Acromegaly: a challenging condition to diagnose and manage. C. L. Chik, MD, PhD, FRCPC University of Alberta, Edmonton
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1 Acromegaly: a challenging condition to diagnose and manage C. L. Chik, MD, PhD, FRCPC University of Alberta, Edmonton
2 Acromegaly: a challenging condition to diagnose and manage? Objectives: n Know the clinical presentations of acromegaly n Know the treatment goals of acromegaly n Know the therapeutic options
3 Clinical Manifestations of Acromegaly Case 1 45 year old male changes in ring and shoes size for several years headaches, fatigue, sweating, carpal tunnel symptoms GH 88 µg/l IGF µg/l Other anterior pituitary function, normal MRI, 1.5 cm sellar mass
4 Case 1
5 Clinical Manifestations of Acromegaly Case 2 28 year old woman Headaches and visual loss, cannot read across the line irregular menses, with increasing alopecia, on Diane 35 mild increase in shoes size, excessive sweating possible sleep apnea according to her boy friend GH 77.0 µg/l IGF µg/l No thyroid or adrenal dysfunction MRI, 2.4 x 2.2 x 1.6 cm sellar mass
6 Case 2
7 Clinical Manifestations of Acromegaly Case 3 54 year old female n n n n n n Presented to ER with 3-hour history of right-sided weakness associated with slurred speech, which has since improved Known hypertension n On ramipril but did not take her medication that morning No history of diabetes or dyslipidemia Non-smoker HR = 78 bpm, regular; BP= 160/100 mmhg Normal neurological exam
8 Clinical Manifestations of Acromegaly Case 3 Endocrine consult n n n Physical examination revealed typical facial features of acromegaly Neck exam showed a twice normal-sized thyroid gland with prominent nodules on both lobes Euthyroid on examination
9 Additional Investigations
10 Clinical Manifestations of Acromegaly Case 3 n MRI sella n n 4 cm sellar/suprasellar mass with left cavernous sinus invasion and chiasmal compression Ultrasound thyroid n Multinodular goitre with a dominant 2.5 cm nodule Diagnosis: Acromegaly with a recent TIA Newly diagnosed diabetes Uncontrolled hypertension Multinodular goiter with subclinical hyperthyroidism Partial hypopituitarism
11 GH Excess n Despite obvious disadvantages, GH excess can have a few perks. Possible advantages: n A. An athletic career n B. Hollywood movie roles n C. Guinness Book of World Records
12 Hollywood movie roles Richard Kiel, as Jaws in The Spy Who Loved Me and Moonraker Andre the Giant in Princess Bride Gheorghe Muresan, taking time from busy NBA schedule in My Giant
13
14
15 Acromegaly n An uncommon disorder of excessive GH secretion incidence 3-4 cases / million prevalence cases / million More current estimate, could be ~20 x higher n Mortality is potentially two to four times of the general population n Effective treatment reduces morbidity and restores life expectancy to normal
16 Key function of Pituitary Gland
17 Anatomy of the Pituitary Gland n n n n Lateral: Cavernous Sinus (cranial nerves III, IV, VI, and carotid arteries) Superior: suprasellar cistern, optic chiasm, link to the hypothalamus by the pituitary stalk (infundibulum) Pituitary stalk, midline structure Inferior: sphenoid sinus
18 Coronal MRI Imaging with Gadolinium contrast
19
20 Regulation of Growth Hormone Pulsatile Circadian Rhythm Stress-induced secretion Negative feedback by IGF-1 Hypothalamus GHRH Somatostatin
