DISORDERS OF ADRENAL CORTEX

1. DISORDERS OF ADRENAL CORTEX –
Mineralocorticoid excess and
deficiency
Presenter : SNEHA S R
Chairpersons :Dr Manjunath
Dr Rajeev
Dr Arvind
Dr Prashanth

2. ANATOMY AND
PHYSIOLOGY

3. Weight – 6-11 grams each
Arterial supply – superior , middle
and inferior suprarenal arteries
Venous drainage – right and left
suprarenal vein
Adrenal cortex (mesodermal )
from urogenital ridge
Adrenal medulla from neural
crest cells
Sixth to eighth week

4. 17 OH Pregnenolone
17 OH progesterone
11 Deoxycortisol
DHEA
Androstenedion
e
Cholesterol
SYNTHESIS

5. REGULATIO
N

6. E-NaC
MECHANISM OF ACTION
H+ secereted

7. MINERALOCORTICOID
EXCESS

8. PRIMARY
HYPERALDOSTERONISM
abnormality in the adrenal gland
itself
HIGH ALDOSTERONE
LOW RENIN
SECONDARY
HYPERALDOSTERONISM
Results from stimulation of aldosterone
secretion by renin angiotensin system
HIGH RENIN
LOW ALDOSTERONE
PSEUDO- HYPERALDOSTERONISM
Mimics mineralocorticoid excess
LOW RENIN AND LOW ALDOSTERONE

9. PRIMARY HYPERALDOSTERONISM
1. Bilateral Adrenal hyperplasia
• Micro nodular hyperplasia causing
autonomous adrenal excess
• It is more common than adenoma ;
• can be unilateral also;
2. Conn’s syndrome / adrenal adenoma
• Somatic mutations in channels and
enzymes responsible for increased
sodium and calcium influx in zona
glomerulosa has been identified as cause
for aldosterone producing adenomas ;
• usually unilateral and around 2 cm in
diameter

10. 3. Adrenocortical Carcinoma
Very rare – 1-2 per million . Aggressive , poor survival rate
Functional tumours are characterised by Cushing’s syndrome , virilisation, feminization
and hyperaldosteronism
4. Glucocorticoid remediable hyperaldosteronism / Familial hyperaldosteronism
Aldosterone
And Cortisol
• Rare ; Autosomal dominant ;
• Caused by chimeric gene resulting from
crossover promotor sequence responsible
for synthesis of GC and MC
• As a result aldosterone production is
regulated by ACTH production rather than
renin ; classically present as early onset
hypertension and strokes
• Important to identify because here
treatment with glucocorticoids will
suppress ACTH and hence aldosterone
production

11. CLINICAL FEATURES
Loss of potassium
HYPOKALEMIA
muscle weakness ,
hypokalaemia paralysis
severe hypokalemia
with low dose diuretics
Sodium retention
HYPERTENSION
Vascular and cardiac
remodelling
Refractory hypertension
and its complications
Loss of hydrogen ions
METABOLIC ALKALOSIS
Muscle cramps
Tetany
• Hypernatremia doesn’t occur due to sodium retention is accompanied by
concurrent water reabsorption
• Edema is typically absent despite volume expansion due to “aldosterone escape
phenomena” which involves atrial natriuretic peptide causing natriuresis , and
changes in electrolyte channels in distal nephron
• They can also have polyuria or polydipsia from hypokalemia induced nephrogenic
diabetes insipidus

12. ALGORITHM FOR THE MANAGEMENT OF PATIENTS WITH
SUSPECTED MINERALOCOTICOID EXCESS
Clinical suspicion
Patients with hypertension and
• Severe hypertension ( >3 antihypertensive , drug resistant ) or
• Hypokalaemia (spontaneous or diuretic induced ) or
• Family history of early onset hypertension or CVA at <40yrs of age
• Adrenal mass
Screening test
Measurement of aldosterone renin ratio
• Ratio of plasma aldosterone ( in ng/mL)/ plasma renin activity(in ng/ml/hr
• Stop ACE/ARB or spironolactone 4 weeks prior to test

