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Cited by 36Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchPituitary Gland Disorders and Treatments

Endocrine dysfunction following traumatic brain injury: a 5-year follow-up nationwide-based study

Open access
Yang, Wei-Hsun, Chen, Pau-Chung, Wang, Ting-Chung, Kuo, Ting-Yu, Cheng, Chun-Yu, Yang, Yao-Hsu·2016·Scientific Reports
DOI 10.1038/srep32987PMC PMC5017132
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Abstract

Post-traumatic endocrine dysfunction is a complication of traumatic brain injury (TBI). However, there is lack of long-term follow-up and large sample size studies. This study included patients suffering from TBI registered in the Health Insurance Database. Endocrine disorders were identified using the ICD codes: 244 (acquired hypothyroidism), 253 (pituitary dysfunction), 255 (disorders of the adrenal glands), 258 (polyglandular dysfunction), and 259 (other endocrine disorders) with at least three outpatient visits within 1 year or one admission diagnosis. Overall, 156,945 insured subjects were included in the final analysis. The 1- and 5-year incidence rates of post-traumatic endocrinopathies were 0.4% and 2%, respectively. The risks of developing a common endocrinopathy (p < 0.001) or pituitary dysfunction (P < 0.001) were significantly higher in patients with a TBI history. Patients with a skull bone fracture had a higher risk of developing pituitary dysfunction at the 1-year follow up (p value < 0.001). At the 5-year follow up, the association between intracranial hemorrhage and pituitary dysfunction (p value: 0.002) was significant. The risk of developing endocrine dysfunction after TBI increased during the entire 5-year follow-up period. Skull bone fracture and intracranial hemorrhage may be associated with short and long-term post-traumatic pituitary dysfunction, respectively.

AI snapshot

Written from the paper’s full text.

TL;DR

In a nationwide Taiwanese cohort, patients with traumatic brain injury (TBI) had higher risks of endocrine dysfunction and pituitary dysfunction at 1 and 5 years. Skull bone fracture was associated with short-term pituitary dysfunction, while intracranial hemorrhage became significant at 5 years.

Key findings

  • Among 156,945 insured subjects (31,389 TBI; 125,556 non-TBI), 1-year incidence of post-traumatic endocrinopathies was 0.4% in TBI vs 0.3% in non-TBI; 5-year incidence was 2%. TBI was associated with endocrine disorder at 1 year (adjusted HR 1.49; p < 0.001) and at 5 years (HR 1.27; p < 0.001).
  • Pituitary dysfunction at 1 year occurred in 35 (0.1%) TBI patients vs 80 (0.1%) non-TBI patients; TBI had adjusted HR 2.06 (p < 0.001).
  • By TBI type, endocrine disorder risk was significant for intracranial hemorrhage (HR 1.44; p = 0.007) and skull bone fracture (HR 2.05; p < 0.001), but not mild head injury (HR 1.34; p = 0.064). Pituitary dysfunction at 1 year was strongly associated with skull bone fracture (HR 3.77; p < 0.001), while at 5 years intracranial hemorrhage became significant (HR 1.46; p = 0.002) and skull fracture was not (HR 1.41; p = 0.134).

Methods

  • Retrospective nationwide cohort using Taiwan’s National Health Insurance Research Database/LHID 2005. TBI cases (ICD-9: 800–804, 850–854) from 1996–2009 were followed until death or end of 2009; non-TBI subjects were frequency matched 1:4 by age, sex, income, urbanization, diabetes, and hypertension.
  • Endocrine disorders were identified by ICD-9 codes 244, 253, 255, 258, and 259 with at least three outpatient visits within 1 year or one admission diagnosis. Exclusions included pre-existing endocrine dysfunction, stroke, brain tumor, and data errors/missing data.
  • Kaplan–Meier curves and log-rank tests were used, and Cox proportional hazards models computed adjusted hazard ratios after adjustment for comorbidities and sociodemographic characteristics (age, sex, income, urbanization).

Limitations

  • The authors state possible selection bias because patients with pre-existing subclinical endocrinopathy may not have been tested or excluded; the NHIRD lacks laboratory/hormone data, so specific hormone dysfunction types could not be assessed.
  • The authors also state they could not differentiate TBI severity (no coma scale, pupil size, muscle power, or imaging) or TBI mechanism, and mild TBI patients who did not seek care may be missing, potentially overestimating risk.
  • The paper notes the observed incidence may be low because clinicians may attribute nonspecific symptoms to TBI sequelae, severe patients are difficult to assess, and diagnostic tests/cut-offs vary.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/srep32987

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 8 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The risk of developing pituitary dysfunction at 1-year was significantly higher in TBI patients than in non-TBI patients after adjustment (adjusted HR 2.06; p < 0.001).

