affects not only adrenal cortical enzymes but also
products synthesized in the medulla.
 Low cortisol levels + adrenomedullary dysplasia = low
catecholamine secretion
 Predisposing these individuals to hypotension and
circulatory collapse
 Severe enzyme deficiency in infancy can be a life-
threatening condition with vomiting, dehydration, and salt
wasting

 Diagnosis
 Classic CAH can be detected during newborn screening
 Non-classic CAH: demonstration of biosynthetic defects in
steroidogenesis.
 Treatment
 Individuals with CAH – Tx is exogenous glucocorticoids
 Suppresses ACTH levels → decrease the excessive
synthesis of the steroid hormones
 Salt-wasting variants of CAH – Tx is mineralocorticoid
supplementation

Figure X. Pathogenesis of adrenogenital syndromes – 21-hydroxylase

deficiency is highlighted in red “blocks”

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