Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body’s adipose tissue (“lipo” is Greek for “fat”, and “dystrophy” is Greek for “abnormal or degenerative condition”). A more specific term, lipoatrophy, is used when describing the loss of fat from one area (usually the face). This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome.[rx][rx]
Lipodystrophies are the category of conditions that share the common finding of a reduction in subcutaneous fat. There are multiple subtypes of lipodystrophy, which may be either congenital or acquired and vary in the distribution of fat loss. Although all are relatively rare in incidence, acquired variants have become more common as an adverse effect of certain medications and iatrogenic mechanisms. Regardless of subtype, decreases in overall adipose burden may lead to metabolic complications, with subsequent increases in morbidity and mortality in lipodystrophy patients.[rx][rx][rx]
Types
Lipodystrophy can be divided into the following types
- Congenital lipodystrophy syndromes
- Congenital generalized lipodystrophy (Berardinelli-Seip syndrome)
- Familial partial lipodystrophy
- Marfanoid–progeroid–lipodystrophy syndrome
- Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome
- Acquired lipodystrophy syndromes
- Acquired partial lipodystrophy (Barraquer-Simons syndrome)
- Acquired generalized lipodystrophy
- Centrifugal abdominal lipodystrophy (Lipodystrophia centrifugal abdominalis infantilism)
- Lipoatrophia annularis (Ferreira-Marques lipoatrophia)
- Localized lipodystrophy
- HIV-associated lipodystrophy
- Congenital Generalized Lipodystrophy – Congenital generalized lipodystrophy, sometimes referred to as Berardinelli-Seip syndrome, is an uncommon lipodystrophy variant with significant and sometimes near-total fat loss.
- Familial Partial Lipodystrophy – Familial partial lipodystrophy is most often an autosomal dominant condition with fat loss primarily involving the extremities, more commonly lower than upper.
- Acquired Generalized Lipodystrophy – Acquired generalized lipodystrophy is an extremely rare condition of widespread subcutaneous fat loss.
- Acquired Partial Lipodystrophy – Acquired partial lipodystrophy, or Barraquer-Simons syndrome is characterized by gradual loss of fat from the upper body and truncal region during childhood. Over the past few decades, however, highly active antiretroviral therapy-induced lipodystrophy has become the most common form of acquired partial lipodystrophy.
Causes
Congenital Generalized Lipodystrophy[rx][rx][rx] – Congenital generalized lipodystrophy, sometimes referred to as Berardinelli-Seip syndrome, is an uncommon lipodystrophy variant with significant and sometimes near-total fat loss. It has autosomal recessive inheritance and patients present with findings at birth or in early infancy. Mutations in four genes coding for the proteins AGPAT2, seipin, caveolin-1, and cavin-1 have been implicated in the different subtypes of congenital generalized lipodystrophy.
Familial Partial Lipodystrophy – Familial partial lipodystrophy is most often an autosomal dominant condition with fat loss primarily involving the extremities, more commonly lower than upper. To date, seven variants of familial partial lipodystrophy have been described. Multiple genetic defects have been reported which can serve to explain the heterogeneity in clinical findings. The best-characterized variant, familial partial lipodystrophy type 2 or Dunnigan’s lipodystrophy, results from defects in the gene encoding lamins A and C.
Acquired Generalized Lipodystrophy – Acquired generalized lipodystrophy is an extremely rare condition of widespread subcutaneous fat loss. The etiology is poorly understood, but these patients may also have associated autoimmune connective tissue disease.
Acquired Partial Lipodystrophy – Acquired partial lipodystrophy, or Barraquer-Simons syndrome is characterized by gradual loss of fat from the upper body and truncal region during childhood. Though no mechanism for the development of acquired partial lipodystrophy has been confirmed, some studies have linked complement-induced adipocyte lysis to patients with serum positive for nephritic factor. Over the past few decades, highly active antiretroviral therapy-induced lipodystrophy has become the most common form of acquired partial lipodystrophy. It is associated with the use of anti-viral agents including protease inhibitors or nucleoside analogs used to treat human immunodeficiency virus. Although the mechanism is still unclear, it is known that these medications can damage adipocytes.
Lipodystrophy Associated with Insulin Treatment – Lipodystrophy associated with subcutaneous insulin injections may present as either lipohypertrophy (LH) or lipoatrophy (LA). Lipoatrophy presents as a large, often deep, retracted scar on the skin and likely has an immunological basis. LH is a thickened ‘rubbery’ tissue swelling that can be picked up by a directed, accurate physical examination. [rx] Lipodystrophy is associated with increased glycemic variability and unexplained episodes of hypoglycemia further driving up healthcare costs while affecting patient compliance. Studies have shown that the correct rotation technique of insulin sites has the strongest protective value in preventing lipohypertrophy. [rx]
Epidemiology
Congenital Generalized Lipodystrophy[rx]
Congenital generalized lipodystrophy is extremely rare with approximately 250 cases reported in the literature. Assuming that a minority of patients with this condition report, it is estimated that the prevalence worldwide ranges from 1 case per 200,000 persons to 1 case per 12 million persons. Patients present at birth or in early infancy.
