Associations between Gilbert’s syndrome and personality characteristics

Abstract Objective Gilbert’s syndrome (GS) is a benign genetic disorder that is characterized by intermittent mild jaundice in which the liver doesn’t process bilirubin properly. The aim of this study was to determine whether GS patients have a different personality structure and if there are associations between properties of temperament and character and total bilirubin levels. Methods A total of 1665 young male individuals aged from 19 to 30 who were admitted for occupational examinations were included in this study. Careful patient history was taken, a detailed physical examination was conducted, and hematologic and biochemical tests and abdominal ultrasonography were performed. The Turkish version of the Temperament and Character Inventory (TCI) was administered to all participants. 81 patients diagnosed with GS and 150 randomly chosen healthy individuals (control group) were investigated with comparison and correlation analyses. Results GS patients had higher scores than healthy controls for disorderliness (NS4) (p = 0.018), sentimentality (RD1) (p = 0.042), and fatigability (HA4) (p = 0.03). Moreover, Gilbert syndrome patients scored lower than controls for empathy (C2) (p = 0.041) and transpersonal identification (ST2) (p = 0.044). Bilirubin levels were positively associated with disorderliness (NS4) (r = 0.141, p = 0.032) and fatigability (HA4) (r = 0.14, p = 0.033). Conclusions GS patients may have some different personality characteristics from healthy individuals. This study is an initial exploration of the personality structure of GS patients and the findings should be interpreted with caution. Further prospective studies are needed to identify the relationship between Gilbert disease and personality characteristics.


Introduction
Gilbert's syndrome (GS) is a benign genetic disorder that is characterized as intermittent mild jaundice, in which the liver doesn't process bilirubin properly. The mechanism of GS is linked to reduced uridine diphosphate-glucuronyl-transferase (UGT) 1A1 activity, resulting in unconjugated hyperbilirubinemia. 1 Unconjugated hyperbilirubinemia occurs intermittently when patients are subject to stress factors, such as physical stress, prolonged fasting, and/or poor diet. 1 Emotional stimuli are associated with increases in the oxidative metabolites of bilirubin in human urine. 2 On the other hand, GS is believed to reduce the risk of various diseases because of the antioxidant properties of bilirubin. 3 Although associations between emotional stimuli and increased oxidative metabolites of bilirubin in human urine have been demonstrated, it is not obvious whether GS patients have a different personality structure or whether there are associations between properties of temperament and character and total bilirubin levels.
The dimensional method has utility for personality assessment according to Cloninger's psychobiological model. Personality has been modeled as two discrete components: character and temperament. Temperament is defined as a constitutionally or biologically based segment of the personality, expresses the automatic sentimental reaction to events, and is influenced by emotional, motor, and attentional reactivity and self-regulation, underlying a variety of personal decisions. 4,5 Character is defined as a self-concept, and is influenced by our interactions with people and our experiences and facility for learning. Therefore, these interactions and experiences enable greater flexibility and thus organization of personal differences in values and intentions.
Cloninger hypothesized that neurotransmitters were related to behavioral manifestations. 4 In this context, as an inherited disorder, GS could be associated with altered glucuronidation rates of these metabolites and, consequently, with behavioral manifestations.
The aim of this study was to investigate associations with temperament and character properties in GS patients and healthy individuals. These two groups were investigated by comparison and correlation analyses.

Personality characteristics
All study participants were instructed to fill in the Turkish version of the TCI for personality assessment. 4,5,7 Temperament is divided into four different independent parts in this representation, as follows: novelty seeking

Statistical analyses
The Statistical Package for the Social Sciences Whitney U test was used to compare variables which did not fit a normal distribution. We used chi-square tests to compare qualitative data. Pearson and Spearman tests were used for correlation analyses.

Results
There were 81 patients in the GS group and 150 patients in the control group. All of the patients were male. The mean age was 22.7±1.6 years in the GS group and 23.1±1.6 years in the control groups (p > 0.05). There were no differences between the two groups in terms of the following demographic variables: marital status, number of siblings or their order, where or with whom they were living, previous job experience, economic and family status, mothers' and fathers' health status or educational levels, or academic and school performance ( Table 1).
The GS patients had significantly higher scores than the controls for disorderliness (NS4) (p = 0.018), sentimentality (RD1) (p = 0.042), and fatigability (HA4) (p = 0.03) ( Table 2). GS patients scored lower Data presented as percentages, unless otherwise specified. *Including stepfamilies; single-parent families, and other configurations not classified as nuclear or extended families. than controls for the empathy (C2) (p = 0.041) and transpersonal identification (ST2) dimensions (p = 0.044). There were no statistically significant differences between the two groups for any of the other parameters.
The mean scores of the TCI dimensions for GS patients and control subjects are presented in Table 2.
We also applied an effect size (ES) measure to the significance of the statistical differences. ES indicates that if two groups' means do not differ by at least 0.2 standard deviations, the difference is trivial, even if it is statistically significant. Our study groups' results are presented in Table 3.

