Hypothalamic Obesity Complicated by Adipsic Central Diabetes Insipidus Following Surgical Resection of a Craniopharyngioma

The hypothalamus plays a key role in appetite regulation, utilizing both hormonal and neural signaling pathways. Hypothalamic injury is increasingly recognized as a cause of obesity secondary to loss of satiety signals. The hypothalamus also plays a central role in the maintenance of osmotic balance through regulation of both antidiuretic hormone (ADH) and the thirst center. In the following case presentation, we report a patient who developed hyperphagia and aggressive food seeking behavior in addition to severe hyperosmolality following resection of a craniopharyngioma.

Case Report

An 18‐year‐old male was transferred to a tertiary care center from a rural hospital for evaluation and treatment of severe hypernatremia (serum sodium, 180 mmol/L). He was initially admitted to the rural hospital from a nursing facility for evaluation of mental status changes. At the rural hospital, he was obtunded, in respiratory distress, and unable to follow commands. He was intubated for both airway protection and ventilatory assistance.

The patient resided in a skilled nursing facility. He had previously lived in foster care but over the past several months demonstrated increasingly violent behaviors and anger control issues, specifically related to food. He had an insatiable appetite and was severely obese. His foster mother attempted to limit his food intake, but he would steal food. She sought advice from the local clinic. As part of the treatment plan she was advised to lock the refrigerator and food cabinets. However, he then became verbally and physically threatening. When his foster mother could no longer control his outbursts, he was transferred to a state facility.

His medical history was significant for (1) craniopharyngioma resection at age 13; (2) panhypopituitarism, secondary to craniopharyngioma; (3) diabetes insipidus secondary to craniopharyngioma; (4) type 2 diabetes mellitus; and (5) mild mental retardation with associated learning disabilities. His medications were desmopressin acetate 1 μg subcutaneously twice a day, prednisone 7.5 mg by mouth every day, levothyroxine 100 μg by mouth every day, testosterone 50 mg intramuscularly every 4 weeks, glipizide extended release 20 mg by mouth every day, pioglitazone 30 mg by mouth every day, and fluvoxamine maleate 100 mg by mouth twice a day. His family history was not known.

On physical examination, he was an obese male who was sedated and intubated. His vital signs were significant for temperature 37.7°C, blood pressure 114/64 mm Hg, heart rate 122 beats per minute, weight 118 kg, height 170 cm, and body mass index 40.8 kg/m². Other pertinent findings included dry mucosal membranes and tanner stage II development. Neurologic examination was limited but neither hypotonia nor hyporeflexia were present. Additionally, he had no dysmorphic facial features. Significant laboratory analysis is shown in the Table.

Table.

 Admission Laboratory Results

Test	Patient Value	Normal Range
WBC ×10E3	18.8	4.0–10.6
Hematocrit, %	41	42–53
Platelets, ×10E3	388	150–400
Sodium, mmol/L	183	136–146
Potassium, mmol/L	3.6	3.5–5.0
Chloride, mmol/L	>140	96–110
BUN, mg/dL	29	3–25
Creatinine, mg/dL	1.2	0.5–1.5
Glucose, mg/dL	323	60–126

Abbreviations: WBC, white blood cell count; BUN, serum urea nitrogen. ^aAbnormal laboratory results are shown in italic.

Hospital Course

The patient’s electrolytes were corrected over 4 days and his mental status improved. An extensive chart review was performed. Prior to his craniopharyngioma resection, he was a healthy boy with mild mental retardation. He had a normal childhood and was in the early stages of puberty. Specifically, he had no known behavioral problems and was of normal weight and height. He began experiencing headaches at the age of 12. Magnetic resonance imaging was performed as part of the headache workup and a suprasellar mass was discovered. He underwent resection of the mass and histology confirmed a craniopharyngioma. His preoperative and yearly postoperative body mass index are displayed in the Figure. His body mass index rose from 25 kg/m² to 41 kg/m². His weight doubled, with a cumulative increase of 70 kg.

Figure.

 Preoperative (preop) and yearly post‐operative (postop) body mass index in an 18‐year‐old male.

