Treatment Of Lipodystrophy Research Articles

Metreleptin: First Global Approval

Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment. Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy. Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.

Suppression of Adipogenesis by Pathogenic Seipin Mutant Is Associated with Inflammatory Response

BackgroundWhile pathogenic mutations in BSCL2/Seipin cause congenital generalized lipodystrophy, the underlying mechanism is largely unknown. In this study, we investigated whether and how the pathogenic missense A212P mutation of Seipin (Seipin-A212P) inhibits adipogenesis.Methodology/ResultsWe analyzed gene expression and lipid accumulation in stable 3T3-L1 cell lines expressing wild type (3T3-WT), non-lipodystrophic mutants N88S (3T3-N88S) and S90L (3T3-S90L), or lipodystrophic mutant A212P Seipin (3T3-A212P). When treated with adipogenic cocktail, 3T3-WT, 3T3-N88S and 3T3-S90L cells exhibited proper differentiation into mature adipocytes, indistinguishable from control 3T3-L1 cells. In contrast, adipogenesis was significantly impaired in 3T3-A212P cells. The defective adipogenesis in 3T3-A212P cells could be partially rescued by either PPARγ agonist or PPARγ overexpression. Gene expression profiling by microarray revealed that inhibition of adipogenesis was associated with activation of inflammatory genes including IL-6 and iNOS. We further demonstrated that Seipin-A212P expression at pre-differentiation stages significantly activated inflammatory responses by using an inducible expression system. The inflammation-associated inhibition of adipogenesis could be rescued by treatment with anti-inflammatory agents.ConclusionsThese results suggest that pathogenic Seipin-A212P inhibits adipogenesis and the inhibition is associated with activation of inflammatory pathways at pre-differentiation stages. Use of anti-inflammatory drugs may be a potential strategy for the treatment of lipodystrophy.

Impact of Progressive Resistance Training in Brazilian HIV Patients with Lipodystrophy

Background: The objective of the present study was to evaluate the impact of progressive resistance training on the body composition of HIV/AIDS-seropositive patients with lipodystrophy. Methods: The sample consisted of ten individuals with lipodystrophy submitted to a training program. Lean mass and fat mass levels were determined by double energy X-ray absorptiometry (DXA) before and after 36 sessions (12 weeks) of training divided into a preparatory phase (six sessions with three series of 15 repetitions), a transitory phase (six sessions with three series of 15 repetitions with 40 to 50% of maximum muscle strength), and a specific phase (24 sessions with three series of eight repetitions with 70 to 80% of maximum muscle strength). Data were analyzed statistically by the paired sample test. Results: The results showed a significant increase in total lean mass (P=0.039) in the upper limbs (P=0.004) and in the trunk (P=0.019). Conclusions: On this basis, we conclude that progressive resistance training promotes an increase in lean mass and can be useful for the complementary treatment of lipodystrophy by improving the body harmony and quality of life of patients with HIV/AIDS.

Syndromes lipodystrophiques

Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition. Most forms of lipodystrophies are associated with metabolic alterations such as insulin resistance, diabetes and dyslipemia, leading to diabetic complications, increased cardiovascular risk or liver steatosis. Lipodystrophies can be classified as genetic or acquired, generalized or partial. Genetic forms such as Berardinelli-Seip syndrome or partial familial lipodystrophies are uncommon and acquired forms are much more frequent. Beside the rare Lawrence or Barraquer-Simons syndromes, the main forms of acquired lipodystrophies are those observed in HIV-infected people treated with antiretroviral therapies or in people exposed to an endogenous or an exogenous hypercortisolism. The treatment of lipodystrophies is difficult. Lifestyle modifications (e.g., specific diet, physical training) may be helpful but are usually insufficient. Associated metabolic disorders should be treated as soon as possible with insulin sensitizers, insulin and lipid lowering drugs. New therapies such as leptin have been proven to be helpful in some genetic or acquired forms of lipodystrophy.

