Cushing syndrome Flashcards
What is the definition of Cushing’s syndrome?
Cushing’s Syndrome is the clinical state produced by chronic glucocorticoid excess
What is the definition of Cushing’s Disease?
Cushing’s Disease is Cushing’s syndrome caused by bilateral adrenal hyperplasia from an ACTH secreting pituitary adenoma (usually a microadenoma)
What is Nelson’s syndrome?
Occurs post bilateral adrenalectomy resulting in unsuppressed ACTH production
This results in
1) Macroadenomas of the pituitary to inc ACTH production 🡪 mass effects
- visual disturbances (due to compression on optic chiasm)
- headaches (due to infiltration into bony structures / meninges)
2) Excessive ACTH =
- ↑ beta-MSH and ACTH
- hyper-pigmentation of the skin
What are the causes of ACTH independent Cushings?
Adrenal adenoma, carcinoma or Bilateral adrenal hyperplasia (i.e. Primary Hypercortisolism)
Iatrogenic (99%): Steroids, TCM, Jammu
What are the causes of ACTH dependent Cushings?
Pituitary disease (Cushing’s disease)
- Adenoma
- Hyperplasia
Ectopic ACTH
- Small cell lung carcinoma (can also produce PTHrP)
- Carcinoid tumour
Ectopic CRH
- Medullary Thyroid carcinoma
What are the signs suggesting suggesting adrenal carcinoma as underlying cause of Cushing?
- Palpable abdominal mass
- Signs of virilisation in females: acne & hirsutism (since carcinoma will not only increase cortisol production but also androgen production)
- Gynaecomastia in males
What are the signs suggesting suggesting ectopic ACTH production as underlying cause of Cushing?
Ectopic ACTH tumors tend to be more aggressive, releasing more cortisol with lesser time for physical changes to occur
- Absence of Cushingoid body habitus unless tumour has been slow growing and allowed time for Cushingoid features to develop
- More prominent oedema and hypertension
- More severe muscle weakness from hypokalaemia
- History usually of more rapid onset of symptoms and signs
- Pigmentation (only in ACTH dependent)
What are the presenting complications of someone with Cushing’s?
Increase appetite and weight
Skin changes
Change in appearance
Metabolic Syndrome: DM, HTN, HLD
Hypokalaemia due to mineralocorticoid effect: Arrhythmia, Weakness
Muscle weakness (Proximal myopathy)
Osteoporosis: Any recent #, bone pain / spine pain
Poor Immune system: recurrent illnesses
Mood changes (depression, lethargy, irritability, psychosis): Result of cortisol’s effect in the degradation of hippocampus
Sleep disturbances
Erectile dysfunction (men) or amenorrhea & hirsutism (women)
What are the skin changes in a patient with Cushing’s?
- Acanthosis nigricans from IR (areas of dark, velvety discoloration in body folds and creases)
- Easy bruising
- Acne, hirsutism
- Purple striae typically on abdomen
- Hyperpigmentation (only in ACTH dependent cushing’s)
What are the changes in appearance in a patient with Cushing’s?
- Rounded countenance, moon-like facies, lemon on sticks appearance
- Supraclavicular fat pad & dorsocervical fat pad (Buffalo Hump)
- Facial plethora
Why will a patient with Cushing’s have muscle weakness?
Due to catabolic effect of cortisol
Also due to hypoK which causes muscle weakness
What hx would you ask to elucidate aetiology of cushing syndrome?
Use of any exogenous steroids / TCM
Any S&S of
- Lung Ca
- GI Ca, Carcinoid Syndrome
Central
- Hyperpigmentation;
- Mass effect in pituitary – BOV, Headache. Rare B/c most ACTH-producing adenomas are MICROADENOMAS <1cm
Past Medical History/Drugs
- Previous history of endocrine condition
- History of hypertension, diabetes
- Any current treatment with long-term steroids?
- Any TCMs/Jammu?
Family History
- Family history of any pituitary tumours?
What signs to look out for in the upper limbs when examining a patient with Cushing’s?
Thin arms (Lemon on sticks)
Fingers for etiological clues
- Clubbing, tar staining (lung cancer)
- Joint deformities in RA, SLE (exogenous steroid use)
- Rashes: dermatomyositis, psoriasis, SLE
Skinfold thickness on the backs of hands (double pinch test – pinch pt’s skin & your own)
Bruising
Proximal myopathy
What signs to look out for in the face when examining a patient with Cushing’s?
