A new conceptual model for anorexia nervosa: A role for connective tissue?

The etiology of anorexia nervosa (AN) remains to be fully elucidated, and current theories also fail to account for the direct effect of starvation on the health of the organs and tissues, specifically the connective tissue present in most organs of the body. Individuals with hereditary disorders of connective tissue manifest with clinical symptoms that overlap with AN, as the abnormal connective tissue also contributes to many of the other extra-articular manifestations of these hereditary disorders. This article hypothesizes that a similar pathophysiology may also contribute to the clinical presentation of AN. Therefore, a better understanding is needed to elucidate: (1) the relationship between abnormal connective tissue and AN, (2) the impact of starvation toward the development of abnormal connective tissue and how this manifests clinically, (3) the etiology of autonomic nervous system changes contributing to the dysautonomia in AN, and (4) how the sensory signals sent from potentially abnormal connective tissue to the central nervous system impact interoception in AN. A conceptual model incorporating abnormal connective tissue is provided. PUBLIC SIGNIFICANCE: The etiology of AN remains poorly understood and current theories fail to account for the direct impact of starvation on the health of the organs and tissues of the body. There is significant clinical overlap between AN and hereditary connective tissue disorders. This paper attempts to provide a new conceptual model for AN in which abnormal connective tissue contributes to the underlying pathogenesis.

Associations between low body weight, weight loss, and medical instability in adults with eating disorders.

OBJECTIVE: The physical complications of atypical anorexia nervosa remain understudied, with most studies completed in adolescents. This study seeks to examine the impact of various weight measures as predictors of medical instability in a large cohort of adult eating disorder patients. METHODS: In this retrospective cohort study, the impact of admission body mass index (BMI), weight suppression, and recent weight loss (the rate of weight loss within the last 12 months) toward the development of medical complications of malnutrition were examined. Multivariable logistic regression assessed the association of binary clinical outcomes of interest with recent weight loss and weight suppression (adjusting for age, admission BMI, gender, and purging behaviors). Odds ratios (OR) and 99% confidence intervals were reported. RESULTS: Greater recent weight loss increased the odds of developing low prealbumin and reduced hand grip strength. A greater weight suppression was associated with increased likelihood of amenorrhea, reduced systolic blood pressure, nadir hemoglobin, and weekly weight gain upon nutritional rehabilitation. Lower admission BMI was predictive of all the medical outcomes examined, with the exception of bradycardia, and was generally the strongest predictor based on standardized coefficients. DISCUSSION: Recent weight loss and weight suppression are predictive of some of the physiologic changes of malnutrition, although low BMI is seemingly the greatest predictor for the development of these complications. These findings suggest that some patients with aggressive weight suppression and/or acute weight loss would benefit from medical stabilization, although this needs to be further defined. PUBLIC SIGNIFICANCE: In adults, low BMI seems to be a better predictor of medical complications than weight suppression or aggressive recent weight loss. In adults, greater weight suppression is associated with increased likelihood of amenorrhea, reduced systolic blood pressure, nadir hemoglobin, and weight gain upon nutritional rehabilitation.

Atypical antipsychotic use does not impact weight gain for individuals with extreme anorexia nervosa: a retrospective case-control study.

