Adrenal insufficiency (AI) is a condition in which the adrenal glands do not produce adequate amounts of glucocorticoids primarily cortisol; but may also include impaired production of aldosterone (a mineralocorticoid), which regulates sodium conservation, potassium secretion, and water retention. This life-threatening disease may result from disorders affecting the adrenal cortex (primary), the anterior pituitary gland (secondary), or the hypothalamus (tertiary). Adrenal insufficiency can manifest at any age, but often presents between the ages of 20 years and 50 years

1. PATHOPHYSIOLOGY OF
ADRENAL INSUFFICIENCY:
A HORMONAL AND METABOLIC
DISORDER
BY
OSAYANDE CHELSEA IMUETINYANOSA
CHEMICAL PATHOLOGY UNIT, NATIONAL HOSPITAL ABUJA
SUPERVISED BY: DR. DORATHY ANYA (PMLS)
17TH OCTOER, 2022

2. OUTLINE
● INTRODUCTION
● ANATOMY OF THE ADRENAL GLAND
● ADRENAL HORMONES
● WHAT IS ADRENAL INSUFFICIENCY
● BRIEF HISTORY
● TYPES OF ADRENAL INSUFFICIENCY
● CAUSES
● SYMPTOMS
● PATHOPHYSIOLOGY
● LABORATORY DIAGNOSIS
● TREATMENT
● CONCLUSION
● RECOMMENDATION

3. INTRODUCTION
Adrenal glands produce hormones necessary for normal body functioning; the
deficiency of these hormones is called adrenal insufficiency.
Adrenal insufficiency can present along a spectrum ranging from mild nonspecific
symptoms to life-threatening shock.
The decrease in adrenal function may be masked until stress or illness triggers an
adrenal crisis.
This activity reviews the evaluation and management of adrenal insufficiency and
highlights the role of interprofessional team collaboration in the recognition and
management of adrenal insufficiency (Ceccato & Scaroni, 2019).

4. THE ADRENAL GLAND
The adrenal glands are two small,
triangular-shaped glands that sit directly on
top of the kidneys.
The two major parts of the adrenal gland
are the cortex and the medulla. The gland is
surrounded by an adipose capsule, which
acts as a protective barrier.
(Hasan, 2018).

5. ANATOMY OF THE ADRENAL GLAND
Figure 1: Anatomy of the adrenal gland (Ceccato & Scaroni, 2019).

6. ADRENAL HORMONES
CORTICAL SUBSTANCE MEDULLARY SUBSTANCE
zona
glomerulosa
zona
fasciculata
zona
reticularis
MINERALOCORTICOIDS:
Aldosterone,
Deoxycorticosterone
GLUCOCORTICOIDS:
Cortisol,
Cortisone,
Corticosterone
ANDROGENS:
Testosterone,
Estradiol
CATECHOLAMINES:
Noradrenaline
(norepinephrine),
Adrenaline
(Hasan, 2018).

7. WHAT IS ADRENAL INSUFFICIENCY?
Adrenal insufficiency (AI) is a condition in which the adrenal glands do not
produce adequate amounts of glucocorticoids primarily cortisol; but may also
include impaired production of aldosterone (a mineralocorticoid), which
regulates sodium conservation, potassium secretion, and water retention
This life-threatening disease may result from disorders affecting the adrenal
cortex (primary), the anterior pituitary gland (secondary), or the hypothalamus
(tertiary) (Neary & Nieman, 2010).
Adrenal insufficiency can manifest at any age, but often presents between the
ages of 20 years and 50 years (Gjerstad et al., 2018).

8. BRIEF HISTORY
Thomas Addison (1793 – 1860)
15 March, 1849
Endocrine functions
Autoimmune disease
(Science Encyclopedia, 2022)

9. TYPES OF ADRENAL INSUFFICIENCY
Woods et al., 2015
PRIMARY
SECONDARY
TERTIARY

10. CAUSES OF ADRENAL INSUFFICIENCY
Primary AI
• Autoimmune adrenalitis
• Infectious adrenalitis
• Bilateral adrenal hemorrhage
• Bilateral adrenal metastases
• Bilateral adrenalectomy
• Drug-induced adrenal
insufficiency
• Genetic disorders
SECONDARY AI
• Space occupying lesions or
trauma in the pituitary gland
• Genetic disorders
TERTIARY AI
• Space occupying lesions or
trauma in the hypothalamus
• Drug-induced adrenal
insufficiency
• (Nicolaides et al., 2017).