Additionally, he had been hospitalized several times for severe hypernatremia and hyperglycemia, thought to be due to poor adherence to medications. On questioning, he reported never feeling thirsty. After reviewing the data and time course, we felt that this patient was experiencing hypothalamic obesity with associated diabetes insipidus and adipsia as a result of damage to his hypothalamus either from the primary tumor and/or its resection. We will discuss the role of the hypothalamus in regulating plasma osmolality and water homeostasis appetite, and discuss derangements in osmolality and appetite regulation following damage to the hypothalamus.

Discussion

Craniopharyngiomas are the most common intracranial extraneuronal tumors in children. The peak incidence for these tumors is during the 1st and 2nd decades. They arise from the remnants of Rathke’s pouch in the hypothalamic‐pituitary region. Due to the location of the tumor, patients present with visual field defects, endocrinopathies, and headaches. Neuroimaging is usually diagnostic. Surgical resection is the primary treatment for craniopharyngiomas followed by external beam radiation if resection is incomplete. The proximity of these tumors to vital organs including the hypothalamus, pituitary, optic centers, and cranial vessels makes resection difficult. ¹ Postoperative endocrinopathies are not uncommon and include growth hormone deficiency followed in frequency by gonadotrophin and thyroid deficiencies ² , ³ , ⁴ , ⁵ and diabetes insipidus.

Additionally, both the thirst center and the appetite/satiety center are located in the supra optic and paraventricular nuclei of the hypothalamus and can be damaged by the tumor itself or during resection. Obesity is not uncommon following surgical resection of craniopharyngiomas. ⁶ , ⁷ In fact, it is the most common structural cause of hypothalamic obesity. Obesity from hypothalamic injury is thought to result from disruption of the arcuate, paraventricular, ventromedial, and dorsomedial nuclei of the hypothalamus, which control satiety and hunger. ⁸ These areas of the hypothalamus are responsible for integrating metabolic information regarding nutrient stores with afferent sensory information about food availability. When these areas are damaged, hyperphagia and obesity can result. These nuclei are vulnerable to midline lesions of the hypothalamus and pituitary tumors with suprasellar extension. One study of 42 adults with tumors in the hypothalamic region that were treated with surgery and/or radiotherapy demonstrated that 52% of patients were obese after a median of 5 years of follow‐up (compared with 24% at baseline). ⁸ Due to his rapid and persistent weight gain following resection of the craniopharyngioma, we believe that our patient sustained hypothalamic injury to his appetite center.

Hypothalamic damage can also alter water and osmolality balance if either the thirst center or the hypothalamic nuclei responsible for ADH production and regulation are damaged. Normally, plasma osmolality is tightly regulated at the level of the hypothalamus by both hormonal and nonhormonal mechanisms. ADH is synthesized in the hypothalamus and stored in the posterior pituitary. It is released from the posterior pituitary once osmoreceptors in the anterior hypothalamus are activated in response hypersomolality (osmolality 280–285 mosm/dL). ADH acts on water channels, aquapores, in the renal collecting ducts to increase water permeability and increase water reabsorption.

Two further levels of osmolality regulation are present in humans. ADH is released in response to baroreceptor activation if intravascular volume falls significantly. This provides a backup mechanism to maintain osmolality.

Additionally, the osmoreceptors activate the thirst center in the lateral hypothalamus at plasma osmolalities of 285 to 290 mosm/dL. Activation of the thirst receptors leads to a powerful craving of water. Thus, even patients lacking ADH will not develop hypernatremia as long as their thirst centers are intact and they have access to water. However, damage to the osmoreceptors and/or the thirst center will lead to lack of thirst or adipsia. Our patient had both central diabetes insipidus as a result of hypothalamic damage to the ADH neurons and damage to the thirst center as demonstrated by his severe hypernatremia despite access to water.

Conclusions

We described a patient with hypothalamic obesity, central diabetes insipidus, and adipsia following resection of a craniopharyngioma. To our knowledge, this is the first reported case of damage to both the thirst and appetite centers of the hypothalamus occurring in the same patient causing severe obesity and life‐threatening hypernatremia.