eMedicine Specialties > Endocrinology > Metabolic Disorders
Lipodystrophy, Generalized
Updated: Jul 17, 2007
Introduction
Millions of Americans have obesity and type 2 diabetes mellitus. Obesity is characterized by increased body adiposity and leads to insulin resistance. Paradoxically, some conditions characterized by a paucity of fat also cause insulin resistance, namely the syndromes of lipoatrophy. The resemblance between the metabolic abnormalities of these extreme states of adiposity underscores the importance of fat tissue in energy homeostasis.
This article focuses on the syndromes at one extreme of the spectrum: generalized lipoatrophy, also known as Lawrence-Seip syndrome. These are a rare group of syndromes characterized by a near-complete absence of fat. Generalized lipoatrophy may be acquired or congenital. The primary focus of this article is on the genetic syndromes that cause a near-complete absence of fat tissue. However, other diseases are mentioned because they relate to the topic of discussion.
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Lipodystrophy, Lipoatrophy, and Lipoatrophic Diabetes
Lipoatrophy syndromes comprise a heterogeneous cluster in which the common trait is a lack of fat tissue. The deficiency of adipose tissue can be partial or generalized, and the abnormality may be congenital or acquired. In all of these cases, the metabolic consequences are similar, namely, peripheral insulin resistance and hypertriglyceridemia.
In this article, the loss of fat is referred to as lipoatrophy and the abnormal distribution of fat is referred to as lipodystrophy. The term lipoatrophic diabetes refers to diabetes mellitus in association with lipoatrophy. Lipodystrophy encompasses lipoatrophy and other abnormalities of adipose tissue. The focus of this review is on syndromes characterized primarily by adipocyte deficiencies throughout the body.
Another distinction is between syndromes of (1) lipoatrophy, in which an actual insufficiency of adipocytes and/or precursor cells is present and results in metabolic disturbances, and (2) other states of total body fat deficiency, in which the adipocytes are basically normal but are chronically forced to mobilize their stored triglycerides (eg, chronic energy [caloric] depletion, exercise, increased sympathetic drive.1,2,3,4 In the latter group, the adipocytes are still capable of functioning at a level sufficient to prevent metabolic consequences.
The use of genetic engineering approaches that disturb only triglyceride storage into the adipocytes (eg, by perturbing the insulin receptor specifically in the adipocytes5 or by disrupting perilipin protein that coats lipid droplets in adipocytes6 does not lead to metabolic syndrome.
Perilipin-null mice have a greater lean body mass and are more resistant to diet-induced obesity than wild-type mice, although compared to wild-type mice who weigh over 30 grams, perilipin-null mice who weigh over 30 grams may have an increased tendency to develop glucose intolerance and peripheral insulin resistance. Interestingly, plasma leptin concentrations in perilipin-null mice are greater than expected given the decrease in fat mass. This increased leptin might explain the relative absence of lipoatrophic symptoms, such as severe hyperinsulinemia, elevated blood lipids, fatty liver, and organomegaly, in the perilipin-null mice.
In contrast, the approaches that ablate white adipose tissue do lead to metabolic syndrome, regardless of the strategy. These observations underscore the importance of the adipocyte cell as not only a storage space for triglycerides, but as a fundamental regulator of metabolism.
Mechanisms of Disease
Over the last decade, important advances have occurred in understanding the differentiation program of adipocytes. Precursor cells are committed to adipogenesis through transient expression of certain transcription factors such as CCAAT/enhancer-binding protein-beta (C/EBP–beta) and C/EBP-delta and thus become preadipocytes. Preadipocytes gain the ability to store triglycerides and repress cell-cycle genes through the activation of multiple genes controlled by key transcription factors (ie, peroxisome proliferator-activated receptor-gamma [PPAR-gamma] and C/EBT-alpha). Other transcription factors are involved either in activating these key factors or in controlling the synthesis of their ligands (eg, sterol regulatory element binding transcription factor 1 [SREBP1]/adipocyte determination and differentiation factor 1 [ADD1] may regulate synthesis of ligands for PPAR-gamma).
Defects in both of these commitment steps may lead to adipocyte deficiency. Another mechanism for adipocyte deficiency is through increased destruction of these cells (eg, induction of apoptosis). The exact control of adipocyte turnover or constant remodeling in adults is not understood.
Recently, a novel molecule called lipin has been cloned as a result of positional cloning efforts to identify the genetic etiology of a naturally occurring mouse model with partial lipoatrophy and fatty liver. This molecule is a novel protein with nuclear localization and is induced during adipocyte differentiation.7 Its exact role in the adipocyte differentiation pathway remains to be identified.
Adipose tissue is an endocrine organ, an important concept that was proven by the discovery of the hormone leptin. Adipocytes communicate body fat levels to the neuroendocrine system to control food intake and energy expenditure. Leptin has effects (direct or indirect) on the key organs of metabolism, including the liver, muscle, and pancreas.
Another intriguing signal originating from adipocytes is a 30-kd molecule called adipocyte complement–related protein 30 (ACRP 30)8 or adipoQ.9 Other independent groups that have cloned this molecule called it adipocyte most abundant gene transcript 1 (APM1). Now it is most commonly called adiponectin.10 This molecule appears to be important in inducing fat oxidation in the muscle and liver.8 It promotes insulin sensitivity and is found to be decreased in various forms of insulin resistance.11 Lack of adipocytes results in deficiency of these signals, contributing to many of the abnormalities observed in persons with syndromes characterized by an absence of fat.
