INTRODUCTION — The lipodystrophic syndromes are a heterogeneous group of congenital or acquired disorders characterized by either complete or partial lack of adipose tissue (lipoatrophy) [1,2]. In some of these disorders, there is also the apparent accumulation of fat in other regions of the body.
The extent of fat loss correlates with the severity of the metabolic abnormalities. Clinically, patients with severe lipodystrophy have severe insulin resistance and a group of unique features, such as severe hyperlipidemia, progressive liver disease, and increased metabolic rate (table 1). Acquired and congenital lipodystrophies may also be associated with proteinuric kidney diseases, and renal biopsy of patients with nephrotic range proteinuria has revealed focal segmental glomerulosclerosis or membranoproliferative glomerulonephritis [3,4].
There is increasing understanding of the molecular basis for these disorders, but it is likely that multiple molecular defects are responsible (figure 1). A widely accepted classification of the various types of lipodystrophies is presented in the table (table 2). Other disorders that need to be differentiated from lipodystrophies are listed in the table (table 3).
The current most prevalent form, by far, of lipodystrophy is in patients with human immunodeficiency virus (HIV) infection, and is likely related to antiretroviral therapy. HIV-related lipodystrophy is discussed separately. (See "Treatment of HIV-associated lipodystrophy".)
GENERALIZED LIPODYSTROPHY — These are rare but clinically striking disorders that may be congenital (Seip-Berardinelli syndrome) [5,6] or acquired (Lawrence syndrome) [7]. Their prevalence has been estimated to be less than one case per one million people.
Congenital generalized lipodystrophy — Congenital generalized lipodystrophy (CGL) is inherited as an autosomal recessive trait, with frequent parental consanguinity. At least four molecularly distinct forms of congenital lipodystrophy have been defined, with the mutations of AGPAT2 and BSCL2 being responsible for 95 percent of reported cases of CGLs (figure 1) [8-10].
Clinical features — Abnormal appearance due to the absence of subcutaneous fat is noted within the first two years of life, often at or soon after birth. Adipose tissue is almost completely absent from most subcutaneous areas, the abdomen, the thorax, and bone marrow, whereas normal amounts of adipose tissue are present in the orbits, mouth and tongue, palms and soles, scalp, perineum, and periarticular regions [11].
During childhood these patients have a voracious appetite, accelerated linear growth, increased metabolic rate, and advanced bone age. The final height is usually normal. Other abnormalities are acanthosis nigricans and protuberant abdomen due to hepatomegaly caused by fatty infiltration of the liver, which can lead to cirrhosis and its complications. Prominent musculature and precocious secondary sexual development may also occur, and some patients have intellectual impairment (figure 2).
Among the molecularly distinct forms of CGL, the clinical phenotype varies [10,12].
●Type 1 CGL (CGL1) is due to AGPAT2 gene mutations. This gene has been mapped to chromosomes 9q34. It encodes the enzyme acyltransferase 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), which catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triglycerides and glycerophospholipids. AGPAT2 mutations are found predominantly in patients of African ancestry. Individuals have normal intelligence, and their mechanical fat is preserved.
●Type 2 CGL (CGL2) is due to BSCL2 gene mutations. This gene is located in chromosome 11q13 and encodes a 398-amino-acid protein called seipin. The BSCL2 gene mutation has been found in patients of European and Middle Eastern origins but has also been reported as a causative gene in Japanese with CGL. BSCL2 expression is critical for normal adipogenesis in vitro, as cells lacking BSCL2 failed to induce expression of key lipogenic transcription factors, including peroxisome-proliferator activated receptor gamma (PPARG), CCAAT/enhancer binding protein-alpha (C/EBP-alpha), as well as enzymes AGPAT2, DGAT2, and lipin 1.
CGL2 due to seipin mutation appears to manifest itself as a more severe disease phenotype than that due to AGPAT2 mutation (CGL1), with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. In addition, compared with CGL1, CGL2 patients have more pronounced absence of body fat, loss of metabolically active fat (subcutaneous regions, intermuscular regions, bone marrow, intraabdominal and intrathoracic regions), and lack of mechanical fat (orbital regions, palms, soles, and joints). Patients with CGL2 also have a higher prevalence of intellectual impairment and cardiomyopathy than those with CGL1.
