Notes by dr Claudio Italiano
Definition
The hyperfunction of the adrenal cortex may be ACTH-dependent or independent of
ACTH regulation, p. for example, in the case of the production of cortisol by an
adenoma or a corticosurrenal carcinoma. Therapeutic administration of amounts
greater than the physiologic of exogenous cortisol or its synthetic analogs
suppresses the adrenocortical function and mimics the ACTH-independent
hyperfunction. The ACTH-dependent hyperfunction of the adrenal cortex may be due
to:
(1) hypersecretion of ACTH by the pituitary gland;
(2) ACTH secretion from a non-hypophyseal tumor, such as small-cell lung cancer
(ACTH ectopic syndrome); or
(3) administration of exogenous ACTH. While the term Cushing's syndrome has been
applied to the clinical picture deriving from an excess of cortisol regardless
of its cause, the hyperfunction of the adrenal cortex due to excess of
hypophyseal ACTH has often been referred to as Cushing's disease, thus implying
a specific anomaly. physiological. Patients with Cushing's disease may have a
basophilic or chromophobe adenoma of the pituitary gland.
I) Exogenous adrenocortical Hyperfunction
Mostly iatrogenic as a result of chronic treatment with glucocorticoids or ACTH,
the most frequent.
II) Endogenous adrenocortical Hyperfunction
Due to increased secretion of cortisol or ACTH: more rare.
1. ACTH-dependent form with secondary hyperplasia of the adrenal cortex:
a) central Cushing's syndrome (= Cushing's disease): it represents 70% of
endogenous Cushing's syndromes; especially affects women in the middle age. In
80% of cases it is a microadenoma of the lobe of the pituitary gland, not always
provable to neuroradiological techniques. In other cases hypothalamic primary
hypothesis is hypothesized. In some patients it is possible to find the presence
of auto-antibodies directed against cells of the anterior pituitary lobe
b) ectopic secretion (paraneoplasty) of ACTH: ACTH secretion by neoplasms, more
frequently from small cell bronchial carcinomas and carcinoids (more rarely
ectopic secretion of CRH)
c) Cushing's syndrome from ethylism: reversible after alcohol withdrawal.
2. ACTH-independent form (primitive form): Adrenal Cushing syndrome:
a) adrenal tumors producing cortisol; in adulthood predominantly adenomas, in
the child frequently carcinomas of the adrenal cortex
b) rarely, micronodular dysplasia or macronodular hyperplasia.
1. lipid metabolism: lunar facies with plethora, taurine neck, central obesity,
hypercholesterolemia
2. protein metabolism: osteoporosis, with evtr. bone pain, muscle hypotrophy,
adynamia
3. glucose metabolism: tendency to diabetes
4. haematopoietic system: leukocytes, platelets and increased erythrocytes,
eosinophils and decreased lymphocytes
5. hypertension (85%)
6. predisposition to acne, furunculosis, ulcer, appearance of red skin
striations, atrophy of the skin ("parchment" skin).
(Differential diagnosis: clear skin striations in the case of true obesity)
7. virilization, hirsutism, menstrual cycle disorders
8. in the child stunting growth
9. psychic disorders (eg psychotic disorders)
l0. hypokalemia (5%), secondary to mineralpropericoid hyperproduction (relatively
rare). It must be suspected of an ectopic ACTH production or a neoplasm of the
adrenal cortex.
Primitive Adrenocortical Hyperfunctiondue to the presence of adrenal adenomas mostly
involves an increase in glucocorticoids only.
Secondary Adrenocortical Hyperfunction is characterized by an increased ACTH
secretion with bilateral global hyperplasia of the adrenal cortex, which is much
more pronounced with carcinomas; there is also an increase in androgens (and
less than aldosterone), so that in this case there are symptoms conditioned by
excess of androgens (virilization, hirsutism, menstrual disorders, etc.).
purple striae |
- obesity (inhibition test with dexamethasone: normal)
- incidentaloma> sunenal: randomly discovered adrenal tumor (more frequently it
is a non-secretory adenoma of the adrenal cortex) - hypercortisolemia in the
case of contraceptive use, increased cortisol binding globulin (CBG), with
increased hormone concentration total, but normality of the concentration of the
free hormone (moreover, test of inhibition with dexamethasone: normal).
