Aetiol:

• ACTH-dep
• pit-dep Cush=Cushing's dis
• 80-90% of all cases
• NB: can be cyclical (mths/yrs)
• ectopic ACTH syndr
• eg bronchial carcinoid, SCLC, MTC syndr
• usu rapid onset, hyperpig, weakness, little wt gain, no typ Cushingoid appearance
• ectopic CRH syndr
• exogenous ACTH
• ACTH-indep
• adrenal { adenoma | carcinoma }
• ACTH-indep bilat macronod adr hyperplasia=AIMAH [OMIM#219080]
• AIMAH sec to abnml hormone receptor expression/fx [eg GIP, catechol, ...]
• Primary pigmented nodular adr dis=PPNAD: [PPNAD1:OMIM#610489]
• 50% a/w Carney complex [OMIM#160980]: AD dis, mesenchymal tu's (esp atrial myxomas), pigmented skin lesions, endocrine tu's, periph nerve tu's
• 50% sporadic
• McCune-Albright syndr [OMIM#174800]
• exogenous Glucocorticoids:
Dose equivalents (antiinflamm. effect; BNF 2010):
• Betamethasone 0.75mg (Betnesol, Betnelan)
• Dexamethasone 0.75mg
• Methylprednisolone 4mg (Medrone, Solu-Medrone, Depot-Medrone)
• Triamcinolone 4mg (Kenalog)
• Prednisolone 5mg
• Deflazacort 6mg (Calcort)
• Hydrocortisone 20mg (Efcortesol, Solu-Cortef)
• Cortisone acetate 25mg
• DD: Pseudocushing's: some clin features (but usu NOT: myopathy, thin skin, easy bruising) and some hypercortisolaemia
• depression
• alc abuse
• obesity

Investigations:

• NB: exog E2 will icr CBP: stop OCP/oral HRT for 6wk
• UFC: 95% sens [but need multiple collections; check for Crea excretion ~1g/24h: var<10%]
• LDDST: Dex: potency x30, long duration of action [ensure: no malabsorption, no enzyme inducers: Carbamaz, Phenyt, Phenobarb, Rifamp]
• ONDST: 1[-1.5-2]mg Dex at MN, check Cort at 9am (<50nM/L=1.7mcg/dL): sens 98-100%, specif 88%
• LDDST: Dex 0.5mg 6hrly for 48h: sens 95-100%, specif 95-100%; NB: Cort dcrs to <70% suggests CD
• Circad rhythm assessm:
• late night salivary cortisol: sens 92-100%, specif 93-100%
• MN cort: 48h in hosp, asleep
• Other: NB: ITT: { Cush | Pseudo-Cush }: { blunted | nml } cort response
• Differential diagnosis
• ACTH-indep
• ACTH<5pg/mL=1.1pM/L: suggests ACTH-indep Cushing
• HiRes adr CT:
• identifies masses>1cm; if>5cm suspect malignancy; usu: contralat atrophy; bilat atrophy in exog corticosteroids
• AIMAH: bilat >5cm adrenals
• ACTH-dep
• majority CD: { f:92% | m:77% }
• ectopic ACTH syndr: usu higher ACTH, higher Cort (therefore MC effects: majority have hypokal & alkal [vs 10% in CD], and lo Alb)
• ACTH:
• usu higher in ectopic ACTH syndr than Cush dis
• HDDST
• HDDST Dex 2mg q6h for 48h [or ONHDDST: 8mg at 23:00]: Cort at 9:00 dcrs <50% in CD: sens 80%, specif 80
• ? only if IPPSS not avail
• CRH test [or other peptides: AVP/Desmopressin, etc]
• { ovine=o | h=human } CRH 1mcg/kg or 100mcg [SE: hypotens, flushing, metallic taste]: ACTH icr by >=35% suggests CD: sens 93%, specif 100%
• BIPSS: sens 94%, specif near 100%
• Imaging:
• CD: MRI pit [beware mean size 6mm, and 10% incidentalomas]
• ectop ACTH:
• CT/MRI chest/abdo
• 111In-pentetreotide scan for neuroendocrine tu [but rarely better than CT/MRI]
• 
  

Treatment:

• CD
• Transphenoidal surgery
• Gamma-knife radiosurgery
• Adrenal Cush
• Adrenalect
• Ectop ACTH
• surg
• Medical Tx: eg after failed or impossible surgery
• aim mean of 5 Cort =150..300nM/L
• adrenolytic Tx
• Metyrapone: inhib 11beta-hydroxylase: rapid (2h) dcr in Cort: SE hypoadrenalism, hyperandrogenism
• Ketoconazole: slower action: 200mg bd
• Mitotane; Etomidate
• Pasireotide: http://jcem.endojournals.org/cgi/content/abstract/94/1/115?etoc novel multireceptor ligand somatostatin analog, phase-II proof-of-concept open-label trial, 39 pts with de-novo CD, pasireotide 600mcg bd x 15d; outcome: normalization of UFC; results: 22(76%) pts with dcr in UFC, 17% of whom (n=5) with nml UFC; P-Cort and P-ACTH drcd; steady state after 5d

Other Considerations: