New insight into how lipodystrophy can affect overall health

Healthy adipose, or fat, tissues are responsible for storing energy and releasing hormones such as leptin that help regulate appetite, energy balance and body weight.

Lipodystrophy is a group of rare disorders where the body cannot maintain healthy fat tissue.

Additionally, people with lipodystrophy can develop diabetes, hypertriglyceridemia and fatty liver disease at unusually young ages. However, because these disorders are rare and heterogeneous, their long-term health consequences have been difficult to define.

An international team of researchers from the United States, Turkey, Brazil and Hong Kong is working on providing a more comprehensive picture of the natural history of lipodystrophy through an ongoing multicenter registry study known as LD-Lync.

The study is led by Elif Oral, M.D., Professor of Metabolism, Endocrinology and Diabetes and a member of Caswell Diabetes Institute.

The team recently summarized their latest findings from 266 participants who were enrolled in the study from 2018-2023.

Oral and Merve Celik Guler, M.D., Postdoctoral Research Fellow in the Oral group and first author of the study, answer questions about the causes and symptoms of lipodystrophy, results from the study and current treatment options.

What are the symptoms of lipodystrophy? 

Celik Guler: In lipodystrophy, fats that should be stored under the skin ends up in places it doesn't belong, including the liver, muscles and bloodstream.

In generalized lipodystrophy, fat tissue is nearly absent from the whole body. In our cohort, the median age of diagnosis was around 13 years.

In partial lipodystrophy, fat tissue is lost from specific regions, typically the limbs and gluteal area, while it may accumulate in the face, neck or abdomen.

The median age at diagnosis in our study was around 37 years.

Lipodystrophy is not simply a disorder of appearance or adipose tissue.

It can affect multiple organ systems and many aspects of a patient's life.

Patients can develop diabetes that is unusually difficult to control, high triglyceride levels and fatty liver disease.

Some patients have darkened and thickened skin around the neck and armpits and an enlarged liver or abdominal pain from pancreatitis.

Women frequently have irregular menstrual periods and/or polycystic ovary syndrome.

There are also symptoms that are easily overlooked, including chronic pain, fatigue, depression and anxiety.

What are the challenges associated with diagnosis?

Oral: Lipodystrophy is particularly challenging to diagnose because there is no single appearance, laboratory test or genetic cause that defines all forms of the disease.

Numerous genes associated with lipodystrophy have been identified over the last few decades, and we continue to discover new genetic causes.

Some forms are caused by variants in genes that are important for the development and function of adipose tissue.

Environmental and other genetic factors can also modify how the disease presents.

We are increasingly learning that autoimmune and inflammatory processes can cause fat loss in some patients.

The other major challenge is recognition.

A patient may first come to medical attention because of difficult-to-control diabetes, high triglycerides, fatty liver disease or pancreatitis.

Unless a clinician recognizes that these problems may be connected by an underlying disorder of adipose tissue, the diagnosis of lipodystrophy can be missed for years.

It's important to remind patients that they're not alone: there's a community of patients, researchers and clinicians in the U.S. and around the world who have devoted themselves to understanding these disorders.

Why did you create the LD-Lync registry?

Oral: Although we have learned an enormous amount about lipodystrophy from individual patients and smaller cohorts over the years, we lacked data that allowed us to understand how these diseases evolve over a patient's lifetime.

LD-Lync was developed together with the patient community because patients wanted these answers as much as we did.

We want to understand when complications emerge, how they progress, how the different forms of lipodystrophy compare and what determines why one patient develops a particular complication while another does not.

Natural history data are also essential as we develop new treatments.

If we want to know whether a therapy changes the course of a rare disease, we first must understand its natural course.

What are the health complications associated with lipodystrophy?

Celik Guler: The overall burden of disease is substantial: more than 70% of participants had hypertriglyceridemia or diabetes, and more than two-thirds had fatty liver disease.

Nearly half had hypertension.

We also found that approximately one in five patients had experienced at least one episode of pancreatitis, which can lead to serious and sometimes life-threatening complications.

Our study also identified health problems that are not traditionally emphasized on lipodystrophy checklists.

For example, gastroesophageal reflux disease was present in approximately 32% of participants and sleep apnea in approximately 30%.

Cancers, including breast, skin and colon cancers, were also observed in the cohort.

We don't yet know whether cancer risk is increased in people with lipodystrophy compared with the general population.

What differences between generalized and partial lipodystrophy did you find?

Celik Guler: One of the clearest findings was how early metabolic disease can begin in generalized lipodystrophy.

Diabetes and hypertriglyceridemia developed considerably earlier in people with generalized lipodystrophy than in those with partial lipodystrophy.

This finding illustrates how severe the metabolic consequences of near-total adipose tissue deficiency can be.

At the same time, partial lipodystrophy should not be considered a mild disease.

Although metabolic complications generally appeared later in partial lipodystrophy, these patients also experienced serious outcomes, including pancreatitis, cirrhosis and cardiovascular disease.

How is lipodystrophy treated?

Oral: There's currently no therapy that restores normal adipose tissue, so treatment has to address both what is missing and the metabolic consequences that result from fat loss.

One approach is to replace signals that are lost when healthy adipose tissue is absent and leptin is one of those signals.

Patients with generalized lipodystrophy can have profound leptin deficiency, and I was fortunate to be involved in the early studies showing that leptin replacement could substantially improve metabolic disease in these patients.

The FDA approved metreleptin in 2014 as an adjunct to diet in patients with generalized lipodystrophy.

Patients also often require intensive treatment of diabetes and hypertriglyceridemia, as well as careful management of liver, kidney and cardiovascular complications.

The larger challenge is that we still do not have therapies that directly correct the underlying adipose tissue disorder.

We're currently working to bring newer therapies to patients through collaborations at the University of Michigan, including with the Center for RNA Biomedicine, and through partnerships with companies such as Regeneron and Ionis Pharmaceuticals.

Our goal is to move toward more precise treatments based on the mechanisms causing disease in individual patients.

Paper cited: “Unraveling the natural history of lipodystrophy syndromes: insights from the prospective LD-Lync study,” Journal of the Endocrine Society. DOI: 10.1210/jendso/bvag155

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