re-view of physiology of adrenal cortex. congenital adrenal hyperplasia. Disorder of adrenocortical insufficiency - primary and secondary adrenocortical insufficiency.pathology of primary insufficiency. hypoaldosteronism. ACTH stimulation test.
multi day ACTH stimulation test.
4. Adrenal Cortex Disorder
It’s condition that interfere with the normal function of
the adrenal glands
Diseases of Adrenal cortex are classified as resulting
from
hypofunction or hyperfunction of the adrenal
cortex.
Nonfunctional adrenal tumors are diagnosed
histologically
5. Disorders of Adrenocortical
Insufficiency
Deficient adrenal production of glucocorticoids or
mineralocorticoids results in
adrenocortical insufficiency,
which is either the consequence of destruction or dysfunction of
the cortex (primary adrenocortical insufficiency, or Addison
disease)
Or secondary to deficient pituitary ACTH secretion (secondary
adrenocortical insufficiency).
Adrenal insufficiency causing combined mineralocorticoid
and glucocorticoid deficiency is a rare disorder
with a prevalence of only 4 to 11 cases per 100,000
Thomas Addison fist reported hypofunction of the adrenal
cortex in 1855.
6. PRIMARY ADRENOCORTICAL
INSUFFICIENCY
( “ Addison’s disease “ )
Destruction of adrenal cortex
The etiology of primary adrenocortical
insufficiency has changed over time.
Prior to 1920, tuberculosis was the major
cause of adrenocortical insufficiency.
Since 1950, autoimmune adrenalitis with
adrenal atrophy has accounted for about 80%
of cases.
Associated with a high incidence of other
immunologic and autoimmune endocrine
disorders
Characterized by loss of both glucocorticoid
and mineralocorticoid secretion
7. SECONDARY ADRENOCORTICAL
INSUFFICIENCY
Dysfunction of Hypothalamic
pituitary component
ACTH deficiency is the primary event and
leads to decreased cortisol and adrenal
androgen secretion.
Aldosterone secretion remains normal
except in a few cases.
Characterized by loss of
glucocorticoid secretion only
9. Autoimmune
Isolated autoimmune adrenalitis
Autoimmune polyendocrine syndrome (
APS)
Infections
Tuberculosis , Fungal infections
Cytomegalovirus, HIV ,
Infiltrations
Metastases , lymphomas
Amyloidosis , Hemochromatosis
Haemorrhage WaterhouseFriderichsen
syndrome ( after meningococcal
septicemia)
Adrenoleukodystrophy Congenital
adrenal hyperplasia Bilateral
adrenalectomy
Drug induced – mitotane, ketoconazole
Exogenous glucocorticoid therapy
Pituitary tumours
Pituitary irradiation and surgery
Hypopituitarism
Mass lesions affecting HP region like
craniopharyngioma , meningioma
Pituitary apoplexy Haemorrhage
, infarction consequent to major blood loss
, Sheehan syndrome
Pituitary infiltration
(tuberculosis, sarcoid, eosinophilic
granuloma, metastases)
Isolated ACTH deficiency
POMC deficiency
PRIMARY ADRENOCORTICAL
INSUFFICIENCY
SECONDARY ADRENOCORTICAL
INSUFFICIENCY
Causes Causes
10. Pathophysiology of Primary
Adrenal Insufficiency
In primary adrenal insufficiency, although the above mentioned causes
lead to gradual destruction of the adrenal cortex, the symptoms and
signs of the disease appear when the loss of adrenocortical tissue is
higher than 90% .
At the molecular and cellular level, a viral infection, even subclinical, or an
excessive tissue response to inflammatory signals may potentially lead to
apoptosis or necrosis of adrenocortical cells.
Cellular components, such as 21OH-derived peptides, trigger the
activation of local dendritic cells, which then transport and present these
antigens to CD4+ Th1 cells.
Upon activation, CD4+ Th1 cells help the committed clonal expansion of
cytotoxic lymphocytes and autoreactive B cells releasing antibodies
against 21-hydroxylase and possibly other antibodies.
