Lipodystrophy Syndrome Research Articles

Features of the course of non-alcoholic fatty liver disease in HIV-infected individuals

This article reflects the course of non-alcoholic fatty liver disease (NAFLD) in HIV-infected individuals. It is noted that long-term antiretroviral therapy and the use of D-drugs can explain the high prevalence of steatosis in this category of patients. The results of experimental studies that demonstrate the direct effect of HIV on liver steatosis by infection of stellate liver cells, stimulation of abnormal expression of SREBP-1 and PPARγ are considered. The role of HIV-mediated microbial translocation as one of the triggers for the development of non-alcoholic steatohepatitis (NASH), which contributes to chronic inflammation due to an increase in the permeability of the intestinal barrier to bacterial products and endotoxins, is noted. Data are presented confirming the high prevalence of the abnormal distribution of fat and visceral obesity (components of lipodystrophy syndrome) in a cohort of HIV-infected individuals. There was a high prevalence of steatosis and steatohepatitis in HIV-infected patients with lipodystrophy as compared with HIV-infected patients without lipodystrophy. Data showing the high prevalence of NASH in HIV-infected individuals are presented. A high rate of progression of NAFLD in a cohort of HIV-infected individuals was observed, regardless of the presence/absence of a combined viral infection (chronic hepatitis C). It has been established that the classic risk factors for NAFLD (high body mass index, dyslipidemia, metabolic syndrome) can contribute to the rapid progression of the disease in people living with HIV, compared with representatives of the general population.

Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders.

The extracellular matrix microenvironment of adipose tissue is of critical importance for the differentiation, remodeling and function of adipocytes. Fibrillin-1 is one of the main components of microfibrils and a key player in this process. Furin processing of profibrillin-1 results in mature fibrillin-1 and releases the C-terminal propeptide as a circulating hunger hormone, asprosin. Mutations in the fibrillin-1 gene lead to adipose tissue dysfunction and causes Marfan syndrome, marfanoid progeroid lipodystrophy syndrome, and neonatal progeroid syndrome. Increased TGF-β signaling, altered mechanical properties and impaired adipogenesis are potential causes of adipose tissue dysfunction, mediated through deficient microfibrils. Circulating asprosin on the other hand is secreted primarily by white adipose tissue under fasting conditions and in obesity. It increases hepatic glucose production and drives insulin secretion and appetite stimulation through inter-organ cross talk. This review discusses the metabolic consequences of fibrillin-1 and fibrillin-1-derived asprosin in pathological conditions. Understanding the dynamic role of fibrillin-1 in the adipose tissue milieu and of circulating asprosin in the body can provide novel mechanistic insights into how fibrillin-1 may contribute to metabolic syndrome. This could lead to new management regimens of patients with metabolic disease.

LipoDDx: a mobile application for identification of rare lipodystrophy syndromes

BackgroundLipodystrophy syndromes are a group of disorders characterized by a loss of adipose tissue once other situations of nutritional deprivation or exacerbated catabolism have been ruled out. With the exception of the HIV-associated lipodystrophy, they have a very low prevalence, which together with their large phenotypic heterogeneity makes their identification difficult, even for endocrinologists and pediatricians. This leads to significant delays in diagnosis or even to misdiagnosis.Our group has developed an algorithm that identifies the more than 40 rare lipodystrophy subtypes described to date. This algorithm has been implemented in a free mobile application, LipoDDx®. Our aim was to establish the effectiveness of LipoDDx®.Forty clinical records of patients with a diagnosis of certainty of most lipodystrophy subtypes were analyzed, including subjects without lipodystrophy. The medical records, blinded for diagnosis, were evaluated by 13 physicians, 1 biochemist and 1 dentist. Each evaluator first gave his/her results based on his/her own criteria. Then, a second diagnosis was given using LipoDDx®. The results were analysed based on a score table according to the complexity of each case and the prevalence of the disease.ResultsLipoDDx® provides a user-friendly environment, based on usually dichotomous questions or choice of clinical signs from drop-down menus. The final result provided by this app for a particular case can be a low/high probability of suffering a particular lipodystrophy subtype. Without using LipoDDx® the success rate was 17 ± 20%, while with LipoDDx® the success rate was 79 ± 20% (p < 0.01).ConclusionsLipoDDx® is a free app that enables the identification of subtypes of rare lipodystrophies, which in this small cohort has around 80% effectiveness, which will be of help to doctors who are not experts in this field. However, it will be necessary to analyze more cases in order to obtain a more accurate efficiency value.

