Download ADRENAL GLANDS DISEASES

ADRENAL GLANDS DISEASES
TUCOM
Internal Medicine
Dr. Hasan.I.Sultan
Functional anatomy and physiology
The adrenal glands lie at the superior pole of each
kidney. Each adrenal gland weighs approximately
of 4-5 g.
composed of two distinct regions: the cortex and
the medulla
adrenal cortex: represents 90% of adrenal gland,
consists of three anatomic zones;
•
Outer zona glomerulosa, which secretes the
mineralocorticoid aldosterone
• Intermediate zona fasciculata, which secretes
cortisol
• Inner zona reticularis, which secretes adrenal
androgens
The adrenal medulla; represents 10% of adrenal
gland, its the center of the adrenal gland, which
secrets catecholamines: epinephrine,
norepinephrine and dopamine in response to
stress and activation of sympathetic nervous
system.
• The synthesis of all steroid hormones begins with
cholesterol and is catalyzed by a series of
regulated, enzyme-mediated reactions.
Adrenal gland is under control of:
1. Hypothalamic-pituitary-adrenal (HPA) axis;
regulate cortisol and androgen production.
2. Renin-angiotensin-aldosterone (RAA) system.
Regulation of the
hypothalamicpituitary-adrenal
(HPA) axis. CRH,
corticotropinreleasing
hormone; ACTH,
adrenocorticotro
pic hormone.
Glucocorticoids;
o Cortisol is the major glucocorticoid in humans
o Highest in the morning and lowest in the middle of
the night
o Increase in state of stress, including any illness
o Affect metabolism, cardiovascular function,
behavior, and the inflammatory/immune response
o Its secretion is stimulated by (ACTH).
o Cortisol can also activate mineralocorticoid
receptors, but it normally inhibited by 11β-HSD2.
Prereceptor inactivation of cortisol and mineralocorticoid receptor
action.
Mineralocorticoids
Aldosterone is the body's most important sodiumretaining hormone
Under influence of renin-angiotensin-aldosterone
system
Renin secretion from the juxtaglomerular
apparatus in the kidney is stimulated by low
perfusion pressure in the afferent arteriole, low
sodium concentrations at the macula densa, or
increased sympathetic nerve activity.
Regulation of
the reninangiotensinaldosterone
(RAA) system.
Adrenal androgens
Are secreted in response to ACTH
Initiation of puberty (the adrenarche).
Excess adrenal androgen secretion results in acne,
hirsutism, and virilization
Catecholamines:
 Are produced mainly by the chromaffin cells of the
adrenal medulla and the sympathetic nervous fibers.
 Which includes noradrenaline (norepinephrine),
adrenaline (epinephrine) and dopamine.
 Prepare the body for physical activity (fight or flight
response). Some typical effects are increases in heart
rate, blood pressure, blood glucose, and sympathetic
activation.
 No clinical consequences attributable to deficiency of
circulating catecholamines.
Disorders of adrenal glands
1. Cushing's syndrome.
2. Adrenal insufficiency.
3. Other adrenal disease including;
a. Congenital adrenal hyperplasia
b. Primary hyperaldosteronism
c. Phaeochromocytoma
Cushing's syndrome
 Cushing's syndrome is a syndrome that reflects
excessive tissue exposure to cortisol.
 Most common cause is iatrogenic; prolonged
administration of synthetic glucocorticoids
 Non-iatrogenic Cushing's syndrome is rare
 Cushing's disease and adrenal tumour are four
times more common in women
 Ectopic ACTH syndrome is more common in men
Aetiology
ACTH-dependent
• Pituitary adenoma secret ACTH (Cushing's disease)
• Ectopic ACTH syndrome (e.g. bronchial carcinoid,
small-cell lung carcinoma, pancreatic neuroendocrine tumour)
• latrogenic (ACTH therapy)
Non-ACTH-dependent
• Iatrogenic (chronic glucocorticoid therapy for
asthma)
• Adrenal adenoma
• Adrenal carcinoma
Clinical Manifestations
• Fat redistribution (dorsocervical and
supraclavicular fat pads, centripetal obesity,
weight gain) (95%)
• Menstrual irregularities (80% of affected women)
• Thin skin/plethora (80%)
• Moon facies (75%)
• Increased appetite (75%)
• Hypertension (75%)
• Altered mentation (poor concentration, decreased
memory, euphoria) (70%)
• Diabetes mellitus/glucose intolerance (65%),
Striae (65%), Hirsutism (65%), Proximal
muscle weakness (60%), Psychological
disturbances (emotional lability, depression,
mania, psychosis) (50%), Decreased
libido/impotence (50%).
