ENDO 22 SCL Data

interpretation of
adrenocortical dysfunction
 QUESTION 1
A 50 yr old man presented to his physician complaining of unexplained weight gained
mostly around his belly, face and shoulders. In addition, he had purple stretch marks on
his abdomen. On examination, he was hypertensive with blood pressure of
167/110mmHg. He had centripetal (truncal) obesity with thin extremities, a buffalo hump
(interscapular fat accumulation), a “moon” face, and purple striae on his abdomen. Table
1 shows his laboratory results obtained in the fasting state:

A low-dose dexamethasone suppression test was performed which showed that the
patient’s serum cortisol remained elevated. CT scan of the adrenal showed an 8cm mass
(adenoma) on the right adrenal gland. The adenoma was surgically removed 1 week later
a) What is the patient’s diagnosis and why?
- Cushing’s syndrome. It is due to the adenoma (adrenal
tumor) on the adrenal gland which releases excess
amounts of the hormone cortisol.
 b) Which hormone was responsible for his truncal obesity, a buffalo
hump, muscle wasting, striae and hyperglycaemia and how are these
abnormalities caused by the responsible hormone?
The hormone responsible is Cortisol.

Truncal obesity - Fat tissue redistribution in CS leads to central obesity and metabolic
complications

Buffalo hump - High levels of the hormone cortisol can lead to increased fat synthesis. With Cushing
syndrome, the fat produced often deposits in the neck, known as lipodystrophy. This produces the
characteristic buffalo hump.
Muscle wasting - Overproduction of cortisol causes liberation of amino acids from muscle
tissue with resultant weakning of protein structures (specifically muscle and elastic tissue).

Striae - Glucocorticoids also increase catabolism of proteinaceous tissues such as collagen,

causing skin atrophy fragility with striae and easy bruising

Hyperglycemia - Cortisol affects carbohydrate metabolism by increasing blood glucose levels

through ↓ tissue uptake of glucose, ↓ conversion of glucose to G6P (anti insulin) and ↑
gluconeogenesis in liver. Therefore, long term increase in cortisol can cause hyperglycemia.
c) Why was his ACTH level so low?

It is due to negative feedback loop in the

hypothalamic-pituitary-adrenocortical axis
High levels of cortisol will inhibit the release of CRH from
hypothalamus and ACTH from anterior pituitary
Hence, ACTH level is reduced
 d) Which aetiologies of
hypercorticolosm were ruled out by his
decreased serum ACTH?

Pituitary adenoma
Ectopic ACTH secreting tumor
 Q1. e) How do healthy people respond to
low-dose dexamethasone test?

i) Was the patient’s response normal?

The response is normal in healthy subjects which showed presence of suppression.

ii) If not, why?

False positive result may occur due to the:
- use of oral contraceptive pills containing estrogen as estrogen increase
cortisol-binding globulin leading to an increase in total cortisol. Thus, women
who are taking oral contraceptive pills should discontinue use 6 weeks prior to
the test.
- use of phenytoin, phenobarbitone, carbamazepine, rifampicin, and alcohol as it
can induce CYP3A4 and increase hepatic clearance of dexamethasone.

Reference: https://emedicine.medscape.com/article/2114191-overview#a2
 Q1. f) Why was the patient’s blood pressure
increased?

High cortisol stimulates renal reabsorption of sodium and enhances

vascular sensitivity to catecholamine and angiotensin II. Angiotensin II will
stimulate vasoconstriction and thus increasing the blood pressure.

