addison disease , adrenal insufficiency, hypocortisolism

1. Adrenal insufficiency
(AI)
By
Hazem Samy Matar
Ass. Lecturer of internal medicine, diabetes and endocrinology

2. Pathophysiology

6. Definition
a clinical syndrome arising from disruption of the normal hypothalamus–
pituitary–adrenal (HPA) axis regulation of steroidogenesis.
• In 1855, Thomas Addison first described his eponymous syndrome, which
was characterized by wasting and hyperpigmentation, and identified its cause
as destruction of the adrenal gland.

7. Classification
• Primary AI (Addison’s disease) corresponds to dysfunction at the level of
the adrenal gland from any cause.
• Secondary AI refers to ACTH deficiency. It can be due to dysfunction of
either the hypothalamus or pituitary gland.

8. Epidemiology
• Chronic primary adrenal insufficiency has a prevalence of 90 to 140 per
million and an incidence of 4.7 to 6.2 per million/year in Caucasian
populations.
The age at diagnosis peaks in the fourth decade of life.
• Secondary adrenal insufficiency has an estimated prevalence of 150 to
280 per million with a peak age of diagnosis in the sixth decade of life.
• Both conditions are more prevalent in women than in men.

9. Etiology
Primary AI
• When Thomas Addison described his initial case in 1855, tuberculosis was the most
common etiology for primary AI, and it remains a major factor in the developing
world
• Over the years, autoimmune destruction of the adrenal gland (autoimmune
adrenalitis) has emerged as the leading cause of primary AI . It can be isolated or
occur as part of an autoimmune polyglandular syndrome (APS, types I and II).
• Hereditary factors are increasingly recognized in primary AI.

10. Etiology
• Other etiologies to consider for primary AI include the following:
Disseminated tuberculosis, fungal infections, human immunodeficiency virus
(HIV)-related opportunistic infections (most commonly cytomegalovirus
[CMV]).
Bilateral adrenal hemorrhage associated with coagulopathies or sepsis.
Metastatic cancer involving more than 80% to 90% of the total adrenal mass.

11. Etiology
Secondary AI
• Iatrogenic
Sudden cessation of exogenous glucocorticoid therapy is a common clinical
problem and is the most frequent cause of secondary AI. Exogenous
glucocorticoid administration via any route may lead to suppression of the
HPA axis depending on the dose and duration of therapy.

12. Etiology
• Hypothalamic-pituitary
Among patients with pituitary or hypothalamic disorders, a pituitary mass is
usually associated with panhypopituitarism caused either by tumor growth or
treatment with surgery or irradiation.
Other causes include autoimmune lymphocytice hypophysitis, infectious and
infiltrative diseases, pituitary infarction or hemorrhage, and head trauma.

13. DIAGNOSIS
• Diagnosis of AI is critical but often difficult. It depends on a high index of
clinical suspicion for the disease that is further corroborated by biochemical
evidence.
• Despite the various testing options available, no single test classifies all
patients accurately.

14. Clinical Presentation
• The clinical presentation of AI can be variable and is dependent on the level
of the hypothalamic-pituitary–adrenal axis that is affected, as well as the rate
and extent of loss of adrenal function.
• Patients may remain undiagnosed for quite some time until a significant
physical stressor precipitates an adrenal crisis—an endocrine emergency.

15. Acute AI (Adrenal Crisis)
• Acute AI most often occurs in patients with primary AI.
• It is critical to recognize the clinical syndrome because acute adrenal crisis is
an endocrine emergency that requires prompt treatment.

16. Acute AI (Adrenal Crisis)
• Usually precipitated by acute stress (surgery, infection, or bilateral adrenal
hemorrhage).
• Shock with severe volume depletion and hypotension that is out of
proportion to the severity of the current illness.
• May include nausea and vomiting with a history of weight loss and anorexia,
abdominal pain (“acute abdomen” if the etiology is acute adrenal infarction
or hemorrhage), fatigue, fever, confusion or coma, electrolyte abnormalities
(especially hyperkalemia), and eosinophilia.

17. Chronic Primary Adrenal Insufficiency
• more insidious in its onset.
• A significant illness can transform latent chronic primary AI into a life-
threatening adrenal crisis. Hence, early recognition and diagnosis is essential.

