Cushing's Case Teaching PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CASE BASED TEACHING: CUSHING'S Professor O'Reilly Consultant Endocrinologist  History NEW REFERRAL TO THE ENDOCRINE CLINIC Exam Ms. F is a 37-year-old female Refe...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CASE BASED TEACHING: CUSHING'S Professor O'Reilly Consultant Endocrinologist  History NEW REFERRAL TO THE ENDOCRINE CLINIC Exam Ms. F is a 37-year-old female Referred from the GP with a 10-months history: Differential – 12 kg weight gain (which she attributes to recent inactivity) – Easy bruising Investigation – Muscle weakness & fatigue, leading to difficulty in climbing stairs Results – Irregular menstrual cycles Management Follow Up History FURTHER HISTORY Past medical history – Hypertension on Amlodipine, Hydrochlorothiazide, and Ramipril (diagnosed 3 years ago) – Class I Obesity (BMI 31 kg/m2) Past surgical history – Nil Family history – Father with high blood pressure, diagnosed in his 60s Social history – Works as an engineer – Sedentary lifestyle – No significant change in her diet or exercise – Smokes 10 cigarettes/day for 10 years – Drinks 2 glasses of wine on the weekend  VITAL SIGNS Exam Vitals – BP 150/90 mmHg – HR 87 BPM – O2 sat 99% on RA – Apyrexial Height 162 cm, Weight 83.2 kg, BMI 31 kg/m2  COMPARING PICTURES 2 YEARS AGO & NOW WHAT DO YOU NOTICE? Exam 2 years ago Now Comment on these physical exam findings? https://csrf.net/wp-content/uploads/2015/02/Understanding-Cushings-Syndrome-Brochure.pdf  COMPARING PICTURES 2 YEARS AGO & NOW WHAT DO YOU NOTICE? Exam 2 years ago Now MOON FACIES https://csrf.net/wp-content/uploads/2015/02/Understanding-Cushings-Syndrome-Brochure.pdf  PHYSICAL EXAM SIGNS Exam What are these physical exam findings? Note: Please be aware that these images are not intended for the patient featured in the preceding slide; their inclusion is solely for instructional purposes.  PHYSICAL EXAM SIGNS Exam Striae Dorsocervical Fat Pad Ecchymoses (also known as Buffalo Hump) Note: Please be aware that these images are not intended for the patient featured in the preceding slide; their inclusion is solely for instructional purposes.  PHYSICAL EXAM SIGNS Exam What are these physical exam findings? Note: Please be aware that these images are not intended for the patient featured in the preceding slide; their inclusion is solely for instructional purposes.  PHYSICAL EXAM SIGNS Exam Facial Plethora Hirsutism Acne Note: Please be aware that these images are not intended for the patient featured in the preceding slide; their inclusion is solely for instructional purposes.  ON PHYSICAL EXAMINATION Exam Facial plethora Hirsutism- on the side of the face and lower back Acne on chest, back, and face Thyroid examination – unremarkable Purple striae noted on the abdomen Central obesity with increase fat accumulation in the face and trunk Dorsocervical fat pad Proximal muscle weakness  WHAT ARE YOUR DIFFERENTIAL DIAGNOSES? Obesity Differential Metabolic syndrome Type II diabetes Cushing’s Syndrome  CUSHING’S SYNDROME IS DEFINED AS HAVING EXCESS CORTISOL SECRETION Syndrome that results from continued exposure to high levels of glucocorticoid steroids, whether endogenous or exogenous Differential Cushing Syndrome Cushing’s Syndrome (Regardless of the cause or source)  SOME HISTORY ABOUT CUSHING’S This is Minnie G, the index case of Cushing’s She presented to Harvey Cushing in 1910 with a syndrome of obesity, hypertrichosis, and amenorrhea. This case sparked his interest and culminated in a seminal report published 20 years later, the basophil adenomas of the pituitary gland and their pituitary manifestations  CUSHING’S SYNDROME- SIGNS & SYMPTOMS More Common Less Common Decreased libido ECG abnormalities or atherosclerosis Obesity/weight gain Striae Plethora Edema Round face Proximal