ACROMEGALY- DAIGNOSIS, CLINICAL FEATURES

ACROMEGALY

1. ACROMEGALY BY: DR. AMMAR SABIR SIDDIQUI M.D. MEDICINE ASSISTANT PROFESSOR, DEPARTMENT OF MEDICINE IIMSR, LUCKNOW

2. NORMAL PHYSIOLOGY OF GROWTH HORMONE GH is the most abundant anterior pituitary hormone , and GH-secreting somatotrope cells constitute up to 50% of the total anterior pituitary cell population. GH secretion is controlled by complex hypothalamic and peripheral factors. These include GH-releasing hormone (GHRH ) that stimulates GH synthesis and release. Ghrelin , induces GHRH and also directly stimulates GH release. Somatostatin (somatotropin-release inhibiting factor [SRIF inhibits GH secretion. IGF-I , the peripheral target hormone for GH, feeds back to inhibit GH; estrogen induces GH, whereas chronic glucocorticoid excess suppresses GH release. GH secretion is pulsatile, with highest peak levels occurring at night, generally correlating with sleep onset.

3. Actions of growth hormone GH induces protein synthesis and nitrogen retention Impairs glucose tolerance by antagonizing insulin action. Stimulates lipolysis, leading to increased circulating fatty acid levels, reduced omental fat mass, and enhanced lean body mass GH promotes sodium, potassium, and water retention and elevates serum levels of inorganic phosphate. Linear bone growth occurs as a result of complex hormonal and growth factor actions Liver is the major source of circulating IGF-I.

4. Although GH exerts direct effects in target tissues, many of its physiologic effects are mediated indirectly through IGF-I, a potent growth and differentiation factor. IGF-I levels are low with cachexia, malnutrition, and sepsis. In acromegaly, IGF-I levels are invariably high and reflect a log-linear relationship with circulating GH concentrations.

5. GH-secreting tumors rarely arise from ectopic pituitary tissue remnants in the nasopharynx or midline sinuses. Rarely, excess GHRH production may cause acromegaly because of chronic stimulation of somatotropes . The most common cause of GHRH-mediated acromegaly is a chest or abdominal carcinoid tumor . Excessive GHRH also may be elaborated by hypothalamic tumors , usually choristomas or neuromas.

6. ACROMEGALY VS GIGANTISM A)GIGANTISM : Excess GH leads to development of gigantism if hypersecretion is present before epiphysial bone closure — a rare condition There is symmetrical enlargement of body resulting in true giant with overgrowth of long bones, connective tissue and visceral organs. Also puberty is often delayed, often results in hypogonadism and height is increased for the age of the child

7. B) ACROMEGALY : Excess GH leads to acromegaly if hypersecretion occurs after epiphysial bone fusion has occured Elongation of long bones not possible so there is over growth of cancellous bones— protruding jaw, thickening of phalanges, and over growth of visceral organs Puberty and gonadal development remain unaffected. Height is normal for the age of the child

8. Acromegaly It results from GH hypersecreion . Most common cause is a somatotrope adenoma . Rarely caused by extrapituitary lesions. Mixed mammosomatotrope tumors and acidophilic stem-cell adenomas secrete both GH and PRL.

9. Clinical features of acromegaly A) Acral bony overgrowth results in : frontal bossing increased hand and foot size mandibular enlargement with prognathism widened space between the lower incisor teeth B) Soft tissue swelling results in: increased heel pad thickness increased shoe or glove size ring tightening characteristic coarse facial features a large fleshy nose.

10. Generalized visceromegaly occurs, including cardiomegaly, macroglossia, and thyroid gland enlargement. The most significant clinical impact of GH excess occurs with respect to the cardiovascular system. Cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, and hypertension ultimately occur in most patients if untreated.

