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Severe head trauma in patients with unexplained central hypothyroidism
BRIEF OBSERVATION
Severe Head Trauma in Patients with Unexplained Central Hypothyroidism Salvatore Benvenga, MD, Teresa Vigo, MD, Rosaria M. Ruggeri, MD, Daniela Lapa, MD, Barbara Almoto, MD, Francesco LoGiudice, MD, Marcello Longo, MD, Alfredo Blandino, MD, Alfredo Campennı`, MD, Salvatore Cannavo`, MD, Francesco Trimarchi, MD
T
he annual incidence of head trauma that requires hospitalization ranges from 100 to 300 cases per 100,000 inhabitants, with substantial associated health costs (1,2). In the United States, approximately 52,000 persons die from head trauma each year; a similar number survive but often suffer physical, neurological, and psychological disabilities (2). Head trauma accounts for about 0.7% of all cases of hypopituitarism (3), which may explain why it is a frequently overlooked cause (4,5). Symptoms of hypopituitarism are often “ascribed to the post-concussion syndrome and . . . ignored for many years” (5). In addition, the head trauma can be forgotten (4,6) as it may have occurred decades earlier, even at birth (7,8). Rarely, post– head trauma hypopituitarism is reversible (4,9,10). Gonadotropes are considered the most fragile pituitary cells. Clinical or biochemical hypogonadism has been reported in the vast majority of patients with post– head trauma hypopituitarism (4,5), compared with a prevalence of about 50% for corticotropin (ACTH) and thyrotropin (TSH) deficiency (4). Growth hormone and prolactin deficiency are less common (4). Post-traumatic TSH deficiency, however, greatly exceeded the frequency of gonadotropin deficiency in a recent study (11). Hyperprolactinemia occurs in about half of these patients (4). After our observation of a patient with post-traumatic isolated gonadotropin deficiency (9) and another with post-traumatic isolated TSH deficiency, we became aware that patients might not recall earlier trauma. The first patient failed to mention that he had suffered a previous head trauma, for which he had been hospitalized at our institution; a relative disclosed the trauma to us. In the second patient, information about head trauma required asking specifically whether she had ever fallen at home. Central hypothyroidism can be underestimated by the paucity, tolerability, and nonspecificity of symptoms (12,13), particularly in the elderly, and by their similarity with the postconcussion syndrome (5). Convinced that © 2004 by Excerpta Medica Inc. All rights reserved.
central hypothyroidism is more frequent than believed commonly (14), and that head trauma could be a major cause, we have paid more attention to this possibility. We have therefore elicited a history of previous head trauma in patients with otherwise unexplained central hypothyroidism, questioning both patients and relatives.
METHODS Patients Approximately 2000 new patients per year are referred to our division, which is located in a university hospital serving approximately 3.5 million people. Since 1995, we have investigated patients admitted for “unexplained central hypothyroidism,” defined as a low serum free thyroxine (FT4) level and low or borderline low serum TSH level, with none of the following: previous head surgery or irradiation, known pituitary or cerebral tumors, or functional alterations of the hypothalamic-pituitarythyroid axis caused by nonthyroid illness or drugs (15,16). Referring physicians had suspected the diagnosis of primary hypothyroidism, and a low TSH level (rather than the expected high level) was a frequent reason for referral. From January 1995 through December 2001, we observed 15 patients in whom a history of severe head trauma was obtained after in-depth questioning of patients and relatives. For the purpose of this study, severe head trauma required both loss of consciousness and hospitalization. This study was approved by the ethics committee of our university.
Study Protocol The diagnostic workup included history, physical examination, chest radiographs, routine serum chemistry measurement, baseline and dynamic hormone assay, and brain imaging by either computed tomography or magnetic resonance. To exclude genetic and malformation etiologies (17), no patient with short stature, physical malformations, mental retardation, deafness, infertility, or a family history of any of these disorders was included. To facilitate recollection of previous head trauma, questions about specific circumstances were asked of the patient and, separately, of available relatives. For instance, we asked: “Were you/Was your relative involved in any automobile, bicycle, motorcycle, truck, bus, plane, ship, horse accident in which you/your relative hit your/ his/her head?” Two to 4 relatives per patient were questioned.
