Lipodystrophy Syndromes Pedro Herranz, MD*, Raul de Lucas, MD , Luis Perez-Espa~ na, MD , Matias Mayor, MD The term ‘lipoatrophy’ refers to partial or complete decrease of adipose tissue, either localized or generalized. Lipoatrophy and lipodystrophy fre- quently coexist in the same individual, and both terms are interchangeable in clinical practice. Lip- odystrophy implies redistribution of fat tissue and, in many cases, may be considered a compensa- tory mechanism as ‘healthy’ or remnant adipose tissue accumulates and increases its metabolic activity to preserve global body functions. Classification of lipodystrophies includes three main groups: generalized, partial (extensive, but not generalized), and localized (limited to isolated areas). Disorders included in all these groups are divided into familial (inherited) or acquired forms (Box 1). 1 Although many aspects of pathogenesis of lipodystrophies remain unclear, recent advances on this matter are remarkable. The genetic basis of many inherited lipodystrophy syn- dromes has been elucidated by means of system- atic characterization of different clinical entities, along with intense research on molecular biology and genetic grounds. 2 Patients who have generalized lipoatrophy, either in familial and acquired forms, show significant risk for development of severe meta- bolic diseases during the first decades of life (Box 2). The pathogenesis of insulin resistance and the other complications in lipoatrophic patients remain unclear. Because they are seen in patients with different types of lipodystrophies and because the extent of fat loss determines the severity of these complications, a common pathogenic mechanism seems likely. Incompe- tence of atrophic fat tissue to store a normal quan- tity of triglycerides would lead to elevation of free serum triglycerides and its further accumulation in liver and skeletal muscle, contributing to insulin resistance. 3 The resultant trend to hyperglycemia would be compensated by secondary hyperinsuli- nemia, but finally the gradual onset of islet amyloidosis and beta-cell atrophy would lead to pancreatic insufficiency and frank type 2 diabetes mellitus. Other associated anomalies, such as polycystic ovarian syndrome, acanthosis nigri- cans, acromegalic trait, and precocious sexual development, may be related to the growth- promoting effects of extreme hyperinsulinemia by means of direct insulin receptors or indirectly through insulin-like growth factor I receptors. 2,4 CONGENITAL LIPODYSTROPHIES Congenital Generalized Lipodystrophy (Berardinelli-Seipp Syndrome) Congenital generalized lipodystrophy 5,6 is a rare autosomal recessive disorder with an estimated worldwide prevalence of 1 in 10 million. Clinical characteristic presentation is almost complete absence of fat tissue, which leads to a generalized muscular appearance from birth. As fat loss prog- resses, areas of mechanical adipose tissue, such as joints, orbits, palms and soles, scalp, perineum, and perirenal regions, remain spared. 7 Affected infants typically show voracious appetite, acceler- ated linear growth, and advanced bone age. Later in childhood, acanthosis nigricans appears in the neck, axillae, groin, and trunk. Abdominal disten- sion caused by hepatomegaly is universal, herald- ing steatosis hepatica with high risk for later cirrhosis. 2 Department of Dermatology, La Paz University Hospital, Universidad Auto ´ noma, Paseo Castellana 261, 28046 Madrid, Spain * Corresponding author. E-mail address: [email protected] (P. Herranz). KEYWORDS Lipoatrophy Lipodystrophy HIV infection AIDS Dermatol Clin 26 (2008) 569–578 doi:10.1016/j.det.2008.05.004 0733-8635/08/$ – see front matter ª 2008 Elsevier Inc. All rights reserved. derm.theclinics.com
Transcript
LipodystrophySyndromes
Pedro Herranz, MD*, Raul de Lucas, MD, Luis P�erez-Espa~na, MD,Matias Mayor, MD
KEYWORDS� Lipoatrophy � Lipodystrophy � HIV infection � AIDS
The term ‘lipoatrophy’ refers to partial or completedecrease of adipose tissue, either localized orgeneralized. Lipoatrophy and lipodystrophy fre-quently coexist in the same individual, and bothterms are interchangeable in clinical practice. Lip-odystrophy implies redistribution of fat tissue and,in many cases, may be considered a compensa-tory mechanism as ‘healthy’ or remnant adiposetissue accumulates and increases its metabolicactivity to preserve global body functions.
