Chapter 71. Lipodystrophy

Lipodystrophies are a heterogeneous group of disorders characterized by selective loss of adipose tissue.1 The extent of fat loss varies, with some patients losing fat from small areas (localized lipodystrophy), whereas others may have more extensive fat loss, for example, involving the extremities (partial lipodystrophy) or the entire body (generalized lipodystrophy). Depending upon the extent of fat loss, patients may be predisposed to develop complications associated with insulin resistance such as, diabetes mellitus, dyslipidemia, hepatic steatosis, acanthosis nigricans, polycystic ovarian disease, and coronary heart disease.2,3 There are two main types of lipodystrophies: (1) genetic and (2) acquired. A detailed classification of various types of lipodystrophies is given in Table 71-1.

In the last decade or so, considerable progress has been made in elucidation of the molecular basis of many types of genetic lipodystrophies. In general, mutations in genes involved in adipocyte differentiation, triglyceride synthesis, lipid droplet formation, and adipocyte survival have been reported to cause lipodystrophies.

Epidemiology

Although the genetic lipodystrophies are rare, recent advances such as improved definition of the phenotypes and elucidation of the molecular defects, have led to increased recognition of these syndromes. Overall, based on literature reports of less than 1,000 patients, the estimated prevalence of genetic lipodystrophies may be less than 1 in a million. The autosomal recessive, congenital generalized lipodystrophy (CGL) has been reported in fewer than 300 patients, with clustering of patients reported from Lebanon and Brazil where there is increased prevalence of consanguinity. The autosomal dominant, familial partial lipodystrophy (FPL) of the Dunnigan variety due to LMNA mutations is the most common with ∼500 patients being reported; autosomal dominant, FPL due to PPARG mutations with ∼30 patients; autosomal recessive, mandibuloacral dysplasia (MAD) due to LMNA mutations in ∼30 patients and due to ZMPSTE24 mutations in eight patients. Affected females are recognized easily and thus are reported more often than males.

Congenital Generalized Lipodystrophy (CGL, Berardinelli–Seip Syndrome)

Etiology and Pathogenesis

This autosomal recessive disorder can be recognized at birth or soon thereafter due to near total lack of body fat. Genome-wide linkage analysis with positional cloning strategy and candidate gene approach have led to the identification of four genetic loci for CGL: (1) 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) gene on chromosome 9q34,4,5 (2) Berardinelli–Seip congenital lipodystrophy 2 (BSCL2) gene on chromosome 11q13,6 (3) caveolin 1 (CAV1) gene on chromosome 7q31,7 and (4) polymerase I and transcript release factor (PTRF) on chromosome 17q21.8 AGPAT2 is a critical enzyme involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate and is expressed highly in the adipose tissue.9 The BSCL2-encoded protein, seipin, plays a role in lipid droplet formation and may also be involved in adipocyte differentiation.10–12 Caveolin 1 is an integral component of caveolae, specialized microdomains seen in abundance on adipocyte membranes. Caveolin 1 binds fatty acids and translocates them to lipid droplets. PTRF is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3.8

Clinical Findings

Patients with CGL present with near total loss of body fat, marked muscularity, prominent subcutaneous veins, acromegaloid features, acanthosis nigricans, hepatomegaly, and umbilical prominence or hernia (Fig. 71-1A, Table 71-2). During childhood, they have a voracious appetite, and accelerated linear growth. Females usually have hirsutism, clitoromegaly, oligoamenorrhea, and polycystic ovaries. Only a few women have had successful pregnancies. Fertility is normal in men. Some of them develop hypertrophic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty.13–15 Metabolic abnormalities related to insulin resistance, such as diabetes mellitus, hyperlipidemia, and hepatic steatosis, may manifest at a young age and are often difficult to control. Patients with BSCL2 mutations lack mechanical fat located in the retro-orbital region, palm, sole, and in periarticular regions as well as metabolically active adipose tissue located in the subcutaneous (sc), intra-abdominal, intrathoracic, and other areas as compared to those with AGPAT2, CAV1, and PTRF mutations where mechanical fat is preserved.7,16 The only reported patient with CAV1 mutation also had short stature and presumed vitamin D resistance.7 Only 21 patients with PTRF mutations have been reported and they have congenital myopathy, increased creatine kinase levels, percussion-induced myoedema, pyloric stenosis, cardiac rhythm disturbances including prolonged QT interval, exercise-induced ventricular tachycardia, and atlantoaxial instability.8,17,18 Patients of Lebanese origin harbor homozygous c.659delGTATC mutation in BSCL2, whereas those of African origin nearly always have either homozygous or compound heterozygous c.IVS4–2A>G mutation in AGPAT2 gene.5,6,13