Evaluations No patient was taking a drug known to affect the endocrine system. Venous blood was taken between 7:00 and 8:00 AM. We measured anterior pituitary hormone levels, 0002-9343/04/$–see front matter 767 doi:10.1016/j.amjmed.2003.12.038
768
Table 1. Characteristics of the 8 Women (Patients 1 to 8) and 7 Men (Patients 9 to 15) with Central Hypothyroidism Who Had Suffered Severe Head Trauma
June 1, 2004
TSH (mU/L)†
Age (years) at:
Volume 116
Trauma
Observation
Details of Trauma
Symptoms after Trauma*
Baseline
1
30
47
4.55
41
47
0.18
0.78
3
38
46
Amenorrhea, diminished libido, sensitivity to cold Transient diabetes insipidus during hospitalization, fatigue, apathy Amenorrhea, fatigue
0.27
2
Hit head against bottom while diving; unconscious for 3 days; hospitalized for 3 weeks Hit head on stairs at home; unconscious for 2 days, lethargic subsequently; hospitalized for 3 weeks
0.29
2.56
4
45
53
Apathy
0.76
5
22
42
Fatigue, apathy, sleepiness, sensitivity to cold
6
40
60
Fatigue
7
14
19
8
58
68
9
11
52
10
7
29
11
24
51
Iron fell on head; unconscious for 2–3 hours; hospitalized for 2 weeks Fell at home and hit head on floor; unconscious for 3 days; Glasgow coma score ⫽ 8; vertebral fractures; hospitalized for 5 weeks Hit head against windshield in automobile accident; skull fractures; unconscious for 4–5 days, lethargic subsequently; hospitalized for ⬎8 weeks Fell at home and hit head against coffee table; unconscious for 2 days, lethargic subsequently; hospitalized for 4 weeks Hit head against dashboard and door in automobile accident; skull and limb fractures; Glasgow coma score ⫽ 4; unconscious for 2 weeks; hospitalized for ⬎4 months Hit head against dashboard and door in automobile accident; unconscious for 2 days; Glasgow coma score ⫽ 5; hospitalized for 3 weeks Fell from balcony and hit head against pavement; skull and limb fractures; unconscious for several days, lethargic subsequently; hospitalized for ⬎12 weeks Hit head against roof and door in automobile accident; unconscious for 2 days; hospitalized for 4 weeks Fell from top of bunk bed and hit head against bedside table and floor; maxillofacial and skull fractures; unconscious for 3–4 days, lethargic subsequently; hospitalized for ⬎12 weeks
Amenorrhea, fatigue, apathy
Increment
Other Deficient Hormones FSH, LH
Imaging Refused Pituitary hypodensities
Empty sella
3.24
ACTH, FSH, LH, GH, PRL GH
0.25
0.14
GH
Empty sella
1.50
4.51
⬍0.01
⬍0.01
LH
Normal
Empty sella
Empty sella
Apathy
0.84
5.0
GH
Empty sella
Fatigue, erectile dysfunction, diminished libido, apathy
0.31
0.47
ACTH, FSH, LH
Empty sella
Sleepiness, apathy
0.64
5.67
ACTH, FSH, LH
Empty sella
Fatigue, erectile dysfunction, diminished libido, memory impairment
0.20
1.15
LH, GH, PRL
Empty sella
Head Trauma and Central Hypothyroidism/Benvenga et al
THE AMERICAN JOURNAL OF MEDICINE威
Patient
Table 1. continued TSH (mU/L)†
Age (years) at:
Other Deficient Hormones
Observation
Details of Trauma
Symptoms after Trauma*
Baseline
Increment
Imaging
12
59
60
Sensitivity to cold, erectile dysfunction
0.37
2.0
FSH, LH
Normal
13
16
58
4.29
FSH, LH, GH
Normal
20
63
Apathy, sleepiness, memory impairment, erectile dysfunction Fatigue, erectile dysfunction
0.90
14
0.34
2.86
ACTH, LH, GH
Empty sella
15
19
48
Hit head against dashboard in automobile accident; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks Fell from bed and hit head against floor; unconscious for ⬎2 hours; hospitalized for 1 week Two events. The first: age 20 years; fell from electric pylon and hit head against pavement; multiple fractures, including skull; unconscious for ⬎2 weeks; hospitalized for several months. The second: age 35 years; hit head against bottom of bus while changing oil; skull fracture; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks Hit head against dashboard and door in automobile accident; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks
Fatigue
1.40
4.11
THE AMERICAN JOURNAL OF MEDICINE威
Refused
* The interval between head trauma and symptoms is not tabulated because it could not be defined precisely so many years after trauma. † TSH response to TSH-releasing hormone was interpreted as described by Faglia (15). The abnormal responses include the following: absent (increment ⬍1.0 mU/L), impaired (increment of 1.0 to 3.5 mU/L in men or 1.0 to 6.0 mU/L in women), delayed (peak occurring at 60 minutes or later), and prolonged (at 60 minutes after peak, TSH is greater than 40% of the peak value). These last two responses indicate an hypothalamic lesion, usually associated with reduced biologic activity of TSH. To evaluate this, the increment of serum T3 and FT3 levels were measured at baseline and at 180 minutes. The normal increment of either form of T3 is ⬎30%, but was low in all 15 patients, ranging from 4% to 15% (T3) or 0% to 18% (FT3). At the initial evaluation, basal FT3 levels ranged from 1.2 to 3.2 pg/mL (reference, 1.8 to 4.2 pg/mL) and FT4 levels ranged from 6.5 to 9.0 pg/mL (reference, 9.5 to 18.9 pg/mL). To convert FT3 from pg/mL to pmol/L, multiply by 1.536; to convert FT4 from pg/mL to pmol/L, multiply by 1.287.
