27.05.

2015

endocrine diseases

PITUITARY

The normal pituitary. (A) The

gland is bean shaped and
covered by a fibrous capsule.
It hangs from the
hypothalamus by the pituitary
stalk or infundibulum. (B) On
horizontal cross-section the
gland is readily seen to have
two distinct components, the
anterior lobe representing the
larger part (top) and the
posterior lobe, or
neurohypophysis,
representing the smaller
component (bottom).
Between them is the
intermediate lobe, which
consists only of vestigial
structures that are recognized
grossly as tiny cysts with
gelatinous contents

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ADRENAL GLAND

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The cortex, of course, has three "zones":

(1) ZONA GLOMERULOSA: mineralocorticoid
production. Thin and patchy, small cells.
(2) ZONA FASCICULATA: glucocorticoid production
(now seems settled), resting cells (the reserve cells
are at the ZG-ZR interface). Yellow.
(3) ZONA RETICULARIS: glucocorticoid production,
androgen and estrogen production, grossly darker
than outer layers. Brown.

(Salt, sugar, and sex:

the deeper you go, the sweeter it gets.)

CUSHINGS SYNDROME
Etiology
(both Cushing's disease and glucocorticoid-secreting
adenomas are most common in women ages 15 to 45,
but can be diagnosed in anybody and anytime)

Adrenals are:
atrophic if glucocorticoids were administered
hyperplastic if ACTH was administered

CUSHINGS SYNDROME. etiology

3. ADRENAL CORTICAL ADENOMA OR CARCINOMA
("adrenal Cushingism") the tumor may be primary, or an
autonomous adrenal tumor may develop after years of
"pituitary Cushingism")
4. ACTH- (OR CRH-) PRODUCING CANCERS OF OTHER
ORGANS: small-cell carcinoma, bronchial and thymic
carcinoids, medullary thyroid carcinoma, islet cell cancer;
other APUDomas.
Full-blown Cushingism is rare in oat cell patients, only
because they don't live long enough

CUSHINGS SYNDROME
(too much glucocorticoids)
Symptoms and signs:
truncal obesity with "buffalo hump" ("upper trunk fat") and "moon
face"
increased appetite
insomnia and mental changes (Cushing's psychosis)
vascular and connective tissue changes: thinning of the dermis,
bruisability, striae ("purple stripes"), very poor healing, purpura
high blood pressure
glucose intolerance (diabetes, with complications)
osteoporosis
loss of normal circadian rhythm of cortisol secretion
other: acne, cellulitis, edema, gastric ulcers, hirsutism,
oligomenorrhea, hypokalemia, muscle wasting,

CUSHINGS SYNDROME. etiology

1. IATROGENIC (the most common).
2. ACTH-PRODUCING PITUITARY LESION, usually a
basophilic microadenoma ("Cushing's disease", "pituitary
Cushingism")
the adrenals usually are diffusely enlarged (but may be
nodular),
"Nelson's syndrome" - rapid enlargement of the pituitary
adenoma leading to hyperpigmentation, blindness and
death - followed adrenalectomy in many of these
patients

CUSHINGS SYNDROME. etiology

5. Really "primary" adrenal hyperplasia (not due to excess
ACTH):
"primary pigmented nodular adrenocortical
hyperplasia" (part of the autosomal dominant Carney
complex)
circulating antibodies against the ACTH receptor
(analogous to Graves disease) can occasionally stimulate
the gland into hyperactivity
6. Cushingism with a burst of cortisol after eating: inappropriate
expression of GIP receptors on the adrenal cortex/adrenal
adenoma
7. Recurrent cushingism of pregnancy

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PRIMARY HYPERALDOSTERONISM
(Conn's syndrome)
"low-renin hyperaldosteronism": too much
mineralocorticoid
Etiology:
"idiopathic" adrenal hyperplasia, or an adrenal adenoma.
the most familiar cause is an "autonomous" adrenal
cortical adenoma (CONN'S SYNDROME), often very
small
a cause of surgically-correctable high blood pressure
(0.5% of hypertensives have primary
hyperaldosteronism)

SECONDARY
HYPERALDOSTERONISM
is much more common then primary
part of the picture in:
chronic heart failure,
cirrhosis,
nephrotic syndrome,
and other problems.

PRIMARY HYPERALDOSTERONISM
clinic:
classically, patients exhibit:
hypokalemia (muscle weakness, and even
paralysis),
alkalosis,
and low rennin,
surprisingly, these patients do not have
edema

ADRENAL CORTICAL ADENOMAS

round, yellow (like the adrenal cortex) nodules
("nodular hyperplasia")
adrenal cortical adenomas are found in 2% of
autopsies and abdominal CT scans
("incidentalomas", as far as there is no evidence
of steroid or catecholamine over-production)
may cause:
Cushing's syndrome, Conn's syndrome, or virilization,
the vast majority are clinically silent

ADRENAL CORTICAL CARCINOMA

HYPOADRENOCORTICISM
("Addisonism")

rare tumor, but often lethal

many are hormonally active (Cushing's, Conn's,
and/or virilization), mixed endocrine syndromes
usually mean cancer (Adrenal tumors that
feminize, or that produce androgens without
glucocorticoids, are most often malignant)

Insufficient glucocorticoid (and usually insufficient

mineralocorticoid) production.