11. SYMPTOMS OF AI
Løvås & Husebye , 2015)

12. PATHOPHYSIOLOGY OF ADRENAL INSUFFICIENCY
ADRENAL
PITUITARY
HYPOTHALAMUS
PVN
CRH
ACTH
CORTISOL
DHEA
ALDOSTERONE
PVN
CRH
ACTH
CORTISOL
DHEA
NORMAL ALDOSTERONE
PVN
CRH
ACTH
CORTISOL
DHEA
NORMAL ALDOSTERONE
PRIMARY SECONDARY TERTIARY
(Nicolaides et al., 2017, Author’s illustration, 2022).

13. METABOLIC EFFECTS OF AI
Blood pressure
Glucose Metabolism
Lipids and Body Weight
(Ceccato & Scaroni, 2019).

14. LABORATORY
DIAGNOSIS
Routine studies
Endocrine studies
Genetic studies

15. ROUTINE LABORATORY STUDIES
BASAL METABOLIC PANEL
Electrolyte
Creatinine
Blood Urea Nitrogen
Glucose test
Primary adrenal insufficiency: Na ↓, K ↑, Ca ↑
Hypoglycemia
Creatinine↑, BUN↑
Secondary adrenal insufficiency: potentially only ↓ Na or hypoglycemia
(Bornstein et al., 2016)

16. ENDOCRINE STUDIES
Endocrine testing is typically performed sequentially
1. Morning cortisol level: initial test
2. Morning ACTH level: obtain if morning cortisol is low
3. Standard-dose ACTH stimulation test (cosyntropin test): gold standard to
confirm the diagnosis of primary adrenal insufficiency
Screening for hypoaldosteronism and hypoandrogenism
Other dynamic endocrine studies
1. Insulin tolerance test (also insulin hypoglycemia test)
2. Overnight metyrapone stimulation test
3. CRH stimulation test: used to distinguish between secondary and tertiary
adrenal insufficiency
(Bancos et al., 2015)

17. Standard-dose ACTH stimulation test (cosyntropin test)
METHOD
1. Administration of 250 mcg exogenous ACTH to stimulate cortisol secretion
2. Measurement of cortisol levels before and 30 and/or 60 minutes after injection
Physiological response: exogenous ACTH → ↑ cortisol
INTERPRETATION
In primary adrenal insufficiency: peak cortisol level < 18–20 μg/dL (< 500–550 nmol/L)
In secondary/tertiary adrenal insufficiency: usually a rise in cortisol > 18–20 μg/dL (>
500–550 nmol/L)
(Bancos et al., 2015).

18. Table 1: Endocrine testing for adrenal insufficiency
Morning cortisol Morning ACTH ACTH stimulation test
Primary adrenal
insufficiency
↓ cortisol
< 3 mcg/dL strongly
suggest hypocortisolism
Levels ≥ 18 mcg/dL
may rule
out adrenal insufficiency.
↑ ACTH
elevated ACTH
levels > 100 pg/mL
No increase in serum
cortisol after stimulation
Secondary/tertiary
adrenal
insufficiency
↓ cortisol ACTH levels low increase in serum
cortisol after stimulation
(Ospina et al., 2016).

19. OTHER DYNAMIC ENDOCRINE STUDIES
Insulin tolerance test (also insulin hypoglycemia test)
I. Physiological response: administration of insulin → hypoglycemia (strong
stimulator for ACTH and cortisol secretion) → stress-induced ↑ in plasma ACTH
→ ↑ in cortisol levels
II. Secondary adrenal insufficiency: no incremental rise in ACTH and cortisoL
levels
CRH stimulation test: used to distinguish between secondary and tertiary adrenal
insufficiency
I. Physiological response: CRH → ↑ ACTH → ↑ cortisol
II. Secondary adrenal insufficiency: CRH → no increase in ACTH → no increase
in cortisol
III. Tertiary adrenal insufficiency: CRH → ↑ ACTH→ ↑ cortisol
(Bancos et al., 2015).

20. ADDITIONAL EVALUATION
AUTOIMMUNE SCREEN
•Antibodies against 21-hydroxylase
•Consider further screening for autoimmune polyendocrine syndromes if antibodies
against 21-hydroxylase are present
IMAGING
CXR: Screen for tuberculosis if an infective cause is suspected.
CT or MRI adrenal glands: Screen for adrenal hemorrhage and malignant or infiltrative
disease.
MRI head to investigate for pituitary/ hypothalamic lesion
ADVANCED
Screen for congenital disorders, e.g DNA methylation analysis for Prader-
Willi syndrome (Bancos et al., 2015).