BACKGROUND: There are no U.S. Food and Drug Administration (FDA)-approved medications for the treatment of anorexia nervosa (AN). Various medication classes have been evaluated for benefits in this population, including antipsychotics. Studies focused on use of antipsychotics for assistance with weight restoration in AN produced conflicting results. While current evidence does not suggest that antipsychotic medications can be generally recommended for persons with AN, some individuals might benefit from an antipsychotic medication for anxiety, mood, and the cognitive distortions that accompany the illness. It is well-established that atypical antipsychotics can cause weight gain when taken by other psychiatric populations. This published data can understandably limit the willingness of persons with AN to trial these medications. Given the conflicting results of studies examining antipsychotic-related weight gain in AN, it is currently hypothesized that individuals with extreme anorexia nervosa, restricting type, do not experience the weight gain seen in other psychiatric populations utilizing atypical antipsychotics. METHODS: Two hundred seventy-six individuals with extreme AN were enrolled in this retrospective, case-control study between April 1, 2016 and June 30, 2022 utilizing study-specific inclusion and exclusion criteria. Clinical and demographic data, including use of atypical antipsychotics and weights, were retrospectively obtained from chart review. Variables were assessed for normality using univariate statistics. Continuous variables were described using means (M) and standard deviations (SD) or medians and interquartile ranges (IQR) based on normality. Differences in weight gain between cohorts was ascertained via independent samples t-test. P values of < 0.05 were considered statistically significant, and all analyses were completed using SAS Enterprise Guide software version 7.1 (SAS Institute, Cary, NC) and R version 4.3.1 (R Core Team, 2023). RESULTS: Use of antipsychotics in this population of individuals with extreme AN did not impact the rate of weight gain (M: 1.7 kg/week, SD: 0.9 and 0.8, for cases and controls respectively). CONCLUSIONS: Weight gain is often cited by individuals with AN as a feared side effect of antipsychotic medications. In this study, there was no difference in weight trends for individuals taking atypical antipsychotic medications during the refeeding process compared with individuals who were not.

While antipsychotics are not FDA-approved for, and cannot be generally recommended for, people diagnosed with anorexia nervosa, there are those who may derive benefit from utilizing these medications for their rigid and circular thoughts associated with the disorder, or for their mood and anxiety symptoms. Yet, many such individuals are hesitant to take these medications due to their fear of the weight gain which has been associated with their usage. In this study population of individuals suffering from extreme AN, who were undergoing refeeding and weight restoration, there was no impact on weight gain trends in individuals taking atypical antipsychotics compared to individuals who were not taking these medications.

Seizures in eating disorders.

OBJECTIVE: To complete a descriptive study of seizure etiology in a large population of eating disorder (ED) patients and to better understand whether malnutrition itself, in those with EDs, is associated with seizure development. METHOD: In this retrospective study, 75 patients with documented seizures met inclusion criteria from a total of 1664 charts. RESULTS: Prevalence of seizures in this ED cohort was found to be 4.5%, with 29.3% of individuals experiencing seizures due to psychogenic nonepileptic seizures (PNES). Other common causes of seizures included substance abuse/withdrawal (18.7%), primary seizure disorder (12%), and electrolyte abnormalities/hypoglycemia (10.7%). Three patients (4%) also developed their seizures presumably due to Wernicke's encephalopathy (WE). DISCUSSION: Several etiologies of seizures are reported from this large sample of ED patients, and this is also the first study to report on a possible association of WE as a cause of seizures in ED patients. The contribution of WE and malnutrition toward the development of seizures in this population remains to be determined, and future studies should also seek to better understand the inter-relationship between malnutrition and the other variables discussed in this article, such as hypomagnesemia, toward seizure development. PUBLIC SIGNIFICANCE: The medical complications of EDs are myriad but seizures have not historically been considered one of those direct complications of malnutrition. The findings of this retrospective study suggest that seizure development may be a direct and indirect complication associated with EDs. The presentation of Wernicke's encephalopathy, which can also be associated with development of seizures, requires further investigation in those with EDs.

Gastric dilatation in patients with restrictive eating disorders.