●Type 3 CGL (CGL3) is due to a homozygous nonsense mutation of CAV1, probably as a result of a consanguineous union. CAV1 is located on chromosome 7q31 [13]. Its end product, caveolin-1, is a highly conserved 22-KDa protein and a major fatty acid binder on the plasma membranes as well as a crucial component of plasma membrane microdomains known as caveolae. These plasma membrane domains have important roles in regulating signaling pathways and processes such as cell migration, polarization, and proliferation. Mutated function of CAV1 may lead to lipodystrophy by interfering with lipid handling, lipid droplet formation, and adipocyte differentiation.
Patients with CAV1 mutations reportedly have clinical features similar to those of patients with CGL1 and CGL2, with the degree of lipodystrophy being intermediate between these two phenotypes. Individuals have normal intelligence, and their mechanical fat is preserved.
●Type 4 CGL (CGL4) is due to mutations in the PTRF gene [14]. PTRF, also known as cavin, is a polymerase I and transcript release factor involved in biogenesis of caveolae, regulating caveolin 1 and 3 expression. To date, 21 patients with PTRF mutations have been reported in the literature [1]. Clinical features include moderate lipodystrophy in association with congenital myopathy, esophageal dysfunction, pyloric stenosis, atlantoaxial instability, QT interval prolongation with exercise-induced ventricular tachycardia, and sudden death.
Of note, there are several patients with CGL who do not have any of the four known gene mutations, possibly leading to future identification of novel CGL genes.
Metabolic abnormalities — Insulin resistance has been noted at an early age. Diabetes mellitus usually develops in the early teens, but ketosis is rare, and the diabetes is usually refractory to insulin therapy. Hypertriglyceridemia with high serum concentrations of both very low-density lipoprotein and chylomicrons is common, may cause acute pancreatitis, and is related to the fatty liver. Serum leptin concentrations are low, consistent with near total absence of body fat [15].
Acquired generalized lipodystrophy — The characteristics of acquired generalized lipodystrophy are similar to those of the congenital disorder, except that the former develops in a previously healthy child or adult over a period of days to weeks [16]. Only a few dozen cases have been reported.
Pathogenesis — A previous infection has been causally linked to this syndrome because histologic analysis of subcutaneous tissue reveals panniculitis [17]. Antibodies against adipocyte-membrane antigens have been detected in a few patients [18], and the syndrome may coexist with other autoimmune diseases, such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis.
Clinical features — The syndrome can, as noted above, occur in children or adults, and females predominate. In most patients, the loss of fat begins in adolescence and occurs over a period of weeks, months, or years. Superficial veins and musculature are prominent, and hepatomegaly is a consistent finding [19]. Other findings include mild hirsutism, acanthosis nigricans, muscle hypertrophy, and cirrhosis (figure 3).
Adipose tissue distribution — There is generalized loss of subcutaneous adipose tissue.
Metabolic abnormalities — Patients have severe insulin resistance, hyperinsulinemia, hypertriglyceridemia, low serum high-density lipoprotein (HDL) cholesterol concentrations, and often a high metabolic rate. Diabetes, high serum free fatty acid concentrations, and excessive lipolysis are present. Most patients do not become ketotic, but diabetic ketoacidosis has been reported [20]. (See "Insulin resistance: Definition and clinical spectrum".)
CONGENITAL PARTIAL LIPODYSTROPHY — Several distinct syndromes of regional lipoatrophy are associated with a simultaneous hypertrophy of adipose tissue in nonatrophic areas.
Familial partial lipodystrophy — Familial partial lipodystrophy (FPLD) syndromes are rare syndromes characterized by variable loss of adipose tissue that occurs during childhood, puberty, or young adulthood. They are associated with metabolic complications and, in some cases, cardiomyopathy, conduction disturbances, and congestive heart failure.
FPLD type 1 — FPLD type 1 (Kobberling lipodystrophy) is characterized by loss of adipose tissue in the extremities and normal adipose tissue elsewhere. Affected individuals may have excessive amounts of subcutaneous truncal fat. Only a few affected women have been reported [21,22].
The age of onset, mode of inheritance, and characteristic features are not well defined, due to the small number of cases described. Lipodystrophy and remarkable well-defined muscles are the most frequently described clinical characteristics. Most reported patients have had hypertriglyceridemia and diabetes [23].
The genetic defect associated with Kobberling-type lipodystrophy is currently unknown, and no LMNA or PPARG mutations have been identified. Although it appears that this syndrome is familial, it may also occur spontaneously.
