MILITARY MEDICINE, 175, 8:574, 2010 Traumatic Brain Injury-Related Hypopituitarism: A Review and Recommendations for Screening Combat Veterans CPT(P) Arthur F. Guerrero, MC USA ; MAJ Abel Alfonso, MC USA ABSTRACT Recent civilian data obtained in those sustaining head injuries, has found a high prevalence of pituitary dysfunction. Currently, there is no data available in the military population. We reviewed the literature for traumatic brain injury (TBI)-related hypopituitarism and found that the prevalence of anterior hypopituitarism may be as high as 30 80% after 24 36 months. Since many of the symptoms of hypopituitarism are similar to those of TBI, it is important to make clinicians caring for combat veterans aware of its occurrence. Herein, we provide an overview of the literature and recommendations for hormonal testing when TBI-related hypopituitarism is suspected. INTRODUCTION Traumatic brain injury (TBI) has been commonly diagnosed during Operation Iraqi Freedom and Operation Enduring Freedom, with recent data demonstrating that it occurs in as high as 23% of combat soldiers. 1 Some survivors demonstrate persistent cognitive, physical, and emotional defects that prevent functioning at preinjury levels. These defects are often attributed to the traumatic brain injury itself. The first review of over 300 civilian patients with pituitary dysfunction following TBI was published in 2000, noting that endocrine dysfunction may be present more than 10 years following a TBI. 2 More recent civilian data has been obtained in those injured in traffic accidents, falls, assault, and other head injuries, which has confirmed that such an injury results in damage to the pituitary gland and subsequent deficiency of pituitary hormones.2 11 This damage can result in hormone abnormalities that can start immediately, and even up to 3 years after TBI, which has been demonstrated in prospective studies. 5,8 15 Such studies indicate that a prevalence of any anterior hormone pituitary deficiency is as high as 30 80% after 24 36 months, 8,11 with diabetes insipidus present in up to 3% of patients at 12 months. 7,13 Since many symptoms of hypopituitarism are similar to those that have been ascribed to traumatic brain injury, a diagnosis of hypopituitarism may be overlooked and untreated. Currently there is no data looking at hypopituitarism secondary to TBI in the military combat population. This is important to consider, as the mechanism of TBI differs in the combat population, and therefore the incidence of hypopituitarism, both acute and chronic, can only be speculated on based upon civilian studies. The purpose of this review is to enhance the recognition of hypopituitarism by physicians taking care of combat veterans. Endocrinology, Diabetes, and Metabolism Service, Department of Internal Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave. NW, Washington, DC 20307. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of Defense, nor the U.S. government. METHODS The literature was reviewed for traumatic brain injury-related hypopituitarism using a broad Internet search (PubMed and Google Scholar). Specific key words and phrases were used such as traumatic brain injury, endocrinopathy, hypopituitarism, critical illness, neuroendocrine dysfunction, head trauma, combat, and blast injury. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. From these results, 11 prospective studies were identified, as well as 7 cohort studies. Based upon the occurrence of pituitary dysfunction found in these studies, screening guidelines are proposed until further data in the military combat population is obtained. OVERVIEW OF THE LITERATURE Details of the specific studies to include study author, date of publication, number of patients in each study, and percentage of pituitary hormone deficiencies described by the authors are provided in Table I. TBI Pathophysiology TBI is a leading cause of mortality and morbidity worldwide and is the major cause of disability among young adults in the United States. 