Dr. Mohd Ashraf Ganie is a renowned endocrinologist who has specialized in adrenal insufficiency (Addison's disease). He provides a detailed overview of Addison's disease, including its history, physiology, causes, clinical features, laboratory findings, diagnosis, and treatment. Some key points include: - Addison's disease was first described in 1855 and is characterized by destruction of the adrenal glands and a deficiency of cortisol and aldosterone. - The most common cause is an autoimmune process that destroys the adrenal cortex. Other causes include infections, hemorrhage, infiltrative diseases, and metastatic tumors. - Clinical features include fatigue, weight loss, low

1. Dr. MOHD ASHRAF GANIE
MBBS,MD,FRCP,DM
Professor Endocrinology & Metabolism SKIMS Srinagar
Former Associate Professor AIIMS,New Delhi
• President Metabolic syndrome- Prediabetes-PCOS Society (M P PCOS), Chief Coordinator ICMR-
PCOS Task Force, Editor Diabetes Obesity International J.
• T C Anand Kumar Gold Medal, 3 Best paper Awards
• Best DM Scholar AIIMS 2003, Rashtriya Gaurav Award, DSL Award, Best Researcher Award at
SKIMS 2017
• 104 publications including journals like NEJM, Frontiers in Endocrinology, JCEM, Fertility Sterility,
Diabetic Medicine, Gynecol Endocrinol, J of Obesity, Diabetes, Am J Clin Nutr etc.
• REVIWER OF 20 HIGH IMPACT JOURNALS
Primary Adrenal Insufficiency
(Addison’s Disease)

2. Adrenal Insufficiency
First clinical disorder linked to pathology in an
endocrine gland
Clinical syndrome –Thomas Addison in 1855
Named Addison’s disease by Trousseau in
1856
Acute Adrenal crisis in 1962 – surgical patient
in chronic steroid user.

3. … the pioneer in clinical research
who had the ability to observe, the
genius to create, and the courage to
publish his conclusions…
Dr. Kendal (1956), on Dr.
Sorkin’s paper, A Centaury of
Addison's Disease,
presented to New York
Academy of Sciences

4. Patient with typical hyperpigmentation and vitiligo, as
presented by Thomas Addison in his monograph

5. PHYSIOLOGY
Glucocorticoids
Modulates ACTH
secretion
Modulates vascular
response to
catecholamnines
Maintains cardiac
contractility
Required for
glycogenesis

6. PHYSIOLOGY
Glucocorticoid Deficiency
 ACTH mediated hyperpigmentation
 ↓BP (tachycardia, ↓stroke volume, ↓peripheral
vascular resistance)
 Hypoglycemia (occasionally)

7. PHYSIOLOGY [contd.]
Mineralocorticoid
Modulates renal handling of Na+,
K+, and H+ ions
Retains Na+ at expense of K+ & H+
Deficiency
 Hyponatremia,hyperkalemia, and acidosis
 In primary AI combined glucocorticoid and mineralocorticoid deficiency causes
orthostatic hypotension,hyponatremia, hyperkalemia,and mild metabolic acidosis.

8. ADRENAL INSUFFICIENCY
Inadequate Adrenocortical Function
PRIMARY TERTIARYSECONDARY
ADRENAL PITUITARY HYPOTHALAMUS
ADDISON’S DISEASE

9. PRIMARYADRENAL INSUFFICIENCY
(ADDISON’S DISEASE)
 First described by Thomas Addison in 1855 in patient of Adrenal tuberculosis
 In West incidence of TB decreased, presently Autoimmune Adrenalitis
commonest cause of Addison’s disease
 Incidence 40-60 / million adults

10. PRIMARY ADRENAL INSUFFICIENCY
Destruction of
Adrenals
Adrenal Dysplasia
or Hypoplasia
Impaired
Steroidogenesis
 >90 % Gland
destroyed before
manifestation
 Reduction in
all adrenal
hormones
Cortisol
Minerellocorticoid
Androgens
 Defect in
genes for
normal Adrenal
Gland
development
 Presents in
early life

