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Clinical case

Clinical case. 2003… A 30 year-old woman… ...admitted to our hospital due to obesity and diabetes mellitus. Diagnosis of Cushing’s disease. Clinical feature: - Moon shaped face, cervical fat pad, supraclavicular fat accumulation, central fat distribution, thinned skin with easy bruising

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Clinical case

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  1. Clinical case 2003… A 30 year-old woman… ...admitted to our hospital due toobesity and diabetes mellitus...

  2. Diagnosis of Cushing’s disease Clinical feature: - Moon shaped face, cervical fat pad, supraclavicular fat accumulation, central fat distribution, thinned skin with easy bruising - Metabolic syndrome (visceral obesity BMI 35 kg/m2, DM without complications, hypertension without complications, dislipidemia) UFC:120-140-135 µg/24h (1900-2100 cc) (20-90 µg/24 h) Morning cortisol: 25.6-30.6µg/dl (5.0-20 µg/dl) Morning ACTH:57-61 pg/ml (8-53 pg/ml) Midnight plasma cortisol: 28.8-30.2 µg/dl 1 mg DEX test: cortisol 11.4 µg/dl Liddle I test: cortisol7.5µg/dl 8 mg DEX test: cortisol 4.6 µg/dl hCRH test: cortisolpeak vs baseline: 36.5 vs 25.8µg/dl (41% increase) ACTH peak vs baseline: 91.5 vs 58.7 pg/ml (55.8% increase)

  3. Other Exams… • HbA1c: 6.8% (Metformin 1500 mg/die) • Tot col: 214 mg/dl, HDL: 54 mg/dl, TG200 mg/dl, LDL:120 mg/dl • Creatinine: 0.6 mg/dl, urea: 22 mg/dl, creatinine clearance: 81 ml/min, albuminuria: negative • Na: 139 mmol/l, K: 3.8 mmol/l • AST: 16 U/l, ALT: 20 U/l, GGT: 47 U/l • Echocardiography: normal range • Carotid doppler ultrasound: intimal thickenings along the common carotid artery, without flow alterations; carotid intima-media thickness<0.9 mm • ‏Retina evaluation: no diabetic or hypertensive alterations • DEXA: normal (lumbar T score + 0.4)

  4. Pituitary Imaging Therapy Resection of the pituitary adenoma by transsphenoidal surgery ( April 2003) Immunoistochemistry: pituitary adenoma, positive for ACTH Ki-67 <1%, P53 negative

  5. Patient re-tested 2 weeks later (washout cortisone 25 mg po 3 days before) No symtoms of acute hypoadrenalism UFC: 21 µg/24h (1900-2100 cc) (20-90 µg/24 h) Morning cortisol: 7.5µg/dl (5.0-20 µg/dl) Morning ACTH: 19.4 pg/ml (vn 8-53 pg/ml) Midnight plasma cortisol: 7.1 mcg/dl 1 mg DEX test: cortisol 3.6 µg/dl TSH: 0.9 mU/l, fT4: 9.4 pg/ml, fT3: 3.1 pg/ml Remission not complete…

  6. …re-tested 3 months later… No symtoms of hypoadrenalism, occurrence of menses UFC: 32 µg/24h (1900-2100 cc) (20-90 µg/24 h) Morning cortisol: 15.3 µg/dl (5.0-20 µg/dl) Morning ACTH: 32.8 pg/ml (vn 8-53 pg/ml) Midnight plasma cortisol: 8.1 mcg/dl 1 mg DEX test: cortisol 5.8 µg/dl FSH: 3.2 mU/l, LH: 5.6 mU/l, E2: 80pg/ml PRL: 15ng/ml TSH: 1.6 mU/l, fT4: 10.8 pg/ml, fT3: 3.3 pg/ml IGF-I: 215 µg/l DM improved: HbA1c 5.8% (same therapy) Lipid profile improved: LDL 100 mg/dl Blood pressure improved (same therapy) BMI unchanged:35 kg/m2

  7. Pituitary Imaging What can be done?

  8. …the patient underwent a periodic follow up… …she showed a good biochemical and clinical profile for 2 years… …January 2006… Weight increase (BMI 37 kg/m2) DM worsening (HbA1c 8.5%) Lipid profile worsening (LDL 130 mg/dl) Blood pressure worsening (>130/80 mm Hg) UFC:105-103 µg/24h (1900-2100 cc) (20-90 µg/24 h) Morning cortisol: 22.0µg/dl (5.0-20 µg/dl) Morning ACTH: 28.4 pg/ml (vn 8-53 pg/ml) Midnight plasma cortisol: 16.4 µg/dl Pituitary Imaging: unchanged.

  9. What can be done?

  10. Second-line therapeutic options in persistent disease after transsphenoidal surgery Repeat pituitary surgery low rate of success (50-70%) in comparison with the first operation risk of pituitary insufficiency Radiotherapy remission rate 53-100% need of other treatments in the “interim” period risk of pituitary insufficiency risk of CNS complications Medical therapy not definitive therapy variable rate of success (different drugs, site of action, doses) Bilateral adrenalectomy definitive treatment need of lifelong hormonal replacement therapy risk of Nelson’s syndrome From: Biller et al, JCEM 2008

  11. Clinical variables influencing the choice in persistent disease after transsphenoidal surgery Age Entity of hypercortisolism Comorbidities Presence/absence of pituitary deficiencies Pituitary imaging Risk of Nelson’s syndrome Patient’s compliance

  12. Second-line therapeutic options in persistent disease after transsphenoidal surgery Repeat pituitary surgery low rate of success (50-70%) in comparison with the first operation risk of pituitary insufficiency Radiotherapy remission rate 53-100% need of other treatments in the “interim” period risk of pituitary insufficiency risk of CNS complications Medical therapy not definitive therapy variable rate of success (different drugs, site of action, doses) Bilateral adrenalectomy definitive treatment need of lifelong hormonal replacement therapy risk of Nelson’s syndrome From: Biller et al, JCEM 2008

  13. …medical therapy with ketoconazole (400 mg/die) was started… …during the following 12 months… UFC 43-58-95-81-110 µg/24h (1900-2100 cc) (20-90 µg/24 h) Metabolic profile firstly improved but later worsened… …at 12 months: Weight (BMI 36 kg/m2) HbA1c 8.1% (LDL 121 mg/dl) Blood pressure not well controlled What can be done?

  14. …cabergoline (up to 3.5 mg/week) was added… …during the following 6 months… UFC115-102-90-85-95-99 µg/24h (1900-2100 cc) (20-90 µg/24 h) Metabolic profile was not significantly modified… Therapy with metformin was increased (up to 2500 mg/die) and atorvastatin (10 mg/die) was added… What can be done?

  15. … the patient showed no compliance to increased medical therapy and asked for a more definitive treatment … … she underwent a bilateral adrenalectomy … (January 2008) …at the last follow up (2011): • BMI improved: 31 kg/m2 • DM improved: HbA1c 6.7 during Metformin 1000 mg/die • Lipid profile improved: Tot col 162 mg/dl, HDL 55 mg/dl, TG 158 mg/dl, LDL 75 mg/dl during atorvastatin 10 mg/die • Blood pressure normalized medical therapy was stopped Pituitary Imaging

  16. …mild hypercortisolism needs to be counteracted in patients with persistent disease after transsphenoidal surgery… …the best balance between the negative influence of hypercortisolism and the risk of the different treatments must be found, expecially in young patients without hypopituitarism… …the choice of medical therapy should take into account not only efficacy and safety, but also over-treatment risk and patient’s compliance…

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