title: Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing's syndrome.
abstract: BACKGROUND
  Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer.
  
  
  METHODS
  Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls.
  
  
  RESULTS
  Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 ± 13.0 (SEM) vs 17.2 ± 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 ± 76 vs 120 ± 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS.
  
  
  CONCLUSIONS
  Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker.
authors.affiliation: Department of Medicine (G.P.-W., P.U.F., T.P.J., K.M., S.L.W.), Department of Radiology (A.G.K.), Department of Neurological Surgery (J.N.B.), Columbia University College of Physicians & Surgeons, New York, New York 10032; Department of Medicine (S.T.F.), Mt Sinai/St Luke's Roosevelt Hospital, New York, New York 10019; and Faculties of Life Sciences and Medical and Human Sciences (A.W.), University of Manchester, Manchester M13 9PT, United Kingdom.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Page-Wilson
authors.forename: Pamela U
authors.initials: PU
authors.lastname: Freda
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Jacobs
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Khandji
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Foo
authors.forename: Kana
authors.initials: K
authors.lastname: Meece
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Wardlaw
mesh_terms: D000182:ACTH Syndrome, Ectopic / Q000097:blood* / Q000175:diagnosis* / Q000473:pathology; D000310:Adrenal Gland Neoplasms / Q000097:blood / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D054369:Agouti-Related Protein / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003480:Cushing Syndrome / Q000097:blood* / Q000175:diagnosis* / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000556:secondary; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000097:blood / Q000473:pathology; D017591:Petrosal Sinus Sampling; D011333:Pro-Opiomelanocortin / Q000097:blood*; D012680:Sensitivity and Specificity; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000556:secondary
chemical_list: C515198:AGRP protein, human; D054369:Agouti-Related Protein; D015415:Biomarkers; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone