Review

Authors: Iram Hussain, Abhimanyu Garg

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.

Topics: Fatty Liver; HIV Infections; Humans; Hypertriglyceridemia; Insulin Resistance; Lipodystrophy; Syndrome

PubMed: 27823605
DOI: 10.1016/j.ecl.2016.06.012

Review

Authors: Rebecca J Brown, David Araujo-Vilar, Pik To Cheung...

OBJECTIVE

Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes the diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs.

PARTICIPANTS

Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts. Funding was via an unrestricted educational grant from Astra Zeneca to the Pediatric Endocrine Society. Meetings were not open to the general public.

EVIDENCE

A literature review was conducted by the committee. Recommendations of the committee were graded using the system of the American Heart Association. Expert opinion was used when published data were unavailable or scarce.

CONSENSUS PROCESS

The guideline was drafted by committee members and reviewed, revised, and approved by the entire committee during group meetings. Contributing societies reviewed the document and provided approval.

CONCLUSIONS

Lipodystrophy syndromes are heterogeneous and are diagnosed by clinical phenotype, supplemented by genetic testing in certain forms. Patients with most lipodystrophy syndromes should be screened for diabetes, dyslipidemia, and liver, kidney, and heart disease annually. Diet is essential for the management of metabolic complications of lipodystrophy. Metreleptin therapy is effective for metabolic complications in hypoleptinemic patients with generalized lipodystrophy and selected patients with partial lipodystrophy. Other treatments not specific for lipodystrophy may be helpful as well (eg, metformin for diabetes, and statins or fibrates for hyperlipidemia). Oral estrogens are contraindicated.

Topics: Humans; Lipodystrophy; Practice Guidelines as Topic

PubMed: 27710244
DOI: 10.1210/jc.2016-2466

Review

Authors: D Araújo-Vilar, F Santini

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.

Topics: Adipose Tissue; Diet, Healthy; Humans; Insulin Resistance; Leptin; Lipodystrophy; Treatment Outcome

PubMed: 29704234
DOI: 10.1007/s40618-018-0887-z

Review

Authors: Francesca Mainieri, Francesco Chiarelli

BACKGROUND

Lipodystrophy includes a wide group of diseases characterized by reduction, absence, or altered distribution of adipose tissue. Lipodystrophies are classified into generalized or partial, according to the fat distribution, and congenital or acquired, considering the etiology.

SUMMARY

Impaired glucose and lipid metabolism are typically present, thus severe insulin resistance, diabetes mellitus, dyslipidemia, and hepatic steatosis are frequent complications. Because of the rarity and the diversification of lipodystrophies, diagnosis might be challenging, typically for partial forms that cannot be easily recognized, leading to progression of the several metabolic abnormalities associated. First management of lipodystrophy is diet and lifestyle changes, followed by the treatment of metabolic complications. Replacement therapy with metreleptin, currently available in the USA and Europe, has shown improvement of metabolic profile in a great number of patients with lipodystrophy.

KEY MESSAGES

The purpose of this review was to describe the phenotypic characteristics of all the known lipodystrophic types and to present specific steps for obtaining an early diagnosis and assessing the best treatment of lipodystrophy.

Topics: Adipose Tissue; Child; Fatty Liver; Glucose; Humans; Insulin Resistance; Lipodystrophy

PubMed: 35189617
DOI: 10.1159/000522620

Authors: Rasimcan Meral, Merve Celik Guler, Diarratou Kaba...

BACKGROUND

Lipodystrophy encompasses a group of rare disorders associated with severe metabolic disease. These disorders are defined by abnormal fat distribution, with near-total (generalized lipodystrophy, GL) or partial (partial lipodystrophy, PL; i.e. familial partial lipodystrophy, FPLD) absence of adipocyte mass leading to a decreased ability to store lipids safely. Excess lipids are more likely to be stored in non-adipose tissues, which leads to the metabolic manifestations. We have recently shown that glucagon-like peptide-1 agonists are associated with metabolic improvements in FPLD. We hypothesized that tirzepatide, a dual incretin, may also lead to metabolic improvement in patients with lipodystrophy.

METHODS

Observational cohort of patients with PL or GL who received tirzepatide clinically were tracked in the context of ongoing natural history studies.

RESULTS

Seventeen patients received tirzepatide, 14 with FPLD (ages within 30-74 years; 12 female 2 male). After a median 8.7 months of follow-up, BMI (medianΔ -1.7; range -5.9 to 0.9 kg/m ; =0.008), HbA1c (medianΔ -1.1%; range -6.3 to -0.1%; <0.001), triglycerides [medianΔ - 65 mg/dL (-0.73 mmol/L); range -3820 to 43 mg/dL (-43.2 to 0.49 mmol/L); =0.003] and total daily insulin requirements (medianΔ -109; range -315 to 0 units/day; =0.002) were significantly reduced. Three patients with acquired GL (Ages within 35-64 years; all female) also demonstrated a robust response to tirzepatide with reduced BMI (22.2->20.9; 26.2->25.4; 19.5->17.6 kg/m ), HbA1c (8.5%->7.0%; 10.2%->7.8%; 9.1%->6.5%), triglycerides (91->80; 641->293; 1238->100 mg/dL or 1.03->0.90; 7.24->3.31; 14.0->1.13 mmol/L), and total daily insulin requirement (85->0; 0->0; 1000->750 units/day). Three patients did not tolerate dose escalation due to gastroesophageal reflux.

CONCLUSIONS

Tirzepatide may be an effective treatment for patients with lipodystrophy.

PubMed: 39802778
DOI: 10.1101/2024.09.25.24313345

Authors: Yoann Combot, Veijo T Salo, Gilliane Chadeuf...

Deficiency of the endoplasmic reticulum (ER) protein seipin results in generalized lipodystrophy by incompletely understood mechanisms. Here, we report mitochondrial abnormalities in seipin-deficient patient cells. A subset of seipin is enriched at ER-mitochondria contact sites (MAMs) in human and mouse cells and localizes in the vicinity of calcium regulators SERCA2, IP3R, and VDAC. Seipin association with MAM calcium regulators is stimulated by fasting-like stimuli, while seipin association with lipid droplets is promoted by lipid loading. Acute seipin removal does not alter ER calcium stores but leads to defective mitochondrial calcium import accompanied by a widespread reduction in Krebs cycle metabolites and ATP levels. In mice, inducible seipin deletion leads to mitochondrial dysfunctions preceding the development of metabolic complications. Together, these data suggest that seipin controls mitochondrial energy metabolism by regulating mitochondrial calcium influx at MAMs. In seipin-deficient adipose tissue, reduced ATP production compromises adipocyte properties, contributing to lipodystrophy pathogenesis.

Topics: Adipocytes; Adipose Tissue; Animals; Calcium; Cell Line; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Energy Metabolism; GTP-Binding Protein gamma Subunits; Humans; Lipid Droplets; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Mitochondria

PubMed: 35021082
DOI: 10.1016/j.celrep.2021.110213

Authors: Gulcin Akinci, Saif Alyaarubi, Nivedita Patni...

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Topics: Humans; Male; Female; Lipodystrophy, Congenital Generalized; Adolescent; Child; Infant; Child, Preschool; Adult; Young Adult; Arrhythmias, Cardiac; Hypertriglyceridemia; RNA-Binding Proteins

PubMed: 38234231
DOI: 10.1002/ajmg.a.63533