11. Pathophysiology of Primary
Adrenal Insufficiency
The gradual destruction of adrenocortical tissue seems to be
mediated by four distinct and complementary molecular
mechanisms:
direct cytotoxicity by lymphocytes that induce apoptosis;
direct cytotoxic actions by IFN-γ and lymphotoxin-α released
by activated CD4+ Th1 cells;
cellular cytotoxicity by autoantibodies or by autoantibody-
mediated activation of the complement system; and
cytotoxic effects of inflammatory cytokines (IL-1β, TNF-α) and
free radicals (superoxide, NO) secreted by
monocytes/macrophages or by the adrenal cells
12. Cortisol deficiency causes weak
ness, fatigue, anorexia, nausea and
vomiting, hypotension,
hyponatremia, and hypoglycemia.
Mineralocorticoid deficiency
produces
renal sodium wasting and potassium
retention and can lead to
severe dehydration, hypotension,
hyponatremia, hyperkalemia,
and acidosis.
Hyperpigmentation is the classic
physical finding
Prominent features are
weakness, lethargy, easy
fatigability, anorexia,
nausea, and occasionally
vomiting.
Hyperpigmentation not
present.
Volume depletion,
dehydration, and
hyperkalemia are usually
absent
PRIMARY ADRENOCORTICAL
INSUFFICIENCY
SECONDARY ADRENOCORTICAL
INSUFFICIENCY
Clinical Features Clinical Features
13. Hyperpigmentation in areas of increased friction – palmar creases , dorsal
foot oral mucosa and sun exposed areas– Seen in Primary adrenal
insufficiency ; due to excess of ACTH ( and POMC derivatives )
14. Adrenal crisis
Adrenal crisis is a potentially life-threatening medical condition
requiring immediate emergency treatment
Acute adrenal crisis represents a state of acute adrenocortical
insufficiency and occurs in patients with Addison disease who are
exposed to the stress of infection, trauma, surgery, or dehydration
due to salt deprivation, vomiting, or diarrhea
Clinical features;
Hypotension and shock
Fever
Dehydration, volume depletion
Nausea, vomiting, anorexia
Weakness, apathy, depressed mentation
Hypoglycemia
15. Adrenal crisis
Adrenal crisis may be the result of :
either previously undiagnosed or untreated Addison's disease
a disease process suddenly affecting adrenal function (such as
bleeding from the adrenal glands in Waterhouse-Friderichsen
syndrome),
suddenly stopping intake of glucocorticoids
an intercurrent problem (e.g. infection, trauma, in fact any form of
physical or mental stress) in someone known to have Addison's
disease, congenital adrenal hyperplasia(CAH), or other form of
primary adrenal insufficiency.
Diagnosis :
hyponatremia
Hyperkalemia
Lymphocytosis
Eosinophilia
hypoglycemia
20. Laboratory Diagnosis of PRIMARY
ADRENOCORTICAL INSUFFICIENCY
Hyponatremia and hyperkalemia
Hypoglycemia
Aldosterone ,DHEA ,DHEAS and Androsterone - Low
Testosterone – Normal in Man but low in female
Increased plasma renin concentration
Increased Angiotensin II
Basal plasma ACTH concentrations greater than 150 pg/mL, along
with serum cortisol concentrations less than 5 µg/dL,
are diagnostic of adrenal insufficiency
A subnormal cortisol response in the ACTH (Cosyntropin)
stimulation test supports
thediagnosis of primary adrenal insufficiency
Hematologic manifestations
Normocytic, Normochromic anemia, Neutropenia, Eosinophilia, and
a relative lymphocytosis.
21. Laboratory Diagnosis of Secondary
ADRENOCORTICAL INSUFFICIENCY
Same as Primary Adrenal Insufficiency Excepts:
ACTH- Not elevated
Hyperkalemia does not occurs
Plasma renin level are usually normal
but chronic secondary adrenal insufficiency
both plasma rennin activity and aldosterone
concentration may be low.
