Psychosocial Trauma History Negatively Impacts Liver Transplant Access in Women with Chronic Liver Disease

Introduction Few studies have evaluated the impact of psychological trauma (mental, emotional, or physical) on liver transplant (LT) candidacy and outcomes. Methods We performed a single center retrospective analysis of patients who completed routine LT evaluation between October 2017 and June 2021. We identified the prevalence of psychological trauma history in men and women LT candidates and evaluated the association between trauma history and LT access. The primary outcome measure was listing for LT. Results A total of 463 patients completed LT evaluation, of which 17% (n = 79) reported a history of trauma: 49 of 159 women and 30 of 304 men. Trauma history was significantly more common in women than in men (31% vs. 10%, p < 0.001). Women with trauma history were less likely to be listed for LT (80% vs. 93%, p = 0.016). Women with trauma history were also more likely to be removed from the LT waitlist (26% vs. 12%, p = 0.045); this persists when excluding patients removed for transfer to another center or for medical improvement (22% vs. 7%, p = 0.020). In contrast, listing for LT (87% vs. 86%, p = 0.973) and waitlist removal (12% vs. 10%, p = 0.766) did not differ in men with and without trauma history. In those that received a LT (n = 107), post-LT relapse, rejection, readmissions, and death did not differ in patients with (n=13)and without (n=94) trauma history. Conclusions Trauma history is associated with reduced access to LT in women but not men with chronic liver disease. Further studies are needed to understand the impact of psychological trauma on LT access and post-LT outcomes.


Introduction
Up to 90% of adults in the United States experience at least one potentially traumatic event (PTE) in their lifetime, but the prevalence of post traumatic stress disorder (PTSD) is less than 10% [1].Instead, many patients experience distressing symptoms that can lead to developing non-PTSD psychiatric comorbidities such as mood and substance-use disorders after a PTE [2].Psychological trauma is a broad term that encompasses any emotional, painful, distressful, or shocking experiences that result in long term mental and physical efects [2].Rather than a criteria-based diagnosis, psychological trauma relies on an individual's subjective experience [1].Because individuals perceive PTEs diferently, behavioral response, emotional response, and long-term impact can vary from patient to patient [2].
Tere is a wide breadth of literature on sex and genderbased diferences in PTE exposure and response.Tough there is considerable geographic and cultural variation in this, women are more likely to experience sexual and partner violence and men are more likely to experience combatrelated trauma or trauma related to witnessing the harm of others [3][4][5].Women are at greater risk of developing comorbid psychiatric conditions after a PTE, including a twofold greater risk of PTSD when compared to men [4].Some data suggest that men are more like to develop substance use disorders, though substance use is common in women with trauma history as well [5].Tere is signifcant interplay between trauma and the risk of developing an alcohol use disorder, where either of these may increase the risk of developing the other [6].
Te prevalence of trauma-related disorders in patients with cirrhosis is not widely reported, though the prevalence of PTSD may be as high as 34% in patients with severe alcohol use disorder who have developed liver disease [7].
When present, there is potential for psychological trauma to impact liver transplant (LT) outcomes.Trauma history has been associated with alcohol and substance relapse [8][9][10] and poor medication adherence in patients with liver disease [9,11,12].In a very small study of pediatric LT recipients, childhood trauma was associated with a higher risk of transplant rejection [13,14].Whether trauma history is routinely assessed during adult LT evaluation is not clear, as it is not specifcally addressed in the literature related to the psychosocial evaluation [15,16].As such, the infuence of psychological trauma (mental, emotional, or physical) on adult LT is not well described.Our primary objective was to assess for association between psychological trauma history and access to LT in patients with advanced liver disease, with a focus on gender diferences.

Patient Selection.
We performed a single center retrospective analysis of patients with cirrhosis who underwent routine LT evaluation at a large academic tertiary care and LT center between October 2017 and June 2021.Patients undergoing inpatient LT evaluation were excluded, as there are several factors that may interfere with collecting an accurate psychiatric and psychosocial history in the inpatient setting (e.g., hepatic encephalopathy, respiratory failure requiring intubation, and use of collateral information or interviewing family members).