Head Trauma and Central Hypothyroidism/Benvenga et al
Trauma
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Patient
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Head Trauma and Central Hypothyroidism/Benvenga et al
corresponding peripheral hormone levels, and 24-hour urinary excretion of cortisol. When indicated, we performed pituitary stimulation tests (18), each test separated by a 1-week interval. We began with the TSH-releasing hormone test to evaluate prolactin and TSH, as well as the percentage increase in levels of triiodothyronine (T3) and free T3 (FT3) to assess the biological activity of TSH (15,19). The other stimulation tests consisted of the intravenous injection of corticotropin-releasing hormone (for ACTH), growth hormone–releasing hormone, and gonadotropin-releasing hormone; the last test was omitted in postmenopausal women whose gonadotropin levels were appropriately high. The growth hormone–releasing hormone test was potentiated by the oral administration of pyridostigmine (20). TSH, FT4, FT3, and T3 levels were measured with electrochemiluminescent assays (Boehringer, Mannhein, Germany). Prolactin levels were measured with a fluoroimmunoassay (Medical Systems, Genova, Italy); ACTH levels with a chemiluminescent assay (DPC, Los Angeles, California); gonadotropins with an immunoenzymatic kit (CIS, Gif-sur-Yvette, France); and growth hormone with an immunoradiometric kit (CIS). Standard normal ranges were used to separate abnormal from normal results, and a subnormal stimulation test was interpreted to indicate the corresponding tropin deficiency. The TSH-releasing hormone test was interpreted using the criteria of Faglia (19).
RESULTS The mean (⫾ SD) age of the 15 patients with central hypothyroidism and a history of severe head trauma was 50 ⫾ 13 years at the time of examination, and 30 ⫾ 17 years at the time of trauma (Table). Domestic and vehicular accidents accounted for the majority of cases and were reported by 13 patients or by relatives of the remaining 2 patients. Relatives confirmed all accidents reported by patients; in turn, patients confirmed the accidents reported by relatives. Fatigue, the most common symptom, was usually the initial symptom. Aggravation of the initial symptoms or appearance of other symptoms prompted endocrine investigations by the referring physicians. An empty sella was seen in 9 of the 12 patients with pituitary abnormalities. Central hypothyroidism was the only deficiency in 3 patients. At the other extreme, it was associated with deficiency of the other five anterior pituitary hormones in 1 patient. The most common associated deficiencies were gonadotropins (60% [9/15]) and growth hormone (58% [7/12]); prolactin deficiency was the least common (13% [2/15]). There was no evident relation between type or magnitude of hormone deficiency and variables such as age 770
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at trauma, type of trauma, or neuroradiologic findings (Table).
DISCUSSION In contrast with a case-control study, a case-series study cannot reliably identify risk factors or causes. However, during the same 7-year period, we identified 13 cases of pituitary adenomas (the leading cause of central hypothyroidism) among patients admitted with a similar diagnosis of “unexplained central hypothyroidism,” compared with 15 cases of hypothyroidism following head trauma. That the frequency of post-traumatic hypothyroidism was similar to that of pituitary adenoma–related hypothyroidism was also suggested by a recent study (14). In that study, measurement of TSH and T4 levels in 56,000 subjects over 12 months detected 15 patients with unsuspected central hypothyroidism, including 6 with pituitary adenomas and up to 7 who may have been post– head trauma (the study did not mention whether such a history was elicited). The frequency of central hypothyroidism (0.03%) in that study was much higher than commonly believed (0.0002%) (15). On the other hand, central hypothyroidism was seen in 15 (22%) of 70 adults with known head trauma who were recruited from a postacute residential rehabilitation facility and evaluated between 1 month and 23 years after trauma (11). We believe, however, that the frequency of hypothyroidism may have been underestimated because of differences in the test protocol that was used. Indeed, 61 (87%) of patients had both TSH and FT4 levels below the corresponding midnormal level (11). At a cost of approximately $20, an assay of FT4 and TSH levels is justified in the follow-up of patients with known head trauma and in symptomatic persons in whom a history of head trauma can be elicited. Assay of other hormones adds relatively little extra cost. Practitioners should be more alert to, and patients and families be more informed about, the endocrine complications of head trauma.