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.

Tesamorelin: A Growth Hormone-Releasing Factor Analogue for HIV-Associated Lipodystrophy

To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection.

The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation

We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance.

Lipodystrophy Syndromes

Lipodystrophy syndromes comprise a group of rare, heterogeneous disorders characterized by progressive loss of fat tissue, mainly from subcutaneous compartment and occasionally affecting visceral fat. Lipoatrophy may be partial, localized, or generalized. The latter cases are usually accompanied by metabolic-related disorders, including insulin resistance, diabetes mellitus, hyperlipemia, progressive hepatic disease and anabolic state. Treatment for lipodystrophy has increased interest in recent years because a new lipoatrophic population-patients who have HIV-associated lipodystrophy--is much more numerous than the whole number of patients affected by classic lipodystrophy entities.

Diagnosis and Management of Common Chronic Metabolic Complications in HIV-infected Patients

Human immunodeficiency virus (HIV) infection has become a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Metabolic complications such as dyslipidemia, insulin resistance, diabetes mellitus, obesity, and fat distribution abnormalities are associated with increased risk of cardiovascular disease. Cardiovascular disease is now a leading cause of death among HIV-infected patients. Lipid abnormalities, now often characteristically seen with HIV infection, include elevated triglycerides and low elevated total cholesterol (TC), and low high-density lipoprotein (HDL) levels of total and HDL cholesterol. Many antiretroviral drugs are associated with lipid abnormalities, which commonly include hypertriglyceridemia and increased total and low-density lipoprotein cholesterol levels. The management of dyslipidemia includes lifestyle modifications, lipid-lowering therapy, and switching antiretroviral therapy (ART). The increased prevalence of insulin resistance, impaired glucose tolerance, and diabetes is multifactorial in etiology. Management and goals of diabetes should follow the same practice guidelines in non-HIV-infected patients. Drug interactions and switching ART are additional management measures in diabetic HIV-infected patients. Since the treatment of lipodystrophy is a challenge, its prevention by selecting appropriate ART is the key.

Lipoplasty of the face and neck

Facial aesthetic surgery has gained wider acceptance and demand for it is increasing. Patients seeking a more youthful facial look often request lipoplasty. This article reviews the recent advances in lipoplasty and related fat contouring for the face and neck. Lipoplasty of the face and neck continues to be popular. There have been improvements in instrumentation, with laser and powered lipoplasty improving the efficiency of fat removal. Lipoplasty indications for neck lipodystrophy have been extended to patients previously only offered neck lifting. Additionally, limited procedures for patients with isolated anterior neck deformities, including direct lipectomy and skin excision, are gaining in popularity. Considerable attention in the lay and professional literature has been paid to mesotherapy for dissolving unwanted fat. Evidence supporting its efficacy is elusive. Finally, there remains enthusiasm for injection fat transfer for facial volume restoration as a component of rejuvenation. The treatment of lipodystrophy of the face and neck involves the removal of undesirable fat and the transfer of fat to other areas to produce improved aesthetic results. With the current emphasis on restoring volume, lipoplasty and fat transfer will continue to be important in facial plastic surgery.

Tratamiento quirúrgico de la lipodistrofia asociada a la infección por VIH. Conclusiones de una Reunión Multidisciplinar

To discuss the treatment for lipodystrophy associated with antiretroviral therapy, a meeting was held among infectious disease specialists, plastic surgeons and psychologists with extensive expertise in the care of HIV-infected patients. Lipodystrophy has an important impact on the patients' quality of life. There is now sufficient experience with surgical correction of facial lipoatrophy to consider it a useful technique for these patients. This treatment should be provided to patients with moderate to severe lipoatrophy, and to certain patients with mild lipoatrophy under special circumstances. There are no indications for correcting lipoatrophy of the limbs. Ultrasound-assisted liposuction is the technique of choice for the treatment of lipohypertrophy and is indicated in patients with mechanical or functional abnormalities. Patients with clear indications should have access to the surgical techniques that have proven to be useful for correcting lipodystrophy.