Classification of lipodystrophies includes threemain groups: generalized, partial (extensive, butnot generalized), and localized (limited to isolatedareas). Disorders included in all these groups aredivided into familial (inherited) or acquired forms(Box 1).1 Although many aspects of pathogenesisof lipodystrophies remain unclear, recentadvances on this matter are remarkable. Thegenetic basis of many inherited lipodystrophy syn-dromes has been elucidated by means of system-atic characterization of different clinical entities,along with intense research on molecular biologyand genetic grounds.2
Patients who have generalized lipoatrophy,either in familial and acquired forms, showsignificant risk for development of severe meta-bolic diseases during the first decades of life(Box 2). The pathogenesis of insulin resistanceand the other complications in lipoatrophicpatients remain unclear. Because they are seenin patients with different types of lipodystrophiesand because the extent of fat loss determinesthe severity of these complications, a commonpathogenic mechanism seems likely. Incompe-tence of atrophic fat tissue to store a normal quan-tity of triglycerides would lead to elevation of free
Department of Dermatology, La Paz University Hospital,Madrid, Spain* Corresponding author.E-mail address: [email protected] (P. Herranz).
Dermatol Clin 26 (2008) 569–578doi:10.1016/j.det.2008.05.0040733-8635/08/$ – see front matter ª 2008 Elsevier Inc. All
serum triglycerides and its further accumulationin liver and skeletal muscle, contributing to insulinresistance.3 The resultant trend to hyperglycemiawould be compensated by secondary hyperinsuli-nemia, but finally the gradual onset of isletamyloidosis and beta-cell atrophy would lead topancreatic insufficiency and frank type 2 diabetesmellitus. Other associated anomalies, such aspolycystic ovarian syndrome, acanthosis nigri-cans, acromegalic trait, and precocious sexualdevelopment, may be related to the growth-promoting effects of extreme hyperinsulinemia bymeans of direct insulin receptors or indirectlythrough insulin-like growth factor I receptors.2,4
Congenital generalized lipodystrophy5,6 is a rareautosomal recessive disorder with an estimatedworldwide prevalence of 1 in 10 million. Clinicalcharacteristic presentation is almost completeabsence of fat tissue, which leads to a generalizedmuscular appearance from birth. As fat loss prog-resses, areas of mechanical adipose tissue, suchas joints, orbits, palms and soles, scalp, perineum,and perirenal regions, remain spared.7 Affectedinfants typically show voracious appetite, acceler-ated linear growth, and advanced bone age. Laterin childhood, acanthosis nigricans appears in theneck, axillae, groin, and trunk. Abdominal disten-sion caused by hepatomegaly is universal, herald-ing steatosis hepatica with high risk for latercirrhosis.2
Other anomalies include prominent muscledevelopment, acromegalic appearance (ie,enlargement of mandible, hands, and feet) andprecocious development of sexual secondarycharacters. A few patients have hypertrophic car-diomyopathy and mild mental retardation.8
Affected children show severe hyperinsulinemiaand hypertriglyceridemia, which may lead to acutepancreatitis during infancy. Ketosis-resistant dia-betes mellitus may develop during adolescenceor in early adult life.9
Two molecularly distinct forms of congenitalgeneralized lipodystrophy have been identified:types 1 and 2.10 The aberrant gene—1-acylglycerol-3-phosphate O-acyl-transferase-2 (AGPAT2)—islocated on chromosome 9q34.11 Researchershave proposed that this abnormal gene may causelipodystrophy by reducing the synthesis of triglyc-erides in adipose tissue or reducing the bioavail-ability of phosphatidic acid and phospholipidsthat are important for intracellular signaling andmembrane functions.12 Consequently, affectedpatients lack metabolically active adipose tissuein most subcutaneous areas, intra-abdominal
and intrathoracic regions, and bone marrow. Incontrast, the preservation of mechanical adiposetissue in patients with AGPAT2 mutations may becaused by the increased expression of otherAGPAT isoforms in these locations.13