Reference: https://pubmed.ncbi.nlm.nih.gov/20829617/
https://www.endocrine-abstracts.org/ea/0037/ea0037ep29
Q1. g) Why was the patient’s serum potassium decreased?
Cortisol has mineralocorticoid properties that increase K secretion and Na
reabsorption by the renal principal cells; thus, this increase secretion of
potassium will cause hypokalemia

In normal condition, found that the 11β-hydroxysteroid dehydrogenase type 2

(11β-HSD2) enzyme in the renal tubule can convert active cortisol into inactive
cortisone to prevent the MR from binding the cortisol

Patients with CS as well as hypokalemia had relative defects in the 11β-HSD2

activity. Therefore, redundant cortisol played a mineralocorticoid-like effect via
combining with MR, leading to the increased urinary potassium excretion and
sodium retention and further led to hypokalemia
Q1. g) Why was the patient’s serum potassium decreased?
Q1. h) In women, this syndrome causes masculinization,
with increased body hair, acne, and irregular
menses. Why does it have these effects on women?
The adrenal cortex also secretes androgen dehydroepiandrosterone (DHEA).
Adrenal cortex is the major source of androgen in women. The hyperactive
adrenal cortex secretes a large amount of adrenal androgens, which have
masculinizing effect. DHEA is the precursor for testosterone.
 QUESTION 2
A 43-year-old lady recently saw her physician because of several unexplained symptoms,
including weight loss of 8kg, extreme fatigue, decreased body hair in the axillary and pubic
regions and irregular menses. In addition, her skin was very tanned, even though she had not
been in the sun. On examination, she appeared thin with sunken eyes and decreased skin turgor.
Her blood pressure was 90/60 mmHg (supine) and 70/45 mmHg (on standing) with a pulse rate of
105 beats/min. She also had deeply pigmented skin especially her nipples and the creases in the
palms of her hands. Her laboratory investigations are shown in Table 2:
Results of an ACTH Stimulation Test were negative. Based on the symptoms, physical
examination, laboratory values and results of the ACTH stimulation test, the patient was given
a diagnosis and appropriate treatment was commenced. At a follow-up visit 2 weeks later, her
circulating ACTH levels were normal. She had gained 3kg, her blood pressure was normal
(both supine and standing), her tan had started to fade and she had much more energy.
 a) What is the patient’s diagnosis and why?
● Addison disease
● The patient has the clinical features of Addison Disease which are weight loss, hypotension, fatigue,
hyperpigmentation and decreased body hair.
 b) How did this disease cause her decreased blood pressure?

● Decreased blood pressure occurs because serum aldosterone and cortisol are low.
● In low serum aldosterone level, there is decrease Na reabsorption, decrease blood volume hence
decrease BP.
● In low serum cortisol level, there is less b1 adrenergic receptor upregulation which reduces the
responsiveness of blood vessels to catecholamines. This will reduce TPR (total peripheral
resistance) and BP.
c) Why did her blood pressure decrease further when she moved from a supine
position to a standing position?
This condition is called orthostatic hypotension where there is hypovolemia condition. When
she stood up, blood pooled in the veins of the legs, that will be decrease the venous return to
the heart
D) Comment on her following results:

• fasting blood glucose

Hypoglycemia because decreased cortisol level.
• serum potassium concentration
Hyperkalemia because decreased level of aldosterone.
• serum sodium concentration
Hyponatremia because decreased level of aldosterone
e) What acid-base abnormality did the patient have?

Low plasma pH (acidic)

+
Low serum bicarbonate
=
Metabolic acidosis
 What was its cause?
● D/t aldosterone insufficiency
○ role of aldosterone: increase Na reabsorption, K excretion by principal cells
● This leads to failure of
○ aldosterone indirectly stimulates renal acid excretion by enhancing ENaC for sodium reabsorption
○ increased Na reabsorption enhances lumen-negative transepithelial voltage that facilitates proton
secretion by neighboring type A intercalated cells
○ increased K secretion enhances activity of H+/K+-ATPase in type A intercalated cells, promoting
proton secretion
○ this indirect coupling of Na reabsorption, K secretion and proton secretion
● Decreases acid secretion in the kidney
● Higher level of H+ accumulate in the proximal convoluted tubule (for Na+/H+ exchanger)
● Lesser conversion of H2CO3 into H+ and HCO3- occur
● Low serum bicarbonate
● Results in renal tubular acidosis (RTA)
f) If her PCO2 had been measured, would you expect it to be
normal, increased or decreased? Why?
- Decreased