11. PRIMARY ADRENAL INSUFFICIENCY
Destruction of
Adrenals
Adrenal Dysplasia
or Hypoplasia
Impaired
Steroidogenesis
1. Autoimmune
2. Infections
3. Hemmorhage
4. Infiltration
5. Metastasis
1. SF-1
2. DAX-1
3. AHC
4. Corticotropin
resistance
Syn
5. Continous
gene deletion
defect
CHOLESTEROL
1. Smith-lemli-Opitz
2. Abetalipoproteinemia
STEROIDOGENESIS
1. StAR
2. Mitochondrial Dna
del
3. CAH

12. Destruction of Adrenal Glands
Autoimmune Infections Hemorrhage Infiltration Metastasis
 70 % of cases in the West
 Usually associated with APS-1 and APS-2
 In APS symptoms appear over many
years, hence important to screen for
“Adrenal Autoantibody”
APS-1
1. Candidiasis
2. Addison’s (60%)
3. Hypoparathyroidism
APS-2
1. Addison’s (100%)
2. Thyroid Disease
3. Diabetes

13. Destruction of Adrenal Glands
InfectionsAutoimmune Hemorrhage Infiltration Metastasis
1. Tuberculosis
2. AIDS
3. Fungal
Tuberculosis of Adrenal glands

14. Destruction of Adrenal Glands
Autoimmune
Infiltration
1. Amyloidosis
2. Sarcoidosis
3. Hemochrom
atosis
4. Lymphoma
MetastasisInfections Hemorrhage
1. Septic
Shock
(esp.
meningococ
cal)
2. Antiphosph
olipid Syx
3. Anticoagula
nts

15. Dysplasia/ Hypoplasia of Adrenal Glands
SF-1 DAX-1 CRSAHC Cont gene DelA
H
C
Adrenal
Hypoplasia
Hypogonadism
Hypothalamic
Hypoplasia
Adrenal
Hypoplasia
Hypogonadism

16. Dysplasia/ Hypoplasia of Adrenal Glands
SF-1 DAX-1 CRSAHC Cont gene DelA
H
C
4 Clinical forms
I. Sporadic adrenal
insufficiency + Pit
Hypoplasia
II. AR- distinct miniature
Adrenal morphology
III. X-L hypogonadotropic
hypogonadism
IV. X-L With glycerol
Kinase deficiency
I. Familial glucocorticoid
deficiency
 Inactivating mutations
of ACTH Receptor
 Deficient Cortisol and
Androgens
II. Allgrove Syx (Triple A)
 ACTH resistance
 Achalasia
 Alacrimia

17. Dysplasia/ Hypoplasia of Adrenal Glands
SF-1 DAX-1 CRSAHC Cont gene DelA
H
C

18. CLINICAL FEATURES
Adrenal insufficiency
Chronic InsufficiencyAdrenal Crisis
Fever
Vomiting / nausea
Abd Pain
Diarrhoea
Hypotension/Shock
Confusion / coma
+ Features of Ppt.
Event

19. CLINICAL FEATURES
Adrenal insufficiency
Chronic InsufficiencyAdrenal Crisis
General Anorexia Wt. Loss Fatiguiblity Gen. Weakness Salt craving
CVS Postural dizziness Hypotension
GIT Abd Pain Vomiting Diarhhoea
CNS Headache Depression Behavioural Changes
Dermatologic Pigmentation Darkened Skin Creases
Sexual
Characters Loss of Axillary and Pubic Hair in Females with Loss of Libido

20. Lab Abnormalities
 High (supine) Plasma Renin Activity (Earliest Abnormality)
 Increased Nightime ACTH levels
 Low ACTH stimulated Cortisol responses
At Crises Hyponatremia Hypoglycemia Hyperkalemia
Misc Eosinophillia Lymphocytosis

21. Antibodies in Autoimmune Adrenalitis
I. Adrenal Autoantibody (Adrenal Cortex)
II. 21- hydroxylase
III. Steroid Producing Cell Antibody
IV. Steroidgenic Enzyme Antibodies (P450scc, P450c17)
17-alpha hydroxylase Ab in autoimmune Addison’s strong predictor
for developing P.O.F.