16 Pathophysiology is complex and poorly understood, largely due to the broad spectrum of injury severity, injury mechanisms, and brain injury pattern across age ranges. In the most recent combat veteran population, the mechanism of injury that is felt to be the predominant cause of TBI is the blast-induced TBI (btbi). The Centers for Disease Control and Prevention (CDC) defines blast injury in four phases. However, the bulk of injury from btbi occurs in the first three phases. The primary injury phase is composed of the response of brain tissue to the blast wave (an intense overpressurization impulse component of the blast). 17,18 The secondary injury phase results from shrapnel penetration into the head or objects displaced against the head. The tertiary injury phase results from head contact/acceleration forces as the body is moved by the blast wind (a forced superheated airflow). The quaternary injury phase incorporates any injury not covered 574 MILITARY MEDICINE, Vol. 175, August 2010
TABLE I. Incidence in the Literature of Pituitary Dysfunction After Traumatic Brain Injury Study (type) Time Point No. GH Axis (%) Gonadotropic Axis (%) Corticotropic Axis (%) Thyrotropic Axis (%) Prolactin (%) Comb. Dysfunction (%) Any Dysfunction (%) DI (%) Kelly 2000 (P) 26 mo 22 18 23 5 5 0 23 36 0 Liebermann 2001 (C) 13 mo 70 15 (7/48) 2 (1/60) 7 (5/70) 22 (15/69) 1 17 69 0 Agha 2004/2004 (C) 5,6 1 yr 102 18 12 23 1 12 6 28 7 Bondanelli 2004 (C) 12 64 mo 50 14 14 0 10 8 /8 12 54 0 Dimopoulou 2004 (P) 22 d 34 9 24 24 15 59 18 53 Popovic 2004 (C) >1 yr 67 30 9 7 4 5 /7 10 34 5 Agha 2004/2005 (P) 3,4 12 d 50 18 80 16 0.5 52 6 mo 48 13 23 19 0.5 15 1 yr 48 10 13 19 0.5 13 Aimaretti 2005 (P) 1 yr 70 19 11 7 6 6 6 22 3 Giordano 2005 (P) 3 mo 70 39 17 9 6 4 11 33 4 1 yr 70 39 11 7 6 6 10 23 3 Leal-Cerro 2005 (C) >1 yr 170 6 17 6 6 9 25 4 Schneider 2006 (P) 3 mo 78 9 32 19 8 12 10 56 0 1 yr 78 10 21 9 3 13 4 36 0 Tanriverdi 2006 (P) 24 hr 52 20 42 10 6 12 1 yr 52 33 8 19 6 8 20 57 10 51 Bondanelli 2007 (C) 6 12 mo 72 14 14 4 4 3 6 31 1 Klose 2007 (P) 0 12 d 46 67 33 39 28 76 3 mo 42 11 7 7 13 2 1 yr 46 2 2 7 11 Tanriverdi 2008 (P) * 3 yr 30 23 0 7 0 0 30 Kleindienst 2009 (P) 0 7 d 71 36 24 25 24 15 20 70 >2 yr 23 39 0 48 0 5 30 83 P, prospective; C, cohort; DI, diabetes insipidus; *, continuation of previous study;, increased;, decreased. MILITARY MEDICINE, Vol. 175, August 2010 575
in the other three phases such as some of the extracranial injuries or polytrauma including hemorrhagic shock and chemical or thermal burn injuries that can occur. 19 21 The quaternary phase of btbi can significantly alter the timing and consequences of the primary damage occurring in the first three phases, and therefore can be a major contributor to overall brain pathology. This may be particularly true in mild btbi, where there are either minor or no complicating factors.19 The Growing Awareness for TBI-Induced Hypopituitarism Since the 1970s, multiple case reports have been published documenting both anterior and posterior dysfunction. 22 28 This led to the cohort studies and then prospective longitudinal studies, which have reported with varying frequencies either single axis abnormalities or a combination of axes abnormalities as outlined in Table I. Based upon studies completed up to its proposal, civilian guidelines for screening all patients suffering a moderate to severe TBI were proposed by Ghigo et al. in 2005. 29 Despite this, hypoputitarism following TBI is still rarely considered in the treatment of these patients once they leave the acute setting. One reason for this may be that patients with TBI are typically first seen and treated by trauma surgeons and neurosurgeons, and by physiatrists and neurologists if appropriate, with subsequent treatment provided by rehabilitation physicians. In civilian sectors, endocrinologists and internists are generally not among the first physicians called to attend patients with TBI. Applying Civilian Data to the Military Population There are important factors that make military application of civilian data problematic. Firstly, the type of TBI encountered most recently in OIF/OEF (i.e., btbi) is rarely found in the civilian sector. Secondly, the epidemiology of TBI in the military population is unknown. Thirdly, there is a lack of consensus on the criteria for defining TBI as mild, moderate, or severe, among current studies. Finally, there is uncertainty as to which testing should be done to evaluate for a particular pituitary deficiency. Blast TBI obtained in an improvised explosive device (IED)-related injury may differ from TBI obtained in the civilian sector. For example, it has been proposed that the reason the majority of studies find chronic disruption of the GH axis to be more prevalent is due to the fact that somatotroph cells are located in the wings of the pituitary gland and the vascular supply and oxygen they receive come out of the hypothalamic-pituitary portal vessels. 