18. Chronic Primary Adrenal Insufficiency
• In its early stage, the presenting symptoms may be nonspecific:
Chronic malaise, generalized weakness, myalgias, weight loss;
Nausea, vomiting, anorexia, and chronic abdominal pain.

19. Chronic Primary Adrenal Insufficiency
• Primary AI often leads to both glucocorticoid and mineralocorticoid deficiency.
Lack of feedback inhibition on the pituitary by cortisol leads to increased ACTH
secretion and generalized hyperpigmentation of the skin and mucosa.
Mineralocorticoid deficiency results in renal salt wasting manifest as salt craving,
hyponatremia, hyperkalemia, volume depletion and hypotension.
Adrenal androgen secretion is lost, which is clinically more apparent in women who
may complain of loss of axillary and pubic hair, and impairment of wellbeing.

20. Chronic Primary Adrenal Insufficiency
• Autoimmune adrenalitis may be evidence of other autoimmune diseases such
as hypo- or hyperthyroidism, type 1 diabetes, or vitiligo.
• Longstanding adrenal insufficiency can also manifest psychiatric symptoms,
ranging from impairment in memory to depression and psychosis.

23. Secondary AI
• Presents with many of the same symptoms as chronic primary AI.
• May rarely present acutely with pituitary apoplexy.
• In addition to AI symptoms,
may be other pituitary hormone deficiency symptoms such as
amenorrhea, decreased libido, or hypothyroidism.
Mass effects (headaches or visual field defects) from a pituitary or
hypothalamic tumor may also be present.

24. Secondary AI
• In contrast to primary AI,
Patients do not manifest hyperpigmentation, because their ACTH is not
elevated.
Less prominent electrolyte abnormalities, volume depletion, and
hypotension, because the renin–angiotensin–aldosterone system is usually
intact.

25. Diagnostic Testing
• A multistep approach is needed to document:
Whether there is inadequate cortisol secretion by the adrenals.
Whether the cause of adrenal insufficiency is lack of ACTH.
• Once AI is documented, a cause should be sought and treated as appropriate.

26. Diagnostic Testing
Laboratory Studies
A)Testing for Inadequate Cortisol Secretion
(1)Basal Cortisol Measurements
Basal cortisol levels of ≥19 mcg/dL rule out AI, whereas early morning (8 AM to 9
AM) cortisol values ≤3 mcg/dL are indicative of the disorder. All other patients need
dynamic testing.
In interpreting the results, it is important to remember that estrogen therapy raise
plasma corticosteroid-binding globulin and, therefore, cortisol concentrations.

27. Diagnostic Testing
(2)Corticotropin Stimulation Tests
The corticotropin (standard 250 mcg or low-dose 1 mcg) can be given intravenously or
intramuscularly. Plasma cortisol is measured before and 30 and 60 minutes after
corticotropin.
Peak serum cortisol levels >18 mcg/dL (500 nmol/L) or, preferably, 20 mcg/dL(550
nmol/L), excludes primary adrenal insufficiency and severe chronic secondary adrenal
insufficiency.
The low-dose corticotropin stimulation test has been proposed as a more sensitive test,
especially for mild secondary AI and after treatment with glucocorticosteroids.
However, this concept remains controversial.

28. Diagnostic Testing
• It is important to note that the corticotropin stimulation tests may be normal in
recent-onset secondary AI.
• Most steroid replacements (e.g., cortisone, hydrocortisone, and prednisone) interfere
with the radioimmunoassay for serum cortisol. Therefore, patients already receiving
such replacement should have their dose delayed on the day of testing.
• If adrenal crisis is suspected, intravenous saline and dexamethasone should be
started until the corticotropin stimulation test can be performed because it does not
cross-react with the cortisol in the assay.

29. Diagnostic Testing
• AI in critically ill patients is best diagnosed by a basal cortisol level of <10
mcg/dL or an incremental response <9 mcg/dL after standard 250 mcg
corticotropin stimulation test.

30. Diagnostic Testing
B)Differentiating Primary and Secondary AI
(1)Baseline ACTH Concentration
A baseline ACTH level obtained at the same time as a basal cortisol level can be
helpful in this regard. A disproportionately elevated baseline plasma ACTH
level with a concurrently low basal serum cortisol suggests primary AI. On the
other hand, secondary AI patients have low serum cortisol with a low or low-
normal baseline plasma ACTH level.