OBJECTIVES: To better understand gastric dimensions in patients diagnosed with restrictive eating disorders (EDs). METHOD: In this retrospective study, 56 patients, with restrictive EDs, and 60 gender/age/race-matched patients from an outpatient clinic, were studied. Difference in stomach size, between cohorts, was ascertained, and regression analyses were used to examine associations with stomach size in the ED cohort. RESULTS: Patients with EDs were found to have significantly enlarged gastric dimensions when compared to the control group (M:14.8 cm [SD: 3.2] vs. 11.4 cm [SD: 2.9], p < .0001). Among the ED cohort, blood urea nitrogen (BUN), on the day of imaging, positively correlated with gastric dimensions (r = .43, p = .0009), while hypoalbuminemia negatively correlated with gastric dimensions (r = -.37, p = .005). BUN and albumin nadir were also significantly associated with stomach size (r2  = .26, F[2,53] = 9.46, p = .0003). There was no significant correlation between gastric dimensions and ED diagnosis, percent ideal body weight, gender, duration of illness, engagement in vomiting behaviors, diagnosis of superior mesenteric artery syndrome, or use of promotility agents. DISCUSSION: Findings in this study suggest that malnutrition, secondary to EDs, may be associated with an enlarged stomach. The relationship between the gastric dimensions and reported GI symptoms in this population remain to be determined. PUBLIC SIGNIFICANCE: There are many physiologic changes to the gastrointestinal system that develop with malnutrition but the contribution of these physiologic changes toward the reported GI symptoms and refeeding difficulties is unclear. This is the first study to suggest that patients with malnutrition, secondary to EDs, may be associated with an enlarged stomach, and this potential relationship requires further investigation.

Pneumatosis Intestinalis and Anorexia Nervosa.

Background: Pneumatosis intestinalis (PI), the presence of gas within the intestinal wall, is a condition historically associated with many diagnoses and can be life-threatening. The purpose of this article is to understand PI better in the setting of malnutrition secondary to anorexia nervosa (AN), a condition not historically affiliated with PI. Patients and Methods: In this retrospective study, the clinical findings of seven patients with AN are reported. Results: The patients were all found to have PI involving the right colon, with only a single patient also found to have PI involving additional colonic areas. No patients had small intestine involvement, and most of the patients were also diagnosed with the binge-purge subtype of AN, were receiving tube feeds, and had tenderness on abdominal examination. All seven patients were managed non-operatively. Conclusions: The authors propose that there may be an association between AN and PI. Given the surgical risks associated with malnutrition, the decision to pursue surgery, in the absence of the discussed pathologic risk factors, should be made in a very thoughtful manner. Future studies are warranted to better understand this potential association between PI and AN.

A Case of Mitochondrial Neurogastrointestinal Encephalomyopathy with Metabolic Complications During Refeeding.

BACKGROUND Anorexia nervosa has been referred to as the "great pretender" of medicine and is often misdiagnosed. We present a rare genetic disorder that was misdiagnosed as anorexia nervosa. This case highlights the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy in a patient with previously diagnosed anorexia nervosa, which was discovered due to the metabolic abnormalities and intolerance of nutrition encountered during refeeding. CASE REPORT A 24-year-old woman with a previous diagnosis of type 2 diabetes mellitus and psychogenic anorexia and recent diagnosis of avoidant restrictive food intake disorder presented to a medical stabilization unit for weight restoration and treatment of medical complications associated with extreme malnutrition. She reported being underweight her entire life, and had a body mass index of 12 kg/m2 for a year prior to admission. She reported a long-standing intolerance to enteral feeding and had not gained weight when prescribed parenteral nutrition. She reported a desire to gain weight and denied any body dysmorphia. Upon nutritional rehabilitation, the patient was found to have extreme insulin resistance, with serum glucose values exceeding 400 mg/dL, and multiple neurologic findings that were incongruent with the medical complications of anorexia nervosa. These metabolic abnormalities, with her physical examination findings, allowed for a diagnosis of mitochondrial neurogastrointestinal encephalomyopathy. CONCLUSIONS This case report highlights the clinical presentation of mitochondrial neurogastrointestinal encephalomyopathy, including the newly described extreme insulin resistance, and showcases the importance of avoiding confirmation bias and working through differential diagnoses that are inconsistent with a clinical presentation to arrive at the correct diagnosis.

Personality characteristics and medical impact of stimulant laxative abuse in eating disorder patients-a pilot study.

