NORD gratefully acknowledges Abhimanyu Garg, MD, Professor of Internal Medicine, Chief, Division of Nutrition and Metabolic Diseases, Distinguished Chair in Human Nutrition Research, UT Southwestern Medical Center at Dallas, for assistance in the preparation of this report.
Acquired lipodystrophy is a general term for types of lipodystrophy that are not inherited, but rather acquired at some point during life. Acquired lipodystrophies do not have a direct genetic cause, but rather many different factors may be involved. Acquired lipodystrophies can be caused by medications, autoimmunity or for unknown reasons (idiopathic). Subtypes of acquired lipodystrophy include acquired generalized lipodystrophy (Lawrence syndrome), acquired partial lipodystrophy (Barraquer-Simons syndrome), localized lipodystrophy, and high active antiretroviral induced lipodystrophy, which may develop in HIV-infected individuals undergoing a specific form of treatment. Onset of acquired forms of lipodystrophy can occur during childhood, adolescence or adulthood. Affected individuals develop characteristic loss of body fat (adipose tissue) affecting specific areas of the body, especially the arms, legs, face, neck, and chest or thoracic regions. In some cases, metabolic complications associated with insulin resistance can develop. Such complications include an inability to break down glucose (glucose intolerance), elevated levels of triglycerides (a type of fat) in the blood (hypertriglyceridemia), and diabetes. Additional symptoms such as fat accumulation in the liver (fatty liver or hepatic steatosis) may also occur.Introduction
Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. Some forms of lipodystrophy are acquired; others are genetic. The degree of severity and the specific areas of the body affected can vary among the lipodystrophies. Some physicians refer to the loss of adipose tissue that characterizes these disorders as lipoatrophy rather than lipodystrophy.
Acquired lipodystrophy encompasses several subtypes. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of acquired lipodystrophy and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype. It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.
ACQUIRED GENERALIZED LIPODYSTROPHY (AGL; LAWRENCE SYNDROME)
Individuals with this form of lipodystrophy experience the loss of subcutaneous fat from the face, neck, and arms and legs. The overall extent and pattern of fat loss in AGL is highly variable and can differ significantly from one person to another. In some cases, fat may also be lost from the palms of the hands and the soles of the feet. Intra-abdominal fat may be lost in some people, but preserved in others. The loss of bone marrow fat rarely occurs. Fat loss associated with AGL may occur rapidly over a few weeks or slowly over several months or even years. Fat loss can be severe. Eventually, generalized and near complete loss of fat may occur resulting in prominent veins that bulge out from underneath the skin and an overall muscular appearance.
AGL usually develops during childhood or adolescence, but can occur at any age. During childhood, affected individuals are described as being voracious eaters and may experience accelerated growth. Affected individuals may also experience fatigue.
Individuals with AGL often develop severe insulin resistance, which can result in a variety of metabolic complications. Affected individuals may develop acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and “velvety” thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Diabetes often occurs after the development of lipodystrophy, but in some cases may occur almost simultaneously.
Some individuals develop abnormal enlargement of the liver (hepatomegaly) due to the infiltration and accumulation of fat within the liver. This can be known as hepatic steatosis or fatty liver. Fatty accumulation of the liver in individuals with AGL is often severe and can cause damage and scarring (cirrhosis) to the liver and, eventually, liver dysfunction. In some patients, liver enlargement may be due to autoimmune hepatitis. However, the diagnosis of autoimmune hepatitis should be made after review by expert pathologists.
Some individuals may experience extreme hypertriglyceridemia and chylomicronemia, a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. In some cases, this can result in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
After puberty, some women with AGL may develop polycystic ovary syndrome (PCOS). PCOS is characterized by an imbalance of sex hormones. Affected women have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin.
AGL can be subdivided into three separate subtypes, known as panniculitis-associated AGL, autoimmune-associated AGL, and AGL of unknown cause (idiopathic).
Individuals with panniculitis-associated AGL generally have a less severe form of the disorder. Panniculitis is inflammation of subcutaneous fat. Individuals with panniculitis-associated AGL may have less severe fat loss and metabolic complications. Fat loss in panniculitis-associated AGL may be localized to a specific part of the body. Lipodystrophy in panniculitis-associated AGL is preceded by the development of painful subcutaneous nodules or lesions consisting of small spots or bumps (maculopapular lesions).
Individuals with autoimmune-associated AGL have past or present evidence of an autoimmune disorder in addition to lipodystrophy. In these cases, AGL is believed to be caused by underlying autoimmune abnormalities. Autoimmune disorders that have been associated with AGL include juvenile dermatomyositis, Sjogren’s syndrome, and rheumatoid arthritis.
In the third type of AGL, panniculitis and autoimmune disorders do not occur and the underlying cause is unknown (idiopathic).
