eMedicine Specialties > Dermatology > Diseases of the Subcutaneous Tissue

Lipodystrophy, HIV

David T Robles, MD, PhD, Dermatologist, Kaiser Permanente Southern California
Jonathan M Olson, BS, University of Washington School of Medicine; Roy M Colven, MD, Associate Professor of Medicine (Dermatology), University of Washington School of Medicine; Section Head of Dermatology, Harborview Medical Center; Attending Physician, Department of Dermatology, Harborview Medical Center, Madison and Medical Specialties Clinics

Updated: Dec 8, 2008

Introduction

Background

HIV-associated lipodystrophy is a syndrome that occurs in individuals with HIV infection who are being treated with antiretroviral medications. Although the term HIV-associated lipodystrophy refers to abnormal central fat accumulation (lipohypertrophy) and localized loss of fat tissue (lipoatrophy), some patients have only lipohypertrophy, some have only lipoatrophy, and, less commonly, a subset of patients exhibits a mixed clinical presentation. Because no uniform morphologic changes occur with HIV lipodystrophy, lipohypertrophy and lipoatrophy are considered distinct entities with different risk factors and metabolic processes underlying their development. In this article, both lipohypertrophy and lipoatrophy are addressed, with a focus on the morphologic changes and underlying pathophysiology of HIV-associated lipodystrophy.

Lipohypertrophy in this syndrome is characterized by the presence of an enlarged dorsocervical fat pad, circumferential expansion of the neck, breast enlargement, and abdominal visceral fat accumulation. Lipoatrophy is exemplified by peripheral fat wasting with loss of subcutaneous tissue in the face, arms, legs, and buttocks. Involvement of the face is most common and carries a social stigma that may negatively affect the quality of life of patients with HIV disease and may pose a barrier to treatment and reduce medical adherence. Other features of HIV lipodystrophy syndrome include hyperlipidemia, insulin resistance, hyperinsulinemia, and hyperglycemia. Patients with HIV lipodystrophy syndrome are at increased risk for the development of atherosclerosis and diabetes mellitus.

The following eMedicine articles address other forms of lipodystrophy:

• Lipodystrophy, Generalized
• Lipodystrophy, Acquired Partial
• Lipodystrophy, Progressive
• Lipodystrophy, Localized

• HIV Pathogenesis Resource Center
• HIV Transmission & Prevention Resource Center

Pathophysiology

Although the precise mechanisms underlying this syndrome are not well understood, several hypotheses based on in vitro and human studies may explain the pathogenesis of the changes. Most experts presently believe that HIV type 1 (HIV-1) protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine and zidovudine, are implicated as follows:

• Decreased production of retinoic acid and triglyceride uptake: PIs have a high affinity for the catalytic site of HIV-1 protease, which shares a 60% sequence homology with 2 proteins involved in lipid metabolism, cytoplasmic retinoic acid–binding protein type 1 (CRABP-1) and low-density lipoprotein receptor–related protein (LDLR-RP). Inhibition of CRABP-1 impairs the production of retinoic acid, leading to decreased fat storage and adipocyte apoptosis with the subsequent release of lipids into the circulation. Inhibition of LDLR-RP results in hyperlipidemia secondary to the failure of hepatic and endothelial removal of chylomicrons and triglycerides from the circulation. 
• Inhibition of mitochondrial DNA (mtDNA) polymerase gamma: NRTIs inhibit mtDNA polymerase gamma, leading to mtDNA depletion, respiratory chain dysfunction, and reduced energy production, which, in turn, causes insulin resistance and secondary dyslipidemia.^1,2 Interestingly, mtDNA is depleted only at normal oxygen levels—hypoxic adipocytes do not take up triglycerides and are resistant to mtDNA-induced damage, except after treatment with NRTIs.³
• Inhibition of lipid metabolism: Some PIs, particularly ritonavir, inhibit cytochrome P450 3A, a key enzyme in lipid metabolism. 
• Prevention of the development of adipocytes: Saquinavir, ritonavir, and nelfinavir (all PIs) directly inhibit the development of adipocytes from stem cells and increase the metabolic destruction of fat in existing adipocytes.