Lipohypertrophie induite par l'insuline traitée par liposuccion

The incidence of insulin-dependent diabetes mellitus increase permanently, with early diagnosis. Insulin is the treatment of this pathology. Insulin therapy is associated with complication such as lipodystrophies at injection sites leading functional and aesthetics disorders (pain, reduction of treatment efficiency, haematomas and oedemas). Our report two cases to illustrate the effectiveness of the suction-assisted lipectomy (SAL) on these lipodystrophies. We present two cases of insulin dependent diabetics patients with lipodystrophies of thighs, abdomen, and shoulders treated by SAL. The various analyzed parameters are: aesthetic aspect, efficiency of insulin treatment, ease injection, and pain reduction. We observe a significant reduction of insulin dose necessary to obtain a normoglycema half time. This treatment allow a better control of pain, control of haematomas and oedemas at the injection sites and an aesthetic improvement. The lipoaspiration is thus a simple and effective treatment of lipodystrophies due to insulin.

Carboxytherapy for gynoid lipodystrophy treatment: The Brazilian experience

Carboxytherapy for gynoid lipodystrophy treatment: The Brazilian experience

Balancing disfigurement and fear of disease progression: Patient perceptions of HIV body fat redistribution

This study was conducted to identify and describe the perceived morphologic changes of body fat redistribution and related distress among persons taking combination antiretroviral therapy. Six focus group interviews were conducted in four different US cities with men and women (n=58) who reported antiretroviral-related symptoms of body fat loss and/or gain. Interview data were audiotaped, transcribed verbatim and systematically analysed using inductive techniques. Physical discomfort and impairment and psychological and social distress were reported across sex, sexual orientation and geographic subgroups. While participants acknowledged that antiretroviral drugs were keeping them alive, there was tension between the desire for life-sustaining treatment and optimal quality of life. Some participants engaged in harmful heath behaviours in an attempt to control bodily changes (e.g. non-adherence to antiretroviral regimen). Participants feared that fat loss represented disease progression and worried that visible changes would lead to unintentional disclosure of their HIV status. Although a potential source of support, healthcare providers were commonly perceived as ignoring and, in so doing, discrediting patient distress. Participants recognised the limitations of current lipodystrophy treatment options, yet a cure for the syndrome seemed less important to them in the short term than simply being listened to and the powerful, but oblique sources of distress addressed.

Use of a Biopolymer Polyalkylimide Filler for Facial Lipodystrophy in HIV-Positive Patients Undergoing Treatment with Antiretroviral Drugs

To evaluate the efficacy, overall esthetic effect, and safety of a new permanent, polyalkylimide dermal filler in HIV-infected patients with severe facial lipodystrophy. Eleven subjects with severe facial lipodystrophy secondary to HIV infection were injected bilaterally with 15 and 30 cm3 of a polyalkylimide gel into the buccal, malar, and temporal areas of the face in an attempt to restore their facial contour. The youngest treated subject was 31 years of age and the oldest 73 years of age. All 11 subjects received an immediately acceptable therapeutic esthetic effect. Injections were generally well tolerated, with only three adverse events (swelling and bruising) recorded. Subjects, assessed at 3 and 18 months after treatment, continued to show improvement. The immediate benefits of a polyalkylimide gel in the correction and restoration of facial contour in subjects having severe HIV-related facial lipodystrophy were demonstrated. This improvement was still noted at 18 months. The efficacy, ease of injection, and safety profile of polyalkylimide gel make this filling material a potentially attractive treatment for lipodystrophy. These data must be tempered with the need for significant further safety studies to determine whether this long-term filler has a safety profile consistent with other currently popular fillers.

