1. Hypothalamic Obesity In Humans Christina Daousi Diabetes & Endocrinology University Hospital Aintree Liverpool Cdaousi@liverpool.ac.uk

2. Monogenic obesity syndromes associated with hypothalamic dysfunction Prader-Willi syndrome Prader-Willi syndrome Leptin/leptin receptor mutations Leptin/leptin receptor mutations POMC mutation POMC mutation Prohormone convertase-1 mutation Prohormone convertase-1 mutation Melanocortin-4 receptor mutation Melanocortin-4 receptor mutation

3. Hypothalamic Obesity Structural damage to hypothalamus Structural damage to hypothalamus - craniopharyngioma - craniopharyngioma - meningioma - meningioma - germ cell tumour - germ cell tumour - glioma - glioma - teratoma - teratoma - pituitary adenomas with suprasellar extension - pituitary adenomas with suprasellar extension - metastasis - metastasis - aneurysm - aneurysm - surgery - surgery - radiotherapy/chemotherapy - radiotherapy/chemotherapy Pinkney JH et al. Obes Rev 2002; 3(1):27-34 Pinkney JH et al. Obes Rev 2002; 3(1):27-34

4. Diabetes insipidus and blindness caused by a suprasellar tumour (1590)

5. “…upon opening the skull I found a significant vesicle that had occupied the optic nerves close to their crossing, and when I cut it open half a pound of the clearest of watery material flowed out…” “…upon opening the skull I found a significant vesicle that had occupied the optic nerves close to their crossing, and when I cut it open half a pound of the clearest of watery material flowed out…”

11. Idiopathic hypothalamic syndrome N=5 cases N=5 cases No tumoural or genetic alterations No tumoural or genetic alterations Obesity before 6 years old, compulsive eating, behavioural disturbances Obesity before 6 years old, compulsive eating, behavioural disturbances Breathing and thermoregulatory problems Breathing and thermoregulatory problems GHD, raised prolactin, hypogonadotropic hypogonadism, precocious puberty GHD, raised prolactin, hypogonadotropic hypogonadism, precocious puberty Water and electrolyte disturbances (?CDI) Water and electrolyte disturbances (?CDI) Reynaud R et al, Arch Pediatr. 2005 May;12(5):533-42 Reynaud R et al, Arch Pediatr. 2005 May;12(5):533-42

12. Definition: Acute increase in body weight following a clear hypothalamic insult. Acute increase in body weight following a clear hypothalamic insult. Weight gain faster than any expected age- related increase in BMI. Weight gain faster than any expected age- related increase in BMI. Other coexistent pituitary hormone deficiencies must be treated. Other coexistent pituitary hormone deficiencies must be treated.

13. How common is hypothalamic obesity in the paediatric population? Weight gain and obesity observed in 50-80% of children treated for craniopharyngioma. Weight gain and obesity observed in 50-80% of children treated for craniopharyngioma. Amount of weight gain variable. Amount of weight gain variable. Course of weight gain variable but most occurs within the first 6 months. Course of weight gain variable but most occurs within the first 6 months.

14. Sequelae of HO Pituitary hormone deficiencies Pituitary hormone deficiencies Poor sympatho-adrenal counter-regulation following insulin-induced hypoglycaemia (?adrenal medullary dysfunction) Poor sympatho-adrenal counter-regulation following insulin-induced hypoglycaemia (?adrenal medullary dysfunction) Reduced sympathetic metabolites in urine of obese children with cranios; those with most severe obesity displayed the lowest levels and also lower physical activity Reduced sympathetic metabolites in urine of obese children with cranios; those with most severe obesity displayed the lowest levels and also lower physical activity Roth CL et al, Pediatr Res. 2007 Apr;61(4):496-501 Roth CL et al, Pediatr Res. 2007 Apr;61(4):496-501

15. Sequelae of HO Longitudinal study on QOL in 102 survivors of childhood craniopharyngioma Longitudinal study on QOL in 102 survivors of childhood craniopharyngioma Long-term QOL negatively affected by obesity and associated with: Long-term QOL negatively affected by obesity and associated with: Hypothalamic involvement Tumour progression Relapse Muller HL et al, Childs Nerv Syst. 2005 Nov;21(11):975-80 Muller HL et al, Childs Nerv Syst. 2005 Nov;21(11):975-80

16. Sequelae of HO Cross-sectional study on 212 patients with childhood craniopharyngioma Cross-sectional study on 212 patients with childhood craniopharyngioma Hypothalamic involvement resulted in obesity and had major impact on functional capacity in survivors Hypothalamic involvement resulted in obesity and had major impact on functional capacity in survivors Muller HL et al, Klin Padiatr. 2003 Nov-Dec;215(6):310-4 Muller HL et al, Klin Padiatr. 2003 Nov-Dec;215(6):310-4