Frequency

United States

Wide variation exists in the literature regarding the prevalence of HIV lipodystrophy. Various studies show the prevalence rate of this syndrome is 2-60% in all patients who are HIV positive; a 2007 meta-analysis found a prevalence rate of 14-40% in HIV-positive patients on HAART.⁶ In untreated patients with HIV infection, a 4% prevalence rate is reported. The incidence of associated new-onset hypercholesterolemia, hypertriglyceridemia, and hyperglycemia is 24%, 19%, and 5%, respectively.

International

Rates of HIV-associated lipodystrophy vary according to country. A prospective cohort study in England demonstrated a 17% prevalence rate after an 18-month follow-up. Variations in the reported prevalence rates are related to a variety of many factors, including age, genetics, HIV medications, and case definition.

Mortality/Morbidity

To the authors’ knowledge, no studies have been conducted to determine the morbidity and mortality from the body morphologic changes of HIV-associated lipodystrophy per se. However, the syndrome associated with insulin resistance and hyperlipidemia is associated with excess morbidity and mortality. 

Race

The risk of lipoatrophy is increased in whites (5.4 odds ratio) compared with blacks.

Sex

Women are at a higher risk of lipodystrophy than men (1.9 relative risk). Women are more likely to report fat accumulation in the abdomen and breasts and hypertriglyceridemia, whereas men are more likely to describe fat depletion from the face and extremities along with hypertension and hypercholesterolemia.⁷

Age

Increasing age is a risk factor in the development of this syndrome.

Clinical

History

• HIV-associated lipodystrophy is a progressive disease; its severity is directly proportional to age, duration of disease, and length of PI and/or NRTI treatment.
• Lipodystrophy can be disfiguring cosmetically, and the physical findings may stigmatize the individual as one with HIV disease; patients are more likely to have decreased body image and quality of life.⁸
• The incidence of diabetes mellitus or atherosclerotic cardiovascular disease is increased secondary to hyperglycemia (from insulin resistance) or hyperlipidemia, respectively.

Physical

Pertinent physical findings:

• Abnormal fat accumulation (lipohypertrophy)  
  • The dorsocervical fat pad (commonly called "buffalo hump") becomes variably enlarged.
  • The circumference of the neck expands by 5-10 cm.
  • Breast hypertrophy occurs.
  • Central truncal adiposity results from abdominal visceral fat accumulation ("Crix belly" [referring to Crixivan, the trade name for indinavir, a PI] or "protease paunch").
  • Symmetric and asymmetric lipomatoses may occur. A rare pattern of lipoaccumulation involving bandlike lipomatosis tissue symmetrically from the breasts, laterally to the axillae, has been reported.⁹
  • Suprapubic fat pads (pubic lipomas) occur in nearly 10% of patients with lipodystrophy.¹⁰
  • The development of multiple angiolipomas is associated with PI therapy.¹¹
• Lipoatrophy
  • Temporal wasting and loss of subcutaneous fat from the cheeks (buccal fat pad) produces an emaciated appearance with prominent nasolabial creases.
  • Subcutaneous tissue is depleted from the arms, shoulders, thighs, and buttocks (peripheral wasting), with prominence of the superficial veins in these sites.

Causes

Part of the early difficulty in establishing the risk factors for HIV-associated lipodystrophy has been agreement on a case definition. Fat accumulation and lipoatrophy are clinically distinct and appear to have separate risk factors. Because most patients are taking a regimen of combined antiretroviral medications, identifying a specific class of antiretroviral associated with lipodystrophy has proven difficult. Despite this, the most common culprits of HIV-associated lipodystrophy appear to be those regimens containing PIs and thymidine analogue NRTIs. 