Animal models of lipoatrophy have been engineered via either disruption of adipogenesis or induction of adipocyte death. These models help explain the pathophysiology of fat loss. These models use an adipose-specific promoter/enhancer to introduce a transgene. Reviews of animal models of lipoatrophy can be found elsewhere.12,13
There are 2 consequences of fat loss that could explain the insulin resistance and other metabolic abnormalities seen in lipoatrophy syndromes.14 One is that the inability to store triglycerides in adipocytes leads to abnormal deposition of triglycerides in other tissues such as the liver, skeletal muscle, and pancreas (lipotoxicity), resulting in hypertriglyceridemia, insulin resistance, hepatic steatosis (fatty liver), impaired insulin secretion and eventually type 2 diabetes.
Second, adipocytes are either absent or immature and therefore unable to synthesize and release adipocytokines that may be important to maintain normal metabolism. Two such adipocytokines, leptin and adiponectin, have been shown to be low in patients with lipoatrophy syndromes. Leptin acts on the central nervous system to regulate food intake and energy expenditure. Leptin deficiency can lead to decreased metabolic rate and voracious appetite with overconsumption of calories and worsening metabolic state. Cases of dramatic leptin deficiency or receptor nonrecognition of leptin have been described15,16
Both leptin and adiponectin promote the storage of fat in adipose tissue and inhibit the deposition of excess fat in other tissues such as liver and muscle. These hormones can also promote free fatty acid oxidation in skeletal muscle and liver, increase glucose uptake and decrease hepatic gluconeogenesis. Leptin replacement therapy is currently being used as an investigational therapy in patients with lipoatrophy syndromes. Adiponectin replacement has not yet been studied in humans, although animal studies suggest that it may also have some benefit by significantly improving insulin sensitivity.
Classification of Lipoatrophy Syndromes
Absence of fat can be partial or generalized, and the syndrome can manifest at birth or later in life.17,18 If fat loss is partial, the residual fat undergoes compensatory hypertrophy. Usually, a rough correlation exists between the severity of metabolic consequences and the degree of fat loss.
An entity exists called focal lipoatrophy, in which the loss of fat involves a single region in the body such as the gluteal area, usually following intramuscular injections,19 or on the face (ie, Romberg syndrome).20 Other specific distributions are reported in the literature, and other descriptive terminology is used, including annular or semicircular lipoatrophy21 22 (see Lipodystrophy, Localized).
Therapy with protein hormones such as insulin23,24 and growth hormone25 also may lead to focal lipoatrophy. Usually, the isolated loss of fat from a limited body region is not associated with metabolic consequences, supporting the hypothesis that a crucial degree of fat loss is required to observe the metabolic abnormalities. While the various lipodystrophy syndromes can be classified in many ways, one proposed scheme is demonstrated in Table 1 in Treatment of Lipoatrophy/Lipodystrophy.
Congenital generalized lipoatrophy
This condition is a genetic disease with heterogenous causes (see Image 1). This condition is also known as Seip-Berardinelli syndrome.26,27 In this syndrome, children present with a generalized absence of fat within the first year of life. This is followed by insulin resistance, acanthosis nigricans, and diabetes mellitus before adolescence. Hypertriglyceridemia is severe and is accompanied by frequent bouts of pancreatitis. Affected patients have a high basal metabolic rate28 and an increased appetite. Circulating leptin levels are usually below detection limits.29,30
This syndrome has an autosomal recessive (AR) mode of inheritance and has been described in persons of all ethnic groups. Arioglu et al observed a sexual dimorphism in the severity of metabolic complications: female patients manifest diabetes and hypertriglyceridemia much earlier and usually more severely than male siblings in the same family.
Initial genetic studies using the candidate gene approach were unsuccessful in identifying the genes responsible for this syndrome. Among the excluded genes were those for PPAR-gamma, beta3-adrenergic receptor, leptin, leptin receptor, and lipoprotein lipase.31,32,33 In subsequent genetic studies, the disease was mapped to band 9q34 in some but not all pedigrees.34 Later this gene was identified as the AGPAT2 or CGL1 gene.35 This gene encodes the enzyme AGPAT2, which catalyzes the formation of phosphatidic acid, an important intermediate in the synthesis of triacylglycerol and glycerophospholipids.17
Magre et al cloned a second gene responsible for congenital generalized lipoatrophy using a large consanguineous pedigree from Lebanon. This CGL2 gene is located on band 11q13 and is a separate gene from the CGL1 gene located on band 9q34. Magre et al called this new gene seipin as a tribute to Seip who was the first to describe the gene.36 Several names have been used for the seipin gene in the published literature, including CGL2, BSCL2, and Gng3lg.
The protein product of the seipin gene is most likely a signaling molecule. It has 3 trans-membrane domains, and the ligand is not known. The mouse orthologue of the gene is a G-protein–related receptor gene. Contrary to the predictions that prevailed prior to the discovery of this gene, seipin is not abundantly expressed in fat cells. It is expressed predominantly in the central nervous system and especially in the pituitary. Another location where it is expressed in high levels is the testes. As evident from these facts, the discovery of the seipin gene has led to many new questions and is likely to change current views on adipocyte differentiation mechanisms. This exciting discovery also underscores the potential link between the central nervous system and the energy storage sites of the body.
Some CGL pedigrees do not have mutations in either of these two genes. Therefore, other causative genes must be involved. In addition, subjects with the same genetic mutation can have widely different clinical manifestations.35 This suggests that other genes, the environment, or both may also play a role.
