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Disorders of adrenal
cortex
Hari sharan makaju
M.Sc. Clinical biochemistry
PG Resident
Previous class
Cholesterol (C27)
Prognenolone (C21)
Progesterone (C21)
17-α-Hydroxyprogesterone C21)
Testosterone (C19)
Estradiol (C18)
11- Deoxycorticosterone
11- Deoxycortisol
Aldosterone Cortisol
Congenital Adrenal Hyperplasia
Desmolase
NADPH
O2
3-β-Hydroxysteroid
dehydrogenase
17-α-Hydroxylase
11-β-Hydroxylase
21 α hydroxylase
Defect in either the steroidogenic
acute regulatory protein (StAR)
Congenital lipoid adrenal hyperplasia
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
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.
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
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
Types of Adrenal Hypofunctions
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
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.
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
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
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 )
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
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
Hpofunction of  adrenal cortex
Hpofunction of  adrenal cortex
ADRENAL HYPOFUNCTION
Addison’s Disease: Diagnosis
 Decrease cortisol
 Increase ACTH
 Decrease Sodium
 Increase Potassium
 Hypoglycemia
 Hypotension
 Hyperpigmentation
 Confirmatory: ACTH Stimulation Test (Cosyntropin)
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.
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.
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)
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
Hpofunction of  adrenal cortex
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)
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
Hypoaldosteronism
Hyperreninemia hypoaldosteronism
(synthetic deficiency)
Primary adrenal insufficiency
Selective aldosterone deficiency
Inborn errors (e.g., CYP11B2 mutations)
Drug-induced aldosterone suppression
Heparin (direct inhibition of aldosterone secretion)
Angiotensin-converting enzyme (ACE) inhibitors
Hypoaldosteronism in critical illness/hypotension (e.g.,
selective zona glomerulosa injury)
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
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.
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,
Hpofunction of  adrenal cortex
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
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.
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
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
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.
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
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
Hpofunction of  adrenal cortex
Hpofunction of  adrenal cortex

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Hpofunction of adrenal cortex

  • 1. Disorders of adrenal cortex Hari sharan makaju M.Sc. Clinical biochemistry PG Resident
  • 3. Cholesterol (C27) Prognenolone (C21) Progesterone (C21) 17-α-Hydroxyprogesterone C21) Testosterone (C19) Estradiol (C18) 11- Deoxycorticosterone 11- Deoxycortisol Aldosterone Cortisol Congenital Adrenal Hyperplasia Desmolase NADPH O2 3-β-Hydroxysteroid dehydrogenase 17-α-Hydroxylase 11-β-Hydroxylase 21 α hydroxylase Defect in either the steroidogenic acute regulatory protein (StAR) Congenital lipoid adrenal hyperplasia
  • 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
  • 8. Types of Adrenal Hypofunctions
  • 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
  • 19. Addison’s Disease: Diagnosis  Decrease cortisol  Increase ACTH  Decrease Sodium  Increase Potassium  Hypoglycemia  Hypotension  Hyperpigmentation  Confirmatory: ACTH Stimulation Test (Cosyntropin)
  • 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
  • 27. Hypoaldosteronism Hyperreninemia hypoaldosteronism (synthetic deficiency) Primary adrenal insufficiency Selective aldosterone deficiency Inborn errors (e.g., CYP11B2 mutations) Drug-induced aldosterone suppression Heparin (direct inhibition of aldosterone secretion) Angiotensin-converting enzyme (ACE) inhibitors Hypoaldosteronism in critical illness/hypotension (e.g., selective zona glomerulosa injury)
  • 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

  1. Cortisol deficiency is classified as (1) primary, (2) secondary, or (3) tertiary .Glucocorticoid therapy is the most common cause of secondary adrenocortical insufficiency
  2. 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.
  3. ACTH 10-60pg/ml