17. Sequelae of HO NAFLD among patients with hypothalamic and pituitary dysfunction NAFLD among patients with hypothalamic and pituitary dysfunction Mayo clinic, 21 cases Mayo clinic, 21 cases Mean 6.4 years after Dx of hypothalamic dysfunction Mean 6.4 years after Dx of hypothalamic dysfunction Yearly weight gain 2.2 units BMI Yearly weight gain 2.2 units BMI 10 biopsies (6 cirrhosis, 2 NASH, 2 steatosis)-2 required liver Tx 10 biopsies (6 cirrhosis, 2 NASH, 2 steatosis)-2 required liver Tx Adams LA et al, Hepatology. 2004 Apr;39(4):909-14 Adams LA et al, Hepatology. 2004 Apr;39(4):909-14

18. Sequelae of HO NAFLD & HO- further reports NAFLD & HO- further reports 16 years old female with NASH+ cirrhosis, Dx with cranio aged 5 16 years old female with NASH+ cirrhosis, Dx with cranio aged 5 18 years old male, Dx aged 10, NASH+fibrosis 18 years old male, Dx aged 10, NASH+fibrosis Nakajima K et al, J Gastroenterol. 2005 Mar;40(3):312-5 Nakajima K et al, J Gastroenterol. 2005 Mar;40(3):312-5

19. Sequelae of HO Daytime hypersomnolence Daytime hypersomnolence Secondary narcolepsy may be a causative factor of increased daytime sleepiness in obese childhood craniopharyngioma patients (PSG) Secondary narcolepsy may be a causative factor of increased daytime sleepiness in obese childhood craniopharyngioma patients (PSG) Muller HL, J Pediatr Endocrinol Metab. 2006 Apr;19 Suppl 1:423-9 Muller HL, J Pediatr Endocrinol Metab. 2006 Apr;19 Suppl 1:423-9 Correlation with serum/CSF orexin-A levels not consistent ? Loss of hypothalamic hypocretin-secreting neurons Impaired melatonin secretion Muller HL et al, J Clin Endocrinol Metab. 2002 Aug;87(8):3993-6. Muller HL et al, J Clin Endocrinol Metab. 2002 Aug;87(8):3993-6.

20. How common is hypothalamic obesity in adults? After a median of 5 years of follow-up, 52% of patients with hypothalamic damage were obese compared with only 24 % at the time of diagnosis of their tumour. After a median of 5 years of follow-up, 52% of patients with hypothalamic damage were obese compared with only 24 % at the time of diagnosis of their tumour.

21. Distribution of BMI at diagnosis and latest follow up

22. Comparison with the general population:

23. Neuroimaging Neuroimaging size of tumour size of tumour encroachment of pituitary tumours on optic chiasm encroachment of pituitary tumours on optic chiasm invasion or compression of hypothalamic tissue invasion or compression of hypothalamic tissue abnormalities of 3 rd ventricle abnormalities of 3 rd ventricle breach of the infundibulum by the tumour breach of the infundibulum by the tumour infiltration of the thalamus or temporal lobes infiltration of the thalamus or temporal lobes

24. TREATMENTP-value Desmopressin0.016 Growth hormone 0.017 HydrocortisoneNS ThyroxineNS Sex steroids NS Transphenoidal surgery NS Transfrontal surgery NS RadiotherapyNS VP shunt NS Conservative management NS Dopamine agonists NS

25. Findings from neuroimaging did not predict weight gain. Findings from neuroimaging did not predict weight gain. Requirement for desmopressin (ADH) and growth hormone were the strongest predictors of current obesity and weight gain. Requirement for desmopressin (ADH) and growth hormone were the strongest predictors of current obesity and weight gain.

27. Mechanisms giving rise to hypothalamic obesity Increased energy intake Increased energy intake Hyperphagia Hyperphagia Autonomic dysfunction Autonomic dysfunction vagally-mediated hyperinsulinaemia vagally-mediated hyperinsulinaemia low resting metabolic rate low resting metabolic rate Reduced voluntary energy expenditure Reduced voluntary energy expenditure Impaired gut-brain satiety signalling? Impaired gut-brain satiety signalling? 11-b-HSDH ? 11-b-HSDH ? Hormone deficiencies Hormone deficiencies GH, TSH, LH/FSH GH, TSH, LH/FSH Pinkney JH et al. Obes Rev 2002; 3(1): Pinkney JH et al. Obes Rev 2002; 3(1):

28. Ghrelin, P-YY, insulin and leptin probably do not play a central role in the control of appetite and the pathogenesis of obesity in adults with hypothalamic damage. Ghrelin, P-YY, insulin and leptin probably do not play a central role in the control of appetite and the pathogenesis of obesity in adults with hypothalamic damage. No differences in HRV, REE No differences in HRV, REE Impaired satiety may be an aetiological factor of obesity in this group. Impaired satiety may be an aetiological factor of obesity in this group.

