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. The 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.
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.
Types
Congenital generalized lipodystrophy
Congenital generalized lipodystrophy (CGL) is genetic lipodystrophy characterized by a generalized lack of fat, present from birth or developing within the first year of life. This striking loss of fat reveals prominent musculature and veins, and as a result, CGL is often diagnosed at birth or in early childhood.
There are several subtypes of CGL, all of which have an autosomal recessive pattern of inheritance. Children with CGL exhibit hyperphagia as a result of low serum leptin, a hormone involved in regulating appetite.
Other features include:
- Accelerated growth
- Advanced bone age
- Acanthosis nigricans
- Enlargement of the hands, feet, and jaw suggestive of acromegaly.
Severe metabolic complications are a major feature of CGL, and include:
- Adolescent onset diabetes with high insulin levels due to insulin resistance.
- Severe hypertriglyceridemia resulting in pancreatitis.
- Early enlargement of the liver and spleen can occur as well as severe hepatic steatosis which can progress to cirrhosis and liver failure.
- Females may also suffer from irregular periods, polycystic ovaries, infertility, and hirsutism.
Familial partial lipodystrophy
Familial partial lipodystrophy (FPLD) is genetic lipodystrophy that usually begins in late childhood or puberty. It is characterized by progressive loss of fat from the upper and lower limbs and gluteal region. There may also be variable fat loss around the trunk. Additionally, patients can accumulate excess fat around the face and neck, giving the appearance of a “buffalo hump” which may raise suspicion of Cushing syndrome.
Fat loss may be subtle and difficult to detect clinically, particularly in males for whom a muscular appearance can be normal.
There are several subtypes of FPLD, most of which have an autosomal-dominant pattern of inheritance.
Other features:
- Severe hypertriglyceridemia is common, resulting in pancreatitis.
- Cardiac conduction system abnormalities, cardiomyopathies, and myopathies may also occur.
- Acanthosis nigricans and hepatic steatosis are less severe in FPLD compared to CGL.
- For women, metabolic complications, features of masculinization, and irregular periods are more common in those who have excess fat accumulation.
- Despite a high prevalence of polycystic ovarian syndrome, fertility is not commonly affected.
Acquired generalized lipodystrophy
Acquired generalized lipodystrophy (AGL) is characterized by generalized and gradual loss of fat, affecting those born with a normal distribution of fat. Fat is lost at a variable rate ranging from weeks to years and affects all areas of the body, in particular the limbs and face. Fat may be lost from the palms and soles while there is variable loss of intra-abdominal fat; bone marrow stores and fat around the eyes appear to be spared. Fat loss in AGL usually begins in childhood or adolescence, however, in some rare cases it may begin after age 30. Females are affected more often than males with a ratio of 3:1.
As with CGL, patients with AGL often suffer from severe metabolic complications including diabetes mellitus and hypertriglyceridemia with associated pancreatitis.
There are 3 main classifications of AGL:
- Panniculitis-associated AGL (~25%)
- Autoimmune AGL, is associated with juvenile dermatomyositis (~25%)
- Idiopathic AGL has no clear cause (~50%).
Lipodystrophy
- Markes fat loss in a woman over the torso in acquired generalized lipoatrophy
- Facial lipoatrophy with peripheral T cell lymphoma
- Lipoatrophy in peripheral T cell lymphoma
Acquired partial lipodystrophy
Acquired partial lipodystrophy (APL) is characterized by gradual loss of upper body fat, including the upper trunk, arms, neck, and face, often beginning in late childhood or adolescence. Fat in the lower part of the body including the legs, hips, and lower abdomen tends to be spared, with fat often accumulating in these areas in females post-puberty. Females are affected more often than males with a ratio of 4:1.
Patients are less likely to suffer from metabolic complications compared to other types of lipodystrophy. However, around a fifth of all patients suffer from membranoproliferative glomerulonephritis with some going on to require renal transplantation due to end-stage renal failure.
APL is associated with autoimmune disorders, with the majority of patients having low levels of circulating serum complement 3 and a circulating autoantibody known as complement 3 nephritic factor.
