What is Lipodystrophy?

Lipodystrophy is a rare group of disorders characterized by abnormal or loss of body fat (adipose tissue). The fat loss can be generalized (whole body) or partial (specific areas). Loss of normal fat tissue leads to severe metabolic complications including insulin resistance, diabetes, high triglycerides, and fatty liver disease.

Types:

1. Congenital (Genetic) Lipodystrophy:

• Congenital Generalized Lipodystrophy (CGL/Berardinelli-Seip): Nearly complete absence of body fat from birth; very rare
• Familial Partial Lipodystrophy (FPL): Loss of fat from limbs, buttocks; fat accumulates in face, neck, abdomen; onset in puberty

2. Acquired Lipodystrophy:

• Acquired Generalized Lipodystrophy (AGL/Lawrence Syndrome): Progressive loss of body fat starting in childhood or adulthood; often autoimmune
• Acquired Partial Lipodystrophy (APL/Barraquer-Simons Syndrome): Fat loss from upper body (face, arms, trunk); lower body fat preserved or increased
• HIV-Associated Lipodystrophy: From antiretroviral therapy (especially older drugs); fat loss from face, limbs, buttocks ± fat accumulation in abdomen, neck ("buffalo hump")
• Drug-Induced: Insulin injections (localized fat loss at injection sites)

Why Fat Loss Causes Metabolic Problems:

• Normal fat tissue stores excess energy and produces hormones (leptin, adiponectin) that regulate metabolism
• Without adequate fat tissue:
  • Insulin Resistance: Fat accumulates in muscle, liver instead → severe insulin resistance
  • Leptin Deficiency: Low leptin → uncontrolled appetite, hyperglycemia, fatty liver
  • Ectopic Fat Deposition: Fat stored in liver, muscles, pancreas → organ dysfunction

Symptoms and Features:

Physical Appearance:

• Generalized Lipodystrophy: Muscular appearance, prominent veins, loss of subcutaneous fat
• Partial Lipodystrophy: Disproportionate fat distribution (e.g., thin face/arms, fat abdomen/hips)
• Acanthosis nigricans (dark, velvety skin—sign of severe insulin resistance)
• Hepatomegaly (enlarged liver from fatty liver)
• Eruptive xanthomas (if very high triglycerides)

Metabolic Complications:

• Severe Insulin Resistance
• Diabetes (Early Onset, Difficult to Control): Often requires very high insulin doses
• Hypertriglyceridemia: Often extreme (>1000 mg/dL); risk of pancreatitis
• Fatty Liver Disease (NAFLD/NASH): Can progress to cirrhosis
• Polycystic Ovary Syndrome (PCOS)-Like Features: In women—irregular periods, infertility, excess hair growth
• Cardiovascular Disease: Early onset due to diabetes, high triglycerides, low HDL
• Kidney Disease: From diabetes, proteinuria
• Excessive Hunger (Hyperphagia): From leptin deficiency

Diagnosis:

Clinical Diagnosis:

• Physical exam: Abnormal fat distribution
• Personal/family history

Labs:

• Fasting Glucose, HbA1c: Assess for diabetes
• Lipid Panel: Very high triglycerides, low HDL
• Liver Enzymes (ALT, AST): Elevated in fatty liver
• Fasting Insulin, C-Peptide: Very high (severe insulin resistance)
• Leptin Level: Very low or undetectable
• Kidney Function, Urine Protein

Imaging:

• MRI or CT: Assess fat distribution, confirm diagnosis
• Liver Ultrasound or MRI: Assess fatty liver
• DEXA Scan: Measure body fat percentage

Genetic Testing:

• For congenital/familial forms; identifies specific mutations

Treatment:

1. Lifestyle Modifications:

• Low-Fat Diet: <15-20% of calories from fat (reduces fatty liver, triglycerides)
• Restrict Simple Carbs/Sugars: Worsens hyperglycemia, triglycerides
• Calorie Control: Prevent weight gain (despite low fat mass, can gain ectopic fat)
• Exercise: Improves insulin sensitivity

2. Metreleptin (Myalept®)—Leptin Replacement (MOST EFFECTIVE):

• FDA-approved for generalized lipodystrophy
• Daily subcutaneous injection
• Effects:
  • Dramatically improves metabolic control
  • Lowers blood sugar (reduces insulin requirements)
  • Lowers triglycerides by 50-70%
  • Improves fatty liver
  • Reduces appetite
• Side Effects: Hypoglycemia, weight loss, injection site reactions, possible antibody formation
• Note: Very effective but expensive and limited availability

3. Diabetes Management:

• Metformin: Improves insulin sensitivity
• Thiazolidinediones (Pioglitazone): Improve insulin sensitivity; may worsen fluid retention
• GLP-1 Agonists: Help glucose control, reduce appetite
• SGLT2 Inhibitors: Lower glucose, protect liver/kidneys
• Insulin: Often required; very high doses may be needed

4. Hypertriglyceridemia Management:

• Fibrates: Fenofibrate
• High-Dose Omega-3 Fatty Acids: Icosapent ethyl (Vascepa®)
• Severe Cases: Very low-fat diet, avoid alcohol

5. Fatty Liver Management:

• Weight loss (if overweight), low-fat diet
• Metformin, pioglitazone
• Vitamin E (if NASH)

6. Cardiovascular Risk Management:

• Statins for cholesterol
• Blood pressure control
• Aspirin (for primary prevention in high-risk patients)

Monitoring:

• Every 3-6 Months: HbA1c, lipid panel, liver enzymes, kidney function
• Annually: Liver ultrasound or elastography (fibrosis assessment), cardiovascular risk assessment

Prognosis:

• Without treatment, metabolic complications lead to early cardiovascular disease, cirrhosis, kidney failure
• With metreleptin and aggressive metabolic management, outcomes significantly improved
• Generalized forms more severe than partial forms