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Acquired Lipodystrophy

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NORD is very grateful to 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.

Synonyms of Acquired Lipodystrophy

Disorder Subdivisions

General Discussion

Summary
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.

Symptoms

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. 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.

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 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 sports 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, Sjogre'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.

Many 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) 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 in the membranes of the eyes (drusen). 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 association with autoimmune disorders including lupus, dermatomyosistis, 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 tonicity of treatment. In many individuals, protease inhibitors and nucleoside reverse transcript 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 progressive 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.

LOCALIZED LIPODYSTROPHY
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.

Causes

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. 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 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. 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.

Affected Populations

Acquired lipodystrophies 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 ration 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 ration of 1:3. Most cases have been reported in Caucasians. LD-HIV is estimated to affect approximately 100,000 individuals in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of acquired lipodystrophy. Comparisons may be useful for a differential diagnosis.

Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) in various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the chest and trunk of the body. Conversely, affected individuals may also have excess subcutaneous fat deposits in other areas of the body, especially the neck, face and intra-abdominal regions. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include glucose intolerance, hypertriglyceridemia and diabetes. Additional findings can occur in some cases. Five different subtypes of FPL have been identified. Each subtype is caused by mutations in a different gene. Three forms of FPL are inherited as autosomal dominant traits. One form is inherited as an autosomal recessive trait. The mode of inheritance of one form is not fully understood. (For more information on this disorder, choose "familial partial lipodystrophy" as your search term in the Rare Disease Database.)

Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some cases, atrophy may also affect the limbs usually on the same side of the body as the facial atrophy. The severity and specific symptoms of Parry-Romberg syndrome are highly variable from one person to another. Additional symptoms can potentially develop in some people including neurological abnormalities or abnormalities affecting the eyes or teeth. Parry-Romberg syndrome usually becomes apparent during the first decade of life or early during the second decade. The majority of individuals with Parry-Romberg syndrome experience symptoms before the age of 20 years. The exact cause of Parry-Romberg syndrome is unknown; cases appear to occur randomly for unknown reasons (sporadically).

Cushing syndrome is a rare endocrine disorder that results from excessive production of the hormone cortisol by the adrenal glands. Affected individuals may gain excessive amounts of weight (central obesity) and/or may have a round, moon-shaped face. They may also have abnormally pigmented, thin, fragile skin; abnormally high blood pressure (hypertension) and blood sugar (hyperglycemia); and/or weakened bones that may fracture easily. In addition, some individuals with Cushing syndrome may demonstrate depression or other emotional changes. (For more information on this disorder, choose "Cushing" as your search term in the Rare Disease Database.)

A variety of syndromic disorders may be associated with lipodystrophy and/or have symptoms similar to CGL including Rabson-Mendenhall syndrome, SHORT syndrome, mandibuloacral dysplasia, Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome), Hutchinson-Guilford progeria syndrome, Werner syndrome, and leprechaunism. Individuals with lipodystrophy should also be differentiated from individuals with anorexia nervosa, cachexia, diencephalic syndrome, multiple symmetric lipomatosis, and other disorders that affect growth and development. NORD has individual reports on most of these disorders. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

The characteristic pattern of fat loss in acquired lipodystrophies can be noted on 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.

Treatment
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 and thiazolidinediones may be recommended to treat hyperglycemia, although their long-term safety and efficacy is unknown. Insulin can also be used to treat individuals with FPL 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.

Investigational Therapies

Research is underway to study the use of leptin for the treatment of individuals with lipodystrophy. Leptin is a hormone found in adipocytes. 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. Metreleptin is an analog of leptin. An analog drug has the same or similar physical structure to another drug or chemical, but differs chemically. Currently, the availability of leptin is restricted to clinical trials and the drug has not yet been approved by the Food and Drug Administration (FDA).

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 the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

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 at Dallas
5323 Harry Hines Boulevard, K5.214
Dallas, TX 75390-8537
Phone: 214-648-2895
Fax: 214-648-0553

Organizations related to Acquired Lipodystrophy

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

References

TEXTBOOKS
Simha V, Agarwal A. Inherited and Acquired Lipodystrophies. In: Nutrition and Health: Adipose Tissue and Adipokines in Health and Disease, Fantuzzi G, Mazzone T, editors. 2007 Humana Press, Totowa, NJ. pp. 237-254.

Garg A. Acquired Generalized Lipodystrophy. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:320.

Garg A. Acquired Partial Lipodystrophy. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:321.

JOURNAL ARTICLES
Garg A. Clinical review: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96:3313-3325. http://www.ncbi.nlm.nih.gov/pubmed/21865368

Savage DB, Semple RK, Clatworthy MR, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab. 2009;94:10-16. http://www.ncbi.nlm.nih.gov/pubmed/18854390

Bingham A, Mamyrova G, Rother KI, et al. Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity. Medicine (Baltimore). 2008;87:70-86. http://www.ncbi.nlm.nih.gov/pubmed/18344805

Hegele RA, Joy TR, Al-Attar SA, Rutt BK. Thematic review series: adipocyte biology. Lipodystrophies: windows on adipose biology and metabolism. J Lipid Res. 2007;48:1433-1444. http://www.ncbi.nlm.nih.gov/pubmed/17374881

Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350:1220-1234. http://www.ncbi.nlm.nih.gov/pubmed/15028826

Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Baltimore). 2003;82:129-146. http://www.ncbi.nlm.nih.gov/pubmed/12640189

Oral EA, Simha V, Ruiz E. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570-578. http://www.ncbi.nlm.nih.gov/pubmed/11856796

INTERNET
Griffing GT, Gabbay RA. Acquired Partial Lipodystrophy. Emedicine Journal, May 11, 2012. Available at: http://emedicine.medscape.com/article/123039-overview Accessed on: August 15, 2012.

Vantyghem MC. Partial Acquired Lipodystrophy. Orphanet Encyclopedia, January 2009. Available at: http://www.orpha.net Accessed on: August 15, 2012.

Vantyghem MC. Acquired Congenital Lipodystrophy. Orphanet Encyclopedia, October 2006. Available at: http://www.orpha.net Accessed on: August 15, 2012.

Lipodystrophy. University of Texas Southwest Medical Center. Division of Nutrition and Metabolic Diseases. Available at: http://www.utsouthwestern.edu/education/medical-school/departments/internal-medicine/divisions/nutrition/lipodystrophy/index.html Accessed on: August 15, 2012.

Report last updated: 2012/10/08 00:00:00 GMT+0