The differential diagnosis of congenital generalized lipoatrophy includes acquired generalized lipoatrophy, leprechaunism, Werner syndrome, pubertal-onset generalized lipodystrophy due to LMNA mutations, and neonatal progeroid syndrome.14
Other genetic lipoatrophy syndromes
There are autosomal dominant (AD) forms of congenital lipodystrophy (characterized by an absence of fat from the face, upper trunk, arms, and below the knees) associated with a progressive neurodegenerative disorder (characterized by progressive spinocerebellar ataxia, pyramidal weakness and spasticity, and autonomic insufficiency) and congenital cataracts. In this small pedigree, affected individuals also have insulin resistance and dyslipidemia, and both the neurodegenerative disorder and dyslipidemia are more severe in affected female members.
Some unusual congenital disorders, such as vitamin D resistance and persistent müllerian ducts,37 retinal pigmentation abnormalities38 and sensorineural deafness,39 have been reported in association with lipodystrophy in isolated cases. These unusual patients present as pediatric patients or young adults.
Other complex monogenic syndromes are not characterized as primary lipodystrophy syndromes but are associated with abnormal body fat distribution, among other complex abnormalities. Progeria syndromes such as Werner syndrome (adult progeria syndrome, Image 4, left40 Cockayne syndrome (a juvenile progeria syndrome41,42 carbohydrate-deficient glycoprotein syndrome type 143 short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome;44,45 and mandibuloacral dysplasia46,47 (Image 4, right) are among such syndromes. Acral, renal, and ectodermal dysplasia in association with generalized lipodystrophy (AREDYLD) syndrome48 probably represents another complex progeria syndrome.
Mandibuloacral dysplasia is another genetic disorder with multisystem involvement and AR inheritance. This extremely rare syndrome is characterized by multiple skeletal abnormalities, acroosteolysis, and joint and skin problems and is associated with lipodystrophy and metabolic abnormalities.46,47 Two forms of lipodystrophy have been observed in patients with mandibuloacral dysplasia.14 Type A involves partial loss of subcutaneous adipose tissue from the extremities. Type B involves a more generalized loss of subcutaneous adipose tissue from the face, trunk, and extremities.
Familial partial lipodystrophy
Also referred to as Kobberling-Dunnigan syndrome, familial partial lipodystrophy (FPLD) or Dunnigan syndrome (see Image 2) is inherited in an AD fashion. It is observed mostly in white persons of northern European descent, but pedigrees of persons of Asian descent have also been described. Although the condition is rare, pediatricians may be presented with the question of whether a child of an affected parent also has the disease. Distinguishing affected patients from unaffected patients before the onset of puberty is usually impossible.
Patients are born with normal fat distribution but notice a loss of subcutaneous fat in the extremities and in some cases also the trunk with early puberty, which produces a muscular appearance with prominent superficial veins. This is followed by increased fat in the face and neck as puberty is completed.49,50 The visceral fat and interfascicular intramuscular fat depots are preserved.51,34 The Kobberling subtype, sometimes referred to as FPLD1, is characterized by loss of subcutaneous adipose tissue from the extremities only, whereas Dunnigan syndrome, or FPLD2, is characterized by loss of fat from the extremities and trunk.
The diagnosis may be suspected in nonobese individuals who develop early onset diabetes and hypertriglyceridemia, especially if there is significant loss of fat from the extremities and hips.14 Differential diagnoses for familial partial lipodystrophy include Cushing syndrome, truncal obesity, multiple symmetric lipomatosis secondary to alcohol intake, acquired partial lipodystrophy, and HIV-associated lipodystrophy.
While the disease affects both sexes, the phenotype is much easier to discern in females, leading to ascertainment bias of female probands. Up to one third of affected women may develop acanthosis nigricans, hirsutism, menstrual irregularities, and polycystic ovaries.14 Overall, female patients develop diabetes and dyslipidemia earlier and more severely. For example, from one case series, affected females develop diabetes approximately 73% of the time and hypertriglyceridemia 90% of the time. In contrast, the incidence is 36% and 45%, respectively, in affected males. These observations are similar to the recently published observations of another group.52
An exciting advance in the understanding of the syndrome has been the discovery that the disease is caused by mutations in the lamin A/C gene (LMNA) located at band 1q21-23.53,54,55,56,57 Lamin A and C are alternatively spliced products of the same gene and are ubiquitously, but not equally, expressed.58 They belong to a family of intermediate filament proteins that form the nuclear matrix,59,60 which is located just inside the nuclear membrane. Lamins dimerize and oligomerize within the structure of the nuclear matrix.60 Developmental regulation of the expression of lamins occurs in humans.
In addition to Dunnigan syndrome/FPLD, 2 other diseases are associated with mutations in LMNA. The first is Emery-Dreifuss muscular dystrophy, which is a progressive muscular dystrophy of the upper and lower extremity muscles, with prominent contractures of ankles and elbows and cardiac conduction abnormalities.61,62 The other is a familial cardiomyopathy associated with conduction abnormalities63,64 The degree of overlap between these 2 diseases and FPLD is a subject of research. In addition, how the mutations in LMNA result in 3 different diseases and how the mutations in a ubiquitously expressed gene cause various syndromes with a strong regional distribution are questions that remain unanswered.
A third form of familial partial lipodystrophy, FPLD3, was first identified in a patient who developed diabetes mellitus and hypertriglyceridemia at age 32 and loss of fat from the extremities and face at age 50 years. This patient had a mutation in the PPAR-gamma gene, which encodes peroxisome proliferator-activated receptor-gamma, the target of the thiazolidinedione medications used to treat insulin resistant diabetes.65 Heterozygous mutations in the PPAR-gamma mutation have since been identified in several other patients with FPLD. In these patients, the onset of lipodystrophy occurred as early as the second decade of life.14 All affected patients had loss of subcutaneous adipose tissue from the distal extremities. The face was spared in some and affected in others.