Familial Partial Lipodystrophy[rx]
Familial partial lipodystrophies, including the variants of Dunnigan’s lipodystrophy and Kobberling lipodystrophy, are uncommon. It is thought that the prevalence of the Dunnigan’s variant is less than 1 case in 15 million persons. The mode of transmission is autosomal dominant. The Kobblering variant is less well characterized regarding prevalence and mode of transmission, though some sporadic cases have been reported.
Acquired Generalized Lipodystrophy[rx]
Acquired generalized lipodystrophy has been described in at least 100 patients though this may be under-recognized or reported. Patients most often present in adolescence. Recent proposals seek to further categorize these patients into one of three categories: panniculitis, autoimmune, and idiopathic; patients either have one of these pre-existing conditions before the development of generalized lipodystrophy or have spontaneous development of generalized lipodystrophy. Women have been affected more than men in approximately a 3:1 ratio.
Acquired Partial Lipodystrophy[rx]
Acquired partial lipodystrophy is also rare with approximately 250 cases described. The typical age of presentation is after puberty, with one study showing a median age of 25 years. Patients have been identified from multiple ethnic backgrounds, but the largest studies to date involve patients primarily of European descent. Women are again affected more than men with ratios that range from 4:1 to 8:1.
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, 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 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 reviewing 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 a 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 bloodstream. 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 an abnormal 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 seeing fine details.
APL is often associated with autoimmune disorders including lupus, dermatomyositis, Celiac disease, pernicious anemia, and vasculitis. Abnormal enlargement of the 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. A 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.
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 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.
Overall Symptoms
The symptoms of acquired lipodystrophy can be different in the case of each type. Loss of subcutaneous fat is a common sign in each category. Apart from that here is the list of symptoms that can help you identify the presence:
Symptoms of ALG
- Loss of subcutaneous fat from the face, neck, arms, and legs.
- FatigueHypertriglyceridemia.
- Diabetes.
- Pancreatitis.
- Polycystic ovary syndrome (PCOS).
- Severe insulin resistance.
- Autoimmune hepatitis.
- Hypertriglyceridemia.
- Chylomicronemia.
- Glucose intolerance.
- Acanthosis nigricans (group of diseases composed through the development of hyperpigmentation, hyperkeratosis, axillae).
- Hepatomegaly can also lead to hepatic steatosis, cirrhosis, or fatty liver.
Symptoms Of Acquired Partial Lipodystrophy:
- Membranoproliferative glomerulonephritis (a form of kidney disorder)
- Glomerulonephritis
- Drusen
- Macular degeneration
- Lupus
- Insulin resistance
- Hepatomegaly
- Dermatomyositis
- Celiac disease
- Pernicious anemia
- Vasculitis
Symptoms of Induced Lipodystrophy (Ld-Hiv):
- Hypertriglyceridemia.
- Double chin.
- Lose subcutaneous fat from the arms, legs, face, upper back, and waist.
- Diabetes.
- The hump on the upper back.
- Coronary heart disease.
Symptoms of Localized Lipodystrophy:
- Insulin injection.
- Loss of subcutaneous fat from the chin.
Diagnosis
The metabolic alterations seen in patients with lipodystrophies result from an overall decrease in adipose tissue burden. Adipose is a metabolically active tissue that has many physiologic functions. Adipose tissue not only provides insulation but also serves to mediate inflammation and secrete many hormones involved in endocrine regulation. In patients with lipodystrophies, a reduction in adipose leads to a deficiency in certain hormones. In particular, a decrease in leptin has been described in many lipodystrophy patients. Leptin is a proinflammatory adipokine secreted by adipose tissue. It is often referred to as the “satiety hormone” because it regulates mediators of appetite and energy expenditure. A decrease in leptin, whether in the setting of intrinsic leptin deficiency or lipodystrophy, leads to the downstream complications of hyperinsulinemia, insulin resistance with possible progression to diabetes, hypertriglyceridemia, and hepatic steatosis.[rx][rx][rx]
When obtaining a biopsy from patients with suspected lipodystrophy, it is important to consider the depth of pathology. An ideal specimen would extend to at least include the epidermis, dermis, and subcutaneous fat. There may be a benefit to increasing the depth of the biopsy to include fascia to allow visualization of the full subcutis. The histopathological findings of the lipodystrophy syndromes are somewhat nonspecific. The background is typically pauci-inflammatory, and individual adipocytes become shrunken and separated. In certain circumstances with localized involvement, perivascular lymphocytic inflammatory infiltrates may be seen.[rx]
Congenital Generalized Lipodystrophy
The extent of fat loss results in a striking clinical appearance. Patients not only have a widespread fat loss but also have skeletal muscle hypertrophy due to excess adipose deposition within the musculature. As is common to many lipodystrophies, metabolic anomalies including hyperinsulinemia, insulin resistance, and hypertriglyceridemia often occur. Due to the early onset of this condition, these findings occur before adulthood. The life expectancy of patients with congenital generalized lipodystrophy is reduced due to complications of diabetes or liver or heart disease.
