Traumatic Brain Injury: Research Study on Endocrinological Aspects

Project location: Italy, Pisa
Project start date: January 2011 - Project end date: December 2012
Project number: 2010-81
Beneficiary: Department of Endocrinology and Metabolism University of Pisa

Every year a large number of people experience traumatic brain injury (TBI), principally from vehicular incidents, falls, acts of violence and sports injuries, often with severe consequences. The highest incidence is among persons 15 to 24 years of age and 75 years and older, with an additional less striking peak in incidence in children ages 5 and younger. Since TBI may result in lifelong impairment of an individual's physical, cognitive, and psychosocial functioning and prevalence is estimated to be 2.5 million to 6.5 million individuals, it represents a disorder of major public health significance. Furthermore, mild TBI is significantly under diagnosed, and the likely societal burden therefore is even greater. Recently it has been reported that TBI is also associated with high risk for hypopituitarism. The reported prevalence of post-trauma hypopituitarism varies between the various studies from 20% to 80%; these differences are probably due to the different timing of functional pituitary evaluation. Post-head trauma hypopituitarism is more frequent in young age and in male (F/M 5:1) and can become clinically evident in every moment after the trauma, also many years later.
A recent study of Aimaretti et al., conducted on 70 patients with a history of mild (Glasgow Coma Scale: 15-13), moderate (GCS: 9.12) or severe (GCS <8) head injury, showed 3 months after the trauma a prevalence of partial or total hypopituitarism of 32.8%. The retesting performed at 12 months, showed a reduction in prevalence to 22.7%; if present, panhypopituitarism was confirmed also 12 months after trauma. The pituitary deficit more commonly observed involved GH axis: 22.8% at 3 months and 20% at 12 months. In this study it was suggested to check regularly patients with a history of head trauma, because some deficit can appear at a distance (> 12 months) from the traumatic event.

The primary objective of this study is to investigate the prevalence of hypopituitarism in patients with prior TBI focusing, in particular, on the frequency of single pituitary deficits (GH, TSH, ACTH, LH / FSH, ADH), singularly or in association with each other.

To this purpose, it will be investigated in these patients the incidence of:
• TSH deficiency (central hypothyroidism)
• GH deficiency
• Gonadotropin deficiency (LH / FSH) (central hypogonadism)
• ACTH deficiency (central hypoadrenalism)
• ADH deficiency (central diabetes insipidus)

The secondary objective of this study is to evaluate the potential benefits of hormonal replacement therapy (rhGH, cortone acetate / hydrocortisone, testosterone / estrogen, L-thyroxine, desmopressin acetate) on well-defined biochemical and instrumental parameters and on cognitive-behavioral functions in the subgroup of patients suffering from hypopituitarism after TBI in comparison to a the control group with normal pituitary function.
This study will enroll approximately 25 patients with prior TBI (study group) and 25 healthy subjects with normal pituitary function (control group) with characteristics of sex, age, ethnic background comparable to those of the study group's subjects. The study will comprise of 4 phases:

a. Screening phase: in the screening phase, all subjects will be submitted to medical history and a careful physical examination in order to verify the eligibility within the study and the control groups. Before inclusion in the study, all study participants must provide their written informed consent. Urine will be collected for pregnancy testing from females of childbearing potential only

b. Recruitment phase: During this phase all patients who met the inclusion criteria will be submitted to:

1. Baseline blood tests: blood count, blood glucose, electrolytes, creatinine, uric acid, GOT, GPT, gamma-GT, LDH, CPK, urine test standard; total cholesterol, HDL, LDL, triglycerides, blood glucose, glycosilated hemoglobin
2. Assessment of 24 hours fluid intake and output, plasma osmolality, urinary osmolality
3. Basal hormonal evaluation: a. FT4, FT3, TSH, LH, FSH, estradiol / testosterone, ACTH, cortisol, PRL, GH, IGF-I
4. dynamic testing
a. GHRH + arginine test: i.v. injection of 1 mcg / kg GHRH at time 0' followed by the infusion in 30' minutes 0.5 g / kg arginine hydrochloride with blood samples for GH every 15 minutes to 90 minutes.
b. TRH test: i.v. injection of 200 micrograms of TRH with blood samples for TSH at 0'-15'-30'-45'-60'-90'-120 'minutes
c. GnRH test: i.v. injection of 100 micrograms of GnRH with blood samples for LH / FSH at 0'-15'-30'-45'-60'-90 minutes
d. ACTH test: i.m. injection of 250 micrograms of tetracosactide-esacetate with samples for cortisol at 0'-30'-60 minutes.
5. Hydric deprivation test (in patients with suspect central diabetes insipidus)
6. Femoral and vertebral computerized bone mineralometry and body fat assessment report / lean
7. Assessment of quality of life by the administration of well-defined questionnaires (QoL)

c. Treatment phase: During this phase, the hypopituitaric patients in the study group will be treated with an adequate replacement therapy (L-thyroxine, cortone acetate /hydrocortisone, testosterone / estrogen, rhGH) for 1 year.

d. Phase of follow-up: Patients will be re-evaluated after 6 and 12 months (Table), checking the stability or possible changes in biochemical / instrumental / cognitive parameters evaluated in the research project

Patients with a history of TBI frequently present with chronic disabilities due to physical, psychological, and cognitive sequelae. Many patients suffer from deficits in their mental health, with depression and anxiety being particularly common. These symptoms are very similar to those in hypopituitary patients and are therefore often not attributed to pituitary dysfunctions, explaining the large amount of hypopituitarism related to brain damage which currently remains undiagnosed. Neuroendocrine dysfunction, in particular GH deficiency, may compound the physical and psychological complications of TBI and may thus interfere with the rehabilitation process. Therefore, adequate hormone replacement is suggested to play an important role for successful rehabilitation and long-term outcome. Since impairments of cognitive and psychosocial functioning after TBI are major contributors to the chronic disability of these patients, improvements in cognitive and physical function by hormonal replacement therapy would be of major clinical significance in this group of patients.

Research timetable: 

Time (months)

0

  6

12

Written informed consent

x

 

 

Clinical history / inclusion+exclusion criteria

x

 

 

Physical examination (weight, height, BMI, waist to hip ratio, blood pressure, heart rate)

x

x

x

Electrolytes, plasmatic  and urinary osmolality

x

 

 

Lipidic and glucidic profile

x

x

x

Basal Hormonal evaluation

x

x

x

Dinamic testing

x

 

x

QoL questionnaire

x

x

x

Bone mineralometry

x

 

x


The anticipated results of this project which received a grant from the Nando Peretti Foundation are described below.
Systematic clinical studies in together more than 700 TBI patients reported some degree of hypopituitarism in the chronic phase after trauma in 35% of the investigated patients. The estimated overall incidence of TBI in Europe is 235 cases per 100.000 per year. 90% of these injuries are of mild severity, the other 10% are moderate or severe. When using a very conservative approach and including only those 10% of patients with moderate or severe TBI, these frequencies of TBI would result in an estimated incidence of 8.2 new cases of hypopituitarism per 100.000 per year, indicating that brain injury is a major cause of hypopituitarism.
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