Defning Trauma History.
Each patient underwent a complete psychosocial and psychiatric assessment conducted by experienced transplant psychiatrists and transplant social workers on the multidisciplinary transplant team.Evaluations were performed in clinic or via telehealth during the COVID-19 pandemic and support persons were present during the evaluation at the discretion of the patient.All patients were informed of the role of the transplant social worker and psychiatrists and the intended purpose and documentation of information collected during the interview.During the interview, patients were asked if they had a history of trauma in the form of an open-ended question.Because the experience of trauma is subjective, patients were categorized into one of two groups, "trauma" or "no trauma," based on their response to this question.Patients reporting trauma related to the liver disease diagnosis or the transplant process were not included in the trauma group.Tose with a history of trauma were further characterized by the source and type of trauma.Category selection was informed by existing psychology literature and trends identifed in our patient cohort [5].Te source of trauma was categorized as one of the following: childhood, adult, work related, death of another person, and others.Te type of trauma was categorized as one of the following: sexual violence, physical violence, experienced event without direct harm, physical trauma without directed violence, and other.Examples of trauma type can be found in Supplemental Table 1.

Data Collection.
Data were extracted directly from the electronic health record.Demographic data included age, race (White vs. non-White), ethnicity (Hispanic vs. non-Hispanic), highest level of education (high-school vs. >high school), and primary language (English vs. non-English).Biologic sex and patient gender were collected; because all patients were cisgender, male and female patients are referred to as men and women, respectively.Liver disease etiology was defned using the primary diagnosis in the transplant encounter; primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis were collapsed to autoimmune liver diseases (AILDs) for analytic simplicity.Body mass index (BMI) and Model for End Stage Disease-Sodium (MELD-Na) score were collected from the time of LTevaluation.Psychosocial variables included relationship status (partner vs. no partner), occupational status in the preceding year (employed vs. unemployed), and living situation (lives with family vs. does not live with family).Comorbid psychiatric disorders (anxiety, depression, and bipolar depression) and substance-use history (tobacco, cocaine, marijuana, and opioid) were collected as well.Post-LT substance use, biopsy-proven rejection, hospital readmissions, and two-year survival were recorded for patients who underwent LT.Data were managed using the REDCap electronic data capture tools at our institution [17,18].

Analysis.
Te primary aim of the analysis was to assess for association between psychological trauma history and LT access in women and men.Outcome measures included waitlist registration (listing), waitlist removal, and receipt of LT.Multivariable logistic regression was used to evaluate for association between trauma history and outcomes measures.We opted to use augmented backward logistic regression for these analyses to increase the reliability of the model by accounting for pertinent demographic and psychosocial factors [19,20].Te following variables were included on initial entry: trauma history, age, MELD-Na, BMI, race, ethnicity, liver disease etiology, education, employment, primary language, relationship status, living with family, depression, anxiety, psychotropic medications, tobacco use, cocaine use, marijuana use, and opioid use.Strength of association is reported as odds ratio (OR) with 95% confdence interval (95% CI).Statistical analyses were performed in SPSS 29.Tis study was reviewed and approved with a waiver of informed consent by the institutional review board at our medical center.