    “The risks of developing a common endocrinopathy (p < 0.001) or pituitary dysfunction (P < 0.001) were significantly higher in patients with a TBI history.”
    • Also stated in: § Pituitary dysfunction · boosted
      “Using multivariable regression analysis, patients in the TBI group demonstrated a significantly higher risk of developing a pituitary disorder during the 1-year follow up when compared with the non-TBI patients (adjusted HR: 2.06; p < 0.001; Table 3).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.
  • Findingown data

    The association between hemorrhagic head injury and risk of developing an endocrinopathy was significant (p = 0.007; HR 1.44).

    “but the association is significant in the group with hemorrhagic head injury (p value: 0.007, HR: 1.44).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.
  • Findingown data

    The association between skull bone fracture and risk of developing an endocrinopathy was more significant (p < 0.001; HR 2.05).

    “Moreover, the association was more significant in the skull bone fracture group (p value < 0.001, HR: 2.05).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.
  • Findingown data

    The association between post-traumatic endocrinopathies and TBI remained at the 5-year follow-up (p < 0.001; HR 1.27).

    “The association between post-traumatic endocrinopathies and TBI remained at the 5-year follow up (p value < 0.001, HR: 1.27; Table 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.
  • Findingown data

    The incidence of post-traumatic endocrinopathies at the 1-year follow-up in this study (0.4%) is far lower than most studies.

    “In our study, the incidence of post-traumatic endocrinopathies at the 1-year follow up was 0.4%, which is far lower than most studies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.
  • May combine two claims. 14
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    The incidence of post-traumatic endocrinopathy and pituitary dysfunction increased linearly over the 5-year period, and the gap between patients with and without TBI increased gradually.

    “According to Fig. 2a,b, the incidence of post-traumatic endocrinopathy and pituitary dysfunction increased linearly over the 5-year period, and the gap between patients with and without TBI increased gradually.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

  • May combine two claims.

    Findingown data

    At the 5-year follow-up, the association between skull bone fracture and pituitary dysfunction became less significant compared with the 1-year follow-up, while the association between intracranial hemorrhage and pituitary dysfunction became stronger.

    “When we evaluated the risk of pituitary dysfunction among the three types of brain injury at the 5-year follow-up, the association between skull bone fracture and pituitary dysfunction became less significant compared with the association at the 1-year follow up. In contrast, the association between intracranial hemorrhage and pituitary dysfunction became stronger.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

  • The quote only partly states this claim.

    Findingown data

    The association between intracranial hemorrhage and pituitary dysfunction was not significant at the 1-year follow-up.

    “In addition, the association between intracranial hemorrhage and pituitary dysfunction was not significant.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

  • Classified as probably not a substantial claim.

    Findingown data

    Overall, 156,945 insured subjects were included in the final analysis.

    “Overall, 156,945 insured subjects were included in the final analysis.”
    • Also stated in: § Study subjects and design · plain
      “Overall, 156,945 insured subjects (31,389 matched sets) were included in the final analysis (Fig. 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There were 31,389 patients in the TBI group and 125,556 patients in the non-TBI group.

    “There were 31,389 patients in the TBI group and 125, 556 patients in the non-TBI group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Thirty-five (0.1%) TBI patients and 80 (0.1%) non-TBI patients were newly diagnosed with a pituitary disorder during the 1-year follow-up.

    “Thirty-five (0.1%) patients in the TBI group and 80 (0.1%) patients in the non-TBI group were newly diagnosed with a pituitary disorder during the 1-year follow-up period (Table 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

  • May combine two claims.

    Findingown data

    Among TBI patients, 11,063 (35.2%) had mild head injury, 14,940 (47.6%) had head injury and intracranial hemorrhage, and 5,386 (17.2%) had a skull bone fracture.

    “Table 1 shows that 11,063 (35.2%) patients had mild head injury, 14,940 (47.6%) had head injury and intracranial hemorrhage, and 5,386 (17.2%) had a skull bone fracture.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Short-term hormone dysfunction after TBI could be explained by acute phase inflammation and stress.

    “Short-term hormone dysfunction could also be explained by acute phase inflammation and stress49505152.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [49] Van den Berghe, G. & de Zegher, F. & Bouillon, R. Clinical review 95: acute and prolonged critical illness as different neuroendocrine paradigms. Journal of clinical endocrinology and metabolism 83, 1827–1834 (1998).

