Lipodystrophies represent a standard pathological pattern of lipid metabolism disorders of hereditary or acquired origin, characterized by generalized or localized loss of adipose tissue, and less commonly by its excessive accumulation.
Pathology TypeDisorder of lipid metabolism (genetic or acquired)
GeneticsMutations in LMNA and AGPAT2 genes
ComplicationsHepatic steatosis and cirrhosis, type 2 diabetes mellitus
AssociationsLinks with autoimmune diseases and panniculitis
Primary (Hereditary) Lipodystrophies
Primary causes of lipodystrophies stem from inherited or congenital genomic alterations, most commonly point mutations.
Familial partial lipodystrophies: Associated with LMNA gene mutations (autosomal dominant inheritance). With the onset of puberty, patients lose subcutaneous fat in the extremities, and later in the abdomen and chest. A cushingoid redistribution may occur, with fat accumulation in the face, neck, and intra-abdominal depots.
Congenital generalized lipodystrophy: An autosomal recessive disorder caused by a mutation in the AGPAT2 gene (chromosome 9q34). It presents with a near-total absence of adipose tissue and pronounced muscle definition even in newborns. Triglyceride synthesis by adipocytes is impaired, leading to a deficiency of phospholipids required for cell membranes and signaling.
Secondary and Acquired Forms
Secondary lipodystrophies develop under the influence of external factors or underlying pathologies:
HIV-associated and therapy-induced: Occur in patients with HIV receiving antiretroviral therapy (specifically protease inhibitors). This manifests as localized fat loss in the face and limbs alongside potential excessive fat accumulation in the neck region due to preadipocyte apoptosis.
Acquired partial lipodystrophy: Characterized by the disappearance of fat from the face, neck, and upper torso with concurrent excessive fat deposition in the gluteal region and thighs. It is frequently associated with autoimmune conditions, such as systemic lupus erythematosus.
Acquired generalized form: Affects extensive areas (face, limbs, palms, soles). In 25% of cases, it is linked to panniculitis (inflammation of subcutaneous adipose tissue with destruction of adipocytes) or autoimmune processes (such as juvenile dermatomyositis).
Complications and Therapeutic Approaches
Deficiency and redistribution of adipose tissue lead to severe systemic disturbances:
Type 2 diabetes mellitus (driven by relative hypoinsulinism or severe insulin resistance).
Acute pancreatitis secondary to hypertriglyceridemia.
Hepatic steatosis and cirrhosis (steatosis develops in the majority of patients with acquired generalized lipodystrophy, and cirrhosis occurs in up to 20% of patients).
Therapeutic Directions:
Etiotropic therapy to eliminate the primary underlying cause.
Surgical correction (reconstructive plastic surgery for fat deficiency, liposuction for excessive fat accumulation in the neck).
Conservative management (dietary modification and weight management to reduce fat accumulation in unaffected areas).
Mnemonic
Lipodystrophy is either genetic (LMNA/AGPAT2), HIV therapy-induced, or autoimmune panniculitis. Key target organs for complications are the liver (steatosis/cirrhosis) and the pancreas (pancreatitis).
Frequently asked questions
Which drug classes cause secondary lipodystrophy in HIV infection?
Secondary lipodystrophy in HIV infection is caused by protease inhibitors. These drugs impair the differentiation of subcutaneous preadipocytes, resulting in apoptosis and localized subcutaneous fat loss.
What autoimmune conditions are associated with acquired partial lipodystrophy?
Acquired partial lipodystrophy is associated with autoimmune diseases, including:
Systemic lupus erythematosus
Juvenile dermatomyositis
What is the pathogenesis of type 2 diabetes mellitus development in lipodystrophies?
In congenital generalized lipodystrophy, type 2 diabetes develops against a background of relative hypoinsulinism and severe insulin resistance. More broadly, impaired development, distribution, or survival of adipocytes prevents adipose tissue from storing lipids adequately; excess lipids are instead deposited ectopically in the liver, skeletal muscle, and pancreas, driving profound insulin resistance.
What genetic mutations cause primary lipodystrophies?
Primary familial forms are linked to mutations in the LMNA gene (autosomal dominant). The congenital generalized form is caused by mutations in the AGPAT2 gene located on chromosome 9.
Why does lipodystrophy develop in HIV infection?
It is typically caused by antiretroviral medications (such as protease inhibitors), which disrupt the normal differentiation of subcutaneous preadipocytes and induce their apoptosis.
What dangerous hepatic complications can occur in lipodystrophies?
Patients frequently develop hepatic steatosis due to prolonged ectopic lipid accumulation in hepatocytes, which in some patients (e.g., those with the acquired generalized form) can progress to liver cirrhosis.
What inflammatory process is associated with the acquired generalized form?
In 25% of cases, it is linked to panniculitis—a progressive inflammatory condition of the subcutaneous adipose tissue that leads to the destruction of adipocytes and their replacement by connective tissue.
Go deeper
Pathogenesis of impaired triglyceride synthesis and phospholipid deficiency in AGPAT2 mutations
The role of protease inhibitors in preadipocyte apoptosis
Visceral panniculitis and involvement of internal organ adipocytes
Mechanisms of hypertriglyceridemia and acute pancreatitis development
Interrelation of lipodystrophies with autoimmune diseases and systemic lupus erythematosus