adrenal gland ll
( Cushing syndrome)
Dr. Haider Abdulridha
Cushing's syndrome (Hypercortisolism)
Cushing's syndrome is the clinical presentation associated with
excessive amounts of endogenous or exogenous
glucocorticoidsthat reflects excessive tissue exposure to cortisol.
By far the most common cause is iatrogenic, due to
prolonged administration of synthetic glucocorticoids such
as prednisolone. Non-iatrogenic Cushing's syndrome is
rare.
Classic features of Cushing's syndrome include weight gain,
plethora, hypertension, and striae
Because many of the signs and symptoms are nonspecific or
common in the general population, the diagnosis may be confused
with psychiatric disorders, polycystic ovary syndrome, the metabolic
syndrome, simple obesity, fibromyalgia, or acute illness
CLASSIFICATION OF CUSHING'S
SYNDROME
Non-ACTH-
ACTH-dependent
dependent
Pituitary adenoma Iatrogenic (chronic
secreting ACTH (i.e. glucocorticoid therapy,
Cushing's disease) e.g. for asthma)
Ectopic ACTH syndrome Adrenal adenoma
(e.g. bronchial carcinoid, Adrenal carcinoma
small-cell lung carcinoma)
latrogenic (ACTH therapy)
Aetiology
Amongst endogenous causes, pituitary-dependent cortisol excess (by convention,
called Cushing's disease) accounts for 80% of cases.
Both Cushing's disease and adrenal tumour are four times more common in
women than men.
In contrast, ectopic ACTH syndrome (often due to a small-cell carcinoma of the
bronchus) is more common in women than men .
Clinical Manifestations
Not all patients have all features
Many of these are not specific to Cushing's syndrome.
Features which have the best predictive value in favour of Cushing's syndrome
in an obese patient are bruising, myopathy and thin skin.
In all patients with features of Cushing's syndrome it is vital to exclude
iatrogenic causes. Even inhaled or topical glucocorticoid administration can
induce Cushing's syndrome in susceptible individuals
Gower sign
The patient is unable to
rise from a squatting
position, indicating
proximal muscle
weakness.
Thin skin and loss of
subcutaneous fat
Cushing’s disease before treatment, and
after treatment
Unlike pituitary tumours secreting ACTH, ectopic
tumours have no residual negative feedback
sensitivity to cortisol, and both ACTH and cortisol
levels are usually higher than with other causes.
Very high ACTH levels are associated with
marked pigmentation.
Very high cortisol cause hypokalaemic
alkalosis. Hypokalaemia aggravates both
myopathy and hyperglycaemia
Does the patient have Cushing's
syndrome?
There is no place for a random measurement of daytime plasma cortisol in the clinic in
either supporting or refuting the diagnosis.
Cushing's syndrome is confirmed by the demonstration of increased secretion of
cortisol (measured in urine) that fails to suppress with relatively low doses of
dexamethasone (measured in plasma or urine)
Loss of diurnal variation, with elevated evening plasma cortisol, is also characteristic of
Cushing's syndrome.
Measurement of salivary cortisol at bedtime or at midnight works just as well and is
more convenient.
When the tumour secreting ACTH is malignant (e.g. small-cell lung
carcinoma), then the onset is usually rapid and may be associated with
cachexia.
For these reasons, the classical features of Cushing's syndrome are less
common in ectopic ACTH syndrome
In Cushing's disease, the pituitary tumour is usually a microadenoma (<
10 mm in diameter); hence other features of a pituitary macroadenoma
(hypopituitarism, visual failure are rare
Diagnosis
Exogenous administration of glucocorticoid should be excluded before
screening for endogenous Cushing’s syndrome
The large number of tests available for Cushing's syndrome reflects the fact that no single
test is reliable and several are needed to establish the diagnosis.
There are two phases to the investigation:
1. confirmation of the presence or absence of Cushing's syndrome
2. differential diagnosis of its cause (e.g. pituitary, adrenal or ectopic).
What is the cause of the Cushing's
syndrome?
measurement of plasma ACTH is the key to establishing the differential diagnosis. In the
presence of excess cortisol secretion, an undetectable ACTH indicates an adrenal tumour,
while any detectable ACTH is pathological.
Pituitary tumours, but not ectopic tumours, retain some features of normal regulation of
ACTH secretion. Thus, in Cushing's disease ACTH secretion is suppressed by
dexamethasone.,
MRI with gadolinium contrast
Techniques enhancement detects around 70% of
for pituitary microadenomas secreting ACTH.
Venous catheterisation with
localisation measurement of inferior petrosal sinus
ACTH may be helpful in confirming
of tumours Cushing's disease if the MRI does not
secreting show a microadenoma.
CT or MRI detects most adrenal
ACTH or adenomas.
cortisol
TREATMENT
Untreated Cushing's syndrome has a very bad prognosis, has a
50% 5-year mortality with death from hypertension, myocardial
infarction, infection and heart failure.