Use of a Biopolymer Polyalkylimide Filler for Facial Lipodystrophy in HIV-Positive Patients Undergoing Treatment with Antiretroviral Drugs

OBJECTIVES To evaluate the efficacy, overall esthetic effect, and safety of a new permanent, polyalkylimide dermal filler in HIV-infected patients with severe facial lipodystrophy. METHODS Eleven subjects with severe facial lipodystrophy secondary to HIV infection were injected bilaterally with 15 and 30 cm3 of a polyalkylimide gel into the buccal, malar, and temporal areas of the face in an attempt to restore their facial contour. The youngest treated subject was 31 years of age and the oldest 73 years of age. RESULTS All 11 subjects received an immediately acceptable therapeutic esthetic effect. Injections were generally well tolerated, with only three adverse events (swelling and bruising) recorded. Subjects, assessed at 3 and 18 months after treatment, continued to show improvement. CONCLUSIONS The immediate benefits of a polyalkylimide gel in the correction and restoration of facial contour in subjects having severe HIV-related facial lipodystrophy were demonstrated. This improvement was still noted at 18 months. The efficacy, ease of injection, and safety profile of polyalkylimide gel make this filling material a potentially attractive treatment for lipodystrophy. These data must be tempered with the need for significant further safety studies to determine whether this long-term filler has a safety profile consistent with other currently popular fillers.

Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFalpha, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue.

Cutis marmorata Resemblance After Liposuction

Liposuction is a safe method for the treatment of lipodystrophy. It gives good results in relation to body contours, especially when the superficial and deep layers of the superficial fascia are aspirated. The authors present clinical cases of female patients who underwent liposuction of the abdomen, flanks, and back in which superficial and deep liposuction was used. In the immediate postoperative period, these patients presented a skin pattern of marbled appearance, involving rosy-purplish stains intermingled with other whitish stains on the skin in the areas subjected to surgery and resembling the cutis marmorata described in the literature. Even 1 year after the operation, the stains had not receded. The literature mentions cases of cutaneous necrosis provoked by a temperature increase induced by liposuction cannulas. This trauma said to be the determining factor for local lesions of the subdermal plexus. However, no cases involving lesions of this plexus attributable to mechanical trauma from cannulas are cited. According to several authors, it is important during superficial liposuction to maintain a strip about 1 cm thick under the deep dermis for the preservation of the arterial plexus of the skin. This would avoid the formation of a skin pattern resembling cutis marmorata.

Pharmacologic therapy for HIV-associated lipodystrophy.

To evaluate the efficacy and safety of pharmacologic therapy in the treatment of HIV-associated lipodystrophy, with a focus on the treatment of fat redistribution. Drug therapies that have been shown to be beneficial in other forms of lipodystrophy and are currently being evaluated in HIV-associated lipodystrophy are also discussed. A MEDLINE search was conducted from 1996 to February 2003. Bibliographies of all articles were reviewed and pertinent articles were included. Abstracts from major meetings in 2002 and 2003 were also reviewed. All published studies were included in the review. Lipodystrophy has become more prevalent in patients with HIV. Lipodystrophy consists of adipose redistribution and metabolic abnormalities including dyslipidemia and insulin resistance. Treatment of lipodystrophy has been directed at either decreasing the amount of visceral adipose tissue (VAT), dorsocervical adipose tissue (commonly known as buffalo hump) and/or increase subcutaneous adipose tissue (SAT). Recombinant human growth hormone (rhGH) decreases VAT and buffalo hump, although it has been associated with a high frequency of adverse effects. Metformin and the thiazolidinediones have favorable metabolic effects, but were not found to be effective in correcting body compositional changes associated with lipodystrophy. Anabolic steroids and l-carnitine are not effective in the treatment of lipodystrophy. No drug therapy exists to fully ameliorate or correct the cosmetic changes of HIV-associated lipodystrophy. Clinicians must weigh the benefits and risks of each agent and individualize treatment for each patient.

Insulin resistance in HIV-related lipodystrophy.

Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-a in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome.