Cushings syndrome

Introduction

Signs and symptoms

Basic physiology

Body
system
Fat

Skin

Bone

Muscle

Adrenal cortisol secretion has some circadian

rhythm. Peak in morning and low in evening.
The syndrome is a constellation of clinical
features but can be due to:
ACTH dependent
-

Pituitary corticorope adenoma (Cushings

disease)
o 90% corticotrope pituitary
microadenoma
Ectopic secretion of ACTH by nonpituitary
tumour

ACTH independent
-

Adrenocortical adenoma
Adrenocortical carcinoma
Nodular adrenal hyperplasia

Cardiovasc
ular

Metabolism
Reproductiv
e
CNS

immune
Haem

Signs and symptoms

Weight gain, central obesity, rounded
(moon) face, fat pad on back of neck
(Buffalo hump)
Facial plethora
Thin and brittle skin
Easy bruising
Broad purple stretch marks
Acne
Hirsutism (male features in females)
Hyperpigmentation if ACTH excess
Osteopenia and osteoporosis
(vertebral fractures)
Decreased linear growth in children
Weakness
Proximal myopathy
Hypertension
Hypokalaemia
Oedema
Atherosclerosis
Glucose intolerance
Dyslipidaemia
Decreased libido
Amenorrhoea (cortisol inhibition of
GnRH)
Irritability
Emotional lability
Depression
Cognitive
Paranoid psychosis
Increased infection susceptibility
Hypercoagulation (increase DVT and
PE risk Increased WBC
Eosinopaenia

Risk factors
1.
2.
3.
4.
5.

Female gender
Hypertension
Glucose intolerance or diabetes mellitus
Unexplained fractures
Unexplained nephrolithiasis (kidney
stones)

Diagnostic tests
Initial
1. Urine pregnancy test (negative)
2. Serum glucose (elevated)
3. Late night salivary/plasma cortisol
(elevated)
4. 24 hour urinary free cortisol
(>50micrograms/24hour)
Dexamethasone suppression test
Potent glucocorticoid used to suppress
CRH/ACTH.
Autonomous cortisol production (Adrenal
nodule) = no suppression of cortisol as ACTH
is already suppressed
Ectopic source of ACTH = no effect as tumors
usually resistant to dexmethasone
suppression
ACTH producing pituitary adenoma =
ineffective at low doses, effective at high
doses
1mg overnight = morning >50nmol/L
48 hour 2mg (lose dose) = morning
>50nmol/L
High dose = <50% of baseline value
ACTH stimulation test
Assessment of glucocorticoid deficiency
involving cosyntropin (ACTH) and collecting
samples at 0,30,60 minutes for cortisol.
Normal response >20ug/dL or increment of
>10ug/dL.
Alternative test = insulin tolerance test
(hypoglycaemia)
-

Normal response is cortisol >20ug/dL

and GH >5.1ug/L

Step by step screening of cushings

1. Positive test for increased cortisol
2. Test ACTH
a. High = ACTH dependent
b. Low = ACTH independent

Imaging
Should only be used once it is establish the
cortisol increase is ACTH dependent or
indepent. This is because nodules in the
pituitary or the adrenal are common findings.
CT chest and abdomen lung, thymus and
pancreas
MRI of chest carcinoid tumours show high
signal intensity on T2 weight images.
Bilateral inferior petrosal sinus
sampling
-

Concurrent blood sampling for ACTH

in the right and left inferior petrosal
sinus and a peripheral vein.
Increase in the ratio of ACTH in
central/peripheral measured after
injection of CRH.
Test for cushings disease

Pathogenesis
Excess cortisol
Inhibition of bone formation and
collagen
-

Decreased synthesis of type I collagen

Increased osteoblasts and decrease
osteoclast production
Decreased intestinal calcium
absorption (leads to osteoporosis)

Metabolic
-

Gluconeogenesis = weight gain and

central obesity
Increased protein catabolism
proximal myopathy
Collagen breakdown striae
Increased lipolysis
Decreased insulin sesntivity - diabetic
risk

Differential diagnosis
-

Treatment
Exogenous Cushings involves management of
medications
Cushings disease ACTH secreting pituitary
tumour
-

Androgen
-

Cortisol interacts with adnreogen

receptor
o Acne
o Hirsutism

Renal effects
-

Mineralcortico effects
Hypokalaemia, hypernatremia,
hypertension (also vasoconstriction)

Decreased growth hormone

Immune and anti-inflammatory effects
-

Synthesis of lipocortin that inhibits

phospholipase A2
Inhibite IL2 and T lymphocytes
Inhibit histamine and serotonin from
mast cells and platelets

CNS

Mood changes and depression

If middle age, patient can be difficult to

diagnose from metabolic syndrome in mild
cushings.
Obesity

Transphenoidal pituitary adenomectomy

(higher success rate <1cm)
o Medical therapy before surgery e.g.
somatostatin analogue,
steroidogenesis inhibitors,
glucocorticoid receptor antagonist
o Post surgery corticosteroid therapy
Medical therapy alone
Pituitary radiotherapy

Other tumours
-

Surgery + steroidogenesis inhibitors therapy

Chemotherapy and radiotherapy for primary
tumour

PBL case summary

Initial presenting signs
I had the pleasure to see Maddie today a 15 year old girl presenting with a mild respiratory tract
infection and weight gain on a background of steroid treatment for Systemic Lupus
erythematous. She is prescribe a maintenance dose of 7.5-10mg of Prednisolone orally with
hydroxychloroquine to control her SLE.
Medication non-compliance
She has had two admission for acute SLE exacerbation in the last 6 months with increasing joint
pain and fever. For both admissions high dose prednisolone therapy was started and taper to
maintenance dose for discharge. In addition do that she has had other SLE exacerbations and has
developed red striae. Maddie does not like the prednisone as it makes her tired, gain weight,
hungry and affects her sleep. It is suspected Maddie is non-compliant with her medication which
was later confirmed with low ACTH and Coritsol. Her mother has also concerned about her
medication intake. Review of her SLE medication and education of her condition is considered to
improve compliance and disease control.
Psychiatrics
Maddie also reports of self induce vomiting three times after binge eating. She state she is
depressed about her weight and her physical appearance. She mentioned about a cousin
committed suicide as a teenager. This warrants a psychiatric review.
Sleep
Maddie reports of insomnia and would not fall asleep until early hours of morning. This is
affecting her school performance.
Cushing syndrome
Maddie experiences the side effects of weight gain (BMI of 27.2), sleep disturbance, red striae,
plethoric face and loss of supraclavicular space with small cervical fat pad. Her respiratory
infection could be predisposed by her compromised immunity but her chest exam was
unremarkable with unproductive dry cough. Other aspects of her physical exam were normal. Her
blood results show dyslipidaemia and increased insulin and thus it should be considered to
discuss diet and cardiovascular health.
SLE history
Maddie was diagnosed with SLE at age 12.5 years and responded well to therapy. She has no
evidence of renal or neurological complications. Her disease manifestation mainly consist of fever
and joint pain.
Development
Regarding her development, she is on the lower percentile of height and weight before SLE
diagnosis and her BMI was in normal range. By the time she reach 15 years of age is was in the
overweight range of BMI.
Her first period was just after her 12th birthday and she has periods most months.
Social
Maddies parents are divorced and she lives with her mother and two younger brother. Her
mother is concerned about her condition. Maddie has a small groups of female friends at school.
Teachers at school have commented on a personality change and deterioration in school work.
Summary
Overall, Maddie is a 15 year old girl with SLE presenting with cushing syndromes due to