• Lipodystrophy associated with PIs occurs 2-12 months after starting PI therapy. 
• Previous reports have shown that ritonavir-saquinavir combinations have a stronger association with abnormal fat accumulation than indinavir or nelfinavir. One study revealed that switching from other PIs to nelfinavir led to an improvement in lipodystrophy symptoms.
• The association between ritonavir and hypertriglyceridemia is stronger than that with other PIs. 
• An increased risk of lipodystrophy is reported with the addition of NRTIs (eg, stavudine) to PI treatment compared with treatment with only PIs.
• Of the NRTIs, the thymidine analogues stavudine (d4T) and zidovudine (ZDV, previously known as AZT) are mostly directly implicated in lipodystrophy, particularly lipoatrophy; switching to a different NRTI such as tenofovir or abacavir can produce demonstrable increases in limb fat and can improve lipid profiles.^12,13
• In children with HIV, both thymidine analogue NRTIs and PIs are implicated in the development of lipodystrophy.¹⁴
• Lipodystrophy has been reported in individuals with HIV infection who have never been treated with PIs; possible mechanisms are noted in Pathophysiology.
• Other reported risk factors associated with HIV-associated lipodystrophy are as follows:   
  • Lipohypertrophy  
    • Duration of antiretroviral therapy
    • Female gender
    • Higher body fat at onset of HAART
    • Higher triglyceride levels 
  • Lipoatrophy 
    • Therapy with thymidine analogue NRTIs (eg, stavudine, zidovudine)
    • Lower pretreatment body mass index at onset of HAART
    • Longer duration of HIV infection
    • White race
  • Both 
    • Duration of HAART therapy
    • Increased age
    • Low CD4 count

Differential Diagnoses

Lipodystrophy, Acquired Partial
Lipodystrophy, Generalized
Lipodystrophy, Localized
Lipodystrophy, Progressive

Other Problems to Be Considered

Seip-Berardinelli syndrome
Lawrence syndrome
Dunnigan syndrome
Kobberling syndrome
Barraquer-Simons syndrome
Abdominal carcinoma
Malnutrition

Lipohypertrophy

Cushing disease
Glucocorticoid therapy
Scleredema of diabetes mellitus
Launois-Bensaude syndrome

Lipoatrophy

HIV wasting syndrome
Localized lipodystrophy
Malnutrition
Anorexia nervosa
Hyperthyroidism
Cancer cachexia
Severe chronic infection
Adrenal insufficiency

Workup

Laboratory Studies

Because abnormal glucose and/or lipid metabolism may accompany HIV lipodystrophy, checking the lipid panel and assessing for glucose intolerance is important prior to initiating antiretroviral therapy. Some experts suggest checking these values again at 6 months and then, if the results are normal, yearly.

• Hyperlipidemia
  • Fasting cholesterol level – Greater than 200 mg/dL
  • Fasting triglyceride level - Greater than 150 mg/dL
  • Increased apolipoprotein c-III and apolipoprotein E levels
• Hyperglycemia and/or hyperinsulinemia
  • Diabetes - Fasting plasma glucose level of greater than 126 mg/dL or a 2-hour oral glucose tolerance test result of greater than 200 mg/dL
  • Impaired fasting glucose - Fasting plasma glucose level of 100-125 mg/dL
  • Impaired glucose tolerance: Two-hour oral glucose tolerance test result of 140-199 mg/dL

Imaging Studies

Imaging studies are not generally necessary in the workup of HIV lipodystrophy. Dual energy x-ray absorptiometry scanning, CT scanning, and MRI are limited to research studies to objectively quantify fat abnormalities.

• MRI demonstrates the accumulation of visceral fat in the abdomen compared with subcutaneous fat.
• CT scanning demonstrates abnormal fat proliferation throughout the abdomen in a perivisceral distribution and little subcutaneous fat. Intra-abdominal organs are normal, and no ascites is seen.
• Dual-energy x-ray absorptiometry may demonstrate lumbar spine bone density reduction in association with increased visceral fat accumulation.