- To compensate the metabolic acidosis due to

decreased serum bicarbonate
- Respiratory rate increase
- Hyperventilation occur
- Lungs try to remove as much CO2 as possible
- To reduce acidity of blood
 g) Why did the patient’s skin appear tanned
(hyperpigmentation)?
- Low levels of cortisol in the blood increases the production of ACTH in the
pituitary
- ACTH has melanocyte-stimulating activity that causes the hyperpigmentation
of skin (palmar creases, areola, buccal mucosa)

h) Why did she have decreased pubic and axillary

hair?
- It is due to the lack of adrenal androgen caused by adrenal insufficiency.
- Androgen plays a role in reproductive health and body development.
 i) Why did her ACTH level return to normal within 2 weeks of starting
treatment?
● Because the amount of cortisol released from adrenal is sufficient enough to give negative
feedback to production of ACTH and CRH.
 J) WHAT DO YOU THINK IS THE TREATMENT COMMENCED ?
➔ HORMONE REPLACEMENT THERAPY :-
◆ HYDROCORTISONE (TO REPLACE CORTISOL) - ORAL/IV
◆ FLUDROCORTISONE (TO REPLACE ALDOSTERONE) - ORAL
◆ ADRENAL ANDROGENS (DHEA) - FEMALE

➔ SUPPORTIVE TREATMENT :-
◆ TB - ANTITUBERCULAR THERAPY

➔ NON-PHARMACOLOGICAL :-
◆ HIGH SODIUM INTAKE - IF NEEDED
◆ FOLLOW THE MEDICATION GIVEN
K) The patient was instructed to take the medication in 2 divided doses, with a larger dose at 8am. Why?

This is because to restore the cortisol level to normal,

which is high during morning.Hence, bigger dose is given
during morning. Cortisol level is through/low during
night, therefore the dosage for the medication will be
smaller than the morning dose
 QUESTION 3
A 57-year-old man complained of generalised muscle weakness and headaches. On physical
examination, he appeared healthy. However, his blood pressure was significantly elevated at
180/100, both in the lying (supine) and standing positions. His physician ordered laboratory tests
on his blood and urine (Table 3):

Normal
Hypokalemia
High
Low

Alkalosis
High (Compensation)
High
The physician then suspected that the patient’s hypertension was caused by an
abnormality in the renin-angiotensin II-aldosterone system. He ordered the
following tests (Table 4):
Q3. a) What is the most likely diagnosis and why?

- Conn’s syndrome
- 1 hyperaldosteronism
- Decrease plasma renin
- Hypertension
- Muscle weakness as result to hypokalemia
- Metabolic alkalosis with respiratory compensation
- High bicarbonate level
- Hypocreatinemia
- Elevated potassium excretion
-
 fareesha

Q3. b) Explain his hypokalaemia

In Conn’s syndrome, it will cause cortex to produce too much aldosterone . The
excess aldosterone will stimulate the ENaC in collecting duct to reabsorb more
sodium ions, thus tubular lumen become more negative. This will lead to secretion of
Hydrogen ions and potassium ions into the lumen. Too much loss of K+ into urine
leading to hypokalemia.
Q3. c) What acid-base abnormality did the patient
have? What was its aetiology? What is the appropriate
compensation for this disorder?

- Metabolic alkalosis.
- Due to increased renal hydrogen ion loss mediated by hypokalemia and
hyperaldosteronism.
- Respiratory compensation.
 QUESTION 4
A couple recently had their second child, a baby girl. A day after delivery, the
paediatrician told the couple that their daughter’s clitoris was enlarged. The
paediatrician ordered a chromosomal evaluation, which confirmed an XX
(female) genotype. Other tests showed that she has ovaries, a uterus and no
testes. Her lab investigations are shown in table 5.