21 Causes of Acromegaly GH-secreting Pituitary tumors benign adenoma (most common) carcinoma GHRH-secreting tumors Exogenous sources of GH Genetic causes MEN 1 McCune Albright syndrome Carney s complex
22 Clinical Manifestations of Acromegaly Ezzat et al Medicine, 1994
23 Clinical Impact of Long-term GH and IGF1 Exposure Bone/Joint Acral changes, prognathism, arthritis, osteopenia, vertebral fractures, carpal tunnel syndrome Cardiac hypertension, arrhythmia, cardiomyopathy, valvular disease, heart failure Skin Skin tags, excessive perspiration Pancreas Insulin resistance, diabetes Lung Obstructive sleep apnea Melmed JCI, 2009
24 Clinical Impact of Long-term GH and IGF1 Exposure Kidney Gonads Thyroid Colon Fluid retention, increased aldosterone Hypogonadism Goitre Polyps, diverticular disease Fat Lipolysis Visceromegaly Tongue, thyroid, salivary gland, liver, spleen, kidney, prostate Melmed JCI, 2009
25 Local Tumor Effects in Macroadenoma Headaches Visual field loss Cranial nerve palsies
26 Diagnostic Tests for Acromegaly n Plasma IGF-I n Normal range age-dependent n Glucose tolerance test (GH < 1 µg/l,? 0.4 µg/l) n Incomplete GH suppression or paradoxical rise n? GH every 30 minutes for 2 hours n MRI scan of the sella n Visual Fields if indicated
27 IGF-1 Normal Range (Immulite)
28 Acromegaly n The majority of cases present with macroadenomas n Primary therapy is surgical, < 50% cure rate with macroadenomas n Surgical outcome correlates with tumor consistency, location, size, and the degree of invasiveness into adjacent structure n Multimodal therapy is frequently required n Surgery n Medical therapy, somatostatin analog, pegvisomant, dopamine agonist n Radiotherapy, stereotactic vs conventional
29 Treatment Goals for Acromegaly Improved morbidity and mortality Biochemical control of GH Biochemical control of IGF-1 Reduction / removal of tumor mass Maintain / recover pituitary function
30 Mortality in Acromegaly Holdaway et al JCEM 2004
31 Factors Influencing Mortality in Acromegaly Holdaway et al, JCEM 2004
32 Lowering of GH on mortality in acromegaly: a meta analysis Holdaway et al, EJE 159:89, 2008
33 Lowering of IGF-1 on mortality in acromegaly: a meta analysis Holdaway et al, EJE 159:89, 2008
34 Guideline for Treatment of Acromegaly
35 Management of Acromegaly Monitor and actively treat comorbidities Cardiovascular disease Hypertension Diabetes Sleep apnea Arthritis Colonic polyps Osteoporosis JCEM 95:3141, 2010
36 Management Plan Echocardiogram Colonoscopy Sleep assessment? Baseline abdominal ultrasound Medical vs surgical therapy Pre-operative Rx with a somatostatin analogue?
37
38 Surgical Management Indications n Transsphenoidal surgery (endoscopic vs microscopic) is the primary therapy in most patients n Repeat surgery to be considered if there is residual intrasellar disease Preoperative medical therapy n Routine use is not suggested n Consider Rx with somatostatin analog in selected patients to reduce surgical risk n severe pharyngeal thickness n heart failure
39 Operating Theatre
40 Surgical management Surgical debulking n In the setting of parasellar disease (surgical cure is unlikely), surgical debulking may improve subsequent response to medical therapy Postoperative testing n Electrolytes in 1 week n May be discharged on steroid n Measure an IGF-1 level and a random GH at 12 weeks or later. n Measure a nadir GH level with an OGTT if random GH > 1 µg/l. n Repeat MRI 12 weeks after surgery.