Plasma cortisol normally ranges from 5 to 25 mcg / dl (138 to 690 nmol / l) in
the early morning hours (between 6 and 8) and gradually decreases to <10 mcg /
dl (<276 nmol / l) towards evening (from 18 onwards). Patients with Cushing's
syndrome usually have elevated levels of cortisol in the morning and lose the
normal diurnal decline in hormone production, so that the plasma cortisol serum
levels are higher than normal and the total cortisol production in 24h is high.
Individual determinations of plasma cortisol can be difficult to interpret due
to the episodic secretion responsible for the wide variability of normal values.
Plasma cortisol may be falsely elevated in patients with a congenital increase
in corticosteroid-binding globulin, but diurnal variation in these subjects is
normal. Free urinary cortisol, the best parameter for the evaluation of urinary
excretion (normal values from 20 to 100 mcg / 24 h [55.2 to 276 nmol / 24 h]),
increased> 120 mcg / 24 h (> 331 nmol / 24 h) in patients with Cushing and is
only minimally increased in obese patients, where it is <150 mcg / 24 h (<414
nmol / 24h).
- inhibition test with low dose dexamethasone: the administration of 2 mg of
dexamethasone to triozine determines a partial inhibition of the plasma cortisol
measured at 8.00 am the next morning (in normal <3 μg / dl.) Moreover, the test
can sometimes be positive in patients with endogenous depression, under stress,
after oral contraceptive (increased CBG) or antiepileptic drugs.
- increase of free cortisol in 24-hour urine, suppression of circadian rhythm of
plasma cortisol
b) etiological framing of hyper-adenocortalism
1. CRH test: ACTH determination before and after CRH administration
2. inhibition test with dexamethasone at higher doses
3. localization diagnostics.Inhibition test with high dose dexamethasone:
It is useful for differentiating an ACTH-dependent cushing syndrome from a
non-dependent. In the case of central Cushing's syndrome, the administration of
dexamethasone at a dose of 2 mgx 4 for 2 days determines a 50% inhibition of
cortisolemia. In case of adrenal tumor or ectopic Cushing's syndrome, this
inhibition does not occur. With this test it is not possible to distinguish
between hypophysical microadenoma and hypothalamic hyperfunction (the adenomas
of the anterior pituitary lobe in fact respond, to a certain extent, to the
fee-back mechanism).
stimulation test with CRH:
after CRH administration, in the case of central Cushing's syndrome, there is an
increase in ACTH (this does not occur in the presence of neoplastic Cushing's
syndrome and adrenal cortex tumors).
Complementary diagnostic investigations
- in case of hypothalamic hyperfunction or adenoma of the anterior pituitary
lobe, a blood sample from the petrous sinus or the internal jugular vein
documents, after stimulation with CRH, a concentration gradient of the ACTH, ie
a concentration difference with respect to the peripheral blood; this does not
happen in the case of paraneoplastic Cushing's syndrome
- in the case of paraneoplastic ACTH syndrome, the so-called lipotropin (LPH), a
metabolite of ACTH synthesis that can be used as a neoplastic marker, can be
found in some patients.
a) Adrenal cortex tumors: adrenalectomy;
after surgery, temporary steroid replacement therapy (up to 2 years) is
necessary, until the contralateral atrophic adrenal has reacquired a normal
function. b) Hypothalamic-hypophyseal Cushing syndrome:
- the first choice therapy is the transnasal tran-sphenoid surgical excision of
the adenoma
- in case of contraindications to the intervention or of its failure: radiant
therapy with protons on the pituitary gland.
Successful verification of the intervention: normalization of the concentration
of ACTH.
c) Inoperable carcinoma of the adrenal cortex and paraneoplastic ectopic
production of ACTH:
use of adrenostatic substances (blocking of cortisol synthesis):
- ketoconazole + octreotide
- o-p-DDD
- aminoglutethimide
- metopirone
- glucocorticoid antagonists (RU486).
2. Non-secretory incidentalomas with a diameter <3 cm and without progressive growth, are usually not operated, but only subjected to regular checks.
Test |
Cushing syndrome central = hyperfunction hypothalamic and lobe front of the hypophysis |
Paraneoplastic ectopic Cushing syndrome |
Corticosurrenal tumor = syndrome of Cushing |
ACTH of the serum |
Normal or increased |
Very high |
reduced |
Increase of ACTH after administration of CRH |
yes |
No |
No |
Decreased cortisol after high dose dexamethasone |
yes |
No |
|
Localization diagnostics |
Rx TAC RMN of the sella turcica (microadenoma not always demonstrable) |
Tumor research |
Ultrasound, CT scan, MRI, angiography, scintigraphy of the adrenal cortex |