- Conjunctival pallor (BGIT from steroid)
- Cataracts
- Acne & Hirsutism
- Telangiectasia (small dilated vessels near skin surface/mucous membranes)
- Plethora (red, florid condition: ensure absence of polycythemia)
- Moon-like facies (use “Rounded countenance” instead in the presence of patient)
- Oral thrush
What signs to look out for in the neck when examining a patient with Cushing’s?
- Acanthosis nigricans
- Supraclavicular fat pads
- Dorsocervical fat pad (Buffalo hump)
What signs to look out for in the trunk when examining a patient with Cushing’s?
- Central obesity
- Purple striae
- Palpate for bony tenderness of vertebral bodies (crush fractures from osteoporosis: steroid anti-Vitamin D effect and increased urinary Ca2+ loss)
- Hepatomegaly (fat deposition, adrenal carcinoma deposits)
What signs to look out for in the lower limbs when examining a patient with Cushing’s?
- Proximal myopathy
- Bruising
- Poor wound healing
- Palpate for oedema (salt and water retention)
What are examinations to perform in a patient with Cushing’s?
Blood pressure
Urine dipstick (glycosuria)
Respiratory examination (lung cancer, ILD, asthma)
Abdo Exam for adrenal masses (adrenal carcinoma palpable over renal area)
Visual field testing
- Bitemporal hemianopia in pituitary tumour
- Not likely in Cushing’s because it is usually a microadenoma)
Fundoscopy (optic atrophy, hypertensive, diabetic changes)
What is the workup for exogenous steroid use?
Paired ACTH / SST (Short Synacthen Test)
- Stop steroid / TCM for up to 2 weeks (if outpatient) before Synacthen
- IM/IV Synacthen (250mcg) given & Cortisol measured at 0th (8am), 30th, 60th min
- 0th min: 8am cortisol <250nmol/L due to chronic
- 30th/ 60th min: suboptimal rise in cortisol (normal- cortisol DOUBLES AND > 500nmol/L )
When doing short synacthen test, SST: 200 🡪 220 🡪 250; ACTH high (normal <10.1Umol/L). What are the differential diagnoses?
Acute Primary hypocortisolism: Due to acute dysfunction 🡪 there is loss of adrenal function = suboptimal rise
Eg: Acute adrenal hemorrhage
- APS (Antiphospholipid Syndrome) from SLE
- Waterhouse-Friderichsen Syndrome (from meningococcemia)
When doing short synacthen test, SST: 50 🡪 60 🡪 70; ACTH high (normal <10.1Umol/L). What are the differential diagnoses?
Due to chronic dysfunction 🡪 there is loss of adrenal function = suboptimal rise
Eg: Addison’s
When doing short synacthen test, 50 🡪 300 🡪 600; ACTH inappropriately normal or low (normal <10.1Umol/L). What are the differential diagnoses?
Adrenals are still very responsive due to acute nature = hence optimal rise
Eg: Post Pituitary Surgery, Pituitary Apoplexy (Sheehan’s syndrome from PPH)
OR Patient was given a few doses of dexamethasone by family physician few days before admission (dexamethasone would suppress the exogenous glucocorticoid function, explaining low 0 min level. However, as the adrenals are not atrophied yet, the adrenal would mount a robust response to Synacthen administered).
When doing short synacthen test, 50 🡪 60 🡪 70; ACTH inappropriately normal or low (normal <10.1Umol/L). What are the differential diagnoses?
Adrenals are no longer responsive due to chronic suppression = suboptimal rise
Eg: 6 weeks post Pituitary Surgery; chronic steroid use
What is the management of exogenous Cushing?
Stop all exogenous steroids (esp TCM, b/c steroid dose is uncontrolled)
Give controlled & small steroid dose @ physiological levels
- Hydrocortisone 10mg on waking, 5mg at 5pm
- Mild-moderate illness (eg: runny nose, sore throat) <39 degrees 🡪 2x dose for 2-3 days till mild illness is over
- Severely unwell >39 degrees / severely unwell, diarrhoea, vomiting 🡪 Please come to hospital for parenteral steroids – b/c you are at HIGH RISK of Addisonian crisis
Continue steroid provision until axis “wakes up”: However, if extremely chronic use of TCM 🡪 Axis may NEVER wake up, requiring life-long steroids
What are the 3 tests to confirm Cushing’s if there is no exogenous steroid use?