13. Confirmation of diagnosis
Saline infusion test - Infusion of 2L NS over 4 hrs , serum aldosterone > 10ng/dL
( other tests : Oral salt loading test – 300 mmol Nacl/day
Fludrocortisone suppression test - 0.1mg q6h with 30 mmol NaCl q8h for 4 days)
Ratio > 30 is highly suggestive of primary
hyperaldosteronism
CT ADRENALS
• Fine cut scanning of adrenal region is the method of choice
• Readily identifies larger tumours suspicious of malignancy by may
miss lesions < 5mm
• The differentiation between B/L micronodular hyperplasia and
adenoma is important when surgery is feasible and desired
Ratio <30
Documentation of low renin &
low aldosterone
Urinary steroid profile
Cortisol/cortisone ratio

14. Unenhanced CT Adrenals
Unilateral
Adrenal mass
Normal adrenal
morphology
Bilateral micronodular
hyperplasia
Adrenal venous
Sampling ( AVS)
Medical management
( aldosterone antagonists ,
amiloride )
Unilateral
adrenelectomy
Lateralised
Negative
Age > 40 yrs ( surgery desired )
Age < 40 yrs
Family history of early onset
hypertension ??
Screen for Glucocorticoid
remediable aldosteronism (GRA)
Negative for GRA
Negative after AVS Positive
Dexamethasone
0.125 – 0.5 mg/day

15. Prevalence – 2% in general population
>1cm requires diagnostic evaluation

16. SECONDARY HYPERALDOSTRONISM
Hypertensive
Malignant hypertension
Renal artery stenosis
Renin secreting tumour
Aortic coarctation
Non hypertensive
Salt depletion due to any
cause
Bartter syndrome
Cardiac failure
Nephrotic syndrome
Liver cirrhosis
Clinical features – hypokalaemia , metabolic alkalosis +/-, hypertension +/-, oedema
HIGH RENIN and LOW ALDOSTERONE levels
Management – Treat the cause
ACE inhibitors and Aldosterone antagonists

17. PSEUDO – HYPERALDOSTERONISM
(LOW ALDOSTERONE LOW RENIN)
Acquired causes
• Cushing's syndrome
• Ingestion of licorice
Genetic causes
• Syndrome of apparent
mineralocorticoid excess
( SAME )
• Glucocorticoid resistance
• Liddle syndrome
• Mineralocorticoid receptor
mutation

18. • Cortisol is inactivated to cortisone ( which cannot activate mineralocorticoid
receptor in kidney ) by microsomal enzyme 11B-HSD2 mainly in kidney
• Both Cortisol and aldosterone can bind to mineralocorticoid receptor with equal
affinity and cortisol concentration is thousand fold higher than aldosterone. Thus
only rapid inactivation of cortisol to cortisone by above mechanism prevents
excessive activation of MCR pathway .
Syndome of apparent mineralocorticoid excess
( SAME )
• Cortisol acts as a potent mineralocorticoid if it
escapes this efficient inactivation as in seen in
mutations of 11B-HSD2 enzyme
• Manifests as severe hypokalaemic hypertension in
childhood
Glucocorticoid resistance
Upregulation of cortisol production due to steroid
receptor mutations resulting in flooding of MCR by
cortisol
MCR
Cushing’s syndrome
Cortisol concentration is beyond the inactivating capacity
of the enzyme
Licorice root ( athimadura) intake
has ingredients that inhibit this enzyme
Tissue specific modulator of MCR pathway

19. LIDDLE SYNDROME
Liddle syndrome is an autosomal dominant
disorder caused by mutations in the β- or γ-
subunit of the ENaC prevent binding to Nedd4
protein ,which is involved in degradation of the
channels.
The typical presentation of patients with Liddle
syndrome includes early-onset severe
hypertension, hypernatremia , hypokalemia,
metabolic alkalosis in the setting of low plasma
renin and aldosterone, low rates of urinary
aldosterone excretion, and a family history of
hypertension
The treatment is with a low sodium (low salt) diet and a pottasium sparing diuretics
(amiloride and triampterene ) that directly blocks the sodium channel.
Spironolactone is not effective because it acts by regulating aldosterone and Liddle
syndrome does not respond to this regulation.