FPLD type 2 — FPLD type 2 (Dunnigan lipodystrophy) is associated with fat loss from the extremities, abdomen, and thorax and excess subcutaneous fat in the chin and supraclavicular area [1,24-26].
The patients have normal adipose tissue in childhood but lose subcutaneous adipose tissue from the extremities later, usually with the onset of puberty. The syndrome is associated with increased muscularity, not merely the appearance of increased muscularity that occurs with loss of subcutaneous fat, which makes it relatively easier to recognize in women. Muscle biopsies from individuals with the syndrome reveal hypertrophy of type 1 and 2 muscle fibers [27]. Patients may develop excess supraclavicular fat and round facies later in life. They also may have acanthosis nigricans, hirsutism, and menstrual abnormalities (ovarian hyperandrogenism) (figure 4).
Diabetes and hepatic steatosis may develop prior to the age of 20 years [23,28] and are accompanied by hypertriglyceridemia (hyperchylomicronemia), low serum high-density lipoprotein (HDL) cholesterol concentrations, and high fasting serum free fatty acid concentrations [29,30], leading to increased cardiovascular risk.
Although this disorder was thought to be transmitted as an X-linked dominant trait, there is autosomal dominant transmission in some families [29,31-34]. The locus for the autosomal dominant form is located on chromosome 1q21-22 [32]. The mutations appear to involve the LMNA gene, which encodes nuclear lamins A and C, nuclear envelope proteins that organize nuclear architecture through structural attachments that vary during the cell cycle and cell differentiation (figure 1) [35]. A less severe phenotype has been described in two sisters whose mutation involved lamin A only [36].
Most mutations in LMNA are missense mutations within the 3' end of the gene [37]. The mutant gene products may disrupt interaction with chromatin or other nuclear lamina proteins, resulting in apoptosis and premature death of adipocytes. The accumulation of prelamin A may also impair adipogenesis by interfering with the key adipocyte transcription factors/regulators, including sterol response element binding proteins 1 (SREBP 1) and peroxisome proliferator-activated receptor gamma (PPARG).
FPLD type 3 — FPLD type 3 is associated with heterozygous PPARG gene mutations (figure 1) [37]. Heterozygous mutations may cause loss of function by directly interfering with normal gene function (dominant negative) or by reduction of gene expression (haploinsufficiency). The phenotype is similar to Dunnigan's variety, with the exception that fat accumulation in the head and neck may be spared. Patients with FPLD3 appear to have more severe metabolic abnormalities than those with FPLD2.
FPLD type 4 — FPLD type 4 is associated with a mutation in the PLIN1 gene coding for perilipin 1, which is a required component of lipid droplet membranes and is essential for lipolysis and lipid storage [38]. It is characterized phenotypically by loss of subcutaneous fat from the extremities. Histologically, the six patients with this mutation have small adipocytes with increased macrophage infiltration and abundant fibrosis.
FPLD type 5 — FPLD type 5 is due to an autosomal recessive mutation in the CIDEC gene. The CIDEC gene is located on the short arm of chromosome 3 (3p25.3) and encodes for the CIDEC protein. CIDEC is expressed in the lipid droplets, and mutation(s) of the CIDEC gene result in low levels of functional CIDEC protein, leading to lack of ability of lipid droplets to store fat. Reported symptoms include partial lipodystrophy, severe insulin resistance, fatty liver, acanthosis nigricans, and diabetes.
FPLD type 6 — FPLD type 6 is due to a mutation in the LIPE (lipase E, hormone sensitive type) gene. This form of lipodystrophy is characterized by abnormal subcutaneous fat distribution. Affected individuals may have increased visceral fat, impaired lipolysis, dyslipidemia, hepatic steatosis, systemic insulin resistance, and diabetes. Some patients manifest muscular dystrophy and elevated serum creatine phosphokinase.
Other — FPLD can also be due to a mutation of AKT2 (protein kinase B), a serine/threonine-protein kinase that plays multiple roles in cell signaling, cell growth, and glycogen synthesis as well as insulin-stimulated glucose transport. Lipodystrophy in patients with AKT2 mutations is thought to be due to reduced adipocyte differentiation and dysfunctional post-receptor insulin signaling.