      Not checked in the free run.

    • cites [50] Beishuizen, A., Thijs, L. G. & Vermes, I. Patterns of corticosteroid-binding globulin and the free cortisol index during septic shock and multitrauma. Intensive care medicine 27, 1584–1591 (2001). source

      Not checked in the free run.

    • cites [51] Annane, D. et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. Jama 283, 1038–1045 (2000). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The impact causing a skull bone fracture lasts only a short period, which would only cause short-term pituitary dysfunction.

    “First, the impact that causes a skull bone fracture lasts for only a short period, which would only cause short-term pituitary dysfunction.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The impact that causes a skull bone fracture lasts only a short period.

  • May combine two claims.

    Premisecitation

    Previous studies on post-traumatic endocrinopathies have limitations including small sample size and choice of diagnostic criteria.

    “However, there is lack of long-term follow-up and large sample size studies.”
    • Also stated in: § Abstract · plain
      “However, several review articles have reported a number of limitations on the part of previous studies on post-traumatic endocrinopathies, including small sample size25 and choice of diagnostic criteria26.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Lauzier, F. et al. Clinical outcomes, predictors, and prevalence of anterior pituitary disorders following traumatic brain injury: a systematic review. Critical care medicine 42, 712–721 (2014). source

      Not checked in the free run.

    • cites [26] Klose, M. et al. Prevalence and predictive factors of post‐traumatic hypopituitarism. Clinical endocrinology 67, 193–201 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Skull bone fracture and intracranial hemorrhage may be associated with short-term and long-term post-traumatic pituitary dysfunction, respectively.

    “Skull bone fracture and intracranial hemorrhage may be associated with short and long-term post-traumatic pituitary dysfunction, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TBI may have a greater effect on pituitary than on other non-pituitary hormone tissues because the pituitary gland is located inside the cranial vault and could face direct impact from the injury.

    “This result shows that TBI may have a greater effect on pituitary than on other non-pituitary hormone tissues because the pituitary gland is located inside the cranial vault and could face direct impact from the injury, whereas other endocrine glands, located outside the cranial vault, would not have the same level of risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The impact causing an intracranial hemorrhage lasts for a short time, but once the hemorrhage occurs, it can mean long-term neuron functional loss.

    “Second, although the impact causing an intracranial hemorrhage lasts for a short time, once the hemorrhage occurs, it can mean long-term neuron functional loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Some patients with TBI may not have been recorded because patients with mild head injury do not always seek medical help, which could decrease the risk of post-traumatic endocrinopathy and cause an over-estimate.

    “The fourth limitation was that some patients with TBI may not have been recorded in the database because patients with mild head injury do not always seek medical help and would not be admitted to a hospital. This population could further decrease the risk of post-traumatic endocrinopathy and cause an over-estimate in our study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Mean age and sex distribution were similar because the non-TBI group was age- and sex-matched with the original cohort.

    “Mean age and the sex distribution were similar because the non-TBI group was age- and sex-matched with the original cohort.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Increased intracranial pressure caused by brain edema is a mechanism for pituitary dysfunction after TBI.

    “Wachter et al. reported that the increased intracranial pressure caused by brain edema is a mechanism for pituitary dysfunction after TBI44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Wachter, D., Gündling, K., Oertel, M. F., Stracke, H. & Böker, D.-K. Pituitary insufficiency after traumatic brain injury. Journal of Clinical Neuroscience 16, 202–208 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Clinicians tend to attribute non-specific symptoms such as headache, dizziness, and extremity weakness to head injury sequelae rather than to an endocrinopathy, so patients seldom receive hormonal evaluation.

    “Some of the reasons for this low incidence rate are, initially, that clinicians tend to attribute non-specific symptoms such as headache, dizziness, and extremity weakness to head injury sequelae rather than to an endocrinopathy. Consequently, patients seldom receive a hormonal evaluation to confirm the diagnosis.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The TBI and non-TBI subjects were frequency matched randomly by age, sex, income, urbanization, diabetes, and hypertension at a ratio of 1:4.

    “The TBI subjects and non-TBI subjects were frequency matched randomly by age, sex, income, urbanization, diabetes, and hypertension at a ratio of 1:4 (TBI subjects vs. non-TBI user).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypoxia following brain injury causes pituitary dysfunction.

    “Hypoxia following brain injury also causes pituitary dysfunction6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Kelly, D. F. et al. Hypopituitarism following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a preliminary report. Journal of neurosurgery 93, 743–752 (2000). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cox proportional hazards models were used to compute hazard ratios and 95% confidence intervals after adjustment for comorbidities and sociodemographic characteristics.