Familial Partial Lipodystrophy (FPL)

Etiology and Pathogenesis

FPL is an autosomal dominant disorder characterized by fat loss from the limbs with variable fat loss from the trunk and increased sc fat deposition in nonlipodystrophic regions (Fig. 71-1B). It results from heterozygous missense mutations in one of the four genes: (1) lamin A/C (LMNA) on chromosome 1q21–22,19–22 an integral component of nuclear lamina; (2) peroxisome proliferator-activated receptor γ (PPARG) on chromosome 3p25,23–25 a key transcription factor involved in adipocyte differentiation; (3) v-AKT murine thymoma oncogene homolog 2 (AKT2) on chromosome 19q13,26 involved in downstream insulin signaling; and (4) perilipin 1 (PLIN1) on chromosome 15q26, a key component of lipid droplets.27 Adipocyte loss in patients with LMNA mutations may be due to disruption of nuclear envelope function and integrity resulting in premature cell death.

Clinical Findings

Patients with FPL have normal body fat distribution during early childhood, but around the time of puberty, sc fat from the extremities and trunk is progressively lost (Fig. 71-1B). The face, neck, and intra-abdominal region are spared, and often excess fat accumulates there.28,29 Affected men are often more difficult to diagnose clinically, as many normal men are also quite muscular. Women are more severely affected metabolically.30 Some patients with mutations in amino-terminal region of lamin A/C also develop myopathy, cardiomyopathy, and conduction system abnormalities indicative of a multisystem dystrophy.31 On the other hand, others with mutations in the extreme C-terminal region of lamin A may have mild lipodystrophy.32

Nearly 30 patients with FPL due to heterozygous mutations in PPARG gene have been reported so far. They have more marked fat loss from the extremities, especially from distal regions, but the fat from the face, neck, and truncal area is spared. There is increased prevalence of hypertension among the affected subjects. Four subjects from a single family with diabetes and insulin resistance were reported to harbor a heterozygous mutation in AKT2 gene. The female proband had lipodystrophy of the limbs although detailed studies of body fat distribution were not performed. Recently, five FPL patients were reported to harbor PLIN1 mutations.27

Mandibuloacral Dysplasia (MAD) Associated Lipodystrophy

Etiology and Pathogenesis

Mutations in LMNA and zinc metalloproteinase (ZMPSTE24) on chromosome 1p34 also result in autosomal recessive, MAD-associated lipodystrophies.33,34 ZMPSTE24 is involved in posttranslational proteolytic processing of prelamin A to mature lamin A and its deficiency can result in accumulation of prelamin A in cells which is supposed to cause toxicity.

Clinical Findings

Patients with MAD have characteristic skeletal abnormalities including hypoplasia of the mandible and clavicles, acroosteolysis, cutaneous atrophy, progeroid features such as thin beaked nose, hair loss, thin skin with prominent superficial vasculature and mottled hyperpigmentation, delayed dentition and closure of cranial sutures, joint stiffness, and lipodystrophy.35,36 Those with ZMPSTE24 mutations develop clinical manifestations earlier in life, are premature at birth, and can develop focal segmental glomerulosclerosis and calcified skin nodules.37,38

