Cushing staff 20 de enero 2018
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Síndrome de Cushing
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Cushing staff 20 de enero 2018
- 1. Hipófisis JUNTA MÉDICA SERVICIO DE ENDOCRINOLOGÍA Universidad de Antioquia
- 3. CASO CLÍNICO
- 4. 33 años, vive en una vereda de Guarne, ama de casa (recién separada: hace 6 meses). Antecedentes: • Patológicos: niega • Qx: colecistectomía laparoscópica por colecistitis aguda • Alérgicos: niega • Tóxicos: niega • AGO: G2P2A0, FUM 20/12/17, ciclos regulares 28/5, planifica con DIU (T de cobre). • Farmacológicos: niega. Niega consumo de glucocorticoides por cualquier vía. Historia Clínica
- 6. Tratamiento Inicial • Cefazolina 4 días • Clindamicina 4 días
- 7. Motivo de IC endocrinología
- 8. Evolución de los síntomas 1 3 5 7 9 11 13 Años
- 9. Examen físico • Buenas condiciones generales, alerta, Obesa. • Peso: 86 Kg, talla , IMC 33.9 • PA 108/78, FC 80, FR 16, afebril.
- 10. Examen físico
- 11. Examen físico
- 12. Signo de Gowers
- 13. Laboratorios Cortisoluria 1 217 ug (4.3-176), volumen 1180 mL: 1,2 veces
- 14. Laboratorios Cortisoluria 2 350.9 ug ug (4.3-176), volumen 1640 mL: 1,99 veces
- 15. Laboratorios • Ritmo circadiano cortisol 14.2 10.3 14.6
- 16. Cortisol post dexametasona 1 mg 11 pm 8 am Cortisol 10,2 ug/dL
- 17. ACTH 32,7 pg/mL
- 18. Cortisol post dexametasona 8 mg 11 pm 8 am Cortisol 2,0ug/dL Supresión del 86%
- 19. Otros laboratorios • HbA1C: 6.1% • PTOG: 133-->333 mg/dl • Colesterol hdl 35.7 • Colesterol ldl 197 • Colesterol total 272 • Creatinina sérica 0.76 mg/dl
- 20. RMN silla turca ACI Senos cavernosos Meninges (recubren seno cavernoso)
- 21. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lóbulos temporales y el resto del parénquima cerebral es normal. Isointensa en T1
- 22. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lóbulos temporales y el resto del parénquima cerebral es normal. Isointensa en T1
- 24. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lóbulos temporales y el resto del parénquima cerebral es normal. Hipointensa en T2 ACI Senos cavernosos Meninges (recubren seno cavernoso)
- 25. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lóbulos temporales y el resto del parénquima cerebral es normal. Hipointensa en T2
- 26. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lóbulos temporales y el resto del parénquima cerebral es normal. Hipercaptante ACI Senos cavernosos Meninges (recubren seno cavernoso)
- 28. RMN Silla turca 10 x 9 x 9 mm los hacia el lado izquierdo englobando la carótida aproximadamente un 50%. El quiasma, la cisterna supraselar, el tercer ventrículo, los lbulos temporales y el resto del parénquima cerebral es normal. Hipercaptante
- 29. Paciente 33 años Síndrome de Cushing ACTH dependiente Tumor hipofisiario 1 cm, englobando 50 % de carótida interna izquierda Prueba post dexametasona a favor de: origen hipofisiario Diabetes Dislipidemia Enfermedad de Cushing
- 30. Tratamiento quirúrgico inicial Tratamiento médico inicial ¿Conducta Terapéutica?
- 31. Objetivos del tratamiento Reversión de las características clínicas Normalización de los cambios bioquímicos con una morbilidad mínima Control a largo plazo sin recurrencia Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462
- 32. CIRUGÍA
- 34. Tratamiento de primera línea Cirugía En manos experimentadas • Tasa de éxito inicial de 68 a 98 % en pacientes con microadenoma • Tasas de remisión 50-70 % en pacientes con macroadenoma • La tasa de recidiva del 2 a 26 % (después de 6 a 240 meses) No siempre es factible: Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462 Tritos NA et al. Nat Rev Endocrinol 2011;104:279–289
- 35. • Se correlacionan con la experiencia del neurocirujano • Insuficiencia hormonal 2-40% • Déficit neurológicos • Trombosis venosa profunda • Rinorraquia < 8% • Meningitis < 3% Nat. Rev. Endocrinol. 2011; 7: 279–289 Endocrinol Metab Clin N Am 2005; 34: 459–478 Complicaciones
- 36. • Daño del nervio óptico, daño de otros nervios craneanos • Daño vascular 1-6% • Perforaciones del septo nasal, epistaxis, sinusitis 0.4-0.6% • Diabetes insípida 39% • SIADH 10-25% • Mortalidad 0% a 2% Nat. Rev. Endocrinol. 2011; 7: 279–289 Endocrinol Metab Clin N Am 2005; 34: 459–478 Complicaciones
- 37. Long-term follow-up results of transsphenoidal surgery for Cushing disease in a single centre using strict criteria for remission • Definición remisión: cortisol <50 nmol/L (1.8 ug/dl) • 54 pacientes consecutivos con enfermedad de Cushing que fueron llevados a cirugía transesfenoidal • 42 mujeres, edad promedio 41 años • 1980-2000 • Seguimiento promedio 6 años (6 meses a 21 años) Clin Endocrinol (Oxf). 2002 Apr;56(4):541-51.
