A 78 yo female with spells why did I order a Chromogranin A

1. A 78 yo female with �spells��why did I order a Chromogranin A? Suzanne Breckenridge, MD Washington University March 30, 2006

2. History of Present Illness 78 yo WF with �spells� since summer 2005 Described as acute onset of overwhelming fatigue, weakness, diaphoresis and �trembling inside� 2-4 episodes/week Some flushing, occasional palpitations, some mild dyspnea, 2 pre-syncopal episodes 6 months ago no diarrhea, wheezing or associated HA. Occasional HA described as a BB hitting her face and rolling down her cheek (L) Mild hot flashes when peri-menapausal but none for 20 years

3. History of Present Illness cont No exacerbating/relieving factors No association with intake of certain foods, exercise or Etoh consumption No new medications She was seen by cardiology and pulmonolgy

4. Past Medical History Polymalgia rheumatica �Ice pick headaches� Pulmonary histoplasmosis Hyperlipidemia Mild depression Mild GERD No history of HTN

5. Medications: Prednisone 5mg x 10yrs, lipitor, lexapro, folic acid, vit C, asa, fish oil, PPI prn SH: married w/ 4 children no etoh, no tob FH: uncle and sister w/hyperparathyroism, no FH of carcinoid, gut tumors, pheo or thyroid disorders

6. Physical Exam BP 130/70, HR 80, WT 182 lbs HEENT: EOMI,PEERL, no plethora or evidence of flushing Neck: no goiter CV: RRR w/o M Lungs:CTAB ABD Obese, no striae, no HSM MS: Strength nl Skin-no telangectasia, no rash Neuro: DTR NL, no tremor

7. Laboratory evaluation 5/05 Plasma catecholamines: dopamine <50 Epi <50 and Norepi 821 pg/mL (<700) 11/05 Urinary catecholamines/metanephrines: Dopamine 159 (65-400) Epi 1.7 (0-20) Norepi 45 (15-80) metanepherine 63 (30-180) Normet 363 (148-560)

8. Laboratory Cont 1/06 5HIAA level 8.8 (1-6) Repeat 5HIAA 4.4 plasma metanephrine <0.2 (0-.49) Plasma Normetanephrine 0.47 (0-0.89) Cortrosyn stim test 3.3?15.7 chromogranin A 1290 (<225) Calcitonin <5 Renal/hepatic function nl Oct 2005 CT Abd/pelvis � no mass, pancreas normal, adrenals nl, no liver mets

11. What is Chromogranin A? 49 kDa, 439 AA, monomeric, hydrophilic, acidic glucoprotein First isolated from the chromaffin cells of adrenal medulla 1965 Member of the Chromogranin/Secretogranin family Highly conserved Stable

12. Chromogranin A Functions Extracellular: precursor to biologically active peptides (pancreastatin, chromostatin, vasostatin, parastatin) Intracellular: modulation of protolytic processing/packaging of peptides and directing to regulated pathways of secretion

15. Chromogranin A Location: Anterior Pituitary parafollicular C cells of the thyroid chief cells of parathyroid islet cells chromaffin cells of adrenal medulla wide spread neuro endocrine system including bronchial, GI tract and in Merkel cells of the skin

17. Chromogranin A Elevated levels: liver failure, renal failure, sympatheticoadrenal stimulation (up to 2 x nl), HTN?, PPI, neuroblastoma and other CNS tumors, renal cell carcinoma, hemangioblastoma Also, Prostate CA, Colon CA, breast CA, small cell Lung CA Can be 1000 x ULN metastatic carcinoid but nl in small neuroendocrine tumors CGA concentration correlates with tumor burden (except gastrinomas) and can precede radiographic evidence of recurrence Levels decline with tx with somatostatin High levels in �non-functioning� tumors as well

19. Dx/Follow up of Carcinoid Highest levels are reported with metastatic carcinoid (up to 1000x ULN) Advocated for the initial work-up and follow-up with 5-HIAA levels NCCN oncology guidelines In patients with recurrent/metastatic carcinoid-CGA has better sensitivity and specificity than 5HIAA Prognosis-Janson et al. reported that CGA levels of >5000ug/L in carcinoid was an independent risk factor for death

20. Forgut Carcinoid Midgut carcinoid Hindgut Carcinoid Respiratory Jejunum Colon Stomach Ileum Rectum Pancreas Appendix Duodenum CGA + 80-90% CGA +70-80% CGA + 90-100% 5HIAA may be normal 5HIAA elevated 5HIAA nl +/- carcinoid syndrome + carcinoid syndrome - carcinoid syndrome

23. Pheochromocytoma Used to help diagnose and follow-up Can be markedly elevated Sporatic cases: CGA 83-89% sensitivity and a 96-100% specificity CGA levels correlate with tumor burden Drugs used to treat Pheo/HTN do not alter level May differentiate between malignant and benign

24. Endocrine Pancreatic Tumors CGA usually elevated and can be used to follow patients with gastrinomas, VIPoma, glucagonoma, somatostainoma Clinically non-functioning NET Correlate with progression/regression during treatment Usefulness is limited as CGA can not compete with other peptide hormone markers in sensitivity or specificity

31. Other clinical implications� CGA ectopic ACTH production Nobels et al. 30 pts w/ Cushing�s � 10 with ectopic causes, elevated CGA 7/10 (270-13,900) Prostate CA Immunoscintigraphy with anti-chromogranin monoclonal antibodies

32. How do I order a Chromogranin A? Immunochemiluminometric assay Red top tube $113.90 Send out to Mayo, 6 day turn around time Any value >625 routinely diluted and remeasured

33. Thank you