Histologic Findings

A skin or subcutaneous fat biopsy is not routinely performed to make a diagnosis of HIV lipodystrophy.

Treatment

Medical Care

No specific medical treatment exists for HIV lipodystrophy. Lipodystrophy is often progressive and, in limited cases, may regress after the withdrawal of PI therapy. Withdrawal of thymidine analogues has shown to be effective for reversing lipoatrophy. Treatment of the underlying metabolic derangements of glucose and lipid metabolism is necessary. The evaluation and management of glucose intolerance, diabetes, and hyperlipidemia are discussed elsewhere (see Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Hypercholesterolemia, Polygenic; and Hypertriglyceridemia)

• For the treatment of hyperlipidemia, fibrates and/or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, as well as DHEA alone, improve the lipid profile.
• For treatment of hyperglycemia, metformin, insulinlike growth factor-1, and DHEA improve glycemic control.
• In some studies, treatment with rosiglitazone resulted in positive effects on lipoatrophy, insulin sensitivity, and metabolic indices of HIV-infected patients with lipoatrophy and insulin resistance. Other studies have yielded conflicting results.¹⁵

Surgical Care

• Lipohypertrophy: The effects of treatment with liposuction or lipectomy are variable, and recurrence is common. Fat harvested during liposuction of the dorsocervical fat pad can be used for autologous fat transfer to facial areas exhibiting lipoatrophy. Facial fat grafting is further addressed in Facial Fat Grafting.
• Lipoatrophy: Free flaps, lipotransfer, or commercial fillers or implants can be used to replace adipose tissue. Poly-L-lactic acid (Sculptra) has been used as a semipermanent injectable filler in these patients. Sculptra is approved by the US Food and Drug Administration for the treatment of facial lipoatrophy in HIV-positive patients. Calcium hydroxylapatite (Radiesse) is a soft-tissue filler consisting of 30% calcium hydroxylapatite microspheres and 30% carboxylmethylcellulose and is also approved for the treatment of facial lipoatrophy in HIV-positive patients. Other filler options include injectable bovine and human collagens, hyaluronic acid, and autologous free fat transfer. See Soft Tissue Implants for more information. 

Consultations

• Dermatologist: This consultation can be useful for an evaluation of the underlying causes of lipodystrophy and for consideration of surgical options. Plastic surgeons also may be considered for fillers, fat transfers, and liposuction.
• Internal medicine or endocrinology specialist: These consultations help for an evaluation of the underlying causes of lipodystrophy and for the management of hyperlipidemia and hyperglycemia.
• Infectious diseases specialist: Consultation is useful for the management of HIV infection.
• Psychiatrist or psychologist: A referral to one of these specialists may be necessary because of the psychological impact of body shape changes. See Further Outpatient Care.

Diet

• No specific diet regimen is used in the management of HIV-associated lipodystrophy. Adequate nutrition and exercise may result in modest improvement in lipodystrophy and improve central obesity.
• A balanced low-fat, low-carbohydrate diet is preferable when hypertriglyceridemia is present.

Activity

• Exercise has been proven to improve insulin sensitivity.
• One study showed that progressive resistance training with an aerobic component may reduce trunk fat mass.¹⁶

Medication

• No specific medical therapy for HIV-associated lipodystrophy has proven to be beneficial.
• An improvement of lipohypertrophy and/or lipoatrophy in individuals treated with human growth hormone, anabolic steroids, naltrexone, and a combination DHEA and cyclo-oxygenase inhibitor has been reported in some cases.
• Pharmacotherapy aimed at managing glucose and/or lipid abnormalities associated with HIV lipodystrophy is important to reduce morbidity and prevent complications. 

Dermal Filler

Poly-L-lactic acid (Sculpura)

Preparation of poly-L-lactic acid particles that are injected into the superficial subdermis, where a fibrous response is elicited.