20. ADRENAL INSUFFICIENCY

21. PRIMARY
ADRENAL INSUFFICIENCY
( “ Addison’s disease “ )
Destruction of adrenal cortex
Most common cause in western –
autoimmune adrenalitis
In India – 50% - tuberculosis
Characterised by loss of both
glucocorticoid and mineralocorticoid
secretion
SECONDARY
ADRENAL INSUFFICIENCY
Dysfunction of Hypothalamic pituitary
component
Most common is exogenous
glucocorticoid therapy
Characterised by loss of glucocorticoid
secretion only
ACUTE ADRENAL INSUFFICIENCY / ADRENAL CRISIS
• Crisis in patients with chronic adrenal insufficiency
precipitated by stress
• Sudden withdrawal of exogenous corticosteroids
• Adrenal haemorrhage or thrombosis

22. 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)
APLA syndrome,
Adrenoleukodystrophies
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)
Pituitary apoplexy
Isolated ACTH deficiency
POMC deficiency
PRIMARY ADRENAL INSUFFICIENCY SECONDARY ADRENAL INSUFFICIENCY

24. 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 )

25. ALGORITHM FOR THE MANAGEMENT OF PATIENTS WITH
SUSPECTED ADRENAL DEFICIENCY
Clinical suspicion of adrenal 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 < 18ug Cortisol > 18ug
Primary
adrenal inefficiency
Secondary
Adrenal insufficiency
Plasma ACTH
Normal / undetectable
Increased( >100pg/dL)

26. Primary adrenal inefficiency
High ACTH , low aldosterone ,
low renin
Adrenal glands enlarged
Secondary adrenal 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

27. Role of random serum cortisol
• Random serum cortisol measurements are of limited diagnostic value, because
baseline cortisol levels may be coincidentally low due to the physiologic
diurnal rhythm of cortisol secretion. It can also be affected by stress and
concurrent illness
• Many patients with secondary adrenal insufficiency have relatively normal
baseline cortisol levels but fail to mount an appropriate cortisol response to
ACTH, which can only be revealed by stimulation testing.

28. Insulin Tolerance Test
• ITT was regarded as the gold standard in the assessment of suspected
secondary AI, since hypoglycaemia is a powerful stressor that results in rapid
activation of the HPA axis.
• Intravenous insulin at a dose of 0.1 to 0.15 U/kg is given to achieve
hypoglycemia.
• Plasma glucose and cortisol are measured at 0, 30, 45, 60, 90, and 120
minutes after insulin infusion.
• Adequate hypoglycemia of <40 mg/dL with neuroglycopenic symptoms is
essential. Normal subjects have a plasma cortisol increase to at least 18 mcg/
dL. Plasma cortisol more than 20ug is considered positive for secondary
cushings
• During the test, close supervision is mandatory. Cardiovascular disease or a
history of seizures are contraindications to performing this test.

29. Treatment of
Acute Adrenal Insufficiency

30. ✓ Treatment should not be delayed while waiting for definitive proof of
diagnosis.
✓ Measurement of plasma electrolytes and blood glucose, appropriate samples
for ACTH and cortisol should be taken before giving corticosteroid therapy.
✓ Supportive resuscitation like airway and breathing should be sought
✓ The precipitating cause must be sought and appropriate treatment, e.g.
antibiotics should be instituted simultaneously
• May present with acute abdomen, nausea , vomiting and fever.
• May present as neurological disease with decreased responsiveness
progressing to stupor and coma .

