published: 14 February 2012
Bariatric surgery in hypothalamic obesity
Nathan C. Bingham1, Susan R. Rose1andThomas H. Inge2*
1Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2Division of Pediatric General andThoracic Surgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
Hermann L. Mueller, Klinikum
Oldenburg GmbH, Germany
Roberto Salvatori, Johns Hospital
Fredric Wondisford, Johns Hopkins
University School of Medicine, USA
Christian Roth, University of
Washington School of Medicine, USA
Martin Wabitsch, University of Ulm,
Thomas H. Inge, Cincinnati Children’s
Hospital Medical Center, 3333 Burnet
Avenue, Cincinnati, OH 45229, USA.
Craniopharyngiomas (CP) are epithelial neoplasms generally found in the area of the pitu-
itary and hypothalamus. Despite benign histology, these tumors and/or their treatment
often result in significant, debilitating disorders of endocrine, neurological, behavioral, and
metabolic systems. Severe obesity is observed in a high percentage of patients with
CP resulting in significant comorbidities and negatively impacting quality of life. Obesity
occurs as a result of hypothalamic damage and disruption of normal homeostatic mech-
anisms regulating energy balance. Such pathological weight gain, termed hypothalamic
obesity (HyOb), is often severe and refractory to therapy. Unfortunately, neither lifestyle
intervention nor pharmacotherapy has proven effective in the treatment of HyOb. Given
the limited choices and poor results of these treatments, several groups have examined
evidence exists supporting the use of bariatric surgery in the treatment of exogenous obe-
sity and its comorbidities, its role in the treatment of HyOb has yet to be defined.To date,
the existing literature on bariatric surgery in CP–HyOb is largely limited to case reports and
series with short term follow-up. Here we review the current reports on the use of bariatric
surgery in the treatment of CP–HyOb. We also compare these results to those reported
for other populations of HyOb, including Prader–Willi Syndrome, Bardet–Biedl syndrome,
and hypothalamic melanocortin signaling defects. While initial reports of bariatric surgery
in CP–HyOb are promising, their limited scope makes it difficult to draw any substantial
conclusions as to the long term safety and efficacy of bariatric surgery in CP–HyOb.There
continues to be a need for more robust, controlled, prospective studies with long term
follow-up in order to better define the role of bariatric surgery in the treatment of HyOb.
Keywords: craniopharyngioma, bariatric surgery, gastric bypass, hypothalamic obesity
Craniopharyngiomas (CP) are generally benign, slow-growing
ing within the remnants of the craniopharyngeal duct or Rathke’s
tuber cinereum, although most are located in the sellar/parasellar
region (Harwood-Nash, 1994; Karavitaki et al., 2005). Although
erally low, morbidity as a result of tumor mass effect and/or ther-
apy (resection±radiotherapy) is substantial and nearly universal
(Mortini et al.,2011; Winkfield et al.,2011).
Because of the close proximity to the visual nerve tracts,
hypothalamus, pituitary, and ventricular system, CPs predis-
pose patients to a number of adverse endocrine, metabolic,
psychologic, and neurologic sequelae. As a primary result of
the tumor, the majority of patients present with one or more
hypothalamic-pituitary deficits including growth hormone (GH;
∼75%), gonadotropins (∼60%), adrenocorticotropic hormone
(ACTH; ∼30%), thyroid-stimulating hormone (TSH; ∼25%),
Muller, 2008). In addition, approximately one-third can develop
new or additional endocrinopathies following surgical resection.
In addition to pituitary hormone deficiencies, hypothalamic
involvement has been shown to result in severe metabolic dis-
turbances and weight gain (Muller et al., 2001; Srinivasan et al.,
2004). While a minority (15–20%) of CP patients complain of
nificant obesity following surgical resection (Muller et al., 2004;
Ahmet et al., 2006). This number may be as high as 90% in those
with demonstrable hypothalamic damage, whether from direct
tumor infiltration or as a result of surgical and/or radiation ther-
apy (de Vile et al., 1996; Muller et al., 2004). Such pathological
refractory to therapy,and has a significant negative impact on the
quality of life for patients with CP (Muller et al., 2005; Eyal et al.,
2006; Inge et al., 2007).