• Acne (45%), Osteoporosis/pathologic
fractures (40%), Virilization (in women)
(40%), Easy bruisability (40%), Poor wound
healing (40%), Edema (20%), Increased
infections (10%) and Cataracts (5%).
Ectopic ACTH syndrome
Very high ACTH level (no negative feedback) is
associated with marked pigmentation.
Very high cortisol levels overcome the barrier of
11β-HSD2 in the kidney and cause hypokalemic
alkalosis that leads to myopathy and
hyperglycemia (by inhibiting insulin secretion).
The onset is usually rapid and may be associated
with cachexia.
Prereceptor inactivation of cortisol and mineralocorticoid receptor
action.
Investigations
• Whether the patient has Cushing's syndrome, and
to elucidate the aetiology.
• There is no place for a random measurement of
daytime plasma cortisol.
A-Does the patient have Cushing's syndrome?
1-Urine free cortisol; 24-hr timed collection, normal
range depends on assay
50 μg/24 hours --- normal.
100 and 500 μg/24 hours --- Cushing's disease
greater than 500 μg/24 hours --- ectopic ACTH
syndrome and cortisol-secreting adrenal
adenomas or carcinomas.
2-Diurnal rhythm of plasma cortisol; the plasma
concentration is highest in the early morning
(between 6:00 and 8:00 AM)= 8- 25 μg/dL and lowest
around midnight= less than 5 μg/dL.
3-Overnight dexamethasone suppression test (suspected
Cushing's syndrome); 1 mg orally at midnight;
measure plasma cortisol at 0800-0900 hrs. Plasma
cortisol < 60 nmol/l (< 2.2 μg/dl) excludes Cushing's.
4-Low-dose dexamethasone suppression test (to
confirm Cushing's syndrome); 0.5 mg 6-hourly for 48
hrs; sample 24-hr urine cortisol during second day and
0900-hr plasma cortisol after 48 hrs
Urine cortisol < 100 nmol/day (36 μg/day) or plasma
cortisol < 60 nmol/l (< 2.2 μg/dl) excludes Cushing's
5-Insulin tolerance test; Peak plasma cortisol > 120%
of baseline excludes Cushing's.
B-What is the cause of the Cushing's syndrome?
1-Basal ACTH levels; are normal or elevated in
Cushing's disease and the ectopic ACTH syndrome
and are suppressed in adrenal Cushing's syndrome.
2-High-dose dexamethasone suppression test; 2 mg
6-hourly for 48 hrs; sample 24-hr urine cortisol at
baseline and during second day
• Urine cortisol < 50% of basal suggests pituitarydependent disease.
• > 50% of basal suggests ectopic ACTH syndrome
3-Corticotrophin-releasing hormone test; 100 μg
ovine CRH i.v. and monitor plasma ACTH and
cortisol for 2 hrs Peak plasma cortisol > 120%
and/or ACTH > 150% of basal values suggests
pituitary-dependent disease; lesser responses
suggest ectopic ACTH syndrome.
4- Inferior petrosal sinus sampling;
Catheters placed in both inferior petrosal sinuses
and simultaneous sampling from these and
peripheral blood for ACTH.
• > 200% compared to peripheral ACTH, suggests
pituitary-dependent disease.
• < 150% suggests ectopic ACTH syndrome.
The test is usually
performed by vascular
radiologists on an
outpatient basis. With local
anesthesia, femoral
catheters are advanced
bilaterally up to the inferior
petrosal sinuses. After
confirmation of catheter
location by fluoroscopy,
several ACTH samples are
drawn simultaneously from
the right and left at the
same time that a peripheral
level is being drawn from an
arm vein. CRH can also be
injected to provoke ACTH
release. Samples are then
assayed for ACTH, and the
pituitary-to-peripheral
ratios are calculated.
5-Imaging
• Pituitary gland MRI with gadolinium for localizing a
pituitary microadenomas.
• CT or MRI detects adrenal adenomas or
carcinomas
• CXR ,CT chest or abdomen.
Management
1- Medical therapy; given for a few weeks prior to
operation. (inhibit corticosteroid biosynthesis)
including metyrapone, aminoglutethimide and
ketoconazole.
2- Cushing's disease; Trans-sphenoidal surgery with
selective removal of the adenoma is the treatment
of choice.
Nelson's syndrome (bilateral adrenalectomy in
cushing's disease) that leads to pituitary
macroadenoma and very high ACTH levels causing
pigmentation. Nelson's syndrome can be
prevented by pituitary irradiation.
