Partial lipodystrophy: Clinical presentation and treatment.

Lipodystrophic syndromes are acquired or genetic rare diseases, characterized by a generalized or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They are probably underdiagnosed, especially for partial forms. They are characterized by a lack of adipose tissue or a lack of adipose development leading to metabolic disorders associated with often severe insulin resistance, hypertriglyceridemia and hepatic steatosis. In partial forms of lipodystrophy, these mechanisms are aggravated by excess visceral adipose tissue and/or subcutaneous adipose tissue in the upper part of the body. 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 counseling. Early lifestyle and dietary measures focusing on regular physical activity, and balanced diet avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. 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 syndromes.

Mosbah H ，Vatier C ，Vigouroux C 《-》

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.

Sollier C ，Vatier C ，Capel E ，Lascols O ，Auclair M ，Janmaat S ，Fève B ，Jéru I ，Vigouroux C ... -  《-》

Primary disease of adipose tissue: When to think about and how to evaluate it in clinical practice?

Primary diseases of adipose tissue are rare disorders resulting from impairments in the physiological functions of adipose tissue (lipid stockage and endocrine function). It mainly refers to lipodystrophy syndromes with subcutaneous adipose tissue atrophy and/or altered body distribution of adipose tissue leading to insulin resistance, diabetes, hepatic steatosis, dyslipidemia, cardiovascular complications and polycystic ovary syndrome in women. Those syndromes are congenital or acquired, and lipoatrophy is partial or generalized. The diagnosis of lipodystrophy syndromes is often unrecognized, delayed and/or inaccurate, while it is of major importance to adapt investigations to search for specific comorbidities, in particular cardiovascular involvement, and set up multidisciplinary care, and in some cases specific treatment. Physicians have to recognize the clinical and biological elements allowing to establish the diagnosis. Lipodystrophic syndromes should be considered, notably, in patients with diabetes at a young age, with a normal or low BMI, negative pancreatic autoantibodies, presenting clinical signs of lipodystrophy and insulin resistance (acanthosis nigricans, hyperandrogenism, hepatic steatosis, high insulin doses). The association of diabetes and a family history of severe and/or early cardiovascular disease (coronary atherosclerosis, cardiomyopathy with rhythm and/or conduction disorders) may reveal Dunnigan syndrome, the most frequent form of familial lipodystrophy, due to LMNA pathogenic variants. Clinical assessment is primarily done through clinical examination: acanthosis nigricans, abnormal adipose tissue distribution, lipoatrophy, muscular hypertrophy, acromegaloid or Cushingoid features, lipomas, highly visible subcutaneous veins, may be revealing signs. The amount of circulating adipokines may reflect of adipose dysfunction with low leptinemia and adiponectinemia. Other biological metabolic parameters (hypertriglyceridemia, hyperinsulinemia, increased glycemia and hepatic enzymes) may also represent markers of insulin resistance. Quantification of total body fat by impedancemetry or dual-photon X-ray absorptiometry (DEXA) reveals decreased total body mass, in correlation with adipose tissue atrophy; metabolic magnetic resonance imaging can also quantify intraperitoneal and abdominal fat and the degree of hepatic steatosis. Histological analysis of adipose tissue showing structural abnormalities should be reserved for clinical research. Acquired lipodystrophic syndromes most often lead to similar clinical phenotype as congenital syndromes with generalized or partial lipoatrophy. The most frequent causes are old anti-HIV therapy or glucocorticoid treatments. Family history, history of treatments and clinical examination, including a careful physical examination, are keys for diagnosis.

Vatier C ，Vigouroux C ，Mosbah H 《-》

Leptin replacement therapy in the management of lipodystrophy syndromes.

Lipodystrophy syndromes are rare diseases of genetic or acquired origin, characterized by quantitative and qualitative defects in adipose tissue. The metabolic consequences of lipodystrophy syndromes, such as insulin resistant diabetes, hypertriglyceridemia and hepatic steatosis, are frequently very difficult to treat, resulting in significant risks of acute and/or chronic complications and of decreased quality of life. The production of leptin by lipodystrophic adipose tissue is decreased, more severely in generalized forms of lipodystrophy, where adipose tissue is absent from almost all body fat depots, than in partial forms of the disease, where lipoatrophy affects only some parts of the body and can be associated with increased body fat in other anatomical regions. Several lines of evidence in preclinical and clinical models have shown that leptin replacement therapy could improve the metabolic complications of lipodystrophy syndromes. Metreleptin, a recombinant leptin analogue, was approved as an orphan drug to treat the metabolic complications of leptin deficiency in patients with generalized lipodystrophy in the USA or with either generalized or partial lipodystrophy in Japan and Europe. In this brief review, we will discuss the benefits and limitations of this therapy, and the new expectations arising from the recent development of a therapeutic monoclonal antibody able to activate the leptin receptor.

Vigouroux C ，Mosbah H ，Vatier C 《-》

Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases.

Vatier C ，Vantyghem MC ，Storey C ，Jéru I ，Christin-Maitre S ，Fève B ，Lascols O ，Beltrand J ，Carel JC ，Vigouroux C ，Bismuth E ... -  《-》