Congenital generalized lipodystrophy type 2 isrelated to mutations in the seipin gene (chromo-some 11q13), which encodes a 398 amino-acidprotein of unknown function.2 The function ofseipin gene is unknown; however, high levels ofexpression in the brain and gonads and low levelsin adipocytes suggest the possibility of a subjacentcentral nervous system defect. This theory corre-lates with the higher prevalence of mild mentalretardation and hypertrophic cardiomyopathy inaberrant seipin carriers than in type 1 cases.2,12
Patients with seipin mutations lack metabolicallyactive and mechanical adipose tissue and do notshow any preserved area of fat tissue.2
Finally, a small proportion of patients with con-genital generalized lipodystrophy (< 20%) do notshow mutations of either the AGPT2 or seipingene, which suggests that additional loci and otherpathogenetic mechanisms may be involved.13
Familial Partial Lipodystrophy
Familial partial lipodystrophies are heterogeneous,autosomal dominant disorders with several dis-tinct phenotypes that are usually accompaniedby hypertrophy of nonaffected fat tissue. The Dun-nigan variety14 is the most prevalent form, withapproximately 200 cases reported and a preva-lence of 1 in 15 million persons.2 Affected patientsshow normal tissue distribution during childhood,but with puberty, subcutaneous fat slowly
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disappears from the arms and legs and later fromthe chest and abdominal wall, giving a muscularappearance that is especially significant inwomen. Fat distribution remains unchanged inthe face and orbits and medullar, intrathoracic,and intra-abdominal regions. Some patients—particularly women—may show fat tissue accumu-lation in the face, neck, supraclavicular area, andintra-abdominal region, which results in a cushin-goid appearance.15
Metabolic complications include early-onsetdiabetes mellitus (after the second decade oflife), marked hypertriglyceridemia with risk ofacute pancreatitis, low levels of high-density lipo-protein cholesterol, and atherosclerotic vasculardisease, which is especially significant in affectedwomen.16
The molecular basis of the Dunningan variety offamilial partial lipodystrophy consists of a mutationin the gene encoding lamins A and C (LMNA),which is located on chromosome 1q21-22.17,18
Since its initial recognition, many different mis-sense LMNA mutations have been identified.15,16
The most frequent missense consists of amino-acid substitution (glutamine, leucine, or tryptophanfor arginine) at position 482.17 Lamins belong tothe intermediate filament family of proteins thatcompose the nuclear lamina, a polymeric structureintercalated between chromatin and the innernuclear membrane. These filaments providestructural integrity to the nuclear membrane andassociate with chromatin and other nuclearproteins.18 Loss of adipoctyes associated withLMNA mutation is possibly caused by disruptionof nuclear function, which results in cell death.Molecular defects in patients who have the Dunni-gan variety also affect fibroblasts.
The site of missense mutations influences clini-cal presentation.17 It has been suggested thatLMNA mutations cause a multisystemic dystrophysyndrome, in which the severity and clinical find-ings vary depending on the site of mutations.2
Potential systemic complaints in these patientswho have lipodystrophy include mild myopathy,muscular dystrophies, cardiomyopathy, and car-diac conduction-system disturbances, as seen ina subgroup of patients with LMNA position 482mutation.19,20 Despite increasing understandingof molecular basis of Dunnigan lipodystrophy,the origin of regional differences in fat loss remainsunknown, provided that expression of lamins Aand C is similar in all body areas.2
Recently, a new subgroup of patients with famil-ial partial lipodystrophy was described by Agarwaland Garb.21 Subjacent genetic defect involvesheterozygous missense mutations—three differenttypes have been identified—in the peroxisome
proliferator-activated receptor-gamma gene(PPARg). Protein encoded by this gene is a ligand-inducible nuclear transcription factor, which ispresent at high levels in adipose tissue and playsan essential role in adipogenesis. Mutations inthe PPARg gene may cause lipodystrophy byinhibiting differentiation of adipocites.2 To date,only a few cases have been described. All ofthem show a similar clinical pattern, however,that consists of peripheral fat loss that mainlyaffects arms, legs, and face and spares the trunk.As in generalized lipodystrophies, insulin resis-tance, hypertriglyceridemia, hypertension, and hir-sutism may coexist.
