Generalised Lipodystrophy

Generalised lipodystrophy is near complete loss of subcutaneous fat, with severe insulin resistance, diabetes, severe hypertriglyceridaemia, hepatic steatosis and leptin deficiency.

The congenital form (Berardinelli-Seip syndrome) is autosomal recessive and caused by AGPAT2, BSCL2, CAV1 or PTRF variants, with a prevalence of about 1 in 10 million. The acquired form (Lawrence syndrome) arises in childhood or adolescence, often after autoimmune disease or panniculitis.

BSCL2 disease causes cardiomyopathy and intellectual disability. PTRF disease is associated with myopathy, pyloric stenosis and prolonged QT interval.

Pathophysiology.

Fat cannot be stored, so lipids accumulate in liver and muscle. Leptin and adiponectin are very low, giving hyperphagia, accelerated growth and severe insulin resistance.

Acquired disease is probably autoimmune or inflammatory destruction of adipose tissue.

• Absence of subcutaneous fat from infancy (congenital) or progressive loss over months (acquired), a muscular appearance and prominent veins.
• Acromegaloid features (large hands, feet and jaw), voracious appetite, advanced bone age, acanthosis nigricans and hirsutism.
• Hepatomegaly with steatosis, diabetes, eruptive xanthomata, pancreatitis, hypertension, cardiomyopathy and proteinuria.

Red flags.

• Triglyceride over 10 mmol/L (880 mg/dL) or abdominal pain (pancreatitis).
• Heart failure, arrhythmia or progressive liver or kidney disease.

• Clinical diagnosis from generalised fat loss. Whole body DXA or MRI confirms.
• Leptin very low (under about 4 ng/mL in men and 6 ng/mL in women), fasting insulin very high, glucose and HbA1c, triglyceride (often over 10 mmol/L), liver tests and elastography, urine albumin to creatinine ratio.
• Genetic testing (AGPAT2, BSCL2, CAV1, PTRF). Autoantibodies and panniculitis assessment in acquired disease.
• Echocardiogram, ECG, creatine kinase and liver imaging.

Differential diagnosis.

• Anorexia nervosa, cachexia and diencephalic syndrome.
• HIV-associated lipodystrophy and familial partial lipodystrophy.
• Leprechaunism and Rabson-Mendenhall syndrome (insulin receptor disorders).
• Acromegaly.

• Metreleptin is first line for leptin deficiency: 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. Watch for neutralising antibodies, infections and lymphoma.
• Diet (low fat, energy matched to need) and exercise.
• Diabetes: metformin, then insulin at high doses (concentrated insulin up to 500 units/mL) and pioglitazone if needed.
• Hypertriglyceridaemia: fenofibrate 145 mg daily, omega-3 fatty acids 2 to 4 g daily and statins. Acute pancreatitis: intravenous insulin infusion. Avoid oral oestrogen.
• Treat cardiomyopathy, hypertension and proteinuria. Liver disease: monitor for fibrosis.
• Cosmetic surgery is not first line.
• Evidence for metreleptin is from open label studies.

Special groups. Children: treat early to prevent complications and promote growth. Pregnancy: high risk and requires a specialist team. Genetic counselling: 25% recurrence risk in siblings (congenital).

Monitoring. HbA1c, lipids and liver tests every 3 months, antibody and infection review while on metreleptin, echocardiogram yearly, and liver imaging yearly.

Referral and escalation. Specialist lipodystrophy centre; cardiology, hepatology and nephrology as needed.