Other Types

Etiology and Pathogenesis

Recently, a single patient with autosomal recessive, FPL phenotype was found to harbor a homozygous missense mutation in cell death-inducing DNA fragmentation factor a-like effector c (CIDEC) gene on chromosome 3p25, involved in lipid droplet formation.39 The histopathology of the sc adipose tissue of the patient revealed multilocular, small lipid droplets in adipocytes. Heterozygous LMNA mutations can also cause variable amount of fat loss in patients with atypical progeroid syndrome40 and generalized loss of sc fat in Hutchinson–Gilford progeria syndrome.41 Another distinct autosomal recessive autoinflammatory lipodystrophy syndrome with a spectrum of disease manifestations (see JMP and CANDLE syndromes below) results from mutations in proteasome subunit, beta-type, 8 (PSMB8).42,43,44a,44b PSMB8 encodes the β5i subunit of the immunoproteasome involved in proteolytic cleavage of immunogenic epitopes presented by major histocompatibility complex, class I molecules.44c The molecular genetic basis of many other genetic lipodystrophy syndromes remains unclear (Table 71-1).

Clinical Findings

We recently reported a novel autosomal recessive syndrome with mandibular hypoplasia, deafness, progeroid features (MDP)-associated lipodystrophy.45 All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. The molecular basis of this syndrome remains unclear. PSMB8 mutations present as a spectrum of clinical manifestations ranging from onset during the first months of life46 to later during childhood.47 Early features are recurrent fevers, annular violaceous plaques, poor weight and height gain, persistent violaceous eyelid swelling, hepatomegaly, arthralgias variable muscle atrophy, and progressive lipodystrophy.46 Histopathologic examination of lesional skin shows atypical mononuclear infiltrates of myeloid lineage and mature neutrophils, and laboratory abnormalities include chronic anemia, elevated acute-phase reactants, and raised liver enzymes with a cytokine profile showing high levels of IP-1, MCP-1, IL-6, and IL-1Ra, consistent with an IFN signaling signature.43 This presentation has been called CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature).46 Older individuals with PSMB8 mutations show joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced (JMP) childhood-onset lipodystrophy.47 Other features of JMP syndrome include hypergammaglobulinemia, elevated erythrocyte sedimentation rate, hepatosplenomegaly, and calcification of basal ganglia.42,44a,44b,47 Other rare syndromes of lipodystrophy include SHORT syndrome, which is characterized by the constellation of Short stature, Hyperextensibility or inguinal hernia, Ocular depression, Rieger anomaly, and Teething delay.48,49 This syndrome is reported to have autosomal recessive as well as dominant inheritance patterns and fat loss is usually confined to the face, upper extremities, and trunk, and sometimes the buttocks.48,49 The autosomal recessive, neonatal progeroid (Weidemann–Rautenstrauch) syndrome presents with generalized loss of body fat and muscle mass and progeroid appearance at birth.50

Despite recognition of acquired lipodystrophies for more than a century, progress in understanding underlying pathogenetic mechanisms has been slow.

Epidemiology

Acquired partial lipodystrophy was recognized approximately 125 years ago and only ∼250 cases of various ethnicities with male-to-female ratio of 1:4 have been reported.51 Acquired generalized lipodystrophy has been reported in less than 100 cases, mostly Caucasians with a male-to-female ratio of 1:3.52 The most common type at present is highly active antiretroviral therapy [containing protease inhibitors (PIs)]-induced lipodystrophy in human immunodeficiency virus (HIV)-infected patients, which is estimated to be affecting more than 100,000 patients in the United States and many more in other countries.53

Acquired Partial Lipodystrophy (APL, Barraquer–Simons Syndrome)

Etiology and Pathogenesis

The exact pathogenesis of sc fat loss remains unclear but there is strong evidence of autoimmune-mediated adipocyte loss as more than 80% of the patients have low levels of complement 3 (C3) and presence of a circulating immunoglobulin (Ig) G, C3-nephritic factor that blocks degradation of the enzyme C3 convertase.51 Loss of fat could be due to C3-nephritic factor-induced lysis of adipocytes expressing factor D.54

Clinical Findings

Acquired partial lipodystrophy develops in most patients before age 15. Patients lose sc fat gradually in a symmetric fashion starting with the face and then spreading downwards. Most of them present with fat loss from the face, neck, upper extremities, and trunk with sparing of sc abdominal fat and lower extremities (Fig. 71-1C). Approximately, 20% of the patients develop mesangiocapillary (membranoproliferative) glomerulonephritis, and some develop drusen.51 Usually, patients do not develop metabolic complications.