ACQUIRED PARTIAL LIPODYSTROPHY (APL; BARRAQUER-SIMONS SYNDROME)
This form of acquired lipodystrophy usually has onset during childhood. Fat distribution is normal at birth and during early childhood. However, at some point later during childhood or adolescence, affected individuals lose subcutaneous fat from the face. Most individuals have noticeable fat loss by the age of 13. Eventually, fat loss extends to the arms, neck, chest and sometimes the upper abdomen. The legs, hips and gluteal regions are usually spared. After puberty in some women, these areas may experience disproportionately excess fat accumulation in the hips and legs. Fat loss is often gradual and may occur over a few months to several years.
Approximately, one fourth of individuals with APL eventually develop a kidney disorder known as membranoproliferative glomerulonephritis, which is characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) in the special structures called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waste and fluid products from the body, which then build up in the blood stream. Kidney problems can develop including blood in the urine, dark urine, decreased urine output, and swelling of various parts of the body. Potentially, kidney disease can progress so that the kidneys fail to function adequately (renal failure or insufficiency). Membranoproliferative glomerulonephritis specifically refers to when the condition is caused by an abnormal immune system response.
As they age, some affected individuals may develop abnormally accumulation of yellow or white extracellular material (drusen) in the retina, a membrane in the back of the eyes. Some older affected individuals may develop macular degeneration. Macular degeneration is a general term for a group of eye disorders characterized by the deterioration of the oval-shaped yellow spot (macula) near the center of the retina. The macula is essential for proper vision when looking straight ahead (central vision) and with seeing fine details.
APL is often associated with autoimmune disorders including lupus, dermatomyositis, Celiac disease, pernicious anemia, and vasculitis. Abnormal enlargement of liver (hepatomegaly) has been reported in some cases.
Most forms of lipodystrophy are associated with metabolic complications due to insulin resistance. However, in most cases of APL, insulin resistance and such associated symptoms do not occur. In rare cases, in which insulin resistance does develop, associated symptoms can include glucose intolerance, hypertriglyceridemia, hirsutism, and diabetes.
HIGH ACTIVE ANTIRETROVIRAL THERAPY (HAART) INDUCED LIPODYSTROPHY (LD-HIV)
This form of lipodystrophy occurs in individuals with human immunodeficiency virus (HIV) after receiving antiretroviral therapy known as HIV-1 protease inhibitor-containing HAART. The development of lipodystrophy is related to the intensity and duration of treatment. In many individuals, protease inhibitors and nucleoside reverse transcriptase inhibitors are implicated in the development of lipodystrophy. In most cases, LD-HIV develops in individuals who have received this therapy for 2 years or more.
In most cases, affected individuals gradually lose subcutaneous fat from the arms, legs and face. Some individuals may develop excess fat in the face, neck, upper back and waist. This can cause a double chin, a hump on the upper back, and expand the circumference of the waist. Fat loss gets progressively worse with ongoing HAART therapy and does not reverse when the therapy is discontinued. Many individuals may also develop hypertriglyceridemia. Diabetes may also occur, but is rare. Individuals may be at an increased risk of developing coronary heart disease.
This form of lipodystrophy is characterized by subcutaneous fat loss in a small area of the body only. Localized lipodystrophy may result at the site of a drug injection (such as insulin). Affected individuals have a loss of subcutaneous fat in the affected area that presents as a dimple or crater with overlying skin usually unaffected. In some individuals, large adjacent (contiguous) areas of the body may be involved.
Acquired lipodystrophies can be caused by medications, autoimmune reactions or other unknown mechanisms. Acquired lipodystrophies do not have a direct genetic basis. Some researchers have speculated that individuals may have a genetic predisposition to developing certain forms of acquired lipodystrophy, however, this remains unproven and controversial. Most likely, several different underlying mechanisms are involved in the development of acquired lipodystrophies.
AGL may occur following an infection or autoimmune disease. Infections that have preceded the onset of AGL include varicella, measles, pertussis, diphtheria, pneumonia, osteomyelitis, infectious mononucleosis, and parotitis. Autoimmune disorders that have been linked to AGL include autoimmune thyroiditis, autoimmune hepatitis, juvenile dermatomyositis, rheumatoid arthritis, Sjogren’s syndrome, Sicca syndrome, and autoimmune hemolytic anemia. Some affected individuals have low levels in their blood of complement 4, a protein factor that normally plays a role in the body’s immune system response. However, specific autoantibodies which may cause destruction of fat cells have not been identified. In many cases, the cause of AGL is unknown. (For more information on these conditions, choose the specific disorder name as your search term in the Rare Disease Database.)
APL is believed to be caused because the immune system mistakenly brings about the destruction of fat cells (autoimmune-mediated destruction of adipocytes). More than 80% of affected individuals have low levels in their blood of complement 3, a protein factor that normally plays a role in the body’s immune system response. Affected individuals also have a circulating autoantibody called complement 3-nephritic factor. An autoantibody is an immune protein that mistakenly targets and damages healthy tissue.
