6/15/2018. Hypersomatotrophism in cats in the United Kingdom. Update on feline acromegaly: where are we in 2018? The journey of feline acromegaly:

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1 Update on feline acromegaly: where are we in 2018? David B Church The journey of feline acromegaly: Hypersomatotrophism in cats in the United Kingdom 148 samples submitted - > 80% from England Serum IGF 1 levels in all cats 54 cats with basal IGF1 level > 1000 ng/ml Most were markedly hyperglycaemic with elevated fructosamines 24 cats were evaluated further 23/24 confirmed acromegalic Neissen et al, ECVIM

2 The journey of feline : From a rarely diagnosed, freak of nature disease with an extreme phenotype to a relatively common explanation for the far more common disorder, feline diabetes mellitus 2

3 Update on prevalence pre 2007: acromegaly was considered a relatively uncommon disorder and thus an unimportant underlying cause for feline DM in 2006 and 2007 a prevalence of between 26-32% was reported by Niessen et al 2006, and Berg et al 2007 there have been a number of subsequent prevalence studies Update on prevalence Schaefer abstract ECVIM Congress, JVIM, 2013 N= 225 cats [IGF-1]: ng/ml median % IGF-1 > 1000 Niessen et al PLOS One (2015) N=1221 [IGF-1]: ng/ml mean 767 (+/-563) 26.1% IGF-1 > 1000 CT/MRI/necropsy 95% +ve if IGF-1> 1000 data suggest PPV IGF-1 95% 95% CI: % This suggests prevalence among UK diabetic cats is 24.8% 95% CI: % Only 24% of clinicians indicated a strong pre-test suspicion of the presence of the disease!!! 3

4 Update on the possible causes of feline Do we have any ideas as to why we should see a tumour with such a high prevalence?? Role for changes in feline AIP? majority human somatotrophinomas are sporadic 20-40% familial isolated pituitary adenomas (FIPA) have germ-line mutations in Aryl-hydrocarbon receptor Interacting Protein (AIP) Feline acromegaly has phenotypic and biochemical similarities to FIPA male predominance somatotroph macroadenoma resistance to octreotide tx Feline AIP gene identified: 6 exons AA 98% homology with human AIP protein EDTA samples from acromegalic & control cats Role for changes in feline AIP? non-conservative SNP identified in exon 1 AA change from aspartic to glutamic acid 20% 0% 4

5 Pituitary oncogenesis facts and possibilities Pituitary tumors can be induced by oestrogen Rodents given oestrogen Transgender people Oral anti-conceptives Many oestrogen-induced pituitary tumors are GH-secreting tumors causing acromegaly Ishibashi and Yamaji, 1985; Jeng and Watson, 2011; Sadoul et al., 1992 But how would they have access to oestrogens??? maybe consider xenobiotic contamination.. AIP-protein helps clear xenobiotics. Pituitary oncogenesis facts and possibilities 5

6 Organohalogenated contaminants (OHCs) share chemical structures with oestrogens Xenoestrogens linked with human neoplasia including somatotrophinomas Garcia 1995, Gooren 1988 Role for OHCs? Pets and people exposed by a variety of routes: food indoor contamination direct dust ingestion indirectly through grooming 6

7 Dirtu, Niessen, Jorens, Covaci, Env Int 2013 Suspicion for acromegaly: what should we do? dealing with a diabetic cat that is not behaving in a stable fashion and eating well no obvious reasons for this and we have a low index of suspicion for pancreatitis and upper urinary tract infections... We really should measure IGF1... Can we trust IGF-1? What are the problems with IGF-1? false positives in diabetics false negatives in newly diagnosed diabetics altered effects of binding proteins assay differences 7

8 GH + insulin insulin-like growth factor (IGF 1) normal cats: ng/ml newly diagnosed diabetic cats: < 10 - > 1000 ng/ml well-controlled diabetic cats: ng/ml or >? Can we trust IGF-1? Fruct Insulin BW IGF-1 Month Month Month Can we trust IGF-1? Why the increase?? Duration of exogenous insulin administration has a role in cats 8

9 IGFBP 3 binary and ternary forms in normal & diabetic cats Lewitt et al 2000 Decision making regarding a diagnosis.. Intra-cranial imaging does that help? 9

10 Radiotherapy Medical therapy to reduce GH secretion Hypophysectomy Fluoxetine as a possible mood modifier QoL needs to be closely monitored QoL need to be closely monitored for lots of reasons and.. Don t forget cats with get heart disease 10

11 QoL need to be closely monitored for lots of reasons and.. Don t forget cats with get heart disease Characterised by: Myocardial fibrosis and hypertrophy Inflammatory cell infiltrate Increased left atrial pressure Class I Class II Class III Class IV Ventricle Mitral Atrium Reducing LV compliance Increasing LA pressure Class I Class II Class III Class IV Ventricle Mitral High heart failure risk Atrium Reducing LV compliance Increasing LA pressure 11