Finally, some reports refer to cases of familialpartial lipodystrophy that show a pattern of periph-eral fat loss and spare face and trunk, but they arenot associated with specific genetic defects. Addi-tional genetic defects underlying similar clinicalfindings remain to be elucidated.22
Mandibuloacral dysplasia is a rare autosomalrecessive disorder characterized by mandibularand clavicular hypoplasia (bird-like facies, acro-osteolysis, mottled cutaneous pigmentation, den-tal abnormalities, skin atrophy, and alopecia).Patients show two patterns of associated lipodys-trophy: type A presents with loss of fat exclusivelyfrom arms and legs, and type B shows generalizedfat loss. Typical metabolic disorders related togeneralized lipoatrophy may be present.23 Themolecular basis of this type of lipodystrophyremains unclear, although some patients withtype A carry mutations in the LMNA gene.24
From the first reported case in 1928, this form oflipodystrophy has been reported in fewer than100 individuals, most of whom are white women.1
An episode of granulomatous panniculitis, mani-fested as tender, subcutaneous inflammatory nod-ules, precedes the onset of lipoatrophy in 25% ofcases.25,26 Another group of patients shows anyconcomitant autoimmune disease, particularlyjuvenile dermatomyositis, which suggests a com-mon autoimmune basis for both diseases. Halfthe patients with acquired generalized lipodystro-phy do not show either previous panniculitis orautoimmune processes, however.25 The diseasestarts during childhood or adolescence in previ-ously healthy individuals, and large areas of theface, arms, and legs—including the palms and
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soles—are involved, creating a clinical picture sim-ilar to congenital generalized lipodystrophy,although usually less intense. Although some chil-dren show severe, rapid progression of fat loss inweeks to months, other cases evolve slowly ina protracted course that may last for years.1 Met-abolic complications include precocious acantho-sis nigricans, insulin-resistant diabetes mellitus,hyperinsulinemia, hypertriglyceridemia, and lowhigh-density lipoprotein concentration. Hepaticinvolvement is usually more severe than in con-genital cases and leads to cirrhosis as a latesequela in 20% of patients.25
Fig. 1. Severe facial lipoatrophy in a patient withpartial acquired lipodystrophy and systemic lupuserythematosus.
Acquired partial lipodystrophy (Barraquer-Simmonds syndrome, cephalothoraciclipodystrophy) was considered the most frequentform of lipodystrophy before the recognition ofHIV-associated disease. It is a rare disease (ap-proximately 250 cases described worldwide) thatusually affects women (female:male ratio 3–4:1).2
The clinical picture consists of progressive lossof fat that usually begins in infancy or pubertyand involves the face, neck, arms, and thorax ina descending direction. Affected women mayshow variable degrees of fat accumulation on theirhips and legs. Most patients with Barraquer-Simmonds syndrome do not show associatedanomalies in glucose metabolism. In contrast,renal disease may be associated with fat loss,because mesangiocapillary (membranoprolifera-tive) glomerulonephritis is present in approxi-mately 20% of cases. Association of this type oflipodystrophy with autoimmune diseases isremarkable in sporadic cases, including systemiclupus erythematosus (Fig. 1),26 juvenile dermato-myositis,27,28 vasculitis,29,30 and antiphospholipidsyndrome.31
Pathogenesis of Barraquer-Simmonds syn-drome remains unclear, although a previouslymentioned association with renal and autoimmunedisorders suggests some common pathogeneticmechanism.32 Almost all patients show low serumlevels of C3 accompanied by detection of C3nephritic factor (C3NeF), a circulating polyclonalIgG.33,34 C3NeF stabilizes the enzyme C3 conver-tase, causing unopposed activation of the alter-native complement pathway and excessiveconsumption of C3. The synthesis of C3 conver-tase also involves factor D (adipsin), which is pro-duced mainly by adipocytes. It has been proposedthat C3 nephritic factor would induce lysis of adi-pocytes that express factor D as a pathogeneticfactor in this type of lipodistrophy.33,34 Other
questions remain unexplained, such as the selec-tive distribution of fat loss in the upper part of thebody, whereas the rest remains preserved.