3- Adrenal tumours
• Adenomas: are removed surgically
• Carcinomas are resected if possible + tumour bed
irradiated + adrenolytic drug mitotane
• Metastases; cytotoxic chemotherapy
4- Ectopic ACTH syndrome
• Localised tumours causing this syndrome (e.g.
bronchial carcinoid) should be removed
• Non-resectable malignancies, using medical
therapy
Adrenal insufficiency
• Adrenal insufficiency results from inadequate
secretion of cortisol and/or aldosterone.
• A high index of suspicion is therefore required in
patients with unexplained fatigue, hyponatraemia
or hypotension.
Aetiology; The most common cause is due to an
ACTH deficiency (i.e. secondary adrenocortical
failure), usually because of inappropriate
withdrawal of chronic glucocorticoid therapy.
Secondary (↓ACTH);
 Withdrawal of suppressive glucocorticoid therapy
 Hypothalamic or pituitary disease
Primary (↑ACTH); usually describe as Addison's
disease
Common causes;
 Autoimmune
• Sporadic
• Polyglandular syndromes
 Tuberculosis
 HIV/AIDS
 Metastatic carcinoma
 Bilateral adrenalectomy
Rare causes;
Lymphoma
Intra-adrenal haemorrhage (WaterhouseFriedrichsen syndrome following meningococcal
septicaemia)
Amyloidosis
Haemochromatosis
Corticosteroid biosynthetic enzyme defects;
Congenital adrenal hyperplasias
Drugs: Aminoglutethimide, metyrapone,
ketoconazole, etomidate etc.
Clinical features of adrenal insufficiency
Glucocorticoid
insufficiency
Withdrawal of
+
exogenous
glucocorticoid
Hypopituitarism
+
Addison's disease
+
Congenit adrenal
+
hyperplasia (21
OHase deficiency)
Clinical features Weight loss Malaise
Weakness Anorexia
Nausea Vomiting
diarrhoea or
constipation
Postural
hypotension
Shock
Hypoglycaemia
Hyponatraemia
(dilutional)
Hypercalcaemia
Mineralocortico ACTH excess
id insufficiency
Adren androgen
insufficiency
-
-
+
+
+
+
+
+
+
-
Hypotension
Shock
Hyponatraemia
(depletional)
Hyperkalaemia
Pigmentation
Sun-exposed areas
Pressure areas, e.g.
elbows, knees
Palmar creases,
knuckles
Mucous
membranes
Conjunctivae
Recent scars
Decreased body
hair and loss of
libido, especially
in female
Acute adrenal crisis
• Circulatory shock with severe hypotension
• Hyponatraemia, hyperkalaemia and, in some
instances, hypoglycaemia and hypercalcaemia.
• Muscle cramps, nausea, vomiting, diarrhoea and
unexplained fever may be present.
• The crisis is often precipitated by intercurrent
disease, surgery or infection.
• Treatment should not be delayed pending results
of investigations.
Investigations
A- Assessment of glucocorticoids;
1- Random plasma cortisol is usually low in patients
with adrenal insufficiency, but it may be within the
normal range yet inappropriately low for a
seriously ill patient.
2- ACTH stimulation test
Diagnosis of primary or secondary adrenal
insufficiency
Assessment of hypothalamic-pituitary-adrenal axis in
patients taking suppressive glucocorticoid therapy
• Dose; 250 μg ACTH (Synacthen) by I.M. injection at
any time of day
• 0 and 30 minutes for plasma cortisol
• Normal subjects plasma cortisol > 460 nmol/l
(∼170 μg/dl) either at baseline or at 30 minutes
B- Assessment of mineralocorticoids;
plasma renin activity is high, with plasma
aldosterone is low. Hyponatraemia and
Hyperkalaemia.
Tuberculosis cause adrenal calcification seen on plain abdominal X-ray
Management
1- Glucocorticoid replacement;
Cortisol (hydrocortisone) is the drug of choice,
given by mouth, 15 mg on waking and 5 mg at
∼1800 hrs.
An adrenal crisis; intravenous hydrocortisone
succinate 100 mg and intravenous fluid (normal
saline and 10% dextrose for hypoglycaemia).
Parenteral hydrocortisone should be continued
(100 mg I.M. 6-hourly) until gastrointestinal
symptoms abate before starting oral therapy.