22. Etiology of Adrenal
insufficiency
Idiopathic
(autoimmune
Adrenalitis)
Fungal infections
Adrenal hemorrhage
Metastasis
Sarcoidosis
Amyloidosis
Adrenoleukodystrophy
Adrenomyeloneuropathy
AIDS
CA hyperplasia
CA hypoplasia
ACTH hypo
responsiveness
Toxins/drugs
Tuberculosis
Others
Primary AI (Addison’s Dis.)
1. HPA –Axis suppression
• Exogenous-Glucocorticoids,
ACTH
• Endogenous-Cushing’s
syndrome – treated
2. Hypothalamic – pituitary disease
• Neoplasm-metastasis, pituitary
• Craniopharyngioma
• Infections –TB, Nocardia,
actinomyces
• Sarcoidosis
• Head trauma
• Isolated ACTH deficiencySecondary AI

23. Etiology of Addison’s disease
in developing countries
Addison’s disease in Africa — a teaching hospital experience
Steven Soule. Clinical Endocrinology (1999) 50, 115–120
Idiopathic
Active TB
Previous TB
Autoimmune
Malignancy
Sarcoidosis
Iron overload
Ad.leukodystrophy
(42%)
(18%)
(16%)
(12%)
(6%)
Soule et al. Clinical Endocrinology (1999) 50, 115–120

24. Changing Pattern of
Addison’s Disease

25. Autoimmune adrenal
insufficiency
Most common cause of 10AI
Serum Adrenal antibodies (AA) that react with all 3
zones of the adrenal cortex present in 60-75 %.
AA are more common in women, particularly those
with the polyglandular autoimmune syndrome (APS).
Patients with antibodies develop AI @~19% per yr.
In APS -1, the presence of AA has a 92 % predictive
value for the development of AI
Ahonen, P, et al. J Clin Endocrinol Metab 1987; 64:494.
Gylling, M, et al. J Clin Endocrinol Metab 2000; 85:4434.

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30. Causes of acute Adrenal
Insufficiency
Stress:
– Acute AI precipitated by infection, trauma,
surgery, emotional turmoil, etc
Failure to increase steroids
Bilateral adrenal hemorrhage
Bilateral adrenal artery emboli and
bilateral vein thrombosis
It also may occur as a complication of
radiographic contrast studies involving the
adrenal glands.
Bilateral adrenalectomy for any reason

31. Acute hemorrhage in bilateral
adrenals - caused acute adrenal
insufficiency
(Waterhouse-Friderichsen syndrome)

33. Twenty nine years old South Asian
Generalized hyper pigmentation of one
year duration
Mild asthenia, appetite normal
Ht 170 cm, wt 73 mg, BMI 24.8
BP 110/70 no significant postural fall
Gen. Hyper pigmentation of skin including
nails
Mucosal hyper pigmentation which was patch

35. Addison’s Disease and tuberculosis
Chung et al Clinical endocrinology 2001:54;633-39
Autopsies-
1376
Active TB
871
Extrapulmonary
261
Adrenal TB
52
Addison's Disease-
7

36. Effect of Rifampicin on
cortisol metabolism
Pharmacokinetics of Prednisolone in 8 patients on
rifampicin
Clearence increased by 50%
Tissue availibility reduced by 50%
Doubling of prednisolone dose when given in
combination with prednisolone
Allister et al Thorax 1982;37:792-93

37. Natural history
Some case reports of reversal of adrenal
function
Lack of normalization of adrenal function in 5
cases after one year of ATT
Long-term data not available
Bhatia E Clin endocrinol 1995;2007:20-23

38. CLINICAL AND LABORATORY
FEATURES OF ADRENAL CRISIS
Dehydration, hypotension, or shock out of proportion to severity
of current illness
Nausea and vomiting with a history of weight loss
Unexplained hypoglycemia
Unexplained fever
Hyperpigmentation or vitiligo
Hyponatremia, hyperkalemia, azotemia, hypercalcemia,
eosinophilia
Other autoimmune endocrine diseases like hypothyroidism or
hypogonadism

39. Clinical Features of Primary
Adrenal Insufficiency
100
92
86
75
33
31
16
16
12
10
100
94
91
15
5
Weakness, tiredness, fatigue
Anorexia
Gastrointestinal symptoms
Nausea
Vomiting
Constipation
Abdominal pain
Diarrhea
Salt craving
Postural dizziness
Muscle or joint pains
Weight loss
Hyperpigmentation
Hypotension (<110 mm Hg systolic)
Vitiligo
Auricular calcification
Percent
0 20 40 60 80 100 120

40. Hyperpigmentation of Addison's dis.

41. Lab Features of Primary
Adrenal Insufficiency
92
88
64
6
55
40
17
Electrolyte disturbances
Hyponatremia
Hyperkalemia
Hypercalcemia
Azotemia
Anemia
Eosinophilia
Percent
0 20 40 60 80 100 120

