Cushing's Syndrome and Disease Flashcards
Cushing’s Syndrome - Diagnosis: Example Question
A 40-year-old female presented to Endocrinology Clinic with a 3-month history of weight gain, fatigue and headaches. Over the last 3 weeks, she has also experienced galactorrhoea and reduced libido. She was diagnosed with type 2 diabetes and hypertension 1 month ago and is on diet control for both. She is not currently on any regular medications. On examination, there was evidence of hirsutism and acne, a cervical fat pad, striae on her abdomen and proximal myopathy. Areas of hyperpigmentation were noted on her mucous membrane and palmar creases.
Which of the following investigations will reveal the diagnosis?
Low dose dexamethasone suppression test Prolactin levels Urinary cortisol CT brain > MRI pituitary
The history suggests Cushing’s syndrome, but the occurrence of galactorrhoea and reduced libido brings to attention the possibility of hyperprolactinaemia, and headaches may indicate an intracranial pathology. The diagnosis of a secreting pituitary tumour causing a raised level of prolactin and ACTH (causing hyperpigmentation) and hence, cortisol, should be suspected.
Low dose dexamethasone suppression test and 24-hour urinary cortisol will aid confirming the presence of Cushing’s syndrome. Raised prolactin levels will confirm hyperprolactinaemia, however, it is the MRI pituitary that will lead to the diagnosis of a pituitary tumour.
Cushing’s Syndrome Investigations
Cushing’s syndrome: investigations
Investigations are divided into confirming Cushing’s syndrome and then localising the lesion. A hypokalaemic metabolic alkalosis may be seen, along with impaired glucose tolerance. Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is characteristically associated with very low potassium levels. An insulin stress test is used to differentiate between true Cushing’s and pseudo-Cushing’s
Tests to confirm Cushing’s syndrome
The two most commonly used tests are:
1) 48 hour low dose dexamethasone test (most sensitive) - administration of cortisol in N individuals > reduced secretion of CRH and thus reduced ACTH and thus reduced cortisol release
Patients with Cushings fail to suppress cortisol to <50nmol/L
(NB There is a simpler overnight dexamethasone suppression test but it produces more false positives)
2) 24 hr urinary free cortisol- you have to measure total cortisol output over a 24h period - this should not exceed 280nmol/L
False positives seen in alcoholics and depression
Localisation tests
The first-line localisation is 9am and midnight plasma ACTH and cortisol levels. If ACTH is suppressed then a non-ACTH dependent cause is likely such as an adrenal adenoma
High-dose dexamethasone suppression test
if pituitary source then cortisol suppressed
if ectopic/adrenal then no change in cortisol
(is this correct?)
CRH stimulation
if pituitary source then cortisol rises
if ectopic/adrenal then no change in cortisol
Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary and ectopic ACTH secretion
Adrenal Adenoma causing Cushing’s Syndrome - Example Question
A 45-year-old man presents to the endocrine clinic for review. He has had 3 stones in weight gain over the past 6 months and his GP is concerned about a possible diagnosis of Cushing’s syndrome and has checked an initial 24hr urinary free cortisol which is elevated. He is hypertensive with a blood pressure of 155/90 mmHg, his pulse is 75 beats per minute and regular. His body mass index is 35 kg/m² and there are obvious abdominal striae. Which of the following would be most suggestive of an adrenal adenoma producing cortisol?
Normal 9am serum cortisol Raised urinary free cortisol on repeat testing Serum cortisol of 220 mmol/l at 9am after an overnight dexamethasone suppression test Serum potassium of 2.4 mmol/l > Undetectable levels of ACTH
The key fact is that an adrenal adenoma producing cortisol would suppress the release of ACTH. For this reason, if ACTH is undetectable then an adrenal tumour is the most likely cause. In this case, a CT abdomen would be the obvious next step.
Normal 9 am serum cortisol would make a diagnosis of Cushing’s less likely, and a raised urinary free cortisol on repeat testing is not specific for the underlying cause. Failure to suppress after overnight dexamethasone suppression test merely confirms a diagnosis of Cushing’s. Serum potassium levels as low as 2.4 mmol/l would be very unusual in a case of Cushing’s.
Pseudo-Cushings - Example Question
You are asked to review a 62 year-old Caucasian man who is an inpatient on the medical admissions unit. He is currently being treated for a left lower lobe community acquired pneumonia. You note consumed alcohol excessively prior to admission but has been abstinent for the last four days.
During this admission it has been noted that serial bloods glucose measurements have been elevated and subsequently a new diagnosis type two diabetes has been made. The admission consultant noted Cushingoid featured and requested an overnight low dose dexamethasone suppression test. The results are as follows:
8am Cortisol after 1mg dexamethasone at 11pm the previous day 438 nmol/L
Reference range for serum cortisol 170-540 nmol/L
What is most appropriate next step in the investigation of this gentleman?