29. Sibutramine & Hypothalamic Obesity Double-blind, placebo-controlled, cross-over study (20 wks each) followed by 6 month open phase Double-blind, placebo-controlled, cross-over study (20 wks each) followed by 6 month open phase N = 50 (7-20 yrs old), 42 completed study N = 50 (7-20 yrs old), 42 completed study HO (n=22) and cases of uncomplicated obesity plus aggravating syndromes (n=28) HO (n=22) and cases of uncomplicated obesity plus aggravating syndromes (n=28) -0.70 BMI SDS (mean reduction) (P<0.001) -0.70 BMI SDS (mean reduction) (P<0.001) Weight loss less pronounced in those with HO (partial resistance) Weight loss less pronounced in those with HO (partial resistance) Well tolerated and safe Well tolerated and safe Danielsson P et al, J Clin Endocrinol Metab. 2007 Nov;92(11):4101-6 Danielsson P et al, J Clin Endocrinol Metab. 2007 Nov;92(11):4101-6

30. Octreotide randomized, double-blind, placebo-controlled trial of octreotide therapy for pediatric hypothalamic obesity randomized, double-blind, placebo-controlled trial of octreotide therapy for pediatric hypothalamic obesity N=18, 6 months N=18, 6 months Delta weight (mean +/- SEM) was +1.6 +/- 0.6 vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Delta weight (mean +/- SEM) was +1.6 +/- 0.6 vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Octreotide suppressed insulin, and stabilized weight and BMI. Octreotide suppressed insulin, and stabilized weight and BMI. safe and well tolerated safe and well tolerated Lustig RH et al, J Clin Endocrinol Metab. 2003 Jun;88(6):2586-92 Lustig RH et al, J Clin Endocrinol Metab. 2003 Jun;88(6):2586-92

31. Dextroamphetamine & HO (1) Retrospective review Retrospective review N=12, treated for 13-15 months, low-dose N=12, treated for 13-15 months, low-dose 10/12 experienced either stabilization of weight or weight loss on treatment 10/12 experienced either stabilization of weight or weight loss on treatment median loss -0.7 SDS in males, -0.44 SDS in females median loss -0.7 SDS in males, -0.44 SDS in females improvement in daytime wakefulness and/or concentration and exercise tolerance improvement in daytime wakefulness and/or concentration and exercise tolerance Ismail D et al, J Pediatr Endocrinol Metab. 2006 Feb;19(2):129-34 Ismail D et al, J Pediatr Endocrinol Metab. 2006 Feb;19(2):129-34

32. Dextroamphetamine & HO (2) CNS stimulant CNS stimulant n=5 for 2 years n=5 for 2 years BMI=21 pre-op, BMI=32 at enrolment BMI=21 pre-op, BMI=32 at enrolment Weight gain stabilised Weight gain stabilised Improvements in overall activity and attention Improvements in overall activity and attention Can earlier intervention prevent initial obesity? Can earlier intervention prevent initial obesity? Mason PW et al, Arch Pediatr Adolesc Med. 2002 Sep;156(9):887-92 Mason PW et al, Arch Pediatr Adolesc Med. 2002 Sep;156(9):887-92

33. Melatonin and hypersomnolence Experimental melatonin substitution in 10 adult obese patients (5f/5m) with childhood craniopharyngioma. Experimental melatonin substitution in 10 adult obese patients (5f/5m) with childhood craniopharyngioma. In all 10 patients with childhood craniopharyngioma the degree of daytime sleepiness significantly improved based on activity diaries, ESS, self assessment questionnaires and accelerometry. ? Effects on weight In all 10 patients with childhood craniopharyngioma the degree of daytime sleepiness significantly improved based on activity diaries, ESS, self assessment questionnaires and accelerometry. ? Effects on weight Muller HL et al, Cancer Causes Control. 2006 May;17(4):583-9 Muller HL et al, Cancer Causes Control. 2006 May;17(4):583-9

34. Bariatric Surgery Male aged 13 Dx with cranio Male aged 13 Dx with cranio subtotal surgical resection and XRT subtotal surgical resection and XRT Severe hyperphagia, gaining weight at 70 kg per year Severe hyperphagia, gaining weight at 70 kg per year Failed interventions with dietary measures and physical activity. Multiple co-morbidities Failed interventions with dietary measures and physical activity. Multiple co-morbidities Weight stabilised on octreotide but no weight loss Weight stabilised on octreotide but no weight loss Laparoscopic Roux-en-Y-gastric bypass aged Laparoscopic Roux-en-Y-gastric bypass aged Marked reductions in food cravings, reduction in hyperinsulinaemia Marked reductions in food cravings, reduction in hyperinsulinaemia 49 kg weight loss over ensuing 2.5 years 49 kg weight loss over ensuing 2.5 years Inge TH et al, Nat Clin Pract Endo Metab 2007; 3(8):606-609 Inge TH et al, Nat Clin Pract Endo Metab 2007; 3(8):606-609

35. The optimal treatment of hypothalamic obesity remains elusive, but increased awareness of the existence of the problem could help prevent obesity. The optimal treatment of hypothalamic obesity remains elusive, but increased awareness of the existence of the problem could help prevent obesity. Management of these patients requires a multidisciplinary approach Management of these patients requires a multidisciplinary approach