Patient Characteristics.
A total of 463 patients completed routine LT evaluation, of which 17% reported a history of trauma (49 of 159 women and 30 of 304 men).Patients with trauma history were younger (p < 0.001) and more likely to be White (p � 0.032).Women were signifcantly more likely to report a history of trauma than men 2 Journal of Transplantation (31% vs. 10%, p < 0.001) (Table 1).In general, patients were diagnosed with liver disease 3-4 years prior to LT evaluation.Mean BMI (p � 0.229) and MELD-Na scores (p � 0.676) were similar between the groups (Table 1).
Tere were multiple psychosocial diferences in patients with and without trauma history.Patients with a history of trauma were less likely to be living with a family member (58% vs. 76%, p � 0.002) and less likely to have a stable relationship partner (42% vs. 63%, p < 0.001) (Table 1).Psychiatric comorbidities including depression (p < 0.001), anxiety (p < 0.001), and bipolar disorder (p < 0.001) were more prevalent in patients with a history of trauma, and these patients were more likely to be prescribed a psychotropic medication at the time of LT evaluation (51% vs. 26%, p < 0.001) (Table 1).Prior diagnosis of acute alcohol associated hepatitis (AAH) was signifcantly more common in patients with a history of trauma (32% vs. 14%, p < 0.001).Substance-use history including marijuana (p � 0.028), opioid (p � 0.002), and cocaine (p < 0.001) use were more common as well, though tobacco-use history did not difer between the groups (p � 0.136) (Table 1).Te relationship between trauma history andseveral psychosocial variables observed in the total cohort difered when stratifed by gender (Table 1).

Trauma History.
Of the patients that reported a history of trauma (n = 79), 87% patients completed their psychosocial evaluation in clinic and 67% were accompanied by a support person.Almost all patients reported the source of their trauma history (n = 76, 96%).Childhood trauma was the most common source of trauma history (n = 31, 39%) followed by physical abuse and/or intimate partner violence (n = 18, 23%).Most patients also shared details of their trauma history (n = 66, 86%).Twenty-seven patients (34%) reported experiencing physical violence and twelve patients (15%) reported trauma related to sexual violence.Patients with a history of sexual trauma were 5.3 times more likely to be a woman (95% CI 1.1-25.6,p � 0.040), and trauma related to partner violence was exclusively reported in women (18 of 49 women).Disclosure of trauma details did not difer in patients who completed their evaluation in clinic compared to via telehealth (86% vs. 90%, p � 0.701) or in patients who were accompanied during their visit compared to alone (85% vs. 87%, p � 0.668).A similar proportion of men and women provided details of their trauma history (80% vs. 90%, p � 0.222).See Table 2 for a summary of trauma experiences and Supplemental Table 1 for examples within each categorization.

Study Outcomes.
In total, 14 of 79 (18%) of patients with a history of trauma and 45 of 384 (12%) patients without a history of trauma were declined for listing during LT evaluation.Te most common reasons patients were declined for listing were clinical improvement (n = 12, 20%), medical contraindication to transplant (n = 12, 20%), and substance use (n = 12, 20%).Of those declined, patients with trauma history were more likely to be declined for substance use (43% vs. 13%, p � 0.017) (Figure 1).

Waitlist Access.
Women with trauma history were signifcantly less likely to be listed for LT than women without trauma history (80% vs. 93%, p � 0.016) (Figure 2(a)).Te reasons for which women were declined for listing did not difer between those with and without trauma history.On multivariable analysis, trauma history was independently associated with being declined for listing in women (OR 0.2, 95% CI 0.1-0.69,p � 0.011, Table 3).Waitlist enrollment did not difer in men with and without a history of trauma (87% vs. 86%, p � 0.973) (Figure 2(a)).

Waitlist Removal.
Of those that were listed for LT, 10 of 39 (26%) women with trauma history were removed from the waitlist compared to 14 of 102 (14%) women without trauma history (Figure 2(b)).Excluding those removed due to improvement in condition (n = 4), at patient request (n = 3), or at the time of transfer to another center (n = 2), women with trauma history were signifcantly more likely to be removed from the waitlist compared to women without trauma history (22% vs. 7%, p � 0.020).Women with trauma history were more likely to be removed for substance use or poor psychosocial support than women without trauma history (70% vs. 17%, p � 0.027).On multivariable analyses, trauma history was associated with over fvefold greater odds of being removed from the LT waitlist for unfavorable reasons (OR 5.8, 95% CI 1.6-20.8,p � 0.013) (Table 4).Te rate of waitlist removal did not difer by trauma group in men (12% vs. 10% p � 0.761) (Figure 2(b)).