Partial lipodystrophy due to CAV1 mutation — A mutation in CAV1 was identified as a rare cause of partial lipodystrophy [39]. Two cases with different frameshift CAV1 mutations have been reported to have partial lipodystrophy with subcutaneous fat loss in the face and upper body, micrognathia, and congenital cataracts. One case was also associated with abnormal neurologic findings. Diabetes, hypertriglyceridemia, and recurrent pancreatitis were reported in both cases.
Mandibuloacral dysplasia — Mandibuloacral dysplasia (MAD) is an extremely rare, autosomal recessive, premature aging (progeroid) syndrome, which has been reported in approximately 40 case reports [40]. There are two distinctive phenotypes. Type A is considered to be due to mutations of the LMNA gene and involves the loss of subcutaneous fat from the arms and legs but normal or excessive deposition of fat in the face and neck. Type B is characterized by more generalized loss of subcutaneous fat.
These patients carry compound heterozygous mutations in the gene encoding an endoprotease, zinc metalloprotease (ZMPSTE24), on chromosome 1q34 [41-43]. The enzyme is important in posttranslational processing of prelamin A to mature lamin A.
Clinical features — Lipoatrophy is first noted in childhood or early adolescence and is more marked in females [41]. In addition to lipodystrophy, this disorder is characterized by postnatal growth retardation, craniofacial and skeletal abnormalities (mandibular and clavicular hypoplasia, delayed closure of the cranial sutures, acro-osteolysis, joint contractures, bird-like face, dental abnormalities), and cutaneous changes (restrictive dermatopathy, skin atrophy, alopecia, and mottled cutaneous pigmentation). Dysmorphic manifestations and progeroid features become more prominent with time, and the full clinical phenotype is recognizable during the early school years. The patients have normal intelligence.
Metabolic abnormalities — Hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes mellitus, and hyperlipidemia have been reported in some patients. Serum leptin concentration can be low or normal. In one study, individuals with pathogenic variants of the PPARG gene had less prominent fat loss and relatively higher levels of leptin than those with pathogenic variants of the LMNA gene [44].
Focal segmental glomerulosclerosis has been reported in patients with ZMPSTE24 deficiency [45].
Autoinflammatory syndromes — JMP (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy) syndrome of childhood is a rare, autosomal recessive, autoinflammatory syndrome that has been reported in three individual patients from Japan and two families from Mexico and Portugal [1]. Clinical features include hepatosplenomegaly, intermittent fever, calcification of the basal ganglia, and hypergammaglobulinemia. Sequencing of candidate genes demonstrated a loss-of-function mutation of the proteasome subunit, beta-type, (PSMB)-8 gene on chromosome 6. PSMB8 encodes b5i, a catalytic subunit of immunoproteasomes, which mediates proteolysis and generates major histocompatibility complex (MHC) class 1 molecules. Mutations may result in adipose tissue lymphocytic infiltrations and loss of surrounding fat tissue.
CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) is another described syndrome causing partial lipodystrophy, currently reported in six patients, and likely characterized by an autosomal recessive mode of inheritance [1]. Infants present with annular violaceous plaques and recurrent fevers, with eventual loss of adipose tissue from the upper limbs and face. Associated clinical characteristics include hepatosplenomegaly, anemia, eyelid swelling, and calcifications of the basal ganglia. The molecular mechanism of this syndrome remains unknown.
Other syndromes with a component of lipodystrophy — Multiple other syndromes are also linked to lipodystrophy. Several of them have also been identified as laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS, a very rare and uniformly fatal segmental progeroid syndrome with progressive and generalized fat loss), restrictive dermopathy, progeria-associated arthropathy, and atypical progeroid syndrome [46]. The majority of these syndromes are associated with de novo LMNA mutations, yielding a MAD type A (MADA)-type lipodystrophy.
Other progeroid syndromes have also been associated with lipodystrophy. Werner syndrome (short stature, birdlike appearance of the face, and early onset of aging processes) has been linked to homozygous mutations in RECQL2, which encodes a DNA helicase [47]. In contrast, the molecular genetic basis and inheritance patterns have yet to be clarified for the following syndromes: Cockayne syndrome (short stature, photosensitivity, hearing loss, premature aging), carbohydrate-deficient glycoprotein syndrome (nonprogressive ataxia associated with cerebellar hypoplasia, stable developmental delay, variable peripheral neuropathy, and strabismus), SHORT syndrome (S-short stature; H-hyperextensibility of joints and/or hernia [inguinal]; O-ocular depression; R-Rieger anomaly; T-teething delay), and ectodermal dysplasia in association with generalized lipodystrophy acral renal ectodermal dysplasia lipoatrophic diabetes (AREDYLD) syndrome [1].