Serum ACTH measurement > Midnight serum cortisol Inferior petrosal sinus sampling post CRH administration High dose dexamethasone suppression test MRI pituitary
Pseudo-Cushing’s syndrome is common in those with excessive alcohol consumption. The physical signs resemble true Cushing’s syndrome however the aetiology is idiopathic rather than dysfunction of the hypothalamic-pituitary axis. It is therefore important to exclude pseudo-Cushing’s prior to further investigation.
The hallmark of true Cushing’s syndrome is lack of diurnal variation in serum cortisol. However in pseudo-Cushing’s diurnal variation is normally maintained. Those with pseudo-Cushing’s will have elevated 24 hour urinary cortisol and will also fail to suppress serum cortisol with a low dose dexamethasone suppression test. The correct approach in this case is therefore to measure a midnight cortisol prior to proceeding to further investigation.
Papanicolaou DA, Yanovski JA, Cutler GB Jr. A single midnight serum cortisol measurement distinguishes Cushing’s syndrome from pseudo-Cushing states. J Clin Endocrinol Metab. 1998 Apr. 83(4):1163-7.
Cushing’s Syndrome - Causes
Cushing’s syndrome: causes
ACTH dependent causes
Cushing’s disease (80%): pituitary tumour secreting ACTH producing adrenal hyperplasia
ectopic ACTH production (5-10%): e.g. small cell lung cancer
ACTH independent causes
iatrogenic: steroids
adrenal adenoma (5-10%)
adrenal carcinoma (rare)
Carney complex: syndrome including cardiac myxoma
micronodular adrenal dysplasia (very rare)
Pseudo-Cushing’s
mimics Cushing’s
often due to alcohol excess or severe depression
causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
insulin stress test may be used to differentiate
Ectopic ACTH Cushings - Example Question
A 58 year-old man presents with a two month history of weight loss and a one week history of increasing confusion. His partner reports that his clothes are now loose on him and that he has started to forget things and that he has been unable to reach for objects off the top shelf at the supermarket over the last two months due to increasing weakness. Six weeks ago he had been treated for an islet cell carcinoma of the pancreas with chemotherapy and has no other past medical history.
Examination reveals an abbreviated mental test score of 5/10 and weakness in the shoulders and getting out of the chair. Heart sounds 1 and 2 are present with no added sounds, his chest is clear and the abdomen is soft and non-tender.
Observations reveal a blood pressure of 158/95 mmHg, a pulse rate of 90 beats per minute, a temperature of 37.5ºC and a respiratory rate of 14 breaths per minute. Random blood glucose is 16.2 mmol/L.
Blood tests are performed and reveal:
Hb 14.2 g/l Platelets 180 * 109/l WBC 4.9 * 109/l Na+ 150 mmol/l K+ 2.6 mmol/l Urea 5.2 mmol/l Creatinine 100 µmol/l Bilirubin 15 µmol/l ALP 70 u/l ALT 28 u/l γGT 47 u/l Albumin 48 g/l
What is the most likely diagnosis?
Paraneoplastic encephalitis Cerebral metastases Post chemotherapy Cushing's syndrome Post chemotherapy hypothyroidism > Ectopic ACTH secretion
The confusion, hypertension and proximal myopathy, along with the hypernatraemia, hypokalaemia and hyperglycaemia all point towards a diagnosis of Cushing’s syndrome. The subtype is most likely ectopic secretion of ACTH by the islet cell carcinoma, a neuroendocrine tumour and can release ectopic hormones. The post-chemotherapy Cushing’s syndrome is unlikely, as the chemotherapy started after the proximal myopathy had begun to take effect. Further, in ectopic ACTH secretion, the hypokalaemia tends to be more pronounced, as in this case.
Cushing’s Syndrome and Undetectable levels of ACTH
The key fact is that an adrenal adenoma producing cortisol would suppress the release of ACTH. For this reason, if ACTH is undetectable then an adrenal tumour is the most likely cause. In this case, a CT abdomen would be the obvious next step.
Differentiating Cushings from Pseudo-Cushings e.g. in alcoholics
The hallmark of true Cushing’s syndrome is lack of diurnal variation in serum cortisol. However in pseudo-Cushing’s diurnal variation is normally maintained. Those with pseudo-Cushing’s will have elevated 24 hour urinary cortisol and will also fail to suppress serum cortisol with a low dose dexamethasone suppression test. The correct approach in this case is therefore to measure a midnight cortisol prior to proceeding to further investigation.