Both AGL and APL may be associated with complement proteins, which are specialized proteins found in the blood that help fight off infection and disease. These proteins are also believed to be involved in the metabolic functions associated with body fat (adipose tissue). In affected individuals, these proteins may render fat cells susceptible to improper destruction by the immune system.
The exact reason why therapy with protease inhibitors and reverse transcriptase inhibitors (nucleoside analogues) in individuals with HIV causes lipodystrophy is not fully understood.
Localized lipodystrophy may be caused by the injection of various drugs, such as insulin, into the subcutaneous tissue. Panniculitis, pressure on a specific area of the body, and other mechanisms may also cause localized lipodystrophy.
The underlying issue in individuals with acquired lipodystrophy is the complete or partial loss of adipose tissue. The primary role of adipose tissue is to store fat for energy. Adipose tissue also secretes a variety of molecules that are involved with or influence various hormonal functions. For example, patients with AGL may have reduced levels of leptin, a hormone or cytokine produced by adipose cells which plays a role in controlling appetite by working centrally in the brain and hypothalamus. Adipose tissue is made up of fat cells (adipocytes). Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Damage to adipose tissue in acquired lipodystrophy prevents proper fat storage. Consequently, fat is lost from adipose tissue and, in some cases, is improperly stored in other tissue of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance.
AGL and APL generally affect women more than men, although this may be due in part to ascertainment bias because women tend to be more severely affected and more easily recognized. APL has been reported in approximately 250 individuals with a male to female ratio of 1:4. It has been reported in individuals of various different ethnicities. AGL has been reported in approximately 100 individuals with a male to female ratio of 1:3. Most cases have been reported in Caucasians. LD-HIV is estimated to affect approximately 100,000 individuals in the United States. Consistent with the increase prevalence of HIV in males, LD-HIV is also more prevalent in males.
A diagnosis of acquired lipodystrophies is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. AGL may be suspected in individuals who have a generalized lack of subcutaneous fat and overall muscular appearance during childhood.
The presence of panniculitis preceding the development of lipodystrophy is supportive of a diagnosis of AGL. The presence of an autoimmune disease preceding the development of lipodystrophy is supportive of AGL or APL. With APL, a progressive loss of fat from the upper body that spares the lower body in children under the age of 16 is suggestive of a diagnosis.
Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid. Individuals with APL may have decreased serum C3 levels, normal C1 and C4 levels, and high levels of the autoantibody C3NeF, while some patients with AGL may have low serum C4 levels.
The characteristic pattern of fat loss in acquired lipodystrophies can be noted on whole body magnetic resonance imaging (MRI).
A renal biopsy, the surgical removal and microscopic examination of kidney tissue, may be performed to assess kidney involvement in individuals with APL.
The treatment of acquired lipodystrophies is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Individuals with acquired lipodystrophies and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.
Despite the lack of clinical trial evaluation, individuals with acquired lipodystrophy are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.
Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with acquired lipodystrophy, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face or neck.
Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids supplementation from fish oils.
The characteristic loss of adipose tissue in individuals with acquired lipodystrophy cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).
In some cases, liver disease associated with acquired lipodystrophy can ultimately require a liver transplantation.
Additional therapies to treat individuals with acquired lipodystrophy are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin, sulfonylureas, thiazolidinediones and other agents may be recommended to treat hyperglycemia, although their long-term safety and efficacy is unknown. Insulin can also be used to treat individuals with acquired lipodystrophy and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL.
In February 2014, metreleptin (an analogue of leptin) was been approved in the United States for patients with generalized lipodystrophies, including AGL and congenial generalized lipodystrophy. An analog drug has the same or similar physical structure to another drug or chemical, but differs chemically. Severe lipodystrophy is sometimes associated with leptin deficiency. Initial studies have shown that leptin-replacement therapy (metreleptin) has improved the symptoms of AGL including hyperglycemia and hypertriglyceridemia and reduced liver size in affected individuals. However drug related risks, cost and benefits should be carefully weighed prior to considering the treatment. Metreleptin therapy has been associated with two important side effects (black box warnings): development of neutralizing anti-leptin antibodies, and lymphomas in patients with AGL. While the precise health effects of neutralizing anti-leptin antibodies remain unclear, there is a possibility that these may reduce the efficacy of metreleptin in such individuals and may induce unwanted weight gain. The precise causal relationship of development of lymphomas to metreleptin therapy is not clear as lymphomas have been reported in some AGL patients who never took metreleptin therapy. Metreleptin, however, is not approved for treating metabolic complications in patients with partial or localized lipodystrophies, such as APL or LD-HIV.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at UT Southwestern Medical Center at Dallas, visit the webpage, www.lipodystrophy.info.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about acquired lipodystrophy:
Abhimanyu Garg, M.D.
Professor of Internal Medicine,
Chief, Division of Nutrition and Metabolic Diseases,
Distinguished Chair in Human Nutrition Research
UT Southwestern Medical Center
5323 Harry Hines Boulevard, K5.214
Dallas, TX 75390-8537
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