Cardiovascular complications of lipodystrophic syndromes – focus on laminopathies

Cardiovascular complications of lipodystrophic syndromes – focus on laminopathies

Lipodystrophic syndrome of HIV and associated factors: a study in a university hospital.

The use of antiretroviral drugs has increased the survival of HIV patients, but may have side effects, such as lipodystrophic syndrome. This article aims to identify the frequency of the lipodystrophic syndrome and its associated factors in patients with HIV using antiretroviral therapy. It involved a cross-sectional study with HIV patients, monitored on an outpatient basis. The syndrome was evaluated by the association of two parameters: peripheral weight loss through the lipodystrophy severity scale and central fat accumulation, measured by the hip waist ratio. Poisson regression analysis was performed to identify the associated variables. Of the 104 patients evaluated, 27.9% presented the syndrome. After adjustment, the female sex (PRadjusted = 2.16 CI95% 1.43-3.39), being overweight (PRadjusted = 2.23 CI95% 1.35-2.65) and a longer period of use of antiretrovirals (PRadjusted = 1.64 CI95% 1.16-2.78), remained positively associated with the syndrome. On the other hand, a negative association with CD4 count £ 350 (PRadjusted = 0.39 CI95% 0.10-0.97) was observed The high prevalence of the syndrome and its association with specific groups reinforce the need for adequate follow-up and early identification to intervene in modifiable factors.

Current Diagnosis, Treatment and Clinical Challenges in the Management of Lipodystrophy Syndromes in Children and Young People

Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.

Acquired generalized lipodystrophy type 2-lawrence syndrome: a rare case report

Lawrence syndrome (Acquired Generalized Lipodystrophy) is a rare disorder, characterized by various dermatological and systemic manifestations such as lipodystrophy, hypertriglyceridemia, hepatomegaly, acanthosis nigricans and acromegaloid features. Because of its rare occurrence we are reporting a case with similar manifestations in a 10 years old child.

Investigation of SIRT1 gene variants in HIV-associated lipodystrophy and metabolic syndrome.

HIV-infected individuals on chronic use of highly active antiretroviral therapy (HAART) are more likely to develop adipose tissue and metabolic disorders, such as lipodystrophy (LD) and metabolic syndrome (MetS). The development of these phenotypes is known to be multifactorial. Thus, variants in genes implicated in adipogenesis and lipid metabolism may increase susceptibility to LD and MetS. Sirtuin 1 (SIRT1) may influence the outcome of these disturbances due to its role in the regulation of transcription factors involved in energy regulation. Therefore, we genotyped four polymorphisms located in SIRT1 (rs2273773 T>C, rs12413112 G>A, rs7895833 A>G, rs12049646 T>C) in 832 HIV-infected patients receiving HAART by real-time polymerase chain reaction. The prevalence of LD was 55.8% and MetS was 35.3%. Lipoatrophy was the most prevalent subtype in all samples (38.0%) and showed significant difference between white and non-white individuals (P = 0.002). None of the genetic variants investigated in SIRT1 was associated with LD and MetS. White individuals and those in longer time of HAART use were more likely to develop LD. We concluded that these SIRT1 polymorphisms are not predictive factors to the development of lipodystrophy and metabolic syndrome in HIV-infected individuals from Brazil.

Adipocyte differentiation impairment as well as lipid metabolism and transport problems – major causes of genetic lipodystrophies

Lipodystrophies are heterogenic group of adipose tissue disorders with its general or partial atrophy. In case of congenital lipodystrophies disturbances of adipogenesis or/and alterations of adipocyte differentiation often occur leading to thermogenic adipocytes formation. Basic adipocyte functions can be perturbed, including improper synthesis of triacylglycerols and phospholipids of lipid droplet, but also impaired fatty acids release and intracellular lipid traffic. Lipodystrophy can result from weakening of adipose tissue structure, but also from improper function of both cytoskeleton and nuclear lamina leading to cell dysfunction. Lack of adipose tissue leads to a) increased plasma triacylglycerols level and ectopic fat accumulation in other tissues; b) total plasma cholesterol increase; c) plasma HDL-cholesterol decrease. Ectopic fat accumulation in liver can cause fatty liver and with time can lead to hepatomegaly and liver cirrhosis. Dysfunctions are proportional to the extent of fat tissue loss with generalized lipodystrophies patients developing complications at early ages. Diabetes and insulin resistance are common comorbidities. Improvement of diagnostic methods of medical genetics allows precise determination of their genotypes and correct diagnosis of patients suffering from lipodystrophy. For that reason number of described cases increased in recent years, also in Poland. New lipodystrophy types were described. Therefore there is a need to bring lipodystrophy syndromes for the attention of primary care physicians, pediatricians and endocrinologists.

