Anorexia Nervosa (AN) is a severe psychiatric condition characterized by self-imposed starvation, an intense fear of weight gain, and a distorted perception of body shape. The disorder’s persistence and life-threatening nature stem from a complex breakdown of biological and neurological systems. AN involves genetic predisposition, altered brain circuitry, and metabolic adaptations that conspire to maintain the illness. Understanding these underlying biological mechanisms is essential for developing more effective and targeted treatments.
Genetic and Epigenetic Underpinnings
Anorexia Nervosa has a significant heritable component, with genetic factors accounting for approximately 50% to 70% of the risk. This strong familial link suggests an underlying biological vulnerability that can be triggered by environmental factors. Recent Genome-Wide Association Studies (GWAS) have begun to pinpoint specific regions of the genome associated with AN risk.
Genetic variants identified through GWAS suggest a connection between AN and both psychiatric and metabolic traits. AN risk genes correlate with conditions like Obsessive-Compulsive Disorder and anxiety, as well as metabolic measures such as body mass index, lipid levels, and glycemic traits. This finding encourages viewing AN as a “metabo-psychiatric disorder,” where an innate tendency toward a lower body mass index may be a predisposing factor.
Beyond the fixed DNA sequence, epigenetic mechanisms influence gene expression through modifications like DNA methylation. Environmental factors, such as chronic starvation or early life stress, can induce these changes, contributing to the development or persistence of AN. These epigenetic alterations are notable because some appear reversible upon weight restoration, suggesting they may serve as markers of the disease state.
Neurobiological Alterations
The persistence of restrictive behaviors in AN is rooted in alterations within the brain’s signaling molecules and structures. The dopamine system, which governs reward processing, is significantly affected, potentially contributing to the disorder’s self-perpetuating nature. For individuals with AN, restricting food and subsequent weight loss may become abnormally rewarding, replacing the natural pleasure derived from eating or social interactions.
Serotonin is implicated in mood, anxiety, and obsessive-compulsive traits frequently observed in AN patients. Dysregulation of serotonin pathways controlling behavioral inhibition may explain the cognitive rigidity and perfectionism associated with the illness. These alterations translate into a rigid adherence to dietary rules and excessive, compulsive exercise.
A failure in interoception, the brain’s ability to accurately sense internal bodily states, also plays a role in the disorder. This includes the inability to correctly perceive signals like hunger, satiety, or emotional distress. This disruption contributes to the disconnect between the patient’s severely low weight and their lack of perceived need to eat, reinforcing the distorted body image.
Brain imaging studies consistently show structural changes, including reduced gray and white matter volume, especially in areas involved in emotion and cognition. This brain matter loss is largely a consequence of severe malnutrition and typically shows partial reversal following nutritional rehabilitation.
Endocrine and Metabolic Dysregulation
Chronic starvation forces the body into a state of endocrine and metabolic dysregulation as it struggles to conserve energy. The balance of appetite-regulating hormones is altered, yet this fails to correct the restrictive eating behavior. For instance, levels of ghrelin, the “hunger hormone,” are paradoxically high, serving as an adaptive signal attempting to stimulate appetite.
Conversely, leptin, the hormone released by fat cells that signals satiety, is suppressed due to the near-total loss of body fat. Despite the high ghrelin and low leptin signals—a combination that should drive intense hunger—patients often report a blunted appetite. This suggests a central resistance or signaling failure within the brain’s appetite centers, where the brain overrides the body’s desperate attempts to initiate refeeding.
The Hypothalamic-Pituitary-Adrenal (HPA) axis, the body’s stress response system, is chronically activated in AN, leading to elevated cortisol levels. This hypercortisolemia is an adaptation that helps mobilize energy stores and prioritize glucose delivery to the brain. However, chronic high cortisol contributes to anxiety and metabolic shifts that reinforce the illness.
The metabolic paradox of AN is the body’s shift into a highly efficient, energy-conserving state. Resting energy expenditure drops significantly, an adaptation to minimize energy use during fasting. This metabolic efficiency makes weight gain difficult and explains why patients struggle to maintain a healthy weight after initial refeeding, perpetuating the cycle of restriction.