This presentation highlights different causes of central adrenal insufficiency, its evaluation and treatment. The presentation focuses on adrenal insufficiency due to withdrawal of exogenous glucocorticoid with a case story.

1. Central Adrenal
Insufficiency
Dr Sudeep Adhikari, MD

4. Renin- angiotensin- aldosterone axis

6. Adrenal insufficiency
● Primary- disease of adrenal cortex
● Central
○ Secondary- interference with ACTH production by pituitary gland
○ Tertiary- interference with CRH production by hypothalamus
○ Inappropriately low ACTH value in the setting of diminished cortisol
concentrations

7. Secondary adrenal insufficiency
Panhypopituitarism
● Mass lesions – Pituitary adenomas, other benign tumors, cysts
● Pituitary surgery
● Pituitary radiation
● Infiltrative lesions – Hypophysitis, hemochromatosis
● Infection/abscess- Tuberculosis, histoplasmosis
● Infarction – Sheehan syndrome (PPH)
● Apoplexy
● Genetic mutations- PROP 1 gene mutation
● Empty sella

8. Secondary adrenal insufficiency
Isolated ACTH deficiency- rare disorder, no ACTH secretory response to CRH
● Autoimmune
● Genetic causes- extremely rare
○ POMC gene mutation
○ Cleavage enzyme defect
○ TPIT gene mutation

9. Secondary adrenal insufficiency
Familial CBG deficiency
Drugs
○ High dose progestin- medroxyprogesterone acetate/ megestrol acetate-
cause HPA suppression due to intrinsic glucocorticoid activity
○ Opiate
Traumatic brain injury

10. Tertiary adrenal insufficiency
Interference of CRH secretion by hypothalamus
● Abrupt cessation of high-dose glucocorticoid therapy
● Correction (cure) of hypercortisolism (Cushing's syndrome)
● Diseases involving hypothalamus- tumors, infiltrative diseases such as
sarcoidosis, and cranial radiation

11. Central vs Primary
● Hyperpigmentation is not present, because of low ACTH
● Dehydration and hypovolemia- less prominent
● Hyponatremia- due to increased action of ADH
● Hyperkalemia- absent due to presence of aldosterone
● GI symptoms are less common
● Hypoglycemia- more common than in primary
● Other features of pituitary or hypothalamic tumor
● History compatible with possible pituitary infarction or hemorrhage
● Features of other pituitary hormone deficiencies

13. Case
● A 56 years female
● History of RA for 10 years
● Taking sulfasalazine, leflunomide and methotrexate currently
● Was prescribed 2.5 mg of prednisolone daily
● However she took 10 mg prednisolone on usual days to get relieved of pain
since 5 years
● Left hip pain since 2 years with inability to walk (developed AVN left hip
probably due to long term steroid)

14. Case contd.
● Admitted for doing total hip replacement of left side
● On admission, vitals including BP were normal
● Random blood sugar- 65 mg/dl (low)
● Sodium- 132 mmol/L (low), potassium- 3.6 mmol/L (normal)
● Serum cortisol (8 AM)- 92 nmol/L (normal range: 123-626)
● Diagnosed as secondary adrenal insufficiency due to long term steroid use
with AVN left hip with rheumatoid arthritis
● Treated with injection hydrocortisone 50 mg 6 hourly initially, later changed to
oral prednisolone and tapered slowly to maintenance prednisolone of 5 mg
daily

15. Case contd.
On presentation to our ER
● Ill looking
● Temperature- 100 F
● Tachycardic (112/min), regular
● BP- 90/70 mm Hg
● Chest- creps at left infrascapular area
● CVS, P/A- no abnormality

16. Case contd.
On presentation to our ER
● Cushingoid appearance
● Tenderness and swelling over small joints of hands and legs
● Deformities present
● Generalised maculopapular rashes over skin (? drug rash)

19. Case contd.
● CBC- TLC- 14500, N77 L27 E05, Hb- 11.3 gm/dl, Platelets- 429000
● Urea- 19 mg/dl, Creatinine- 1.4 mg/dl, Na- 136 mmol/L, K- 4.7 mmol/L
● Urine- pus cells packed, Culture- no growth
● Chest X-ray- hazy at left lower zone
● ESR- 125
● CRP- 237

21. Case contd.
● Initially diagnosed as RA flare with left pneumonia with UTI with right protrusio
acetabuli with Cushingoid feature
● Treatment started with IV antibiotics (amikacin and piperacillin/tazobactam),
IV fluids, prednisolone 5 mg