HIV-Associated Lipodystrophy
From the mid-1990s, the management of HIV in-fection in developed countries has been basedon complex and active combinations of antiretro-viral drugs belonging to four different pharmaco-logic classes. Highly active antiretroviral therapy(HAART) has resulted in successful control of HIVinfection, as reflected in decreases in plasma HIVviral loads to undetectable levels, increases inCD4 counts, and a significant fall in HIV morbidity(expressed as a decay in opportunistic infectionsand tumors) and mortality.35 Unfortunately, thisscenario of benefits also has a dark side, whichis represented by the appearance of new clinicalproblems associated with chronic HIV infection.36
Lipodystrophy, expressed as fat redistribution,including peripheral lipoatrophy, central fat accu-mulation, and lipomatosis, was first related toHIV infection in 1988and has become one ofmost important problems for HIV-1–infected indi-viduals under HAART.37 Body changes affectadults and infants who take protease inhibitors,nucleoside analog reverse transcriptase inhibitors,or both. Progressive disease is often disfiguringand potentially stigmatizing, which leads to lossof adherence to HAART and may lead to reducedeffectiveness of the drug or higher risk for develop-ment of drug resistance.38,39 Affected patients fre-quently show some associated metabolic features
Fig. 3. Dorsocervical fat accumulation in a patient withHIV lipodystrophy.
Lipodystrophy Syndromes 573
(eg, reduced high-density lipoprotein cholesterol,hypercholesterolemia, hypertriglyceridemia, insu-lin resistance, type 2 diabetes, and lacticacidemia) that might increase the risk for cardio-vascular disease.40–42
As in genetic lipodystrophy syndromes, fatredistribution may precede the development ofmetabolic complications in HIV-positive patientsreceiving HAART. It usually starts in the first 6 to12 months after beginning therapy. Although fattissue abnormalities have been described in vary-ing combinations in this population, they seem toappear in three main forms: (1) generalized orlocalized lipoatrophy of the face (Fig. 2), extre-mities, and buttocks, (2) lipohypertrophy withgeneralized or local fat deposition involving theabdomen, breasts, and supraclavicular, and dor-socervical regions (‘buffalo hump’) (Fig. 3), and(3) a mixed pattern with central adiposity andperipheral lipoatrophy. Sudden development ofangiolipomas soon after the initiation of HAARTis also considered a manifestation of lipodystrophyin some cases.43
Despite years of in-depth research on clinicaland molecular grounds, pathogenesis of HIV-associated lipoatrophy is still unknown. Proteaseinhibitors and nucleoside analogs are thought toinhibit adipocyte differentiation, alter mitochon-drial function in adipocytes, and interfere withleptin, adiponectin, and cytokine expression in ad-ipose tissue of treated patients.44 There is a strongassociation between d-nucleoside reverse tran-scriptase inhibitors, specifically stavudine (d4T),and facial lipoatrophy, most likely through an inter-ference with mitochondrial DNA in a similar patho-genetic mechanism as proposed for multiplesymmetric lipomatosis type 1.45 Protease inhibi-tors are also associated with lipodystrophy. Thepathogenesis of lipid abnormalities related tothese drugs is likely the result of the homologybetween HIV protease and human proteins
Fig. 2. Cadaveric appearance in a patient with late-stage HIV lipoatrophy.