Discussion
The Temperament and Character Inventory-240 (TCI-240) has not been used with GS patients up to the present. Our current study showed that GS patients have a characteristic personality profile with higher scores for disorderliness, sentimentality, and fatigability and lower scores for empathy and transpersonal identification than healthy individuals.

Stress factors are associated with increased bilirubin
and its metabolites in urine. Urinary excretion of bilirubin oxidative metabolites increases in septic patients. 8 Novío et al. 9 reported that stressed mice had higher oxidative metabolites of bilirubin than non-stressed mice and observed that levels declined after alprazolam doses were given to the stressed animals.

On the other hand, bilirubin has important antioxidant
properties, which has been confirmed over the last 2 decades, contributing to defense against increased oxidative stress. Experimental and also clinical studies have indicated associations between low bilirubin concentrations and cardiovascular diseases, diabetes mellitus, certain cancers, autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, and psychiatric disorders such as schizofrenia. 7 Subjects with mildly elevated blood bilirubin levels, typical of GS, have decreased risk of these diseases. 10  With regard to temperament, individuals who score low on the disorderliness subscale have a tendency to be disorganized, disordered, chaotic, and unsystematic.
They do not like activities with strict rules and regulations. 4,5 High harm avoidance scores are related to depression and anxiety symptoms, but there was no difference in harm avoidance parameters except fatigability. Although there is no consensus on fatigue as a symptom of GS, higher fatigability may be an expected outcome for GS patients. 18,19 Moreover, with a significant low correlation between serum bilirubin levels and fatigability, our study may have revealed new evidence on the subject of fatigability for GS patients.
Reward dependence reflects behavior response, which stimulates a social reward and reflects a genetic tendency that stimulates continuation of this behaviour. 4,5 In the present study, scores for the reward dependence subscale sentimentality were higher among patients with GS than in the control group. Significantly higher sentimentality scores in patients with GS may be due to placing more importance on social consent and to being susceptible or easily impressionable by others.
Character consists of three parts; cooperativeness (C), self-directedness (SD), and self-transcendence (ST). Within these, our study demonstrated lower scores for empathy and transpersonal identification in GS patients. Empathy is described as a sensation of unity or identification with other individuals and is said to enable improved communication and compassion for others. 4,5 Transpersonal identification is related to spiritual acceptance or to apprehension of relationships that cannot be explained by analytical reasoning or demonstrated to others by objective observations. 4,5 Cloninger hypothesized that neurotransmitters were related with behavioral manifestations, such as, for example, serotonin with harm avoidance (behavioral inhibition); norepinephrine with reward dependence (behavioral maintenance); dopamine with novelty seeking (behavioral activation), and glutamine with persistence (behavioral perseverance). 4,5 In this context, as an inherited disorder, GS may be associated with altered glucuronidation rates of these metabolites.
Lee et al. 20  Thirdly, the TCI is a self-report questionnaire and may be influenced by environmental factors. Fourthly, all the subjects were male and young, but this may also have ensured greater homogeneity of the groups and exclusion of age and gender effects on TCI results.
Additionally, GS was diagnosed from clinical and laboratory parameters in this study, whereas definitive diagnosis can be made by genetic mutation analysis.
Finally, the detailed results of medical departments' clinical and psychiatric evaluations were not available, only their final assessments and decisions, which could constitute a potential confounding factor between groups. Nevertheless, the study also included subjects who were assessed as 'healthy' by each of the departments. Subjects with any pathological conditions were excluded from the study.
In conclusion, our findings demonstrate significant differences in personality features (TCI 240) between GS patients and healthy individuals. There might be a relationship between GS and personality characteristics and therefore patients' personality features might merit attention when evaluating patients with GS. On the other hand, our findings were statistically significant, but the effect size was small and there are some confounding factors and limitations. Further prospective studies are needed to identify the relationship between Gilbert's disease and personality characteristics.

Disclosure
No conflicts of interest declared concerning the publication of this article.