Lipodystrophy syndromes (LDS) are rare, complex disorders characterized by an extreme deficiency in body fat, despite adequate or even excessive food intake. This absence of body fat can be profound, leading to metabolic imbalances that affect multiple organ systems. LDS can be broadly categorized into complete versus partial forms, and further divided into inherited (genetic) and acquired types. Complete LDS results in a near-total loss of fat tissue across the body, while partial LDS affects specific areas, sparing some fat depots.
Because body fat plays a crucial role in regulating metabolism and hormone production, LDS disrupts these processes in ways that can be devastating to health. Individuals with uncontrolled LDS often develop complications involving major organs, including the heart, liver, kidneys, and pancreas. A range of metabolic disorders are common, particularly severe diabetes, hypertriglyceridemia (high blood triglyceride levels), and non-alcoholic fatty liver disease (NAFLD). These complications not only heighten the risk of cardiovascular disease but also can lead to organ damage if left unmanaged.
Management of LDS focuses heavily on diet and exercise. A controlled diet low in simple sugars and refined carbohydrates, combined with regular physical activity, can help mitigate some of the metabolic complications. However, these lifestyle modifications are often insufficient on their own, particularly in more severe cases.
For individuals with severe metabolic abnormalities, a medication called metreleptin—a synthetic form of the hormone leptin—may be prescribed. Leptin is a hormone typically produced by fat cells that helps regulate energy balance, hunger, and insulin sensitivity. Because people with LDS have extremely low leptin levels, metreleptin therapy can help restore some metabolic balance, improving blood sugar control and reducing triglyceride levels. However, metreleptin is typically reserved for patients with the most severe forms of LDS, as it can carry risks of its own and requires careful monitoring.
In essence, while lipodystrophy syndromes are rare, they demand an intensive, personalized approach to manage the far-reaching effects on the body’s metabolism and organ function.
JCEM, Practical Guidelines, October 2016
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.
More Information From the Article
The lipodystrophy syndromes are a heterogeneous group of rare disorders that have in common selective deficiency of adipose tissue in the absence of nutritional deprivation or catabolic state. Lipodystrophies are categorized based on etiology (genetic or acquired) and distribution of lost adipose tissue, affecting the entire body (generalized) or only regions (partial).
Major causes of mortality include heart disease (cardiomyopathy, heart failure, myocardial infarction, arrhythmia), liver disease (liver failure, gastrointestinal hemorrhage, hepatocellular carcinoma), kidney failure, acute pancreatitis, and sepsis.
Lipodystrophy should be suspected in patients with regional or generalized lack of adipose tissue outside of the normal range by physical examination, which can be supported by anthropometry, DEXA, and whole-body magnetic resonance imaging
Because serum leptin assays are not standardized and leptin concentrations in patients with lipodystrophy (especially partial forms) overlap the general population, leptin levels do not help in diagnosis but may help with the choice of therapies.
Differential diagnosis should include conditions presenting with severe weight loss (malnutrition, anorexia nervosa, uncontrolled DM, thyrotoxicosis, adrenocorticalinsufficiency, cancer cachexia, HIV-associated wasting, chronic infections).
The CORNERSTONE of therapy for metabolic complications of lipodystrophy is diet. Studies of specific diets in lipodystrophy are lacking, and recommendations rely on sparse literature and clinical experience.
Patients with lipodystrophy, especially generalized forms, are typically hyperphagic due to leptin deficiency. Energy-restricted diets in adolescents and adults lower triglycerides and glucose, but dietary restriction is challenging to achieve. Food restriction to control metabolic complications must be balanced by requirements for growth in children. Overfeeding to achieve normal weight may worsen metabolic complications and hepatic steatosis.
Patients should follow a 50–60% carbohydrate, 20–30% fat, and approximately 20% protein diet. Simple sugars should be restricted in preference for high-fiber complex carbohydrates, distributed evenly among meals and snacks and consumed in combination with protein or fat. Dietary fat should be primarily cis-mono-unsaturated fats and long-chain omega-3 fatty acids. In extremely hypertriglyceridemic infants, medium-chain triglyceride-based formula may help. During acute pancreatitis, bowel rest followed by a very-low-fat (<20 g) diet should be used.
Individuals with lipodystrophy engaged in intense exercise have amelioration of metabolic complications. Most patients should be encouraged to be physically active. However, strenuous exercise should be avoided in patients with cardiomyopathy. Contact sports should be avoided in patients with severe hepatosplenomegaly and CGL patients with lytic bone lesions.
Currently, METRELEPTIN (recombinant human methionyl leptin) is the only drug approved specifically for lipodystrophy. It is approved in the United States as an adjunct to diet for treatment of metabolic complications in patients with generalized lipodystrophy. In Japan, it is approved for both generalized and partial lipodystrophy. It is available in other parts of the world (eg, Europe) through compassionate use programs. There is no age limit for initiation of metreleptin; children as young as 6 months have been treated. Dose adjustments should be made in response to metabolic parameters and weight change, with clinical and laboratory assessment performed every 3–6 months.
Metreleptin decreases hyperphagia, frequently leading to weight loss. Reduced food intake is at least partially responsible for many of the metabolic improvements. If excessive weight loss occurs, the dose of metreleptin should be reduced
GENERALIZED form: In generalized lipodystrophy, metreleptin (with diet) is a first-line treatment for metabolic and endocrine abnormalities and may be considered for prevention of these comorbidities in children.
PARTIAL form: Metreleptin may be considered for hypoleptinemic (leptin <4 ng/mL) patients with partial lipodystrophy and severe metabolic derangements (HbA1c >8% and/or triglycerides >500 mg/dL).