(cytoplasmic retinoic-acid binding protein type 1and low-density lipoprotein receptor-related pro-tein) involved in lipid metabolism. Protease inhibi-tors bind to cytoplasmic retinoic-acid bindingprotein type 1 and interfere with normal adipocyteapoptosis and differentiation. Current researchsuggests that the origin of HIV lipodystrophy ismultifactorial, however.46,47
To date, objective physical or metabolicmarkers that reliably define HIV lipodystrophyhave not been identified, perhaps because of thehigh variability in clinical and metabolic findingsamong affected patients. An objective case defini-tion is still lacking, despite some efforts in this mat-ter. In 2003, a case control study proposed aninteresting model based on clinical, morphologic,and metabolic parameters.48 This study resultedin a high specific and sensitive (> 80%) definitionof lipodystrophy but unfortunately used too com-plex parameters for clinical daily practice. In con-clusion, a simple but sensitive and specificdefinition is still lacking. Consequently, the use ofnonuniform diagnostic criteria has led to substan-tial variations in terms of prevalence (20%–80%),incidence, severity, risk factors, and treatmentresponse among the results of different clinicalseries.
Although the underlying cause of facial lipoatro-phy may be unknown, its psychosocial effects areclear. Loss of facial fat pads is the most stigma-tizing aspect of HIV-associated lipodystrophy.Progressive disfigurement usually results in de-pression and low self-esteem, which lead to poorsocial functioning and social isolation becausepatients feel that their HIV status is unmasked bythe appearance of facial lipoatrophy. Thesefeelings of social discrimination—perceived or
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real—frequently have profound consequences onHIV therapy, specifically in terms of adherence toantiviral drugs.49 The unsupervised cessation oftherapy poses a real risk of increasing drug-resistant strains of HIV-1 or treatment failure.50
Fortunately, there has been an increase in recogni-tion of the impact of facial lipoatrophy and need fortreatment for HIV patients.51
LOCALIZED LIPODYSTROPHIES
Localized lipodystrophies are characterized byregional loss of adipose tissue and absence ofmetabolic complications, as seen in extensive lip-oatrophies. They are mainly related to injectionsites of different drugs, chemical compounds,trauma, previous panniculitis,52 and factitial origins(Fig. 4).1,2 Most cases of drug-induced localizedlipoatrophy are related to the use of subcutaneousinsulin therapy, especially with longer acting prep-arations. Currently, these cases are rare becauseof the use of highly purified soluble insulins.53,54
Other drugs that cause lipodystrophy include glu-cocorticoids, antibiotics, and methothrexate.55,56
Recurrent pressure may explain many cases oflocal lipoatrophy, formerly considered idiopathic.Lipoatrophy semicircularis is characterized by hor-izontal linear depressions on the anterior aspectsof the thighs and is related to repeated micro-traumas, perhaps caused by certain posturalhabits.57,58 Annular lipotrophy presents as a per-sistent, deep pseudosclerotic band that surroundsthe arms or ankles. Lesions may be preceded bylocal inflammatory symptoms and persistent painor may be accompanied by regional arthritis.59
Lipodystrophia centrifugalis abdominalis isa rare form of acquired, localized lipoatrophy thataffects abdominal fat in Asian children—usuallyyounger than 3 years. The process is benign but
usually slowly progresses for several years untillate spontaneous recovery, which is seen in halfthe patients.60
DIAGNOSIS OF FACIAL LIPOATROPHY
There no current consensus about the bestmethod for diagnosing and measuring facial lipoa-trophy. The increased number of HIV-infectedindividuals, along with the great number of der-moaesthetic devices that promise to restore thefacial defects, has generated growing interest inthis area. The measurement of subcutaneous fatseems to be the most relevant parameter for eval-uation of facial lipoatrophy, its progression, andresponse to treatment. Several techniques havebeen used, including radiography, CT, MRI, andultrasound. In contrast with the others, ultrasoundis simple to use, is fast, and does not involvepatient exposure to electromagnetic radiation.These techniques may be used to assess the effi-cacy of new treatments (eg, novel implants suchas poly-L-lactic acid) in patients with lipoatro-phy.61,62 Finally, a new technique that offers prom-ise in measuring the success of soft tissueaugmentation procedures is an advanced photo-graphic three-dimensional microtopography imag-ing system. The new devices are designed todetect changes in topographic facial architecture;they are gaining acceptance among dermatolo-gists, plastic surgeons, and aesthetic physicians.The devices are still not validated as alternativesto ultrasound, however.63
