Diagnosis and treatment of lipodystrophy: a step-by-step approach

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Abstract

Aim

Lipodystrophy syndromes are rare heterogeneous disorders characterized by deficiency of adipose tissue, usually a decrease in leptin levels and, frequently, severe metabolic abnormalities including diabetes mellitus and dyslipidemia.

Purpose

To describe the clinical presentation of known types of lipodystrophy, and suggest specific steps to recognize, diagnose and treat lipodystrophy in the clinical setting.

Methods

Based on literature and in our own experience, we propose a stepwise approach for diagnosis of the different subtypes of rare lipodystrophy syndromes, describing its more frequent co-morbidities and establishing the therapeutical approach.

Results

Lipodystrophy is classified as genetic or acquired and by the distribution of fat loss, which can be generalized or partial. Genes associated with many congenital forms of lipodystrophy have been identified that may assist in diagnosis. Because of its rarity and heterogeneity, lipodystrophy may frequently be unrecognized or misdiagnosed, which is concerning because it is progressive and its complications are potentially life threatening. A basic diagnostic algorithm is proposed. Effective management of lipodystrophy includes lifestyle changes and aggressive, evidence-based treatment of comorbidities. Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval in Europe.

Conclusions

Here, we describe the clinical presentation of known types of lipodystrophy, present an algorithm for differential diagnosis of lipodystrophy, and suggest specific steps to recognize and diagnose lipodystrophy in the clinical setting.

Related collections

Most cited references 44

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Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome.

Hiroyuki Mishima, Keiko Tanaka, Takeumi Kaneko … (2011)

Nakajo-Nishimura syndrome (NNS) is a disorder that segregates in an autosomal recessive fashion. Symptoms include periodic fever, skin rash, partial lipomuscular atrophy, and joint contracture. Here, we report a mutation in the human proteasome subunit beta type 8 gene (PSMB8) that encodes the immunoproteasome subunit β5i in patients with NNS. This G201V mutation disrupts the β-sheet structure, protrudes from the loop that interfaces with the β4 subunit, and is in close proximity to the catalytic threonine residue. The β5i mutant is not efficiently incorporated during immunoproteasome biogenesis, resulting in reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins within cells expressing immunoproteasomes. As a result, the level of interleukin (IL)-6 and IFN-γ inducible protein (IP)-10 in patient sera is markedly increased. Nuclear phosphorylated p38 and the secretion of IL-6 are increased in patient cells both in vitro and in vivo, which may account for the inflammatory response and periodic fever observed in these patients. These results show that a mutation within a proteasome subunit is the direct cause of a human disease and suggest that decreased proteasome activity can cause inflammation.

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Perilipin deficiency and autosomal dominant partial lipodystrophy.

Yves Reznik, Inês Barroso, G. Mark Lathrop … (2011)

Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.

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Cockayne syndrome: the expanding clinical and mutational spectrum.

Vincent Laugel (2013)

Cockayne syndrome is a progressive multisystem disorder characterized by a specific cellular defect in transcription-coupled repair. Typical features include developmental delay, failure to thrive, microcephaly, cutaneous photosensitivity, dental anomalies, progressive hearing loss, pigmentary retinopathy, cataracts and enophthalmia. Various levels of severity have been described including the "classical" or moderate type I CS, the early-onset or severe type II and the mild or late-onset type III. Adult-onset cases with prolonged survival and normal initial development have also been identified. At the opposite end of the scale, the most severely affected patients, showing a prenatal onset of the symptoms, are overlapping with the cerebro-oculo-facio-skeletal (COFS) syndrome. These overlapping subtypes build a continuous spectrum without clear thresholds. Revised diagnostic criteria are proposed to improve the recognition of the disease. Two thirds of the patients are linked to mutations in the CSB (ERCC6) gene, one third to mutations in the CSA (ERCC8) gene. At least 78 different mutations are known in the CSB gene and 30 in the CSA gene to date, in more than 120 genetically confirmed patients. Large clinical and molecular databases are needed to unravel genotype-phenotype correlations and to gain more insight into the underlying molecular mechanisms. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Contributors

D. Araújo-Vilar:

ORCID: http://orcid.org/0000-0003-2852-7851

+34 639 393 458 , david.araujo@usc.es

Journal

Journal ID (nlm-ta): J Endocrinol Invest

Journal ID (iso-abbrev): J. Endocrinol. Invest

Title: Journal of Endocrinological Investigation

Publisher: Springer International Publishing (Cham )

ISSN (Print): 0391-4097

ISSN (Electronic): 1720-8386

Publication date (Electronic): 27 April 2018

Publication date PMC-release: 27 April 2018

Publication date (Print): 2019

Volume: 42

Issue: 1

Pages: 61-73

Affiliations

[1 ]ISNI 0000000109410645, GRID grid.11794.3a, UETeM-Molecular Pathology Group, Institute of Biomedical Research (CIMUS), School of Medicine, , University of Santiago de Compostela, ; Santiago de Compostela, Spain

[2 ]ISNI 0000 0004 1756 8209, GRID grid.144189.1, Endocrinology Unit, Obesity Center, , University Hospital of Pisa, ; Pisa, Italy

Author information

D. Araújo-Vilar http://orcid.org/0000-0003-2852-7851

Article

Publisher ID: 887

DOI: 10.1007/s40618-018-0887-z

PMC ID: 6304182

PubMed ID: 29704234

SO-VID: 0f61d2f0-97e4-4e3f-9b3f-8a9749acebd2

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 6 December 2017

Date accepted : 9 April 2018

Funding

Funded by: Aegerion

Custom metadata

Keywords: diabetes,dyslipidemia,insulin resistance,leptin replacement,metreleptin

Data availability:

Keywords: diabetes, dyslipidemia, insulin resistance, leptin replacement, metreleptin