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Analysis of Electrolyte Abnormalities in Adolescents and Adults and Subsequent Diagnosis of an Eating Disorder

Key Points Question Are electrolyte abnormalities in outpatient lab work associated with an eating disorder diagnosis in the future? Findings In this population-based case-control study of individuals with and without an incident eating disorder, an outpatient electrolyte abnormality 3 years to 30 days prior to diagnosis was associated with 2.1-fold higher odds for the subsequent diagnosis of an eating disorder, a significant difference. Meaning These results suggest that otherwise unexplained outpatient electrolyte abnormalities may serve to identify individuals who should be screened for an underlying eating disorder.


Introduction
Eating disorders, such as anorexia nervosa and bulimia nervosa, are defined as disturbances in eating behaviors that compromise health and impair normal functioning. 1 The lifetime prevalence of an eating disorder is approximately 2% and is more common among women and adolescents. 2 Eating disorders are strongly linked to increased morbidity and mortality along with reduced quality of life. [3][4][5] These conditions present many challenges to both patients and clinicians. [6][7][8] Such challenges include an overall lack of adequate treatment options along with patient-centered factors such as denial, lack of self-awareness, social stigma, and shame surrounding the diagnosis that may limit forthcoming discussion and delay both diagnosis and treatment. 9 Further tools to aid in prompting or confirming suspicion into an underlying eating disorder may improve screening and promote early detection.
The acute presentations of eating disorders may involve marked electrolyte abnormalities.
These include imbalances in potassium, sodium, magnesium, and phosphate along with acid-base disturbances. [10][11][12][13][14] In terms of prevalence, a study of 1026 consecutive adults admitted for an eating disorder found that at the time of admission, 25.8% had hypokalemia, 14.0% had hyponatremia, and 16.6% had metabolic alkalosis. 15 The prevalence of electrolyte abnormalities in the outpatient setting among individuals with eating disorders is not well understood. These electrolyte abnormalities are often severe and predispose to such adverse and potentially fatal health consequences as cardiac arrhythmias, muscle weakness, and mental status changes. The pathogenesis underlying these electrolyte abnormalities can be explained by a number of etiologies relating to behaviors directly tied to the eating disorder including purging by vomiting, diuretic or laxative abuse, inadequate intake, and dehydration. However, it remains largely unknown whether early electrolyte abnormalities, prior to the acute presentation of an eating disorder, are associated with the future diagnosis of an eating disorder.
While several screening tools to identify individuals with eating disorders have been developed, such as the SCOFF questionnaire (Sick, Control, One stone, Fat, Food), 16,17 they require an index of suspicion prior to screening. Incidentally discovered electrolyte abnormalities, if associated with the subsequent diagnosis of an eating disorder, may help raise suspicion for clinicians to identify patients in whom more intensive screening into a potential eating disorder may be warranted. Herein, we conducted a large population-level case-control study of individuals in Ontario, Canada to evaluate the association between outpatient electrolyte abnormalities and the future diagnosis of an eating disorder.

Study Design and Setting
We conducted a population-level, case-control study of individuals aged 13 years or older in Ontario, Canada from January 1, 2008, through June 30, 2020. Ontario is Canada's largest province with approximately 15 million residents. 18 We used linked data sets held at ICES (formerly the Institute for Clinical Evaluative Sciences). ICES is an independent, nonprofit research institute whose legal status under Ontario's health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement. ICES captures data on all Ontario residents who undergo a health care encounter including health care visits,

Case and Control Definitions
Cases and controls were defined as individuals in Ontario who were aged 13 years or older and had at least 1 outpatient electrolyte test between 3 years and 30 days prior to index (Figure 1). Cases were individuals diagnosed with an incident eating disorder between January 1, 2008, and June 30, 2020.
The index date for cases was the first diagnosis date of an eating disorder within the accrual period.
Controls were randomly assigned a pseudoindex date according to the distribution of index dates in the case population. 19 Eating disorder diagnoses were based upon diagnostic codes for anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified. Eating disorder diagnoses were captured in all clinical settings (ie, inpatient, outpatient, and emergency department encounters). Individuals were excluded if they had any prior history of an eating disorder diagnosis before the study period. Controls were matched 4:1 to cases by age (exact) and sex.

