LIPODYSTROPHY SYNDROMES

SYNOPSIS

Lipodystrophies are a group of heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance and its metabolic complications. They are subclassified depending on the degree of fat loss and whether the disorder is genetic or acquired. The two most common genetic varieties include congenital generalized lipodystrophy and familial partial lipodystrophy; and the two most common acquired varieties include acquired generalized lipodystrophy and acquired partial lipodystrophy. Highly active antiretroviral therapy-induced lipodystrophy in HIV-infected patients and drug-induced localized lipodystrophy are other common subtypes. The metabolic abnormalities associated with lipodystrophy include insulin resistance, often leading to diabetes mellitus and its complications, hypertriglyceridemia that may be severe enough to cause acute pancreatitis, and hepatic steatosis that may lead to cirrhosis. The severity of the metabolic abnormalities is usually proportional to the extent of fat loss, with patients with congenital and acquired generalized lipodystrophies developing complications at early ages. Localized lipodystrophy does not have associated metabolic derangements and it is mostly a cosmetic problem. Management of lipodystrophies focuses on preventing and treating metabolic complications. Diet and exercise are an integral part of management. Conventional therapies, including metformin and insulin, are used to treat diabetes mellitus and lipid-lowering drugs are used to treat dyslipidemia. Patients with generalized lipodystrophy have markedly reduced serum leptin levels and metreleptin replacement therapy has been used successfully in such patients to improve metabolic profile.

INTRODUCTION

Lipodystrophies are a group of rare disorders of diverse etiology which are characterized by variable loss of body fat. The loss of body fat may affect nearly the entire body (generalized), only certain body regions (partial) or small areas under the skin (localized). Depending upon the severity and extent of body fat loss, patients may be predisposed to metabolic complications associated with insulin resistance^1,2. These metabolic complications include early onset of diabetes mellitus, hypertriglyceridemia and hepatic steatosis^1–3. In some patients, these metabolic complications are challenging to manage and can lead to complications including diabetic nephropathy and retinopathy, acute pancreatitis (from extreme hypertriglyceridemia and chylomicronemia), hepatic cirrhosis and premature cardiovascular disease. Other common clinical manifestations include polycystic ovarian syndrome (PCOS), acanthosis nigricans as a result of severe insulin resistance, and eruptive xanthomas due to extreme hypertriglyceridemia^1–3.

The loss of body fat can result from underlying genetic defects (genetic lipodystrophies including autosomal recessive or dominant subtypes) or from autoimmune mechanisms (acquired lipodystrophies including generalized or partial subtypes) or drugs (e.g. highly active antiretroviral therapy (HAART)-induced partial lipodystrophy in human immunodeficiency virus (HIV)-infected patients or localized lipodystrophies from insulin and other injected drugs)^1–3. The localized lipodystrophies and lipodystrophy in HIV-infected patients are the most prevalent subtype of lipodystrophies while the other genetic and acquired lipodystrophies are quite rare². Localized lipodystrophies do not predispose to metabolic complications as the loss of fat is trivial; however, other partial or generalized lipodystrophies cause variable predisposition to metabolic complications (Figure 1).

Fig. 1.

Clinical features of patients with various types of lipodystrophies. A. Lateral view of an 8-year-old African-American female with congenital generalized lipodystrophy (also known as Berardinelli-Seip congenital lipodystrophy), type 1 due to homozygous c.377insT (p.Leu126fs*146) mutation in AGPAT2. The patient had generalized loss of sc fat at birth and developed mild acanthosis nigricans in the axillae and neck later during childhood. She had umbilical prominence and acromegaloid features (enlarged mandible, hands and feet). B. Anterior view of a 65-year-old Caucasian female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous p.Arg482Gln mutation in LMNA. She noticed loss of sc fat from the limbs at the time of puberty and later lost sc fat from the anterior truncal region. The breasts were atrophic. She had increased sc fat deposits in the face, anterior neck, suprapubic and vulvar region, and medial parts of the knees. C. Lateral view of an 8-year-old German boy with acquired generalized lipodystrophy. He started experiencing generalized loss of sc fat at age 3 with marked acanthosis nigricans in the neck, axillae and groin. He developed Crohn’s disease at age 11 requiring hemicolectomy at age 13. D. Anterior view of a 39-year-old Caucasian female with acquired partial lipodystrophy (Barraquer-Simons syndrome). She noticed marked loss of sc fat from the face, neck, upper extremities, chest and abdomen at the age of 12 years but later developed increased sc fat deposition in the lower extremities. E. Lateral view of a 39-year-old Caucasian male infected with human immunodeficiency (HIV) virus with protease inhibitor containing highly active antiretroviral therapy induced lipodystrophy. He had marked loss of sc fat from the face and limbs but had increased sc fat deposition in the neck region anteriorly and posteriorly showing buffalo hump. Abdomen was protuberant due to excess intra-abdominal fat. He had been on protease inhibitor containing antiretroviral therapy for more than 7 years.

From Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab 96:3313–25, 2011, with permission.

The major subtypes of lipodystrophy have been described in Table 1. However, it is important to note that given the heterogeneity of manifestations, variable patterns of fat loss and genetic bases that have yet to be identified, all lipodystrophy syndromes cannot be classified into these categories⁴. Regardless of the etiology, patients with generalized lipodystrophy have extremely low serum levels of adipocytokines, such as leptin and adiponectin^5,6, whereas serum leptin and adiponectin levels in those with partial lipodystrophies can range from low to high. Marked hypoleptinemia may induce excessive appetite and can exacerbate metabolic complications of insulin resistance³. This review will cover the major types of lipodystrophy syndromes.

Table 1.

General Classification of Major Lipodystrophy Subtypes

Lipodystrophy Subtype	Main Characteristics
Congenital generalized lipodystrophy (CGL)	Presents with near total loss of body fat at birth or during infancy. Autosomal recessive inheritance.
Familial Partial lipodystrophy (FPL)	Presents with variable loss of sc fat from the upper and lower extremities and the truncal region at puberty or later. Autosomal dominant inheritance.
Acquired generalized lipodystrophy (AGL)	Characterized by gradual loss of sc fat from nearly all over the body. Associated with auto-immune diseases.
Acquired partial lipodystrophy (APL)	Characterized by gradual loss of fat from the upper body, including head, neck, upper extremities and truncal region during childhood. Associated with autoantibodies called complement 3 nephritic factor and in ~20% of patients with membranoproliferative glomerulonephritis.
HAART-induced lipodystrophy in HIV patients	Associated with therapy including HIV-protease inhibitors or nucleoside analogues.
Localized lipodystrophy	Usually due to insulin injections or other injectables such as steroids

Abbreviations: HIV, human immunodeficiency virus; HAART, highly active antiretroviral therapy; sc, subcutaneous

GENETIC LIPODYSTROPHIES

The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL), an autosomal recessive syndrome (Table 2 and 3) and familial partial lipodystrophy (FPLD), mostly an autosomal dominant syndrome (Table 4). There are other extremely rare types which have been reported in approximately 30 patients or less (Table 5). These extremely rare types of genetic lipodystrophies are not discussed further in details in this review.

Table 2.

Subtypes of congenital generalized lipodystrophy (CGL) on the basis of genetic mutations

Subtype	Gene	Molecular Basis	Prevalence
CGL1	AGPAT2	AGPAT enzymes play a key role in biosynthesis of triglycerides and phospholipids in various organs. AGPAT isoform 2 is highly expressed in the adipose tissue.	Most common subtype7,8,10
CGL2	BSCL2	Seipin, encoded by BSCL2, plays a key role in fusion of small lipid droplets in the adipocytes and in adipocyte differentiation.	Second most common subtype 7–9
CGL3	CAV1	Caveolin 1, is an integral component of caveolae, which are present on adipocyte membranes. Caveolae translocate fatty acids and other lipids to lipid droplets.	Only one patient reported11
CGL4	PTRF	PTRF (also known as cavin-1) is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3.	About 20 patients reported12,42,43

Abbreviations: CGL, congenital generalized lipodystrophy; AGPAT2, 1-acylglycerol-3-phosphate O-acyltransferase 2; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CAV1, caveolin 1; PTRF, polymerase I and transcript release factor.

Table 3.