31. Immediate Rehydration with normal saline or dextrose-saline ( around 2-3 litres )
should be started as quickly as possible with continuous cardiac / CVP monitoring
Glucocorticoid replacement with 100 mg hydrocortisone IV bolus and followed by
continuous intravenous infusion at 8 to 10 mg/hour or 50 mg IV/IM 6th
hourly
Once the patient is recovering the dose of hydrocortisone can be gradually tapered
and oral hydrocortisone or prednisolone can be substituted.
Once the dose of hydrocortisone is <50 mg/day, fludrocortisone in a daily dose of
0.1 mg should be added. ( because at higher doses hydrocortisone provides
sufficient stimulation of mineralocorticoid receptors

32. Treatment of
Chronic Adrenal Insufficiency

33. Glucocorticoid replacement for the treatment of chronic adrenal insufficiency
should be administered at a dose that replaces the physiologic daily cortisol
production
The glucocorticoids commonly used are hydrocortisone (15 to 25 mg in two or
three divided doses) or prednisolone (2.5 to 5 mg/day in two divided doses).
In all patients , at least one half of the daily dose should be given in the
morning . The next dose preferably around 4 pm

34. The dose of steroids should be adjusted depending upon features of under-
replacement (weight loss, lack of energy and increasing pigmentation) or over-
treatment (weight gain and hypertension).
Stress doses: Stress doses should be emphasised in all patients with AI.
In less severe forms of stress (fever, infections and surgery under local
anaesthesia) the dose of the glucocorticoid should be increased to 2 to 3 times
of daily dose for the duration of the stress.
In case of severe stress (e.g. surgery under general anaesthesia, severe
infections, major accident) higher doses of glucocorticoids should be provided
parenterally . A dose of hydrocortisone 150 to 200 mg/day in four equal doses
intramuscular or intravenous should be given initially, and gradually tapered
when the stress subsides.
Pregnancy may require an increase in hydrocortisone by 50% during last
trimester

35. Mineralocorticoid replacement in primary adrenal insufficiency should be
initiated at a dose of 100–150 μg fludrocortisone.
The adequacy of treatment can be evaluated by measuring blood pressure,
sitting and standing, to detect a postural drop indicative of hypovolemia. In
addition, serum sodium, potassium, and plasma renin should be measured
regularly
In patients living or traveling in areas with hot or tropical weather conditions,
the fludrocortisone dose should be increased by 50–100 μg during the
summer.
Dose may also need to be adjusted during pregnancy, due to the
antimineralocorticoid activity of progesterone, but this is less often required
than hydrocortisone dose adjustment

36. Adrenal androgen replacement is an option in patients with lack of energy,
despite optimized glucocorticoid and mineralocorticoid replacement.
It may also be indicated in women with features of androgen deficiency like dry
itchy skin and loss of libido.
Adrenal androgen replacement can be achieved by once-daily administration of
25–50 mg DHEA.
Treatment is monitored by measurement of DHEAS, androstenedione,
testosterone, and sex hormone–binding globulin (SHBG) 24 h after the last
DHEA dose.

37. While there is no specific treatment known to reverse features in patients
with an autoimmune (idiopathic) aetiology, these patients need to be
tested at onset and subsequently at yearly intervals for development of
autoimmune thyroid disorders (hypothyroidism or Graves’ disease).
Other organ-specific autoimmune disorders develop less frequently, but
should be kept in mind.
Infectious causes (tuberculosis, histoplasmosis) should be appropriately
treated, though recovery of adrenal function after treatment is unlikely.

38. This is most likely to occur with use of more potent glucocorticoids which
have longer duration of action, e.g. dexamethasone, high doses, prolonged
use and oral/ parenteral administration.
It is unlikely after inhalational or topical steroids, though rare instances of
adrenal insufficiency have been noted.
The use of prednisolone in doses of more than 20 to 30 mg/day for more
than 1 week, or in lower doses for more than 3 weeks , is likely to lead to
significant suppression.
However, glucocorticoids in physiological amounts (prednisolone <5 mg/day,
hydro-cortisone 15 to 20 mg/day), especially if given early morning, are
unlikely to lead to adrenal cortical suppression.
It should be tapered to physiological doses as soon as feasible to allow the
HPA axis to recover and then stopped.
Glucocorticoid-Induced Adrenocortical Deficiency