Most patients are treated surgically with medical therapy given
for a few weeks prior to operation.
A number of drugs are used to inhibit corticosteroid biosynthesis,
including ketoconazole,metyrapone, and mitotane.
Choice of further treatment depends upon the cause
Trans-sphenoidal surgery with selective removal of the adenoma is the
treatment of choice.
If the operation is unsuccessful then bilateral adrenalectomy is an
alternative
Nelson's syndrome
Nelson's syndrome is increased pigmentation
(because of high levels of ACTH) associated with an
enlarging pituitary tumour, which occurs in about 20%
of cases after bilateral adrenalectomy for Cushing's
disease.
The Nelson's adenoma may be treated by pituitary
surgery and/or radiotherapy (unless given previously).
Adrenal tumours
Adrenal adenomas are removed via laparoscopy or a loin
[Link] carcinomas are resected if possible, the
tumour bed irradiated and the patient given the adrenolytic
drug mitotane. Cytotoxic chemotherapy may retard disease
progression in patients with metastases.
Ectopic ACTH syndrome
Localised tumours causing this syndrome (e.g. bronchial
carcinoid) shoul be removed.
During treatment or palliation of non-resectable
malignancies, it is important to reduce the severity of the
Cushing's syndrome using medical therapy
Aldosterone
⚫ Mineralocorticoid Exclusively synthesized in Z. Glomerulosa
⚫ Essential for life.
⚫ Regulates concentration of Na+ and K+.
⚫ Promotes sodium retention and Potassium elimination by the kidney.
⚫ Expands ECF volume.
⚫ Responds to changes in composition of plasma.
⚫ Linked to renin-angiotensin system of kidney
.
Regulation of Aldosterone Secretion
Control of Aldosterone
⚫ Low Blood Pressure, Low Na+.
◦ Juxtaglomerula cells release renin.
◦ Renin converts angiotensinogen to angiotensin I.
◦ Angiotensin I to angiotensin II by ACE.
◦ Angiotensin II stimulates adrenal gland to release aldosterone. ◦ Aldosterone
acts on kidney.
Aldosterone: Role in diseases
⚫Complete failure to secrete aldosterone leads to death (dehydration, low
blood volume).
⚫Hyperalsdosterone states: Contribute to hypertension associated with
increased blood volume.
Primary aldosteronism
Primary aldosteronism (hyperaldosteronism) is common, accounting for 5–
10% of all cases of hypertension.
Patients of all ages may be affected, but the peak incidence is between
30–60 years.
twice as common in women as in men
Excessive aldosterone production increases sodium retention
and suppresses plasma renin.
It increases renal potassium excretion that can lead to hypokalemia
Causes of
Hyperaldosteronism
Primary aldosteronism (Conn's Syndrome)
-Aldosteron-producing adenoma : Conn’s disease
-Idiopathic bilateral adernal hyperplasia
-Adrenal carcinoma < 1%
Most individuals with primary hyperaldosteronism have bilateral adrenal hyperplasia
(idiopathic hyperaldosteronism), while only a minority have an aldosterone-producing
adenoma (APA; Conn’s syndrome)
Clinical assessment
Many patients are asymptomatic, but they may have features of sodium retention or
potassium loss.
Sodium retention may cause oedema.
hypokalaemia causes muscle weakness (or even paralysis), polyuria (secondary to
renal tubular) and occasionally tetany .
Most patients have diastolic hypertension, which may be very severe,
Malignant hypertension is rare.
Symptoms and Signs
Hypersecretion of aldosterone may result in:
◦ Hypernatremia
◦ Hyperchlorhydria
◦ Hypervolemia
◦ Hypokalemic alkalosis manifested by:
episodic weakness
● Paresthesias
● transient paralysis
● tetany
◦ Diastolic hypertension with headache
◦ Hypokalemic nephropathy with polyuria & polydipsia
Signs, Symptoms, and Laboratory Data in
Primary Hyperaldosteronism
Summary slide
✔ Hypertension ✔ Hypokalemia
✔ Headache ✔ No Other Cause For
✔ Weakness/ Fatigue Hypertension Or Hypokalemia
✔ Paresthesia ✔ MetabolicAlkalosis
✔ Muscle Cramps ✔ Hyperaldosteronism
✔ Polyuria/ ✔ Hyporeninemia
Polydepsia
✔ Arrhythmias
Investigations
Biochemical
Plasma electrolytes may show hypokalaemia and elevated bicarbonate. Plasma
sodium is usually towards the upper end of the normal range in primary
mineralocorticoid excess, but is characteristically low in secondary
hyperaldosteronism
Indications of test of meniralocorticoid excess in
Hypertensive patient :
-hypokalemia.
-resistant Hypertension to conventional treatment .
-family history of early Hypertension .
-Hypertension in young age.