els has shown the basal medial hypothalamus to be a key center of
metabolic regulation by the central nervous system (CNS; Het-
herington and Ranson, 1940; Sorva, 1988). The hypothalamus
receives and integrates a variety of afferent signals communicat-
ing the metabolic state of the organism and adjusts autonomic
outputs with the ideal physiologic outcome of maintaining ade-
quate energy stores. The afferent arm of the homeostatic loop
consists of hormones, such as leptin, insulin, and peptide YY,
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Bingham et al. Bariatric surgery
that target receptor fields within hypothalamic nuclei to convey
information on meal size, nutrient composition, and adipose tis-
sue stores. In addition, neurons within the hypothalamus directly
sense and respond to nutrients, such as free fatty acids, glucose,
neuropeptideY (NPY),agouti-related protein (AgRP),and alpha-
melanocyte stimulating hormone (α-MSH),integrate and convey
this information to other brain centers responsible for controlling
A number of monogenetic obesity syndromes have now been
shown to involve mutations in such regulatory hypothalamic
pathways (Clement et al., 1998; Lubrano-Berthelier et al., 2006;
and Bardet–Biedl syndromes (BBS), are associated with obesity,
presumably from hypothalamic dysfunction. PWS results from
the loss of paternally imprinted genes on chromosome 15q11-15
neonatal hypotonia, short stature, hypogonadism, behavioral and
psychiatric phenotypes, aggressive food-seeking behavior, hyper-
phagia, and obesity (Goldstone et al., 2008). PWS patients have
significantly elevated levels of the orexigenic hormone ghrelin, a
finding not observed in other causes of HyOb (Cummings et al.,
2002a; DelParigi et al., 2002). Interestingly, even young, under-
weight patients with PWS exhibit higher BMI-adjusted body fat
in PWS (Eiholzer et al., 1999). BBS is a multisystemic disorder
renal dysfunction, mental retardation, and obesity resulting from
defects in ciliary function. Hypothalamic dysfunction in these
patients is suggested by the study of mice harboring mutations
in BBS genes. BBS mutants have been shown to be hyperleptine-
mic and have defective hypothalamic leptin signaling (Seo et al.,
2009; Guo and Rahmouni, 2011).
Thus, damage to, or dysfunction of the hypothalamus results
in an inability of the CNS to receive proper feedback. Patients,
thus, inappropriately sense a perpetual state of starvation. To
correct the perceived negative energy balance, efferent outputs
are adjusted to promote caloric intake and decreased caloric
adipose tissue lipolysis, and promote pancreatic insulin secre-
tion, respectively. Conversely, increased parasympathetic output
through the vagus nerve slows the heart rate reducing myocar-
dial oxygen consumption, promotes gastrointestinal peristalsis
and substrate absorption, and accentuates post-prandial insulin
secretion (Lustig, 2008). The net result of this reduced sym-
pathetic/parasympathetic ratio is significantly decreased energy
expenditure with partitioning of calories away from energy con-
suming tissue such as muscle and toward energy storage depots
such as adipose tissue.
Accumulating evidence supports the hypothesis that CP and
its therapies often result in dysfunction of the normal homeo-
static mechanisms regulating appetite and metabolism. Leptin,
a potent anorexigenic peptide secreted by adipocytes, has been
found to be elevated in CP patients compared to obese controls
suggesting a defect in the normal feedback inhibition of appetite.
In addition, some CP patients have a blunted post-meal increase
in the anorexigenic hormone peptide YY. Hypersecretion of the
orexigenic gastric hormone ghrelin is thought to contribute to
hyperphagia and obesity in PWS, although this does not seem
to be the case in CP where pre-meal ghrelin levels are lower than
there may be a reduction in the expected magnitude of post-meal
Holmer et al., 2010).
While there are reports of hyperphagia and obsessive food-
seeking behavior after CP (Skorzewska et al., 1989), a number of
studies have now shown that caloric expenditure, and not caloric
intake, may be the largest contributor to post-CP–HyOb (CP–
HyOb). Adults and children with CP–HyOb have been found to
have impaired sympathoadrenal activation in response to hypo-
glycemia, although this defect does not appear to always corre-
late with development of obesity or hypothalamic involvement
(Schofl et al., 2002; Coutant et al., 2003). In a larger study,
CP–HyOb patients were found to have lower levels of urine
catecholamines than BMI-matched controls (Roth et al., 2007),
suggesting decreased sympathetic tone.
