Acromegaly

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Acromegaly

  1. 1. Acromegaly Dr Thomas fox SpR Diabetes and Endocrinology Derriford Hospital
  2. 2. Learning outcomes <ul><li>Incidence and presentation </li></ul><ul><li>The roles of IGF-1 and GH </li></ul><ul><li>An approach to management 2009 </li></ul><ul><li>Prognosis </li></ul><ul><li>Novel therapies </li></ul>
  3. 3. Definition <ul><li>Disproportionate skeletal tissue and soft tissue overgrowth </li></ul><ul><li>Results from hyperplasia of pituitary somatotroph cells and excessive growth hormone production </li></ul><ul><li>First described by Verga in 1864 </li></ul>
  4. 4. Incidence and presentation <ul><li>5 cases per million </li></ul><ul><li>In a study of 600 cases commonest presenting symptoms </li></ul><ul><ul><li>Acral and facial changes </li></ul></ul><ul><ul><li>Hyperhydrosis </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><ul><li>Paraesthesia </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Goitre </li></ul></ul><ul><ul><li>Rarely visual field defects </li></ul></ul><ul><ul><li>Frontal skull bossing </li></ul></ul>
  5. 5. Diagnosis <ul><li>Historically variable reliability of GH assays </li></ul><ul><li>Acronegaly results in </li></ul><ul><ul><li>Excessive GH throughout the day </li></ul></ul><ul><ul><li>Loss of bursts </li></ul></ul><ul><li>High random GH not useful </li></ul><ul><li>Low random GH <0.04µg/l makes diagnosis unlikely </li></ul><ul><li>IGF-I vs OGTT </li></ul>
  6. 6. Loss of pulsatility of GH in acromegaly (umIU/L)
  7. 7. GH physiology <ul><li>Produced in anterior pituitary gland </li></ul><ul><li>Stimulated by </li></ul><ul><ul><li>GHRH from hypothalamus </li></ul></ul><ul><ul><li>Ghrelin (gut) </li></ul></ul><ul><li>Inhibited by </li></ul><ul><ul><li>somatostatin via SSTR 2 and 5 receptor subtypes </li></ul></ul><ul><li>SS regulates the timing and amplitude of GH release </li></ul><ul><li>GH receptors widely expressed in liver, fat and muscle </li></ul>
  8. 8. GH production
  9. 9. OGTT <ul><li>75g oral glucose load is neuroendocrine stimulus that should suppress GH secretion </li></ul><ul><li>GH should drop to <1.0µg/l during 2 hours following glucose load (sample at 0, 30, 60 and 120mins) </li></ul><ul><li>False positives </li></ul><ul><ul><li>Obesity </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>Oestrogen replacement </li></ul></ul><ul><ul><li>Diabetes mellitus </li></ul></ul>
  10. 10. IGF-I <ul><li>Polypeptide target of GH </li></ul><ul><li>Synthesised </li></ul><ul><ul><li>Liver (80%) </li></ul></ul><ul><ul><li>Bone </li></ul></ul><ul><ul><li>Muscle </li></ul></ul><ul><ul><li>Kidney </li></ul></ul><ul><li>Endocrine and paracrine hormone </li></ul><ul><li>Mediates growth actions of GH </li></ul><ul><li>IGF-I receptor found ubiquitously </li></ul>
  11. 11. IGF-I <ul><li>Relatively stable (unlike GH) </li></ul><ul><li>Positively correlated with GH </li></ul><ul><li>Age-matched controlled levels required (levels fall 14% per decade) </li></ul><ul><li>Falsely low levels in </li></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>Hepatic failure </li></ul></ul><ul><ul><li>Oestrogen replacement </li></ul></ul>
  12. 12. Mr IG <ul><li>Referred in 2007 by ENT surgeons </li></ul><ul><ul><li>10 year history of snoring </li></ul></ul><ul><ul><li>Recent onset facial pain </li></ul></ul><ul><ul><li>Acromegalic features </li></ul></ul><ul><ul><li>CT scan arranged by ENT showed a 1cm pituitary adenoma </li></ul></ul><ul><li>On systems review he also had sweating but had not noticed increased size in his hands or feet. </li></ul><ul><li>No headaches/visual disturbances </li></ul><ul><li>BP 185/65mm/Hg </li></ul><ul><li>On clinical examination features of acromegaly </li></ul>