Acquired Generalized Lipodystrophy (AGL, Lawrence Syndrome)

Etiology and Pathogenesis

The exact mechanisms of fat loss are not known. In approximately 25% of patients, sc fat loss occurs following development of sc inflammatory nodules that on biopsy reveal panniculitis.52 These lesions initially result in localized fat loss followed by generalized loss of fat. Another 25% of the patients have associated autoimmune diseases such as juvenile dermatomyositis.52 In the remaining patients with the idiopathic variety, multiple unknown mechanisms are likely involved.52 Patients with the panniculitis-associated variety have less severe fat loss and metabolic complications than seen in other types.

Clinical Findings

Acquired generalized lipodystrophies present with variable amount of sc fat loss usually during childhood. Although many patients have generalized loss of fat, some areas are spared in some of them (Fig. 71-1D). Usually, intra-abdominal or bone marrow fat is spared.52 However, patients develop extremely severe hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia, which are difficult to manage.

Highly Active Antiretroviral Therapy (HAART)-Induced Lipodystrophy in HIV-Infected Patients

Etiology and Pathogenesis

Drugs such as HIV-1 PIs and nucleoside analogs are implicated in causing lipodystrophy in HIV-infected patients. Many, but not all, PIs may induce lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of prelamin A.55 Other mechanisms may include PI-induced alteration of expression of key transcription factors involved in lipogenesis and adipocyte differentiation, such as, sterol regulatory element-binding protein 1c, and PPARG.56 PIs also reduce glucose transporter 4 expression, which may be a mechanism for inducing insulin resistance.57 Nucleoside analogs, especially zidovudine and stavudine, may induce fat loss by inhibiting polymerase-γ, a mitochondrial enzyme involved in replication of mitochondrial DNA.58 Since most patients receive multiple antiretroviral drugs together, the individual effects of PIs or nucleoside reverse transcriptase inhibitors (NRTIs) on the phenotype are not clear.

Clinical Findings

Patients infected with HIV usually lose sc fat from the face, trunk, and extremities 2 years or more after receiving PI-containing HAART (Fig. 71-1E; Figs. 71-2A and 71-2B). Fat loss from the face can be so severe as to result in an emaciated appearance. Some of them develop buffalo hump, double chin, and also gain intra-abdominal fat. The fat loss progressively gets worse with ongoing HAART therapy and does not reverse on discontinuation of PIs. Some cases develop diabetes mellitus and many develop combined hyperlipidemia that can predispose the patients to coronary heart disease.59

Localized Lipodystrophy

Etiology and Pathogenesis

This can occur due to sc injection of various drugs, panniculitis, pressure, and other mechanisms.2

Clinical Findings

Localized lipodystrophies present with sc fat loss from a focal region resulting in a dimple or a crater with overlying skin usually unaffected. In some patients, large contiguous or anatomically distinct areas on any region of the body may be involved.2

Lipodystrophies should be strongly suspected in “lean or nonobese” patients who present with premature onset of diabetes, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. These patients should be examined carefully for evidence of loss of sc fat especially from the hips and thighs, as well as excess sc fat deposition in various anatomic regions. For those presenting with generalized lipodystrophy during childhood, pictures at birth should be evaluated for evidence of fat loss. If lipodystrophy phenotype is discovered at or shortly after birth, CGL should be considered; otherwise, the patient may have acquired lipodystrophy.

Patients should be asked about the age of onset and progression of lipodystrophy and other associated manifestations. Taking a detailed family history, including the history of consanguinity, is very important to understand the mode of inheritance of genetic lipodystrophies. Associated autoimmune diseases, especially juvenile dermatomyositis, should be considered in patients with acquired lipodystrophies. Those with localized lipodystrophies should be asked about local injections, trauma, pressure, or other insults. A detailed history of duration and type of antiretroviral therapy should be obtained from HIV-infected patients with lipodystrophy.