As sympathetic tone correlates with spontaneous motor activ-
ity, one might also expect lower levels of physical activity in CP
patients. Indeed, CP patients consistently report reduced physical
activity, even when compared to controls with similar BMI (Roth
et al., 2007). Using accelerometric data, Harz et al. demonstrated
that obese CP patients had decreased spontaneous motor activity
with hypothalamic damage, despite a significantly increased BMI
(Harz et al., 2003). These findings were substantiated by a recent
study by Holmer et al. in 42 adult patients with childhood CP,
metabolic rate when adjusted for body weight, than age and sex
matched controls. Analysis of energy intake showed lower caloric
consumption in CP patients which was attributed to cognitive
restraint in eating (Holmer et al.,2010).Aside from reduced sym-
pathetic drive, the roadblocks to physical activity are substantial
and likely contribute to reduced energy expenditure and risk for
obesity. Neurological and visual deficits may contribute to limited
movement in some CP patients. In addition,there is evidence that
CP patients have disordered sleep patterns secondary to decreased
melatonin and/or secondary narcolepsy causing daytime sleepi-
ness (Muller et al., 2002, 2006). Obstructive sleep apnea (OSA) in
these patients also likely contributes to poor sleep hygiene.
Under- or overtreatment of hormonal deficiencies may also
contribute to poor metabolic parameters and weight gain in CP
patients. Glucocorticoid excess is a known cause of significant
weight gain,impaired glucose metabolism,sleep disturbance,and
defects in bone metabolism and growth (Debono et al., 2009).
Most significantly, excess glucocorticoid dosing has been associ-
ated with increased mortality from cardiovascular disease. In a
large cohort of Scandinavian patients with hypopituitarism, Fil-
ipsson et al. (2006) showed that those receiving higher doses of
glucocorticoid replacement had significantly higher waist circum-
ference, total cholesterol, serum triglycerides, and HbA1c. Daily
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February 2012 | Volume 3 | Article 23 | 2
Bingham et al. Bariatric surgery
cortisol production rates range from 6 to 8mg/m2/day, much less
than previous estimates (Linder et al., 1990; Esteban et al., 1991;
Kerrigan et al., 1993; Brandon et al., 1999). Thus, the classic adult
dosing of 20mg of hydrocortisone in the A.M. and 10mg in the
P.M.,is likely an excessive dose. Unfortunately,no objective test of
adequate glucocorticoid replacement has been shown to be suffi-
ciently consistent to aid in dosing management and patients must
be followed closely for clinical signs of glucocorticoid deficiency
Hypothyroidism also results in poor metabolic health and is
associated with fatigue, low basal metabolic rate, increased BMI,
and increased cholesterol and triglyceride levels (Kronenberg and
Williams, 2008) and adequate replacement has beneficial effects
on these parameters (Slawik et al., 2007). Management of thyroid
the absence of the patient’s own endogenous “thyrostat” as TSH
levels cannot be used to judge adequacy of treatment. The signifi-
cance of this handicap is highlighted in a recent study comparing
free T4 (fT4) levels in TSH deficient patients to those in primary
hypothyroid patients where TSH levels are used to guide therapy.
Nearly 40% of TSH deficient patients were found to have fT4 lev-
els below the 20th centile range compared to 13.4% of primary
hypothyroid patients (Koulouri et al., 2011).
Growth hormone deficiency is present in a majority of CP
in this patient population. These metabolic effects are particularly
important in adults, where GH replacement results in increased
2008). GH-deficiency has been shown to contribute to increased
cardiovascular risk in hypopituitarism (Abs et al., 2006; Verhelst
does not appear to have any adverse effect on reoccurrence rates
of CP in short term follow-up (Muller et al., 2010; Rohrer et al.,
Hypogonadism and inadequately treated diabetes insipidus
(DI) can also potentiate the effects of hypothalamic damage on
excessive weight gain. Testosterone replacement, in hypogonadal
men has been shown to have beneficial effects on body com-
position, blood pressure, and glucose homeostasis (Katznelson
et al., 1996; Boyanov et al., 2003; Wittert et al., 2003). The effects
of estrogen replacement on weight gain and body composition
are more mixed and unclear, but premenopausal women who
are hypogonadal should be physiologically replaced barring other
can lead to excessive drinking of calories, poor sleep quality, and
increased appetite (Beccuti and Pannain, 2011).