Dosing

Adult

Each carton contains 2 vials, which can be stored at room temperature

Pediatric

Not established

Interactions

No data

Contraindications

Documented hypersensitivity to any components

Precautions

Pregnancy

Precautions

Most common adverse effects are redness, bruising, or swelling; do not inject in areas with active skin infection or inflammation; avoid injection into blood vessels; delayed occurrence of subcutaneous nodules reported; long-term safety and effectiveness beyond 2 y not investigated; safety during pregnancy, breastfeeding, or in patients <18 y not established

Calcium hydroxylapatite (Radiesse)

Susp of calcium hydroxylapatite (CaHA) microspheres.

Dosing

Adult

Prepackaged, sterilized 1.3-mL syringe

Pediatric

Not established

Interactions

Patients who are using medications that can prolong bleeding (eg, aspirin, warfarin, certain vitamins and supplements) may experience increased bruising or bleeding at injection site

Contraindications

Severe allergies, a history of anaphylaxis, or history or presence of multiple severe allergies or hypersensitivity to any ingredients

Precautions

Pregnancy

Precautions

Most common adverse effects are redness, bruising, or swelling; do not inject in areas with active skin infection or inflammation; avoid injection into blood vessels; microspheres can be seen on radiographs and CT scans; safety during pregnancy, breastfeeding, or in patients <18 y not established.

Follow-up

Further Outpatient Care

Follow-up laboratory testing should include assessments of the following: 

• Viral load and/or CD4 counts to evaluate HIV-disease progression
• Fasting lipid profile to evaluate hyperlipidemia
• Fasting blood glucose and/or glucose tolerance test to evaluate hyperglycemia and insulin resistance

Patients should receive follow-up care every 3-6 months, and the aforementioned laboratory examinations should be performed as necessary. See Treatment for a discussion of therapy when any abnormalities are found.

Patients with HIV lipodystrophy may report feelings of anxiety, depression, loss of self-esteem, poor body image, and social and sexual dysfunction. Importantly, ask about these issues and consider referral to a psychiatrist when appropriate.

Complications

• The incidences of diabetes mellitus and atherosclerotic cardiovascular disease are increased secondary to hyperglycemia (from insulin resistance) and hyperlipidemia, respectively.
• Osteopenia of the lumbar spine may be present in patients with increased visceral fat accumulation.
• Dorsocervical fat pad accumulation may result in neck pain and sleep apnea.

Prognosis

HIV-associated lipodystrophy progressively worsens as PI therapy is continued, and the discontinuation of PI therapy may result in regression.

Patient Education

For excellent patient education resources, visit eMedicine's Sexually Transmitted Diseases Center, Cholesterol Center, and Statins Center. Also, see eMedicine's patient education articles HIV/AIDS, High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize underlying dyslipidemia and/or insulin resistance can make the physician liable when the sequelae of metabolic abnormalities result in a poor outcome.
• Rare cases of persistent granulomatous inflammatory reactions to some fillers have been reported; thus, patients undergoing such treatment should understand possible risks.

Multimedia

Media file 1: Facial HIV-associated lipodystrophy in a patient receiving highly active antiretroviral therapy.

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Keywords

lipohypertrophy, lipoatrophy, lipodystrophy, human immunodeficiency virus, HIV, antiretroviral medication, protease inhibitor, highly active antiretroviral therapy, HAART

Contributor Information and Disclosures

Author

David T Robles, MD, PhD, Dermatologist, Kaiser Permanente Southern California
David T Robles, MD, PhD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Jonathan M Olson, BS, University of Washington School of Medicine
Disclosure: Nothing to disclose.

Roy M Colven, MD, Associate Professor of Medicine (Dermatology), University of Washington School of Medicine; Section Head of Dermatology, Harborview Medical Center; Attending Physician, Department of Dermatology, Harborview Medical Center, Madison and Medical Specialties Clinics
Roy M Colven, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Telemedicine Association, Phi Beta Kappa, and Washington State Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist  Speaking and teaching

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Managing Editor

Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Ali Hendi, MD; Jason Whalen, MD; and Suzan Obagi, MD, to the development and writing of this article.

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