The most common cutaneous lesion seen in patients with lipodystrophies is acanthosis nigricans in the axillae, groins, neck, and sometimes even on the knuckles, Achilles tendons, and trunk (Figs. 71-3A and 71-3B). Many patients develop clitoromegaly and hirsutism due to associated polycystic ovarian syndrome. Freckles have been noted in a patient with atypical progeroid syndrome (Fig. 71-3C). Thin beaked nose with loss of the scalp, eyebrow, and axillary hair with cutaneous atrophy and mottled hyperpigmentation can be seen in patients with progeroid syndromes and MAD (Fig. 71-3D) along with acroosteolysis (Fig. 71-3E).35,40,41 Rare patients with MAD develop shiny, taut, atrophic skin with a tendency to breakdown. Eruptive, tuberous, and planar xanthomas are also commonly seen in patients with extreme hypertriglyceridemia (Figs. 71-3F and 71-3G). Loss of sc fat from the soles can result in plantar calluses. Subcutaneous nodules with overlying erythema may be seen in patients with panniculitis.

Laboratory testing depends upon the type of lipodystrophy. Except for patients with localized lipodystrophies, a serum chemistry profile for glucose, lipids, liver enzymes, and uric acid should be obtained. Measurement of fasting and postprandial serum glucose and insulin during an oral glucose tolerance test can provide some estimate of insulin resistance. Serum leptin measurements are not diagnostic, but can help guide treatment decisions as far as investigational human recombinant leptin replacement therapy is concerned. Serum leptin and adiponectin levels are very low in patients with generalized lipodystrophies.60 Patients with acquired partial lipodystrophy should be tested for serum C3 and C3-nephritic factor and annually checked for proteinuria. Radiographs can show presence of lytic lesions in appendicular bones in patients with CGL and skeletal defects in those with MAD. Skin biopsy is useful for patients with localized lipodystrophy or panniculitis-associated varieties.

Distinction between various types of lipodystrophies can be made by physical examination and supported by anthropometry, including measurement of skinfold thickness with calipers at various sites. For in-depth phenotyping of body fat distribution, dual energy X-ray absorptiometry, and a whole body T-1 weighted magnetic resonance imaging can be conducted. For those genetic lipodystrophies whose molecular basis is known, various commercial and research laboratories offer genetic testing. Prenatal genetic testing is also feasible. FPL patients and CGL, type 4 patients who are predisposed to cardiomyopathy should undergo electrocardiography and Holter monitoring to detect arrhythmias and echocardiography to assess cardiac function.

The most important differential diagnosis of generalized lipodystrophies is with conditions presenting with severe weight loss, such as, malnutrition, famine, starvation, anorexia nervosa, uncontrolled diabetes mellitus, thyrotoxicosis, adrenocortical insufficiency, cancer cachexia, HIV-associated wasting, diencephalic syndrome and chronic infections. For partial lipodystrophies, distinction should be made with Cushing syndrome, generalized and truncal obesity, and multiple symmetric lipomatosis (Madelung disease). Patients with MAD and progeroid syndromes-associated lipodystrophies should be differentiated from those with Werner syndrome and leprechaunism (Donahue syndrome).

Some patients develop extreme hypertriglyceridemia and chylomicronemia, which result in acute pancreatitis and even death. Long-term complications of diabetes such as nephropathy, neuropathy, and retinopathy are frequently seen. Many patients develop coronary heart disease and other atherosclerotic vascular complications.30,61 Hepatic steatosis can lead to cirrhosis, necessitating liver transplantation. Sudden death has been reported during childhood in CGL, type 4, likely due to arrhythmias.17 Some patients with APL and membranoproliferative glomerulonephritis may require kidney transplantation.51 Patients with Hutchinson–Gilford progeria syndrome die of acute myocardial infarction or cerebrovascular accidents during teenage years.62 Some patients with atypical progeroid syndrome and FPL, Dunnigan develop cardiomyopathy with valvular dysfunction, congestive heart failure, and arrhythmias requiring pacemaker implantation.31,40 Two adult patients with MAD due to ZMPSTE24 mutations have died of renal failure due to focal segmental glomerulosclerosis.37