Altered carbohydrate and insulin dynamics have been shown
to occur with CP and its treatment. While fasting glucose levels
gerated first and second phase insulin response to carbohydrate
challenge (Lustig et al., 1999). Hyperinsulinism in hypothalamic
pathways and augmented vagal parasympathetic signaling to the
pancreatic β-cell, and is not primarily a response to insulin resis-
tance. Vagally mediated acetylcholine, acting through M3mus-
carinic receptors, promotes depolarization of the β-cell through
stores through activation of the phospholipase C pathway (Miura
of the intestinal peptide glucagon-like peptide-1,itself a potentia-
tor of insulin secretion (Rocca and Brubaker, 1999; Lustig, 2008).
Increased insulin secretion in turn directs calories toward storage
within the adipocyte.
Thus, the disruption of hypothalamic centers that occurs as a
direct result of CP or its treatment creates a situation in which
efferent drives to consume and store energy are disengaged from
afferent signals that would otherwise dampen such drives. The
obesity that results, driven by neural and biochemical stimuli, is
these interventions alone are often not successful,leaving patients
frustrated with cravings, constant hunger, and lack of progress.
Further, in addition to panhypopituitarism, HyOb patients are
susceptible to the same metabolic derangements seen in other
types of obesity such as diabetes, dyslipidemia, and heart disease
(Srinivasan et al., 2004). For patients already facing significant
challenges as a result of their primary disease,the negative impact
of such comorbidities on quality of life adds insult to injury.
Unfortunately, in the last several years pharmacologic agents
available for weight loss treatment have significantly declined,
as the most effective agents (i.e., phen–fen, sibutramine) have
been withdrawn from the market for unacceptable side-effect
profiles. Small studies in CP of stimulants such as modafinil,
methylphenidate, and dextroamphetamine have been shown to
improve daytime sleepiness,affect,and alertness in HyOb (Mason
et al., 2002; Muller et al., 2006), but none have proven truly effec-
tive at reversing the severe weight gain seen in this condition.
Targeting the hyperinsulinism seen in HyOb, Lustig et al. (2006)
demonstrated that octreotide could induce a modest decrease in
formin combined therapy demonstrated a slowing of weight gain
with a stabilization of BMI over the 6-months of therapy (Hamil-
in treating CP–HyOb is tepid at best. Because CP–HyOb results
from damage to the afferent target centers of the hypothalamus,
agents targeting the efferent pathways to increase metabolic rate
Newer agents targeting these efferent pathways are desperately
SURGICAL TREATMENT OF HyOb
Given the limited choices and poor results of pharmacotherapy,
surgery as a viable option for producing sustained weight loss
for patients with CP–HyOb. A range of procedures are available
and are generally divided into three categories: restrictive, malab-
sorptive, and hybrid procedures. Restrictive procedures, such as
gastric banding (GB) or vertical banded gastroplasty (VBG), aim
to reduce stomach volume resulting in early satiety and smaller
meal consumption. The natural course that nutrients follow is
not altered, however. Pure malabsorptive procedures including
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Bingham et al.Bariatric surgery
jejunoileal and duodenal–jejunal bypass,as well as biliopancreatic
diversion (BPD) involve the diversion of ingested food, bypass-
ing one or more sections of intestine. The former two of these
procedures have largely fallen out of favor secondary to associ-
ated nutritional deficits (Organ et al., 1984). A hybrid procedure,
the Roux-en-Y gastric bypass (RYGB) has become the“gold stan-
dard” and the most commonly performed bariatric surgery for
enterostomy is then made between the excluded biliopancreatic
limb and the roux alimentary limb (Karra et al., 2010).
Bariatric surgery remains the most effective treatment for
morbid obesity and is indicated for adult patients with a
BMI>40kg/m2or a BMI of >35kg/m2and significant obesity-
cations have generally been advocated for weight loss surgery in
adolescent patients (see Discussion and Future Directions). An
extensive body of research has shown that patients often show
measurable improvement in metabolic parameters including glu-
cose homeostasis in the early post-operative period, independent
of weight loss. While the exact mechanisms of this phenomenon
teract certain elements of the orexigenic and energy conserving
hormone secreted by enteroendocrine cells of the distal ileum, is
increased following bariatric surgery. The evidence is especially
consistent for bypass procedures, whereas restrictive procedures
have been associated with no change or a decrease in GLP-1 levels
(Sarson et al., 1981; Koopmans et al., 1984; Laferrere et al., 2008).
