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									Hypothalamic Obesity In
      Humans

        Christina Daousi
    Diabetes & Endocrinology
    University Hospital Aintree
             Liverpool
     Cdaousi@liverpool.ac.uk
Monogenic obesity syndromes associated
   with hypothalamic dysfunction

   Prader-Willi syndrome
   Leptin/leptin receptor mutations
   POMC mutation
   Prohormone convertase-1 mutation
   Melanocortin-4 receptor mutation
               Hypothalamic Obesity
   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)
   “…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
   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:
   Acute increase in body weight following a clear
    hypothalamic insult.

   Weight gain faster than any expected age-
    related increase in BMI.

   Other coexistent pituitary hormone deficiencies
    must be treated.
How common is hypothalamic obesity in the
        paediatric population?

   Weight gain and obesity observed in 50-80% of
    children treated for craniopharyngioma.

   Amount of weight gain variable.

   Course of weight gain variable but most occurs
    within the first 6 months.
               Sequelae of HO
   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

            Muller HL et al, Childs Nerv Syst. 2005 Nov;21(11):975-80
              Sequelae of HO
   Cross-sectional study on 212 patients with
    childhood craniopharyngioma

   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
    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
   NAFLD & HO- further reports

   16 years old female with NASH+ cirrhosis, Dx
    with cranio aged 5

   18 years old male, Dx aged 10, NASH+fibrosis

                   Nakajima K et al, J Gastroenterol. 2005 Mar;40(3):312-5
                Sequelae of HO
   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?


   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
                                             % of patients at
   45
                                             diagnosis
   40                                        % of patients at
   35                                        latest follow up
   30
   25
   20
   15
   10
    5
    0
        BMI<25   25<BMI<30   30<BMI<35   35<BMI<40   BMI>40
     Comparison with the general population:

90
                                   % of general population
80

70                             % of study patients

60
50

40

30

20

10
0
        BMI>25   BMI>30   BMI>40
                     Neuroimaging
   size of tumour

   encroachment of pituitary tumours on optic chiasm

   invasion or compression of hypothalamic tissue

   abnormalities of 3rd ventricle

   breach of the infundibulum by the tumour

   infiltration of the thalamus or temporal lobes
TREATMENT                 P-value
Desmopressin              0.016
Growth hormone            0.017
Hydrocortisone            NS
Thyroxine                 NS
Sex steroids              NS
Transphenoidal surgery    NS
Transfrontal surgery      NS
Radiotherapy              NS
VP shunt                  NS
Conservative management   NS
Dopamine agonists         NS
   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.
Mechanisms giving rise to hypothalamic
               obesity
   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):
   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
   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
   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)
   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)
   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
   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
   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
   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

								
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