ACQUIRED PARTIAL LIPODYSTROPHY
Barraquer-Simons syndrome — Approximately 250 patients have been reported with this syndrome (also known as partial acquired cephalothoracic lipodystrophy or acquired partial lipodystrophy). It is characterized by the loss of adipose tissue from the face and upper trunk, with sparing or increased adiposity in the rest of the body (figure 3) [48,49].
Pathogenesis — Most patients with this syndrome have accelerated complement activation and a serum immunoglobulin G, called C3 nephritic factor [50,51], which is thought to cause lysis of adipose tissue expressing adipsin. The heterogeneity in adipsin expression in different sites of adipose tissue may explain selective adipose tissue loss.
Clinical features — This disorder begins in childhood or adolescence, usually in girls and usually after a febrile illness. Fat loss usually occurs over a period of months or years. Autoimmune disorders such as dermatomyositis, hypothyroidism, pernicious anemia, rheumatoid arthritis, temporal arteritis, or mesangiocapillary glomerulonephritis have been reported in these patients [23,52,53]. Some patients have acanthosis nigricans or clinical manifestations of ovarian hyperandrogenism.
Despite the loss of subcutaneous fat in several areas of the body, intramuscular, intraperitoneal, and perirenal fat as well as bone marrow, orbital, and mediastinal fat deposition are normal.
Metabolic abnormalities — The patients may have hyperinsulinemia but not severe insulin resistance. The prevalence of diabetes (approximately 7 percent) is much lower when compared with other types of lipodystrophy (over 50 percent) [49]. Several patients have had serum antinuclear and anti-double stranded DNA antibodies.
Renal disease — As many as 20 percent of patients develop membranoproliferative glomerulonephritis (MPGN), occurring on average 8 to 10 years after initial diagnosis [49]. Presence of renal insufficiency due to MPGN is an important factor in patient prognosis.
Lipodystrophy associated with HIV therapy — Patients with human immunodeficiency virus (HIV) infection who are treated with antiretroviral therapy, and especially HIV-1 protease inhibitors, can develop lipodystrophy, and these drugs are probably the cause (figure 3). HIV-associated lipodystrophy is reviewed separately. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
Localized lipodystrophies — Localized lipodystrophies are characterized by a loss of subcutaneous fat from small areas of the body but not insulin resistance or other metabolic abnormalities. Drug-induced lipodystrophy at the site of injection was a frequent complication of insulin therapy before the availability of purified human insulin but is rare now. Other medications, such as glucocorticoids and antibiotics, can also cause localized lipoatrophy [23].
Other rare causes of localized lipoatrophy include repeated pressure against any body part and lipoatrophy occurring as part of a rare syndrome called lipodystrophia centrifugalis abdominalis infantilis. This is characterized by a centrifugal loss of adipose tissue in the abdomen with somewhat erythematous and scaly changes at the periphery, which usually occurs before the age of three years. More than 50 percent of patients recover spontaneously later in life. Finally, some patients have localized lipoatrophy, ie, lack of adipose tissue in small areas of the trunk or parts of a limb, as an isolated abnormality [23].
LIPODYSTROPHIES AND INSULIN RESISTANCE — The results of studies of the pathogenesis of insulin resistance in the context of lipoatrophy have varied regarding the presence or absence of defects at the level of insulin receptor expression, function, and signaling [54]. (See "Insulin resistance: Definition and clinical spectrum".)
Transgenic mice devoid of white adipose tissue have hypermetabolism, increased appetite, hyperinsulinemia, diabetes, and hepatomegaly, ie, phenotypes remarkably similar to those of humans with generalized lipodystrophy [55,56]. These mice have decreased expression of several molecules, including peroxisome proliferator-activator receptor gamma (PPARG), insulin receptors, insulin receptor substrates 1 and 2, and leptin, whereas expression of tumor necrosis factor alpha is increased [55,56]. Thus, it has been proposed that possible mediators of insulin resistance in lipodystrophy include increased tumor necrosis factor, free fatty acids, or leptin and/or adiponectin deficiency [55-57].