29 Consequently, it is thought that damage in this area impairs the blood and oxygen supply, resulting in cell death. In contrast, cells that secrete adrenocorticotropin hormone (ACTH) and thyroid stimulating hormone (TSH) are located ventrally in the more protected, medial portion of the pituitary, and they receive blood from the portal vessels and the anterior pituitary branch, which provides nutrients and oxygen to this area and to all cells located in the subcapsular portion of the gland. 14 However, this may not be entirely applicable in a btbi, where primary blast injury consists of a pressure wave transmitting throughout the body, as little is known about the response of CNS cells from shockwaves.19 In the military population, primary care physicians, composed largely of internists and family practitioners, are routinely involved in the management of soldiers suffering TBIs soon after discharge from acute care. The importance of recognition of hypopitutarism following TBI in the military has to do with the unique patient population cared for by military primary care providers. Although no rigorous epidemiologic study has been done in the military population yet, this population likely has a higher incidence of TBI, as compared to its civilian counterpart where incidence of TBI has been reported as 100/100,000. 30 Within the military population, there are also variances in subpopulations. For example, in the previously mentioned Terrio study, 907 of 3,973 soldiers in a brigade combat team suffered a clinician-confirmed TBI. Thus, physicians directly responsible for such a brigade at the end of a deployment would find a much higher prevalence in their treatment population as compared to their civilian counterparts. Confounding the issue even further is the lack of consensus on the criteria for defining TBI as mild, moderate, or severe. The Department of Defense (DoD) Health Affairs Workgroup s TBI definition is A traumatically induced structural injury and/or physiological disruption of brain function as a result of an external force that is indicated by new onset or worsening of at least one of the following clinical signs, immediately following the event: (1) any period of loss of or decreased level of consciousness, (2) any loss of memory for events immediately before or after the injury, (3) any alteration in mental state at the time of the injury, (4) neurological deficits, and (5) intracranial abnormalities. This is, for the most part, similar to definitions proposed in civilian studies, such as that proposed by Bondanelli et al. TBI is a non-degenerative, non-congenital insult to the brain from an external mechanical force causing temporary or permanent neurological dysfunction, which may result in impairment of cognitive, physical, and psychosocial functions. 31 However, as seen in Table II, even among civilian studies, there was variance in the classification of severity of TBI, though for the majority, a postresuscitative Glascow Coma Scale (GCS) score of 3 8 corresponded to severe, 9 12 corresponded to moderate, and 13 15 corresponded to mild TBI. The DoD Health Affairs Workgroup also uses the GCS score as a clinical descriptor, however, grades severity of TBI differently, as seen in Table III. Thus a moderate TBI in the DoD system, may not be equivalent to a civilian moderate TBI graded via the GCS. Finally, as seen in Table II, even among the civilian studies, definitions of what quantifies a particular pituitary deficiency varies in accordance to what, if any, dynamic testing was done to evaluate for a particular deficiency. 576 MILITARY MEDICINE, Vol. 175, August 2010
