Description of the Condition

When the hypothalamus is damaged, a syndrome of intractable weight gain can ensue, termed hypothalamic obesity.  Hypothalamic obesity can occur due to the presence of a tumor in or near the hypothalamus, associated with surgery to resect it or due to subsequent radiation therapy.  The most common tumor type associated with the hypothalamus is craniopharyngioma, which accounts for half of all cases of hypothalamic obesity while other posterior fossa tumors contribute smaller numbers.  These tumor types include pilocystic astrocytoma, medulloblastoma, and pineal germinoma.  Rarely, the syndrome has also been reported in cases of trauma or inflammatory diseases of the hypothalamus.

Excessive weight gain can be observed within one month of surgery (i.e. damage to the hypothalamus) and is clearly present at 3 months in all patients who develop hypothalamic obesity.  The caloric intake of hypothalamic obese patients is no different than that of patients with simple obesity.  While these patients have normal muscle mass, they have excessive accumulation of fat mass.  Despite the normal muscle mass, there are dramatic reductions in both resting and voluntary energy expenditure.  The weight gain with hypothalamic obesity is unlike that of simple obesity in that it occurs even with caloric restriction, due to the reductions in resting and voluntary energy expenditure. The most prominent complaint in patients with hypothalamic obesity is the persistent fatigue.

In addition to the progression of obesity, many hypothalamic obesity patients also present with multiple hormone deficiencies and dysregulation of insulin secretion.  For example the vast majority of craniopharyngioma patients are growth hormone (GH) deficient, gonadotrophin deficient, adrenocorticotropic hormone deficient, and hypothyroid.  These deficiencies or abnormalities may further contribute to the risk of development of hypothalamic obesity.  Patients treated for other cranial tumor types which are risk factors for hypothalamic obesity have GH deficiency and hypothyroidism as common characteristics with craniopharyngioma patients.  Insulin levels in these patients increase significantly by 1 month post-surgery and continue to increase thereafter.  The increased insulin levels contribute to weight gain and to reductions in voluntary energy expenditure.

The rate of diabetes insipidus in these patients is very high and rates of dyslipidemia are high.

Hypothalamic obese patients may present with memory defects, disturbed attention and impaired processing speed.

Due to the dramatic reductions in resting and voluntary energy expenditure, attempts at lifestyle modification are useless to prevent or treat the obesity.

Morbidity and Mortality

As obesity persists in these patients, cardiovascular risk and mortality increase.  Hypothalamic obesity patients tend to have higher plasma LDL cholesterol, triglycerides, fibrinogen and high sensitive CRP.   Due both to increased cardiovascular risk and the presence of multiple hormone and endocrine deficiencies and dysregulation, the standardized mortality ratio (SMR) for these patients is very high (8.8), somewhat lower for males than females  These patients have a 3–19 fold higher cardiovascular mortality in comparison to the general population.

Unmet Medical Need

There is no drug which is approved to treat or prevent hypothalamic obesity.  Because the obesity is driven by reductions in resting and voluntary energy expenditure, traditional approaches to the treatment of simple obesity, increased exercise and reduced caloric intake, have been ineffective.

Prevalence

Half of all cases of hypothalamic obesity occur in patients treated for craniopharyngioma.  About half of patients treated for craniopharyngioma may develop hypothalamic obesity.  The prevalence of craniopharyngioma is 1 per 50,000.  The estimated US population of patients with hypothalamic obesity is between 2,000 and 7,800.

Links

Additional information on hypothalamic obesity can be found at:

Some good review articles on the condition

Pituitary Network Association – Hypothalamic obesity page