Unique clinical features in CGL subtypes

Affected feature	CGL type 1 (AGPAT2)	CGL type 2 (BSCL2)	CGL type 3 (CAV1)	CGL type 4 (PTRF)
Body fat loss	Only metabolically active adipose tissue is lost. Mechanical adipose tissue preserved.	Both metabolically active and mechanical adipose tissues are lost.	Absent metabolically active adipose tissue. Preserved mechanical and bone marrow adipose tissue.	Absent metabolically active adipose tissue. Preserved mechanical and bone marrow adipose tissue.
Cardiovascular complications	N/A	Cardiomyopathy	N/A	Cardiomyopathy, Catecholaminergic polymorphic ventricular tachycardia, prolonged QT, and sudden death.
Lytic bone lesions in long bones	Most frequent	Occasional	Not reported	Not reported
Gastrointestinal complications	N/A	N/A	Functional mega- esophagus	Congenital pyloric stenosis requiring surgery
Skeletal muscle	N/A	N/A	N/A	Congenital myopathy Developmental delay. Muscle weakness, Percussion-induced myotonia
Other features	N/A	Terato- zoospermia	Short stature, Hypocalcemia, Vitamin D resistance	Low bone density for age, distal metaphyseal deformation with joint stiffness, atlanto-axial instability. Late onset of lipodystrophy in infancy

Abbreviations: CGL, congenital generalized lipodystrophy; N/A, not applicable.

Table 4.

Subtypes of familial partial lipodystrophy (FPLD)

Subtypez	Genetic Mutation	Prevalence
FPLD 1 (Kobberling-type)	Molecular basis unknown	Rare16
FPLD2 (Dunnigan- type)	Missense mutations in LMNA	Most common subtype. More than 500 patients reported17–19
FPLD3	Heterozygous mutations in PPARG	Second most common subtype. About 30–50 patients reported20,21.
FPLD4	Heterozygous mutations in PLIN1	Reported in three families22.
FPLD5	Homozygous nonsense mutation in CIDEC (Autosomal recessive)	One patient reported23
FPLD6	Homozygous mutation in LIPE (Autosomal recessive)	Six patients reported24,25.
AKT2-linked lipodystrophy	Heterozygous mutation in AKT2	Reported in one family26.

Abbreviations: FPLD, familial partial lipodystrophy; LMNA, lamin A/C; PPARG, peroxisome proliferator-activated receptor gamma; PLIN1, perilipin 1; CIDEC, cell death-inducing DFFA-like effector c; LIPE, hormone sensitive lipase; AKT2, v-akt murine thymoma viral oncogene homolog 2.

Table 5.

Extremely rare genetic lipodystrophy syndromes

Lipodystrophy Type	Gene	Molecular Basis	Clinical features
MAD type A	LMNA	Mutations may disrupt nuclear function resulting in premature cell death in many tissues.	Mandibular and clavicular hypoplasia, acro-osteolysis,. Partial lipodystrophy affecting the extremities and trunk44,45.
MAD type B	ZMPSTE24	Mutations result in accumulation of farnesylated prelamin A that can disrupt nuclear function in several tissues.	Mandibular and clavicular hypoplasia, acro-osteolysis,. More generalized loss of fat, premature renal failure, progeroid features46.
JMP/CANDLE	PSMB8	PSMB8 encodes subunit of immunoproteasomes that degrade abnormal/excess proteins in cells.	Joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy. Recurrent fevers, annular erythematous skin lesions, violaceous eyelid swelling, partial lipodystrophy 47,48
SHORT syndrome	PIK3R1	PIK3R1 plays a role in metabolic actions of insulin, mutations associated with insulin resistance.	Variable loss of sc fat, short stature, hyper-extensibility, ocular depression, teething delay49.
MDP syndrome	POLD1	Critical for DNA replication and repair.	Mandibular hypoplasia, deafness, and progeroid features50,51.
Neonatal progeroid syndrome, type A	FBN1	Fibrillin 1	Generalized loss of body fat and muscle mass, and progeroid appearance at birth. Marfanoid habitus52,53.
Neonatal progeroid syndrome, type B	CAV1	Caveolin 1, present on adipocyte membranes, binds fatty acids and translocates them to lipid droplets.	Generalized loss of body fat and muscle mass, and progeroid appearance at birth 54.
Atypical Progeroid Syndrome	LMNA	Different heterozygous, mostly de novo mutations cause nuclear dysfunction.	Partial or generalized loss of sc fat, progeroid features55.
Hutchinson- Gilford progeria	LMNA	Specific de novo mutations induce abnormal splicing and accumulation of truncated farnesylated prelamin A.	Generalized loss of sc fat, progeroid features56.

