Generalized lipoatrophy syndromes.

Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.

Genetics of lipodystrophy syndromes.

Lipodystrophic syndromes (LS) constitute a clinically and genetically heterogeneous group of diseases characterized by a loss of adipose tissue. These syndromes are usually associated with metabolic complications, which are determinant for morbidity and mortality. The classical forms of LS include partial, generalized, and progeroid lipodystrophies. They are usually due to defects in proteins playing a key role in adipogenesis and adipocyte functions. More recently, systemic disorders combining lipodystrophy and multiple organ dysfunction have been described, including autoinflammatory syndromes, mitochondrial disorders, as well as other complex entities. To date, more than thirty genes have been implicated in the monogenic forms of LS, but the majority of them remain genetically-unexplained. The associated pathophysiological mechanisms also remain to be clarified in many instances. Next generation sequencing-based approaches allow simultaneous testing of multiple genes and have become crucial to speed up the identification of new disease-causing genes. The challenge for geneticists is now the interpretation of the amount of available genetic data, generated especially by exome and whole-genome sequencing. International recommendations on the interpretation and classification of variants have been set up and are regularly reassessed. Very close collaboration between geneticists, clinicians, and researchers will be necessary to make rapid progress in understanding the molecular and cellular basis of these diseases, and to promote personalized medicine.

Autoimmunity in lipodystrophy syndromes.

Lipodystrophy syndromes are rare, heterogeneous disorders characterized by the complete or partial deficiency of adipose tissue and are classified according to the extent of fat loss in generalized or partial subtypes, or based on the pathogenic mechanisms in genetic or acquired. While in most cases of congenital forms of lipodystrophy a genetic alteration can be identified, the pathogenic mechanisms responsible for the acquired diseases are not fully clarified. Based on the evidence of a positive association between most acquired lipodystrophies and autoimmune disorders including immune mediated alterations in the adipose tissue of patients affected by acquired lipodystrophy, a reaction against white adipose tissue antigens is postulated. Recent acquisitions have shed new light on the possible pathogenic mechanisms and identified novel forms of acquired lipodystrophy which are possibly immune-mediated. The aim of this review is to give an update on acquired lipodystrophies describing pathogenic mechanisms involved and the relationships between acquired lipodystrophies and other autoimmune disorders. Larger studies based on international disease registries are needed to collect accurate information on the prevalence, risk factors, genetic predisposition, natural history, disease markers and treatment efficacy of these ultrarare disorders.

Lipodistrofias primarias: presentación clínica y diagnóstico / Clinical presentation and treatment of primary lipodystrophies

Lipodystrophies are a heterogeneous group of syndromes defined by a severe reduction of the adipose tissue. These can be congenital or acquired. Anatomically, they can be partial or generalized. The etiology of several lipodystrophies is well known. However, the cause of many others remains unknown. The commonest lipodystrophy worldwide is secondary to highly active anti-retroviral therapy in HIV-infected patients. By contrast, primary lipodystrophies (those not associated to any known disease or condition) are much less common and represent a diagnostic challenge. The major complications of lipodystrophies are metabolic, often resulting in severe insulin resistance, diabetes and dyslipidemia. No cure is available for lipodystrophies but the supplementation with recombinant leptin potently controls the metabolic abnormalities when there is a leptin deficiency. Herein, we review the clinical presentation, diagnostic process and therapeutic principles of the main primary lipodystrophy syndromes.

[Clinical presentation and treatment of primary lipodystrophies]. / Lipodistrofias primarias: presentación clínica y diagnóstico.

Lipodystrophies are a heterogeneous group of syndromes defined by a severe reduction of the adipose tissue. These can be congenital or acquired. Anatomically, they can be partial or generalized. The etiology of several lipodystrophies is well known. However, the cause of many others remains unknown. The commonest lipodystrophy worldwide is secondary to highly active anti-retroviral therapy in HIV-infected patients. By contrast, primary lipodystrophies (those not associated to any known disease or condition) are much less common and represent a diagnostic challenge. The major complications of lipodystrophies are metabolic, often resulting in severe insulin resistance, diabetes and dyslipidemia. No cure is available for lipodystrophies but the supplementation with recombinant leptin potently controls the metabolic abnormalities when there is a leptin deficiency. Herein, we review the clinical presentation, diagnostic process and therapeutic principles of the main primary lipodystrophy syndromes.

Lipodystrophy Syndromes.

Lipodystrophies are heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance and its metabolic complications. They are subclassified depending on degree of fat loss and whether the disorder is genetic or acquired. The two most common genetic varieties include congenital generalized lipodystrophy and familial partial lipodystrophy; the two most common acquired varieties include acquired generalized lipodystrophy and acquired partial lipodystrophy. Highly active antiretroviral therapy-induced lipodystrophy in patients infected with human immunodeficiency virus and drug-induced localized lipodystrophy are common subtypes. The metabolic abnormalities associated with lipodystrophy include insulin resistance, hypertriglyceridemia, and hepatic steatosis. Management focuses on preventing and treating metabolic complications.