Familial Partial Lipodystrophy[rx]
The patient demonstrates fat loss primarily involving the extremities, more commonly lower than upper. Patients appear normal at birth and throughout childhood regarding fat distribution but develop clinically apparent changes near puberty. In contrast to the fat loss involving the extremities, patients demonstrate a fat gain in the face, neck, and abdomen.
These patients show clinical findings consistent with that described above and additionally may have hypertriglyceridemia severe enough to induce pancreatitis. Insulin resistance, adverse cardiac events, and hepatic steatosis may also be present and sometimes severe.
Acquired Generalized Lipodystrophy[rx]
At birth fat distribution is normal but as time progresses fat loss develops. The face, arms, and legs are most commonly affected. The absence of mature adipocytes inhibits the ability to synthesize adipocytokines which are important for normal metabolism. This loss leads to leptin deficiency and severe metabolic derangements. Fat deposition in the liver may lead to cirrhosis. Diabetes mellitus and hypertriglyceridemia are often also present. One-quarter of patients will develop inflammatory panniculitis at the time the fat loss begins, though this is not specific to acquired generalized lipodystrophy.
Acquired Partial Lipodystrophy[rx]
Acquired partial lipodystrophy is characterized by gradual loss of fat from the upper body and truncal region during childhood. This condition is progressive, and patients may demonstrate compensatory fat deposition in the hips and legs. The metabolic complications seen in the other lipodystrophies do not seem to be as common in patients with acquired partial lipodystrophy. However, these patients may be more susceptible to kidney disease. Most patients with acquired partial lipodystrophy have circulating levels of the nephritic factor.
Highly active antiretroviral therapy-induced lipodystrophy has become the most common form of acquired partial lipodystrophy. The resultant lipodystrophy is well-documented and has a typical clinical presentation. Patients demonstrate subcutaneous fat loss of the extremities and the face and an increase in adiposity of the trunk. Due to this classic clinical picture, the appearance became stigmatized as an association with HIV.
Lipodystrophy Associated With Insulin Treatment[rx]
Patients taking insulin should receive a detailed physical examination. An inspection alone is not sufficient and concerned areas should be palpated to evaluate for lipohypertrophy.
As described above, in patients who present with findings suspicious of a lipodystrophy syndrome, a metabolic workup must be pursued. Patients should have a complete metabolic panel checked for hyperglycemia and any alterations of hepatic enzymes. A cholesterol panel should also be checked to rule out hypertriglyceridemia. Leptin levels can be obtained and, if low, may predict responsiveness to replacement treatment. Genetic testing is not routine at this time but certain subtypes of lipodystrophy may be performed in clinical laboratories. There are ongoing clinical trials that can be reviewed at www.clinicaltrials.gov.
Treatment
Management of lipodystrophies is dependent upon the specific subtype and the extent of associated metabolic abnormalities. For patients with severe metabolic derangement, it is important to implement the use of lipid-lowering agents and diabetic medications. With the goal of increasing insulin sensitivity, pioglitazone is more efficacious than metformin in this patient population. Severe cases may require insulin. Leptin analogs, particularly metreleptin, have shown efficacy in maintaining normal metabolism in patients who cannot effectively synthesize leptin naturally. Metreleptin is recombinant human leptin and the only FDA-approved replacement therapy for certain patients with lipodystrophy. Hypertriglyceridemia may respond to troglitazone, through interventions may not be very effective in fixing dyslipidemias in these patients. Furthermore, patients with lipodystrophy in cosmetically sensitive areas may be treated with fillers such as poly-L lactic acid and calcium hydroxyapatite. More research needs to be done in the field of lipodystrophies to establish diagnostic and management guidelines. As we learn more about the intricacies of metabolic regulation, it is anticipated that more treatment options will emerge for this patient population.[rx][rx][rx]
References