Abbreviations: MAD, mandibuloacral dysplasia; LMNA, lamin A/C; ZMPSTE24, zinc metalloprotease STE24; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; PSMB8, proteasome subunit beta 8; JMP, Joint contractures, Muscle atrophy, Microcytic anemia and Panniculitis-induced lipodystrophy; SHORT, Short stature, Hyper-extensibility or inguinal hernia, Ocular depression, Rieger anomaly and Teething delay; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; MDP, Mandibular hypoplasia, Deafness, Progeroid features; POLD1, polymerase (DNA) delta 1, catalytic subunit; CAV1, caveolin 1

Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is an autosomal recessive disorder characterized by generalized lack of adipose tissue either at birth or within the first year of life. Patients have prominent musculature and subcutaneous (sc) veins^1,7,8. Most cases are diagnosed at birth or early in childhood because of the striking fat loss, but a few patients without access to regular medical care may be identified later in life.

Patients with CGL can develop hyperphagia as a result of profound leptin deficiency in early childhood, and may have accelerated linear growth, advanced bone age and features suggestive of acromegaly such as enlarged hands, feet and jaw^5,6. Severe metabolic complications, along with hepatomegaly and splenomegaly, develop at an early age. Hyperinsulinemia leads to development of widespread acanthosis nigricans, followed by onset of diabetes mellitus during adolescence^7,8. Diabetes is generally ketosis-resistant. Some patients develop extreme hypertriglyceridemia especially after the onset of insulin-resistant diabetes mellitus and are prone to recurrent attacks of acute pancreatitis^7,8

Hepatic steatosis is common and severe, and can progress to steato-hepatitis, cirrhosis and liver failure⁴. Female CGL patients have additional clinical features including hirsutism, clitoromegaly, irregular menstrual periods, polycystic ovaries, and/or infertility¹. There are four genetically distinct subtypes of CGL^{9,10,7,8,11,12} and besides common clinical features listed above, each one has some peculiar clinical features (Tables 2, 3).

Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) is mostly inherited as an autosomal dominant disorder and is characterized by sc fat loss from both the upper and lower extremities and variable fat loss from the trunk^13,14. These patients have normal fat distribution during childhood, followed by onset around late childhood or puberty of progressive and variable sc fat loss typically from the extremities (causing the musculature to appear prominent), but variably from the anterior abdomen and chest^13,14. Some patients may have small size of the breasts due to reduced or lack of overlying sc fat. At the same time, there is often fat accumulation in the face, neck, perineal and intra-abdominal areas, especially in women. Excess fat accumulation in the dorso-cervical (causing a buffalo-hump), supraclavicular and submental regions gives these patients a “Cushingoid appearance” and many of these patients may be confused with having “Cushing’s syndrome”. These patients may be clinically hard to detect if the fat loss is subtle, and particularly males since many normal men are also quite muscular¹³.

FPLD in women may present with masculinization and menstrual irregularity as well as metabolic complications. Women with FPLD have a high prevalence of polycystic ovarian syndrome (PCOS) compared to the 6–8% prevalence observed in the general population, however infertility is not common¹³. This increased prevalence of PCOS and metabolic complications occurs more frequently in those women who have excess fat accumulation in non-lipodystrophic regions.

As compared to patients with generalized lipodystrophies, hepatic steatosis and acanthosis nigricans is less pronounced, however, hypertriglyceridemia is common and severe, with high risk of acute pancreatitis. In addition, these patients may also develop myopathy, cardiomyopathy and/or conduction system abnormalities¹⁵. There are several genetically distinct varieties of FPLD^16–26, however, the clinical differences between these various subtypes have not been very clear so far (Table 4).