12 Restrictive mitral inflow (E:A >2) E wave A wave QoL need to be closely monitored for lots of reasons and.. Don t forget cats with get heart disease Characterised by: Myocardial fibrosis and hypertrophy Inflammatory cell infiltrate Increased left atrial pressure How important is it to correct for the effects of chronic hyperglycaemia? 12

13 Heart disease in diabetic cats QoL need to be closely monitored for lots of reasons and.. Don t forget cats with get heart disease Characterised by: Myocardial fibrosis and hypertrophy Inflammatory cell infiltrate Increased left atrial pressure How important is it to correct for the effects of chronic hyperglycaemia? Radiotherapy will reduce tumour size with few complications is not inexpensive and requires multiple anesthetics/sedations 13

14 Insulin dose went from 35 units twice daily to 2 units twice daily Radiotherapy will reduce tumour size with few complications is not inexpensive and requires multiple anesthetics/sedations disappointingly inconsistent hormonal benefits (50-95%) Preradiation 6 months POST Hormonal effects of radiotherapy 14

15 Radiotherapy Medical therapy to reduce GH secretion Radiotherapy Medical therapy to reduce GH secretion aimed at use of somatostatin analogues, growth hormone receptor antagonists or dopamine receptor agonists Radiotherapy Medical therapy to reduce GH secretion aimed at use of somatostatin analogues, growth hormone receptor antagonists or dopamine receptor agonists generally disappointing or inconsistent results with various agents including: octreotide, lanreotide, carbergoline 15

16 N o r m a l i s e d S S T R m R N A E x p r e s s i o n N o r m a l i s e d S S T R m R N A E x p r e s s i o n * * N o r m a l i s e d S S T R m R N A E x p r e s s i o n N o r m a l i s e d S S T R m R N A E x p r e s s i o n 6/15/2018 Somatostatin receptor expression H S T H S T HST C o n t r o l C o n t r o l Control * * * * * * S S T R 1 S S T R 1 S S T R 2 S S T R 2 S S T R 5 S S T R 5 SSTR1 = SSTR5 > SSTR S S T R 1 S S T R 1 S S T R 2 S S T R 2 S S T R 5 SSTR5 > SSTR1 = SSTR2 S S T R 5 Carbergoline in 5-10ug/kg/24 hr Scudder et al,

17 Radiotherapy Medical therapy to reduce GH secretion pasireotide novel multi-receptor somatostatin analogue Radiotherapy Medical therapy to reduce GH secretion pasireotide novel multi-receptor somatostatin analogue high binding affinity for somatostatin receptor subtypes 1, 2, 3 & 5 (40x) Radiotherapy Medical therapy to reduce GH secretion pasireotide novel multi-receptor somatostatin analogue high binding affinity for somatostatin receptor subtypes 1, 2, 3 & 5 (40x) suppresses GH & IGF-1 & ACTH in rodents and.. in humans with and in humans with PDH 17

18 Pasireotide in P=0.04 P<0.001 P< ug/kg/12h for 3-5 days then, 6-8mg/kg/31 days of the LAR form Radiotherapy Medical therapy to reduce GH secretion Hypophysectomy 18

19 Adapted transsphenoidal approach Similar to reported by Meij 4 Rigid fixation of head by stereotactic frame 5 4. Meij BP, Voorhout G, van den Ingh TS, et al. Transsphenoidal hypophysectomy for treatment of pituitarydependent hyperadrenocorticism in 7 cats. Vet Surg 2001; 30: Chen AV, Wininger FA, Frey S, et al. Description And Validation Of A Magnetic Resonance Imaging-guided Stereotactic Brain Biopsy Device In The Dog. Vet Radio & Ultrasound : (BRAINSIGHT TM ) Hypophysectomy corrects cardiac changes Reduced diastolic dysfunction Reduced E:A ratio Fewer cats in Class 3 Reduced LV wall thickness 19

20 Hypophysectomy for feline given twice daily insulin (glargine/pzi) insulin generally reduced within hours post surgery 85% of survivors off insulin within a month thyroxine once daily (20ugm/kg) cortisone once daily (0.25mg/kg) given once daily DDAVP peri-ocularly (~20%) between 4,500-6,500 Hypophysectomy for feline highly successful treatment option in certain circumstances owner not excessively risk averse tumor not particularly large dependent upon a skilled surgical team and appropriate peri-operative care almost instantaneous normalisation of IGF1 high chance of achieving diabetic remission Team RVC Acro UK veterinary surgeons Petplan Charitable Trust Clinical Investigation Centre at RVC All the cat owners and of course... 20

21 Professor Boyd Jones 21