21. NORMAL RANGE
PANEL ANALYTE RANGE
METABOLIC SODIUM Adult 135 – 150 Mmol/L
POTASSIUM Adult 3.5 – 5.3 Mmol/L
CALCIUM All 2.10 – 2.55 Mmol/L
UREA All 2.5 – 6.4 Mmol/L
CREATININE Male 50- 106 Mmol/L
Female 44 – 100Mmol/L
ENDOCRINE CORTISOL All 10 – 20 ug/dL
ALDOSTERONE Adult 7 – 30 ng/dL
ACTH Adult 6-76 pg/ml
CRH Adult 0.77-2.5 pmol/l
(Chemical Pathology Lab, NHA. 2022)

22. INSTRUMENTATION
Abbott Architect i 1000sr Roche Cobas e411

23. TREATMENT
Drug-induced adrenal insufficiency: Consider
medication adjustment.
Hypopituitarism: Substitute other pituitary hormones
Infectious adrenalitis: Treat Tuberculosis or manage
other causes “ e.g HIV and “Cytomegalovirus infection
Infiltration of the adrenal glands: Treat malignancy, e.g.,
via tumor resection.
Autoimmune adrenalitis: Treat other associated
autoimmune endocrinopathies.
Treatment of the underlying cause and
associated conditions
Steroid replacement
• GLUCOCORTICOIDS
• Agents: Hydrocortisone,
Cortisone acetate,
Prednisolone
• MINERALOCORTICOIDS
• Agent: fludrocortisone;
• ANDROGENS
• Agent: DHEA
(Bornstein et al., 2016).

24. FUTURE TREATMENT
Future treatment may eventually involve using
adrenocortical stem cells combined with
immunomodulatory treatment — modifying the immune
response or the immune system — as well as gene
therapy (Ceccato & Scaroni, 2019).

25. CONCLUSION
In conclusion adrenal insufficiency can be a life threatening disease if not diagnosed
early. Researchers are working to develop delayed-release corticosteroids, which act
more like the human body. They are also working on pumps implanted under the skin
that can deliver steroids in more-accurate doses. This is a potential future treatment
and should be encouraged.

26. RECOMMENDATION
Testing kits and reagents should e made available in screening centers
Replacement therapy should be checked routinely
Patients should be enlightened properly as this can help reduce incidence of fatal crisis

27. SELECTED REFERENCES
•Bancos, I., Hahner, S., Tomlinson, J., & Arlt, W. (2015). Diagnosis and management of adrenal
insufficiency. The Lancet Diabetes & Endocrinology, 3(3), 216–226. doi:10.1016/s2213-
8587(14)70142-1
•Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Torpy, D. J.
(2016). Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical
Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 101(2), 364–
389. doi:10.1210/jc.2015-1710
•Ceccato, F., & Scaroni, C. (2018). Central adrenal insufficiency: open issues regarding diagnosis
and glucocorticoid treatment. Clinical Chemistry and Laboratory Medicine (CCLM),
0(0). doi:10.1515/cclm-2018-0824
•Gjerstad, J. K., Lightman, S. L., & Spiga, F. (2018). Role of glucocorticoid negative feedback in the
regulation of HPA axis pulsatility. Stress, 1–14. doi:10.1080/10253890.2018.1470238
•Hasan, N. (2018). Adrenal gland: Structure, Hormones and clinical disorders - part 1.
•Jessani, N., Jehangi, W., Behman, D., Yousif, A., Spiler, I. J. (April 2015). "Secondary Adrenal
Insufficiency: An Overlooked Cause of Hyponatremia". Journal of Clinical Medicine Research. 7 (4):
286–288. doi:10.14740/jocmr2041w.

28. SELECTED REFERENCES
•Løvås K, Husebye ES. Addison's disease. Lancet 2005; 365(9476):2058-61
•Nicolaides NC, Chrousos GP, Charmandari E. Adrenal Insufficiency. [Updated 2017 Oct 14]. In: Feingold
KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.;
2000-.
•Ospina, N. S., Al Nofal, A., Bancos, I., Javed, A., Benkhadra, K., Kapoor, E., Murad, M. H. (2016). ACTH
Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. The
Journal of Clinical Endocrinology & Metabolism, 101(2), 427–434. doi:10.1210/jc.2015-1700
•Science Encyclopedia Addison's Disease - The Adrenal Glands, History Of Addison's Disease, Addison's
Disease, Treatment - JRank Articles https://science.jrank.org/pages/77/Addison-s-
Disease.html#ixzz7gygmeR00
•Woodcock, T., Barker, P., Daniel, S., Fletcher, S., Wass, J. A. H., Tomlinson, J. W., Vercueil, A.
(2020). Guidelines for the management of glucocorticoids during the peri-operative period for patients
with adrenal insufficiency. Anaesthesia. doi:10.1111/anae.14963
•Woods, C. P., Argese, N., Chapman, M., Boot, C., Webster, R., Dabhi, V., Tomlinson, J. W. (2015). Adrenal
suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be
guided by morning cortisol. European Journal of Endocrinology, 173(5), 633–642. doi:10.1530/eje-15-
0608

29. THANKS FOR LISTENING
chelseaosayande.i@gmail.com