  13. 13. Initial investigations <ul><li>IGF-I 85.5 </li></ul><ul><li>OGTTT (GH 0-10mIU/L old units) </li></ul><ul><ul><li>12.4 0mins </li></ul></ul><ul><ul><li>9.8 30 </li></ul></ul><ul><ul><li>8.5 60 </li></ul></ul><ul><ul><li>8.1 90 </li></ul></ul><ul><ul><li>10.9 120 </li></ul></ul>
  14. 14. Other endocrine parameters <ul><li>TSH 0.7 </li></ul><ul><li>FT4 18.3 </li></ul><ul><li>FSH 6.3 </li></ul><ul><li>Lh 3.1 </li></ul><ul><li>Testosterone 8.7 </li></ul><ul><li>PRL 279 </li></ul><ul><li>ITT cortisol peak 668 </li></ul>
  15. 15. Pre-treatment MRI (pre and post-contrast)
  16. 16. Treatment <ul><li>Acromegaly with macroadenoma </li></ul><ul><ul><li>Enrolled in Medical Therapy For Acromegaly Trial (MTAT) </li></ul></ul><ul><ul><li>Dose titrated up to 120mg monthly of lantreotide Autogel </li></ul></ul><ul><li>Disappointing response after 6 months treatment </li></ul><ul><ul><li>IGF-I remained elevated at 94 </li></ul></ul><ul><ul><li>OGTT </li></ul></ul><ul><ul><ul><li>Basal 10.7 mIU/L (reduced from 12.4) </li></ul></ul></ul><ul><ul><ul><li>Nadir 8.1 mIU/L </li></ul></ul></ul><ul><li>On balance decided to continue in the trial </li></ul>
  17. 17. Interval MRI (pre and post-contrast)
  18. 18. At trial end <ul><li>No significant reduction in tumour size </li></ul><ul><li>He underwent transphenoidal hypophysectomy </li></ul><ul><li>3 month following surgery MRI demonstrated tumour size reduction </li></ul>
  19. 19. Post TSH MRI (pre and post-contrast)
  20. 21. Post TSH <ul><li>IGF-I 42.4 </li></ul><ul><li>ITT (hypoglycaemia to glucose of 0.6 – seizure) </li></ul><ul><ul><li>Peak cortisol 745 </li></ul></ul><ul><ul><li>Basal GH 0.33 µg/L </li></ul></ul><ul><ul><li>Peak GH 19.9 µg/L </li></ul></ul><ul><ul><li>OGTT low basal level and supressed </li></ul></ul><ul><li>TSH 0.85 </li></ul><ul><li>FT4 21.1 </li></ul><ul><li>FSH 3.1 </li></ul><ul><li>LH 2.5 </li></ul><ul><li>PRL 73 </li></ul>
  21. 22. Follow-up <ul><li>MR IG continued to feel unwell </li></ul><ul><li>Repeat MRI – no change </li></ul><ul><li>Repeat OGTT </li></ul><ul><ul><li>Basal 0.19 µg/L </li></ul></ul><ul><ul><li>Nadir 0.1 µg/L </li></ul></ul><ul><li>Repeat IGF-I 45-48 </li></ul><ul><li>Discordant results </li></ul><ul><li>what to do next? </li></ul>
  22. 23. IGF-I and GH discordance <ul><li>Belgian registry </li></ul><ul><li>229 patients </li></ul><ul><li>65% concordance in GH and IGF=I results </li></ul><ul><li>Mostly IGF-I was not suppressed </li></ul><ul><li>General feeling that IGF-I gives a better idea of cure and also determines clinical prognosis </li></ul>
  23. 24. The role of surgery <ul><li>Transphenoidal hypopyhsectomy gold standard in dedicated centre </li></ul><ul><ul><li>`75-95% cure rate in intrasellar microadeomas </li></ul></ul><ul><ul><li>40-65% cure for macroadenomas </li></ul></ul><ul><li>Complications on 1% of patients </li></ul><ul><ul><li>Transient occulomotor palsies </li></ul></ul><ul><ul><li>Deterioration of vision </li></ul></ul><ul><ul><li>Carotid artery injury </li></ul></ul><ul><ul><li>Epistaxis/CSF leak </li></ul></ul><ul><ul><li>DI (transient or permanent) </li></ul></ul>
  24. 25. Primary medical therapy? <ul><li>Only indicated in treatment of macroadenomas </li></ul><ul><ul><li>ie invasion into the cavernous sinus </li></ul></ul><ul><li>May increase the cure rate with tumour shrinkage prior to surgery </li></ul>
  25. 26. Medical therapy <ul><li>3 drug classes </li></ul><ul><ul><li>Somatostatin receptor ligands </li></ul></ul><ul><ul><li>Dopamine agonists </li></ul></ul><ul><ul><li>GHRH antagonists </li></ul></ul>