REFERENCES 1. Masson F. Epidemiology of severe cranial injuries. Arch Fr Anesth Reanim. 2000;19:261–269. 2. Rehabilitation of persons with traumatic brain injuries. NIH Consensus Statement. 1998;16:1– 41. 3. Escamilla RF, Lisser H. Simmonds disease. J Clin Endocrinol Metab. 1942;2:65–96. 4. Benvenga S, Campennı` A, Ruggeri MR, Trimarchi F. Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab. 2000;85: 1353–1361. 5. Edwards OM, Clark JDA. Post-traumatic hypopituitarism. Six cases and review of the literature. Medicine (Baltimore). 1986;65: 281–290.
Head Trauma and Central Hypothyroidism/Benvenga et al 6. Becker DP. Head injuries. In: Wyngaarden JB, Smith LH Jr, eds. Cecil’s Textbook of Medicine. 16th ed. Philadelphia, Pennsylvania: WB Saunders; 1982:2126 –2142. 7. Gacs G. Perinatal factors in aetiology of hypopituitarism. Helv Paediatr Acta. 1987;42:137–144. 8. Minutti CZ, Zimmerman D. Traumatic hypopituitarism due to maternal uterine leiomyomas. J Endocrinol Invest. 2002;25:158 – 162. 9. Benvenga S, Lo Giudice F, Campennı` A, Longo M, Trimarchi F. Post-traumatic selective hypogonadotropic hypogonadism. J Endocrinol Invest. 1997;20:675–680. 10. Iglesias P, Gomez-Pan A, Diez JJ. Spontaneous recovery for posttraumatic hypopituitarism. J Endocrinol Invest. 1996;19:320 –323. 11. Lieberman SA, Oberoi AL, Gilkinson CR, Masel BE, Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. J Clin Endocrinol Metab. 2001;86: 2752–2756. 12. Oelkers WKH. Hypopituitarism. In: Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. St. Louis, Missouri: Mosby; 1997:27–31. 13. Gunn IR, Beastall GH, Matthews DM, Bath JCJL. Post-traumatic hypothalamic-pituitary dysfunction presenting with biochemical features of primary hypothyroidism. Ann Clin Biochem. 1991;28: 327–330. 14. Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid function test. Lancet. 2001;357: 1013–1014. 15. Martino E, Bartalena L, Pinchera A. Central hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pennsylvania: Lippincott, Williams & Wilkins; 2000:762–773.
16. Stockigt JR. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pennsylvania: Lippincott, Williams & Wilkins; 2000:376 –392. 17. Collu R. Central hypothyroidism: genetic aspects. J Endocrinol Invest. 2000;23:125–134. 18. Eastman RC, de la Pena MS, Moore WT, Hao E-H, Merriam GR. Acromegaly, hyperprolactinemia, gonadotropin-secreting tumors and hypopituitarism. In: Moore WT, Eastman RC, eds. Diagnostic Endocrinology. Toronto, Canada: BC Decker; 1990:5–56. 19. Faglia G. The clinical impact of the thyrotropin-releasing hormone test. Thyroid. 1998;8:903–908. 20. Arvat E, Cappa M, Casanueva FF, et al. Pyridostigmine potentiates growth hormone (GH)-releasing hormone-induced GH release in both men and women. J Clin Endocrinol Metab. 1993;76: 374 –377.
From Sezione di Endocrinologia del Dipartimento Clinico Sperimentale di Medicina e Farmacologia (SB, TV, RMR, DL, BA, FL, SC, FT), Programma Infradipartimentale di Endocrinologia Molecolare Clinica (SB), and Dipartimento di Scienze Radiologiche (ML, AB, AC), University of Messina School of Medicine, Policlinico Universitario di Messina, Messina, Italy. Requests for reprints should be addressed to Salvatore Benvenga, MD, Sezione di Endocrinologia, Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Padiglione H, 4 Piano, Policlinico Universitario di Messina, 98125 Messina, Italy, or [email protected]. Manuscript submitted April 14, 2003, and accepted in revised form December 15, 2003.
