Hypothalamic Obesity Hypothalamic Obesity In HumansIn Humans

Christina Daousi Christina Daousi

Diabetes & EndocrinologyDiabetes & Endocrinology

University Hospital AintreeUniversity Hospital Aintree

LiverpoolLiverpool

Cdaousi@liverpool.ac.ukCdaousi@liverpool.ac.uk

Monogenic obesity syndromes Monogenic obesity syndromes associated with hypothalamic associated with hypothalamic

dysfunctiondysfunction

Prader-Willi syndromePrader-Willi syndrome Leptin/leptin receptor mutationsLeptin/leptin receptor mutations POMC mutationPOMC mutation Prohormone convertase-1 mutationProhormone convertase-1 mutation Melanocortin-4 receptor mutationMelanocortin-4 receptor mutation

Hypothalamic ObesityHypothalamic Obesity Structural damage to hypothalamusStructural damage to hypothalamus - - craniopharyngiomacraniopharyngioma - meningioma- meningioma - germ cell tumour- germ cell tumour - glioma- glioma - teratoma- teratoma - pituitary adenomas with suprasellar extension- pituitary adenomas with suprasellar extension - metastasis- metastasis - aneurysm- aneurysm - surgery- surgery - radiotherapy/chemotherapy- radiotherapy/chemotherapy Pinkney JHPinkney JH et al. et al. Obes RevObes Rev 2002; 2002;

3(1):27-343(1):27-34

Diabetes insipidus and blindness Diabetes insipidus and blindness caused by a suprasellar tumour caused by a suprasellar tumour

(1590)(1590)

“…“…upon opening the skull I found a upon opening the skull I found a significant vesicle that had occupied significant vesicle that had occupied the optic nerves close to their the optic nerves close to their crossing, and when I cut it open half crossing, and when I cut it open half a pound of the clearest of watery a pound of the clearest of watery material flowed out…”material flowed out…”

Idiopathic hypothalamic Idiopathic hypothalamic syndromesyndrome

N=5 casesN=5 cases No tumoural or genetic alterationsNo tumoural or genetic alterations Obesity before 6 years old, compulsive Obesity before 6 years old, compulsive

eating, behavioural disturbanceseating, behavioural disturbances Breathing and thermoregulatory problemsBreathing and thermoregulatory problems GHD, raised prolactin, hypogonadotropic GHD, raised prolactin, hypogonadotropic

hypogonadism, precocious pubertyhypogonadism, precocious puberty Water and electrolyte disturbances (?CDI)Water and electrolyte disturbances (?CDI)

Reynaud R et al, Arch Pediatr. 2005 Reynaud R et al, Arch Pediatr. 2005 May;12(5):533-42 May;12(5):533-42

Definition:Definition:

Acute increase in body weight Acute increase in body weight following a clear hypothalamic insult.following a clear hypothalamic insult.

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

Other coexistent pituitary hormone Other coexistent pituitary hormone deficiencies must be treated.deficiencies must be treated.

How common is hypothalamic obesity How common is hypothalamic obesity in the paediatric population?in the paediatric population?

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

Amount of weight gain variable.Amount of weight gain variable.

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

Sequelae of HOSequelae of HO Pituitary hormone deficienciesPituitary hormone deficiencies Poor sympatho-adrenal counter-Poor sympatho-adrenal counter-

regulation following insulin-induced regulation following insulin-induced hypoglycaemia (?adrenal medullary hypoglycaemia (?adrenal medullary dysfunction)dysfunction)

Reduced sympathetic metabolites in urine Reduced sympathetic metabolites in urine of obese children with cranios; those with of obese children with cranios; those with most severe obesity displayed the lowest most severe obesity displayed the lowest levels and also lower physical activity levels and also lower physical activity

Roth CL et al, Pediatr Res. 2007 Roth CL et al, Pediatr Res. 2007

Apr;61(4):496-501Apr;61(4):496-501

Sequelae of HOSequelae of HO Longitudinal study on QOL in 102 Longitudinal study on QOL in 102

survivors of childhood survivors of childhood craniopharyngioma craniopharyngioma