Lipodystrophic syndromes: From diagnosis to treatment

Lipodystrophic syndromes are acquired or genetic rare diseases, characterised by a generalised or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They encompass a variety of clinical entities due to primary defects in adipose differentiation, in the structure and/or regulation of the adipocyte lipid droplet, or due to immune-inflammatory aggressions, chromatin deregulations and/or mitochondrial dysfunctions affecting adipose tissue. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counselling. Early lifestyle and dietary measures focusing on regular physical activity and avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. In case of hyperglycemia, antidiabetic medications, with metformin as a first-line therapy in adults, are used in addition to lifestyle and dietary modifications. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndrome. Metreleptin therapy indications, prescription and monitoring were recently defined in France, representing a major improvement in patient care.

Inactivating Mutations in Exonuclease and Polymerase Domains in DNA Polymerase Delta Alter Sensitivities to Inhibitors of dNTP Synthesis.

POLD1 encodes the catalytic subunit of DNA polymerase delta (Polδ), the major lagging strand polymerase, which also participates in DNA repair. Mutations affecting the exonuclease domain increase the risk of various cancers, while mutations that change the polymerase active site cause a progeroid syndrome called mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome. We generated a set of catalytic subunit of human telomerase (hTERT)-immortalized human fibroblasts expressing wild-type or mutant POLD1 using the retroviral LXSN vector system. In the resulting cell lines, expression of endogenous POLD1 was suppressed in favor of the recombinant POLD1. The siRNA screening of DNA damage-related genes revealed that fibroblasts expressing D316H and S605del POLD1 were more sensitive to knockdowns of ribonuclease reductase (RNR) components, RRM1 and RRM2 in the presence of hydroxyurea (HU), an RNR inhibitor. On the contrary, SAMHD1 siRNA, which increases the concentration of dNTPs, increased growth of wild type, D316H, and S605del POLD1 fibroblasts. Hypersensitivity to dNTP synthesis inhibition in POLD1 mutant lines was confirmed using gemcitabine. Our finding is consistent with the notion that reduced dNTP concentration negatively affects the cell growth of hTERT fibroblasts expressing exonuclease and polymerase mutant POLD1.

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.

Berardinelli Seip Congenital Lipodystrophy Syndrome: 10 Year Follow-up

Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications. Here, we describe a 10-year-old girl with genetically proven Berardinelli Seip congenital generalized lipodystrophy type 2, diagnosed at 10 months of age. She developed comorbidities like proteinuria, hypertension, diabetes mellitus, and liver fibrosis.

Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.

Nakajo–Nishimura syndrome (NNS) is a rare hereditary autoinflammatory disorder with lipodystrophy. This disease is caused by a homozygous mutation of PSMB8 gene, which encodes immunoproteasome subunit β5i. Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers. NNS was considered to be endemic to the Kansai area of Japan, but patients with similar phenotypes and the mutation of PSMB8 gene were reported in other countries, and named Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy (JMP) syndrome. These syndromes are now called proteasome-associated autoinflammatory syndromes (PRAASs), and their main pathophysiological mechanism seems to be interferonopathy. In this review, the history, characteristics, and the pathophysiological mechanism of PRAASs will be discussed, focusing mainly on NNS.

Recent developments in lipodystrophy.