Transplant Outcomes.
A total of 13 patients with a history of trauma (6 women and 7 men) and 94 patients without a history of trauma (20 women and 74 men) underwent LT (Figure 2(c)).Fewer patients with trauma history underwent LT than patients without trauma history (17% vs. 25% p � 0.121).Te mean MELD-Na score at the time of LT did not difer in patients with and without trauma history (21 vs. 19, p � 0.613).Te mean number of hospital readmissions within one year of LT was similar in patients with and without pre-LT trauma history (p � 0.513) and about one half had 2 or more readmissions (54% trauma vs. 48% no trauma, p � 0.682).Te rate of biopsy proven acute cellular rejection did not difer based on pre-LT trauma history (8% trauma vs. 24% no trauma, p � 0.198).Alcohol relapse was similar between groups as well.Of those with ALD, 1 of 9 patients with a pre-LT trauma history experienced alcohol relapse within two years of LT compared to 6 of 54 patients without pre-LT trauma history (p � 1.000).Post-LT outcomes were not analyzed by gender due to the sample size.See Table 5 for a summary of post-LT metrics.

Discussion
Our results suggest that a history of psychological trauma is associated with reduced access to LT, particularly among women.One in three LT candidates in our study was a woman, which is consistent with known trends of liver disease in the United States [21,22].Women were more likely to report a history of trauma than men.Women with a history of trauma were less likely to be listed for LT and more likely to be removed from the LT waitlist to  A total of 20 additional clinically relevant variables, including depression and anxiety, were entered into a single-entry multivariable model (left) to evaluate whether trauma history was associated with listing for LT.Backward conditional logistic regression was applied to identify independent predictors of being listed (right).Trauma history was associated with lower odds of listing and was identifed as an independent predictor of the listing outcome.Additional predictors include disease etiology and BMI.LT: liver transplant; BMI: body mass index; MELD-Na: model for end stage liver disease-sodium score; ALD: alcohol-associated liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease; HCV: chronic hepatitis C; AILD: autoimmune liver diseases.
6 Journal of Transplantation women without a history of trauma.In contrast, there were no diferences in listing or waitlist removal in men with and without a history of trauma.Importantly, in patients who received a LT, trauma history did not afect post-LT rejection, substance relapse, or readmission rates.We analyzed a considerable number of variables to determine potential drivers of the observed gender diferences.Trauma history has been associated with mood and substance use disorders [23].Women with a history of trauma had the highest prevalence of ALD in our study, but high risk alcohol use did not appear to difer between genders.Approximately 30-40% of both men and women with a history of trauma had a prior diagnosis of AAH compared to 15% of both men and women without a history of trauma.Tis suggests that trauma history had a similar association with high-risk drinking behaviors in both genders.
With respect to substance use, women with trauma history were less likely to report prior substance use than men.Furthermore, 100% of the men with a history of trauma that were declined for listing were declined for substance use compared to 20% of women with a history of trauma.Tis fnding may be related to higher rates of cocaine use and hepatitis C virus (HCV) in men in our study.While the trend of increased substance use in men with trauma history was consistent with prior studies, it is somewhat counterintuitive as trauma history did not afect LT access in men.
We did observe higher rates of anxiety and depression in women than men, and previous studies have shown that women are more likely to develop anxious and depressive disorders after a PTE.However, none of the patients in the study were declined for listing or removed from the waitlist for poorly controlled psychiatric comorbidities.Furthermore, we did not fnd depression to be associated with listing on our multivariable analysis.Tese fndings suggest that mood and substance use disorders are not the drivers of the gender disparity observed in this study.
Diferent levels of psychosocial support may play a role in our fndings of reduced LT access in patients with trauma history.Trauma history is associated with long-term efects on interpersonal connections and relationships [2,24].Both men and women with trauma history were less likely to live with family members and less likely to have a stable relationship at the time of LT evaluation.However, women with trauma history were more likely to be declined for listing due to psychosocial reasons compared to both men with trauma and women without trauma.Women with trauma history were also more likely to be lost to follow up during the evaluation process, which may refect lower levels of support.Te connection between gender and psychosocial support may be infuenced by the type of trauma experienced.Specifcally, sexual trauma has been associated with greater impairments in interpersonal relationships [25], and women in our study were signifcantly more likely to experience sexual trauma.Tough we were unable to account for this in our study, it is possible that reduced psychosocial support in women with trauma history was a stronger driver of the observed gender diferences than substance use or mood disorders.
Limitations of this study include its single center and retrospective design.While these factors may afect the generalizability of our fndings, the study's sample size and conduct at a safety net hospital might mitigate some of these limitations.Our study also relied on self-reported trauma history and may be subject to recall or reporting bias.To minimize these biases, we focused our analysis on patients evaluated in the outpatient setting, where they were neither acutely ill nor afected by overt encephalopathy.Our study had a limited racial representation with a notably lower proportion of Black and African American patients than expected compared to the national LTpopulation.While this is representative of the population in Massachusetts, we were not able to address potential diferences related to race.In addition, it should be noted that a relatively small number of patients with a history of trauma underwent LT and fndings related to post-LT outcomes should be interpreted with caution.Despite these limitations, we believe these results are important due to the profound association between psychological trauma history and reduced access to LT.All patients at our institution were asked about trauma history, but it is not known whether trauma history is routinely addressed during the LT evaluation at other institutions.Currently, assessment of trauma history is not discussed in practice guidance about the psychosocial evaluation and is not included in well-known psychosocial evaluation tools like the SIPAT [15,16,26].Tese factors in conjunction with the lack of published data on this topic suggest that trauma history many not be routinely queried during the LT evaluation process.Bringing attention to this may be of increasing importance in the post-COVID-19 era given the number of young people reporting trauma related to the pandemic [27].Future research should investigate the association between trauma history and post-LT outcomes, and explore the relationship between psychological trauma and access to transplantation in other solid organ transplants.Futhermore, qualitative studies assessing for system or provider level bias towards women with complex psychosocial history are needed to further address this disparity.

