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Symposium for Patients
& Caregivers
Hypothalamic Obesity
Constantine Stephen Djedjos MD
Pediatric Endocrinologist
Phoenix Children’s Hospital
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
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
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
Hypothalamus
Stanford CNS Visual Perspectives
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
Hypothalamic Nuclei
Michigan State University Brain Bank and NSF
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
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
Appetite
Nutr J. 2012 Apr 10;11:22.
Gut-central nervous system axis is a target for nutritional therapies.
Pimentel GD, Micheletti TO, Pace F, Rosa JC, Santos RV, Lira FS.
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
Metabolism
• VMH receives
peripheral signals
• VMH increases
sympathetic tone or
parasympathetic tone
• Higher
parasympathetic tone
results in higher
insulin
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
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
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
Treatment
• More severe HyOb is often refractory to diet and lifestyle
• Behavior therapy
• Pharmacologic therapy
• Surgical therapy
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
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
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
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
Pharmacologic Therapy
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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
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
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
Surgical Therapy
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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
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
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
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
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
References
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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 al Hypothalamic 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).
References
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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.
A Special Thanks to our Sponsors
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• KARL STORZ Endoskope