Transplantation of even small amounts of adipose tissue or leptin treatment in diabetic, insulin-resistant mice with lipodystrophy and low serum leptin concentrations results in improved glycemia and decreased serum insulin concentrations [54,58]. In addition, replacing either adiponectin or leptin in an animal model of lipodystrophy, insulin resistance, and the metabolic syndrome improves insulin resistance, whereas replacing both adiponectin and leptin fully normalizes insulin resistance [59]. These results are consistent with the hypothesis that leptin, adiponectin, and/or other substances secreted by adipose tissue are critical mediators of insulin resistance [57], but their role in humans remains to be fully elucidated.
TREATMENT OF LIPODYSTROPHY
General approach — The approach to treatment discussed below is based upon observational or interventional studies and clinical experience.
The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, diabetes, hypertriglyceridemia) is the same as in patients without lipodystrophy. Lifestyle modification (appropriate diet and exercise as needed), metformin, and statins (and/or fibrates) are typically prescribed. Insulin or other antidiabetics (eg, thiazolidinediones, which increase adiponectin levels) can also be used if needed. If metabolic disturbances persist, one could potentially administer metreleptin to patients with acquired or congenital generalized lipodystrophy, as part of a Risk Evaluation and Mitigation Strategy (REMS) program, with careful monitoring. There are few data on the risks and benefits of metreleptin in this patient population. It is likely that more certainty regarding the risk-benefit ratio of using metreleptin will be obtained as results of the REMS program are published.
Cosmetic treatment — Facial reconstruction with free flaps and silicone or other implants have been used to "replace" adipose tissue. Conversely, liposuction or lipectomy has been used for removal of excess fat. The indications for these treatments are not defined, and their effects are variable.
Diet — There is no diet that reverses lipoatrophy, but in general, a low fat diet is recommended. When hypertriglyceridemia is a prominent feature, a balanced low fat, low carbohydrate diet that does not increase serum triglyceride concentrations is preferable. For patients with diabetes, increased physical activity and monitoring carbohydrate intake are important. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education' and "Nutritional considerations in type 2 diabetes mellitus" and "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)
Drugs
Initial treatment — There are few drugs available specifically for lipodystrophy. The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, hyperglycemia, hypertriglyceridemia) is the same as in patients without lipodystrophy. Metformin and statins and/or fibrates are typically prescribed. Thiazolidinediones or other PPARG modulators, which increase adiponectin levels, may also be beneficial. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)
In patients with lipodystrophy and diabetes, both metformin [60] and thiazolidinediones [61-64] may reduce hyperglycemia and hyperlipidemia. Insulin, administered in very high doses and often requiring concentrated insulins, such as U-500, is effective but may fail to provide adequate control of diabetes in cases with extreme insulin resistance [2]; administration of insulin-like growth factor-1 (IGF-1) has led to improvement in glycemic management and insulin resistance in short-term studies, as it does in patients with type 2 diabetes, but is not without side effects [65]. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
A fibrate or the combination of a fibrate and a statin can be given for hypertriglyceridemia, which needs to be controlled to reduce risk of pancreatitis, which can further compromise diabetes control. (See "Hypertriglyceridemia in adults: Management".)
Persistent metabolic disturbances — For patients with acquired or congenital generalized lipodystrophy (not partial lipodystrophy) with persistent metabolic disturbances, one could potentially administer metreleptin, as part of an REMS program, with careful monitoring. The safety and efficacy of metreleptin (leptin analog) have only been evaluated in small numbers of patients with congenital or acquired generalized lipodystrophy [2,66].
Leptin (metreleptin by subcutaneous injection) is approved in Japan as a therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with congenital or acquired lipodystrophy [67]. In 2014, the US Food and Drug Administration (FDA) approved metreleptin for injection, in conjunction with diet, to treat leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy [68]. It is not approved for use in patients with human immunodeficiency virus (HIV)-related lipodystrophy or in patients with metabolic diseases (eg, diabetes mellitus and hypertriglyceridemia) or other lipodystrophies without concurrent evidence of generalized lipodystrophy. Metreleptin should not be used in patients with obesity, and it is not approved for partial lipodystrophy.