TABLE II. Variance of Classification and Diagnosis in the Literature of Hypopituitarism Study Method to Classify TBI Category of Severity Studied Deficiency Evaluated for: Dynamic Testing Performed Kelly 2000 GCS 13 15 with CT findings = Moderate GCS 3 12 = Severe Liebermann 2001 History of Brain Injury With Mild Moderate Cognitive Dysfunction as a Sequel to Brain Injury Agha 2004/2004 5,6 GCS 9 15 = Moderate Bondanelli 2004 Dimopoulou 2004 Popovic 2004 Agha 2004/2005 3,4 Aimaretti 2005 Giordano 2005 GCS 9 13 = Moderate GCS 9 13 = Moderate GCS 9 15 = Moderate GCS 14 15 = Mild GCS 9 13 = Moderate Not Categorized Mod Severe GH + ACTH: ITT LH + FSH: GnRH TSH + PRL: TRH ACTH: 250 mcg cosyntropin GH: If IGF-1 low GST ± L-dopamine LH+FSH: If T low GnRH TSH: If TSH low TRH ADH: overnight water deprivation test or 8-hr deprivation test GH + ACTH: GST used as screen If low ACTH suggested 250 mcg synacthen or ITT If low GH GHRH + ARG or ITT ACTH: 100 mcg hcrh GH: GHRH LH + FSH: GnRH GH: GHRH + GHRP-6 ADH: overnight water deprivation test or 8-hr deprivation test GH + ACTH: GST used as screen If low ACTH suggested 250 mcg synacthen or ITT If low GH GHRH + ARG or ITT Leal-Cerro 2005 Severe Questionnaire was used to screen for any deficiency; if suggestive of deficiency, dynamic testing was done for that suspect hormone as follows: ACTH: ITT GH: IGF-1 If low GHRH + GHRP-6, ITT, and GST (all testing was performed) LH + FSH: GnRH TSH: TRH Schneider 2006 Tanriverdi 2006 Bondanelli 2007 Klose 2007 Tanriverdi 2008 Kleindienst 2009 ACTH: 250 mcg synacthen Of note, for PRL, macroprolactin was also checked ACTH: 1 mcg tetracosartan GHRH + GHRP-6 (at 1 yr only) ACTH: If cortisol 3.5 mcg/dl 1 mcg ACTH stimulation testing ACTH: 250 mcg synacthten GH: ITT or GHRH + ARG ACTH: If low cortisol 7 mcg/dl 1 mcg synacthten GH: GHRH + GHRP-6; if equivocal GST ACTH: 250 mcg synacthten ITT, insulin tolerance test; GnRH, gonadorelin test; TRH, thyrotropin releasing hormone test; GST, glucagon stimulation test; GHRH, growth hormone releasing hormone test; ARG, arginine stimulation test; hcrh, human corticotrophin releasing hormone test; GHRP-6, GH releasing peptide test. MILITARY MEDICINE, Vol. 175, August 2010 577
TABLE III. Severity Classifications in the Department of Defense Health Affairs Workgroup Mild Moderate Severe Normal structural imaging Normal or abnormal structural imaging Normal or abnormal structural imaging LOC = 0 30 minutes LOC > 30 minutes to 24 hours LOC > 24 hours AOC = a moment up to 24 hours AOC > 24 hours; severity based on other criteria PTA = 0 1 day PTA > 1 7 days PTA > 7 days LOC, loss of consciousness; AOC, alteration of consciousness; PTA, post-traumatic amnesia. Screening for TBI-Induced Hypopituitarism Because of the high occurrence of pituitary dysfunction following TBI, all patients with TBI and clinical signs or symptoms associated with hypopituitarism should be screened for pituitary dysfunction. In general, we are in agreement with civilian recommendations put forth by Ghigo et al. in 2005 in regard to a limited evaluation in those in a permanent vegetative state. In these patients, evaluation for diabetes insipidus, hypoadrenalism, and thyroid deficits are indicated, but these patients should be excluded from further testing. Those patients who function at a very low level and consequently are institutionalized as a result of a TBI should also be excluded from replacement therapy beyond hydrocortisone, vasopressin, and T4, along with any other patients who, in the opinion of the physician, would not benefit from therapy. With these exceptions, all patients with TBI should routinely undergo baseline hormonal evaluation for pituitary deficiencies, particularly if they were hospitalized for at least 1 day following injury. RECOMMENDATIONS FOR HORMONAL TESTING All patients who had a TBI of any severity, should undergo baseline hormonal evaluation at 3 6 months after discharge from acute care. Repeat testing should be done at 12 months if any pituitary deficiency is noted or if the patient begins to exhibit symptoms of pituitary deficiency, as new endocrinopathies have been shown to develop at 1 3 years. 3,8,9,11 On the basis of the current evidence, we recommend screening as follows: 1. All critical care physicians are advised to screen for adrenal insufficiency in those suffering a severe or moderate head injury, as prospective data suggest incidence of acute adrenal insufficiency ranging from 16 to 25% as seen in Table I. Screening recommendations are as follows: a. Check 0800 hrs fasting cortisol 1 7 days postinjury. If <7 mcg/dl, treat with glucocorticoids in the acute phase until the patient is stable enough to undergo cosyntropin stimulation testing (see 2.e.iii). b. If the patient is diagnosed with adrenal insufficiency in the acute phase, reassess pituitary corticotroph function in 3 6 months with a cosyntropin stimulation test (see 2.e.iii). i. If the stimulation test indicates persistent adrenal insufficiency at the 6-month point, obtain an endocrine consult for recommendations regarding definitive treatment and follow-up. ii. If adrenal insufficiency has resolved, no further assessment is necessary. 