muscle weakness Menstrual changes Osteopenia or fracture Hirsutism Headache Hypertension Backache Ecchymoses Recurrent infections Lethargy, depression Abdominal pain Dorsal fat pad Acne Abnormal glucose tolerance Female balding (hyperglycemia) HYPOTHALAMIC-PITUITARY-ADRENAL AXIS REVIEW OF PHYSIOLOGY Increased in Cushing’s Syndrome  CUSHING SYNDROME: PATHOPHYSIOLOGIC “DERANGEMENTS” OF THE HPA AXIS 1. Excess cortisol secretion 2. Loss of diurnal variation of cortisol secretion Normal Individual Normal vs Cushing’s 3. Autonomy from “central” ACTH control – loss of response to feedback inhibition  WHAT ARE THE INVESTIGATIONS YOU WOULD Investigation ORDER TO CONFIRM THE DIAGNOSIS?  ESTABLISHING THE DIAGNOSIS: THE FIRST STEP: Does this patient have Cushing’s Syndrome (excess cortisol)? – Clinical Features? – Always rule out exogenous steroid use! Ask about topical, inhaled or intra- articular glucocorticoids as well Investigation – Investigations: 1. 24-hour urine free cortisol (Excess cortisol secretion?) 2. Late night salivary cortisol (Loss of diurnal variation of cortisol secretion?) 3. 1 mg overnight dexamethasone suppression test (Autonomy from “central” ACTH control – loss of response to feedback inhibition?)  EXCESS CORTISOL: 24-HOUR URINARY FREE CORTISOL An integrated measure over 24-hour period Free cortisol is measured Cushing’s is more likely if cortisol >3x Investigation upper limit of normal Serial measurements are necessary The rate of production of cortisol differs over the course of the day, so a 24-hour collection is more accurate than a single cortisol check at one period in time. Collecting urine over a 24-hour period is more practical than collecting multiple blood tests.  LATE NIGHT SALIVARY Loss of Diurnal Variation of Cortisol CORTISOL Measures free cortisol (surrogate for serum free cortisol, free cortisol diffuses freely into the saliva) Easily collected at home at 11 pm and is stable Performed serially (2-3 nights) Beware of patients with disturbed sleep-wake cycle! Investigation The 24-hour urine collection will only tell you a total amount of cortisol excreted in the 24-hour period, it won't show the 'circadian rhythm' fluctuations. The late-night salivary cortisol will demonstrate a loss of this normal rhythm. With normal physiology, late night cortisol level should be low. An elevated result shows loss of diurnal variation  1 MG LOW DOSE DEXAMETHASONE SUPPRESSION TEST CORTISOL AUTONOMY Exogenous dexamethasone substitutes for endogenous cortisol in suppressing ACTH release Dexamethasone is more potent than endogenous cortisol In normal physiology, dexamethasone binds glucocorticoid receptors (GC receptors) in hypothalamic paraventricular nuclei and in pituitary corticotroph cells, and inhibits corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion Investigation If the hypothalamic-pituitary-adrenal (HPA) axis is functioning normally, any supraphysiologic dose of dexamethasone should suppress pituitary ACTH secretion Dexamethasone is taken by patient at 11pm and cortisol measured at 8 am >50 nmol/L (>1.8 mcg/dL) is positive, indicates failure of suppression of cortisol. The DST indicates inappropriate cortisol secretion, but it does not indicate the source of the cortisol secretion.  1 MG LOW DOSE DEXAMETHASONE SUPPRESSION TEST Normal Physiology Dexamethasone should suppress ACTH secretion from the pituitary via negative feedback (in normal physiology)… Normal adrenal tissue should “shut off” cortisol production as no ACTH is present. Investigation Think about it:: Autonomous adrenal tissue will keep generating cortisol and an ACTH producing adenoma will continue to stimulate the adrenals, resulting in a positive test.  24-hour urine free 658 µg/24hrs cortisol (Ref. 20-90) RESULTS: Low dose 331 nmol/L (12 CONFIRMING ELEVATED Dexamethasone µg/dL) CORTISOL (Ref.