ACQUIRED LIPODYSTROPHIES

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy (AGL), or Lawrence syndrome, is characterized by generalized loss of sc fat that occurs gradually in individuals who are born with a normal fat distribution. The fat loss typically begins in childhood or adolescence, but can rarely begin after 30 years of age²⁷. It can occur over a variable time period, ranging from a few weeks to months or years, and affects all sc areas of the body especially the face and extremities and may include the palms and soles. Orbital and bone marrow fat depots appear to be preserved, while intra-abdominal fat loss is variable. AGL is more frequent in the females than males (3:1)²⁷. AGL patients are predisposed to the same metabolic complications as other patients with lipodystrophies such as insulin resistance associated with diabetes mellitus and hypertriglyceridemia, with hypoleptinemia thought to be contributing to the pathogenesis. Usually these complications are quite severe in these patients. Most of the patients have associated autoimmune diseases, especially juvenile dermatomyositis, or panniculitis (pathologically infiltration of adipose tissue with inflammatory cells of various types resulting in loss of sc fat) (Table 6). In some patients, the underlying mechanism of fat loss is not clear (Idiopathic variety). Usually the metabolic complications are less severe in patients with panniculitis-associated AGL as compared to the other two subtypes.

Table 6.

Classification of AGL

Subtype	Prevalence	Clinical Features
Panniculitis- associated AGL	~ 25%	Initial development of panniculitis (sc inflammatory nodules) followed by localized fat loss when these lesions heal. Ongoing panniculitis later on results in generalized loss of sc 27.
Auto-immune AGL	~ 25%	Gradual generalized fat loss associated with auto-immune diseases, especially juvenile dermatomyositis. Some patients have low levels of serum complement 427,57.
Idiopathic AGL	~ 50%	Gradual generalized sc fat loss of unclear etiology27.

Abbreviations: AGL, acquired generalized lipodystrophy

Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome)

Acquired partial lipodystrophy (APL) is characterized by gradual loss of subcutaneous fat from the upper body, i.e., the face, neck, upper extremities and upper trunk²⁸. Usually the lower abdomen, hips and lower extremities are spared and in fact, after puberty, especially female patients may accumulate excess fat there. APL is more frequent in the females than males (4:1). It is frequently associated with autoimmune diseases. Most patients have a circulating auto-antibody called complement 3 nephritic factor, and have low circulating levels of serum complement 3²⁸. Approximately 20% of the patients develop membrano-proliferative glomerulonephritis and some of these patients develop end stage renal disease requiring renal transplantation. Rare patients have drusen on fundus examination. Metabolic complications are not seen as frequently as in other types of lipodystrophy²⁸.

Highly Active Anti-Retroviral Therapy-induced Lipodystrophy in HIV-infected patients

Lipodystrophy in HIV-infected patients usually occurs after approximately 2 – 4 years of highly active anti-retroviral therapy (HAART) consisting of HIV-1 protease inhibitors (PIs) or nucleoside reverse transcriptase inhibitors (NRTIs) (Table 7)^29,30. It is characterized by the loss of subcutaneous fat from the upper and lower extremities as well as from the face, with increased fat accumulation in the neck, anteriorly and posteriorly, as well as in the upper trunk and intra-abdominal region^29,30. Many PIs have been shown to inhibit zinc metalloprotease, the key enzyme involved in post-translation processing of prelamin A to mature lamin A³¹. Thus, PI-based HAART may result in accumulation of toxic prelamin A. NRTIs may induce lipodystrophy by causing mitochondrial dysfunction³².

Table 7.

Etiology of Drug-induced Lipodystrophy in HIV-infected patients

Type/Etiology	Pathogenesis and molecular basis
PI-induced	PIs inhibit ZMPSTE24, which is important for the correct maturation and processing of prelamin A. Thus, PIs result in accumulation of toxic farnesylated prelamin A31. May also cause dysregulation of transcription factors involved in adipogenesis. They may also inhibit glucose transporter 4 expression leading to insulin resistance.
NRTI-induced	NRTIs (especially stavudine and zidovudine) inhibit mitochondrial polymerase- γ and subsequently cause mitochondrial toxicity32.