22. ALGORITHM FOR THE MANAGEMENT OF PATIENTS WITH
SUSPECTED ADRENOCORTICAL DEFICIENCY
Clinical suspicion of ADRENOCORTICAL
insufficiency
Weight loss, fatigue , postural hypotension , hyperpigmentation , hyponatremia
Confirmatory test – Cosyntropin/ synacthen test
Serum cortisol measured 30-60 mins after 250ug of short acting ACTH
Adrenal insufficiency Normal adrenal function
Cortisol < 18-20µg/dl Cortisol > 18-20µg/dl
Primary
adrenal inefficiency
Secondary
Adrenal insufficiency
Plasma ACTH
Normal / undetectable
Increased( >100pg/dL)
23. Primary Adrenocortical
inefficiency
High ACTH , low aldosterone , low
renin
Adrenal glands enlarged
Secondary Adrenocortical
inefficiency
Low ACTH , normal aldosterone
, normal renin
CT Adrenals
Normal or atrophic
Hypothalamo- Pituitary Mass
lesion
Mass
lesion
MRI pituitary
No mass
History of exogenous
glucocorticoids
History of headache ? Trauma ?
( for pituitary apoplexy )
Consider isolated ACTH
deficiency
25. Hypofunction of the adrenal cortex
Hypoaldosteronism
Deficient aldosterone production occurs in conditions other
than Addison disease
Isolated aldosterone deficiency accompanied by normal cortisol
production is seen in patients with
(1) inadequate production of renin by the kidney, which leads
to secondary aldosterone deficiency (hyporeninemic
hypoaldosteronism);
(2) inherited enzyme defects in aldosterone biosynthesis (e.g.,
CYP11B2 defiiency; CYP11B2 = P450 aldo);
(3) acquired forms of primary aldosterone deficiency (heparin
therapy and post surgery)
26. Hypoaldosteronism
Resulting metabolic changes are hyperkalemia and
hyponatremia, often with hypochloremia acidosis.
Mild or moderate volume depletion, often with
postural or unprovoked hypotension, may also occur.
Hyporeninemic hypoaldosteronism can be established
by demonstrating failure of both plasma renin and
aldosterone
to increase in response to furosemide
stimulation
28. DYNAMIC TESTS OF ADRENAL
FUNCTION
Dynamic tests are often considered as the backbone of
endocrinology.
Involve the use of an exogenous agent to manipulate the body's
hormonal milieu
for the diagnosis and characterization of an endocrine
disorder.
In general, if a deficiency is suspected a stimulation test should
be used
If excess is considered likely, a suppression test is required.
These tests are typically designed
to differentiate between primary and secondary causes of
disease,
to detect abnormalities that may not be apparent in the
results of static, baseline laboratory measurements
29. ACTH Stimulation (Cosyntropin) Test
Indication:
Suspect adrenal insufficiency (Addison’s disease) or congenital adrenal hyperplasia
Designed to document the functional capacity of the adrenal glands to synthesize cortisol
1 Hour (Rapid) Cosyntropin Stimulation Test
Principle:
Administration of ACTH to normal subjects results in a rapid rise in the serum cortisol concentration
Patients with adrenal destruction (e.g., Addison disease) show no change or an inadequate change in
serum cortisol concentration after ACTH injection.
Patients with atrophy of the adrenal cortex caused by exogenous glucocorticoid treatment or
dysfunction of the pituitary gland or hypothalamus may show a slight rise in serum cortisol
concentration, but not one of normal magnitude.
30. 1 Hour (Rapid) Cosyntropin Stimulation Test
Procedure
A baseline blood sample is drawn for determination of serum cortisol concentration
Then 250 μg of cosyntropin is given intramuscularly or intravenously.
Additional samples for serum cortisol determination are drawn 30 and 60 minutes after injection.
Interpretation
In normal: serum cortisol concentration peaks to 18 to 20 μg/dL or greater
The expected change in cortisol concentration is 7 to 10 μg/dL( the delta cortisol)
Normal plasma cortisol response, 30 min after cosyntropin (250 μg); adequately excludes ACTH
deficiency,
32. Multiple-day ACTH stimulation test
Required occasionally to evaluate adrenal cortisol responsiveness
Diagnosis of adrenal insufficiency, which is treated with
glucocorticosteroids before a cause has been established.