Long-term QOL negatively affected by Long-term QOL negatively affected by obesity obesity and associated with:and associated with:

Hypothalamic involvementHypothalamic involvementTumour progressionTumour progressionRelapseRelapse

Muller HL et al, Childs Nerv Syst. 2005 Muller HL et al, Childs Nerv Syst. 2005 Nov;21(11):975-80Nov;21(11):975-80

Sequelae of HOSequelae of HO

Cross-sectional study on 212 Cross-sectional study on 212 patients with childhood patients with childhood craniopharyngiomacraniopharyngioma

Hypothalamic involvement resulted Hypothalamic involvement resulted in obesity and had major impact on in obesity and had major impact on functional capacity in survivorsfunctional capacity in survivors

Muller HL et al, Klin Padiatr. 2003 Nov-Muller HL et al, Klin Padiatr. 2003 Nov-Dec;215(6):310-4Dec;215(6):310-4

Sequelae of HOSequelae of HO

NAFLD among patients with hypothalamic NAFLD among patients with hypothalamic and pituitary dysfunctionand pituitary dysfunction

Mayo clinic, 21 casesMayo clinic, 21 cases Mean 6.4 years after Dx of hypothalamic Mean 6.4 years after Dx of hypothalamic

dysfunctiondysfunction Yearly weight gain 2.2 units BMIYearly weight gain 2.2 units BMI 10 biopsies (6 cirrhosis, 2 NASH, 2 steatosis)-2 10 biopsies (6 cirrhosis, 2 NASH, 2 steatosis)-2

required liver Txrequired liver Tx

Adams LA et al, Hepatology. 2004 Adams LA et al, Hepatology. 2004

Apr;39(4):909-14Apr;39(4):909-14

Sequelae of HOSequelae of HO

NAFLD & HO- further reportsNAFLD & HO- further reports

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

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

Nakajima K et al, J Gastroenterol. 2005 Nakajima K et al, J Gastroenterol. 2005 Mar;40(3):312-5 Mar;40(3):312-5

Sequelae of HOSequelae of HO Daytime hypersomnolenceDaytime hypersomnolence Secondary narcolepsySecondary narcolepsy may be a causative may be a causative

factor of increased daytime sleepiness in obese factor of increased daytime sleepiness in obese childhood craniopharyngioma patients (PSG)childhood craniopharyngioma patients (PSG)

Muller HL, J Pediatr Endocrinol Metab. 2006 Apr;19 Suppl Muller HL, J Pediatr Endocrinol Metab. 2006 Apr;19 Suppl

1:423-91:423-9 Correlation with serum/CSF orexin-A levels not Correlation with serum/CSF orexin-A levels not

consistentconsistent? Loss of hypothalamic hypocretin-secreting ? Loss of hypothalamic hypocretin-secreting

neuronsneurons

Impaired melatonin secretionImpaired melatonin secretion Muller HL et al, J Clin Endocrinol Metab. 2002 Muller HL et al, J Clin Endocrinol Metab. 2002

Aug;87(8):3993-6. Aug;87(8):3993-6.

How common is hypothalamic How common is hypothalamic obesity in adults?obesity in adults?

After a median of 5 years of follow-up, After a median of 5 years of follow-up, 52% of patients with hypothalamic 52% of patients with hypothalamic damage were obese compared with only damage were obese compared with only 24 % at the time of diagnosis of their 24 % at the time of diagnosis of their tumour.tumour.

Distribution of BMI at diagnosis and Distribution of BMI at diagnosis and latest follow uplatest follow up

0

5

10

15

20

25

30

35

40

45

50

BMI<25 25<BMI<30 30<BMI<35 35<BMI<40 BMI>40

% of patients atdiagnosis% of patients atlatest follow up

Comparison with the general Comparison with the general population:population:

0

10

20

30

40

50

60

70

80

90

BMI>25 BMI>30 BMI>40

% of general population

% of study patients

NeuroimagingNeuroimaging size of tumoursize of tumour

encroachment of pituitary tumours on optic encroachment of pituitary tumours on optic chiasmchiasm

invasion or compression of hypothalamic tissueinvasion or compression of hypothalamic tissue

abnormalities of 3abnormalities of 3rdrd ventricle ventricle

breach of the infundibulum by the tumourbreach of the infundibulum by the tumour

infiltration of the thalamus or temporal lobesinfiltration of the thalamus or temporal lobes

TREATMENTTREATMENT P-valueP-value

DesmopressinDesmopressin 0.0160.016

Growth hormoneGrowth hormone 0.0170.017

HydrocortisoneHydrocortisone NSNS

ThyroxineThyroxine NSNS

Sex steroidsSex steroids NSNS

Transphenoidal surgeryTransphenoidal surgery NSNS

Transfrontal surgeryTransfrontal surgery NSNS

RadiotherapyRadiotherapy NSNS

VP shuntVP shunt NSNS

Conservative managementConservative management NSNS

Dopamine agonistsDopamine agonists NSNS

Findings from neuroimaging did not Findings from neuroimaging did not predict weight gain.predict weight gain.

Requirement for Requirement for desmopressin desmopressin (ADH)(ADH) and and growth hormonegrowth hormone were were the strongest predictors of current the strongest predictors of current obesity and weight gain.obesity and weight gain.

Mechanisms giving rise to Mechanisms giving rise to hypothalamic obesityhypothalamic obesity

Increased energy intakeIncreased energy intake HyperphagiaHyperphagia Autonomic dysfunctionAutonomic dysfunction vagally-mediated hyperinsulinaemiavagally-mediated hyperinsulinaemia low resting metabolic ratelow resting metabolic rate Reduced voluntary energy expenditureReduced voluntary energy expenditure Impaired gut-brain satiety signalling?Impaired gut-brain satiety signalling? 11-b-HSDH ?11-b-HSDH ? Hormone deficienciesHormone deficiencies GH, TSH, LH/FSHGH, TSH, LH/FSH Pinkney JHPinkney JH et al. et al. Obes RevObes Rev 2002; 3(1): 2002; 3(1):

Ghrelin, P-YY, insulin and leptin Ghrelin, P-YY, insulin and leptin probably do not play a central role in probably do not play a central role in the control of appetite and the the control of appetite and the pathogenesis of obesity in adults pathogenesis of obesity in adults with hypothalamic damage.with hypothalamic damage.

No differences in HRV, REENo differences in HRV, REE Impaired satiety may be an Impaired satiety may be an

aetiological factor of obesity in this aetiological factor of obesity in this group.group.

Sibutramine & Hypothalamic Sibutramine & Hypothalamic ObesityObesity

Double-blind, placebo-controlled, cross-over Double-blind, placebo-controlled, cross-over study (20 wks each) followed by 6 month study (20 wks each) followed by 6 month open phaseopen phase

N = 50 (7-20 yrs old), 42 completed studyN = 50 (7-20 yrs old), 42 completed study HO (n=22) and cases of uncomplicated HO (n=22) and cases of uncomplicated

obesity plus aggravating syndromes (n=28)obesity plus aggravating syndromes (n=28) -0.70 BMI SDS (mean reduction) (P<0.001)-0.70 BMI SDS (mean reduction) (P<0.001) Weight loss less pronounced in those with Weight loss less pronounced in those with

HO (partial resistance)HO (partial resistance) Well tolerated and safeWell tolerated and safe

Danielsson P et al, J Clin Endocrinol Metab. 2007 Danielsson P et al, J Clin Endocrinol Metab. 2007 Nov;92(11):4101-6 Nov;92(11):4101-6

OctreotideOctreotide randomized, double-blind, placebo-controlled randomized, double-blind, placebo-controlled

trial of octreotide therapy for pediatric trial of octreotide therapy for pediatric hypothalamic obesity hypothalamic obesity