Investigations
Aldosterone / Renin Ratio
1. Normal & Patients With Essential Hypertension ? < 20
2. Primary Aldosteronism ? > 30
3. > 90% Sensitivity & Specificity
Localisation
☆Abdominal CT
☆adrenal vein catheterisation
with measurement of
aldosterone
Management
⚫Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are valuable
in treating both hypokalaemia and hypertension in all forms of mineralocorticoid
excess.
⚫ High doses of spironolactone (up to 400 mg/day) may be required .
⚫Amiloride (10–40 mg/day), which blocks the epithelial sodium channel regulated
by aldosterone, is an alternative.
⚫patients with Conn's adenoma, medical therapy is usually given for a few weeks
to normalise whole-body electrolyte balance before unilateral adrenalectomy.
⚫Laparoscopic surgery cures the biochemical abnormality but hypertension remains in
as many as 70% of cases, probably because of irreversible damage to the systemic
microcirculation
Adrenal Medulla:
A Modified Sympathetic
Ganglion
< Sympathetic stimulation
◦ Catecholamine release to blood
● Epinephrine
● Norepinephrine
◦ Travel to:
● Multiple targets
● Distant targets
Catecholamines:
Activity
⚫ Stimulates the “fight or flight” reaction
⚫ Increased plasma glucose levels
⚫ Increased cardiovascular function
⚫ Increased metabolic function
⚫ Decreased gastrointestinal
and genitourinary function
Phaeochromocytoma
and paraganglioma
⚫These are rare neuro-endocrine tumours that may secrete
catecholamines (adrenaline/epinephrine, noradrenaline/
norepinephrine).
⚫Approximately 80% of these tumours occur in the adrenal
medulla (phaeochromocytomas), while 20% arise elsewhere in the
body in sympathetic ganglia (paragangliomas.
⚫ 0.01-0.1% of HTN population
● Found in 0.5% of those screened
⚫M=F
⚫ 3rd to 5th decades of life
⚫ 40% associated with inherited disorders (neurofibromatosis , von
HLD,MEN 2 a and b)
⚫ Rare, investigate only if clinically suspicion:
●Signs or Symptoms
● Severe HTN, HTN crisis
● Refractory HTN (> 3 drugs)
● HTN present @ age < 20 or > 50 ?
● Adrenal lesion found on imaging (ex. Incidentaloma)
Pheo:‘Rule of 10’
10% extra-adrenal (closer to 15%)
10% occur in children
10% familial (closer to 20%)
10% bilateral or multiple (more if
familial)
10% recur (more if extra-adrenal)
10% malignant
10% discovered incidentally
Pheo: Signs & Symptoms
(very important)
⚫ The five P’s:
● Pressure (HTN) 90%
● Pain (Headache) 80%
● Perspiration 71%
● Palpitation 64%
● Pallor 42% ●Paroxysms (the sixth P!)
⚫ The Classical Triad:
● Pain (Headache), Perspiration, Palpitations
●Lack of all 3 virtually excluded diagnosis of pheo in a
series of > 21,0000 patients
These paroxysms generally last less than an hour and
may be precipitated by
surgery,
positional
changes,
exercise,
pregnancy,
urination (particularly bladder
pheochromocytomas), and various medications
(e.g., tricyclic antidepressants, opiates,
metoclopramide).
Clinical features of
phaeochromocytom
a paroxysmal; often postural drop of blood
•Hypertension (usually
pressure)
• Paroxysms of:
Pallor (occasionally flushing)Palpitations, sweating Headache
Anxiety (angor animi)
• Abdominal pain, vomiting • Constipation
• Weight loss
• Glucose intolerance
Investigations
❑ Excessive secretion of catecholamines
can be confirmed by measuring the hormones (epinephrine,
norepinephrine and dopamine) in plasma or their metabolites
(e.g. vanillyl-mandelic acid,VMA; conjugated metanephrine and
normetanephrine) in urine .(should be repeated due to high
false positive result)
❑ Clonidine suppression
May precipitate hypotensive shock!
Unlike normals, pheo patients won’t suppress their plasma norepi
with clonidine
Localization
Phaeochromocytomas are usually identified by abdominal CT or MRI .
Localisation of paragangliomas may be more difficult. Scintigraphy
using meta-iodobenzyl guanidine (MIBG) can be useful, particularly if
combined with CT, for adrenal phaeochromocytoma but is often
negative in paraganglioma.
18F-deoxyglucose PET is especially useful for detection of malignant
disease and for confirming an imaging abnormality as a
paraganglioma in an individual with underlying risk due to genetic
mutation.
Biochemical Tests: Summary
Management
Medical therapy is required to prepare the patient for surgery,
preferably for a minimum of 6 weeks to allow restoration of
normal plasma volume.
The most useful drug is the α-blocker phenoxybenzamine (10-20
mg orally 6-8-hourly). If α-blockade produces a marked tachycardia,
then a β-blocker (e.g. propranolol) or combined α- and β-antagonist
(e.g. labetalol) can be added.
On no account should the β-antagonist be given before the α-
antagonist, as it may cause a paradoxical rise in blood pressure due
to unopposed α-mediated vasoconstriction.