June 1, 2004
THE AMERICAN JOURNAL OF MEDICINE威
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Severe Head Trauma in Patients with Unexplained Central Hypothyroidism Salvatore Benvenga, MD, Teresa Vigo, MD, Rosaria M. Ruggeri, MD, Daniela Lapa, MD, Barbara Almoto, MD, Francesco LoGiudice, MD, Marcello Longo, MD, Alfredo Blandino, MD, Alfredo Campennı`, MD, Salvatore Cannavo`, MD, Francesco Trimarchi, MD
T
he annual incidence of head trauma that requires hospitalization ranges from 100 to 300 cases per 100,000 inhabitants, with substantial associated health costs (1,2). In the United States, approximately 52,000 persons die from head trauma each year; a similar number survive but often suffer physical, neurological, and psychological disabilities (2). Head trauma accounts for about 0.7% of all cases of hypopituitarism (3), which may explain why it is a frequently overlooked cause (4,5). Symptoms of hypopituitarism are often “ascribed to the post-concussion syndrome and . . . ignored for many years” (5). In addition, the head trauma can be forgotten (4,6) as it may have occurred decades earlier, even at birth (7,8). Rarely, post– head trauma hypopituitarism is reversible (4,9,10). Gonadotropes are considered the most fragile pituitary cells. Clinical or biochemical hypogonadism has been reported in the vast majority of patients with post– head trauma hypopituitarism (4,5), compared with a prevalence of about 50% for corticotropin (ACTH) and thyrotropin (TSH) deficiency (4). Growth hormone and prolactin deficiency are less common (4). Post-traumatic TSH deficiency, however, greatly exceeded the frequency of gonadotropin deficiency in a recent study (11). Hyperprolactinemia occurs in about half of these patients (4). After our observation of a patient with post-traumatic isolated gonadotropin deficiency (9) and another with post-traumatic isolated TSH deficiency, we became aware that patients might not recall earlier trauma. The first patient failed to mention that he had suffered a previous head trauma, for which he had been hospitalized at our institution; a relative disclosed the trauma to us. In the second patient, information about head trauma required asking specifically whether she had ever fallen at home. Central hypothyroidism can be underestimated by the paucity, tolerability, and nonspecificity of symptoms (12,13), particularly in the elderly, and by their similarity with the postconcussion syndrome (5). Convinced that © 2004 by Excerpta Medica Inc. All rights reserved.
central hypothyroidism is more frequent than believed commonly (14), and that head trauma could be a major cause, we have paid more attention to this possibility. We have therefore elicited a history of previous head trauma in patients with otherwise unexplained central hypothyroidism, questioning both patients and relatives.
METHODS Patients Approximately 2000 new patients per year are referred to our division, which is located in a university hospital serving approximately 3.5 million people. Since 1995, we have investigated patients admitted for “unexplained central hypothyroidism,” defined as a low serum free thyroxine (FT4) level and low or borderline low serum TSH level, with none of the following: previous head surgery or irradiation, known pituitary or cerebral tumors, or functional alterations of the hypothalamic-pituitarythyroid axis caused by nonthyroid illness or drugs (15,16). Referring physicians had suspected the diagnosis of primary hypothyroidism, and a low TSH level (rather than the expected high level) was a frequent reason for referral. From January 1995 through December 2001, we observed 15 patients in whom a history of severe head trauma was obtained after in-depth questioning of patients and relatives. For the purpose of this study, severe head trauma required both loss of consciousness and hospitalization. This study was approved by the ethics committee of our university.
Study Protocol The diagnostic workup included history, physical examination, chest radiographs, routine serum chemistry measurement, baseline and dynamic hormone assay, and brain imaging by either computed tomography or magnetic resonance. To exclude genetic and malformation etiologies (17), no patient with short stature, physical malformations, mental retardation, deafness, infertility, or a family history of any of these disorders was included. To facilitate recollection of previous head trauma, questions about specific circumstances were asked of the patient and, separately, of available relatives. For instance, we asked: “Were you/Was your relative involved in any automobile, bicycle, motorcycle, truck, bus, plane, ship, horse accident in which you/your relative hit your/ his/her head?” Two to 4 relatives per patient were questioned.
