Dr Ann McCormack

Comprehensive new guidelines on the diagnosis and management of Cushing’s disease are difficult to implement in Australia due to lack of access or funding for some of the recommended tests and medications.

Co-author on the international consensus guidelines Dr Ann McCormack told the limbic that Cushing’s disease was one of the hardest diagnoses to make.

“Patients should be worked up by a pituitary endocrinologist – someone with experience – and definitely have the cases discussed in large MDT teams to support those patients through their whole journey.”

Dr McCormack, Group Leader in Hormones and Cancer at the Garvan Institute of Medical Research and a staff specialist at St Vincent’s Hospital Sydney, said there was typically a reliance on using a urinary free cortisol for screening in Australia and increasing recognition that more than one test was required to make a diagnosis.

However the weight of the evidence was now to use salivary cortisol in screening and in follow-up of patients

“The switch to late night instead of midnight salivary cortisol is a bit of a change in that people are recognising that if you force people to stay up to midnight to do the test, it might be a little bit artificial.”

“The lowest cortisol level you are going to get is when they are feeling their usual level or tiredness… rather than forcing someone to stay up to midnight.”

Dr McCormack said there was also a shift away from using the invasive inferior petrosal sinus sampling (IPSS) to sample ACTH levels around the pituitary and distinguish between Cushing’s disease and ectopic ACTH-dependent Cushing’s syndrome.

“It is still the gold standard but because it is invasive and limited to certain centres that might do it well, there is also a shift to using a combination of other tests which may be equivalent to IPSS.”

The guidelines, published in the Lancet Diabetes and Endocrinology, recommend a combination of corticotropin-releasing hormone (CRH), desmopressin test plus a whole body CT.

“One of the problems with the desmopressin test… is it is not used very much at all here. Australian endocrinologists are not used to doing desmporessin testing…so some of what the guidelines are saying there is limited again to how confident clinicians would feel with that.”

Dr McCormack said there was also a move towards use of functional imaging as opposed to anatomic imaging with MRI.

However one of the barriers to imaging in Cushing’s in Australia was the lack of reimbursement for either FDG-PeT or Ga-DOTATATE.

“That’s definitely looking more superior than MRI alone and so we are going to have to push to allow us to order those tests,” she said.

Management of Cushing’s disease

Dr McCormack said the new guidelines probably had an increased focus on comorbidities.

“There is definitely an increasing understanding of the risk of DVT/PE particularly in the perioperative period to-30 days after surgery.”

However surgeons in particular were more wary of the risk of bleeding.

“It would be good to get some more guidelines about safety and benefits. You need to know which patients should be anticoagulated and the time frame.”

She added that other complications such as mood disorders were quite pervasive and don’t always improve.

“There is a lot more data coming out that suggests these things really persist and so you need to aggressively manage them. You can’t just say to the patient ‘your depression is going to get better’ because often it doesn’t.”

“Patients really suffer with Cushing’s effects all their life. They are never the same,” she said.

Dr McCormack said access to guideline-recommended treatment was also limited in Australia.

“There are actually no PBS-listed medications for Cushings. You either have to apply to the hospital using special access or use a private script.”

“So not only are none of the drugs PBS-listed – ketoconazole, metyrapone, the things we use – hard to get access to and often at cost to the hospital or the patient but secondly, two of the better medications, osilodrostat and pasireotide, we don’t have availability in Australia.”

“Pasireotide has been around for a number of years…[but] basically ….you can’t get hold of it at the moment in Australia.”

In addition, newer drugs such as the FDA-approved osilodrostat, which looks more effective and potentially a little bit safer than other agents, is not available in Australia.

Genetics of Cushing’s disease

The guidelines said somatic activating driver mutations in USP8 were present in 36–60% of corticotroph adenomas.

“We do understand this a little bit more now. The big discussion is the use of sub-classifying tumours on the basis of their USP8 mutational status, which indicates high activation of the EGFR pathway and increases ACTH production, is important.”

“They are suggesting that the people who have positive USP8 might have a higher chance of recurrence following pituitary surgery.”

However genetic testing is not performed routinely in Australia, again, “because to do that would actually require subsidies for genetic testing which we don’t have for pituitary patients.”

“Cushing’s is one of those things which requires lots and lots of diagnostic testing and monitoring… yet there is very little reimbursement for it.”

The Garvan Institute’s Emeritus Professor Ken Ho was another Australian co-author on the guidelines.