QUESTION-Our unit has recently encountered an interesting Cushing's patient which was a bit of a puzzle to us, and we'd love to see your opinion on the matter. (3/17/2014)
History-48 yo female p/c with 3-4 month hx of moon face/buffalo hump/ thin skin/proximal weakness Bhx
- ESRF : rapidly progressive in the last 12 month and has become dialysis dependent for 10 month prior to onset of symptoms, renal biopsy showed tubular fibrosis only. currently Anuric
- Turner's Syndrom: on oral contraceptive pill prior to presentation.complication including bicuspid aortic valve, hearing loss, short stature, amenorrhoea
- dilated cardiomyopathy: TTE 2014 Grade 3 LV with free TR and RV systolic dysfunction. She has had previous aortic repair in 2009 and a Ross procure in 2013. her cardiomyopathy has progressed at least from 2011 where she was last to be having a documented normal systolic function with mild MR/TR and severe AS...she has clinical evidence of right heart failure with increasing weight, hepatomegaly/ascites.
- Crohn's : last exacerbation in 2010, steroids free since then. previously on methotrexate , ceased due to pancytopenia complications in 2013, currently on mesalazine only
Medication: -mesalasine 1g tds, OCP - logynon I daily, folic acid 5mg daily, sertraline 50mg mane, pantoprazole 20mg , lanthanum 500mg BD
On initial examination. she was clearly cushingnoid with a comparative photo from her mother showing her to be very much different 4 month ago. she has progressed from independent and working in government sector to unable to work due to her weakness, in particular when she squat she can not get herself up without assistance.non drinker, non smoker, and no exogenous steroids use (including inhalers/eye drops)
Her initial biochemical investigation shows:
- persistant elevation of free plasma cortisol ranging from 600-800 with lost of diurnal variation- her K level has dropped and without correction on her K bath during dialysis or external replacement, it can drop down to 2.7, 2.8, therefore over the month her K bath has increased from 1 to 3 during dialysis
- her ACTH was elevated at 2-3
- her salivary cortisol was elevated in the 20s on repeated occasions.
*to note her cortisol was done on both dialysis and non dialysis days with similar pattern - lost of diurnal variation.
further test showed:
- 1 mg dexmethasone test: cortisol was 390 after suppression
- CRH : showed no change of cortisol almost at 45 mins ( 636 baseline to 674), and her ACTH rose from 2.7 to 4.11 at highest (30 min mark) before decreasing downy o2.69 at 45 min mark
- MRI pituatory (non contrast due to her ESRF - risk of systemic sclerosis) : showed normal size pituitary with no evidence of macro adenoma (discussion with radiology is that it can miss micro adenomas but the risk of giving her contrast and causing systemic sclerosis is high and concerning)
- CT chest/abdo, US pelvis and dedicated CT adrenal showed no evidence of ectopic or adrenal adenoma, (only evidence of right heart failure and progressive dilated cardiomyopathy)
- GA DOTATE whole body PET : showed no evidence of ectopics or abnormal trace.
We commenced her on metyrapone at current 250mg tds, and after 10 days, her cortisol level dropped to 347 at 8am (halved ) , she's been closely followed up in our clinic with plan to re-image her in coming month. Sprionolactone 12.5mg was also commenced for cardiomypathy and hypokelaemia management.We'd greatly appreciate your take on her case. Regards. Angeline Shen
RESPONSE--Dear Dr. Shen, Many thanks for sending details of your very intestine (and complex) case. It does appear that your patient has Cushing's syndrome, although the interpretation of cortisol levels is rendered very difficult in patients on oral oestrogen replacement as CBG is greatly increased, although this should not alter salivary cortisol. In addition, cardiac failure can alter cortisol levels and the circadian rhythm. Did you stop the oestrogens? but taking these values and the clinical phenotype I am reasonably happy with the diagnosis. However, I am puzzled by the ACTH levels as you did not give the units or your normal ranges. I therefore cannot say whether this is ACTH-dependent or ACTH-independent disease. I am not clear what you mean that 'her ACTH was elevated at 2-3'.
However, I would agree that treatment with metyrapone, at least in the short term is good therapy. If the ACTH levels are indeed high, then the odds are on an occult ectopic source from your f]dat. i assume a bilateral petrosal sinus sampling is not possible in view of her clinical state? If she improves clinically on metyrapone I would seriously consider bilateral adrenalectomy for long-term cure. Regards, Ashley Grossman FMedSci