- 38. Clin Endocrinol (Oxf). 2002 Apr;56(4):541-51.
- 39. Outcome of Cushing's disease following transsphenoidal surgery in a single center over 20 years J Clin Endocrinol Metab 97:1194-1201, 2012 J Clin Endocrinol Metab. 2012 Apr;97(4):1194-201 La mediana de seguimiento de los datos clínicos fue de 4,6 años.
- 40. Long-term remission and recurrence rates in Cushing’s disease: predictive factors in a single-centre study • 131 pacientes • Remisión: • 72.8% en microadenomas • 42.9% en macroadenomas • Recurrencia: • 22.7 en microadenomas • 33.3%% en macroadenomas • Recuperación del eje en <3 años predice recurrencia European Journal of Endocrinology (2013) 168 639–648
- 41. Tratamiento Cirugía • Definiciones: • Cura→ diferentes criterios pos-Qx • 2 semanas, medir cortisol am→ <1.8µg/dl, sensib 67%, especif 79% predecir cura • 6-12 semanas <5 µg/dl, sensib 94% y especif 79% • Si > 5 µg/dL considerar reintervención temprana • Remisión → Cortisol sérico entre 1.8 – 10.8 µg/dl al 5º día • Persistencia → Cortisol sérico >10.8 µg • Otras definiciones: • A las 48 h: Cortisol sérico: < 2 µg/dL, UFC < 20 µg/24, ACTH < 5 pg/mL • Otros reportes indican que cortisol basal al día 3, 4 o 5 sin esteroides < 1 µg/dL es el mejor predictor clínico (96% de precisión diagnóstica) Surgical management of Cushing's disease. Pituitary. 2015 Apr;18(2):211-6.
- 42. /best-practice/images/bp/en-gb/205-3 Algorithm for the treatment of Cushing's
- 43. Nat. Rev. Endocrinol. 2011; 7: 279–289
- 44. Horm Metab Res. 2013 Feb;45(2):109-17. TRATAMIENTO ENFERMEDAD DE CUSHING E. CUSHING CONFIRMADA Cirugía trasesfenoidalCura/remisión Persistencia/recurr encia Nueva qx Terapia medica Terapia medicaCura/remisión Persistencia/recurr encia Terapia medica Adrenalectomía bilateral Radioterapia Terapia medica
- 46. En quienes terapia médica No son candidatos a cirugía • Comorbilidades • No disponibilidad de cirujano experto • Intervención técnicamente difícil/riesgosa Cirugía no exitosa • No es candidato a segunda cirugía Radioterapia • En espera al efecto
- 49. Fármaco Dosis Mecanismo de acción Efectividad Efectos adversos Comentarios adicionales Cabergolina 1-7 mg/sem (biw- diario) Agonista receptor D2 50-75%(corto plazo), 30-40% (2- 3 años) en EC Nausea, vomito, vértigo, manifestaciones psiquiátricas, valvulopatía? > Efectividad en combinación ketoconazol y/o pasireotide; efectivo en algunos pacientes con Sd. Nelson Octreotide Lib inmediata:200- 1000 mg tid; LAR 10- 30 mg IM c/ 4 sem Agonista receptor somatostatina (*SSR2) Algunos ACTH ectópicos y Sd Nelson Alt. gi, colelitiasis o barro biliar, ↑glicemia, ↓glicemia, bradicardia sinusal, caída de cabello. Pasireotide 600-900 mcg SC bid Agonista receptor somatostatina (Isoformas 1, 2, 3, 5) 76-88% EC Alt. gi, colelitiasis o barro biliar, ↑glicemia, bradicardia sinusal. Aprobado FDA el 14 de diciembre del 2012 Discov Med. 2012 Feb;13(69):171-9. TRATAMIENTO Medicamentos de acción central
- 50. PASIREOTIDE
- 52. M. Boscaro et al A. Colao et al Pacientes 29 (Fase 2) 162 (Fase 3) Seguimiento 15 días 12 meses Dosis 600ug s.c B.I.D 600ug - 900ug s.c B.I.D Desenlaces Normalización UFC 17% 13 - 25% Disminución >50% - 49% Promedio disminución UFC 44,9% 47,9% Disminución del volumen tumoral - 9,1% - 43,8% Efectos adversos Gastrointestinales 54% 58% Hiperglucemia 36% 40% Boscaro M et al. J Clin Endocrinol Metab 2009;94:115–122 Colao A et al. N Engl J Med 2012;366:914–924 Pasireotide en enfermedad de Cushing
- 53. Ketoconazol
- 54. Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015 Apr;18(2):245-52.
