Symposium for Patients & Caregivers

1. Symposium for Patients & Caregivers

2. HypothalamicObesity Constantine Stephen Djedjos MD Pediatric Endocrinologist Phoenix Children’s Hospital

3. Hypothalamic Obesity • Significant advances in basic science have greatly improved our understanding of the mechanisms of hypothalamic obesity • Unfortunately, these advances have not yet translated into therapeutic advances for patients, many of whom are struggling with the nightmare of disordered eating and obesity

4. Hypothalamic Obesity • Weight gain and obesity are common long term problems in patients with structural hypothalamic damage • Exact incidence is unknown. Each individual cause is rare and taken in aggregate HyOb is still relatively uncommon • Can be due to structural or genetic abnormalities • Significant percentage of patients gain weight after hypothalamic surgery

5. Hypothalamic Obesity • First case reports of hypothalamic tumors resulting in obesity published around the turn of the 20th century • Initially identified the ventromedial hypothalamus (VMH) associated with polyphagia • Later demonstrated polyphagia is sufficient but not required • Later identification of peripheral and central neurochemicals and cytokines

6. Hypothalamus Stanford CNS Visual Perspectives

7. Anatomy • Only 4ml in volume • Organized into discrete nuclei or collections of similar neurons • ‘Dual-Center’ hypothesis – experimental lesions in the medial (midline) hypothalamus result in weight gain while lesions in the lateral areas result in wasting

8. Hypothalamic Nuclei Michigan State University Brain Bank and NSF

9. Mechanism • The hypothalamus controls energy balance by integrating the neuroendocrine signals from other brain areas and the periphery • Controls energy intake by regulating appetite • Controls energy expenditure by regulating metabolism via sympathetic and parasympathetic nervous system

10. Appetite • Hypothalamus receives signals from periphery • Hypothalamus controls appetite by balancing orexigenic and anorexegenic signals • Appetite regulated by the arcuate nucleus (ARC) by 2 types of neurons • AGRP/NPYY neurons stimulate appetite (orexigenic) • POMC/CART neurons signal satiety (anorexegenic) via MC4R receptor

11. Appetite Nutr J. 2012 Apr 10;11:22. Gut-central nervous system axis is a targetfor nutritional therapies. Pimentel GD, Micheletti TO, Pace F, Rosa JC, Santos RV, Lira FS.

12. Metabolism • Hypothalamus controls metabolism by balancing sympathetic and parasympathetic signals • Hypothalamus via the locus ceruleus stimulates sympathetic nervous system (Fight or Flight) which increases metabolism • Stimulates via the vagus nerve the parasympathetic nervous system which lowers metabolism

13. Metabolism • VMH receives peripheral signals • VMH increases sympathetic tone or parasympathetic tone • Higher parasympathetic tone results in higher insulin

14. Peripheral Signals • Leptin produced by fat cells signals fat storage • Adiponectin is decreased in obesity • Ghrelin stimulates appetite and food intake and secreted from stomach • Many others

15. Mechanism • In HyOb damage to the hypothalamus results in altered appetite and metabolism • Increased appetite due to damage to POMC neurons and resulting in decreased MC4R signaling • Decreased metabolism from increased parasympathetic tone and decreased sympathetic tone resulting in decreased resting energy expenditure, elevated insulin • Leptin resistance and Ghrelin have a role as well

16. Treatment • For mild-moderately overweight patient without overt food seeking or hyperphagic behaviors, we should focus on diet and lifestyle modification • Requires full participation from the family and the school in order to make the home and school environments more conducive to weight loss

17. Treatment • More severe HyOb is often refractory to diet and lifestyle • Behavior therapy • Pharmacologic therapy • Surgical therapy

18. Pharmacologic Therapy • No standard intervention and no medication has been proven successful in randomized clinical trials • Due in part to small numbers of patients and also ineffectiveness of therapy • Because of decreased sympathetic activity and decreased POMC/CART signaling, treatment with amphetamine derivatives has been considered

19. Pharmacologic Therapy • Dextroamphetamine started 10months post surgery and lasting 24 months in CP patients showed less weight gain and stabilization of BMI • Treatment with ephedrine/caffeine has also showed some promise • Also had increased activity and wakefulness • No large trials • Polyphagia not significantly reduced likely because of damage to responsive neurons

20. Pharmacologic Therapy • Leptin ‘resistance’ is possible cause of obesity • Leptin therapy has been ineffective for weight loss • Once forced weight loss is achieved, leptin supplementation has resulted in better success in weight maintenance

21. Pharmacologic Therapy • Increased parasympathetic activity via vagus nerve activity results in insulin secretion • Insulin is anabolic and contributes to appetite and weight gain • Treatments aimed at lowering vagus nerve activity and insulin secretion have been considered • Treatment with metformin which lowers insulin levels has been ineffective in HyOb

22. Pharmacologic Therapy • Sandostatin is a medication that lowers insulin secretion • Initial trial with small number of patients was successful • Larger trial demonstrated no benefit • Much controversy about the discordant results • Vagus nerve blockade is being considered and is in early trials

23. Pharmacologic Therapy • Increased parasympathetic activity results in lower thyroid hormone levels and very small trials have demonstrated some benefit with treatment • Increased 11-beta hydroxysteroid dehydrogenase activity is also seen in HyOb patients but no selective inhibitor is yet available • Concomitant growth hormone deficiency is often seen, despite normal growth, and treatment with GH has been tried