4hr Urinary Free Cortisol (Preferred method)
- +ve if urine cortisol is 2-3x the ULN
- How: ask patient to pee into a bottle for the entire day
- C/I in pt w/ CKD or ESRF and reduced urine o/p
Overnight Low-Dose (1mg) Dexamethasone suppression test
- How: Take 1mg at 11pm 🡪 check cortisol next morning 8am, looking for suppression of cortisol levels
- If completely suppressed: normal = suppressed to <50
- If not completely suppressed: Cushing’s
Late-night Salivary Cortisol: Cortisol is supposed to drop at night, hence if high = absence of diurnal variation
What are the investigations to determine the etiology of Cushing’s disease?
1) First assess ACTH levels: to assess if ACTH
- Dependent or ACTH independent
- If low = adrenal problem: i.e. ACTH INDEPENDENT
- If high = non-adrenal problem 🡪 may be pituitary or CA i.e. ACTH DEPENDENT
2) If ACTH Dependent
- to assess if CD or Ca
- We can differentiate between the 2 via either of 2 tests below
OPTION 1: Overnight High Dose Dexamethasone Suppression test (8mg)
- How: 8mg Dexa at 11pm 🡪 check cortisol at 8am
- If >50% suppression = likely pituitary tumor
- Confirm w/ MRI scan for tumor 🡪 Trans-sphenoidal resection
- If <50% suppression = likely ectopic ACTH production
- Rationale: Pit tumor is believed to be less aggressive than Ectopic, and hence High Dose should be able to suppress!
OPTION 2: Bilateral IPSS (Inferior Petrosal Sinus Sampling): GOLD STANDARD
- How: To take blood from petrosal sinus VS bloods from peripheral (femoral V) 🡪 compare the ACTH levels to see which is higher!
- If Petrosal Sinus ACTH higher = Cushing’s Disease
- If Peripheral ACTH same as Petrosal Sinus = Ectopic ACTH
- ☹ Invasive test
Other investigations after the above tests
1) MRI pituitary
- ☹ Adenoma is often small (a microadenoma) hence MAY NOT be visible
- ☹ May pick up inceidentalomas esp in Elderly
- But should still be done to confirm the Dx!
2) Adrenal CT/MRI
- Helps to localise disease in Primary Cushing’s
- Tumors are relatively large and always detectable by CT scan.
What is the management of cushing’s disease?
Trans-sphenoidal removal of the tumour 🡪 FIRST LINE!
- Overall, pituitary surgery results in remission in 75–80% of cases
- If fails – can consider 1) Re-Op 2) Medical Tx 3) Radiotherapy
External pituitary Radiotherapy (stereotactic therapy)” slow acting, only effective in 50–60% even after prolonged follow-up and mainly used after failed pituitary surgery
Medical Therapy to reduce CTH
Bilateral adrenalectomy
- Effective last resort in emergency
- May lead to Nelson’s Syndrome (See 1st page)
What is the medical therapy given to first achieve remission for cushing syndrome?
Pituitary level
- Cabergoline” DA agonist, also has some effect on inhibiting ACTH producing pituitary tumors, and not just on Prolactin
- Pasireotide: Somatostatin Analogue
Adrenal level synthesis
- Ketoconazole (Antifungal)
- Metyrapone
- Mitotane
Adrenal level Cortisol receptor blocker
- Mifepristone
How do you withdraw glucocorticoid therapy safely?
For patients with adrenal insufficiency: will require lifelong replacement BUT
Otherwise, patients on chronic steroid therapy can tail down steroid use via:
- Tail down current steroid dose in a stepwise manner over weeks until minimum replacement dose (Prednisolone 7.5mg OM or Dexamethasone 2mg OM)
- At minimum replacement dose 🡪 convert to Hydrocortisone 10mg OM and 5mg at 5pm
- Omit Hydrocort for 24 hours 🡪 perform SST
- Restart PO hydrocortisone whilst awaiting the results of SST
- IF 30min or 60min cortisol < 500nmol/L 🡪 keep pt on Hydrocortisone 10mg OM & 5mg at 5pm for another 3 months 🡪 repeat SST
- IF 30min or 60min cortisol > 500nmol/L 🡪 safe to discontinue completely
