1 ACROMEGALY & SHORT STATURE which is a lecture in medicine

Acromegaly

1. ACROMEGALY DR C.B.NWATU.

2. INTRODUCTION Clinical condition resulting from PROLONGED and EXCESSIVE secretion of GROWTH HORMONE (GH) and Insulin-like growth factor-1 (IGF-I) in adults GH secretion triggers the release of IGF-1 by the liver. IGF-1 is a hormone that functions as the major mediator of GH-stimulated somatic growth, as well as GH-independent/anabolic responses in many cells and tissues. In acromegaly, normal pulsatile secretion of GH is blunted such that during a 24-hour day, GH fails to become undetectable - a feature not observed in normal individuals.

3. EPIDEMIOLOGY Condition is rare No gender predilection Approx. 50 cases/million population Insidious onset Typical delay between onset of disease to clinical features Dx usually btw 4 th -6 th decade of life. Older patients – milder disease b/c smaller tumour hence better prognosis.

4. CAUSES 1. PITUITARY ADENOMAS (99% of cases) macro adenomas > micro adenomas. Local invasion common Frank carcinomas are very rare. 2. ↑GHRH Secretion Hypothalamic secretion Ectopic GHRH secretion (carcinoids; neuroendocrine tumours ) 3. Ectopic GH Secretion – very rare.

5. Associations I. MEN – I II. Carney Complex III. Isolated Familial Somatotrophinomas IV. Existence of 2 or more cases of Acromegaly or Gigantism in a family that dosen’t exhibit MEN-I or Carney Complex.

6. Clinical Features Basically arise from effects of excess GH/IGF-I in addition to excess Prolactin as there is co-secretion of PRL in 30% of cases plus the mass effects. SYMPTOMS Headaches, excessive sweating, tiredness and lethargy, joint pains, change in shoe/ring size SIGNS Coarse facies , oily skin, frontal bossing, enlarged nose, prognathism , increased interdental separation, deepening of voice, macroglossia ; spade-like hands and feet, degenerative joint changes, generalized myopathy, entrapment neuropathies eg . Carpal tunnel syndrome, goiter and other organ enlargement.

7. Complications Hypertension Impaired glucose tolerance and DM Obstructive sleep apnoea Risk of colonic polyps and carcinoma Ischemic heart disease and CVA CCF and regurgitant valvular disease Visual field defects – mass effect Hypopituitarism – mass effect

8. Investigations 1. OGTT : In Acromegaly, there’s failure to suppress GH to <1 mu/L in response to 75g oral glucose load. The normal response is GH suppression to undetectable levels. 2. IGF-I levels : hormone is mainly produced in the liver, skeletal mzl and other tissues in response to GH stimulation . Increased in Acromegaly, has a long half life and reflects the effect of GH on tissues 3. TRH test : In normal subjects, 200g of TRH given IV leads to GH suppression but 80% of Acromegalics do not suppress.

9. Investigations Contd. 4. MRI of Brain : demonstrates the tumour (98%), also shows any extra- sella extensions. 5. Pituitary fxn testing : esp Prolactin levels, as some tumours co-secrete PRL with GH. 6. Serum Calcium: Some pxs have ca levels hypercalciuria due to 1,25-DHCC and hence renal stones. Differential Diagnosis of Elevated serum GH levels: Puberty, Pregnancy, CRF, DM, Malnutrition, Severe illness, Prolonged fast, Stress, Heroin addiction.  

10. Management Depends on index patient and tumour size Large compressive tumours – definitive tx is surgery. Microadenomas may respond to medical tx . TRANS SPHENOIDAL surgery is the 1 st line of tx . and cure rates better for micro than macro adenomas and depend on surgical expertise. Adjunct medical or radiotherapy may be indicated if GH levels still high (>5mu/L) post surgery Medical tx may be used to shrink tumour size pre-op for better surgical outcomes.

