Criteria and Basic Classification
Pathological weight loss is generally divided into two stages depending on severity. Emaciation is diagnosed when the deficit of adipose tissue is 20–25% or more, and the body mass index (BMI) drops below 18.5 kg/m². Cachexia is a critical condition where the BMI falls below 17 kg/m², more than 50% of fat mass is lost, and marked loss of muscle and connective tissue begins.
Globally, these disorders are divided into exogenous (caused by a simple lack of food) and endogenous. Endogenous forms are further classified into primary (hypothalamic) and secondary (symptomatic), which develop secondary to other severe diseases.
Primary (Centrogenic) Emaciation
Primary forms are associated with a breakdown in central neuroendocrine regulation—the so-called "adipocyte-hypothalamus" axis (or lipostat system). The main regulator of energy balance here is neuropeptide Y, which is synthesized in the hypothalamus and normally stimulates appetite.
Causes of this disruption can include traumatic brain injury, hypothalamic ischemia, CNS tumors, or severe, prolonged psychogenic stress.
The pathogenesis develops via two main mechanisms:
- Suppression of neuropeptide Y synthesis. This often occurs due to excessive synthesis of leptin, which blocks peptide production. No neuropeptide Y means no feeling of hunger.
- Hyposensitization. Peptide synthesis may remain normal, but target cells lose their sensitivity to it.
As a result, trans- and parahypophyseal activation of endocrine glands decreases, metabolism becomes inefficient, and fat accumulation in adipocytes is completely halted.
Secondary Cachexia and the Role of TNF-α
Secondary (symptomatic) emaciation is a consequence of other pathologies: malabsorption syndrome, hypoinsulinemia (type 1 diabetes mellitus), glucocorticoid deficiency, somatostatin or glucagon hyperproduction, and insufficient thymic hormone activity.
A special place is occupied by the cachectin (cytokine) variant, which is characteristic of oncology and chronic inflammation. A key role is played by tumor necrosis factor alpha (TNF-α), also known as cachectin. It is produced by macrophages and adipocytes themselves, acting simultaneously in four directions:
- Central action: suppresses the synthesis of neuropeptide Y in the brain.
- Intracellular action: inhibits protein kinase activity, completely halting lipogenesis.
- Vascular action: reduces the activity of lipoprotein lipase in the endothelium, preventing fatty acids from being transported into adipocytes.
- General metabolism: strongly stimulates catabolic processes (breakdown) and suppresses anabolic reactions.
Anorexic and Exogenous Variants
The anorexic variant of pathogenesis is characteristic of neuropsychiatric disorders (anorexia nervosa). The risk group mainly includes adolescent girls (16–18 years old) with body dysmorphia or dysmorphophobia—a critical, distorted perception of their body as overweight. The triggering factor is repeated emotionally negative stress responses. They lead to excessive production of anorexigenic substances (serotonin, cholecystokinin), elevated cachectin levels, and decreased neuropeptide Y synthesis. The result is prolonged episodes of food refusal.
Exogenous emaciation develops due to a physical shortage of food products (starvation). Two parallel processes are triggered in the body: depletion of fat reserves (lipolysis) and general metabolic disorders. Biological oxidation becomes deficient, and plastic processes (synthesis of proteins and structural cell components) are suppressed, ultimately leading to severe multiple organ dysfunction syndrome.