●Efficacy – Metreleptin is an analog of human leptin made through recombinant DNA technology. Leptin replacement therapy may be effective in patients with generalized lipodystrophy who are leptin-deficient. In open-label, non-randomized, uncontrolled studies that included small numbers of patients with congenital or acquired generalized lipodystrophy who had diabetes, hypertriglyceridemia, and/or elevated levels of fasting insulin, recombinant leptin administered subcutaneously once or twice daily for up to 12 months to achieve physiologic serum leptin concentrations resulted in significant clinical improvements [2,66,69-76]. The studies showed reductions in glycated hemoglobin (A1C), fasting glucose, and triglycerides. In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis [70]. Satiation (time to voluntary cessation of eating) and satiety (inter-meal interval) also improved with exogenous leptin therapy [71]. Long-term (12 months) recombinant human leptin therapy was effective in treating insulin resistance in two subjects with type 1 diabetes and acquired lipodystrophy with insulin resistance [77].
Randomized trials of metreleptin in patients with various metabolic abnormalities and lipodystrophy are necessary to confirm its therapeutic role, mechanism of action, and longer-term safety.
●Adverse effects – The most common side effects observed in patients treated with metreleptin were fatigue, hypoglycemia, headache, decreased weight, and abdominal pain [2,66]. The development of non-neutralizing and, rarely, neutralizing antibodies to leptin has been reported [72,73]. Development of neutralizing antibodies is the reason underlying the FDA's restriction of metreleptin use exclusively to subjects with generalized lipodystrophy who have minimal, if any, circulating leptin levels to start with. In addition, the development of T-cell lymphoma has been described in patients with acquired lipodystrophy who had immunodeficiency before beginning metreleptin [66,72,76].
●REMS program – Given the reported risk for development of neutralizing antibodies and lymphoma, metreleptin is available in the United States only through an REMS program. Under this REMS program, prescribers must be certified by enrolling in and completing specific training. Pharmacies must also be certified and only dispense metreleptin after receipt of the REMS Prescription Authorization Form for each new prescription. Metreleptin will be accompanied by a medication guide and instructions for use that provide patients with important information about the medication, which will be distributed each time a patient fills a prescription. Health care professionals should carefully consider the benefits and risks of treatment with metreleptin in lipodystrophy.
HIV lipodystrophy — To date, there are several potential treatments for human immunodeficiency virus (HIV) lipodystrophy, including thiazolidinediones (such as pioglitazone), metformin, growth hormone, growth hormone-releasing hormone, and recombinant human leptin, which have been tried in the context of clinical trials (some in blinded, randomized, controlled trials). Treatment of HIV lipodystrophy is discussed in detail separately. (See "Treatment of HIV-associated lipodystrophy".)
SUMMARY
●The lipodystrophic syndromes are a heterogeneous group of congenital or acquired disorders characterized by either complete or partial lack of adipose tissue (lipoatrophy) (table 2). In some of these disorders, there is also the apparent accumulation of fat in other regions of the body. (See 'Introduction' above.)
●The extent of fat loss correlates with the severity of the metabolic abnormalities. Clinically, patients with severe lipodystrophy have severe insulin resistance and a group of unique features, such as severe hyperlipidemia and progressive liver disease (table 1). (See 'Generalized lipodystrophy' above.)
●There is an increasing understanding of the molecular basis for these disorders, and it is likely that multiple molecular defects are responsible (figure 1). (See 'Congenital generalized lipodystrophy' above.)
●The initial treatment of the metabolic disturbances associated with lipodystrophy (eg, diabetes, hypertriglyceridemia) is the same as in patients without lipodystrophy. Lifestyle modification (weight loss, exercise) may reduce serum triglyceride levels and improve glycemic management. There is no diet that reverses lipoatrophy, but in general, a low fat diet is preferred. (See 'General approach' above and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Diabetes education' and "Hypertriglyceridemia in adults: Management", section on 'Treatment goals'.)
A fibrate or the combination of a fibrate and a statin can be given for hypertriglyceridemia. Insulin sensitizers (metformin, thiazolidinediones) may be helpful, and insulin, usually administered in very high doses, is effective but may fail to provide adequate control of diabetes in cases with extreme insulin resistance. (See 'Initial treatment' above.)
For patients with acquired or congenital generalized lipodystrophy with persistent metabolic disturbances, one could potentially administer metreleptin, as part of a Risk Evaluation and Mitigation Strategy (REMS) program, with close monitoring after careful consideration of both the extremely high cost and the risk benefit ratio in each case. (See 'Persistent metabolic disturbances' above.)