More recently, a mutation in the AKT2, or protein kinase B, gene has been identified in a patient with FPLD affecting only the extremities. Many patients with FPLD do not have mutations in Lamin A/C, PPAR-gamma, or AKT2. Therefore, other genetic loci for FPLD likely exist and have yet to be identified.
Acquired lipoatrophy syndromes
Some cases of acquired lipodystrophy are believed to be autoimmune in nature, as suggested by the presence of a population of circulating autoantibodies or an association with another autoimmune disease (eg, juvenile dermatomyositis). Chronic (>3 mo), generalized inflammation of the subcutaneous tissue, referred to as panniculitis (either clinically or based on biopsy results), has been described as preceding the fat loss in some cases.66 The evidence for long-sought specific antifat cell autoantibodies or specific activated T-cell clones remains weak. The results of studies from the 1970s showing a urinary lipolytic factor have not been reproduced.67
A portion of patients with acquired lipodystrophy have low C3 levels,68 and adipsin, a factor produced by fat cells, is thought to be responsible for alternative activation of the complement pathway. In addition, generalized or partial fat loss has been described in association with familial69 or acquired70,71,72 hypocomplementemia.
A clear association exists between lipodystrophy and juvenile dermatomyositis.73,74,75,76 These patients typically present before adolescence. The fat loss can be either generalized or partial. Usually, increased visceral fat is present despite very severe peripheral fat loss and a specific asymmetric pattern of fat loss on the extremities (Image 5).
Two specific eponyms are used in the literature to refer to acquired lipodystrophy syndromes, Lawrence syndrome and Barraquer-Simons syndrome. These eponyms are mostly descriptive and do not necessarily indicate diseases caused by a unique etiology. These terms should perhaps be replaced by acquired generalized or acquired partial lipodystrophy, respectively.
Lawrence first described acquired generalized lipoatrophy (also known as Lawrence syndrome) with the onset of the disease during childhood.77 More recent case reports in the literature indicate that acquired generalized lipoatrophy can present at any age.78 Lawrence's original report remains an excellent description of generalized lipoatrophy.
Fat loss is usually a remarkable event leading to a dramatic change in physical features (see Image 6). The median time to develop diabetes after loss of fat tissue is approximately 4 years. Both the basal metabolic rate and hepatic glucose output are increased. While these patients are known to lack fully differentiated adipocytes, whether they also lack adipocyte precursors remains unclear.79 Patients with this type of lipodystrophy may have very severe fat loss, including retro-orbital fat and supportive fat in their hands, feet, and genital area. Bone marrow fat is lost in some cases, but preserved in others.
The case reports that refer to Barraquer-Simons (or acquired partial lipodystrophy) syndrome describe a wide range of variation with few shared features. Patients are usually women in their second or third decade of life who also have well-described autoimmune disorders such as scleroderma or glomerulonephritis presenting with partial fat loss.80,18,81 Fat loss usually starts in the face and descends to the gluteal line. Usually, increased adiposity is present in unaffected fat depots (lower extremities). The prevalence rate of diabetes and hypertriglyceridemia is approximately 50% in these cases and seems to cosegregate with lower total body fat in this series.
Other causes of acquired lipodystrophy
Some patients who are infected with HIV and are undergoing aggressive treatment, particularly with protease inhibitors, develop a partial lipoatrophy characterized by loss of subcutaneous fat from the face, extremities, and trunk. In contrast, visceral fat increases, and a buffalo hump similar to that observed in persons with Cushing syndrome develops.82,83,84 This is accompanied by the development of insulin resistance and hypertriglyceridemia. The changes in body composition and metabolic parameters are usually apparent within 3-6 months of therapy, and the onset is usually quicker when more than one protease inhibitor is used. The syndrome is recognized in persons of both sexes and in pediatric and adult patients.
The reason why patients with HIV infection who are undergoing treatment develop this characteristic phenotype remains unknown. One hypothesis is that an aspartyl protease (like the HIV protease) may be important in the differentiation of adipocytes. In support of this hypothesis, several groups reported that protease inhibitors blocked preadipocyte differentiation in vitro.85,86 Interestingly, some groups reported the development of a similar phenotype when patients infected with HIV were treated aggressively with antiretroviral agents other than protease inhibitors, including nucleoside analogues,87,88,88 This suggests that the lipodystrophy may be related to aggressively treated HIV infection rather than to a specific therapy.88,89
Further details about some specific forms of lipodystrophy can be found elsewhere (see Lipodystrophy, Acquired Partial, Lipodystrophy, HIV, Lipodystrophy, Progressive).
Clinical Abnormalities Observed in Lipoatrophy/Lipodystrophy Syndromes
Despite the heterogeneity in clinical presentation, the similarities in metabolic abnormalities (insulin-resistant diabetes and hypertriglyceridemia) observed in different forms of lipoatrophy suggest that the lack of fat may be the primary cause of insulin resistance and dyslipidemia. In support of this hypothesis, ablation of white adipose tissue via genetic engineering produces phenotypes similar to human lipoatrophies.90,91,92 Furthermore, transplantation of fat into one of the models remarkably reverses the metabolic abnormalities.93
In general, the more severe the lack of fat, the more severe the metabolic abnormalities (see Table 2 in Treatment of Lipoatrophy/Lipodystrophy). Circulating free fatty acid levels are increased in most patients studied at the US National Institutes of Health. Because of the relative paucity of adipose tissue, triglycerides accumulate excessively in multiple locations, most notably in the liver and in the muscles.