Lipodystrophy syndromes have an estimated prevalence of 1.3-4.7 cases per million and as with other rare diseases conducting research can be challenging. The present review highlights recently published work that has provided insights into the field of non-HIV--associated lipodystrophy syndromes. Lipodystrophies are a heterogenous group of disorders, as such research is often focused on specific subtypes of the condition. The identification of children carrying LMNA mutations has provided insights into the natural history of FPLD2, specifically that the adipose tissue phenotype predates the onset of puberty. Recent reports of PLIN1 heterozygous null variant carriers and the apparent absence of a lipodystrophy phenotype challenges our understanding of the molecular biology of perilipin 1 and its role in the pathogenesis of FPLD4. With a focus on therapeutics, studies delineating the differential responsiveness of PPARγ mutants to endogenous and synthetic ligands has illustrated the potential for pharmacogenetics to inform therapeutic decisions in lipodystrophy related to PPARG mutations, whereas robust human studies have provided insight into the food independent metabolic effects of leptin in lipodystrophy. Finally, rare syndromes of lipodystrophy continue to serve as an exemplar for the contribution of genetically determined adipose tissue expandability to metabolic disease in the general population. Lipodystrophy research continues to illuminate our understanding of this rare disease and the possibility that lipodystrophy syndromes and the metabolic syndrome may have shared pathophysiology.

Comorbidities and Survival in Patients With Lipodystrophy: An International Chart Review Study.

Limited natural history data are available in patients with non-HIV-related lipodystrophy syndromes who never received disease-specific therapies, making interpretation of benefits of therapies in lipodystrophy syndromes challenging. We assessed the natural history of non-HIV-related generalized lipodystrophy (GL) and partial lipodystrophy (PL) in patients who have never received leptin or other lipodystrophy-specific therapies. We conducted an international chart review of 230 patients with confirmed GL or PL at five treatment centers who never received leptin or other lipodystrophy-specific therapies. Patients were observed from birth to loss to follow-up, death, or date of chart abstraction. Lifetime prevalence of diabetes/insulin resistance and select organ abnormalities, time to diabetes/insulin resistance, first organ abnormality, disease progression, and mortality were described. Diabetes/insulin resistance was identified in 58.3% of patients. Liver abnormalities were the most common organ abnormality (71.7%), followed by kidney (40.4%), heart (30.4%), and pancreatitis (13.0%). Kaplan-Meier estimates of mean (SE) time to first organ abnormality were 7.7 years (0.9) in GL and 16.1 years (1.5) in PL (P < 0.001). Mean time to diabetes/insulin resistance was 12.7 years (1.2) in GL and 19.1 years (1.7) in PL (P = 0.131). Mean time to disease progression was 7.6 years (0.8) and comparable between GL and PL subgroups (P = 0.393). Mean time to death was 51.2 years (3.5) in GL and 66.6 years (1.0) in PL (P < 0.001). This large-scale study provides comprehensive, long-term data across multiple countries on the natural history of non-HIV-related lipodystrophy.

Adherence\xa0with metreleptin therapy and health self-perception in patients with lipodystrophic syndromes

BackgroundAlthough metreleptin replacement therapy was shown to improve metabolic alterations in lipodystrophic syndromes, patients’ adherence and satisfaction with treatment have never been evaluated. The 20 patients with lipodystrophic syndromes participating in the French compassionate program of metreleptin therapy filled in a self-questionnaire including an Adherence Evaluation Test, the Treatment Satisfaction Questionnaire for Medication (TSQM®-vII), and items about physical appearance.Results15 patients were women, median age was 32.5 years (IQT 25–75 (16.2;49.5), 18 had diabetes. Adherence with metreleptin (one daily subcutaneous injection) was poor in 25%, excellent in 25% and acceptable in 50% of patients. On a 0-to-100 scale, patients’ satisfaction scores reached 66.7 (52.1;81.2) for effectiveness, 55.6 (44.4;66.7) for ease/comfort of use, and 83.3 (52.1;83.3) for global satisfaction with metreleptin therapy. Self-reported side effects were frequent injection site reactions 100 (79.2;100). Satisfaction scores did not differ in patients with partial (n = 10) or generalized (n = 10) lipodystrophic syndromes, did not correlate with metabolic improvement, but were significantly higher in compliant patients with fewer side effects. Morphological appearance was reported improved under metreleptin therapy in 13 among 17 patients.ConclusionsMetreleptin increases health self-perception and decreases morphotype-associated stigmatization in most patients with lipodystrophic syndromes, but poor comfort of use and local side effects weaken adherence.