Exposure
The primary study exposure was at least 1 outpatient electrolyte abnormality, defined by any of the following test results: hypokalemia (serum potassium level 3.5 mmol/L or lower), hyperkalemia (serum potassium, 5.5 mmol/L or higher), hyponatremia (serum sodium, 130 mmol/L or lower), hypernatremia (serum sodium, 150 mmol/L or higher), hypomagnesemia (serum magnesium, 0.50 mmol/L or lower), hypophosphatemia (serum phosphate, 0.80 mmol/L or lower), metabolic acidosis (serum bicarbonate, 22 mmol/L or lower), or metabolic alkalosis (serum bicarbonate, 30 mmol/L or higher). We included only outpatient electrolyte measurements so as to avoid common acute medical issues that can result in electrolyte disturbances. The exposure was labeled categorically in regard to whether they developed an electrolyte abnormality within the study window or not. Only electrolyte measurements between 3 years and 30 days prior to the index date were included. Electrolyte abnormalities within 30 days prior to index were excluded as they may be associated with the acute presentation of an eating disorder diagnosis. We further examined each individual electrolyte abnormality separately. Individuals who developed more than 1 type of electrolyte abnormality (eg, hypokalemia and metabolic alkalosis) within the study period were labeled accordingly. Moreover, in an additional analysis we incorporated a more severe definition for each electrolyte abnormality as follows: hypokalemia (serum potassium levels of 3.0 mmol/L or below), hyperkalemia (serum potassium, 6.0 mmol/L or higher), hyponatremia (serum sodium, 128 mmol/L or lower), hypernatremia (serum sodium, 155 mmol/L or higher), hypomagnesemia (serum magnesium, 0.40 mmol/L or lower), and hypophosphatemia (serum phosphate, 0.60 mmol/L or lower).

Outcomes
The outcome of interest was the diagnosis of an eating disorder based upon diagnostic codes for anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified. These validated codes have previously been used to identify eating disorders in Ontario, Canada. 20,21 Eating disorder diagnoses were captured in all clinical settings (ie, inpatient, outpatient, and emergency department encounters).

Statistical Analysis
We compared characteristics between the cases (individual diagnosed with an eating disorder) and controls (age-and sex-matched individuals without an eating disorder diagnosis). Continuous variables were reported as mean (with standard deviation [SD]) while categorical variables were reported as overall number (with percentages). We then calculated the percentage of cases and controls with electrolyte abnormalities detected between 3 years and 30 days prior to the index date. We used both univariable and multivariable logistic regression models to measure both crude and adjusted odds ratios (aOR) along with 95% CIs in the association between any electrolyte abnormality and an eating disorder diagnosis. Our models adjusted for the following covariates selected a priori: age, sex, year of index, neighborhood income quintile, rural residence, number of hospitalizations in the prior 2 years, prior health care visit for mental health, prior outpatient psychiatry visit, anxiety, asthma, chronic kidney disease, chronic obstructive pulmonary disease, congestive heart failure, depression, diabetes mellitus, inflammatory bowel disease, liver disease, myocardial infarction, personality disorder, and substance abuse. Race and ethnicity data is not available in ICES and therefore was not included in the study. We repeated our models using the more severe definitions for electrolyte abnormalities described above. We conducted all analyses using SAS Enterprise Guide version 7.1 (SAS Institute Inc). Confidence intervals that did not overlap with 1.0 and 2-sided P values <.05 were treated as statistically significant.

Patient Characteristics
The study included 6970 eligible Ontario residents diagnosed with an eating disorder (cases; mean

Association Between Electrolyte Abnormalities and the Subsequent Diagnosis of an Eating Disorder
Any outpatient electrolyte abnormality was associated with an over 2-fold higher odds of a subsequent eating disorder diagnosis (aOR, 2.12; 95% CI, 1.86-2.41) (Figure 3). The association between electrolyte abnormalities and the subsequent diagnosis of an eating disorder was also analyzed using more severe cutoffs (hypokalemia, serum potassium levels of 3.0 mmol/L or lower; hyperkalemia, serum potassium 6.0 mmol/L or higher; hyponatremia, serum sodium 128 mmol/L or lower; hypernatremia, serum sodium 155 mmol/L or higher;  There was no significant difference in the risk of a subsequent eating disorder diagnosis with severe hypophosphatemia (aOR, 1.84; 95% CI, 0.66-5.13). Severe hypernatremia and severe hypomagnesemia were not examined in our models as there were 10 individuals or fewer in the overall study population with these electrolyte abnormalities.

Discussion
Diagnosing an eating disorder is often challenging and, as such, routinely and readily available tests that may prompt health care providers to screen for these conditions may be beneficial. In this large population-based case-control study of individuals ages 13 years or older in Ontario, Canada without a prior eating disorder diagnosis, we found that an outpatient electrolyte abnormality was associated with an over 2-fold higher odds of a subsequent eating disorder diagnosis. The median time from the earliest electrolyte abnormality to eating disorder diagnosis exceeded one year. Hypokalemia was the most common electrolyte abnormality occurring in 12.1% of individual diagnosed with an eating disorder compared with 4.6% in matched controls. Additional electrolyte abnormalities such as hyponatremia, hypernatremia, hypophosphatemia, and metabolic alkalosis, although less frequent in their occurrence, were independently associated with an even higher odds of an eating disorder diagnosis. Our findings were consistent when we examined more severe electrolyte abnormalities including severe hypokalemia (serum potassium levels of 3.0 mmol/L or lower) and severe hyponatremia (serum sodium, 128 mmol/L or lower), which were associated with over 7-fold and 5-fold higher odds for the diagnosis of an eating disorder, respectively.

Strengths and Limitations
We would like to highlight several unique strengths with our current study. Rather than a singlecenter or multi-center design, our study was population-based and covered a wide, heterogeneous landscape across Canada's largest province of Ontario. Also, we only included outpatient electrolyte measurements so as to avoid common acute medical issues that can result in electrolyte disturbances. We also required that the electrolyte measurements be taken beyond 30 days prior to the eating disorder diagnosis. In fact, we found that the median time from the earliest electrolyte abnormality within the study window to the diagnosis of an eating disorder was greater than 1 year. to a discrepancy in which types of clinicians employ these codes. This may have resulted in some individuals being labeled as controls despite potentially being treated for eating disorders and biasing the results toward the null. Finally, as this study was performed using administrative health data, we cannot comment on the reason that electrolyte measurements were performed on an individual patient basis. Eating disorders often predispose to concurrent illnesses (eg, volume depletion, infections) that may have prompted the laboratory testing and may explain why individuals with an eating disorder had a higher median number of electrolyte measurements. Furthermore, we cannot rule out whether a clinician may have had an index of suspicion for an eating disorder which was the reason behind measuring electrolyte levels in certain instances.

Conclusions
In this population-based case-control study, we found that outpatient electrolyte abnormalities may serve as a precursor to future eating disorder diagnoses. Electrolyte abnormalities commonly occurred well ahead of the time at which an eating disorder diagnosis was made. Hypokalemia was the most common electrolyte abnormality identified while hyponatremia, hypernatremia, hypophosphatemia, and metabolic alkalosis were the most specific for a subsequent eating disorder diagnosis. These results suggest that incidentally discovered electrolyte abnormalities may serve to identify individuals who may benefit from targeted screening for an underlying eating disorder.
Ultimately, this may allow for more timely diagnosis and intervention to mitigate the negative impact that eating disorders have on patient morbidity, mortality, and quality of life.