The prognosis is dependent upon the type of lipodystrophy. Most of the published cases of CGL have been children and thus there is lack of data about their prognosis. In our experience, some have died of complications of acute pancreatitis, cirrhosis, or developed end-stage renal disease, requiring renal transplantation, and blindness due to diabetic retinopathy. Patients with FPL are also predisposed to metabolic complications and die of atherosclerotic vascular and coronary heart disease or cardiomyopathy and rhythm disturbances. Some patients with MAD have reportedly died during childhood and some died later in the 3rd and 4th decades of complications of renal failure.37,63 Patients with AGL suffer severe metabolic complications. Patients with APL and membranoproliferative glomerulonephritis develop renal failure, but others have normal life span as do those with localized lipodystrophy. HIV-infected patients with lipodystrophy are predisposed to developing coronary heart disease.

Treatment of various types of lipodystrophies is quite challenging. There is no specific treatment available to reverse the loss of body fat. The mainstay of treatment includes cosmetic surgery and management of complications. Patients with partial lipodystrophies can undergo autologous adipose tissue transplantation or implantation of dermal fillers such as hyaluronic acid, calcium hydroxylapatite, silicone, polyacrylamide gels, or poly-L-lactic acid.64 Unwanted excess adipose tissue can be surgically excised or removed by liposuction. Those with CGL can undergo reconstructive facial surgery including fascial grafts from thighs, free flaps from anterolateral thigh, anterior abdomen, or temporalis muscle.1 Support of the parents is critical for preventing unwanted stress and psychological sequelae in children affected with lipodystrophies.

All patients are advised to consume low-fat diets. These diets can improve chylomicronemia in patients with extreme hypertriglyceridemia. However, high carbohydrate intake may also raise very low-density lipoprotein triglyceride concentrations. Increased physical activity should be encouraged to mitigate insulin resistance and its complications except in those with FPL who have cardiomyopathy. Lytic bone lesions in appendicular bones in patients with CGL usually do not pose an increased risk of fractures.

There are no well-controlled trials available to guide treatment decisions about how to manage metabolic complications. For severe hypertriglyceridemia, an extremely low-fat diet along with fibrates and n-3 polyunsaturated fatty acids should be used. Statins can be added if required. Any form of estrogen therapy should be avoided, as it can pose the risk of severe hypertriglyceridemia-induced acute pancreatitis. Diabetes should be managed initially with metformin. Thiazolidinediones should be used with caution in patients with partial lipodystrophies as they can potentially increase unwanted fat deposition in nonlipodystrophic regions.65 Although thiazolidinediones can be useful in FPL patients with PPARG mutations, the data on their efficacy are equivocal.66 If hyperglycemia persists despite using various combinations of oral antidiabetic drugs, insulin therapy should be initiated. For those with extreme insulin resistance, U-500 insulin should be used. No specific therapy is available at this time for hepatic steatosis. Although, subcutaneous metreleptin replacement therapy has been shown to improve diabetes control, hepatic steatosis, and hypertriglyceridemia in markedly hypoleptinemic patients with generalized lipodystrophies,67,68 its effects in patients with FPL so far have been equivocal.69 Metreleptin therapy is investigational and not approved by the Food and Drug Administration of US. Switching PIs and NRTIs strongly associated with lipodystrophy to other regimen may improve dyslipidemia and insulin resistance in HIV-infected patients with lipodystrophy; however, loss of sc fat may not improve.70

With the discovery of the molecular genetic basis of many types of inherited lipodystrophies, prenatal diagnosis can be offered for those families with an affected child. Premarital genetic counseling can be provided to those with high prevalence of consanguinity and CGL such as those from Lebanon and certain regions of Brazil. If the newer HAART regimen (not including PIs) are proven not to be associated with lipodystrophy and are deemed to be efficacious and safe, we may be able to prevent development of lipodystrophy in HIV-infected patients.