42. Endocrine testing
1. Urinary excretion of adrenal steroids and their metabolites
cumbersome -- rarely used (and needed)
2. Random serum cortisol measurements useless (secretion
pulsatile)
3. Plasma ACTH (N up to 50 pg/ml) elevated
usually>200pg/ml)in primary AI and low or Inappropriately
normal in secondary AI
4. ACTH stimulation test: Standard test for AI 0.25 mg
synacthen,cosyntropin (synthetic ACTH 1-24) given I/V or
I/M any time of day. Blood drawn for cortical 30 & 60
minutes later
– Normal response defined as peak cortisol of 18 to 20 mcg/dl or more

43. Logarithmic Plot of
plasma Cortisol as a
function of plasma
ACTH in pts with 10
AI, either untreated
or 24h after a dose
of hydrocortisone
(O), Normal
subjects (), & pts
with Pituitary
disease with or
without AI ().

44. Endocrine testing [contd.]
5. Low dose (1mcg) ACTH test recommended by
some; may diagnose subtle abnormalities of
HPA axis; difficult to organize
6. Insulin tolerance test ; tests entire HPA axis
– Intrepetation same as ACTH test
7. Prolonged ACTH stimulation test
– Used as alternative to plasma ACTH to tell between
primary and secondary AI.

45. Treatment of Acute Adrenal
insufficiency Adrenal Crisis)
Emergency Measures
1. Establish intravenous line with large –gauge
needle
2. Draw blood for electrolytes, glucose, cortisol, and
ACTH. DO NOT wait for results
3. Infuse 2 to 3 L of isotonic saline or 5% glucose in
isotonic saline. Monitor for signs of volume
overload. Reduce infusion rate, if indicated.
4. Supportive measures as needed.

46. TREATMENT OF AI DURING
STRESS
Intercurrent febrile illness, accident,or mental stress-double
daily glucocortocoid dose
Parenteral steroids if vomiting precludes oral intake
Minor surgery-50-100 mg hydrocortisone with premedication
Major operations-follow above with regimen for acute AI
In pregnancy,5-10 mg additional hydrocortisone needed per
day
In labor give saline drip & 50 mg hydrocortisone q 6 hrs

47. Addisonian crisis-Therapy
1. Hydrocortisone Na succinate /phosphate
– infusion @10-15 mg / hr ideal – pump.
2. Hydrocortisone Na succinate /phosphate
– boluses, 100 mg stat followed by 50 mg 4 hrly for 24 hours
3. Step down gradually over 72 hrs & overlap with orals.
4. Replace salt and fluid losses according to grade of dehydration.
5. Primary cases – mineralocorticoids
6. Dx and addressing precipitating illness.
7. Antibiotics

48. Addisonian crisis - Treatment
(Subacute Measures After
Stabilization of the Patient)
Search and treat the precipitating cause of the crisis
Short ACTH test to confirm AI (if not previously known)
Determine type and cause of AI (if not previously known)
Taper glucocorticoids to maintenance doses over 1-3
days, if precipitating illness permits.
Begin mineralocorticoid replacement with
fludrocortisone(0.1 mg PO daily)

49. TREATMENT OF CHRONIC
INSUFFICIENCY
Replace missing hormones –
– Glucocorticoids & mineralocorticoids in primary AI
– Glucorticoids in secondary AI
Hydrocortisone most appropriate glucocorticoid preparation; usual daily
dose 12-15 mg/sq m BSA; 50% on rising & 25% each at lunchtime &
early evening (Over treatment hazardous especially in children)
Fludrocortisone-only mineralocorticoid available;dose 0.05-0.2 mg daily
Females with 10 & 20 AI may benefit from adrenal androgen replacement
with DHEA at 25-50 mg/day (improves sexual function & well-being)
EDUCATION OF CRITICAL IMPORTANCE TO AVOID MORBIDITY
AND DEATH

50. Summary
Clinical presentation of Addison’s disease
can be very bizarre ; we need high index
of suspicion to diagnose it
Addison’s disease is not that rare in the
subcontinent in view of wide spread
presence of tuberculosis
Hypocortisol state because of postpartum
pituitary disease is likely to be a significant
problem particularly in rural areas