BACKGROUND: Stimulant laxative abuse as a purging behavior can be profound in those with eating disorders. However, the psychopathology leading to stimulant laxative abuse is poorly understood. Furthermore, the medical impact of stimulant laxative abuse has not been studied in this population. METHODS: Six individuals abusing stimulant laxatives underwent a barium enema to assess for evidence of the cathartic colon syndrome and 29 individuals engaging in any purging behaviors completed the Tri-dimensional Personality Questionnaire-Short Form, Sensitivity to Punishment/Sensitivity to Reward Questionnaire-Short Form, Beck Depression Inventory, and the State Trait Anxiety Inventory questionnaires. RESULTS: Three of the six patients completing the barium enema had the radiographic findings consistent with cathartic colon. Individuals engaging in laxative abuse showed higher Novelty Seeking compared to those engaging in other forms of purging, and those engaging in any form of purging behavior showed greater Sensitivity to Punishment compared to Sensitivity to Reward. There was also the presence of greater Harm Avoidance than Reward Dependence in this population. CONCLUSION: There may be different psychopathology that contributes to the abuse of stimulant laxatives than that associated with other forms of purging. Regardless of the driving factor, further research is warranted to discover best therapeutic interventions given the potential to develop the cathartic colon syndrome with ongoing use of stimulant laxatives. Cathartic colon is a condition whereby the colon, or lower intestine, is converted into an inert tube incapable of propagating fecal matter. It is thought to develop due to over-use of stimulant laxatives. However, it is unclear if this condition truly exists and whether it contributes to the constipation experienced by individuals with eating disorders who have extensive past histories of abusing laxatives. It is also unclear if laxative abuse presents with different medical complications than other forms of purging. The purpose of this study is to determine whether radiographic evidence of cathartic colon can be found in eating disorder patients abusing stimulant laxatives, whether there are different medical complications with laxative abuse versus other forms of purging, and to examine the psychological composition of individuals who engage in severe laxative abuse. Specifically, the authors investigated the interrelationship between Harm Avoidance and Reward Dependence, with emphasis on gaining a better understanding of Reward Dependence by examining both Sensitivity to Reward and Sensitivity to Punishment in patients who engage in severe laxative abuse. Our findings suggest that stimulant laxative abuse may cause the development of cathartic colon changes and that there may be unique psychopathology that contributes to the abuse of stimulant laxatives. Given the higher Novelty Seeking personality-dimension in those abusing laxatives, it is possible that this purging behavior may be considered addiction-like in nature, which would have distinct treatment implications.

Medical complications of bulimia nervosa.

Bulimia nervosa, a mental illness 4 times more common than anorexia nervosa, is characterized by binge-eating followed by compensatory purging behaviors, which include self-induced vomiting, diuretic abuse, laxative abuse, and misuse of insulin. Patients with bulimia nervosa are at risk of developing medical complications that affect all body systems, especially the renal and electrolyte systems. Behavior cessation can reverse some, but not all, medical complications.

The intersect of gastrointestinal symptoms and malnutrition associated with anorexia nervosa and avoidant/restrictive food intake disorder: Functional or pathophysiologic?-A systematic review.

OBJECTIVE: Although multiple pathophysiologic changes develop within the gastrointestinal (GI) system in the setting of malnutrition, the etiology of the reported multitude of symptoms in those with anorexia nervosa and avoidant restrictive intake disorder, as well as their contribution toward disordered eating, remain poorly understood. This systematic review seeks to better understand how these physiologic changes of malnutrition of the esophagus, stomach, intestines, and pancreas contribute toward the reported GI symptoms, as well as better understand how celiac disease, inflammatory bowel disease, pelvic floor dysfunction, and Ehlers-Danlos syndrome contribute toward disordered eating. METHODS: Studies of any design exploring the pathogenesis of complications and treatment strategies were included. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used to structure and complete the review. RESULTS: A total of 146 articles were used for the review. The majority of studies were observational or case reports/case series. DISCUSSION: Pathophysiologic changes of the esophagus, stomach, and intestines develop with malnutrition, although these changes do not consistently correlate with expressed GI symptoms in patients with restrictive eating disorders. Celiac disease and inflammatory bowel disease also contribute to disordered eating through the associated somatic GI complaints, while pelvic floor dysfunction and Ehlers-Danlos syndrome contribute through both somatic symptoms and functional symptoms. Indeed, functional GI symptoms remain problematic during the course of treatment, and further research is required to better understand the extent to which these symptoms are functional in nature and remit or remain as treatment ensues.