Liposuction-Assisted Short-Scar Brachioplasty: Technical Highlights.

Upper arm contouring is based on the location and amount of excess skin and fat. The short-scar brachioplasty addresses minimal to moderate skin laxity and lipodystrophy in the proximal arm in patients with appropriate skin tone and quality. This article highlights technical refinements of the senior author's (R.J.R.) approach to short-scar medial liposuction-assisted brachioplasty to maximize results and minimize incision length. To highlight this simple and safe approach with high patient/surgeon satisfaction, the authors discuss the following in this Video Plus article: patient examination, preoperative assessment, surgical pearls, and postoperative outcomes.

Metreleptin Treatment in Patients with Non-HIV Associated Lipodystrophy.

Lipodystrophies are a heterogeneous group of disorders characterized by congenital or acquired loss of adipose tissue. Recently, metreleptin, a recombinant human leptin analog, has been approved for the treatment of patients with generalized lipodystrophy. Leptin is an adipokine which has a fundamental role in glucose and lipid homeostasis. Metreleptin treatment has been demonstrated to improve metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, increased hepatic fat content and elevated liver enzymes alanine transaminase and aspartate transaminase in patients with generalized lipodystrophy, and to correct hyperphagia that likely occurs as a result of leptin deficiency. Limited data has also suggested that metreleptin treatment might be beneficial on metabolic abnormalities in patients with partial lipodystrophy. This review focuses on potential benefits of metreleptin in various forms of non-HIV associated lipodystrophy. Safety issues have been discussed. Recent patent submissions have also been reviewed.

Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives.

INTRODUCTION: Metreleptin was recently approved by the Food and Drug Administration for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency. Its efficacy as hormone replacement therapy suggests broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity. Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity. AREAS COVERED: This review covers the physiology of leptin, the pharmacologic properties of recombinant methionyl human leptin (R-metHu-Leptin, metreleptin), evidence for metreleptin's efficacy in the treatment of generalized lipodystrophy from both completed and ongoing clinical trials, safety concerns, and future directions in metreleptin research. EXPERT OPINION: Metreleptin's approval for generalized lipodystrophy is the first step in defining and expanding its role to other metabolic diseases. Clinical trials are underway to delineate its efficacy in FPLD, human immunodeficiency virus/highly active anti-retroviral therapy-associated acquired lipodystrophy (HAL), and NAFLD. Additionally, there is growing data that support a therapeutic role in obesity. One of the barriers to development, however, is metreleptin's safety and immunogenicity. Further advances in biologic compatibility are required before metreleptin can be approved for additional indications.

Lipodystrophic diabetes mellitus: a lesson for other forms of diabetes?

Lipodystrophies are a genetically heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue and metabolic dysfunction, including insulin resistance, increased levels of free fatty acids, abnormal adipocytokine secretion, and ectopic fat deposition, which are also observed in patients with visceral obesity and/or type 2 diabetes mellitus. Pathophysiological, biochemical, and genetic studies suggest that impairment in multiple adipose tissue functions, including adipocyte maturation, lipid storage, formation and/or maintenance of the lipid droplet, membrane composition, DNA repair efficiency, and insulin signaling, results in severe metabolic and endocrine consequences, ultimately leading to specific lipodystrophic phenotypes. In this review, recent evidences on the causes and metabolic processes of lipodystrophies will be presented, proposing a disease model that could be potentially informative for better understanding of common metabolic diseases in humans, including obesity, metabolic syndrome, and type 2 diabetes.

Lipodystrophy: Syndrome of severe insulin resistance.

CONTEXT: Lipodystrophy (LD) is a relatively rare complex collection of diseases that can be congenital or acquired. It is commonly missed in the clinical setting. Thus, the spectrum of disease presentation mandates clinician expertise in the pathophysiology and management of all forms of LD, obesity, and insulin resistance. METHODS AND MATERIALS: An extensive literature search of clinical trials, systematic reviews, and narrative reviews was completed in PubMed for the years 1970 to 2013. The search terms were lipodystrophy, congenital LD, acquired LD, HIV-associated LD, severe insulin resistance, adiposity, obesity, and dyslipidemia. EVIDENCE SYNTHESIS: Lipodystrophies are a heterogeneous group of disorders with abnormal adipose tissue distribution, utilization, and metabolism. Adipose tissue can undergo significant changes in composition (hypertrophy and atrophy) in response to a nutritional state. Paradoxically, both excess and deficient adipose tissue is associated with insulin resistance and the metabolic syndrome. Bone density scan (DEXA) for body fat composition analysis or magnetic resonance imaging are optimal modalities for the assessment of abnormal adipose tissue distribution. Ongoing clinical studies suggest thiazolidinediones, insulin like growth factor-1, leptin, and growth hormone-releasing hormone as possible treatment for LPD; however, none of them is approved to reverse fat loss or treat severe insulin resistance due to LPD. CONCLUSION: The underlying mechanisms for LPD causing insulin resistance may be lipotoxicity and derangements in adipose tissue-derived proteins (adipocytokines). However, the lack of evidence to support this model means that clinicians are on their own as they navigate through the phenotypic presentation of lipodystrophies, obesity, insulin resistance, and the metabolic syndrome.