    “Finally, Cox proportional hazards models were used to compute the hazard ratios (HRs) and 95% confidence intervals (CIs) after adjustment for comorbidities and sociodemographic characteristics (age, sex, income, and level of urbanization).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by the ethics review board of Chang Gung Memorial Hospital, Chia-Yi Branch, and informed consent was waived.

    “This study adhered to strict confidentiality guidelines, in accordance with regulations regarding personal electronic data protection, and was approved by the ethics review board of the Chang Gung Memorial Hospital, Chia-Yi Branch(No: 103-0504B). The data were analyzed anonymously and the requirement for informed consent was waived by institution of review board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Brain injury from a shearing force could result in a hypothalamic-pituitary injury.

    “Salehi et al. also stated that brain injury from a shearing force could result in a hypothalamic-pituitary injury45.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Salehi, F., Kovacs, K., Scheithauer, B. W., Pfeifer, E. A. & Cusimano, M. Histologic study of the human pituitary gland in acute traumatic brain injury. Brain Injury 21, 651–656 (2007). source

      Not checked in the free run.

22 of 22

  • The paper relies on this without support.

    The ICD-9 codes used to identify TBI and endocrine disorders accurately classify these conditions in the NHIRD.

    “Endocrine disorders were identified using the following ICD codes: 244 (acquired hypothyroidism), 253 (pituitary dysfunction), 255 (adrenal gland disorders), 258 (polyglandular dysfunction), and 259 (other endocrine disorders) with at least three records of outpatient visits within 1 year or one admission diagnosis during the study period.”
    “This study included patients who suffered from TBI (ICD9:800–804, 850–854) during 1996–2009.”

  • The paper relies on this without support.

    The energy needed to cause a skull bone fracture is greater than the energy required to cause a mild head injury.

    “Second, impact power differs, as the energy needed to cause a skull bone fracture is probably greater than the energy required to cause a mild head injury.”

  • The paper relies on this without support.

    The impact that causes a skull bone fracture lasts only a short period.

    “First, the impact that causes a skull bone fracture lasts for only a short period, which would only cause short-term pituitary dysfunction.”

  • The paper relies on this without support.

    The LHID 2005 is representative of all Taiwanese beneficiaries.

    “The NHRI extracted one million randomly sampled representative data from the registry of all enrollees and created the Longitudinal Health Insurance Database in 2005 (LHID 2005), which is representative of all beneficiaries.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A study of Taiwan health insurance records found that rates of pituitary deficiencies increased nationally over the first 5 years after TBI.

    “A study of Taiwan health insurance records found that rates of deficiencies increased nationally over the first 5 years after TBI [22].”

    From Neuroendocrine Disruptions Following Head Injury (2023) · cites this paper as [22]

  • Pituitary deficiencies may develop at a delay, appearing months to years later after TBI.

    “Notably, pituitary deficiencies may also develop at a delay, appearing months to years later.”

    From Neuroendocrine Disruptions Following Head Injury (2023) · cites this paper as [22]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Cyran, E. Hypophysenschädigung durch schädelbasisfraktur. Dtsch Med Wschr 44, 1261 (1918).

Cited by

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Related

Authors
Yang, W.-H., Chen, P.-C., Wang, T.-C., Kuo, T.-Y., Cheng, C.-Y., & Yang, Y.-H.
Affiliations
  • Chang Gung Memorial Hospital (TW)
  • National Taiwan University (TW)
Corresponding author
  • Chen, Pau-Chung
  • Yang, Yao-Hsu
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-09-09
Volume
6
Issue
1
Pages
32987-32987
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep32987
PMC
PMC5017132
OpenAlex
W2515229191
Semantic Scholar
6921197e18861d4259e52135612d823f2080f1ba
Cited by
36
References
57
Citations by year
2026: 1 · 2025: 5 · 2024: 6 · 2023: 6 · 2022: 1 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 3
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Chang Gung Medical Foundation (CORPG6D0161)
  • National Health Research Institutes
  • Chiayi Chang Gung Memorial Hospital
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
Keywords
traumatic brain injury, pituitary dysfunction, acquired hypothyroidism, adrenal disorders, intracranial hemorrhage, incidence, long-term follow-up, health insurance claims
MeSH terms
Brain Injuries, Traumatic, Adolescent, Adult, Aged, Child, Child, Preschool, Endocrine System Diseases, Female, Humans, Male, Middle Aged, Skull Fractures, United States, Incidence, Risk Assessment, Young Adult

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