Prolonged ACTH stimulation is used to distinguish primary from
secondary and/or tertiary causes of adrenal insufficiency.
Procedure:
A total of 250 μg of cosyntropin is injected daily for 3 days
This is followed by an 8 hour infusion of 250 μg of cosyntropin
Urinary free cortisol and serum cortisol are measured daily
33. Interpretation
Serum cortisol values
of 18 to 20 μg/dL or
greater
• exclude primary adrenal
insufficiency
Little or no increase
cortisol secretion
• seen in primary adrenal failure even
over successive days
A progressive staircase
rise in cortisol over 2
to 3 days
• seen in adrenal insufficiency
caused by pituitary or
hypothalamic disease or steroid
concentration suppression.
Little or no response • Seen in congenital adrenal
hyperplasia (CAH) caused by 21-
and 17-hydroxylase deficiencies.
34. Metyrapone Stimulation Test
Indirect test of hypothalamic-pituitary-adrenal axis
function.
Principle:
Metyrapone inhibits 11-beta-hydroxylase (CYP11B1), the
enzyme that converts 11-desoxycortisol to cortisol.
As the blood concentration of cortisol falls, the negative feedback
effect is diminished, causing the release of ACTH from the
pituitary gland.
The stimulatory effect of ACTH on the adrenal cortex leads to
a rise in 11-deoxycortisol
35. Procedure
Metyrapone (30 mg/kg body weight) is given orally at midnight with milk or
a snack (to delay absorption).
At the following morning at 8am, blood is drawn for determination of 11-
deoxycortisol, cortisol, and ACTH concentrations.
In normal subjects • 11-desoxycortisol increases from less than
μg/dL to greater than 7 μg/dL after
metyrapone stimulation, and
• ACTH values exceed 150 pg/mL.
No response or an impaired
response seen in
• pituitary or hypothalamic disease combined
with inadequate enzyme blockade (plasma
cortisol >3 μg/ dL) or
Plasma 11-Deoxycorticol <7µg/dl in secondary and tertiary adrenal
insufficiency
Plasma ACTH <150pg/dl in secondary and tertiary adrenal
insufficiency
Interpretation
36. Mineralocorticoid Stimulation Tests
Furosemide Stimulation Test
Principle:
Administration of furosemide, a potent diuretic, provides a stimulus to
increase plasma renin secretion as the Plasma renin activity (PRA) varies
with the patient’s state of hydration and sodium intake.
Procedure
Furosemide 40 to 80 mg is given orally after an overnight fast.
The subject is maintained in an upright posture (sitting, standing, or walking)
throughout the test.
Blood is drawn for determination of PRA before and 4 hours after furosemide
administration.
37. Interpretation
Increased PRA following
furosemide
seen in:
• patients with high-renin essential
hypertension,
• Pheochromocytoma
Patients with hyporeninemic
hypoaldosteronism
usually have low concentrations of plasma
renin and low aldosterone concentrations
38. Adrenocortical Insufficiency
Normal Primary Secondary Tertiary
Screening test
Plasma ACTH
(0800hours)
10-85pg/ml Increased Normal or
decreased
Normal or
decreased
Serum cortisol
(0800hour)
5-23µg/dl Decreased Normal or
decreased
Normal or
decreased
Challenge Tests
Rapid ACTH stimulation
Peak cortisol >20µg/dl < 20µg/dl Any Any
Overnight Metyrapone test
Plasma 11-
Deoxycorticol
>7µg/dl Not indicated <7µg/dl <7µg/dl
Plasma ACTH >150pg/ml Not indicated <150pg/ml <150pg/dl
CRH stimulation test
Plasma ACTH Not indicated Not indicated Decreased
response
Increased
response
Summary of TESTs
Hinweis der Redaktion
Cortisol deficiency is classified as (1) primary, (2) secondary, or (3) tertiary .Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency
Increased Urea and creatinine, Mild to moderate hypercalcemia ,Mild acidosis .Azotemia with increased concentrations of blood urea nitrogen and serum creatinine is due to volume depletion and dehydration. Mild acidosis is frequently present.