This study addresses an important gap in the literature, namely whether peripheral blood-based biomarkers associated with length of stay can be identified. In the initial analyses, two variables at admission predicted longer length of stay on an inpatient unit: lower magnesium and higher active ghrelin. Our findings highlight the potential for using biological indices as additional indicators of length of stay and implicate metabolic traits as contributors to treatment course.
Low magnesium levels are common in individuals with severe AN, with hypomagnesemia occurring in up to 16% of patients at admission (Birmingham et al., 2004; Raj et al., 2012). Hypomagnesemia is a marker of refeeding syndrome (Skowrońska et al., 2019), which can ultimately lead to significant medical complications of AN, including cardiovascular disorders and sudden cardiac death (Di Cola et al., 2014). Therefore, low magnesium may predict a longer length of stay for two interrelated reasons: (1) it is indicative of more severe illness and thus (2) patients require longer refeeding periods in efforts to decrease risk of refeeding syndrome. Importantly, our results suggest that patients with lower magnesium, even if it is not at the level of clinical hypomagnesemia, may still have longer lengths of stay.
Secondly, our results indicate the potential utility of ghrelin monitoring, which is not routinely assessed during AN treatment. Active ghrelin represents the acetyl isoform of ghrelin and is an appetite stimulant, rising before food intake, along with involvement in a number of other physiological functions such as lipid storage, body weight, energy expenditure, learning and memory and mood and anxiety (Hillman et al., 2011; Müller et al., 2015). Active ghrelin has a short half-life and is subsequently converted to non-acetyl (i.e., inactive) ghrelin (Tong et al., 2013). Total ghrelin represents active plus inactive ghrelin.
Although our results are consistent with previous findings suggesting that patients with AN have increased plasma ghrelin levels compared with those without an eating disorder, our results extend this research by showing that patients with higher admission or persistent elevations in active ghrelin may need longer inpatient stay. Nutritional rehabilitation and initial weight gain do not necessarily equate with metabolic “recovery” as indexed by ghrelin, and thus higher active ghrelin may display a need for a longer stay to ensure medical stabilization and appropriateness for. Because ghrelin is involved in a number of indices likely relevant to AN treatment (e.g., appetite, mood, weight), this could suggest that persistently elevated active ghrelin levels may represent a biomarker of more severe, chronic, or metabolically unstable AN symptomatology requiring longer inpatient stays.
Collectively, our results indicate that biomarkers may be useful for predicting AN inpatient treatment length of stay. Although other disease-specific markers have been used previously [e.g., duration of illness, (Lievers at al., 2009), BMI and previous hospital admissions (Maguire et al., 2003), early treatment response (Wales et al., 2016), and autonomous control over treatment (Thaler et al., 2016)], their predictive abilities are limited and only marginally improve when combined with psychotherapist prognosis rating (Fichter & Quadflieg, 2020). Biomarkers have the benefit of being objective measures that do not rely on self-report or subjective clinical judgment. Additionally, peripheral blood-based biomarkers can be easily integrated into routine collection procedures. In particular, our findings suggest active ghrelin could be a useful addition for regular monitoring throughout routine clinical care given the prospective nature of active ghrelin at admission ultimately predicting inpatient length of stay. Definitions of AN outcome and recovery may need to be reconceptualized to include hormone regulation and metabolic recovery.
There are limitations of this study that should be considered. First, although our total sample size (n=59) had enough power to detect statistically significant biomarkers of length of stay, we had limited statistical power when conducting sensitivity analyses. In our first sensitivity analysis, removing individuals who self-discharged, we did not replicate findings from the total sample. Theoretically, lack of replicability may also have been due to removing individuals who self-discharge, however we believe this explanation to be unlikely due to the heterogeneity of individuals who self-discharged in this sample. The range of days spent on the inpatient unit was wide (10 to 78 days), indicating that this was not simply a group of individuals initiating discharge soon after admission and therefore receiving limited treatment. Additionally, the average length of stay of those who did self-discharge was not significantly different from those who did not. Secondly, our effect sizes had minimal change in our sensitivity analysis excluding individuals who self-discharged, further implicating a lack of power as a reason for these findings. However, it is important to note that we do not have the specific details about the reasons for premature discharge (i.e., initiated by the patient, whether the stay was truncated by insurance coverage, other reasons), as reasons for such discharge may modify observed effects (e.g., group interaction).
In addition to limitations related to those who self-discharged, our sample included a small number of adolescent patients (n=10) which may have influenced results. Importantly, a sensitivity analysis excluding adolescents showed larger effect sizes for both magnesium and active ghrelin in the adult group. Biomarker predictors of inpatient length of stay may differ between adolescents and adults, and further research examining biomarkers solely in adolescents may be important. Studies of AN biomarkers including both adults and adolescents can lead to mixed findings (Peyser et al., 2021) and remains a limitation of research on biomarkers of AN. Although ghrelin is higher in both adolescent and adult females with AN compared to healthy controls (Misra et al., 2005; Tolle et al., 2003), to our knowledge, no research has examined the difference in this biomarker between age groups with AN. Therefore, research examining the predictive nature of both ghrelin and magnesium on length of stay in adolescents is vital. Importantly, this sensitivity analysis was also under-powered.
In addition to low power in sensitivity analyses and thus an inability to directly compare groups (e.g., self-discharge versus clinician-discharge, adolescents versus adults, AN-BP versus AN-R), our study was limited to solely females with AN. It is unclear if there are gender differences in biomarkers of AN, as most research has been conducted on females. Larger studies with appropriate power to conduct analyses by age group, subtype of AN, and other demographic characteristics must be conducted to replicate our findings across groups. Finally, our study did not include a comparison of controls without a lived experience with eating disorders.
Despite the limitations, the results of this study identified objective peripheral blood-based biomarkers associated with length of stay on an inpatient unit that may aid in identifying patients who require more time on an inpatient unit and, with continued research, could lead to prospective identifiers of treatment needs and readiness for discharge. Particularly important, this study may be more representative of patients with AN given the research was conducted in a treatment setting and not in a strictly research setting (e.g., clinical trial) and thus, displays additional utility of biological indices already being collected throughout treatment. Finally, using these biomarkers may aid in our ability to argue for a longer length of inpatient stays for patients with AN; one concern for Americans with eating disorders is limited insurance coverage for inpatient treatment (Escobar-Koch et al., 2010). Future research should examine the predictive nature of the identified biomarkers across follow-up periods, and whether or not they remain associated with treatment outcomes beyond discharge.