Evaluations No patient was taking a drug known to affect the endocrine system. Venous blood was taken between 7:00 and 8:00 AM. We measured anterior pituitary hormone levels, 0002-9343/04/$–see front matter 767 doi:10.1016/j.amjmed.2003.12.038
768
Table 1. Characteristics of the 8 Women (Patients 1 to 8) and 7 Men (Patients 9 to 15) with Central Hypothyroidism Who Had Suffered Severe Head Trauma
June 1, 2004
TSH (mU/L)†
Age (years) at:
Volume 116
Trauma
Observation
Details of Trauma
Symptoms after Trauma*
Baseline
1
30
47
4.55
41
47
0.18
0.78
3
38
46
Amenorrhea, diminished libido, sensitivity to cold Transient diabetes insipidus during hospitalization, fatigue, apathy Amenorrhea, fatigue
0.27
2
Hit head against bottom while diving; unconscious for 3 days; hospitalized for 3 weeks Hit head on stairs at home; unconscious for 2 days, lethargic subsequently; hospitalized for 3 weeks
0.29
2.56
4
45
53
Apathy
0.76
5
22
42
Fatigue, apathy, sleepiness, sensitivity to cold
6
40
60
Fatigue
7
14
19
8
58
68
9
11
52
10
7
29
11
24
51
Iron fell on head; unconscious for 2–3 hours; hospitalized for 2 weeks Fell at home and hit head on floor; unconscious for 3 days; Glasgow coma score ⫽ 8; vertebral fractures; hospitalized for 5 weeks Hit head against windshield in automobile accident; skull fractures; unconscious for 4–5 days, lethargic subsequently; hospitalized for ⬎8 weeks Fell at home and hit head against coffee table; unconscious for 2 days, lethargic subsequently; hospitalized for 4 weeks Hit head against dashboard and door in automobile accident; skull and limb fractures; Glasgow coma score ⫽ 4; unconscious for 2 weeks; hospitalized for ⬎4 months Hit head against dashboard and door in automobile accident; unconscious for 2 days; Glasgow coma score ⫽ 5; hospitalized for 3 weeks Fell from balcony and hit head against pavement; skull and limb fractures; unconscious for several days, lethargic subsequently; hospitalized for ⬎12 weeks Hit head against roof and door in automobile accident; unconscious for 2 days; hospitalized for 4 weeks Fell from top of bunk bed and hit head against bedside table and floor; maxillofacial and skull fractures; unconscious for 3–4 days, lethargic subsequently; hospitalized for ⬎12 weeks
Amenorrhea, fatigue, apathy
Increment
Other Deficient Hormones FSH, LH
Imaging Refused Pituitary hypodensities
Empty sella
3.24
ACTH, FSH, LH, GH, PRL GH
0.25
0.14
GH
Empty sella
1.50
4.51
⬍0.01
⬍0.01
LH
Normal
Empty sella
Empty sella
Apathy
0.84
5.0
GH
Empty sella
Fatigue, erectile dysfunction, diminished libido, apathy
0.31
0.47
ACTH, FSH, LH
Empty sella
Sleepiness, apathy
0.64
5.67
ACTH, FSH, LH
Empty sella
Fatigue, erectile dysfunction, diminished libido, memory impairment
0.20
1.15
LH, GH, PRL
Empty sella
Head Trauma and Central Hypothyroidism/Benvenga et al
THE AMERICAN JOURNAL OF MEDICINE威
Patient
Table 1. continued TSH (mU/L)†
Age (years) at:
Other Deficient Hormones
Observation
Details of Trauma
Symptoms after Trauma*
Baseline
Increment
Imaging
12
59
60
Sensitivity to cold, erectile dysfunction
0.37
2.0
FSH, LH
Normal
13
16
58
4.29
FSH, LH, GH
Normal
20
63
Apathy, sleepiness, memory impairment, erectile dysfunction Fatigue, erectile dysfunction
0.90
14
0.34
2.86
ACTH, LH, GH
Empty sella
15
19
48
Hit head against dashboard in automobile accident; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks Fell from bed and hit head against floor; unconscious for ⬎2 hours; hospitalized for 1 week Two events. The first: age 20 years; fell from electric pylon and hit head against pavement; multiple fractures, including skull; unconscious for ⬎2 weeks; hospitalized for several months. The second: age 35 years; hit head against bottom of bus while changing oil; skull fracture; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks Hit head against dashboard and door in automobile accident; unconscious for 1 day, lethargic subsequently; hospitalized for 2 weeks
Fatigue
1.40
4.11
THE AMERICAN JOURNAL OF MEDICINE威
Refused
* The interval between head trauma and symptoms is not tabulated because it could not be defined precisely so many years after trauma. † TSH response to TSH-releasing hormone was interpreted as described by Faglia (15). The abnormal responses include the following: absent (increment ⬍1.0 mU/L), impaired (increment of 1.0 to 3.5 mU/L in men or 1.0 to 6.0 mU/L in women), delayed (peak occurring at 60 minutes or later), and prolonged (at 60 minutes after peak, TSH is greater than 40% of the peak value). These last two responses indicate an hypothalamic lesion, usually associated with reduced biologic activity of TSH. To evaluate this, the increment of serum T3 and FT3 levels were measured at baseline and at 180 minutes. The normal increment of either form of T3 is ⬎30%, but was low in all 15 patients, ranging from 4% to 15% (T3) or 0% to 18% (FT3). At the initial evaluation, basal FT3 levels ranged from 1.2 to 3.2 pg/mL (reference, 1.8 to 4.2 pg/mL) and FT4 levels ranged from 6.5 to 9.0 pg/mL (reference, 9.5 to 18.9 pg/mL). To convert FT3 from pg/mL to pmol/L, multiply by 1.536; to convert FT4 from pg/mL to pmol/L, multiply by 1.287.