The lack of a uniform grade scale for facial lip-oatrophy is another question to be resolved,because this lack of common criteria to evaluatethe severity of the process obstructs communica-tion among physicians from different specialtiestreating lipodistrophy.64 Some grading scaleshave focused on HIV-associated lipoatrophy48,51
and are of no use in patients who have lipodystro-phy caused by other disorders. Recently, theFacial Lipoatrophy Panel developed a new andpromising grading scale that embraces a widespectrum of lipoatrophy caused by inherited oracquired disorders and aging in the sane popula-tion. This scale includes Grades 1 to 5, with 5being the most severe.64 Patients are classifiedaccording to factors such as facial contour,bony prominence, and visibility of musculature,which are studied in all facial areas: cheeks,temples, and preauricular, perioral, and periorbitalregions. Although still not validated, this gradingscale seems a plausible effort toward consensusin clinical evaluation of all kinds of lipoatrophy,regardless of origin.
Lipodystrophy Syndromes 575
THERAPY FOR LIPODYSTROPHIES
Treatment of lipodystrophy must evaluate threemain problems: cosmetic problems, treatment ofmetabolic disease, and systemic associations. Inaddition to psychologic disturbance caused byloss of fat, especially in generalized cases or pa-tients with severe facial lipoatrophy, metabolic dis-ease is the main cause of morbidity and mortalityin individuals with severe lipodystrophy becausethey are at risk of recurrent pancreatitis fromsevere hypertriglyceridemia, hepatic steatosisleading to cirrhosis, early atherosclerotic vasculardisease, and long-term complications of diabetesmellitus.2 Control of hyperglycemia is essential,and patients may require oral hypoglycemic drugsor insulin at high doses. Metformin may be partic-ularly helpful because of its activity in reduction ofappetite, induction of weight loss, and improve-ment of hepatic steatosis and polycystic ovariansyndrome.65,66 Patients with hyperglycemia orhyperlipidemia must be engaged in a dynamicexercise training program. In the case of signifi-cant hypertriglyceridemia, an extremely low fatdiet must be recommended. Further interventionsinclude treatment with fibrates and high doses offish oil containing n-3 polyunsaturated fats. Useof estrogens and alcohol intake must be precludedin these patients.
Additional interventions in selected, severecases include hepatic transplantation for end-stage liver disease and renal transplantation forend-stage renal disease caused by diabeticnephropathy or mesangiocapillary glomerulone-phritis. Preliminary results of therapy with subcuta-neous recombinant leptin for patients withlipodystrophy and hypoleptinemia are promisingbut still remain in the investigative stage.2
Cosmetic complaints must not be underesti-mated. Facial atrophy may require dermoaesthetictechniques to recover a healthy appearance, withspecial interest in the paranasal area, cheeks, tem-ples, and mandibular areas. Cosmetic surgeryoffers diverse possibilities, including long-lastingimplants and fillers, transplantation of autologousfat, and surgical procedures. Weight loss may bebeneficial for reducing excess adiposity in nonlipo-dystrophic areas. Patients with HIV lipodystrophyor partial familial lipodystrophy may requirerepeated surgical removal of deposits in the neckand dorsolumbar regions by liposuction orlipectomy.67
In view of the growing spectrum of reconstruc-tive procedures, commercial and financial inter-ests, and nonscientific publicity about many ofthese techniques and the fact that many of themare not based on solid medical or experimental
grounds, it is mandatory to counsel patients interms of realistic expectations about the mostappropriate treatment, final aesthetic results, andlong-term adverse effects. This is especiallyimportant in the HIV lipoatrophic population, inwhom psychologic stress may play a negativerole when choosing the appropriate option.