Acquired partial lipodystrophy
- Acquired progressive acral lipoatrophy over the buttock
- Acquired progressive acral lipoatrophy (fat loss) on the lower arm, preservation over deltoids
Bone marrow transplant-associated lipodystrophy
Bone marrow transplant-associated lipodystrophy is a form of APL affecting patients that have undergone treatment for childhood leukemia which included total body irradiation, chemotherapy, and allogeneic bone marrow grafting. The pattern of fat loss and associated complications are similar to FPLD.
HAART-induced lipodystrophy
HAART-induced lipodystrophy occurs in HIV patients receiving highly active antiretroviral therapy (HAART) most often after 3-4 years of treatment. HAART-induced lipodystrophy features fat loss from the arms, legs, and face with excess fat accumulation around the neck, upper trunk, and intra-abdominally.
Localized lipodystrophy
Localized lipodystrophy is the most common form of fat loss and can affect single or multiple areas ranging from a small dent in the skin, whole areas of a limb, or large areas of the trunk. Metabolic complications are not a feature of localized lipodystrophy as the degree of fat loss is trivial.
- Drug-induced localized lipodystrophy can occur at the site of injection of medications such as insulin, steroids, and antibiotics.
- Pressure-induced localized lipodystrophy can result from repeated pressure and trauma which often resolves when pressure is avoided.
- Panniculitis-associated localized lipodystrophy is the result of an inflammatory process involving the subcutaneous fat and is associated with autoimmune diseases such as lupus.
- Idiopathic localized lipodystrophy may also occur with no cause identified.
- Centrifugal lipodystrophy is a peculiar variety with no known cause which affects infants, particularly those of Asian descent. There is a pattern of centrifugal fat loss around the abdomen and groin. Often self-resolves in late childhood with no intervention required.
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. 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 destroy 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 analogs) 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 play 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.
Diagnosis
A diagnosis of acquired lipodystrophies is based upon the 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 in whole-body magnetic resonance imaging (MRI).
A renal biopsy, 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 affected 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 are 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 fabric 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 the appearance and managing 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 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 are 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 metabolic complications in individuals with FPL.
In February 2014, metreleptin (an analog of leptin) was been approved in the United States for patients with generalized lipodystrophies, including AGL and congenital 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, costs, and benefits should be carefully weighed before considering the treatment. Metreleptin therapy has been associated with two important side effects (black box warnings): the 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 between the 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.
OR
The initial and general approaches for AGL patients are to treat metabolic complications such as leptin-replacement therapy and/or to control the abnormal levels of lipids or glucose levels.[rx] Anti-diabetic medications such as insulin, metformin, or thiazolidinediones are used for insulin resistance or high glucose levels, or statins or fibrates are used for hyperlipidemia. If symptoms persist, metreleptin can be prescribed.
Metreleptin (MYALEPT) is a recombinant human leptin analog and was approved by FDA in 2014 for generalized lipodystrophy as an adjunct therapy to diet to treat the complication of leptin deficiency.[rx] It is the only drug option approved for generalized lipodystrophy-related symptoms and is not intended to use for patients with HIV-related lipodystrophy or complications of partial lipodystrophy.[rx] Although it is a recombinant human leptin analog, it is not completely the same as natural leptin as it is produced in e. coli and has added methionine residues at its amino terminus.[rx] It works by binding to the human leptin receptor, ObR, and activates the receptor.[14] The receptor belongs to the Class I cytokine family and signals the JAK/STAT pathway. It is available as 11.3 mg powder in a vial for subcutaneous injection upon reconstitution and needs to be protected from the light. For treatment, patients and their doctors need to be enrolled and certified in the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program because people on this treatment have a risk of developing anti-metreleptin antibodies that decrease the effectiveness of metreleptin, and increased the risk of lymphoma.[tx] Clinical study with GL patients who took metreleptin had increased insulin sensitivity, as indicated by decreased HbA1c and fasting glucose level, and reduced caloric intake as well as fasting triglyceride levels.[rx]
Plasmapheresis was previously an option for lowering extremely high triglyceride levels for preventing pancreatitis and painful xanthoma, but its use has decreased after the approval of metreleptin.[rx]
Cosmetic treatments, such as facial reconstruction or implants, can be done to replace adipose tissues.
References
Acquired Hemophilia