31. Diagnostic Testing
(2)CRH Stimulation Test
• The CRH stimulation test has utility for differentiating a pituitary from
hypothalamic etiology of AI.
• Limited usefulness due to its cost, availability, and limited data.

32. Diagnostic Testing
Renin and Aldosterone Concentrations
usually affected in primary AI. Aldosterone levels are typically low, associated with
elevated rennin activity in this setting.
Autoantibodies
At the time of onset of clinically apparent autoimmune AI, adrenal antibodies are
detected in more than 90% of patients.
The presence of autoantibodies will often predate the onset of AI.
More common if there is associated vitiligo or alopecia.

33. Diagnostic Testing
Imaging
Radiologic imaging should only be performed once laboratory diagnosis of
adrenal insufficiency is made.
MRI imaging of the hypothalamic-pituitary region
CT and MRI are often used to image the adrenal glands: small or absent adrenal
glands in autoimmune adrenalitis, Enlarged or calcified adrenals may suggest an
infectious, hemorrhagic or malignant diagnosis.

35. TREATMENT
Acute Treatment
• Adrenal crisis is a life-threatening condition requiring immediate treatment.
• Therapy should not be delayed to perform diagnostic studies or await laboratory
results.
• If there is no history suggestive of adrenal insufficiency, other causes of shock also
need to be considered.
• Volume replacement using normal saline is essential to reverse hypotension and
electrolyte abnormalities.

36. TREATMENT
• While blood for serum cortisol, ACTH, and serum chemistry is drawn, “stressdose”
steroids should be started.
If the diagnosis is unclear, 4 mg IV dexamethasone (instead of hydrocortisone)
should be given first, followed by corticotropin stimulation testing.
In patients with a clearly identified history of adrenal insufficiency, either
dexamethasone (4 mg IV q12h) or hydrocortisone (50 to 100 mg IV q6–8h) can be
given until their condition has stabilized.
Once the stressor has been alleviated, steroid doses can be tapered over 1 to 3 days
to an oral maintenance daily dose.

37. TREATMENT
Maintenance Treatment
• glucocorticoid replacement with hydrocortisone 15 to 30 mg/day PO or its
equivalent (prednisone 4.0 to 7.5 mg/day PO).
• The glucocorticoids can be administered in 1 to 3 divided doses. It is
generally best to give a single dose in the morning to mimic the
physiologic diurnal variation. If the patient thinks he or she could benefit
from a split-dose regimen, usually the larger dose is given in the morning and
the smaller dose later in the day.

38. TREATMENT
• primary adrenal insufficiency should also receive mineralocorticoid
replacement. Fludrocortisone is given at a dose of 0.05 to 0.2 mg PO daily.

39. TREATMENT
Treatment for Specific Situations
Stress dosing
• Supplementary glucocorticoid dosing should be based on the likelihood and
degree of adrenal suppression, the degree of medical or surgical stress, and
the cardiovascular and metabolic response to the therapy.
• In addition to aggressive hydration, the usual daily dose can initially be
doubled and then doubled again if symptoms of AI persist.

40. TREATMENT
Perioperative dosing
• For minor procedures with local anesthesia and most radiologic studies, the
patient’s usual daily dose should suffice.
• For moderate procedures involving general anesthesia, patients should continue
their usual daily steroid dose preoperatively and then receive hydrocortisone 25 mg
IV q8h intravenously during the procedure.
• For major operations involving cardiothoracic or abdominal cavities, patients
should be given their baseline daily dose preoperatively and then receive
hydrocortisone 50 mg IV q8h during the procedure.

41. TREATMENT
Thyroid disease
• If a patient is concurrently diagnosed with both adrenal insufficiency and
hypothyroidism, the patient must first receive adequate glucocorticoid
replacement before initiating thyroid hormone therapy to avoid precipitating
adrenal crisis.
• In patients with adrenal insufficiency and unresolved hyperthyroidism,
glucocorticoid replacement should be doubled or tripled, since
hyperthyroidism increases cortisol clearance

42. PATIENT EDUCATION
• Medical-alert bracelet.
• Prefilled syringes of dexamethasone (4 mg/mL in saline solution).
• Seek medical attention immediately in presence of symptoms of adrenal crisis.

43. Thank You