N=18, 6 monthsN=18, 6 months Delta weight (mean +/- SEM) was +1.6 +/- 0.6 Delta weight (mean +/- SEM) was +1.6 +/- 0.6

vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). vs. +9.1 +/- 1.7 kg for placebo (P < 0.001). Octreotide suppressed insulin, and stabilized Octreotide suppressed insulin, and stabilized

weight and BMI. weight and BMI. safe and well tolerated safe and well tolerated

Lustig RH et al, J Clin Endocrinol Metab. 2003 Lustig RH et al, J Clin Endocrinol Metab. 2003 Jun;88(6):2586-92 Jun;88(6):2586-92

Dextroamphetamine & Dextroamphetamine & HO (1)HO (1)

Retrospective reviewRetrospective review N=12, treated for 13-15 months, low-doseN=12, treated for 13-15 months, low-dose 10/12 experienced either stabilization of 10/12 experienced either stabilization of

weight or weight loss on treatment weight or weight loss on treatment median loss -0.7 SDS in males, -0.44 SDS in median loss -0.7 SDS in males, -0.44 SDS in

femalesfemales improvement in daytime wakefulness and/or improvement in daytime wakefulness and/or

concentration and exercise tolerance concentration and exercise tolerance

Ismail D et al, J Pediatr Endocrinol Metab. 2006 Ismail D et al, J Pediatr Endocrinol Metab. 2006

Feb;19(2):129-34Feb;19(2):129-34

Dextroamphetamine & Dextroamphetamine & HO (2)HO (2)

CNS stimulantCNS stimulant n=5 for 2 yearsn=5 for 2 years BMI=21 pre-op, BMI=32 at enrolmentBMI=21 pre-op, BMI=32 at enrolment Weight gain stabilisedWeight gain stabilised Improvements in overall activity and Improvements in overall activity and

attentionattention Can earlier intervention prevent initial Can earlier intervention prevent initial

obesity?obesity?

Mason PW et al, Mason PW et al, Arch Pediatr Adolesc Med. 2002 Arch Pediatr Adolesc Med. 2002 Sep;156(9):887-92 Sep;156(9):887-92

Melatonin and Melatonin and hypersomnolencehypersomnolence

Experimental melatonin substitution in Experimental melatonin substitution in 10 adult obese patients (5f/5m) with 10 adult obese patients (5f/5m) with childhood craniopharyngioma. childhood craniopharyngioma.

In all 10 patients with childhood In all 10 patients with childhood craniopharyngioma the degree of craniopharyngioma the degree of daytime sleepiness significantly improved daytime sleepiness significantly improved based on activity diaries, ESS, self based on activity diaries, ESS, self assessment questionnaires and assessment questionnaires and accelerometry. ? Effects on weightaccelerometry. ? Effects on weight

Muller HL et al, Cancer Causes Control. 2006 Muller HL et al, Cancer Causes Control. 2006 May;17(4):583-9 May;17(4):583-9

Bariatric SurgeryBariatric Surgery Male aged 13 Dx with cranioMale aged 13 Dx with cranio subtotal surgical resection and XRTsubtotal surgical resection and XRT Severe hyperphagia, gaining weight at 70 kg per Severe hyperphagia, gaining weight at 70 kg per

yearyear Failed interventions with dietary measures and Failed interventions with dietary measures and

physical activity. Multiple co-morbiditiesphysical activity. Multiple co-morbidities Weight stabilised on octreotide but no weight lossWeight stabilised on octreotide but no weight loss Laparoscopic Roux-en-Y-gastric bypass agedLaparoscopic Roux-en-Y-gastric bypass aged Marked reductions in food cravings, reduction in Marked reductions in food cravings, reduction in

hyperinsulinaemiahyperinsulinaemia 49 kg weight loss over ensuing 2.5 years49 kg weight loss over ensuing 2.5 years

Inge TH et al, Nat Clin Pract Endo Metab 2007; Inge TH et al, Nat Clin Pract Endo Metab 2007; 3(8):606-6093(8):606-609

The optimal treatment of The optimal treatment of hypothalamic obesity remains hypothalamic obesity remains elusive, but increased awareness elusive, but increased awareness of the existence of the problem of the existence of the problem could help prevent obesity.could help prevent obesity.

Management of these patients Management of these patients requires a multidisciplinary requires a multidisciplinary approachapproach