Transcript Document

Hypothalamic Obesity In
Humans
Christina Daousi
Diabetes & Endocrinology
University Hospital Aintree
Liverpool
[email protected]
Monogenic obesity syndromes associated
with hypothalamic dysfunction
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Prader-Willi syndrome
Leptin/leptin receptor mutations
POMC mutation
Prohormone convertase-1 mutation
Melanocortin-4 receptor mutation
Hypothalamic Obesity
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Structural damage to hypothalamus
- craniopharyngioma
- meningioma
- germ cell tumour
- glioma
- teratoma
- pituitary adenomas with suprasellar extension
- metastasis
- aneurysm
- surgery
- radiotherapy/chemotherapy
Pinkney JH et al. Obes Rev 2002; 3(1):27-34
Diabetes insipidus and blindness caused by a
suprasellar tumour (1590)
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“…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…”
Idiopathic hypothalamic syndrome
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N=5 cases
No tumoural or genetic alterations
Obesity before 6 years old, compulsive eating,
behavioural disturbances
Breathing and thermoregulatory problems
GHD, raised prolactin, hypogonadotropic
hypogonadism, precocious puberty
Water and electrolyte disturbances (?CDI)
Reynaud R et al, Arch Pediatr. 2005 May;12(5):533-42
Definition:
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Acute increase in body weight following a clear
hypothalamic insult.
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Weight gain faster than any expected agerelated increase in BMI.
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Other coexistent pituitary hormone deficiencies
must be treated.
How common is hypothalamic obesity in the
paediatric population?
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Weight gain and obesity observed in 50-80% of
children treated for craniopharyngioma.
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Amount of weight gain variable.
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Course of weight gain variable but most occurs
within the first 6 months.
Sequelae of HO
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Pituitary hormone deficiencies
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
Roth CL et al, Pediatr Res. 2007 Apr;61(4):496-501
Sequelae of HO
Longitudinal study on QOL in 102 survivors of
childhood craniopharyngioma
 Long-term QOL negatively affected by obesity
and associated with:
Hypothalamic involvement
Tumour progression
Relapse
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Muller HL et al, Childs Nerv Syst. 2005 Nov;21(11):975-80
Sequelae of HO
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Cross-sectional study on 212 patients with
childhood craniopharyngioma
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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
Sequelae of HO
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NAFLD among patients with hypothalamic and
pituitary dysfunction
Mayo clinic, 21 cases
Mean 6.4 years after Dx of hypothalamic dysfunction
Yearly weight gain 2.2 units BMI
10 biopsies (6 cirrhosis, 2 NASH, 2 steatosis)-2
required liver Tx
Adams LA et al, Hepatology. 2004 Apr;39(4):909-14
Sequelae of HO
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NAFLD & HO- further reports
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16 years old female with NASH+ cirrhosis, Dx
with cranio aged 5
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18 years old male, Dx aged 10, NASH+fibrosis
Nakajima K et al, J Gastroenterol. 2005 Mar;40(3):312-5
Sequelae of HO
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Daytime hypersomnolence
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
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.
How common is hypothalamic obesity in
adults?
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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.
Distribution of BMI at diagnosis and latest follow up
50
45
40
35
30
25
20
15
10
5
0
% of patients at
diagnosis
% of patients at
latest follow up
BMI<25
25<BMI<30
30<BMI<35
35<BMI<40
BMI>40
Comparison with the general population:
90
% of general population
80
% of study patients
70
60
50
40
30
20
10
0
BMI>25
BMI>30
BMI>40
Neuroimaging
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size of tumour
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encroachment of pituitary tumours on optic chiasm
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invasion or compression of hypothalamic tissue
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abnormalities of 3rd ventricle
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breach of the infundibulum by the tumour
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infiltration of the thalamus or temporal lobes
TREATMENT
P-value
Desmopressin
Growth hormone
Hydrocortisone
Thyroxine
Sex steroids
Transphenoidal surgery
Transfrontal surgery
Radiotherapy
VP shunt
Conservative management
Dopamine agonists
0.016
0.017
NS
NS
NS
NS
NS
NS
NS
NS
NS
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Findings from neuroimaging did not predict
weight gain.
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Requirement for desmopressin (ADH) and
growth hormone were the strongest predictors
of current obesity and weight gain.
Mechanisms giving rise to hypothalamic
obesity
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Increased energy intake
Hyperphagia
Autonomic dysfunction
vagally-mediated hyperinsulinaemia
low resting metabolic rate
Reduced voluntary energy expenditure
Impaired gut-brain satiety signalling?
11-b-HSDH ?
Hormone deficiencies
GH, TSH, LH/FSH
Pinkney JH et al. Obes Rev 2002; 3(1):
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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
Impaired satiety may be an aetiological factor of
obesity in this group.
Sibutramine & Hypothalamic Obesity
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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
HO (n=22) and cases of uncomplicated obesity plus
aggravating syndromes (n=28)
-0.70 BMI SDS (mean reduction) (P<0.001)
Weight loss less pronounced in those with HO (partial
resistance)
Well tolerated and safe
Danielsson P et al, J Clin Endocrinol Metab. 2007 Nov;92(11):4101-6
Octreotide
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randomized, double-blind, placebo-controlled trial of
octreotide therapy for pediatric hypothalamic obesity
N=18, 6 months
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.
safe and well tolerated
Lustig RH et al, J Clin Endocrinol Metab. 2003 Jun;88(6):2586-92
Dextroamphetamine & HO (1)
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Retrospective review
N=12, treated for 13-15 months, low-dose
10/12 experienced either stabilization of weight or
weight loss on treatment
median loss -0.7 SDS in males, -0.44 SDS in females
improvement in daytime wakefulness and/or
concentration and exercise tolerance
Ismail D et al, J Pediatr Endocrinol Metab. 2006 Feb;19(2):129-34
Dextroamphetamine & HO (2)
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CNS stimulant
n=5 for 2 years
BMI=21 pre-op, BMI=32 at enrolment
Weight gain stabilised
Improvements in overall activity and attention
Can earlier intervention prevent initial obesity?
Mason PW et al, Arch Pediatr Adolesc Med. 2002 Sep;156(9):887-92
Melatonin and hypersomnolence
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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
Muller HL et al, Cancer Causes Control. 2006 May;17(4):583-9
Bariatric Surgery
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Male aged 13 Dx with cranio
subtotal surgical resection and XRT
Severe hyperphagia, gaining weight at 70 kg per year
Failed interventions with dietary measures and physical activity.
Multiple co-morbidities
Weight stabilised on octreotide but no weight loss
Laparoscopic Roux-en-Y-gastric bypass aged
Marked reductions in food cravings, reduction in
hyperinsulinaemia
49 kg weight loss over ensuing 2.5 years
Inge TH et al, Nat Clin Pract Endo Metab 2007; 3(8):606-609
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The optimal treatment of hypothalamic
obesity remains elusive, but increased
awareness of the existence of the problem
could help prevent obesity.
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Management of these patients requires a
multidisciplinary approach