Lipodystrophies

Lipodystrophies are a group of rare disorders characterized by abnormal or absent adipose tissue distribution. They involve loss of subcutaneous fat in defined regions and often accumulation of fat in non-adipose tissues, leading to metabolic complications such as insulin resistance, hypertriglyceridemia, and fatty liver disease.

Classification includes congenital forms, such as generalized lipodystrophy with near-total fat loss from birth, and familial partial lipodystrophy, where fat loss and sometimes fat gain occur in characteristic body regions and emerge during childhood or adolescence. Acquired lipodystrophies develop later in life and can be associated with autoimmune diseases, infections, or medications (notably HIV-related lipodystrophy linked to antiretroviral therapy). Genetic causes involve mutations in genes including AGPAT2, BSCL2, LMNA, CAV1, PTRF, and PLIN1, among others.

Pathophysiology reflects impaired adipocyte function and reduced fat storage capacity, causing ectopic lipid deposition in liver and muscle, insulin resistance, dyslipidemia, and fatty liver. Adipokine profiles are often disrupted, with low levels of leptin and adiponectin contributing to metabolic complications.

Clinical features vary by subtype. Generalized forms show widespread fat loss from birth, while partial forms present fat loss in limbs and trunk with possible facial or neck fat changes. Metabolic consequences—diabetes or impaired glucose tolerance, hypertriglyceridemia, hepatic steatosis, and reproductive or menstrual disturbances—are common and require ongoing monitoring.

Diagnosis relies on clinical assessment, imaging to quantify fat distribution, and confirmatory genetic testing. Management focuses on treating metabolic complications with diet, exercise, lipid-lowering and glucose-lowering therapies, and, in eligible patients, metreleptin therapy. Regular follow-up aims to monitor liver status and cardiovascular risk.