11. Medical Treatment 1. Somatostatin Analogues – lead to suppression of GH secretion in 60% of pxs . Comes in depot preparations eg Octreotide , Lanreotide . May be used for primary treatment or as adjuncts to surgery or radiotheraphy . Octreotide LAR 20mg IM 4 weekly, gradually step down to 10-30 mg every 3 months. Lanreotide (deep sub-cut) 90mg 4 weekly (60-120 mg every 3 months. 2. Dopamine Agonists : eg Cabergoline GH levels though not to normal levels  

12. Medical Tx Contd. Cabergoline esp. useful if co-existent PRL secretion tumour shrinkage. 3. GH Receptor Antagonists – eg PEGVISOMANT. Leads to normalization of IGF-I levels in >90% of pxs . Can be combined with O ctreotide or Lanreotide . Aim of Tx – a mean GH level <5 mu/L  

13. SHORT STATURE

14. Introduction Normal human growth has 3 overlapping stages ( Karlberg model) 1. INFANCY growth: nutritional regulated, from birth-2yrs. (concept of “catch up” and “catch down” 2. CHILDHOOD growth: reg by GH & Thyroxine . Xrized by mini growth spurts and intervening stasis, each lasting several weeks. 3. PUBERTY : reg by GH & SEX H. - a rapid acceleration in growth – Growth Spurt.  

15. Gender differences Adult males on average 13cm taller than females Pubertal growth spurt earlier in females hence females, generally taller than males btw 10-13 years. Final height is the ht. reached when the growth velocity drops to <2cm/yr. & usually coincides with epiphyseal fusion on hand ± knee radiograph. Final ht. mostly genetically determined and can be estimated from parent’s height using the Mid Parental Height (MPH) formula

16. Final Ht.= Mother’s ht + Father’s ht /2 (+7cm for boys and -7cm for girls) For most pp there’s a wide target range hence MPH± 10cm for boys MPH ± 8.5cm for girls SHORT STATURE- height <2 nd centile for age & sex on the UK 1990 growth chart. Short stat. may be shown up earlier by assessing growth velocity and monitoring serial Ht. measurements

17. History Who is worried? – Child or Parents ? Recent onset Preg . Hx . - ?maternal illness, ?substance abuse, drugs, diet/malnutrition, HBP GA and Birth weight Childhood illness, Developmental milestones Systemic illness (asthma, cong. heart disease, SCD) Parental heights ?Family hx . of short stature or Pubertal delay ?Psycho-social deprivation

18. Examination Assess ht. and ht. velocity over 6months to 1 yr. ? Dysmorphic features or skeletal disproportion ? Suggestions of chronic diseases ? Any Endocrinopathies Check pubertal stage – Tanner’s criteria Measure parent’s ht. and calculate MPH

19. Investigations IGF-I levels TFT Karyotyping GH provocation tests - arginine, insulin or glucagon Skeletal survey FBC+ ESR Electrolytes, Calcium, Phosphate Urinalysis

20. Causes 1. Genetic short stature 2.Constitutional delay in growth and puberty 1&2 – majority of cases (up to 50%) 3. Psycho-social deprivation 4. Small for GA 5. Chronic illness 6. Malnutrition 7. Dysmorphic syndromes 8. Skeletal dysplasia ( achondroplasia etc ) 9. Endocrinopathies (hypothyroidism, cushing’s etc ) 10. Metabolic bone dz ( nutritional or hypophosphatemic rickets)

21. GH Deficiency (8-10%) Idiopathic GH Resistance Congenital malformation of hypoth /pituitary/ GH gene or receptor Acquired hypoth /pit disorders ( craniopharyngiomas ; trauma) TREATMENT – Recombinant human GH Sc. daily injections. For childhood GH def : 25-50 mcg/kg/d. Catch up growth optimized if tx commenced early. S/e of GH replacemt – local atrophy, benign IH, unmasking of other pit. H. def – do TFT from 4 wks of starting tx .

22. Tx . continued till adulthood when most individuals subsequently develop normal independent GH secretion Continue tx . in adults who do not dev. independent secretion. GH RESISTANCE: tx . with Recombinant IGF-I Note LARON syndr .: a rare auto recessive genetic defect of GH receptor – extreme short stature, GH levels, IGF-I and impaired GH induced IGF-I generation. HYPOTHYROIDISM: replacement with oral levo-thyroxine (100 mcg/d) titrated with TFT.  

23. Coeliac dz : gluten-free diet – catch up growth. Skeletal dysplasias – high dose GH tx . Small for GA – GH tx used only if catch up growth did not occur by 4 years of age Turner’s syndrome: High dose GH + Oxandralone added at abt 9 years to promote growth then oral estrogen given at 12-14 yrs to promote sexual dev and pubertal growth.

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