Head Trauma and Central Hypothyroidism/Benvenga et al
Trauma
June 1, 2004
Patient
Volume 116 769
Head Trauma and Central Hypothyroidism/Benvenga et al
corresponding peripheral hormone levels, and 24-hour urinary excretion of cortisol. When indicated, we performed pituitary stimulation tests (18), each test separated by a 1-week interval. We began with the TSH-releasing hormone test to evaluate prolactin and TSH, as well as the percentage increase in levels of triiodothyronine (T3) and free T3 (FT3) to assess the biological activity of TSH (15,19). The other stimulation tests consisted of the intravenous injection of corticotropin-releasing hormone (for ACTH), growth hormone–releasing hormone, and gonadotropin-releasing hormone; the last test was omitted in postmenopausal women whose gonadotropin levels were appropriately high. The growth hormone–releasing hormone test was potentiated by the oral administration of pyridostigmine (20). TSH, FT4, FT3, and T3 levels were measured with electrochemiluminescent assays (Boehringer, Mannhein, Germany). Prolactin levels were measured with a fluoroimmunoassay (Medical Systems, Genova, Italy); ACTH levels with a chemiluminescent assay (DPC, Los Angeles, California); gonadotropins with an immunoenzymatic kit (CIS, Gif-sur-Yvette, France); and growth hormone with an immunoradiometric kit (CIS). Standard normal ranges were used to separate abnormal from normal results, and a subnormal stimulation test was interpreted to indicate the corresponding tropin deficiency. The TSH-releasing hormone test was interpreted using the criteria of Faglia (19).
RESULTS The mean (⫾ SD) age of the 15 patients with central hypothyroidism and a history of severe head trauma was 50 ⫾ 13 years at the time of examination, and 30 ⫾ 17 years at the time of trauma (Table). Domestic and vehicular accidents accounted for the majority of cases and were reported by 13 patients or by relatives of the remaining 2 patients. Relatives confirmed all accidents reported by patients; in turn, patients confirmed the accidents reported by relatives. Fatigue, the most common symptom, was usually the initial symptom. Aggravation of the initial symptoms or appearance of other symptoms prompted endocrine investigations by the referring physicians. An empty sella was seen in 9 of the 12 patients with pituitary abnormalities. Central hypothyroidism was the only deficiency in 3 patients. At the other extreme, it was associated with deficiency of the other five anterior pituitary hormones in 1 patient. The most common associated deficiencies were gonadotropins (60% [9/15]) and growth hormone (58% [7/12]); prolactin deficiency was the least common (13% [2/15]). There was no evident relation between type or magnitude of hormone deficiency and variables such as age 770
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at trauma, type of trauma, or neuroradiologic findings (Table).
DISCUSSION In contrast with a case-control study, a case-series study cannot reliably identify risk factors or causes. However, during the same 7-year period, we identified 13 cases of pituitary adenomas (the leading cause of central hypothyroidism) among patients admitted with a similar diagnosis of “unexplained central hypothyroidism,” compared with 15 cases of hypothyroidism following head trauma. That the frequency of post-traumatic hypothyroidism was similar to that of pituitary adenoma–related hypothyroidism was also suggested by a recent study (14). In that study, measurement of TSH and T4 levels in 56,000 subjects over 12 months detected 15 patients with unsuspected central hypothyroidism, including 6 with pituitary adenomas and up to 7 who may have been post– head trauma (the study did not mention whether such a history was elicited). The frequency of central hypothyroidism (0.03%) in that study was much higher than commonly believed (0.0002%) (15). On the other hand, central hypothyroidism was seen in 15 (22%) of 70 adults with known head trauma who were recruited from a postacute residential rehabilitation facility and evaluated between 1 month and 23 years after trauma (11). We believe, however, that the frequency of hypothyroidism may have been underestimated because of differences in the test protocol that was used. Indeed, 61 (87%) of patients had both TSH and FT4 levels below the corresponding midnormal level (11). At a cost of approximately $20, an assay of FT4 and TSH levels is justified in the follow-up of patients with known head trauma and in symptomatic persons in whom a history of head trauma can be elicited. Assay of other hormones adds relatively little extra cost. Practitioners should be more alert to, and patients and families be more informed about, the endocrine complications of head trauma.