In addition, the respiratory quotient (RQ) has been observed to be elevated in patients with lipoatrophy/lipodystrophy. The RQ is the ratio of carbon dioxide production to oxygen consumption and reflects the relative contributions of carbohydrates and fat in providing fuel for metabolism. The elevated RQ suggests that either the rate of fat oxidation is decreased or the rate of lipogenesis is increased; both of which might contribute to the observed elevation in the levels of free fatty acids and triglycerides.94
Further, fatty acids antagonize insulin's effects on glucose metabolism, and this provides a potential mechanism to account for the state of insulin resistance.95 Increased fatty deposition in the muscle or in the beta cell can be responsible for insulin resistance and diabetes, ie, lipotoxicity.96,96,97
Patients with congenital generalized lipoatrophy present with generalized absence of fat tissue within the first year of life. The musculature is typically well-defined with prominent superficial veins due to the paucity of adipose tissue.14 Severe hypertriglyceridemia may be present early on and result in eruptive xanthomas and recurrent pancreatitis. Insulin resistance is also present early on and acanthosis nigricans and type 2 diabetes usually occurs by adolescence.
The accumulation of triglycerides in hepatocytes may somehow cause the injury associated with nonalcoholic steatohepatitis (NASH).98 NASH is observed in approximately one third of patients with lipoatrophy and may progress to end-stage liver failure with childhood death from bleeding esophageal varices. The insulin resistance leads to hyperinsulinemia, and clinical features of hyperinsulinemia (eg, acanthosis nigricans, hyperandrogenism in female patients) are common.
Patients with the early-onset hyperinsulinemia in combination with congenital generalized lipoatrophy develop acromegaloid features (large hands, feet, and jaw) with soft tissue hyperplasia, somatomegaly, and bony abnormalities. This is believed to be caused by insulin cross-reacting with the IGF-1 receptor. The kidneys may also be affected and renal failure is a common cause of death. Hypertrophic cardiomyopathy and mild mental retardation may also occur in some forms of congenital lipoatrophy.14
Another notable finding in patients who are the most severely fat-deficient is food-seeking behavior. They may consume large amounts of food (similar to patients with bulimia) and may have the urge to eat frequently. They have low levels of circulating leptin, which may contribute to their increased appetite.
Females with congenital lipoatrophy may exhibit clitoromegaly, hirsutism, or both at birth. The hirsutism usually increases with age. Reproductive abnormalities are common. Some women have hypogonadotropic amenorrhea, probably due to leptin deficiency. Many have a form of polycystic ovary syndrome, with irregular or infrequent menstrual cycles, hyperandrogenism, and ovarian cysts.14 Affected men usually have normal reproductive function.
Acquired generalized lipoatrophy presents with widespread loss of adipose tissue in persons of any age. It has been reported to occur in persons as old as 74 years.78 Acquired forms of lipodystrophy are typically preceded by an illness, often an infection. A female preponderance appears to exist. Many of the same metabolic abnormalities that occur in the congenital lipodystrophies are also found in the acquired forms of generalized lipoatrophy, including insulin resistance, diabetes mellitus, hypertriglyceridemia, hypermetabolism, and low leptin levels. Mild hirsutism, prominent musculature and superficial veins, acanthosis nigricans, hepatomegaly and cirrhosis may also be present. Autoimmune disorders are common. Some patients may have an increased susceptibility to infection due to C3 deficiency.
Treatment of Lipoatrophy/Lipodystrophy
The clinical problems requiring treatment in lipoatrophy syndromes are diabetes and hypertriglyceridemia. Although several classes of antidiabetic drugs are marketed in the United States, achieving good glycemic control (glycated hemoglobin <7.2%) is difficult for most patients with lipoatrophic diabetes.
Insulin
Because of their extreme insulin resistance, extremely high doses (eg, >1000 U/d) are often necessary in patients with various syndromes of lipoatrophy.99 The volume of injections is more difficult to tolerate for younger patients. Nevertheless, insulin remains the only approved medication for the treatment of children with diabetes.
Insulin secretagogues
The principal mechanism of action for this class of drugs is to promote insulin secretion by beta cells.100 Because patients with isolated insulin resistance may not have an independent defect in insulin secretion, sulfonylureas are frequently ineffective in patients with lipoatrophic diabetes.
Metformin
This drug primarily works by inhibiting hepatic glucose output. Metformin may help decrease insulin requirements in some patients with lipoatrophy/lipodystrophy. To this author's knowledge, no systematic trials are investigating the efficacy of this drug in patients with lipoatrophy/lipodystrophy. Metformin is approved by the US Food and Drug Administration (FDA) for the treatment of type 2 diabetes in adults and children older than 10 years. Use of metformin in younger children is best administered by clinicians who have prior experience with treatment with this drug, ideally in facilities specialized in treating children with unusual forms of diabetes.
Acarbose
This drug interferes with GI absorption of many carbohydrates.101 While this author is not aware of systematic studies on the efficacy of this drug in patients with lipoatrophy, it has relatively limited efficacy to decrease glucose levels in persons with type 2 diabetes mellitus.
Thiazolidinediones
Members of this class are agonists of PPAR-gamma, thereby stimulating adipocyte differentiation.102 In vivo, this class of drugs functions as insulin sensitizers, and they increase insulin-stimulated glucose uptake by the muscle.103,104 These effects of thiazolidinedione compounds seem ideally suited to treat the problems encountered in lipoatrophy/lipodystrophy syndromes. In addition, troglitazone has exerted favorable effects in an animal model of lipoatrophy.90
This author undertook a treatment trial with troglitazone in patients with lipoatrophy. The primary endpoints were metabolic control and adipose tissue mass.105 Six months of troglitazone therapy led to significant improvement in metabolic control, with a reduction in glycosylated hemoglobin (HbA1c), triglyceride, and free fatty acid levels. In addition, a small but statistically significant increase in body fat was noted. Interestingly, the increase was predominantly in the subcutaneous compartment. Furthermore, body weight did not change significantly and liver size deceased.