OBJETIVO: Aunque en el contexto de la desnutrición se desarrollan múltiples cambios fisiopatológicos dentro del sistema gastrointestinal (GI), la etiología de la multitud de síntomas reportados en aquellos que padecen anorexia nerviosa y trastorno evitativo restrictivo de la ingesta, así como su contribución a la alimentación disfuncional, siguen siendo poco entendidos. Esta revisión sistemática busca entender mejor cómo estos cambios fisiológicos de la desnutrición del esófago, estómago, intestinos y páncreas contribuyen a los síntomas gastrointestinales reportados, así como entender mejor cómo la enfermedad celíaca, la enfermedad inflamatoria intestinal, la disfunción del piso pélvico y el síndrome de Ehlers Danlos contribuyen a la alimentación disfuncional. MÉTODOS: Se incluyeron estudios de cualquier diseño que exploraran la patogénesis de las complicaciones y las estrategias de tratamiento. Los lineamientos PRISMA se utilizaron para estructurar y completar el examen. RESULTADOS: Se utilizaron un total de 146 artículos para la revisión. La mayoría de los estudios fueron observacionales o reporte de caso o series de casos. DISCUSIÓN: Los cambios fisiopatológicos del esófago, el estómago y los intestinos se desarrollan con la desnutrición, aunque estos cambios no se correlacionan consistentemente con los síntomas gastrointestinales expresados en pacientes con trastornos de la conducta alimentaria restrictivos. La enfermedad celíaca y la enfermedad inflamatoria intestinal también contribuyen a la alimentación disfuncional a través de las quejas gastrointestinales somáticas asociadas, mientras que la disfunción del piso pélvico y el síndrome de Ehlers Danlos contribuyen a través de síntomas somáticos y síntomas funcionales. De hecho, los síntomas gastrointestinales funcionales siguen siendo problemáticos durante el curso del tratamiento, y se requiere más investigación para comprender mejor hasta qué punto estos síntomas son de naturaleza funcional y se remiten o permanecen a medida que se produce el tratamiento.

Nontuberculous mycobacterial lung infections in patients with eating disorders: plausible mechanistic links in a case series.

Nontuberculous mycobacteria (NTM) are widely distributed in the environment and are almost always acquired into the lungs by bioaerosol inhalation or aspiration of NTM-contaminated water, biofilms, and soil. NTM are increasingly recognized as causes of lung diseases in immunocompetent hosts, a not insignificant number of whom have a life-long or nearly life-long slender body habitus as well as thoracic cage abnormalities such as scoliosis and pectus excavatum. While several hypotheses have been offered to explain the purported increase in susceptibility to NTM lung disease in such individuals, the precise explanation remains unknown. We described three patients with eating disorders associated with severe malnutrition and either purging behaviors or other risks for aspiration who were diagnosed with NTM lung infections-the largest number of such patients to date in a single report. We discuss the clinical and experimental evidence that low body weight and chronic vomiting with attendant jeopardy for aspiration, as seen in patients with eating disorders, may represent risk factors for NTM lung disease. We also speculate the possibility of occult and undiagnosed eating disorders in some of the slender NTM lung disease patients with no known risk factors for the opportunistic infection other than their low body weight.

Extreme anorexia nervosa: medical findings, outcomes, and inferences from a retrospective cohort.