- 55. Tratamiento Manejo médico Ketoconazol • Imidazol sintético • Antifúngico • Dosis inicial de 200 – 400 mg c/día • Incrementos a 600 – 800 mg/día Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Pituitary. 2015 Apr;18(2):245-52.
- 56. Ketoconazole revisited: a preoperative or postoperative treatment in Cushing's disease 38 pacientes (17 operados) • Seguimiento a 23 meses • Dosis de 200 a 1200mg día Control del hipercortisolismo 50% Descontinuación por efectos adversos 13% Fenómeno de escape 13% Castinetti F et al. Eur J Endocrinol 2008;158:91–99
- 58. Tratamiento combinado Medical combination therapies in Cushing's disease. Pituitary. 2015 Apr;18(2):253-62.
- 59. Fin
Editor's Notes
- http://images.wisegeek.com/highlighted-thyroid.jpg
- After pituitary surgery it takes around 3 to 4 months for the postoperative changes within the sella to regress to allow for assessment of the true volume of residual pituitary tissue
- Transsphenoidal surgery is safe and effective for the treatment of Cushing’s disease. The incidence of complications after transsphenoidal surgery generally correlates with the experience of the surgeon [19,20]. Postoperative complications include those resulting in pituitary hormonal insufficiency, new neurologic deficits, or other medical problems. Patients who have Cushing’s disease are more prone to systemic complications caused by inherent metabolic and cardiovascular abnormalities associated with the disorder. In particular, perioperative deep venous thrombosis was reported in approximately 4% of cases [21]. Additional complications include diabetes insipidus, syndrome of inappropriate antidiuretic hormone, cerebrospinal fluid rhinorrhea, meningitis, optic nerve injury, other cranial nerve palsies, vascular injury, nasal septum perforations, epistaxis, sinusitis, and graft site dehiscence. The perioperative mortality ranges from 0% to 2%
- Transsphenoidal surgery is safe and effective for the treatment of Cushing’s disease. The incidence of complications after transsphenoidal surgery generally correlates with the experience of the surgeon [19,20]. Postoperative complications include those resulting in pituitary hormonal insufficiency, new neurologic deficits, or other medical problems. Patients who have Cushing’s disease are more prone to systemic complications caused by inherent metabolic and cardiovascular abnormalities associated with the disorder. In particular, perioperative deep venous thrombosis was reported in approximately 4% of cases [21]. Additional complications include diabetes insipidus, syndrome of inappropriate antidiuretic hormone, cerebrospinal fluid rhinorrhea, meningitis, optic nerve injury, other cranial nerve palsies, vascular injury, nasal septum perforations, epistaxis, sinusitis, and graft site dehiscence. The perioperative mortality ranges from 0% to 2%
- Transsphenoidal selective adenomectomy (TSA) is widely accepted as the treatment of choice for Cushing's disease but not all patients are cured by this procedure. The success of surgery depends on the skill and experience of the surgeon but the criteria used to define remission are highly variable. We have analysed the outcome following surgery in our centre using the stringent requirement of a postoperative serum cortisol of < 50 nmol/l as our definition of remission and assessed whether changes in surgical policy, including a greater emphasis on selective procedures and the move in recent years to a single surgeon undertaking all pituitary surgery, have improved complication and remission rates. PATIENTS AND METHODS: The case notes, histology and pituitary imaging of 54 consecutive patients (42 females, mean age 41 years) with pituitary-dependent Cushing's syndrome who had undergone transsphenoidal surgery between January 1980 and November 2000 were reviewed. Follow-up was for a median of 6 years (range 6 months to 21 years). RESULTS: One patient died within 1 week of surgery (1.9%) and major morbidity occurred in eight patients (15%). Clinical and biochemical remission was achieved in 41 patients (77%) with only two recurrences (5%) to date. Success was related to tumour size with 37 (86%) of 43 intrasellar lesions successfully resected compared with only four (40%) of 10 extrasellar adenomas. Twenty-four (59%) of those in remission developed partial or complete hypopituitarism compared with four (33%) of those not in remission. The extent of surgical exploration predicted the development of hypopituitarism (88% total hypophysectomy, 33% hemihypophysectomy, 14% selective adenomectomy) but not remission (75% total hypophysectomy, 87% hemihypophysectomy, 71% selective adenomectomy). Among complications, an excess of venous thromboembolic disease was noted, with three patients (6%) developing deep venous thrombosis or pulmonary embolism postoperatively. Comparison of the data for individual surgeons revealed an improvement in outcome over time, with 100% remission of microadenomas, 29% hypopituitarism and 12% complications following the move to a single surgeon undertaking all pituitary surgery. CONCLUSION: Transsphenoidal surgery is a safe and effective treatment for Cushing's disease and our results compare favourably with those from published series, the majority of which comprise relatively small numbers. The presence of an intrasellar lesion and postoperative serum cortisol < 50 nmol/l are good predictors of remission in the long term but historically in our centre this can only be achieved in a significant number of patients at the expense of some degree of hypopituitarism. However, the surgical outcome for Cushing's disease, including a reduced frequency of hypopituitarism, can be improved if patients are operated on by a single pituitary surgeon, using selective adenomectomy as the preferred surgical approach wherever possible.
