Lipodystrophy Syndromes: Presentation and Treatment

Excerpt

Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by selective absence of adipose tissue. In one sense, these diseases are lipid-partitioning disorders, where the primary defect is the loss of functional adipocytes, leading to ectopic steatosis, severe dyslipidemia, and insulin resistance. These syndromes have attracted significant attention since the mid-1990s as the understanding of adipose tissue biology grew, initially spurred by the discovery of the pathways leading to adipocyte differentiation and maturation, and then by the discovery of leptin. Although lipodystrophy syndromes are known since the beginning of the 20th century, significant progress in understanding these syndromes were made in the last two decades, placing these syndromes at the forefront of the translational metabolism field. Currently, more than 20 distinctive molecular etiologies have been attributed to cause human diseases most of which map to adipocyte differentiation or lipid droplet pathways. Seemingly acquired syndromes are recently reported to have a genetic basis, suggesting that our “pre-genome” understanding of the syndromes was inadequate and that we need to likely change our classification schemes. Regardless of the etiology, it is the selective absence of adipose tissue and its function, leading to the reduced ability to store long-term energy that perturbs insulin sensitivity and lipid metabolism. The treatment of these syndromes has also attracted considerable interest. The most successful example of the treatment of these syndromes came from the demonstration that leptin replacement strategy improved insulin resistance and dyslipidemia in the most severely affected forms of the disease, leading to an FDA approved therapy for generalized lipodystrophy syndromes. In the partial forms of the disease, the phenotypes are more complex, and the efficacy of leptin is not as uniform. Currently, standard treatment-resistant partial lipodystrophy is an EMA-approved indication, and numerous trials are in progress, either evaluating the efficacy of leptin in familial partial lipodystrophy or aiming to develop potential new treatments for the partial forms of the disease. These rare metabolic diseases are likely to continue to fuel novel breakthroughs in the field of metabolism in the foreseeable future. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.