GLP-1 has been shown to have a number of positive effects
on glucose metabolism including potentiating glucose-dependent
insulin secretion, improving insulin sensitivity, and suppressing
glucagon secretion. In addition, it has been shown to slow gastric
effect by acting on specific receptors located on pancreatic β-cells,
peripheral vagal afferent fibers, as well as centrally located neu-
rons (Baggio and Drucker, 2007). In addition, bariatric surgery
has been shown to increase other anorexigenic hormones such
as PYY and decrease orexigenic hormones such as ghrelin (Cum-
appear to indicate that exposure of the distal gut to nutrient-rich,
partially digested food results in increased secretion of hormones
such as GLP-1 and PYY. This altered hormonal milieu accounts
for the greater than 80% remission in diabetes following RYGB,
sorption, gastric restriction, and hormonal changes that accounts
for the consistent and durable weight loss seen following such
procedures (Buchwald et al., 2004; Karra et al., 2010).
Despite the large body of evidence demonstrating the ben-
efits of bariatric surgery in treating exogenous obesity and its
comorbidities, its role in the treatment of HyOb has yet to be
defined. To date, the existing literature on bariatric surgery in
CP–HyOb is largely limited to case reports and series with short
term follow-up. A PubMed search for “craniopharyngioma” and
“bariatric surgery” results in four citations with a total of eight
patients. Procedures performed include two RYGB, four laparo-
scopic adjustable band (LAGB),one distal gastric bypass,and one
biliopancreatic derivation with duodenal switch.
In the first report of RYGB for CP–HyOb, we reported on an
18-year-old male who underwent a successful RYGB with ante-
rior truncal vagotomy (due to the presumed importance of vagal
efferents in CP-related hyperinsulinemia) for massive weight gain
following the resection of a CP 3years previous.At the time of CP
resection, he developed hyperphagia and significant weight gain
(70kg/year) despite outpatient and inpatient dietary and physi-
cal activity interventions. Significant hyperinsulinism was noted
and the patient was started on octreotide therapy with signifi-
cant deceleration in weight gain but no weight loss. At the time
of his bariatric surgery consultation, he had developed severe
OSA, left ventricular hypertrophy, and hypertriglyceridemia. The
post-operative course was significant for a 49-kg weight loss
over 2.5years, although weight appeared to stabilize thereafter
(BMI ∼50kg/m2). Further, serum triglycerides and left ventric-
ular hypertrophy normalized. Hyperphagia decreased and food
cravings (as measured by a Food Craving Inventory) diminished
for all food types. Ten days following RYGB surgery, there was a
fivefold decrease in fasting insulin, with normalization of fasting
CP resection 21years previous, the patient had experienced con-
for diabetes treatment. To promote preoperative weight loss, he
vised diet and exercise regimen which resulted in 9kg weight loss
commonchannelof 80cm,wasperformedwiththegoalof induc-
ing a strong malabsorption component. Following surgery, the
patient experienced a precipitous weight loss, losing over 50kg
(∼30% of preoperative weight) over 18months. In addition, the
patient exhibited complete resolution of his diabetes and OSA
and distinct reduction feelings of hunger and disinhibition on the
three factor eating questionnaire (Schultes et al.,2009). The post-
operative course was largely uneventful, although the patient did
develop mild nutritional deficiencies despite standardized supple-
and zinc as well as hypoproteinemia.
In a series of four adolescent patients with childhood CP
and obesity, Muller et al. found significant weight loss in all
patients after LAGB. Patients participated in the German mul-
ticenter surveillance study on childhood CP termed “HIT-Endo-
Kraniopharyngeom.” The age of the patients ranged from 13 to
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Bingham et al. Bariatric surgery
24years of age and BMI–SDS scores ranged from +7.3 to +13.9.
Following surgery,BMI–SDS scores improved on average by −0.7
Patients also reported significant changes in eating behavior, with
reduced food cravings especially for sweets. Quality of life and
functional capacity, measured by a standardized and validated
scale, remained stable following surgery. Of the four patients,
two experienced dislocation of the LAGB resulting in tempo-
rary weight gain and requiring laparoscopic revision. No other
side-effects were reported (Muller et al., 2007).