Abbreviations: PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; ZMPSTE24, zinc mellatoproteinase STE24; polymerase-γ, polymerase gamma.

Localized Lipodystrophies

Localized lipodystrophies are characterized by loss of fat from small areas, either single or multiple. Sometimes it can affect portions of the limbs or large contiguous areas on the trunk. Patients with localized lipodystrophies do not develop any metabolic abnormalities. There are several etiologies of localized lipodystrophies (Table 8)³³.

Table 8.

Characteristics of different types of localized lipodystrophies

Type	Etiology	Clinical Features
Drug-induced localized lipodystrophy	Insulin therapy (more common before purified/human insulin was available), steroids and antibiotics. High local production of TNF-α may cause dedifferentiation of adipocytes. Other mechanisms include presence of lipases, repeated trauma and/or auto- immune processes.	More common in patients with high titers of anti-insulin antibodies. May have deposition of IgA and C3 locally. Sometimes responds to local corticosteroids.
Pressure-induced localized lipodystrophy	Trauma and decreased perfusion caused by repeated pressure to the same area over a long period of time.	Fat atrophy localized to the area exposed to repeated pressure. This tends to improve when the pressure is avoided.
Panniculitis- associated localized lipodystrophy	Associated with serum ANA or anti dsDNA antibodies; may also have auto-immune diseases such as SLE.	Initial development of panniculitis (sc inflammatory nodules in several areas) followed by localized fat loss when these lesions heal.
Centrifugal lipodystrophy (lipodystrophia centrifugalis abdominalis infantalis)	Cause is unknown and most patients recover spontaneously with no intervention.	More common in Asians. Fat loss spreads in a centrifugal pattern from abdomen and groin area and is associated with peripheral panniculitis. It begins in infancy, stops spreading between the ages of 3 and 8 and then in most cases, resolves by itself.
Idiopathic localized lipodystrophy	Undetermined etiology.

Abbreviations: TNF-α, tumor necrosis factor alpha; IgA, immunoglobulin A; C3, complement 3; ANA, anti-nuclear antibodies; anti dsDNA Ab, anti-double stranded deoxyribonucleic acid antibodies; SLE, systemic lupus erythematous; AGL, acquired generalized lipodystrophy.

Data from Garg A. Lipodystrophies. Am J Med. 2000;108(2):143–152.

MANAGEMENT

The treatment of lipodystrophy is focused on managing the metabolic abnormalities to prevent complications, and cosmetic appearance. Although there is no cure for lipodystrophy, morbidity and mortality can be improved through early intervention. Diet and exercise form an integral part of the treatment plan, although clinical trial data are not available.

A diet with a well-balanced macronutrient composition of about 50 – 60% carbohydrates, 20 – 30% fat and about 10 – 20% protein is appropriate for most patients. Over-feeding should be avoided, especially in infants and children (despite their lack of weight gain), as this can accelerate hepatic steatosis and worsen diabetes and hyperlipidemia. Energy restricted diets are more appropriate in adults, as children with growth and developmental needs may otherwise develop deficiencies.

Exercise, in the absence of contraindications, can help improve metabolic parameters, so patients should be encouraged to be physically active. Those who are predisposed to cardiomyopathy, such as patients with CGL, FPLD2, and progeroid syndromes should undergo a cardiac evaluation before engaging in an exercise program, and should avoid strenuous exercise. To avoid traumatic injuries, patients with severe hepatosplenomegaly and CGL patients with lytic lesions in the bones should avoid contact sports.

Strategies to reduce hypertriglyceridemia include medium chain triglyceride-based formulas in infants³⁴, and very low fat diets in older individuals. Any fat intake should be in the form of cis-mono-unsaturated fats and long chain omega-3 fatty acids. Patients who have developed acute pancreatitis secondary to hypertriglyceridemia, parental nutrition should be administered until they recover and they should subsequently be on an extremely low fat (total dietary fat less than 20 grams/day) diet. In patients who have not reached lipid-lowering goals after diet and lifestyle intervention, lipid-lowering drugs may be used.

