Acromegaly Patommatat MD

Content Physiology of growth hormone (GH) Etiology of Acromegaly Clinical manifestation & prognosis Diagnosis Treatment & monitoring

Sleep  GH secretion

Factors affecting GH secretion Increased GHRH Fasting Ghrelin Estrogen High protein diet Decreased Somatostatin Aging & obesity IGF-1 Excess Glucocorticoids Glucose load

Insulin Growth Factor (IGF) Liver synthesis peripheral target hormone of GH  negative feedback GH  เพิ่ม IGF-1  Induction of Cell proliferation & Inhibit apoptosis

IGF IGF-I & -II  bind IGFBPs (IGF-binding-protein) IGFBP3  major carrier protein for IGF-1  level correlate with GH level

Physiology of IGF Anabolic effect  nitrogen retention & ลด Cholesterol Induced hypoglycemia improve insulin sensitivity Induced bone formation & bone turnover

Etiology 98%

Clinical manifestation Indolent course มักมีอาการมาก่อนพบแพทย์เป็น 10 ปี Acral bony overgrowth Soft tissue swelling Generalized organomegaly Coexisting illness

Generalized organomegaly Cardiomegaly Thyroid enlargement Macroglossia Salivary gland Liver & spleen Kidney Prostate

Other sign Hyperhidrosis deep hollow-sounding voice oily skin Arthropathy Kyphosis carpal tunnel syndrome proximal muscle weakness acanthosis nigricans skin tags

Coexisting illness Cancer Skeletal disorder large-joint and axial arthropathy thickened articular cartilage periarticular calcifications osteophyte overgrowth synovitis OA Kyphoscoliosis Vertebral Fracture Cancer Rate of death from CA colon สูงกว่า normal population (standardized mortality ratio, 2.47; 95% CI, 1.31 to 4.22) Risk CA colon 2x normal แนะนำ Screening colonoscopy & F/U

Coexisting illness Respiratory System Central sleep apnea (central effect of GH) OSA Soft tissue swelling nasal polyps macroglossia pneumomegaly Cardiovascular Arrthythmia HT (irreversible) VHD (irreversible) Concentric LVH Heart failure (reverse with octreotide)

Prognosis แม้จะ Control GH ได้แต่ก็จะมี Average age < คนปกติ 10 ปี Common cause of death  CVS, RS, Malignancy, CVA overall standardized mortality ratio of patients with acromegaly is 1.48

Factor independently predict longer survival growth hormone levels of less than 2.5 μg per liter Younger age Shorter duration of disease Absence of hypertension

Diagnosis 1. Screening = IGF-1 2. Confirm = Glucose tolerance test 3. Imaging

Treatment RT Pharmacological Surgery

Transphenoidal surgical resection GH กลับเป็นปกติเร็ว, IGF-1 กลับปกติใน 3-4 day Response ดีถ้า : GH < 40mcg/L, ก้อน <1cm Macroadenoma  Cure rate < 50% ไม่เป็น 1st line ถ้าก้อนโตมากหรือ invade cavernous sinus, ผู้ป่วยปฏิเสธผ่าตัด, ก้อนอยู่ใกล้ structure ที่เป็นอันตราย 10% จะ recurrence Complication = Panhypopituitarism, Injury adjacent st Recent surgical advance imaging guidance, navigation and endoscopic approaches perioperative pharmacotherapy of the tumor

Radiotherapy Slow response (5-15yr) มักต้องใช้ยาไปก่อน Late hypopituitarism (PostRT 10yr  50%) Ineffective in normalizing IGF-1 Indication : recurrence or persistence after surgery in patients with resistance to or intolerance of medical treatment

Stereotactic Ablation by Gamma Knife Less evidence about long term result Equal effective with similar Complication Benefit Minimal tissue injury spare optic tract Less duration of fraction

Pharmacological therapy Somatostatin analogue Dopamine agonist GH Antagonist

Somatostatin analogue Mechanism Of Action bind somatostatin receptor inhibit GH secretion inhibit Proliferation of Somatotropes Inhibit IGF-1 liver synthesis

Somatostatin analogue Indication Adjuvant therapy before surgery No evidence of central compressive effects Too frail to undergo surgery Decline surgery

Somatostatin analogue Drugs in class Octreotide  ทนต่อ Plasma degradation  Potency 40 เท่า Somatostatin Dose 50 mcg TID  เพิ่มได้จนเป็น 1500 mcg/d สามารถกด GH ได้ & normalize IGF-1 ได้ 75% ช่วยลดขนาด Tumour size ได้เล็กน้อย และจะโตขึ้นถ้า off Sandostatin-LAR  sustained release, long acting (MONTHLY IM) Lanreotide  30 mg IM อยู่ได้ 10-14 day Pasireotide  Selective activation of somatostatin receptors, มี additive effect ต่อการกด GH, ได้ผลแม้ cell ที่ resist ต่อ Octreotide

Dopamine agonist Bromocriptine ใช้ high dose >20mg/d เพื่อกด GH ได้ผล normalize IGF-1 แค่ 10%  poor efficacy โอกาสได้ผลเพิ่มถ้ามี Co-secretion of PRL Combine กับ Octreotide  additive benefit Newer Generation = Carbergolide Additive with Somatostatin

GH antagonist  Pegvisomant Pegylated Growth analog & substitution of some Amino acid competitive inhibitor to GH enhanced affinity for the growth hormone receptor and prevention of functional growth hormone–receptor signaling. Indication: Resistant or Intolerance to Octrotide Dose  40 mg injection OD  block growth hormone–mediated generation of IGF-I ประมาณ 90% of patients

GH antagonist  Pegvisomant Combine with somatostatin analog  decrease dose Somatostatin Additional benefit ในการกด IGF-1 & เพิ่ม Glucose tolerance Disadvantage  Cost  No effect on Pitu adenoma (peripheral tissue action)

Monitoring & Clinical Goal First Goal = Symptom control Second Goal = Biochemical control tight biochemical control is required to reduce complications and restore adverse rates of death to control levels. Check biochemical test & Pituitary MRI ทุกปี Persistent elevation of GH แม้จะ normal IGF-1  บอก recurrence ซึ่งบอกว่าต้องทำ imaging และเริ่ม start Rx (ใน กรณี clinical inactive)หรือเปลี่ยน Rx (ในกรณี Rx อยู่แล้ว) OTHER endogenous pituitary reserve cardiovascular function (Including Echo) pulmonary status sugar control