22. Case contd.
Possibility of long term exogenous glucocorticoid use in our patient
● Cushingoid appearance
● Possible use of steroid in the form of alternative medicine for long duration
● Developed DM (may be steroid induced)
● Developed AVN right hip (possibly due to long term steroid)
● Started to develop joints pain after stopping the alternative medicine use
causing flare of RA (possibly due to steroid withdrawal)
● Developed chest infection, that could have precipitated adrenal insufficiency

23. Exogenous glucocorticoid
● Most common cause of adrenal insufficiency
● Withdrawal of high dose glucocorticoid
● Decreases hypothalamic CRH synthesis and secretion (tertiary)
● Also blocks CRH action in pituitary (secondary)
● Decreased synthesis of POMC, hence ACTH
● Atrophy of pituitary corticotrophs
● Atrophy of zona fasciculata and reticularis in adrenal

24. HPA Axis Suppression with prolonged glucocorticoid
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely

25. HPA Axis Suppression with prolonged glucocorticoid
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely
● > 20 mg/day of prednisolone
equivalent for > 3 weeks
● Evening/bedtime dose of ≥5 mg of
prednisone for more than a few
weeks
● Cushingoid appearance

26. HPA Axis Suppression with prolonged glucocorticoid
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely
● 10- 20 mg/day of prednisolone for >
3 weeks
● < 10 mg/day of prednisolone for
more than a few weeks (provided
that it is not taken as a single
bedtime dose)

27. HPA Axis Suppression with prolonged glucocorticoid
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely
● Any dose of glucocorticoid for < 3
weeks
● Alternate-day prednisolone at a
dose < 10 mg

28. Evaluation of HPA Axis Suppression
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely

29. Evaluation of HPA Axis Suppression
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely
● Do not need morning cortisol
testing to diagnose HPA
suppression
● Consider adrenal insufficiency if
presence of unexplained nausea,
vomiting, hypotension, orthostasis,
change in mental status,
hyponatremia, or hyperkalemia
● Check a random cortisol, and give
empiric additional corticosteroid

30. Evaluation of HPA Axis Suppression
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely ● Check serum morning cortisol (8
AM)
○ < 138 nmol/l- highly
suggestive of impaired HPA
axis, need additional steroid
○ 138- 275 nmol/l- ACTH
stimulation test or empiric
additional steroid
○ > 275 nmol/l- HPA
suppression unlikely, no need
of additional steroid

31. Evaluation of HPA Axis Suppression
● HPA suppression likely
● Intermediate/uncertain risk of HPA suppression
● HPA suppression unlikely
● No need of evaluating for HPA axis
suppression
● Can continue with usual steroid
regimen

32. Evaluation of HPA Axis Suppression
● Low dose ACTH (1 mcg) stimulation test is typically used
● Cortisol level before and 30 min after the injection
● The criteria for serum cortisol is a minimum value ≥18 mcg/dL (500 nmol/L)

33. Case contd.
● Morning cortisol (8 AM)- 67.5 nmol/L
Normal range (123-626 nmol/L)
● Diagnosis of central adrenal insufficiency was made
● Inj Hydrocortisone 50 mg QID started
● Later changed to prednisolone and tapered slowly

34. Cortisol response during stress
● Acute physical or psychological stress activates the HPA axis, resulting in
increased ACTH and serum cortisol concentrations
● Normal basal secretion of cortisol from the adrenal gland is 8-10 mg/day
● Minor surgery or illness- 50 mg/day
● Greater surgical stress (eg, subtotal colectomy)- 75 to 100 mg/day
● Severe stress (such as major trauma)- 200 to 500 mg/day

35. Cortisol response during stress
Patients with HPA axis suppression
● Unable to increase cortisol level while on stress such as acute illness or
surgery
● Land up on adrenal crisis (adrenal insufficiency)
● Hence require additional glucocorticoid

36. Treatment during stress
● Little information about how much additional glucocorticoid is needed
● Minor illnesses (eg URTI)- 3 by 3 rule
Increasing the usual glucocorticoid use to 3 times for 3 days

37. Treatment during stress
● Minor surgery- hydrocortisone 25 mg for the day of operation only, with a
return to the usual replacement dose on the second day
● Moderate surgical stress (cholecystectomy, joint replacement)-
hydrocortisone 50- 75 mg on the day of surgery and the 1st POD, with a
return to the usual dose on the 2nd POD
● Major surgery (cardiac bypass)- 100- 150 mg hydrocortisone for 2- 3 days,
then returning to the usual dose