Patients with insulin resistance and diabetes mellitus should be treated with conventional therapies, including both oral (metformin is the first-line drug) and insulin. Insulin therapy often provides the mainstay of treatment, and many patients require concentrated forms (such as U-500 regular insulin) because of severe insulin resistance. Whether thiazolidinediones are particularly efficacious in FPLD patients with PPARG mutations remains unclear. Simple sugars should be avoided in favor of high-fiber complex carbohydrates consumed throughout the day in combination with protein and/or fat, to avoid blood glucose spikes. The treatment goals are similar to diabetic patients without lipodystrophy.

Hypertension, if uncontrolled, may be treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, as these medications also have favorable effects on proteinuria. No specific treatments have been shown to be particularly effective for hepatic steatosis or steato-hepatitis associated with lipodystrophy.

Generalized lipodystrophies are characterized by extremely low serum leptin levels⁵, which led to research into recombinant human leptin (metreleptin) as a treatment option³⁵, and since then several long term studies have shown beneficial effects^36–39.

Metreleptin therapy has been shown to improve metabolic abnormalities in generalized lipodystrophy patients, including decreased serum triglyceride levels, increased insulin sensitivity and reduced hepatic steatosis (Table 9)³. It is currently the only drug specifically approved for treatment of lipodystrophy³. It is administered as a daily sc injection⁴⁰, and dose adjustments are made every 3 – 6 months based on metabolic parameters and weight change. The most common side effects include hypoglycemia and injection site reactions such as erythema and/or urticaria. The other side effects include development of neutralizing antibodies to metreleptin, and development of cutaneous T cell lymphomas especially in patients with AGL⁴¹. The precise significance of neutralizing antibodies to leptin remains unclear at this time and some patients with AGL who have never received metreleptin therapy have also been reported to develop lymphomas. Because of paucity of data, approval of metreleptin for different types of lipodystrophy varies by country, depending on their regulatory boards.

Table 9.

Approval and indications of metreleptin therapy.

Type of Lipodystrophy	Approvals	Indications	Clinical considerations
Generalized lipodystrophy (both CGL and AGL)	USA: approved as adjunct to diet for treatment of metabolic complications. Japan: approved Europe: available through compassionate care programs.	First line drug treatment (after diet /exercise intervention) for metabolic and endocrine abnormalities. May prevent comorbidities and metabolic complications in young children.	Decreases hyperphagia, leading to weight loss. May need to be discontinued if excessive weight loss occurs.
Partial lipodystrophy (both FPLD and APL)	USA: not approved. Japan: approved as an adjunct to diet Europe: through compassionate care programs.	May be considered for hypoleptinemic (leptin < 4 ng/mL) patients who have severe metabolic abnormalities such as HbA1c > 8% and/or triglycerides > 500 mg/dL.	Clinical response not as good as in generalized lipodystrophy. Patients with lower leptin levels show the most benefit.

Abbreviations: CGL, congenital generalized lipodystrophy; AGL, acquired generalized lipodystrophy; FPLD, familial partial lipodystrophy; APL, acquired partial lipodystrophy; USA, United States of America; HbA1c, glycated hemoglobin.

Change in body shape caused by lipodystrophy can often lead to psychological distress, and sometimes even physical discomfort, such as from absent fat pads on the feet and buttocks. Patients should be referred to appropriate mental health providers for emotional distress. Plastic surgery may improve appearance in some people, though data are limited. Possible interventions include autologous fat transfer, dermal fillers or muscle grafts to treat facial lipoatrophy; surgical reduction or liposuction of areas with excessive fat; and breast implants for improved cosmetics in women.

KEY POINTS.

• Lipodystrophies are a group of heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance related metabolic complications.

• The two main subtypes of lipodystrophies are genetic and acquired lipodystrophies.

• Highly active antiretroviral therapy-induced lipodystrophy in HIV-infected patients and drug-induced localized lipodystrophy are common subtypes followed by genetic and acquired autoimmune lipodystrophies.

• Common metabolic abnormalities and complications associated with lipodystrophies include insulin resistance and diabetes mellitus, hypertriglyceridemia and hepatic steatosis.

• Management options include diet and exercise, conventional anti-hyperglycemic agents and lipid-lowering therapy, and metreleptin therapy, which is the only drug approved specifically for generalized lipodystrophy.