Lipodystrophy Syndrome

Lipodystrophy syndromes are a group of disorders with selective loss of subcutaneous fat and metabolic complications: severe insulin resistance, diabetes, hypertriglyceridaemia and hepatic steatosis. They are inherited or acquired, and generalised or partial.

Congenital generalised lipodystrophy (AGPAT2, BSCL2, CAV1, PTRF) is very rare. Familial partial lipodystrophy (LMNA, PPARG and others) is the commonest inherited form. Acquired generalised lipodystrophy (autoimmune, panniculitis associated) and acquired partial lipodystrophy (Barraquer-Simons, with complement C3 nephritic factor) are also rare.

HIV-associated lipodystrophy was linked to older antiretroviral drugs. Localised lipodystrophy follows repeated injection of insulin or other drugs.

Pathophysiology.

Failure of adipose tissue storage causes spill over of lipids into liver, muscle and pancreas (ectopic fat), causing insulin resistance. Low adipose mass reduces leptin and adiponectin, causing hyperphagia and further metabolic harm.

Leptin deficiency is greatest in generalised disease.

• Loss of subcutaneous fat (generalised or in limbs, face or trunk), prominent muscles and veins, and in partial forms fat excess in the face, neck and trunk.
• Acanthosis nigricans, hirsutism and menstrual disturbance, hepatomegaly, severe hypertriglyceridaemia with eruptive xanthomata and pancreatitis.
• Diabetes that is difficult to control, hypertension, cardiomyopathy and proteinuria.

Red flags.

• Triglyceride over 10 mmol/L (880 mg/dL) or abdominal pain (pancreatitis).
• Heart failure or arrhythmia (LMNA, BSCL2).
• Progressive liver fibrosis or proteinuria.

• Clinical examination, with fat distribution by DXA (trunk to leg fat ratio) or whole body MRI.
• Fasting glucose, HbA1c, lipids (triglyceride often very high), liver tests, liver ultrasound or elastography, urine albumin to creatinine ratio, and fasting leptin (low in generalised disease; under about 4 ng/mL in men and 6 ng/mL in women suggests it).
• Genetic testing (AGPAT2, BSCL2, CAV1, PTRF, LMNA, PPARG and others). Complement C3 and C3 nephritic factor in acquired partial disease. Autoantibodies and a skin biopsy for panniculitis in acquired generalised disease.
• ECG and echocardiogram.

Differential diagnosis.

• Insulin resistance syndrome with obesity, polycystic ovary syndrome and Cushing syndrome.
• Anorexia nervosa, cachexia, HIV-related wasting and thyrotoxicosis.
• Progeroid syndromes and severe insulin receptor disorders.

• Diet (energy matched to need, low fat if triglyceride is very high) and regular exercise.
• Diabetes: metformin first, then pioglitazone (15 to 45 mg daily) in partial forms, and insulin, often at high doses (concentrated insulin up to 500 units/mL). GLP-1 receptor agonists are used with caution.
• Hypertriglyceridaemia: fenofibrate 145 mg daily, omega-3 fatty acids 2 to 4 g daily, and statins. Acute pancreatitis: intravenous insulin infusion and supportive care. Avoid oral oestrogen.
• Metreleptin for leptin deficiency in generalised lipodystrophy (and selected partial disease with severe metabolic problems): weight over 40 kg, men 2.5 mg and women 5 mg subcutaneously daily, titrated by 1.25 to 2.5 mg to a maximum of 10 mg daily; 40 kg or under, 0.06 mg/kg daily to a maximum of 0.13 mg/kg daily. Neutralising antibodies and lymphoma have been reported. It is not for HIV lipodystrophy or ordinary obesity.
• Tesamorelin 2 mg subcutaneously daily reduces visceral fat in HIV lipodystrophy.
• Cosmetic surgery for facial fat loss. Treat hypertension and proteinuria.

Special groups. Pregnancy: plan with a specialist team, since insulin needs, triglyceride and pancreatitis risk rise. Children: early treatment limits complications.

Monitoring. HbA1c, lipids and liver tests every 3 months, liver imaging yearly, urine albumin yearly, echocardiogram and ECG yearly (LMNA).

Referral and escalation. Endocrinology with a lipid service; cardiology for LMNA and BSCL2; hepatology and nephrology as needed.