2. Outpatient screening for endocrinopathy related to TBI should be accomplished by primary care physicians at 3-6 months after acute injury care in those suffering from TBI symptoms such as depression, cognitive impairment, and/or emotional lability; as well as those with symptoms and other findings suggestive of hypogonadism (anemia, loss of muscle mass, decreased energy, sudden change in mood, loss of libido/morning erections, change in menstrual pattern), growth hormone deficiency (hypoglycemia, loss of muscle mass), hypothyroidism (weight gain, cold intolerance, constipation), hyperprolactinemia (change in menstrual pattern, breast discomfort, loss of libido), or adrenal insufficiency (lassitude and weakness, fatigue, anorexia, orthostatic hypotension, nausea, hyponatremia). a. Testing for hypogonadism: i. 0800 hrs fasting free testosterone, LH, and FSH. ii. If total testosterone is <300 ng/dl (or lower limit of normal established by the reference laboratory), routine endocrine consult is appropriate. b. Screening for growth hormone deficiency: i. 0800 hrs fasting IGF-1. ii. If IGF-1 is less than age appropriate range established by the reference laboratory, routine endocrine consult is appropriate. c. Testing for hypothyroidism: i. TSH and f T4 at any time of day. ii. If both TSH and ft4 are below the reference range, this is suggestive of central hypothyroidism, and routine endocrine consult is appropriate. Therapy with levothyroxine may be started with goal ft4 in mid normal range (after ruling out concurrent adrenal insufficiency, which would require treatment before thyroid hormone replacement). iii. If TSH is above the reference range, and ft4 is low or low-normal, this is suggestive of primary hypothyroidism unrelated to the TBI, and may be managed by the primary care provider. d. Testing for hyperprolactinemia: i. Measure serum prolactin at any time of day. 578 MILITARY MEDICINE, Vol. 175, August 2010
ii. If elevated for sex and age, routine referral to endocrinology is appropriate. e. Testing for adrenal insufficiency: i. Measure 0800 hrs fasting cortisol. ii. If cortisol is 12 mcg/dl, no further testing is necessary. iii. If cortisol is <12 mcg/dl, perform a 250-mcg cosyntropin stimulation test (a baseline cortisol followed by levels at 30 and 60 minutes after intravenous injection of 250 mcg of Cortrosyn). If there is failure to stimulate to a cortisol of 18 mcg/dl in 30 or 60 minutes, start hydrocortisone therapy 10 mg po qam (0800 hrs), and 5 mg po qhs (1400 hrs), and place routine referral to endocrinology. Counsel patient to double dose for 2 3 days in the event of acute illness. Emergency Alert ID bracelet or tags are recommended in patients with adrenal insufficiency. 3. Patients who have positive screening test results for pituitary hormone deficiency should be referred to an endocrinologist for further evaluation and management. CONCLUSION Results of recent studies make clear that TBI poses substantial risk to pituitary function. Given the current increased rate of TBI sustained as a result of OIF and OEF, it is essential that combat veterans sustaining TBI be screened for pituitary deficits. Patients with obvious TBI-induced hypopituitarism should initially receive critical replacement such as glucocorticoids, thyroid hormone, and antidiuretic hormone. Gonadal and growth hormone replacement therapy should also be implemented if there are persistent demonstrated deficiencies in the outpatient setting. Whereas the data used in establishing the above recommendations comes solely from civilian studies, these recommendations likely apply to the military population, and those who suffer a btbi. Additional studies will be required to determine whether these recommendations will need to be modified to suit the unique needs of the combat veteran population. 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