Cushing’s Probably Due to Ectopic ACTH–Source-Unclear

Question

I have a patient who I believe has Cushing's syndrome secondary to ectopic ACTH, but have been unable to find a source and have had difficulty managing her profound hypercortisolism.

The patient is a 28 year old female, who was diagnosed with Cushing’s syndrome in February 2012. Work-up revealed ACTH-dependent hypercortisolemia. 24-hour urine cortisol was markedly elevated (> 600 mcg) and 1-mg dexamethasone suppression test revealed a non-suppressed cortisol level of > 60 mcg/dL. ACTH has ranged from 150 to 250 pg/mL. MRI (02/23/12) revealed just a prominent pituitary, but no adenoma. Subsequent 03/21/12 IPSS revealed central-to-peripheral ACTH gradient < 2:1 before and < 3:1 after CRH, with ACTH increase < 50% (actual data from the IPSS is attached), suggestive of ectopic ACTH. An 8-mg overnight dexamethasone suppression test on 04/09/12, also suggested ectopic ACTH with cortisol > 60 (ACTH not run by the lab) prior to the dose and ACTH 173.5 and cortisol 51 after the dose.

Work-up for the source of the ectopic ACTH has thus far been negative. CT of the abdomen/pelvis on 02/22/12, was unremarkable. CT of the neck/chest on 03/26/12, revealed thyroid nodules only, but no other masses. An ultrasound of the thyroid on 02/22/12, revealed two subcentimeter nodules in the right lobe, but calcitonin level on 03/26/12, was negative. Additional labs checked on 03/26/12, were also normal, including normal 24-hour urine metanephrines, 24-hour urine 5-HIAA, and gastrin (only mildly elevated at 103 [N < 100], but while non-fasting). MRI was repeated again on 04/03/12, during a hospitalization for hypertension and headache, which also revealed a prominent pituitary, but no clear adenoma. Chromogranin A checked on 04/16/12, was negative. Octreotide scan on 04/23/12, was normal.

She started ketoconazole at 200 mg BID on 04/11/12. I increased the dose to 400 mg BID after two weeks, and just yesterday increased her to 400 mg TID. Prior to her most recent dose change, her serum cortisol remained > 60 (24 hour urine cortisol is pending).

My questions for the expert would include:

1) Do you have any suggestions regarding the next step in localizing the ACTH source?

2) Do you have recommendations regarding the medical management of her hypercortisolism at this time? I am thinking about adding metyrapone to her ketoconazole therapy, but was wondering if you have additional suggestions? Brandon Chock, M.D Ontario, California

Response

Thanks, all the right things seem to have been done, and it certainly looks very like an ectopic source.My own plan in such cases is to get the chest CT reviewed by a real expert (that worked with our last patient; a 'negative' CT was reviewed by our local Head of Dept., a source found, and then video-thorascopically removed).

However, in terms of therapy I would now move towards bilateral adrenalectomy. In the short-term I would add metyrapone up to 1g 4x/daily, with careful assessments of cortisol levels as these may fall abruptly. A block-and-replace regime may be required. Then book for adrenalectomy in the near future. These patientrs are at significant risk of overwhelming sepsis or pulmonary embolism and effective therapy should not be delayed. Ashley Grossman, MD

Cushing’s Probably Due to Ectopic ACTH–Source-Unclear

Question

I have a patient who I believe has Cushing's syndrome secondary to ectopic ACTH, but have been unable to find a source and have had difficulty managing her profound hypercortisolism.

The patient is a 28 year old female, who was diagnosed with Cushing’s syndrome in February 2012. Work-up revealed ACTH-dependent hypercortisolemia. 24-hour urine cortisol was markedly elevated (> 600 mcg) and 1-mg dexamethasone suppression test revealed a non-suppressed cortisol level of > 60 mcg/dL. ACTH has ranged from 150 to 250 pg/mL. MRI (02/23/12) revealed just a prominent pituitary, but no adenoma. Subsequent 03/21/12 IPSS revealed central-to-peripheral ACTH gradient < 2:1 before and < 3:1 after CRH, with ACTH increase < 50% (actual data from the IPSS is attached), suggestive of ectopic ACTH. An 8-mg overnight dexamethasone suppression test on 04/09/12, also suggested ectopic ACTH with cortisol > 60 (ACTH not run by the lab) prior to the dose and ACTH 173.5 and cortisol 51 after the dose.

Work-up for the source of the ectopic ACTH has thus far been negative. CT of the abdomen/pelvis on 02/22/12, was unremarkable. CT of the neck/chest on 03/26/12, revealed thyroid nodules only, but no other masses. An ultrasound of the thyroid on 02/22/12, revealed two subcentimeter nodules in the right lobe, but calcitonin level on 03/26/12, was negative. Additional labs checked on 03/26/12, were also normal, including normal 24-hour urine metanephrines, 24-hour urine 5-HIAA, and gastrin (only mildly elevated at 103 [N < 100], but while non-fasting). MRI was repeated again on 04/03/12, during a hospitalization for hypertension and headache, which also revealed a prominent pituitary, but no clear adenoma. Chromogranin A checked on 04/16/12, was negative. Octreotide scan on 04/23/12, was normal.

She started ketoconazole at 200 mg BID on 04/11/12. I increased the dose to 400 mg BID after two weeks, and just yesterday increased her to 400 mg TID. Prior to her most recent dose change, her serum cortisol remained > 60 (24 hour urine cortisol is pending).

My questions for the expert would include:

1) Do you have any suggestions regarding the next step in localizing the ACTH source?

2) Do you have recommendations regarding the medical management of her hypercortisolism at this time? I am thinking about adding metyrapone to her ketoconazole therapy, but was wondering if you have additional suggestions? Brandon Chock, M.D Ontario, California

Response

Thanks, all the right things seem to have been done, and it certainly looks very like an ectopic source.My own plan in such cases is to get the chest CT reviewed by a real expert (that worked with our last patient; a 'negative' CT was reviewed by our local Head of Dept., a source found, and then video-thorascopically removed).

However, in terms of therapy I would now move towards bilateral adrenalectomy. In the short-term I would add metyrapone up to 1g 4x/daily, with careful assessments of cortisol levels as these may fall abruptly. A block-and-replace regime may be required. Then book for adrenalectomy in the near future. These patientrs are at significant risk of overwhelming sepsis or pulmonary embolism and effective therapy should not be delayed. Ashley Grossman, MD