39. If daily dose of prednisolone is >30 mg, -- reduced by 10 mg weekly
once the daily dose is <30 mg– reduce by 5 mg weekly
After dose of <20 mg/day is reached -- by 2.5 mg every 2 to 4 weeks, can be
done.
After reaching physiological doses, the glucocorticoid can be given on
alternate days, thus allowing the HPA axis to recover faster.
At this time, the adrenal recovery should be studied by measuring the basal
cortisol or more accurately by using the short ACTH stimulation test (described
earlier). An 8 am serum cortisol or stimulated cortisol of >20 ug/dL, suggests
normal adrenal function and glucocorticoids can be discontinued. Testing may
have to be done on more than one occasion until recovery is documented.
Overall recovery of the HPA axis may take weeks to >1 year and is longer with
a higher dose and longer duration of treatment.

40. Congenital Adrenal Hyperplasia
(CAH)
▪ Mutations in genes encoding steroidogenic enzymes
▪ Depending on the exact step of enzymatic block , precursors
accumulate subsequent products are deficient
▪ All types are characterised by adrenal hyperplasia due to
increased ACTH
▪ Diagnosis is readily established by measurement of precursor
steroids accumulated , either in serum or urine

42. 21- Hydroxylase deficiency
Girls ­ Ambiguous genitalia
hirsutism and oligomenorrhea
Boys ­ precocious puberty and
advanced bone age.Salt loosing crisis ­ Na↓ K↑
and dehydration
Diminished feedback leading to increased ACTH which drives towards androgen synthesis

43. Diagnosis
• The diagnosis of classic 21 hydroxylase deficiency is made by measurement of
serum
17 OHP or its urinary metabolite pregnanetriol.
• Serum 17 OHP is >10,000 ng/dL and plasma renin activity is elevated. Supportive
tests include electrolytes and blood gas analysis.
• Late onset CAH on the after hand, has lower levels of 17 OHP, necessitating
stimulation by ACTH to establish a firm diagnosis. Basal 17 OHP (done at 8 to 9 AM)
is usually > 200 ng/ dL and stimulated 17 OHP ranges from 1500 to 2000 ng/dL.
Treatment
• This is aimed at replacing cortisol, with hydrocortisone or prednisolone, which will
also bring about the suppression of precursors and thereby androgen formation.
Simultaneously, fludrocortisone is administered. Added salt must be provided in the
first year of life, till the baby starts getting salt from table foods.
• Treatment of Late onset CAH includes glucocorticoids for suppressing androgen and
bringing about ovulation. Spironolactone may be added to give better relief of
hirsutism and estrogen – progesterone pills may be needed for regularisation of
menstrual cycles.

44. 11Beta- Hydroxylase deficiency
Deoxycortcosterone is a
potent mineralocorticoid
Hence accumulation causes
hypertension

45. 17a Hydroxylase deficiency
Girls – normal
Boys – ambiguous genitalia
Excess of mineralocorticoid causes
hypertension
Precursors accumulate
Subsequent hormones are deficient

46. Autoimmune polyendocrine
Syndromes ( APS)
“ Primary adrenal insufficiency is most commonly caused by
autoimmune adrenalitis. Isolated autoimmune adrenalitis accounts
for 30–40%, whereas 60–70% develop adrenal insufficiency as part of
autoimmune polyglandular syndromes (APS)”

48. Therapy of individual disease components is carried out as outlined
in other relevant chapters. Replacement of deficient hormones (e.g.,
adrenal, pancreas, ovaries/testes) will treat most of the
endocrinopathies
Understanding these syndromes and their disease manifestations
can lead to early diagnosis and treatment of additional disorders in
patients and their family members.

49. REFERENCES
• Williams textbook of Endocrinology
• Oxford Endocrinology and diabetes
• Harrison’s Principles of Internal Medicine ,19th
edition
• Medicine Update 2017
• API textbook of Medicine 10th
edition

50. THANK YOU