Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease

Abstract

Lipodystrophies are rare, heterogeneous, genetic or acquired, disorders characterised by varying degrees of body fat loss and associated metabolic complications, including insulin resistance, dyslipidaemias, hepatic steatosis and predisposition to atherosclerotic cardiovascular disease (ASCVD). The four main types of lipodystrophy, excluding antiretroviral therapy-induced lipodystrophy in HIV-infected patients, are congenital generalised lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalised lipodystrophy (AGL) and acquired partial lipodystrophy (APL). This paper reviews the literature related to the prevalence of dyslipidaemias and ASCVD in patients with lipodystrophies. Patients with CGL, AGL and FPLD have increased prevalence of dyslipidaemia but those with APL do not. Patients with CGL as well as AGL present in childhood, and have severe dyslipidaemias (mainly hypertriglyceridaemia) and early onset diabetes mellitus as a consequence of extreme fat loss. However, only a few patients with CGL and AGL have been reported to develop coronary heart disease. In contrast, data from some small cohorts of FPLD patients reveal increased prevalence of ASCVD especially among women. Patients with APL have a relatively low prevalence of hypertriglyceridaemia and diabetes mellitus. Overall, patients with lipodystrophies appear to be at high risk of ASCVD due to increased prevalence of dyslipidaemia and diabetes and efforts should be made to manage these metabolic complications aggressively to prevent ASCVD.

Keywords: Lipodystrophy; acquired generalised lipodystrophy; acquired partial lipodystrophy; congenital generalised lipodystrophy; familial partial lipodystrophy; metreleptin.

Published by Elsevier B.V.

Figures

Fig. 1

Clinical features of patients with various types of lipodystrophies. (A) Anterior view of a 33-year-old Hispanic female with congenital generalised lipodystrophy (also known as Berardinelli–Seip congenital lipodystrophy) type 1, due to homozygous c.589-2A>G mutation in AGPAT2 gene. The patient had generalised loss of subcutaneous (sc) fat with acanthosis nigricans in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands and feet). (B) Anterior view of a 27-year-old Native American Hispanic female with familial partial lipodystrophy of the Dunnigan variety (FPLD2) due to heterozygous p.Arg482Trp mutation in LMNA gene. She had marked loss of sc fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased sc fat deposits in the face, anterior neck and vulvar regions. (C) Anterior view of an 8-year-old German boy with acquired generalised lipodystrophy. He had severe generalizsed loss of sc fat with marked acanthosis nigricans in the neck, axillae and groin. (D) Anterior view of a 39-year-old Caucasian female with acquired partial lipodystrophy (Barraquer–Simons syndrome). She had marked loss of sc fat from the face, neck, upper extremities, chest and on some areas of anterior thighs. She had increased sc fat deposition in the lower extremities. Modified and reproduced with permission from Fitzpatrick's Dermatology in General Medicine.

Fig. 2

Prevalence of hypertriglyceridaemia in various types of genetic and acquired lipodystrophies from UT Southwestern Lipodystrophy Database. Hypertriglyceridaemia is defined as fasting serum triglyceride concentrations ≥150 mg/dL. The number of male (M) and female (F) patients in each group, along with their age ranges are provided under the x-axis. AGL, acquired generalised lipodystrophy; APL, acquired partial lipodystrophy; CGL, congenital generalised lipodystrophy; FPLD, familial partial lipodystrophy. Reproduced with permission from Dyslipidemias. Pathophysiology, Evaluation and Management.

Fig. 3

Serum triglycerides and HDL-cholesterol levels in patients with familial partial lipodystrophy, Dunnigan variety (FPLD2) due to LMNA mutations previously reported in the literature according to age. Data in males are shown as squares and in females as circles. (A) Serum triglyceride levels in males (n = 25) showing that the majority have hypertriglyceridaemia, with some patients with triglyceride levels over 1,000 mg/dL. (B) Serum triglyceride levels in females (n = 93) showing that the majority have hypertriglyceridaemia. Females with serum triglyceride levels over 2,000 mg/dL (n = 8) are indicated with open circles. In these females, serum triglyceride values ranged from 2,500 mg/dL to 10,000 mg/dL. (C) Serum high-density lipoprotein (HDL)-cholesterol levels in males (n = 20) showing that the majority have levels below 40 mg/dL. (D) Serum high-density lipoprotein (HDL)-cholesterol levels in females (n = 69) showing that the majority have levels below 50 mg/dL.

Fig. 4

Analysis of cohorts of FPLD2 patients with various heterozygous missense LMNA mutations reported by several authors showing mean serum triglyceride levels with standard deviations in these groups. Black bars indicate that males and females were not reported separately in the cohort. Blue bars indicate only males were reported. And red bars indicate only females were reported. Three patients from the Garg 2001 cohort had heterozygous LMNA mutation p.R582H and had their lipid panels reported separately (second black bar), whereas the other 20 patients had various other mutations (1 patient had p.G465D; 4 patients had p.R482Q; and 15 patients had p.R482W) and lipid panels reported together for these patients (first black bar). M, male; F, female; N, number of patients reported; y, years.,,,,,,

Fig. 5

Serum triglycerides and HDL-cholesterol levels in patients with familial partial lipodystrophy, type 3 (FPLD3) due to PPARG mutations previously reported in the literature according to age. Data in males are shown as squares and in females as circles. (A) Serum triglycerides levels in males (n = 12) showing that the majority have hypertriglyceridaemia. (B) Serum triglyceride levels in females (n = 41) showing that the majority have hypertriglyceridaemia. (C) Serum high-density lipoprotein (HDL)-cholesterol levels in males (n = 13) showing that the majority have levels below 40 mg/dL. (D) Serum high-density lipoprotein (HDL)-cholesterol levels in females (n = 36) showing that the majority have levels below 50 mg/dL.