38. Treatment during stress
Emergency precautions
● Medical alert bracelet including the diagnosis and dose of usual steroid
● Should carry injectable glucocorticoids (100 mg hydrocortisone/ 4 mg
dexamethasone)
● Family members should be instructed to inject the glucocorticoids in following
scenarios
○ Injury with substantial blood loss or fracture
○ Nausea and vomiting and inability to retain oral medications
○ Symptoms of acute adrenal insufficiency
○ Patient is found unresponsive

39. Maintenance steroid to those with HPA suppression
● Hydrocortisone 15 to 25 mg orally in 2-3 divided doses (largest dose in
morning upon awakening; typically 10 mg upon arising in morning, 5 mg early
afternoon, 2.5 mg late afternoon)
● Prednisone 5 mg (range: 2.5 to 7.5 mg) orally at bedtime
● Dexamethasone 0.75 mg (range: 0.25 to 0.75 mg) orally at bedtime
● Monitor clinical symptoms and morning plasma ACTH

40. Glucocorticoid tapering regimen
To prevent acute adrenal crisis in patients taking long term glucocorticoid with
likely HPA suppression
Prednisolone dose Tapering by
> 40 mg/day 5- 10 mg/day every 1-2 weeks
20-40 mg/day 5 mg/day every 1-2 weeks
10-20 mg/day 2.5 mg/day every 2-3 weeks
5-10 mg/day 1 mg/day every 2-4 weeks
</= 5 mg/day 0.5 mg/day every 2-4 weeks

41. Glucocorticoid tapering
● Patients with rheumatic diseases may complain of recurrent symptoms of the
underlying disease, during the tapering of steroid
● May be difficult to distinguish between mild symptoms of glucocorticoid
withdrawal (ie, arthralgia and myalgia or "pseudorheumatism") or
recrudescence of the underlying rheumatic disease
● If mild symptoms, NSAIDs for 7-10 days, if symptoms resolve-
pseudorheumatism
● If symptoms do not subside, then possible flare, increase the prednisone
dose by 10-15 % followed by taper

42. Adrenal crisis
● Common with primary adrenal insufficiency
● Uncommon in central insufficiency- due to presence of aldosterone
● May occur in
○ HPA axis suppressed patients during acute stress
○ Abrupt withdrawal of glucocorticoid in those using long term

43. Adrenal crisis
pathogenesis

44. Adrenal crisis

45. Adrenal crisis
Precipitants
● Infections, gastroenteritis
● Injuries and surgery
● Procedures such as vaccination, zoledronate infusion
● Immunotherapy/ chemotherapy
● Non adherence to glucocorticoid replacement therapy
● Undiagnosed coexisting thyrotoxicosis, or the initiation of thyroxine therapy in
a patient with undiagnosed hypoadrenalism
● Use of CYP3A4 inducers, withdrawing the use of CYP3A4 inhibitors

46. Adrenal crisis
Management
● Serum electrolytes and glucose and routine measurement of plasma cortisol
and ACTH. Do not wait for lab results
● Infuse 2- 3 liters of NS or 5 % DNS as quickly as possible. Frequent
hemodynamic monitoring and measurement of serum electrolytes to avoid
iatrogenic fluid overload
● 4 mg dexamethasone as IV bolus over 1-5 minutes and every 12 hours
thereafter. Dexamethasone does not interfere with the measurement of
plasma cortisol
● IV hydrocortisone 100 mg immediately and every 6 hours thereafter if
dexamethasone is unavailable

47. Sheehan Syndrome
● Postpartum hypopituitarism
● Rare but potentially life threatening complication of PPH
● Pituitary gland is enlarged during pregnancy
● Hence prone to infarction during hypovolemic shock due to PPH
● Pituitary damage can be mild to severe
● Secretion of one or all hormones affected

48. Sheehan Syndrome
● Commonest presentation-
○ Failure to lactate post-delivery and amenorrhea or oligomenorrhea
● Can present with hypotension, hyponatremia or hypothyroidism
● Occur any time from the immediate postpartum period to years after delivery

49. Sheehan Syndrome
● If the patient remains hypotensive after control of hemorrhage and volume
replacement, she should be evaluated and treated for adrenal insufficiency
immediately
● Evaluation of other hormonal deficiencies can be deferred until four to six
weeks postpartum

50. THANK YOU