  26. 27. SRLs <ul><li>Target the somatostatin 2 and 5 receptor subtypes in pituitary and directly on the liver to inhibit IGF-I synthesis </li></ul><ul><li>Octreotide LAR and lanreotide Autogel no head-to-head stduies </li></ul><ul><li>Indications </li></ul><ul><ul><li>Those who refuse surgery/are too unfit </li></ul></ul><ul><ul><li>Failure of surgical cure </li></ul></ul><ul><ul><li>Primary therapy if surgical cure unlikely </li></ul></ul><ul><ul><li>Whilst waiting for radiotherapy to take effect </li></ul></ul><ul><li>75% will see a 25% tumour shrinkage </li></ul><ul><li>Biochemical control in 34-45% of patients </li></ul><ul><li>SE – abdominal bloating, gallstones/sludge </li></ul><ul><li>NB may interfere with GH response to OGTT </li></ul>
  27. 28. GHR antagonist <ul><li>Pegvisomant </li></ul><ul><ul><li>Binds to peripheral GH receptors blocking function </li></ul></ul><ul><ul><li>GH levels increase ?due to impairment of IGF-I negative feedback on somatotroph secretion </li></ul></ul><ul><li>Daily injection 1030mg (£50-100 daily!) </li></ul><ul><li>Indicated </li></ul><ul><ul><li>No biochemical control despite surgical and medical therapy </li></ul></ul><ul><li>Risks </li></ul><ul><ul><li>Tumour growth </li></ul></ul><ul><ul><li>Abnormal LFTs (25%) </li></ul></ul><ul><ul><li>lipohypertrophy </li></ul></ul><ul><li>?GHR antagonist in combination with SRL </li></ul>
  28. 29. Radiotherapy <ul><li>Fractionated or gamma-knife </li></ul><ul><li>50% biochemical cure at 10 years </li></ul><ul><li>Usually second or third line </li></ul><ul><li>Indicated in those </li></ul><ul><ul><li>Not cured by surgery to remove need for lifelong medical Rx </li></ul></ul><ul><ul><li>After debulking surgery </li></ul></ul><ul><ul><li>In those who have failed SRL therapy and are at risk of tumour growth from GHR antagonist Rx </li></ul></ul>
  29. 30. Risks of radiotherapy <ul><li>Hypopituitism in 50% </li></ul><ul><ul><ul><li>TSH 27% </li></ul></ul></ul><ul><ul><ul><li>LH/FSH 18% </li></ul></ul></ul><ul><ul><ul><li>ACTH 15% </li></ul></ul></ul><ul><li>Visual defects 5% </li></ul><ul><li>Secondary tumours? </li></ul><ul><li>Radiation vasculopathy </li></ul><ul><li>Neurocognitive defects </li></ul>
  30. 31. Prognosis <ul><li>Life expectancy reduced by 10% </li></ul><ul><li>Mortality determined by </li></ul><ul><ul><li>Random GH<2.5µg/L or suppressed <1µg/L </li></ul></ul><ul><ul><li>Normalisation of IGF-1 </li></ul></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>HTN </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Cardiac disease </li></ul></ul><ul><ul><li>Duration of disease </li></ul></ul><ul><li>GH <2.5µg/L RR 1.1 </li></ul><ul><li>GH > 2.5µg/L RR 1.9 </li></ul><ul><li>IGF-I>95% confidence interval – SMR 3.4 fold increase </li></ul><ul><li>IGF-I <2SD below the mean had only 1.2 fold increase in SMR </li></ul><ul><li>Effects on tumour mass </li></ul>
  31. 32. Follow-up <ul><li>IGF-I and OGTT at 3 months </li></ul><ul><li>Continued follow-up biochemically </li></ul><ul><ul><ul><li>(GH is not measured in GHR antagonist therapy) </li></ul></ul></ul><ul><ul><ul><li>OGTT not helpful in SRL therapy </li></ul></ul></ul><ul><li>MRI </li></ul><ul><ul><li>3-6 months post-op </li></ul></ul><ul><ul><li>May not need to be regular if biochemically “cured”6 months after commencing GHR antagonist </li></ul></ul><ul><li>Pituitary function 3 months post-surgery </li></ul><ul><li>ITT </li></ul>
  32. 34. Summary <ul><li>Diagnosis and natural history of acromegaly </li></ul><ul><li>IGF-I and GH measurements and relevance as prognostic indicators </li></ul><ul><li>Surgical, medical and radiotherapy options </li></ul><ul><li>A management and follow-up strategy for acromegaly </li></ul>

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