51. Summary
Chronic glucocorticoid replacement consists of hydrocortisone 15-25
mg/day in divided doses and dose monitoring is largely based on
clinical judgement.
Fludrocortisone 0.05-0.2 mg/day is given for substitution in
mineralocorticoid deficiency aiming at normotension,
normokalaemia and a plasma renin activity in the upper normal
range
It has recently been shown that, despite adequate glucocorticoid
and mineralocorticoid replacement well being in patients with
adrenal insufficiency is still impaired.
Several studies have demonstrated that dehydroepiandosterone 25-
50 mg/day p.o. may improve mood, fatigue, well-being and, in
women, also sexuality, suggesting that dehydroepiandosterone
should become part of the standard treatment regime.

52. Summary [contd.]
However, large trials of dehydroepiandosterone for adrenal
insufficiency are still lacking and it has not yet been approved
for the treatment of this disease.
Patients with adrenal insufficiency are at risk of adrenal crisis,
usually precipitated by major stress, such as severe infection
or surgery.
Early dose adjustments are required to cover the increased
glucocorticoid demand in stress.
Careful & repeated education of patients & their partners is
the best strategy to avoid this life-threatening emergency.

53. Central Hypocortisolism
Panhypopituitarism
Sheehan’s
Post surgery-tumours
Radiation
MPH Deficiency
Trauma
Developmental anomlies

54. Sheehan's syndrome
Eponyms & Synonyms:
Glinski-Simmonds syndrome
Reye-Sheehan syndrome
Simmonds-Sheehan syndrome
Simmonds cachexia
Simmonds syndrome
Reye's syndrome

55. History of SS
Superinvolution of uterus-gynecologists
Simpson-cl.course
Morris Simmonds-1914-pit destruction
German Medical Society 1939-proposed
Simmond’s disease to it.
1937 –Sheehan –clinical syndrome
(J Pathol Bacteriol)

56. Presentation
Acute-hemorrhage/shock- death
Sub-acute-lactation failure
Chronic-trophic hormone deficiency-lag
Atypical –
Psychogenic,hypoglycemia,Diabetes
Insipidus, Hyponatremia, Anemia etc.

57. Pathogenesis
ISCHEMIA –necrosis
physiological
enlargement in pregnancy and
Spasm/thrombosis
SCHWARTZMAN’S REACTION-endotoxin
AUTOIMMUNITY ( Engelberth 1965 Lancet)
Auto antibodies against 49-Kd cytosolic
antigen
19 SS & 28 controls.63.1% and 14.2% had
Pit-ab +
(R Goswami et al JCEM,2002)

58. Pathology
Pituitary.
Fibrillary scars- Normal- empty sella
Lymphocytic infiltration
Target organ.
Atrophy of varying grades-all target organs

59. Endocrine evaluation
Basal- T3,T4,TSH,LH,FSH,PRL.
Dynamic tests
1, HGH- ITT(Insulin tolerance test)
0.1U/kg I/V-0,30,60,90 &120 mt
Arginine ()
GHRH/GHRP2-6
L-Dopa (10 mg /KG)-
2,Prolactin-
CPZ (50 mg I/M)
PRL =20,30,60,90 and 120 mts
Metaclopramide test(10 mg I/V)=20,40,60
TRH(200 mcg I/V)-0,20,40 Serum TSH

60. Evaluation-contd
3, ACTH
Synacthene-250 mcg I/V-0,60 mts
cortisol (N>20mcg/dl)
Glugagon (1mcg I/V)
ITT
4, TSH
TRH/Triple test
5, Auto-antibodies
49-KDa

61. Evaluation-contd
Imaging
CT/MRI-
Empty sella
Sellar mass
Lympocytic hypophysitis
-uniform ,homogenous enlargement
- Dural enhancement
-sparing PP
MRS
-p/creatine ratio

62. MRI

63. Management
Acute-
Resuscitation-prevent severe
hypotension
Replacement
Steroids-Hydrocortisone/predinisolone-
Thyroxine-LT4 100-125 mcg/day
E+P = Cyclic
HGH= 0.1 U/kg/wk
Adult GHD-

64. Take home message
Secondary Adrenal insufficiency is not un
common
Autoimmunity is rarest
India-Sheehan's commonest
Tumours-pit
Hypophysistis Granulomatus causes –TB