PDF icon Download PDF
Open Access
CC BY 4.0 · Indian Journal of Neurotrauma
DOI: 10.1055/s-0045-1809174
Review Article

Liver Dysfunction in Patients with Neurotrauma

Luis Rafael Moscote-Salazar 
1   Department of Research, AV HealthCare, Innovators, LLC, Madison, Wisconsin, United States
,
Tariq Janjua 
2   Department of Research, Aneuclose, Eagan, Minnesota, United States
,
Ved Praksh Maurya 
3   Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow, Uttar Pradesh, India
,
Amit Agrawal 
4   Department of Neurosurgery, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
› Author Affiliations
› Further Information
Also available ateRefMedOne
 
 PDF Download Permissions and Reprints

Abstract

Traumatic brain injury (TBI) has emerged as a leading cause of morbidity and mortality around the world, often instigating systemic complications. An underappreciated consequence of TBI is hepatic dysfunction, which can potentiate neuroinflammation and worsen the patient's prognosis. This mini-review describes how neurotrauma drives liver dysfunction mechanisms, alongside the involvement of the systemic inflammatory response and possible treatment modalities to prevent secondary organ injury. A literature review was performed to assess current evidence on TBI-induced hepatic dysfunction, inflammatory mediators, and liver–brain interactions. Neurotrauma activates the systemic acute-phase response that brings hepatocellular injury, metabolic disruption, and immune dysfunction. Changes in the gut–liver–brain axis, an increase of oxidative stress, and changes in cytokine signaling altogether result in secondary liver injury following TBI. Liver dysfunction should be considered a secondary complex consequent with TBI to derive better management for patients. Future studies should be directed toward brain–liver axis-targeted therapeutic interventions to manage systemic inflammatory responses.


 

Keywords

traumatic brain injury (TBI) - hepatic dysfunction - neuroinflammation - systemic complications - systemic inflammatory response - neurotrauma - hepatocellular injury - metabolic disruption

Introduction

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, often extending its effect beyond the confines of the head.[1] TBI is associated with approximately 30% of all injury-related deaths. Hepatic dysfunction is seldom appreciated during this unstable period of TBI care.[2] The liver is an essential organ from a metabolic, detoxifying, and immunological perspective, which is prone to injuries after TBI.[3] While it is established that brain injury leads to systemic inflammation and disrupts homeostasis, the exact pathways that TBI uses to influence the liver are complicated and not well understood ([Fig. 1]).[2] This review will comment on the mechanisms behind hepatic damage after traumatic brain injury, clinical expressions, and potential targets of treatment to counter damage.

Zoom
Fig. 1 Physiopathological effects associated with neurotrauma and liver dysfunction.

 

Mechanisms of Hepatic Dysfunction after TBI

TBI incites a series of neuroinflammatory responses leading to systemic impact.[4] Damage-associated molecular patterns and proinflammatory cytokines released from the brain can activate the peripheral immune system and cause generalized inflammation.[5] This inflammatory response may then spread to the liver, motivating the aggravation of existing liver conditions or causing further liver damage.[5] [6] Thus, the activation of the microglial cells in the brain can incite the release of cytokines like tumor necrosis factor-α (TNF-α) and interleukins, which ultimately promote liver injury ([Fig. 2]). On the other side, our group proposes the concept of neurogenically originated systemic inflammatory response syndrome (SIRS) to highlight the potential role of SIRS as a secondary systemic complication after acute TBI.[7]

Zoom
Fig. 2 Damage-associated molecular patterns (DAMPs) and cytokines release followed by hepatic impact.

 

Autonomic Regulation Disruption

Acute autonomic dysregulation occurs due to TBI, and it refers to the balance of sympathetic and parasympathetic functions.[8] The development of dysregulation has implications for hepatic function, which leads to changes in hepatic blood flow perfusing the liver.[9] This is impacted at the microcirculation level, which could influence its functional state. The disruption of hepatic blood flow might affect metabolic processes at the systemic level.[9]


 

Gut–Liver Axis and TBI

The gut–liver axis also plays a central role by which neurotrauma can affect hepatic health.[10] Following brain injury, changes in gut permeability and microbiome composition can cause bacterial translocation and endotoxins released into the bloodstream. [3] [11] [12] These toxins can induce systemic inflammation and liver dysfunction, further aggravating the original brain injury. This pathway has received interest as a contributor toward hepatic and neuroinflammatory processes after TBI.[3] [12]


 

Fructose and Liver Metabolism

Fructose significantly impacts the inflammatory response and contributes to lipid peroxidation in the liver, potentially leading to various metabolic disturbances and liver-related complications.[13] Metabolism of fructose occurs in the liver. Overconsumption of fructose impacts metabolic processes, including the desensitization of insulin receptors, leading to insulin resistance, particularly in TBI patients.[14] Insulin resistance promotes de novo lipogenesis, the metabolic process where excess carbohydrates (like fructose) are converted into fatty acids and stored as triglycerides in the liver. This accumulation of fat can lead to nonalcoholic fatty liver disease and worsen overall liver function.[15] 4-HNE (4-hydroxynonenal), a marker of lipid peroxidation, is elevated following TBI and excessive fructose consumption. Elevated 4-HNE levels indicate oxidative stress and tissue damage, which can further impair liver function.