Despite the favorable effects of troglitazone, a risk of hepatotoxicity was associated with therapy. The FDA withdrew troglitazone from the US market in March of 2000 because of concerns of hepatotoxicity. Despite the serious risk of hepatotoxicity, patients with lipoatrophy experienced significant clinical benefit from treatment with troglitazone.
The newer members of the class, rosiglitazone and pioglitazone, remain in clinical use. The preclinical studies with these 2 medications suggest that they do not have the same risk of hepatotoxicity. In vitro, rosiglitazone has been shown to stimulate subepidermal fibroblast-like cells from an infant with congenital generalized lipodystrophy to differentiate into adipocytes.106 In patients with acquired partial lipodystrophy, one report showed that rosiglitazone improved fat distribution; however, preferential fat gain in the lower body occurred.
The US Food and Drug Administration issued an alert on May 21, 2007 to patients and health care professionals regarding rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity. The drug is highly selective and a potent agonist for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD) including the following articles: 1) Rosiglitazone increases MI and CV death in meta-analysis, 2) The rosiglitazone aftermath: Legitimate concerns or hype? and 3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers.
Treatment of dyslipidemia in lipoatrophic diabetes
The dyslipidemia of severe lipoatrophy is difficult to treat with currently available therapeutic interventions. This problem causes significant morbidity and mortality. Patients with triglyceride levels greater than 1000 mg/dL are at risk of developing acute pancreatitis. Recurrent episodes lead to pancreatic insufficiency. Chronically elevated triglyceride levels in the setting of hyperinsulinemia and low high-density lipoprotein (HDL) levels increase the predisposition for coronary artery disease. Severely elevated triglyceride levels may lead to painful cutaneous eruptive xanthomata.
Troglitazone is remarkable in its ability to improve hypertriglyceridemia in addition to improving glycemia. This author prefers to use fibrates and statins as opposed to niacin because of severe insulin resistance. These 2 classes may need to be used in combination, with careful monitoring for adverse effects. Again, the pediatric experience with these medications is extremely limited. Limitation of energy (caloric) intake may be useful for short-term results, but continuing this for long-term treatment is not possible. Medium-chain triglycerides and fish oil have not been tested in a systematic fashion, but they may prove useful. This author has attempted to use intestinal lipase inhibitors in a few severely affected pediatric patients, with some positive results. Another study showed marked improvement with intensive plasma exchange therapy in a 15-year-old girl with acquired generalized lipoatrophy and severe hypertriglyceridemia that was refractory to medical therapy.107
In women with lipoatrophy syndromes, oral estrogens should be avoided as they can exacerbate the hypertriglyceridemia and result in acute pancreatitis.14
Role of diet and lifestyle
There is no evidence supporting the use of a specific diet for lipodystrophy.14 Total calories, saturated fat, and simple carbohydrates are typically restricted. A low fat diet is especially important if hypertriglyceridemia is present. In children, care must be taken to ensure that the energy intake is sufficient for normal growth and development. Alcohol should be avoided in patients with hypertriglyceridemia and fatty liver. Regular exercise should be encouraged to improve metabolic status. Lifestyle modifications alone may not be sufficient and may need to be implemented along with pharmacotherapy.
Other potential therapies from the laboratory to clinical trials
Two encouraging interventions in mouse models of lipoatrophy are worth mentioning because they suggest novel therapeutic approaches for the treatment of patients with lipoatrophy. One intriguing experiment is transplantation of white fat into transgenic mice with severe lipoatrophy.93 This model exerted very severe metabolic abnormalities and had the least amount of white adipose tissue among the viable animal models of lipoatrophy. Transplantation of fat ameliorated the diabetes in a dose-dependent manner. This is currently a difficult therapy to undertake in humans because of the requirement for long-term immunosuppression and technical difficulties. Nevertheless, this experiment unequivocally establishes that insulin resistance and diabetes in lipoatrophy are caused by the absence of fat tissue.
The reason replacement of fat reverses the diabetes remains unknown. One hypothesis is that the absence of adipocytes causes an absence of hormones produced by these cells. Therefore, replacement of these hormones may lead to reversal of the metabolic findings. Shimomura et al administered one such factor, leptin, to lipoatrophic mice. These mice exhibited diabetes, hypertriglyceridemia, and hepatic steatosis in addition to severe leptin deficiency. Interestingly, 3 weeks of leptin therapy ameliorated all the metabolic abnormalities, ie, normalizing glycemia and triglyceridemia and decreasing the degree of steatosis in the liver.108
The results with leptin administration in another model of lipoatrophy are less dramatic, but they still demonstrate a significant effect on plasma insulin levels.109 These results from animal models warranted a clinical trial, which inspired a similar set of studies with a replacement approach of adipocyte-specific hormones, opening an era of rediscovery of the adipocyte as an endocrine organ.
Several small studies in patients with generalized lipodystrophy and familial partial lipodystrophy have shown that recombinant human Leptin replacement improves metabolic abnormalities, reducing hyperglycemia, hyperlipidemia, insulin resistance, fatty infiltration of the liver, and hypermetabolism.110,111,112 Another study showed that leptin normalized menstrual irregularity and reduced circulating testosterone levels in ten women with a severe form of polycystic ovary syndrome due to generalized lipoatrophy.113 However, leptin is still an investigational therapy.
