Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease - ScienceDirect

Pathology

Volume 51, Issue 2, February 2019, Pages 202-212

Pathology

https://doi.org/10.1016/j.pathol.2018.11.004 Get rights and content

Summary

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.

Introduction

Lipodystrophies are a group of rare, heterogeneous, genetic or acquired, disorders characterised by varying degrees of body fat loss.¹ Fat loss may be restricted to only small areas (localised), on the extremities (partial), or all over the body (generalised), as seen in Fig. 1. Depending upon the extent of fat loss, these patients suffer from metabolic complications, such as insulin resistance, impaired glucose tolerance, diabetes mellitus, dyslipidaemia, hepatic steatosis, polycystic ovarian syndrome, acanthosis nigricans, and their sequelae. A classification of various types of lipodystrophies is given in Table 1.

The prevalence of lipodystrophies (excluding antiretroviral therapy-induced lipodystrophy in HIV-infected patients) in the general population is estimated to be only 1.3–4.7 cases per million, establishing these as rare disorders.² The four most prevalent types of lipodystrophies are congenital generalised lipodystrophy (CGL), familial partial lipodystrophy (FPLD), acquired generalised lipodystrophy (AGL) and acquired partial lipodystrophy (APL) (Fig. 1). CGL and FPLD are autosomal recessive and autosomal dominant genetic disorders, respectively; each reported in approximately 500 patients worldwide, with most of the other genetic lipodystrophies reported in about 30 patients or less. Thus, it is difficult to ascertain the prevalence of dyslipidaemias or atherosclerotic cardiovascular disease (ASCVD) in these extremely rare subtypes of lipodystrophies.

The dyslipidaemia in patients with lipodystrophies is characterised by hypertriglyceridaemia, and low levels of high-density lipoprotein (HDL)-cholesterol. Some patients develop extreme hypertriglyceridaemia and chylomicronaemia resulting in recurrent attacks of acute pancreatitis, lipaemia retinalis, and tuberous and eruptive xanthomas. Even planar xanthomas in the palms and soles have been observed in some patients. Dyslipidaemia and diabetes mellitus can also predispose these patients to ASCVD, including coronary heart disease, cerebrovascular accidents and peripheral vascular disease. However, because these disorders are rare, only anecdotal and limited data from some cohorts of patients are available about the prevalence of dyslipidaemia and ASCVD.

This paper reviews available literature on dyslipidaemias and ASCVD among various subtypes of genetic and acquired lipodystrophies. Localised lipodystrophies do not often result in metabolic complications because of the small amount of fat loss. The paper does not review dyslipidaemias in human immunodeficiency virus (HIV)-infected patients with highly active antiretroviral therapy-induced lipodystrophy, and readers are referred to other recent reviews.3, 4, 5, 6 We reviewed the literature for anecdotal case reports of dyslipidaemia and ASCVD amongst the four major types of lipodystrophies. While there were only a few anecdotal reports of ASCVD among CGL, AGL and APL patients, there was more substantial literature on ASCVD among patients with FPLD. We also collected and analysed the data from case reports of FPLD patients to ascertain the prevalence of dyslipidaemia, diabetes mellitus, other risk factors and ASCVD.

We have estimated the prevalence of hypertriglyceridaemia (fasting serum triglyceride level greater ≥150 mg/dL) in our cohort of patients at UT Southwestern Medical Center with lipodystrophies (Fig. 2). Patients with AGL had the highest prevalence of hypertriglyceridaemia, i.e., ∼80% of patients, followed closely by patients with CGL and FPLD. Patients with APL had a relatively low prevalence of dyslipidaemia with less than 20% having hypertriglyceridaemia.

Section snippets

Congenital generalised lipodystrophy (CGL)

CGL is an autosomal recessive disorder with generalised lack of body fat and extreme muscularity present at birth or soon thereafter.⁷ The population prevalence of CGL has been estimated to be 1 in 10 million.7, 8 CGL type 1 and type 2 are the most common subtypes of CGL, each reported in about 200–250 patients. CGL type 3 has only been reported in a single patient.⁹ CGL type 4 has been reported in ∼30 patients to date.10, 11, 12, 13, 14, 15, 16, 17, 18 Patients with CGL have acromegaloid

Familial partial lipodystrophy (FPLD)

FPLD is characterised by fat loss mostly involving the extremities (especially prominent on the lower extremities), with variable fat loss from the face, neck and trunk. Most FPLD patients have an autosomal dominant inheritance, but there are extremely rare patients with autosomal recessive inheritance.

Acquired generalised lipodystrophy (AGL)

Patients with AGL usually have generalised loss of subcutaneous fat loss associated with panniculitis (type 1) or autoimmunity (type 2). An idiopathic variety (type 3) where the cause of lipodystrophy is not identified is also recognised.¹⁰⁸ A recent paper reports anti-perilipin 1 autoantibodies as a cause of generalised lipodystrophy in these patients.¹⁰⁹ However, only limited number of patients were studied by the authors. Approximately 80 patients have been reported in the literature.

Acquired partial lipodystrophy (Barraquer–simons syndrome)

Acquired partial lipodystrophy is characterised by progressive loss of subcutaneous fat which initially starts in the face and then affects the arms and torso, but spares the lower extremities. This usually begins in childhood, and is associated with several autoimmune diseases, most commonly systemic lupus erythematosus and dermatomyositis. Patients have often been reported to have had various infections preceding the development of lipodystrophy. About 20–25% of these patients go on to

Management of dyslipidaemia

Aggressive management of dyslipidaemias is important for lowering the risk of acute pancreatitis as well as ASCVD. For those with chylomicronaemia, an extremely low fat diet is recommended. In addition, fibrates as well as n-3 fatty acids from fish oils alone or in combination may lower serum triglycerides. Combination therapy with statins and fibrates should be used in rare patients with caution to avoid risk of myopathy. Patients with diabetes need to be managed intensively to achieve near

Conclusions and future directions

Patients with lipodystrophies appear to be at high risk of ASCVD due to increased prevalence of dyslipidaemia and diabetes. However, because these disorders are rare, increased prevalence of atherosclerotic vascular complications has not been documented and only anecdotal reports are available. Multicentre, collaborative effort is needed to characterise, the severity of dyslipidaemia and diabetes among various different types and subtypes of lipodystrophies, and the age of onset and prevalence

Acknowledgements

We would like to thank Chandna Vasandani, PhD, for literature review and collecting data for FPLD3 patients, Carmel Tovar, BS, for creating figures and graphs, Beverley Adams-Huet, MS, for statistical analysis, and Claudia Quittner, RN, for data collection.

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