REFERENCES 1. Masson F. Epidemiology of severe cranial injuries. Arch Fr Anesth Reanim. 2000;19:261–269. 2. Rehabilitation of persons with traumatic brain injuries. NIH Consensus Statement. 1998;16:1– 41. 3. Escamilla RF, Lisser H. Simmonds disease. J Clin Endocrinol Metab. 1942;2:65–96. 4. Benvenga S, Campennı` A, Ruggeri MR, Trimarchi F. Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab. 2000;85: 1353–1361. 5. Edwards OM, Clark JDA. Post-traumatic hypopituitarism. Six cases and review of the literature. Medicine (Baltimore). 1986;65: 281–290.
Head Trauma and Central Hypothyroidism/Benvenga et al 6. Becker DP. Head injuries. In: Wyngaarden JB, Smith LH Jr, eds. Cecil’s Textbook of Medicine. 16th ed. Philadelphia, Pennsylvania: WB Saunders; 1982:2126 –2142. 7. Gacs G. Perinatal factors in aetiology of hypopituitarism. Helv Paediatr Acta. 1987;42:137–144. 8. Minutti CZ, Zimmerman D. Traumatic hypopituitarism due to maternal uterine leiomyomas. J Endocrinol Invest. 2002;25:158 – 162. 9. Benvenga S, Lo Giudice F, Campennı` A, Longo M, Trimarchi F. Post-traumatic selective hypogonadotropic hypogonadism. J Endocrinol Invest. 1997;20:675–680. 10. Iglesias P, Gomez-Pan A, Diez JJ. Spontaneous recovery for posttraumatic hypopituitarism. J Endocrinol Invest. 1996;19:320 –323. 11. Lieberman SA, Oberoi AL, Gilkinson CR, Masel BE, Urban RJ. Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury. J Clin Endocrinol Metab. 2001;86: 2752–2756. 12. Oelkers WKH. Hypopituitarism. In: Bardin CW, ed. Current Therapy in Endocrinology and Metabolism. 6th ed. St. Louis, Missouri: Mosby; 1997:27–31. 13. Gunn IR, Beastall GH, Matthews DM, Bath JCJL. Post-traumatic hypothalamic-pituitary dysfunction presenting with biochemical features of primary hypothyroidism. Ann Clin Biochem. 1991;28: 327–330. 14. Wardle CA, Fraser WD, Squire CR. Pitfalls in the use of thyrotropin concentration as a first-line thyroid function test. Lancet. 2001;357: 1013–1014. 15. Martino E, Bartalena L, Pinchera A. Central hypothyroidism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pennsylvania: Lippincott, Williams & Wilkins; 2000:762–773.
16. Stockigt JR. Serum thyrotropin and thyroid hormone measurements and assessment of thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, Pennsylvania: Lippincott, Williams & Wilkins; 2000:376 –392. 17. Collu R. Central hypothyroidism: genetic aspects. J Endocrinol Invest. 2000;23:125–134. 18. Eastman RC, de la Pena MS, Moore WT, Hao E-H, Merriam GR. Acromegaly, hyperprolactinemia, gonadotropin-secreting tumors and hypopituitarism. In: Moore WT, Eastman RC, eds. Diagnostic Endocrinology. Toronto, Canada: BC Decker; 1990:5–56. 19. Faglia G. The clinical impact of the thyrotropin-releasing hormone test. Thyroid. 1998;8:903–908. 20. Arvat E, Cappa M, Casanueva FF, et al. Pyridostigmine potentiates growth hormone (GH)-releasing hormone-induced GH release in both men and women. J Clin Endocrinol Metab. 1993;76: 374 –377.
From Sezione di Endocrinologia del Dipartimento Clinico Sperimentale di Medicina e Farmacologia (SB, TV, RMR, DL, BA, FL, SC, FT), Programma Infradipartimentale di Endocrinologia Molecolare Clinica (SB), and Dipartimento di Scienze Radiologiche (ML, AB, AC), University of Messina School of Medicine, Policlinico Universitario di Messina, Messina, Italy. Requests for reprints should be addressed to Salvatore Benvenga, MD, Sezione di Endocrinologia, Dipartimento Clinico Sperimentale di Medicina e Farmacologia, Padiglione H, 4 Piano, Policlinico Universitario di Messina, 98125 Messina, Italy, or [email protected]. Manuscript submitted April 14, 2003, and accepted in revised form December 15, 2003.
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