AILD:
Autoimmune liver diseases PTSD: Posttraumatic stress disorder LT: Liver transplant MELD-Na: Model for End Stage Disease-Sodium BMI: Body mass index DSM: Diagnostic and statistical manual of mental disorder OR: Odds ratio 95% CI: 95% confdence interval ALD: Alcohol-associated liver disease MASLD: Metabolic dysfunction-associated steatotic liver disease HCV: Chronic hepatitis C AAH: Acute alcohol-associated hepatitis.

Figure 1 :Figure 2
Figure 1: Reasons patients were declined for listing by patient gender and trauma history group.

Figure 2 :
Figure 2: Transplant-related outcomes by patient gender and trauma history, reported as percentages.(a) Listing rates by patient gender and history group.Trauma history was associated with lower waitlist registration in women (p � 0.016) but not in men (p � 0.973).(b) Waitlist removal by patient gender and trauma history group.Trauma history was associated with higher waitlist removal in women (p � 0.027) but not in men (p � 0.761).(c) Transplant rate by patient gender and trauma history group.Fewer men and women with trauma history received a liver transplant, though this did not reach statistical signifcance (p � 0.121).

Table 2 :
Trauma experiences by patient gender.

Table 1 :
Patient demographics by Trauma and No trauma status in men, women, and the total cohort.
Post-LT outcomes were evaluated in the total cohort only due to sample size.Demographics are compared between patients with (+) and without (− ) a history of trauma in the total cohort, in men, and in women using chi squared or Students t tests.Signifcance was evaluated at p < 0.05.BMI: body mass index; MELD-Na: Model for End Stage Liver Disease-Sodium score; ALD: alcohol-associated liver disease; MASLD: metabolic dysfunction-associated steatotic liver disease; HCV: chronic hepatitis C; AILD: autoimmune liver diseases.

Table 3 :
Predictors of listing for LT among women LT candidates using multivariable and backward logistic regression analyses.

Table 4 :
Multivariable and backward logistic regression for predictors of being removed from the LT waitlist in women.