Rottembourg et al. (2009) reported on two adolescents with
post-CP–HyOb who underwent bariatric surgery as treatment for
of hypoventilation. Postoperatively, she demonstrated sustained
weight loss over 4years (BMI 43kg/m2at last follow-up). In
addition, dyslipidemia normalized, sleep patterns improved, and
she had no further respiratory infections. She was subsequently
diagnosed with fibromyalgia and symptomatic hyperuricemia,
which were treated with regular analgesia and allopurinol. She
also required ongoing treatment for depression. In addition, she
developed a dumping-type syndrome (pallor, diaphoresis, and
shakiness following meals) without associated hypoglycemia. The
second patient was a 15-year-old male, diagnosed with CP at age
of 4years, also with panhypopituitarism and rapid weight gain
following gross total resection. Comorbidities included dyslipi-
a trial of octreotide led to no reduction of weight gain. At the
time of bariatric surgery, his BMI was 42kg/m2. Given that the
underlying cause of obesity was biological and would be present
life-long, the surgeons involved felt that a diversionary surgical
procedure would be a better option than LAGB. Following a BPD
with duodenal switch, his BMI decreased to 32kg/m2over the
2-year follow-up. The post-operative course was complicated by
bradycardia requiring pacemaker placement, and stenosis of the
distal surgical anastomosis requiring several laparoscopic repairs.
Overall,both patients exhibited robust,sustained weight loss with
resolution of metabolic comorbidities.
The efficacy of bariatric surgery for weight loss has also been
examined in other HyOb patient populations. Scheimann et al.
recently reported a retrospective critical analysis of bariatric pro-
cedures in PWS. PWS is a complex genetic disorder that results
in marked hyperphagia and obesity felt to be secondary to hypo-
thalamic dysfunction. The critical analysis revealed that a number
of procedures,including BPD,RYGB,VBG,and endoscopic intra-
gastric balloon placement have been used in this population. A
review of 60 PWS patients highlighted the limited effectiveness
and concerning safety profile of operations for weight loss in
this unique population (Scheimann et al., 2008). In the short
term, there appears to be some limited weight loss that is vari-
able across different procedures. For RYGB, average weight loss
was 4.2% for PWS patients after 6months. Twelve month and
24month follow-up revealed 6.5 and 2% weight loss,respectively.
This weight loss is far less than the 35% reduction in BMI we see
1year after RYGB for adolescents who do not have PWS. Five year
follow-up, while limited, showed only a 2.4% weight loss in PWS
patients after RYGB (n =9). Long term weight loss was worse
with VBG, with PWS patients experiencing a 3.5% weight gain
after 5years (n =2). Patients undergoing BPD had higher weight
lossof 27.6%at12-months,butnearlyhalf regainedweightwithin
2–5years. In addition, the report highlights what appears to be a
revision after RYGB and 27% experiencing acute gastric dilation
(Scheimann et al., 2008).
with BBS. Patients with BBS demonstrate hyperphagia and obe-
sity which have been linked to disruption of primary cilia in
POMC neurons in the hypothalamus and possibly to altered
leptin receptor functioning. In this 16-year-old with a BMI of
and hyperuricemia was also observed.
Finally, as melanocortin 4 receptor (MC4R) variants represent
documented MC4R mutations. Surgical experience in this special
group of HyOb patients is very limited. A group of investigators
at the University of California San Francisco (UCSF) described
surgical outcomes in an adolescent patient with a complete loss of
a preoperative weight of 166kg and BMI of 54kg/m2and under-
went bilateral truncal vagotomy and laparoscopic adjustable GB.
In this patient, the surgical intervention did not result in success-
ful weight loss. Indeed, after an initial modest weight reduction
of 12kg over the first 4months, the patient regained weight and
by 1year was 6.5kg over his preoperative weight. Several features
of the case however are relevant to interpretation of the outcome.
First, the patient had moved away to college 4months prior to
the operation, and had in that time experienced a 66-kg weight
gain. Also, the patient returned for only two band adjustments in
the 1-year period of time, which is markedly less than the typi-
cally recommended post-operative adjustment schedule. Finally,
the authors described an insatiable hunger 1year after the oper-
ation, which was almost certainly a factor contributing to weight
gain (Aslan et al., 2011b).
first report of an experience with gastric bypass in the setting of
mutant MC4R contrasts with the results obtained after GB. Aslan
et al. analyzed 1year outcomes of four adults with heterozygous
MC4R mutations in comparison to matched controls with nor-
subjects was identical to the 60–70% EWL seen in matched con-
trols. There was no mention of changes in post-operative appetite
in these patients, nor any changes in metabolic features in this
cohort (Aslan et al., 2011a).