11. Upper airway obstruction with sleep apnea occurs in >60% of patients Diabetes mellitus develops in 25% of patients with a cromegaly , and most patients are intolerant of a glucose load Associated with an increased risk of colon polyps and mortality from colonic malignancy

12. LABORATORY INVESTIGATIONS Age-matched serum IGF-I levels are elevated in acromegaly. GH Suppression test: The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <0.4 μg /L within 1–2 h of an oral glucose load (75 g). Prolactin should be measured, as it is elevated in ~25% of patients with acromegaly MRI Brain to look for sella tursica .

13. Treatment GOALS OF TREATMENT: The goal of treatment is To control GH and IGF-I hypersecretion Ablate or arrest tumor growth Ameliorate comorbidities Restore mortality rates to normal Preserve pituitary function.

14. Treatment modalities A) SURGICAL Surgical resection of GH-secreting adenomas is the preferred modality treatment for most patients (unlike in prolactinomas where the preferred modality of treatment is medical) Transsphenoidal surgical resection is the preferred primary treatment for both microadenomas (remission rate ~70%) and macroadenomas (<50% in remission). Soft tissue swelling improves immediately after tumour resection. GH levels return to normal within an hour, and IGF-I levels are normalized within 3–4 days. Hypopituitarism develops in up to 15% of patients after surgery.

15. B) MEDICAL Somatostatin analogues : They exert their therapeutic effects through SSTR2 and SSTR5 receptors, both of which are expressed by GH-secreting tumors . Octreotide (t 1/2 - 2 hours) possesses 40-fold greater potency than native somatostatin to suppress GH. Administered by s.c. injection, beginning with 50 μg tid ; the dose can be increased gradually up to 1500 μg /day.

16. The long-acting somatostatin depot formulations, octreotide and lanreotide , are the preferred medical treatment for patients with acromegaly. For those resistant to octreotide , pasireotide , with preferential SST5 binding, has been shown to exhibit efficacy. Rapid relief of headache and soft tissue swelling occurs in ~75% of patients within days to weeks of somatostatin analogue initiation. Most patients report symptomatic improvement, including amelioration of headache, perspiration, obstructive apnea , and cardiac failure.

17. Side effects: Adverse effects are short-lived and mostly relate to drug-induced suppression of gastrointestinal motility and secretion. Transient nausea, abdominal discomfort, fat malabsorption, diarrhea , and flatulence occur in one-third of patients Other side effects include mild glucose intolerance due to transient insulin suppression, asymptomatic bradycardia and hypothyroxinemia .

18. b) GH Receptor antagonist: Pegvisomant antagonizes endogenous GH action by blocking peripheral GH binding to its receptor Pegvisomant is administered by daily s.c.injection (10–20 mg) and normalizes IGF-I in ~70% of patients. GH levels, however, remain elevated as the drug does not target the pituitary adenoma .

19. Side effects: reversible liver enzyme elevation and lipodystrophy . Combined treatment with monthly somatostatin analogues and weekly or biweekly pegvisomant injections has been used effectively in resistant patients.

20. c) Dopamine agonists: Bromocriptine and cabergoline may modestly suppress GH secretion in some patients. Very high doses of bromocriptine (≥20 mg/d) or cabergoline (0.5 mg/d) are usually required to achieve modest GH therapeutic efficacy

21. C) RADIATION THERAPY External radiation therapy or high-energy stereotactic techniques are used as adjuvant therapy for acromegaly An advantage of radiation is that patient compliance with long-term treatment is not required Tumor mass is reduced, and GH levels are attenuated over time. The high rate of late hypopituitarism and the slow rate (5–15 years) of biochemical response are the main disadvantages of radiotherapy Somatostatin analogues may be required while awaiting the full benefits of radiotherapy

22. TAKE HOME MESSAGE Acromegaly is a disorder of somatotrope cells of pituitary gland presenting as somatotrope adenoma. GH hypersecretion occurring after epiphyseal fusion is the primary pathological cause for development of acromegaly. It is characterized by over growth of cancellous bones— prognathism , thickening of phalanges, and visceromegaly . Standard diagnostic criteria is to look for GH suppression with glucose load which if not occurring confirms acromegaly. Sella tursica is deformed and is well visualized by MRI Brain Treatment modalities are medical, surgical and radiation therapy.