Cyclophosphamide in the Treatment of Associated Acquired Lipodystrophy Syndrome With Type 1 Diabetes

Cyclophosphamide in the Treatment of Associated Acquired Lipodystrophy Syndrome With Type 1 Diabetes

A Treg-specific deletion of Helios causes autoimmune lipodystrophy and metabolic syndrome

Abstract Regulatory T (Treg) cells suppress immune activation in a dominant manner and play a critical role in the maintenance of self-tolerance. A subpopulation (60–75%) of Foxp3+T regulatory (Treg) cells express the transcription factor Helios. To examine the function of Helios in Treg cells, we have generated Treg-specific Helios deficient mice (cKO, Heliosflxflx Foxp3cre). Although both Treg development in the cKO mice and their in vitro suppressor function are normal, the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation with a Th1 phenotype, hypergammaglobulinemia, and enhanced germinal center formation. Initially, we observed significant lymphocytic infiltrates only in the salivary gland and not in any other organs typically affected by Treg dysregulation. Strikingly, the mice developed lipodystrophy, hepatic steotosis and insulin resistance. Further analysis revealed a significant lymphocytic infiltrate in both the inguinal and perigonadal adipose tissue, indicating autoimmune mediated destruction of the white adipose tissue (WAT). We have further shown that the lymphocytic infiltrate specific to WAT can be transferred from mice with lipodystrophy to immunodeficient mice, confirming the autoimmune nature of the lipodystrophy. Thus, Helios deficiency in Treg disrupts immune homeostasis in the adipose tissue, leading to the destruction of WAT and redirection of lipids to the liver, and ultimately causes metabolic dysfunction. Supported by the Intramural Research Program of the NIAID, NIH.

SUN-087 Effects of Leptin Replacement on Circulating Plasma Inhibitors of Lipoprotein Lipase in Patients with Lipodystrophy

Lipodystrophy syndromes (LD) result from selective deficiency of adipose tissue, leading to low leptin. Low leptin leads to hyperphagia and ectopic lipid storage, causing severe insulin resistance and metabolic complications including high triglycerides (TG) and subsequent pancreatitis. Replacement of leptin using metreleptin (ML) in LD decreases TG. TG are broken down to non-esterified fatty acids (NEFA) by lipoprotein lipase (LPL). We previously demonstrated that patients with LD had high apoCIII and ANGPLT8 (inhibitors of LPL) that decreased with ML, suggesting that ML may lower TG by reducing inhibition of LPL activity. We hypothesized that plasma from patients with LD would cause greater inhibition of LPL compared to controls, and that ML would ameliorate this. We further hypothesized that net inhibition of LPL in LD would be reflected by a decreased ratio of apoCII (an LPL stimulator) to apoCIII (an LPL inhibitor) vs. controls. METHODS: Plasma from ML-naive patients with LD (n=14) and a pooled high-TG control group (651 mg/dL, n=10) were diluted to the same concentration of TG. Samples were incubated with bovine LPL, and NEFA produced was measured enzymatically over 1hr at 37⁰C. Because the concentrations of added LPL and TG were equal in each patient sample, NEFA generation (nmole) reflected the net effect of LPL stimulators and inhibitors in plasma. To test the effects of ML, the same method was applied to samples from patients with LD after ML 5 mg Q12h for 2 weeks and 6 months. ApoCII and apoCIII were compared in patients with LD (n=14) versus healthy controls (TG = 74 [54, 97] mg/dL, n=28). RESULTS: Patients with LD had baseline TG 492 [208, 1016] mg/dL which decreased to 279 [171, 648] after 2 weeks of ML (n=14, p=.0023) and to 223 [118, 335] after 6 months of ML (n=11, p=0.15). Prior to ML, patients with LD had higher NEFA generation vs. controls (patients 0.79 ± 0.08; controls 0.59 ± 0.1; p<0.0001), consistent with less net inhibition of LPL. NEFA generation did not change with ML therapy after 2 weeks (0.77 ± 0.09) or 6 months (0.78 ± 0.12) compared to baseline (p>0.05). ApoCII:apoCIII ratio did not differ in LD vs controls (0.63±0.31 vs 0.54±0.17, p=0.6), and did not change after ML. CONCLUSIONS: Counter to our hypothesis, patients with LD had higher NEFA generation compared to high TG controls, consistent with less net inhibition of LPL, while the ratio of LPL activator (apoCII) to inhibitor (apoCIII) did not differ in LD vs normal TG controls. Furthermore, NEFA generation and apoCII:apoCIII ratio did not change after ML therapy, suggesting no net change in inhibition of LPL with ML. These findings suggest that changes in circulating activators and inhibitors of LPL are not a major mechanism by which ML lowers TG in LD. Studies including direct measurement of LPL activity after heparin stimulation are needed to further explore the role of LPL in regulating TG in LD.