DISCUSSION AND FUTURE DIRECTIONS
Hypothalamic obesity is observed in a high percentage of patients
with CP, resulting in significant comorbidities and negatively
impacting quality of life. Unfortunately, few treatments have
February 2012 | Volume 3 | Article 23 | 5
Bingham et al.Bariatric surgery
proven effective in this patient population. First line therapy for
HyOb should include aggressive lifestyle modification including
appropriate caloric intake and activity. Pituitary hormone defi-
ciencies, if any, should be replaced and doses optimized. As men-
tioned previously, glucocorticoid replacement should be targeted
at replacement doses (8–10mg/m2/day hydrocortisone equiva-
lent) and patients should be given the lowest dose possible that
is adequate to avoid symptoms of adrenal insufficiency. Thyroid
replacement should generally target the fT4 at the upper third
of the normal range and patients should be clinically and bio-
roidism (Rose,2010). The decision to replace GH should be made
in consultation with the patient, family, and other team mem-
should be titrated to keep IGF-1 levels within the median range.
weight should be pursued through approved protocols at centers
of patientssothatrisksandbenefitsof treatmentcanbemorepre-
surgery in this population.
Here,we have reviewed the current body of published research
on bariatric surgery in CP–HyOb. We have also included sev-
eral published reports of bariatric surgery in other populations of
HyOb, including PWS, BBS, and patients with MC4R mutations.
While the limited scope of these reports makes comparison dif-
ficult, the experience in PWS patients demonstrates that all cases
of HyOb should not be treated equally. Likely as a result of the
multisystemic nature of their disorder, PWS patients have a sig-
surgery without the benefits of sustained weight loss. In addition,
gate weight gain this population (Schmidt et al., 2008). Thus, the
risk–benefit ratio of bariatric surgery in PWS does not appear to
The initial reports of bariatric surgery in CP–HyOb and
patients with MC4Rappear more promising, but again, their lim-
ited scope makes it difficult to draw any substantial conclusions as
to the long term safety and efficacy of these procedures in this
population. The limited number of cases inhibits comparison
among various procedures. For instance, how does RYGB com-
pare to LAGB with regard to long term, sustained weight loss, or
with regard to safety and side-effects? In addition, more work is
needed to understand the hormonal alterations that occur in CP–
HyOb following bariatric surgery. Are such alterations similar to
thoseseenindiet-inducedobesity?If not,why?If so,doCP–HyOb
patients derive the same benefits given their underlying hypothal-
amic damage? If hyperinsulinism is an underlying factor in the
development of HyOb, will patients benefit or be harmed from
increased levels of the insulin secretagogues such as GLP-1. Will
potentiating insulin secretion place these patients at higher risk
of hypoglycemia secondary to the mismatch of insulin secretion
and carbohydrate absorption? These and other questions remain
should be the subject of future work.
In addition, as 50% of patients diagnosed with CP are chil-
regarding bariatric surgery that must be considered in this pop-
ulation (Inge et al., 2004). Generally, adolescent candidates for
bariatric surgery must meet more conservative patient selection
criteria than are acceptable in adults. However, exact criteria are
with the Pediatric Endocrine Society,published a Clinical Practice
Guideline on the Prevention and Treatment of Pediatric Obesity,
wherein the task force recommended limiting bariatric surgery
to adolescents with a BMI≥50kg/m2or a BMI≥40kg/m2with
significant, severe comorbidities. In addition, the task force rec-
ommended that candidates have attained Tanner 4 or 5 pubertal
development and near-final adult height, experienced continued
weight gain despite following a formal program of lifestyle modi-
fication, and belong to a stable, medically competent family unit.
The patient and family should understand that bariatric surgery
is not a cure for obesity, but rather an adjunct to a continued
commitment to lifestyle modifications in diet and activity. The
surgery should be performed by an experienced surgeon in a
medical center employing a team capable of long term follow-
up and participating in a study of bariatric surgery outcomes.
These recommendations largely agree with guidelines previously
published and advocate the priority of avoiding unforeseen com-
plications associated with life-long exposure to anatomical and
functional alterations above the value of weight loss and ame-
lioration of obesity-related complications provided by bariatric
surgery (August et al., 2008).