The disruption of membrane integrity caused by excessive fructose intake can interfere with the metabolism of essential fatty acids like docosahexaenoic acid (DHA).[12] A deficiency or disruption in DHA could compromise brain health, especially in TBI patients, whose neuronal membranes and repair mechanisms are already under strain.[12] DHA is crucial for maintaining membrane fluidity and function in the brain and the body.[12] Increased plasma levels of 14,15-epoxyeicosatrienoic acid (EET), a product of soluble epoxide hydrolase (sEH) metabolism, mediate the neuroprotective effects of hepatic sEH ablation. Higher levels of sEH activity in the liver may exacerbate the damage and hinder recovery from TBI. By manipulating hepatic sEH activity, mainly through genetic alterations or modulation of sEH metabolites like EETs, there may be potential for novel therapeutic approaches to TBI.[16]


 

Oxidative Stress and Mitochondrial Dysfunction

TBI causes the production of reactive oxygen species, resulting in oxidative stress in the brain and the liver. Oxidative stress damages cellular membrane lipids, proteins, and nucleic acids. In the liver, this ultimately leads to apoptosis among hepatocytes and impaired function, which may cause advanced liver failure.[17] Mitochondrial dysfunction is also a critical part of the whole process, further disrupting energy metabolism in either tissue.


 

Clinical Manifestations of Liver Dysfunction Following TBI

Elevated levels of liver enzymes such as alanine aminotransferase and aspartate aminotransferase are often detected in patients following TBI, indicating hepatic injury.[18] While these markers are commonly used for liver injury detection, they lack specificity and can be elevated due to various causes, including muscle injury or systemic inflammation.[18] However, persistent elevation of these markers may indicate underlying liver dysfunction.


 

Coagulopathy and Jaundice

TBI can disrupt the liver's ability to synthesize clotting factors, leading to coagulopathy.[19] This dysfunction is particularly concerning in patients with severe brain injuries, as it can worsen bleeding tendencies and complicate surgical interventions.[20] Additionally, impaired bilirubin metabolism due to liver injury can result in jaundice, another clinical manifestation of hepatic dysfunction post-TBI.[21]


 

Acute Liver Injury and Failure

The ability of the liver to regenerate after acute liver injury may be impaired after trauma or injury; thus, this could lead to other systemic complications. Acute liver injury, and rarely, acute liver failure, can generally impair the patient's recovery to an immense extent and may warrant liver transplantation in the most severe cases.


 

Potential Therapeutic Targets

Anti-inflammatory strategies for the inflammation, which represent a major roadblock in the liver dysfunction associated with neurotrauma, interfering with inflammatory pathways, offer great hopes for therapy.[22] Drugs inhibiting cytokines such as TNF-α and interleukins or blocking other pathways, such as nuclear factor-kappa B signaling, are likely to reduce liver injury and provide beneficial patient outcomes.[22] Studies are ongoing in this regard, and clinical trials are investigating the usefulness of anti-inflammatory agents in TBI patients and the mechanisms through which they could provide hepatic protection.[22]


 

Modulation of the Gut–Liver Axis

Approaches to modulating the gut microbiome could be beneficial for reducing liver injury immediately after TBI.[23] Probiotics, prebiotics, and antibiotics have been tested in models to see whether they restore gut integrity and lessen inflammatory parameters.[23] Such treatments could lessen the impact on the liver by preventing bacterial translocation and its response.


 

Antioxidant Therapy

Oxidative stress is present in hepatic damage after traumatic brain injury; hence, antioxidant treatments have been submitted on the principle of reducing free radical production while partially protecting the brain and the liver.[24] Antioxidants such as N-acetyl cysteine as well as other mitochondrial dysfunction-targeting compounds might contribute toward the advantage of therapy for the prevention of liver damage that ensued due to TBI.[25]


 

Liver Regeneration and Support

It would be interesting to examine stem cell or liver assist device approaches toward severe liver injury caused by neurotrauma.[26] The development of bioengineered livers and regenerative medicine may provide bridge options for liver treatment until recovery.[27] Preclinical models: Several animal models have been created to study the relationship between TBI and liver injury, giving an understanding of the molecular and cellular mechanisms that underlie hepatic dysfunction after brain trauma.[28] Further investigations need to continue before translating them into clinical practice. Although there are studies focused on understanding liver injury following TBI, there have not been large randomized controlled trials that assess this. Future studies will focus on understanding the potential for liver protection by anti-inflammatory drugs, antioxidants, and modifications of the gut microbiome in TBI patients, thus increasing knowledge in this area. Gene therapy, nanomedicine, and bioengineering have opened up outstanding new opportunities for addressing liver injury after TBI. A combination of a targeted drug delivery system aimed exclusively at hepatic dysfunction on a molecular basis could be a new avenue in the management of such complex complications of TBI.


 

Conclusion

Hepatic damage after traumatic brain injury is a critical, yet less recognized complication seen after TBI. The interplay of neuroinflammation and oxidative stress on the gut–liver axis emphasizes the need for tailored therapeutic strategies. Although significant progression has been made in understanding the mechanisms behind liver injury after TBI, there are still challenges before these findings can be effectively employed in clinical treatment. Future research directions should include pinpointing novel therapeutic targets, patient monitoring improvements, and attempts to develop promising technologies for protecting the liver and overall patient outcomes in TBI.


 

 

Conflict of Interest

None declared.


Address for correspondence

Luis Rafael Moscote-Salazar, MD
AV Healthcare, Innovators, LLC, Madison, Wisconsin 53716
United States   

Publication History

Article published online:
20 June 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India


  Permissions and Reprints
Zoom
Fig. 1 Physiopathological effects associated with neurotrauma and liver dysfunction.
Zoom
Fig. 2 Damage-associated molecular patterns (DAMPs) and cytokines release followed by hepatic impact.