The consulting paediatric endocrinologist made a diagnosis and recommended that

the baby girl receives hormone replacement therapy. She was also to undergo
surgery to reduce the size of her clitoris.
 a) What is the diagnosis? Give your reasons.
➔ Congenital adrenal hyperplasia (21-hydroxylase deficiency)

➔ High plasma 17-OHP level

➔ Enlarged clitoris (ambiguous genitalia due to high adrenal
androgens)
➔ Low-normal serum cortisol with high serum ACTH causing the
hyperplasia of adrenal glands(partial enzyme deficiency)
 b) Using your knowledge of biosynthetic pathways of the adrenal
cortex, predict consequences of enzyme deficiency in this case.
Which adrenocortical hormones will be deficient? Which
hormones will be produced in excess?
In this patient, the blood test result shows elevated concentration
of 17-hydroxyprogesterone within a day after birth. A greatly
increased concentration of 17-hydroxyprogesterone may indicate
21-hydroxylase enzyme deficiency. There will then be a deficiency of
cortisol and aldosterone. Accumulation of 17-hydroxyprogesterone
will later convert to adrenal androgen.
c) What are the expected physiologic consequences of
the hormonal deficiencies you predicted in (b)?
Cortisol deficiency: hypotension and hypoglycemia.

Aldosterone deficiency: hypotension, hyperkalemia, and metabolic

acidosis.
 d) why was the baby’s serum ACTH level increased?
21a-hydroxylase deficiency lead to
- reduce conversion of 17a-hydroxyprogesterone to 11-deoxycortisol (precursor of cortisol)
-reduce conversion of progesterone to 11 deoxycorticosterone (goes to form aldosterone)
-as a result, adrenal steroid precursors are shunted into androgen pathway
-Because negative feedback by cortisol to the hypothalamic-pituitary-adrenal axis is lacking in
fetus
-Adrenal gland experience high level of ACTH.
 e) The baby’s blood glucose and serum cortisol were both low-normal. Why
weren’t these values more obviously abnormal?
Blood glucose and serum cortisol were both low-normal, because there is an increase in the
level of ACTH. High levels of ACTH will cause hyperplasia of the adrenal cortex. The
hyperplastic adrenal cortex will synthesize more cortisol that masked the original deficiency.
Low glucose seen is due to the presence of gluconeogenesis..

The patients might also be experiencing partial enzyme deficiency, because cortisol is still
being produced.
 f) Why was the baby’s clitoris enlarged at birth?

● genetic defect in one of the adrenal enzymes involved in synthesizing adrenal

steroid hormones from cholesterol occur
● causing low cortisol and aldosterone
● Low cortisol cannot regulate ACTH level, ACTH continue to increase &
overstimulate adrenal glands
● The accumulating precursors act as substrate to androgen production
● High androgen cause virilization(manly development) of external genitalia in
the female affected
● Thus clitoromegaly occur
 g) Did she have partial or complete deficiency of the
enzyme?

Partial deficiency of 21B-hydroxylase. This is because the adrenal cortex still

managed to produce low normal level of cortisol. If she had complete
21B-hyrdoxylase deficiency, she would have secreted no cortisol and no
aldosterone
 h) What hormone replacement therapy did she receive?
● Replacement of glucocorticoid (hydrocortisone) to suppress ACTH
production which causes excessive androgen synthesis
● Mineralocorticoid (fludrocortisone) may be given but plasma 17-OHP,
androstenedione and testosterone level must be monitored
i) In terms of later development, what might have happened if
the baby’s condition had not been diagnosed (and she did not
receive hormone replacement therapy)
She would further masculinize due to continuously high levels of adrenal
androgen. She would have increased muscle mass, increase body hair,
irregular menses, or amenorrhea. Finally, because androgen can cause
closure of epiphyseal growth plate, her final adult height would be
shortened
THANKS!