histology: usually obviously malignant, grossly

and microscopically, with ten or more mitotic
figures per high power field

There are several etiologies of chronic

hypoadrenocorticism:

chronic hypoadrenocorticism (ADDISON'S DISEASE,

now regardless of etiology)
troubles start when 80% of the gland tissue is gone,

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HYPOADRENOCORTICISM
INFECTIONS
most of Dr. Addison's patients had bovine TB of the
adrenals,
worldwide:
fungal infections (histoplasmosis, coccidioidomycosis and South
American blastomycosis)

other important causes:

HYPOADRENOCORTICISM
AUTOIMMUNE
the most prevalent non-iatrogenic cause of Addison's
disease in the US
the adrenals are typically loaded with lymphocytes.
most of patients have autoantibodies against 21hydroxylase ("adrenal cortex antibodies)

leprosy,
now AIDS is too.

autoimmune adrenalitis often occurs jointly with Hashimoto's

thyroiditis, type I diabetes mellitus, vitiligo, gluten enteropathy,
and/or pernicious anemia ("autoimmune polyendocrine
deficiency syndrome II", "Schmidt's syndrome", etc.)

HYPOADRENOCORTICISM

HYPOADRENOCORTICISM

IATROGENIC
results from too-rapid withdrawal of glucocorticoid
medication,
post-adrenalectomy for breast cancer or Cushingism,
etc.,
ketoconazole or fluconazole (antifungal drug therapy),
removal of a "non-functioning adenoma" (rare).
CORTICOSTEROID INSUFFICIENCY OF CRITICAL
ILLNESS
a newly-characterized entity, seen especially in severe
systemic infections, in which the body does not put out
enough glucorticoid to handle the extra stress

SECONDARY HYPOADRENOCORTICISM
(ACTH deficiency)
patients almost always with lost of adenohypophysis and
"panhypopituitarism".
less often, selective, presumably autoimmune, loss of
the ACTH-producing cells.

OTHERS:
amyloidosis
congenital hypoplasia
hemochromatosis (a common disease still underdiagnosed in the U.S.)
sarcoidosis
DAX1 mutations
metastatic cancer to adrenal glands
anticoagulant therapy
CMV infection (in AIDS, it's almost the rule)
adrenal leukodystrophy (one male in 17,000)

SECONDARY HYPOADRENOCORTICISM
(ACTH deficiency)
Clinical picture ("Addisonian" patients):
weakness, nausea, and weight loss, and are usually
hypotensive and other complaints (like in most endocrine
patients, the problems are likely to appear "emotional")
In primary hypoadrenocorticism, the skin and buccal mucosa
will usually be hyperpigmented, due to increased ACTH
(MSH?)
Lab studies typically show hyponatremia, hyperkalemia,
metabolic acidosis, hypoglycemia, low serum cortisol, low
urinary 17-OH-steroids, and (most important) failure to
respond to various "stimulation tests" by increasing cortisol
output.
commonly patients die suddenly and unexpectedly before
anyone thinks of adrenocortical insufficiency

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WATERHOUSE-FRIDERICHSEN
SYNDROME

ACUTE HYPOADRENOCORTICISM
"adrenal apoplexy", "Addisonian crisis
Sudden collapse, often fatal
(opening of the peripheral vasculature and shock with high
cardiac output)

It may result from undiagnosed adrenal insufficiency

iatrogenic,
infection,
surgery,
or treatment

"adrenal apoplexy"
features hemorrhage, fibrin thrombi, and sometimes
necrosis in the adrenals in a setting of sepsis
is not rare (often overlooked (patients in shock
WITHOUT elevated serum cortisol)
occurs when there is overwhelming sepsis with
hemorrhage into, and destruction of, the adrenals,
patients develop: purpura, shock, and die in a few hours.
etiology:
classically the meningococcus,
staphylococci
pneumococci, and H. influenza

ADRENAL MEDULLA
around 10% of the normal adrenal by weight
produce "adrenalin" (epinephrine, also norepinephrine)
"Adrenal medullary hyperplasia" is a marker for MEN II
and a few rarities
any nodule bigger than 1 cm is a pheochromocytoma.
- pheochromocytoma (well-differentiated, adults)
- neuroblastoma (poorly-differentiated, children)

PHEOCHROMOCYTOMA
Clinic:
The infamous paroxysms of extreme hypertension,
accompanied by sweating, headache, and other
autonomic disturbances, probably result from physical
compression and/or ischemia
Even a tiny (1 gm) benign pheochromocytoma can make
a person very sick and will eventually cause death
Regardless of location and appearance, the patients will
report anxiety, headache, palpitations, "panic attacks",
sweating, dizziness, etc. (the basic problem is emotional.
"Pheo is a great imitator.")

PHEOCHROMOCYTOMA
"paraganglioma",
formerly "10% tumor":

in young patients (10-20 yrs)

cases involve both adrenals,
are familial,
and 10% metastasize

- is named for its colorful reaction in fixatives containing

chromic acid salts
- secrete norepinephrine (most common) and/or
epinephrine (usually less, and often others: dopamine,
serotonin, ACTH, somatostatin, neuropeptide Y, and/or
VIP)
- IHC: chromogranin+ and/or synaptophysin+

PHEOCHROMOCYTOMA
"pheochromocytoma" is defined to arise in the adrenal
medulla, however similar tumors (less common) arise
elsewhere are called "extra-adrenal paragangliomas."
Macro:
- are very bloody (because they are very vascular), and
often show fibrosis, calcification, cystic change, or even
fatty change
Microscopically:
resemble adrenal medulla, there are no histologic criteria
for malignancy, not even vascular invasion.
5-year survival rate with malignant pheo is around 50%