2- Mineralocorticoid replacement;
fludrocortisone from being metabolised by 11βHSD2 and thereby confers a longer half-life and
access to mineralocorticoid receptors. The usual
dose is 0.05-0.1 mg daily
In adrenal crisis, however, rapid replacement of
sodium deficiency is more important than
administration of fludrocortisone. Intravenous
saline should be infused as required to normalise
haemodynamic indices
Advice to patients on glucocorticoid replacement
1-Intercurrent stress; e.g. Febrile illness-double dose
of hydrocortisone
2-Surgery;
Minor operation; hydrocortisone 100 mg i.m. with
pre-medication
Major operation; hydrocortisone 100 mg 6-hourly
for 24 hours, then 50 mg i.m. 6-hourly until ready
to take tablets
3-Vomiting; Must have parenteral hydrocortisone if
unable to take by mouth
4- Steroid card; Patient should carry this at all times
give information regarding diagnosis, steroid, dose
and doctor
5- Bracelet; Patients should be encouraged to buy
one of these
Primary hyperaldosteronism
Hypertensive patients with hypokalaemia (including
hypokalaemia induced by thiazide diuretics), poor
control of blood pressure with conventional
therapy, or presentation at a young age, or family
history of early onset hypertension.
Most patients with Primary hyperaldosteronism
have Idiopathic bilateral adrenal hyperplasia, while
only minority have adrenal adenoma secreting
aldosterone (Conn's syndrome)
Clinical features
• Asymptomatic
• Sodium retention may cause oedema.
• Hypokalaemia causes muscle weakness (or even
paralysis, especially in Chinese), polyuria
(secondary to renal tubular damage which
produces nephrogenic diabetes insipidus) and
occasionally tetany (because of associated
metabolic alkalosis and low ionised calcium).
• B.P is elevated but accelareted phase is rare.
Investigations
Biochemical;
• Hypokalaemia and elevated bicarbonate. Plasma
sodium is usually in upper end of normal range.
• Measurements of plasma renin activity and
aldosterone . renin is low and aldosterone level is
high.
Localisation;
Abdominal CT: to localize the tumour.
adrenal CT should only be performed when the
biochemistry supports the diagnosis of adrenal
tumour.
Conn's adenoma.
A-CT scan of left adrenal adenoma (arrow).
B- 131Iodo-norcholesterol scan showing uptake in left adrenal adenoma (arrow).
C-The tumour is 'canary yellow' because of intracellular lipid accumulation.
Management
Idiopathic bilateral adrenal hyperplasia:
Mineralocorticoid receptor antagonists
(spironolactone or eplerenone) or potassium
sparing diuretics are used.
Conn's adenoma;
Medical therapy few weeks before unilateral
adrenalectomy.
Phaeochromocytoma
 This is a rare tumour of
chromaffin tissue that
secretes catecholamines and
is responsible for less than
0.1% of cases of
hypertension.
 Rule of tens
 ∼10% are malignant
 ∼10% are extra-adrenal (i.e.
elsewhere in the sympathetic
chain)
 ∼10% are familial
Clinical features
These depend on the pattern of catecholamine secretion
• Hypertension (usually paroxysmal; often postural drop
of blood pressure)
• Paroxysms of:
–
–
–
–
–
•
•
•
•
Pallor (occasionally flushing)
Palpitations
Sweating
Headache
Anxiety (fear of death-angor animi)
Abdominal pain, vomiting
Constipation
Weight loss
Glucose intolerance
• Complication of hypertension: e.g. stroke,
myocardial infarction, left ventricular failure,
hypertensive retinopathy or accelerated-phase
hypertension.
• Familial syndromes associated with
phaeochromocytoma including neurofibromatosis,
Von Hippel-Lindau syndrome and MEN type 2.
Investigations
 Biochemical; Measuring the hormones
(adrenaline/epinephrine,
noradrenaline/norepinephrine and dopamine) in
plasma or their metabolites (e.g. vanillyl-mandelic
acid (VMA), conjugated metanephrine and
normetanephrine) in urine.
• Samples should be collected during a period of
attacks.
 Localisation; abdominal CT or MRI.
CT scan of abdomen showing large left adrenal phaeochromocytoma.
The normal right adrenal (white arrow) contrasts with the large heterogeneous
phaeochromocytoma arising from the left adrenal gland (black arrows).
Mottled brown tan mass is the neoplasm filling up the adrenal medulla.
• Blue arrow points to residual normal medulla.
• Yellow arrows point to golden yellow adrenal cortex.
• Black discoloration around the specimen is india ink applied to assess the margins of the
specimen
Management
• Surgery is the curative treatment
• Patient should be prepared before surgery for at
least 6 weeks with oral α-blocker
phenoxybenzamine and restoration of normal
plasma volume.
• During surgery sodium nitroprusside and the
short-acting α-antagonist phentolamine are useful
in controlling hypertensive episodes which may
result from anaesthetic induction or tumour
mobilisation
• Post-operative hypotension may occur and require
volume expansion and, very occasionally,
noradrenaline (norepinephrine) infusion.
Thanks
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