24. Pharmacologic Therapy • Unlike patients with GH from other causes, treatment of HyOb patients with GH did NOT result in weight loss or changes in body fat distribution • Surgical therapy has had mixed results

25. Surgical Therapy • Criteria are unclear • Some have suggested BMI >40 (above 99.5%) • Failed 6-12 month organized weight loss attempt • Skeletal and anatomic maturity • Able to commit to rigorous psychologic and medical evaluation pre and post op • Willing to participate in a multidisciplinary program

26. Surgical Therapy • Restrictive procedures • Gastric banding • Adjustable band placed around the stomach • Poor weight loss and frequent complications • Sleeve Gastrectomy • Removal of part of the stomach • Not enough evidence yet with HyOb but appears promising

27. Surgical Therapy • Malabsorption procedures • Gastric bypass • Stomach is bypassed surgically • Restrictive and malabsorptive component • Excellent weight loss but higher complications • No significant experience with HyOb • Duodenal switch • Severe malabsorption and not routinely performed

28. Bariatric Surgery Complications • Operative mortality varies • Leaks, strictures, infection, blood clots, hernia, obstruction, nausea, vomiting have all been reported • Nutritional deficiencies from malabsorption are not uncommon especially iron, b12, fat soluable vitamins (ADEK), trace minerals • Dumping syndrome

29. Conclusions • HyOb is a common, frustrating complication of hypothalamic disease and treatments • Polyphagia and decreased metabolism play a role • Advances in the last 10 years in basic science have helped unravel many of the mechanisms • Treatment has lagged behind but still some promising therapies are being considered • Behavior therapy and exercise are the cornerstones for current treatment

30. References • A. Bereket et al Hypothalamic obesity in children Obesity reviews 2000 13,780-798 • J. Pinkney et al Hypothalamic obesity in humans: what do we know and what can be done? Obesity reviews 2002 3, 27-34 • R. Lustig Hypothalamic obesity after craniopharyngioma: mechanisms, diagnosis, and treatment • https://www.msu.edu/~brains/brains/human/hypothalamus/index.html • Babinski, J Tumeur du corps pituitaire sans acromegalie et avec arret developpment des organes de genitaux Rev Neurol 1900; 8,531-534 • Zhang Y et al Positional cloning of the mouse obese gene and its human homologue Nature 1994; 372,425-432 • Kreir et al Selective parasympathetic innervation of subcutaneous and intra-abdominal fat – functional implications J. Clin Invest 2002;110, 1243-1250 • Lustig RH et alHypothalamic obesity in children caused by cranial insult: altered glucose and insulin dynamics, and reversal by a somatostatin agonist. J Pediatr 1999;135: 162–168. • Lustig RH, Hinds PS, Ringwald-Smith K et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metabol 2003; 88: 2586–2592. • Mason PW, Krawiecki N, Meacham LR. The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma. Arch Pediatr Adolesc Med 2002; 156:887–892. • Ismail D, O’Connell MA, Zacharin MR. Dexamphetamine use for management of obesity and hypersomnolence following hypothalamic injury. J Pediatr Endocrinol Metab 2006; 19: 129–134. • Greenway FL, Bray GA. Treatment of hypothalamic obesity with caffeine and ephedrine. Endocr Pract 2008; 14: 697–703. • Danielsson P, Janson A, Norgren S, Marcus C. Impact of sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. J Clin Endocrinol Metab 2007; 92: 4101–4106. • Weiss R. [WWW document]. URL http://clinicaltrials.gov/ ct2/show/NCT00076362 (accessed January 2012).

31. References • Aslan IR, Ranadive SA, Ersoy BA, Rogers SJ, Lustig RH,Vaisse C. Bariatric surgery in a patient with complete MC4R deficiency. Int J Obes 2011; 35: 457–461. • Lanthaler M, Aigner F, Kinzl J, Sieb M, Cakar-Beck F, Nehoda H. Long-term results and complications following adjustable gastric banding. Obes Surg 2010; 20: 1078–1085. • Milone L, Strong V, Gagner M. Laparoscopic sleeve gastrectomy is superior to endoscopic intragastric balloon as a first stage procedure for the super-obese patient (BMI > 50). Obes Surg 2005; 15: 612–617. • Himpens J, Dapri G, Cadiere GB. A prospective randomized study between laparoscopic gastric banding and laparoscopic isolated sleeve gastrectomy: results after 1 and 3 years. Obes Surg2006; 16: 1450–1456. • Baltasar A, Serra C, Bou R, Bengochea M, Andreo L. Sleeve gastrectomy in a 10-year-old Child. Obes Surg 2008; 18:733–736. • Dan D, Harnanan D, Seetahal S, Naraynsingh V, Teelucksingh S. Bariatric surgery in the management of childhood obesity: should there be an age limit? Obes Surg 2010; 20: 114–117. • Ramos A, Neto MG, Galvao M, Evangelista LF, Campos JM, Ferraz A. Laparoscopic greater curvature plication: initial results of an alternative restrictive bariatric procedure. Obes Surg 2010; 20: 913–918. • Sugerman HJ, Sugerman EL, DeMaria EJ et al. Bariatric surgery for severely obese adolescents. J Gastrointest Surg 2003; 7: 102–107.

32. A Special Thanks to our Sponsors • Aesculap • Barrow Neurological Institute @ St. Joseph’s Hospital • Barrow Neurological Institute @ Phoenix Children’s Hospital • Great Council for the Improved • Hope for Hypothalamic Hamartoma Foundation • KARL STORZ Endoskope