BACKGROUND: Extreme anorexia nervosa (AN) is defined as a BMI < 15 kg/m2 in those meeting DSM-V diagnostic criteria for AN. This study seeks to define the frequency of medical complications in this group of patients in order to help inform the care of individuals < 65% ideal body weight who seek treatment for their extreme eating disorders. METHODS: Through retrospective chart review and computerized data collection, we obtained the baseline characteristics and medical findings of 281 adult patients, with AN restricting and binge-purge subtypes, admitted to the ACUTE unit for medical stabilization between May 2013 and August 2018. RESULTS: In this population, with a mean admitting BMI of 12.1 kg/m2 (range = 7.5-15.7), 56% admitted with bradycardia, 45% demonstrated increased liver function tests (LFTs) on admission, 64% admitted with leukopenia, 47% with anemia, and 20% presented with thrombocytopenia. During admission, 38% developed hypoglycemia, 35% developed refeeding hypophosphatemia, nearly 33% of patients developed edema, and low bone mineral density was diagnosed in almost 90% of the patients. Highly elevated LFTs (>3x upper limits of normal) predicted hypoglycemia, and low BMI predicted refeeding hypophosphatemia (p = .001). CONCLUSIONS: Although conclusions drawn from the findings presented in this descriptive study must be tempered by relevant clinical judgement, these findings showcase that patients with extreme AN are at significantly increased risk for many serious medical complications secondary to their state of malnutrition and also with initial refeeding.

Superior mesenteric artery syndrome in severe anorexia nervosa: A case series.

Superior mesenteric artery syndrome presents with nonspecific GI complaints, hindering weight restoration in those with anorexia nervosa. Diagnosis is made with radiologic testing, and treatment requires only weight restoration, negating the need for surgical intervention.

Anorexia Nervosa and the Immune System-A Narrative Review.

The pathogenesis of an increasing number of chronic diseases is being attributed to effects of the immune system. However, its role in the development and maintenance of anorexia nervosa is seemingly under-appreciated. Yet, in examining the available research on the immune system and genetic studies in anorexia nervosa, one becomes increasingly suspicious of the immune system's potential role in the pathophysiology of anorexia nervosa. Specifically, research is suggestive of increased levels of various pro-inflammatory cytokines as well as the spontaneous production of tumor necrosis factor in anorexia nervosa; genetic studies further support a dysregulated immune system in this disorder. Potential contributors to this dysregulated immune system are discussed including increased oxidative stress, chronic physiological/psychological stress, changes in the intestinal microbiota, and an abnormal bone marrow microenvironment, all of which are present in anorexia nervosa.

Medical Complications of Anorexia Nervosa and Bulimia Nervosa.

Anorexia nervosa and bulimia nervosa are mental illnesses with associated complications affecting all body systems with arguably the highest mortality of all mental health disorders. A comprehensive medical evaluation is an essential first step in the treatment of anorexia nervosa and bulimia nervosa. Weight restoration and cessation of purging behaviors are often essential components in the management of medical complications of these illnesses.

Metformin abuse: A novel and dangerous purging behavior in anorexia nervosa.

OBJECTIVE: To report a case of severe multisystem illness, near death and permanent kidney failure in a woman with a history of anorexia nervosa-binge purge type due to abuse of prescription metformin, an approved oral diabetes medication obtained surreptitiously via the internet. METHOD: Psychiatric and medical records were reviewed from the medical care of this patient. A literature search was also performed on prescription medication abuse as a mode of purging. DISCUSSION: Metformin abuse in a patient with an eating disorder as a purging behavior is a rarely reported, albeit very dangerous entity. Clinicians treating eating disorders should increasingly be aware of the potential abuse of prescription medications, unapproved for weight loss but which have weight loss, as a reported side effect. This is particularly important as the ability to obtain prescription medications via the internet, without a prescription, becomes more ubiquitous.

Critical gaps in the medical knowledge base of eating disorders.

Eating disorders are unique in that they inherently have much medical comorbidity both as a part of restricting-type eating disorders and those characterized by purging behaviors. Over the last three decades, remarkable progress has been made in the understanding and treatment of the medical complications of eating disorders. Yet, unfortunately, there is much research that is sorely needed to bridge the gap between current medical knowledge and more effective and evidence-based medical treatment knowledge. These gaps exist in many different clinical areas including cardiology, electrolytes, gastrointestinal and bone disease. In this paper, we discuss some of the knowledge gap areas, which if bridged would help develop more effective medical intervention for this population of patients.

Medical complications of bulimia nervosa.

Bulimia nervosa is a psychiatric disorder with many different medical sequelae. This article reviews the principal medical complications associated with bulimia nervosa, and emphasizes the importance of a timely approach to diagnosis and management.