Although the current standard therapy for lipodystrophy is medical management, a recent report showed that gastric bypass surgery dramatically improved metabolic control in a 55-year-old woman with familial partial lipodystrophy.114
Table 1. Genetic Syndromes of Lipoatrophy
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Table
| Syndrome | Lipoatrophy | Gene/Locus | Inheritance | OMIM* |
|---|---|---|---|---|
| Primary Lipoatrophy Syndromes | ||||
| Congenital generalized lipoatrophy (Seip-Berardinelli)† | Generalized See text for details (Congenital generalized lipoatrophy) | AGPAT2/9q34 seipin/11q13 | AR | 608594 269700 |
| Kobberling-Dunnigan syndrome | Partial See text for details (Familial partial lipodystrophy) | 1q21-22 Lamin A/C PPAR-gamma AKT2 Others - Unknown | AD | 151660 604367 164731 |
| Others | Numerous distributions | Unknown | AD/AR | N/A |
| Complex Syndrome Associated With Lipoatrophy | ||||
| Mandibuloacral dysplasia | Congenital, partial involving extremities only OR generalized | Lamin A/C ZMPSTE24 Others-Unknown | AR | 248370 608612 |
| Werner syndrome | Congenital, partial Involves extremities | 8p12 Werner helicase | AR | 277700 |
| Cockayne syndrome | Congenital, partial Involves extremities | 5 CSA | AR | 216400 |
| Carbohydrate-deficient glycoprotein syndrome | Transient, partial Buttocks | 16p.13.3 PMM 1 and 2‡ | AR | 212065 |
| SHORT syndrome | Congenital, generalized or partial | Unknown | AR/AD | 269880 |
| AREDYLD§ syndrome | Generalized, congenital | Unknown | – | 207780 |
| Syndrome | Lipoatrophy | Gene/Locus | Inheritance | OMIM* |
|---|---|---|---|---|
| Primary Lipoatrophy Syndromes | ||||
| Congenital generalized lipoatrophy (Seip-Berardinelli)† | Generalized See text for details (Congenital generalized lipoatrophy) | AGPAT2/9q34 seipin/11q13 | AR | 608594 269700 |
| Kobberling-Dunnigan syndrome | Partial See text for details (Familial partial lipodystrophy) | 1q21-22 Lamin A/C PPAR-gamma AKT2 Others - Unknown | AD | 151660 604367 164731 |
| Others | Numerous distributions | Unknown | AD/AR | N/A |
| Complex Syndrome Associated With Lipoatrophy | ||||
| Mandibuloacral dysplasia | Congenital, partial involving extremities only OR generalized | Lamin A/C ZMPSTE24 Others-Unknown | AR | 248370 608612 |
| Werner syndrome | Congenital, partial Involves extremities | 8p12 Werner helicase | AR | 277700 |
| Cockayne syndrome | Congenital, partial Involves extremities | 5 CSA | AR | 216400 |
| Carbohydrate-deficient glycoprotein syndrome | Transient, partial Buttocks | 16p.13.3 PMM 1 and 2‡ | AR | 212065 |
| SHORT syndrome | Congenital, generalized or partial | Unknown | AR/AD | 269880 |
| AREDYLD§ syndrome | Generalized, congenital | Unknown | – | 207780 |
*Online Mendelian Inheritance of Man; database providing information about genetic syndromes
†Evidence for genetic heterogeneity
‡Phosphomannomutase 1 and 2
§Not clear if this is a variation of Berardinelli-Seip syndrome
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Table
| General Characteristics | Generalized | Partial | |
| Male/female | 2/8 | 4/23 | |
| Age range, y | 6-19 | 26-65 | |
| Genetic/other | 4/6 | 10/17 | |
| Clinical Characteristics | | | |
| Diabetes/IGT*/IR† | 9/1/0 | 15/5/3 | |
| Acanthosis nigricans, % | 70 | 56 | |
| Hyperandrogenism, % | 50 | 70 | |
| Central hypogonadism, % | 50 | 0 | |
| NASH, % | 70 | 33 | |
| Laboratory Characteristics | | | Reference Range |
| HbA1c, % | 9.9 ±3.5 | 7.2 ±0.8 | <6.2 |
| Triglycerides‡, mg/dL | 2015 ±1463 | 426 ±164 | 35-155 |
| Free fatty acids, µmol/L | 926 ±156 | 693 ±115 | 50-550 |
| HDL cholesterol§, mg/dL | 21.4 ±10.3 | 22.7 ±11.9 | 35-85 |
| Leptin||, ng/mL | 1.8 ±1.0 | 10.5 ±6.3 | Variable |
| Body fat by DEXA¶, % | 7.7 ±2.6 | 23.8 ±2.5 | Variable |
| General Characteristics | Generalized | Partial | |
| Male/female | 2/8 | 4/23 | |
| Age range, y | 6-19 | 26-65 | |
| Genetic/other | 4/6 | 10/17 | |
| Clinical Characteristics | | | |
| Diabetes/IGT*/IR† | 9/1/0 | 15/5/3 | |
| Acanthosis nigricans, % | 70 | 56 | |
| Hyperandrogenism, % | 50 | 70 | |
| Central hypogonadism, % | 50 | 0 | |
| NASH, % | 70 | 33 | |
| Laboratory Characteristics | | | Reference Range |
| HbA1c, % | 9.9 ±3.5 | 7.2 ±0.8 | <6.2 |
| Triglycerides‡, mg/dL | 2015 ±1463 | 426 ±164 | 35-155 |
| Free fatty acids, µmol/L | 926 ±156 | 693 ±115 | 50-550 |
| HDL cholesterol§, mg/dL | 21.4 ±10.3 | 22.7 ±11.9 | 35-85 |
| Leptin||, ng/mL | 1.8 ±1.0 | 10.5 ±6.3 | Variable |
| Body fat by DEXA¶, % | 7.7 ±2.6 | 23.8 ±2.5 | Variable |
*Impaired glucose tolerance
†Insulin resistance
‡Conversion factor to mmol/L: 0.01129X
§Conversion factor to mmol/L: 0.02586X
||Conversion factor to nmol/L: 0.08X
¶Dual-energy x-ray absorptiometry
Multimedia