More recently, Pratt et al. (2009) suggest that adolescents with
a BMI≥35kg/m2and serious comorbidities including Type 2
diabetes, moderate to severe OSA, and/or pseudotumor cerebri
or those with BMI≥40kg/m2with less serious comorbid condi-
tions such as hypertension, dyslipidemia, gastroesophageal reflux
disease, and/or psychosocial stress should be considered as can-
didates for bariatric surgery. While concurring with the other
physical, lifestyle, and psychosocial criteria previously published,
they use several lines of evidence to defend the lower BMI criteria.
First, they cite data to indicate that patient safety and weight loss
outcomes for extremely obese adolescents who undergo bariatric
surgery are comparable to, or better than, those seen in adults.
Second, even with the lower BMI criteria of 35kg/m2, candidates
under the age of 18 would still be above the 99th BMI percentile
ical comorbidities. Third, they stress that selection for bariatric
surgery during adolescence should be closely linked to obesity-
related comorbidities. The less severe comorbidities and/or fewer
risk factors for long term disease, the higher the BMI cut point
should be before considering bariatric surgery. Finally, some have
suggested that because younger patients will generally have fewer
advanced comorbidities, early bariatric surgery may decrease the
is delayed until adulthood (Garcia and DeMaria, 2006).
Importantly, none of the guidelines for bariatric surgery
directly addresses the use of bariatric surgery in HyOb generally
or CP–HyOb in particular. In general, we believe that most cri-
teria from the published guidelines can be applied to the HyOb
patients, especially in adults. Whether one or more of the pub-
lished criteria should be modified in the context of children and
adolescents is subject to ongoing debate. Given what is known
Frontiers in Endocrinology | Pituitary Endocrinology
February 2012 | Volume 3 | Article 23 | 6
Bingham et al. Bariatric surgery
about the natural history of HyOb, its resistance to diet and
lifestyle modification, and the extreme and progressive weight
gain involved, some may consider bariatric surgery appropriate
at ages currently considered too young in patients with exogenous
obesity. However, in general, the younger the patient the more
compelling and serious the comorbidities must be to justify surgi-
optimal care of HyOb patients will be best met in the setting of
tertiary care centers where they can receive treatment in a coor-
the primary care physician and as needed subspecialists in neu-
rosurgery, neurology, oncology, endocrinology, bariatric surgery,
and mental health. Ideally, ancillary support by nutrition, phys-
ical therapy, nursing, and social work should also be available.
be properly informed regarding specific risks and benefits asso-
ciated with surgical weight loss and age appropriate consent or
assent obtained. To facilitate needed research in this area,patients
of HyOb are limited in scope and number, but give us a glimpse
of the possible role of surgery in treatment of these conditions.
They also make evident the need for more robust, controlled,
prospective studies with long term follow-up in order to better
define the role of medical as well as surgical therapies in the treat-
ment of HyOb. In order to ultimately understand the outcome
of surgical therapy for HyOb, sufficiently long follow-up of suffi-
cient numbers of similar patients who undergo surgery as well as
els might also in the future permit a better understanding of the
mechanisms of obesity, and the importance of tailoring specific
operative elements to each unique population.
the relative rarity of the condition, it would take a single insti-
tution many years to put together a study large enough to reach
valid, persuasive conclusions regarding the treatment of HyOb –
surgical or otherwise. In order to increase public awareness of
HyOb, facilitate future research and ultimately improve the man-
agement of HyOb, the International Registry for HyOb Disorders
(www.IRHOD.org) has been established. The web-based interface
accumulation of a large world-wide cohort of patients with HyOb
will facilitate recognition of individuals eligible for participation
in studies of HyOb and its treatment. This registry, therefore, has
potential to fill many of the numerous knowledge gaps around
pathogenesis, coexisting disease, and treatment outcomes for this
debilitating form of obesity.
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 27 October 2011; accepted: 30
January 2012; published online: 14 Feb-
Citation:Bingham NC,Rose SRandInge
amic obesity. Front. Endocrin. 3:23. doi:
This article was submitted to Frontiers
in Pituitary Endocrinology, a specialty of
Frontiers in Endocrinology.
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Inge. This is an open-access article dis-
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February 2012 | Volume 3 | Article 23 | 9