Case Description
A 27 year old male, presented at age 8 with failure to thrive. His Magnetic Resonance Imaging (MRI) revealed a multi-locular cystic mass, consistent with a craniopharyngioma which was resected with subsequent radiotherapy. His most recent MRI reveals no tumour recurrence. Other medical issues include narcolepsy and childhood epilepsy. He lives in supported accommodation with a disability pension but is independent with his activities of daily living and involved in volunteer work.
He developed pan hypopituitarism and diabetes insipidus with initial treatment consisting of hydrocortisone acetate 8mg orally in the morning and 4mg in the afternoon, thyroxine 150 mcg daily, testosterone undecanoate 1-gram IM three monthly and desmopressin 400mcg twice daily. Since the Pharmaceutical Benefits Scheme subsidised the growth hormone, he has commenced somatropin 0.2mg daily and is being titrated to a target Insulin like growth factor 1 (IGF1) level in mid-normal range. His Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA) score was 18/25 prior to commencing Growth Hormone and 9/25, one-year post Growth Hormone replacement, where a lower score indicates a better quality of life.
He developed hypothalamic hyperphagia resulting in morbid obesity (peak BMI 39.4 g/m2) and subsequent metabolic syndrome including Type 2 Diabetes and non-alcoholic fatty liver disease. He was treated with metformin extended release 1000mg daily, gliclazide modified release 120mg, insulin glargine U100 (70 units mane and 10 units nocte) and insulin aspart (28 units three times a day) prior to the initiation of a Glucagon Like Peptide 1 Receptor Agonist (GLP1RA) ; dulaglutide 1.5mg weekly
He subsequently lost 15kg over a 12-month period in addition to normalisation of his ALT and AST. A Sodium Glucose Transport Type 2 Inhibitor (SGLT2) was also initiated and he eventually was able to discontinue all insulin. He is now on metformin XR 2g, dulaglutide 1.5mg weekly and empagliflozin 12.5mg daily with a HbA1c of 7.0%.
He reported a low mood and an inability to ‘feel emotions’. After assessment from psychology, depression was excluded and the association with hypothalamic damage and oxytocin deficiency was considered.
Discussion
100% of children have at least one pituitary axis affected, 80% developed metabolic syndrome and 6% suffered from depression post craniopharyngioma resection (1). This case report raises management of these complications, with a focus on growth hormone replacement, GLP1RA in hypothalamic obesity and oxytocin to improve mood.
Growth hormone (GH) deficiency is the most common endocrine disturbance that occurs secondary to craniopharyngioma (2). Replacement in GH-deficient children has been proven to have a positive impact on body composition and cardiovascular risk factors, including serum lipid profiles, insulin sensitivity and quality of life (3). A meta-analysis of 3487 children demonstrated that children treated with GH replacement had a lower recurrence rate of craniopharyngioma compared to those who were not (4). In assessing long term survival, psychological status and quality of survival with GH replacement, it was proven that early initiation of GH had better scores for emotional functioning and a lower physical fatigue than late substitution or patients who did not receive any GH substitution (5). Hence there is evidence to suggest early initiation of GH substitution after craniopharyngioma resection in young patients might have beneficial effects on quality of life and growth while reducing the rate of tumour recurrence.
The link between hypothalamic injury and obesity was first described by Dr. Fröhlich in 1993 (2) . Since then hypothalamic obesity has been associated with trauma, aneurysms, infiltrative diseases, tumours such as craniopharyngioma, genetic syndromes such as Prader-Willi syndrome, leptin deficiency, and melanocortin four receptor (MC4R) mutations. Risk factors for the development of hypothalamic obesity includes tumour location, radiation dose, extent of surgery, GH deficiency and tumour histology (6). Hypothalamic obesity complicates up to 52% of paediatric craniopharyngioma patients, however there are currently limited therapeutic options. These patients have an increased prevalence of Type 2 Diabetes Mellitus, Hypertension, Sleep Apnoea, Non Alcoholic Fatty Liver Disease and cardiovascular risk. Conventional treatments include a calorie-restricted diet, exercise therapy, pharmacologic treatment or bariatric surgery. Pharmacotherapy focuses on alterations in pathways, such as sympathomimetics, triiodothyronine, GLP1RA and somatostatin analogues. GLP-1 is secreted from L cells in the intestine and increases insulin secretion while inhibiting gastric emptying and subsequently food intake. It also acts on the GLP-1 receptor in the brain to suppress hunger. For this reason, GLP1RA are currently used as pharmacological therapies for Type 2 Diabetes Mellitus and obesity. A study by Zoicas et al observed nine patients with moderate to severe hypothalamic obesity treated with GLP1RA for up to 51 months. Eight of the nine patients experienced 13.1±5 kg weight loss (7). Weight loss was associated with improved insulin sensitivity, glycaemic control and lower triglycerides however cholesterol levels were not improved. GLP1RA work on receptors in the hindbrain, which are believed to be intact in patients with hypothalamic hyperphagia. A newer GLP1RA, Semaglutide, offers additional weight loss and glycaemic benefits over Dulaglutide, likely due to the smaller molecular size with a free, non-protein bound form able to cross the blood brain barrier and act on central nervous system receptors(8).
Oxytocin plays a role in the development of attachment, trust, behaviour and body composition (9). Following craniopharyngioma resection, patients report social-behavioural impairment, which may be a result of oxytocin deficiency (10). Gebert et al compared salivary oxytocin at baseline and following exercise in patients with and without craniopharyngioma and proved reduced oxytocin in craniopharyngioma patients with MRI proven hypothalamic damage (11). Oxytocin influences an individual’s response to emotional situations, improving trust and social connnectivity in children with autism spectrum disorder, conduct disorders, attachment disorders, anxiety, and depression (10). Another case report described a 13-year-old boy with hypothalamic obesity post craniopharyngioma resection, who received 10 weeks of oxytocin. Following this he was found to lose 4.4kg, improved satiety, decreased preoccupation with food, implying a benefit of oxytocin replacement in this cohort of patients (12). However, peripherally administered oxytocin only has a 2-8 minute half-life and displays poor permeability across the blood‐brain barrier, making it challenging to use as a therapeutic drug (13). Furthermore, it cannot be administered orally due to metabolism in the gut by chymotrypsin (14). Intranasal oxytocin is believed to be absorbed through the nasal mucosa and delivered to the central nervous system where it can exert its effect. While there is evidence that Oxytocin supplementation can be beneficial in improving mood in patients with craniopharyngioma, current limitations include difficulties in measuring oxytocin levels to confirm oxytocin deficiency, determining the optimal mode of administration for oxytocin therapy and the safety profile for long‐term use (13).
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