 | Media file 1: Generalized lipodystrophy. Clinical spectrum of adiposity. T1-weighted magnetic resonance images in which lipid appears white. Transverse sections of the torso at the level of the fifth lumbar vertebra (top panels) and midthigh (bottom panels). Generalized lipoatrophy (top left, bottom left), a healthy individual with a body mass index of 24 kg/m2 (top center, bottom center), and an individual who is obese with a body mass index of 38 kg/m2 (top right, bottom right). Note the marked absence of all fat depots in the patient with generalized lipoatrophy, with preservation of marrowfat and a lipid-filled liver. In addition, the bright color of the muscle is indicative of lipid-filled myocytes. |
 | Media file 2: Generalized lipodystrophy. Congenital generalized lipoatrophy in a 16-year-old girl. Picture (right) and T1-weighted magnetic resonance images (left). Transverse sections of the torso at the fifth lumbar vertebra demonstrate markedly deficient subcutaneous and visceral fat (top left). Transverse sections of the midthigh demonstrate an absence of subcutaneous, deep, intrafascicular, and marrowfat. Note light-colored, lipid-filled muscle tissue (bottom left). Note absence of fat throughout the body (right). Note the differences between these images and those presented in Image 1. |
 | Media file 3: Generalized lipodystrophy. Dunnigan familial partial lipodystrophy. Pictures of a 26-year-old woman (top). Note increased fat around the face/neck (top left) and deficiency in the gluteal region and lower extremities (top right). T1-weighted magnetic resonance images (bottom). Transverse sections of the torso at the fifth lumbar vertebra demonstrate markedly deficient subcutaneous and increased visceral fat (bottom left). Transverse sections of the midthigh demonstrate absence of subcutaneous fat with preservation of deep fat, intrafascicular fat, and marrowfat (bottom right). |
 | Media file 4: Generalized lipodystrophy. On the left is Werner syndrome in a 37-year-old woman. Clinical features evident include premature aging, alopecia, sclerodermalike changes in the skin, and peripheral lipoatrophy (shown). Insulin-resistant diabetes is an associated feature. On the right is mandibuloacral dysplasia in a 14-year-old girl. This rare recessive syndrome is characterized by acroosteolysis, widened sutures, and hypoplastic mandible (shown) and clavicles (shown). Marked peripheral lipoatrophy and insulin resistance are associated features. |
 | Media file 5: Generalized lipodystrophy. Acquired generalized lipoatrophy is in the differential diagnosis of congenital generalized lipoatrophy. The patient had completely normal fat distribution at age 3 years 8 months (left) and acutely lost her body fat with a febrile illness at age 6 years 10 months (right). |
 | Media file 6: A case with severe juvenile dermatomyositis and generalized lipodystrophy. The physical appearance of the 19-year-old woman (right). She has severe loss of both muscle and fat tissue. T1-weighted magnetic resonance images of the patient are also presented (left). Transverse sections of the torso at the fifth lumbar vertebra demonstrate markedly deficient subcutaneous fat and markedly increased visceral fat (top left). Transverse sections of the midthigh demonstrate asymmetrical absence of subcutaneous fat with preservation of medial subcutaneous fat and marrow fat (bottom left). |
Keywords
body adiposity, lipoatrophy syndrome, adipose tissue deficiency, peripheral insulin resistance, hypertriglyceridemia, lipoatrophic diabetes, adipocyte deficiency, congenital generalized lipoatrophy, Seip-Berardinelli syndrome, progeria syndromes, Werner syndrome, Cockayne syndrome, carbohydrate-deficient glycoprotein syndrome, short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, teething delay, SHORT syndrome, mandibuloacral dysplasia, AREDYLD syndrome, Kobberling-Dunnigan syndrome, familial partial lipodystrophy, FPLD, Dunnigan syndrome, Emery-Dreifuss muscular dystrophy, acquired lipodystrophy syndrome, Lawrence syndrome, Barraquer-Simons syndrome, Lawrence-Seip syndrome
More on Lipodystrophy, Generalized |
| References |
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Further Reading
Keywords
body adiposity, lipoatrophy syndrome, adipose tissue deficiency, peripheral insulin resistance, hypertriglyceridemia, lipoatrophic diabetes, adipocyte deficiency, congenital generalized lipoatrophy, Seip-Berardinelli syndrome, progeria syndromes, Werner syndrome, Cockayne syndrome, carbohydrate-deficient glycoprotein syndrome, short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, teething delay, SHORT syndrome, mandibuloacral dysplasia, AREDYLD syndrome, Kobberling-Dunnigan syndrome, familial partial lipodystrophy, FPLD, Dunnigan syndrome, Emery-Dreifuss muscular dystrophy, acquired lipodystrophy syndrome, Lawrence syndrome, Barraquer-Simons syndrome, Lawrence-Seip syndrome