Prosthetic guidelines for ocular rehabilitation in patients with phthisis bulbi: a treatment-based classification system.

Prosthetic rehabilitation of phthisis bulbi defects is the only treatment option for cosmetic rehabilitation of patients with such defects. Currently, there is no treatment-based classification for prosthetic rehabilitation of patients with phthisis bulbi. Phthisical ocular defects and/or prosthetic rehabilitation were evaluated in an attempt to establish prosthetic guidelines that could be organized into a classification system. Fifty patients who received rehabilitation for phthisis bulbi were reviewed. Phthisis bulbi defects were divided into 4 classes. All the patients had rehabilitation, depending upon the class to which they were assigned. The aim of this treatment-oriented classification system was to organize and define the complex nature of the restorative decision-making process for patients with phthisis bulbi.

Lipodystrophy: beyond generalization?

Genetic and acquired lipodystrophies are disorders of adipose tissue distribution. In this review we will emphasize its phenotype, metabolic and genetic particularities. Special stress will be given to the most prevalent lipodystrophy ­that associated with HIV infection - describing the similarities with congenital lipodystrophies and its pathogenic mechanisms. It will be discussed the pathways involved in development, differentiation and death of adipocytes, emphasizing that both genetic and acquired, including that associated with HIV can induce changes in adipogenesis and how the two main adipose tissue dysfunctions - obesity and lipodystrophy - can cause a similar metabolic profile (diabetes, hypertension, dyslipidemia) with increased cardiovascular risk. Rare monogenic laminopathies and other genetic lipodystrophies could be relevant to understand common pathways - physiopathology of aging, atherosclerosis process, vascular endothelial cell dysfunction, frailty syndrome and common disorders such as type 2 diabetes, insulin resistance, dyslipidemia, hypertension and metabolic syndrome. Also, some lipodystrophies can be associated with premature aging and precocious cardiovascular disease. The authors aimed to give a focus on the particularities of each of the issues addressed.

Effect of ultrasound and hyaluronidase on gynoid lipodystrophy type II - an ultrasonography study.

INTRODUCTION: The objective of this study was to evaluate the effect of ultrasound and the technique of phonophoresis with hyaluronidase in patients with cellulite edematous type II in the gluteal region. METHODS: Forty-two individuals, all females, were selected and randomly divided into two groups with 21 patients in each. Group I was treated with ultrasound without hyaluronidase and Group II was treated with ultrasound with hyaluronidase. To evaluate individuals, inspection, palpation, photography data and diagnostic ultrasound were performed before and after the treatment. The gluteal region was divided into four areas of 2.5 cm(2); each area received an application of ultrasound. RESULTS: After 10 days of application, both treatments were effective in improving skin appearance and reducing its thickness (epidermis and dermis), as well as that of the hypodermis (p > 0.05). Ultrasound with hyaluronidase induced a larger reduction in skin thickness in the upper medial quadrant and in the lower lateral and medial quadrants, compared to treatment without hyaluronidase. Moreover, there was a significant reduction of the hypodermis in the upper lateral quadrant with hyaluronidase (p > 0.05). CONCLUSION: Both treatments effectively reduced the thickness of skin and the hypodermis; however, the group treated with hyaluronidase-associated ultrasound showed more significant results than that treated with ultrasound only.

How to diagnose a lipodystrophy syndrome.

The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders.

Clinical classification and treatment of congenital and acquired lipodystrophy.

OBJECTIVE: To review the initial clinical manifestations of congenital and acquired lipodystrophy syndromes, discuss novel classifications associated with genetic mutations, and assess currently available therapeutic options for patients with lipodystrophy. METHODS: This review is the result of the authors' collective clinical experience and a comprehensive MEDLINE literature search on the English-language literature published between January 1966 and October 2009 on "lipodystrophy." This review focuses primarily on severe dystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy. RESULTS: Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and classified on the basis of the extent of fat loss and heritability Paradoxically, they are associated with metabolic abnormalities often found in obese patients, including insulin resistance, diabetes, and severe hypertriglyceridemia. Patients with severe forms of lipodystrophy are also deficient in adipokines such as leptin, which may contribute to metabolic abnormalities. The search for molecular defects has revealed a role for genes that affect adipocyte differentiation (for example, peroxisome proliferator-activated receptor gamma), lipid droplet morphology (seipin, caveolin-1), or lipid metabolism (AGPAT2). Others (lamin A/C) are known to be associated with completely different diseases. There are also acquired forms of lipodystrophy that are thought to occur primarily attributable to autoimmune mechanisms. Recently, recombinant leptin has emerged as a useful therapy. CONCLUSION: Lipodystrophy syndromes have advanced our understanding of the physiologic role of adipose tissue and allowed identification of key molecular mechanisms involved in adipocyte differentiation. Novel therapeutic strategies are being developed on the basis of the pathophysiologic aspects of these syndromes.