41 Medical Therapy n Medical therapy for persistent disease following surgery n Somatostatin analog or pegvisomant for those with moderate-to-severe signs and symptoms of GH excess and without local mass effects n Cabergoline for those with only modest elevations of serum IGF-1 and mild signs and symptoms of GH excess
42 Medical Therapy n If inadequate response to a somatostatin analogue, add pegvisomant or cabergoline n Somatostatin receptor ligand as primary therapy
43 Why Primary Medical Therapy for Acromegaly? Low cured rates after surgical treatment for macroadenomas (20 50%) Sinus invasion likely precludes cure Variability in surgical experience and skill Peri-operative side effects Post-op hypopituitarism Unacceptable anesthetic risks Refusal of surgery
44 Medical Therapy Efficacy of somatostatin analog n % IGF-1 normalization vs % response rate in trials n > 50% tumor reduction in more than 50% patients (meta-analysis) Efficacy of pegvisomant n 95 % normalization (up to 40 mg daily) vs 63% ACROSTUDY
45 Combination Therapy SSA + pegvisomant n Normalization of IGF-1 in 95% of patients n Enhance quality of life and tumor size control n Elevation of ALT, AST in 27 % SSA + cabergoline n Normalization of IGF-1 in 42-60% Pegvisomant + cabergoline n Limited data, may be helpful
46 Emerging Therapy n Pasireotide LAR n more effective than octreotide LAR or lanreotide autogel n increased risk of hyperglycemia n Oral octreotide (Octreolin)
47 Radiotherapy (RT) / Stereotactic RT n Consider RT for residual tumor mass n If medical therapy is unavailable, unsuccessful, or not tolerated. n SRT is suggested over conventional RT with the following exceptions: n Lack of availability n Significant residual tumor burden n Tumor too close to the optic chiasm
48 Radiotherapy (RT) / Stereotactic RT Monitoring post RT n n Annual GH/IGF-1 reassessment following medication withdrawal Annual hormonal testing for hypopituitarism and other delayed radiation effects. Efficacy of RT n n 10-60% remission after 15 years with SRT Hypopituitarism in >50% within 5 to 10 years
49
50 Case Resolution Case 1 45 year old male changes in ring and shoes size for several years headaches, fatigue, sweating, carpal tunnel symptoms GH 88 µg/l IGF µg/l Other anterior pituitary function, normal MRI, 1.5 cm sellar mass
51 Case 1
52 Case Resolution Case 1 Test dose - octreotide 100 µg SC GH 88 µg/l 8 µg/l in 4 hours octreotide LAR 30 mg q28d x 3 doses no headaches improved fatigue, sweating, carpal tunnel symptoms GH 88 4 µg/l IGF µg/l (N )
53 Case 1 Pre Post
54 Case Resolution Case 1 octreotide LAR 30 mg q28d x 3 Repeat MRI GH µg/l IGF µg/l significant tumor shrinkage octreotide LAR 30 mg q21d After 12 m of medical therapy GH µg/l IGF µg/l (N ) Repeat MRI, no further shrinkage
55 Case Resolution Case 1: Transsphenoidal surgery GH 0.7 µg/l GH post OGTT - <0.1 µg/l IGF µg/l Other AP function intact GH and IGF-1 remained normal 8 years post surgery
56 Case 1
57 Case Resolution Case 2 28 year old woman Headaches and visual loss, cannot read across the line irregular menses, with increasing alopecia, on Diane 35 mild increase in shoes size, excessive sweating possible sleep apnea according to her boy friend GH 77.0 µg/l IGF µg/l No thyroid or adrenal dysfunction MRI, 2.4 x 2.2 x 1.6 cm sellar mass
58 Case 2
59 Case 2 3 years post surgery GH: from 77 to 1.2 µg/l ogtt GH: 0.5 µg/l IGF-1: from 1406 to 207 µg/l 5 years post surgery GH and IGF-1 normal normal pregnancy
60 Case Resolution Case 3 54 year old female n n n n n Presented to ER with 3-hour history of right-sided weakness associated with slurred speech, which has since improved Known hypertension Physical exam: acromegalic features and a nodular thyroid gland MRI 4 cm sellar mass with left cavernous sinus invasion and chiasmal compression Thyroid ultrasound multinodular goitre with a 2.5 cm dominant nodule
61 Case Resolution Case 3 Diagnosis Acromegaly Management Transsphenoidal surgery Post surgery, IGF-1 normalized with pegvisomant and lanreotide autogel Newly diagnosed diabetes Uncontrolled hypertension Multinodular goiter Partial hypopituitarism insulin and metformin ramipril and amlodipine thyroid surgery (papillary carcinoma) no management required
62 Current Canadian Perspectives Acromegaly is a rare disease, individualized treatment plan is required to achieve normalization of IGF-1 and/or GH levels. Delay in the diagnosis of acromegaly remains an important deterrent in the management of acromegaly. An action plan is needed to enable early recognition of the condition, i.e. targeting screening of patients in the presence of several common manifestations of acromegaly. Surgery should be done by experienced/dedicated pituitary surgeons
63 Current Canadian Perspectives Lack of funding could be a factor that leads to sub-optimal management of this condition. SSA is the only class of drug listed by CADTH for the treatment of acromegaly Cabergoline is used off label Pegvisomant, the more effective drug, is not recommended by CADTH, coverage is an issue Management of co-morbidities remains suboptimal and this has an adverse impact on the quality of life of patients
64 Questions???
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