No pharmacologic therapy is currently availableto manage HIV lipodystrophy, and medicationssuch as rosiglitazone,68 pioglitazone, metfor-mine,69 and growth hormone have proved ineffec-tive. Metformine should be used with cautionbecause it can induce lactic acidosis in thesepatients. Diet is not useful unless advised for con-trol of metabolic disorders. Physical exercise maycontribute to improved intra-abdominal accumula-tion and hypertriglyceridemia, but it comes at theexpense of losing subcutaneous fat.70
Several trials focused on switching strategies inHIV therapy and replacing protease inhibitors withefavirenz, nevirapine, or abacavir.71 Unfortunately,these changes did not improve morphologicchanges, as confirmed by anthropometric tests.Subsequently, the relationship between peripherallipoatrophy and nucleoside analogs by means ofmitochondrial toxicity has led to combinationswith decreasing doses or even elimination of thesedrugs, especially stavudine. These ‘nucleosideanalogous-sparing strategies’ have shown prom-ising results, with reduction in the number ofpatients with lipodystrophy and some improve-ment in fat accumulation in individual cases.72,73
Finally, structured interruptions of antiretroviraltherapy are rejected as an ordinary approach forlipodystrophy because of the associated risk ofdisease progression or emergence of resistantviral strains.74 In summary, although changes inHAART may contribute to improved metaboliccomplications, they are not effective enough toreverse lipodystrophy. Most patients seek medicalcounseling to compensate for facial fat loss bymeans of surgical or dermoaesthetic procedures.
Until recently, the only way to restore facial con-tour was by autologous fat transfer.75 Although stilla reasonable risk-benefit option, the technique hassome disadvantages because it offers variableresults and is limited by the availability of patientdonor sites. The transferred fat is also furthermetabolized by the ongoing lipodystrophicprocess.
In this setting, older and newer implants and fill-ing materials—traditionally used for age rejuvena-tion—have been tried for facial restoration inlipoatrophic individuals, most of whom have HIV.Preferred materials belong to semi-permanent(lasting for 1–2 years) or permanent types,because temporary fillers are unacceptable for
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maintained facial restoration. Assuming that theideal filler (well tolerated, biologically inert, nonim-munogenic, easy to use, long-lasting, and notexpensive) does not exist, available candidatesmust show long-lasting efficacy and a goodlong-term safety profile. This seems simple, but itrepresents a real challenge for many marketedmaterials. In recent years, poly-L-lactic acid hasgained favor in patients who have HIV lipodystro-phy because it has advantages over the more per-manent dermal fillers with respect to its safetyrecord and efficacy.76 Its recent approval by theUS Food and Drug Administration in 2005 wasbased on several clinical trials. Data from investiga-tors showed satisfactory improvement in physicaland psychosocial effects after poly-L-lactic acidinjections and an adequate safety profile.77 Todate, similar results from other agents are still lack-ing, awaiting definitive results from ongoing trials.
Use of a biopolymer polyalkilimide filler for HIVlipoatrophy showed satisfactory immediate resultsand safety in a recent study.78 This permanent ma-terial may be considered an attractive option insevere cases of lipoatrophy; however, the numberof patients from published data are still limited,and the long-term safety profile of the producthas yet to be determined. Great caution is advis-able when counseling permanent materials forHIV lipodystrophy, taking into account thatpatients may be at risk for developing delayedallergic or hypersensitivity reactions to foreignmaterials, because they maintain chronic immuneactivation features accompanying the benefits ofCD4 recovery. Other marketed fillers used in facialrestoration, such as liquid silicone79 or calciumhydroxylapatite,80 need further evaluation toexamine treatment efficacy, particularly in patientswho have HIV.81
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