Tutorial Notes HUF2-30 Endocrine Tutorial II (Cushings Syndrome)

Some of the mucosa of the colon is inflamed.

Sulphasalazine is a first-line anti-inflammatory drug
Prednisone is a synthetic corticosteroid has a longer half-life and has little mineralocorticoid effect
Part 1
Q1.
Mild hypertension Mineralocorticoid effect of glucocorticoid; when there is excessive cortisol, cortisol
conversion to cortisone in the distal tubule of kidney is saturated and cortisone binds to
mineralocorticoid receptors.
Also, glucocorticoids stimulate vasoconstriction.
Weight gain but thin arms and legs ; Round and full face Central obesity due to lipogenesis in the
central trunk but lipolysis in the peripheral body.
Reduction in height bone density lowered due to increased bone resorption and reduction in
osteoblast activity.
Purplish stretch marks large amount of fat accumulated.
Skin bruises easily - thin and fragile capillary damaged.
Q2.
Due to mineralocorticoid effect of cortisol, excessive sodium is reabsorbed from the distal kidney tubule
in exchange for potassium and hydrogen ions, resulting in hypokalemia.
Glucocorticoid induces expression of gluconeogenic enzymes, promoting gluconeogenesis, thus
hyperglycaemia / anti-insulin effect
Q3.
The insulin level is higher due to hyperglycaemia. The increased gluconeogenesis is stimulated by
cortisol.
Q4.
Under CRH stimulation, ACTH level should rise but not cortisol level.
During exogenous cortisol administration, the high level of exogenous cortisol suppresses ACTH and CRH
release. Low ACTH results in atrophy of the cortisol-secreting cells in the zona fasiculata and zona
reticularis of the adrenal gland. Therefore, endogenous cortisol secretion is low even when stimulated by
ACTH induced by CRH stimulation.

Forensics 2019 Keith

Part 2
Sudden withdrawal of prednisone will result in secondary adrenal insufficiency. Postural hypotension is
observed in the patient.
Q1.
Glucocorticoid deficiency reduces vascular responsiveness to catecholamines and angiotensin, and loss
of inhibition on endothelial production of vasodilators, leading to hypotension.
Hypotension is worsened by diarrhoea and vomiting.
Also, atrophy of zona reticularis results in mineralocorticoid deficiency, leading to hypotension.
Low blood pressure is detected by the carotid sinus, stimulating tachycardia to increase cardiac output
to compensate the lowered blood pressure

Q2a
Hypotension, hypokalaemia due to deficiency of mineralocorticoid

Q2b
Pigmentation in primary adrenal insufficiency due to ACTH excess.
Aldosterone decreases in primary adrenal deficiency but not in secondary adrenal deficiency
Measurement of ACTH can differentiate between the two adrenal insufficiencies.
Primary adrenal insufficiency could be due to mechanical injury / autoimmune response against adrenal
gland; secondary adrenal insufficiency could be due to pituitary tumour.

Forensics 2019 Keith

 MEDU3400
HUF2-30 Endocrine Tutorial II
Cushings syndrome and secondary adrenal insufficiency
13 October 2015 (Tuesday)
14:30-15:15 h; Group s16A - s16H
15:30-16:15 h; Group s16I - s16P

Part 1

A 48-year-old woman was first diagnosed with ulcerative colitis about four years ago.
Crampy abdominal discomfort and explosive diarrhea led to the initial discovery of her
condition, and she was first treated using sulphasalazine (azulfidine). Eventually she required
glucocorticoid treatment (daily dose of 20 mg prednisone) to keep her symptoms under better
control, and this represented 4 times the physiological effect produced by normal daily output
of endogenous cortisol.

After several months of daily prednisone therapy, she developed mild hypertension (150/100
mm Hg). Her face became round and full. Though she gained 10 kg in weight and appeared
obese with a protuberant abdomen, her arms and legs were relatively thin. There were some
purplish stretch marks on her abdomen, but no palpable visceromegaly. She complained that
her skin tended to bruise easily. Over this period, she lost about 2 cm in height. More
recently, she experienced several episodes of lower back pain that eventually led her to be
hospitalized for further management. DEXA (dual-energy X-ray absorptiometry) scan
showed evidence of osteoporosis in the spine, wrist and femur.

Laboratory measurements gave the following plasma values:

Analyte Plasma values Reference intervals

Na+ 140 mmol/L 135-145 mmol/L
K+ 3.1 mmol/L 3.5-5.0 mmol/L
Glucose (fasting) 6.8 mmol/L 3.9-6.1 mmol/L, fasting
Cortisol (8 a.m.) 28 nmol/L 140-690 nmol/L (8 a.m.)
ACTH (8 a.m.) 0.7 pmol/L 2-11 pmol/L (8 a.m.)

Questions:

1. Explain how the glucocorticoid treatment would produce the various symptoms and signs
described in this patient.

2. How could you account for the abnormal plasma analyte values found in this patient?

3. How would the plasma insulin level of this patient compare with that of normal subjects?

4. How would you expect the plasma ACTH and cortisol levels in this patient to respond to
CRH stimulation?

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Part 2

Since lowering the dose of prednisone in this patient resulted in the re-emergence of
symptoms associated with ulcerative colitis, she eventually decided to have a colectomy.
Shortly after receiving surgery, the dose of prednisone was gradually reduced. About 8
weeks into the tapering process, she suffered gastroenteritis resulting in diarrhea and
vomiting. On the way to the washroom, she lost consciousness but quickly recovered and
found herself lying on the floor. She immediately sought help and was taken to the Accident
and Emergency Department where on examination, she was found to have a blood pressure
of 90/60 mm Hg supine, 60/40 mm Hg sitting, and her pulse rate/min was 110 supine and 134
sitting.

Laboratory measurements gave the following plasma values:

Analyte Plasma values Reference intervals

Na+ 130 mmol/L 135-145 mmol/L
K+ 3.6 mmol/L 3.5-5.0 mmol/L
Glucose (fasting) 2.9 mmol/L 3.9-6.1 mmol/L, fasting

Questions:

1. Explain why this patient gave such values in blood pressure and pulse rate.

2. In what ways the clinical presentation and the findings of plasma analyte values in this
subject (a) have in common, and (b) differ from those of a patient with primary adrenal
insufficiency. The measurement of which hormone(s) can help in differentiating between
primary and secondary adrenal insufficiency.

Useful references:
Cushings syndrome
http://www.niddk.nih.gov/health-information/health-topics/endocrine/cushings-
syndrome/Documents/Cushings_Syndrome_508.pdf
Adrenal insufficiency and Addisons disease
http://www.niddk.nih.gov/health-information/health-topics/endocrine/adrenal-insufficiency-addisons-
disease/Documents/addisons_508.pdf

Adrenal Insufficiency published in Lancet, 361: 1881-1893, 2003

(http://ac.els-cdn.com/S0140673603134927/1-s2.0-S0140673603134927-main.pdf?_tid=ba7fe314-
6cc0-11e5-83d2-00000aacb35e&acdnat=1444201252_32013295de4e1c4be42967dfb48d43cd)

Adrenal Insufficiency published in Lancet, 383: 2152-2167, 2014

(http://ac.els-cdn.com/S0140673613616840/1-s2.0-S0140673613616840-main.pdf?_tid=a2f13856-
6cc0-11e5-aceb-00000aab0f26&acdnat=1444201212_631e402b8b07c426208a6bc898080036)

The approach to the adult with newly diagnosed adrenal insufficiency published in Journal of
Clinical Endocrinology and Metabolism, 94: 1059-1067, 2009
(http://jcem.endojournals.org/cgi/content/full/94/4/1059)

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