- Abstract CONTEXT: Historically, Cushing's disease (CD) was associated with a 5-yr survival of just 50%. Although advances in CD management have seen mortality rates improve, outcome from transsphenoidal surgery (TSS), the current first-line treatment, varies significantly between centers. OBJECTIVES: The aim of the study was to define outcome including mortality in a cohort of CD patients treated with TSS over 20 yr. DESIGN: We conducted a retrospective cohort study of 80 patients who underwent TSS to treat CD between 1988 and 2009. In 72 cases, data on clinical features and outcomes were collected from medical records. In eight patients, records were unavailable, but in all cases mortality data were obtained from National Health Service (NHS) registries and recorded as standardized mortality ratio. SETTING: The study was conducted in a United Kingdom tertiary referral center. PATIENTS OR OTHER PARTICIPANTS: Adult patients confirmed to have CD participated in the study. INTERVENTIONS: All patients underwent TSS. MAIN OUTCOME MEASURE: Patients were subdivided into groups based on disease response after initial treatment. Mortality according to subgroup was also assessed. RESULTS: Median follow-up for clinical data was 4.6 yr. Three outcome groups were identified: cure, 72% (52 of 72); persistent disease, 17% (12 of 72); and disease recurrence, 11% (eight of 72). Median time to recurrence after initial remission was 2.1 yr (interquartile range, 1.3-3.1 yr). Mean follow-up for mortality was 10.9 yr. Thirteen of 80 patients had died: five of 52 in the cure group, two of eight in the disease recurrence group, two of 12 with persistent disease, and four of eight of those followed up by NHS registry search only. Overall, the standardized mortality ratio was 3.17 [95% confidence interval (CI), 1.70-5.43], whereas in the cure group it was 2.47 (95% CI, 0.80-5.77), and it was 4.12 (95% CI, 1.12-10.54) for disease recurrence/persistent disease groups. CONCLUSIONS: We report long-term cure rates in excess of 70%. Mortality is increased in CD and may be higher in patients with persistent/recurrent disease compared to patients cured after initial treatment.
- Objective: To investigate the early and late outcomes of patients with Cushing’s disease (CD) submitted to a neurosurgical procedure as first-line treatment. Design: In this single-centre retrospective case notes study, 131 patients with CD with a minimum follow-up period of 6 years (124 operated by transsphenoidal surgery (TSS) and seven by the transcranial approach) were studied. Apparent immediate cure: post-operative 0900 h serum cortisol level !50 nmol/l; remission: cortisol insufficiency or restoration of ‘normal’ cortisol levels with resolution of clinical features; and recurrence: dexamethasone resistance and relapse of hypercortisolaemic features. Results: In patients operated by TSS, remission of hypercortisolaemia was found in 72.8% of 103 microadenomas and 42.9% of 21 macroadenomas, with recurrence rates 22.7 and 33.3% respectively with a 15-year mean follow-up (range, 6–29 years). Of 27 patients with microadenomas operated after 1991, with positive imaging and pathology, 93% obtained remission with 12% recurrence. In multivariate analysis, the time needed to achieve recovery of hypothalamo-pituitary–adrenal axis was the only significant predictor of recurrence; all patients who recurred showed recovery within 3 years from surgery: 31.3% of patients had total hypophysectomy with no recurrence; 42% of patients with selective adenomectomy and 26.5% with hemi–hypophysectomy showed recurrence rates of 31 and 13% respectively (c2 Z6.275, PZ0.03). Strict remission criteria were not superior in terms of the probability of recurrence compared with post-operative normocortisolaemia. Conclusions: Lifelong follow-up for patients with CD appears essential, particularly for patients who have shown rapid recovery of their axis. The strict criteria previously used for ‘apparent cure’ do not appear to necessarily predict a lower recurrence rate.
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