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Lipodystrophy, HIV

Last Updated: January 18, 2006

Synonyms and related keywords: lipohypertrophy, lipoatrophy, human immunodeficiency virus, antiretroviral medication, protease inhibitor, highly active antiretroviral therapy, HAART

AUTHOR INFORMATION Section 1 of 11

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Author: Ali Hendi, MD, Assistant Professor, Department of Dermatology, Mayo Clinic College of Medicine at Jacksonville; Consulting Staff, Mayo Clinic
Coauthor(s): Jason Whalen, MD, Dermatology, University of Pittsburgh Medical Center; Suzan Obagi, MD, Assistant Professor, Department of Dermatology, University of Pittsburgh School of Medicine

Ali Hendi, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Mohs Micrographic Surgery and Cutaneous Oncology, American Society for Dermatologic Surgery, and Phi Beta Kappa

Editor(s): David P Fivenson, MD, Director, Wound Care Service, Department of Dermatology, Henry Ford Health System; David F Butler, MD, Professor, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; and Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Disclosure

INTRODUCTION

Section 2 of 11

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Background: HIV-associated lipodystrophy is a syndrome that occurs in individuals with HIV who are being treated with antiretroviral medications (typically protease inhibitors); this treatment results in lipohypertrophy and lipoatrophy in various anatomic locations.

Lipohypertrophy is characterized by the presence of a hypertrophied 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. In addition, this syndrome is associated with hyperlipidemia, insulin resistance, hyperinsulinemia, and hyperglycemia.

Pathophysiology: Although the precise mechanisms underlying this syndrome are not known, 2 hypotheses based on in vitro studies may explain the pathogenesis of the changes. Most experts presently believe that HIV type 1 (HIV-1) protease inhibitors are implicated. The hypotheses are as follows:

Decreased production of retinoic acid and triglyceride uptake: Protease inhibitors 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, ie, cytoplasmic retinoic acid–binding protein type 1 and low-density lipoprotein receptor–related protein. Inhibition of cytoplasmic retinoic acid–binding protein type 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 lipoprotein receptor–related protein results in hyperlipidemia secondary to the failure of hepatic and endothelial removal of chylomicrons and fatty acids from the circulation.
Prevention of the development of adipocytes: Saquinavir, ritonavir, and nelfinavir directly inhibit the development of adipocytes from stem cells and increase the metabolic destruction of fat in existing adipocytes.

Evidence also suggests decreased insulin sensitivity and beta-cell dysfunction in patients with HIV-associated lipodystrophy. Additionally, researchers have found that estrogen receptor expression is down-regulated in the subcutaneous adipose tissue of these patients. This is due to the effects of highly active antiretroviral therapy (HAART) regimens, including protease inhibitors. Stavudine has been particularly implicated in the apoptosis of adipocytes.

Frequency:

In the US: At present, various studies show that the prevalence of this syndrome is 2-60% in patients who are HIV positive. The most recent 5-year retrospective cohort study of patients with HIV infection who were treated with protease inhibitors demonstrated a 13% prevalence of lipodystrophy. 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.

Internationally: Rates of HIV-associated lipodystrophy vary according to country. For example, the most current prospective cohort study in England demonstrated a 17% prevalence rate after an 18-month follow-up.

Mortality/Morbidity: To the author's knowledge, no studies have been conducted to determine the morbidity and mortality from HIV-associated lipodystrophy.

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, whereas men are more likely to describe fat depletion from the face and extremities.

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

CLINICAL

Section 3 of 11

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History:

HIV-associated lipodystrophy is a progressive disease; its severity is directly proportional to age, duration of disease, and length of protease inhibitor treatment.

Lipodystrophy can be disfiguring cosmetically.

Characteristic physical findings may stigmatize the individual as one with HIV disease.

In addition, the incidence of diabetes mellitus or atherosclerotic cardiovascular disease is increased secondary to hyperglycemia (from insulin resistance) or hyperlipidemia, respectively.

Physical: Pertinent physical findings are limited to the skin.

Lipohypertrophy

The dorsocervical fat pad becomes variably enlarged (ie, buffalo hump).

The circumference of the neck expands by 5-10 cm.

Breast hypertrophy occurs.

Central truncal adiposity results from abdominal visceral fat accumulation (crix belly or protease paunch).

Lipoatrophy

The loss of subcutaneous fat from the cheeks produces an emaciated appearance.

Subcutaneous tissue is depleted from the arms, shoulders, thighs, and buttocks (peripheral wasting), with prominence of the superficial veins in these sites.

Causes: The most common cause of HIV-associated lipodystrophy is HAART, particularly with HIV-1 protease inhibitors, in individuals with HIV infection. The median time from the use of protease inhibitors to the development of lipodystrophy is 18 months.

Prior reports had shown that ritonavir/saquinavir combinations had a stronger association with lipodystrophy than indinavir or nelfinavir. One study revealed that switching from other protease inhibitors to nelfinavir led to an improvement in lipodystrophy symptoms; however, recent findings suggest that the incidence of lipodystrophy does not vary significantly across different protease inhibitors.

The association between ritonavir and hypertriglyceridemia is stronger than that with other protease inhibitors.

Hyperglycemia and hypercholesterolemia did not vary significantly across different protease inhibitors.

An increased risk of lipodystrophy is reported with the addition of nucleoside reverse transcriptase inhibitors (eg, stavudine) to protease inhibitor treatment compared with treatment with only protease inhibitors.

The effect on body structure and lipid profiles is minor when HIV-1 protease inhibitors are switched to non-nucleoside reverse transcriptase inhibitors, such as efavirenz and nevirapine.

Lipodystrophy has been reported in individuals with HIV infection who have never been treated with protease inhibitors.

Other reported risk factors associated with HIV-associated lipodystrophy are as follows:

Lipohypertrophy
- Increasing patient age
- Duration of HAART
- Body mass index gain

Lipoatrophy
- Increasing patient age
- Any use of stavudine
- Use of protease inhibitor for longer than 2 years
- Body mass index loss
- Duration and severity of HIV disease
- White race

DIFFERENTIALS

Section 4 of 11

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Lawrence-Seip Syndrome
Lipodystrophy, Localized

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

Lipotrophy

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

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WORKUP

Section 5 of 11

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Lab Studies:

Hyperlipidemia

Fasting cholesterol level - Greater than or equal to 5.5 mmol/L

Fasting triglyceride level - Greater than or equal to 2 mmol/L

Increased apolipoprotein c-III and apolipoprotein E levels

Hyperglycemia and/or hyperinsulinemia

Fasting C-peptide (proinsulin fragment) level - Greater than 2.5 mmol/L

Decreased fasting glucose (6.1-7.0 mmol/L) level or diabetes mellitus with fasting blood glucose level of (>7.0 mmol/L)

Impaired glucose tolerance (7.8-11.1 mmol/L) or diabetes mellitus (>11.1 mmol/L), as indicated with 2-hour blood glucose results with oral glucose tolerance test

Increased levels of serum plasminogen activator inhibitor type 1, tissue-type plasminogen activator, and soluble type 2 tumor necrosis factor-a receptor

Decreased level of serum insulinlike growth factor binding protein type 1

Increased cortisol levels - Dehydroepiandrosterone (DHEA) ratios with serum and urinary cortisol levels in the reference range

Imaging Studies:

MRIs demonstrate the accumulation of visceral fat in the abdomen compared to subcutaneous fat.

CT scans demonstrate 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: All forms of lipoatrophy are characterized by a loss of subcutaneous fat in fully developed lesions. Fat lobules are miniaturized and associated with prominent microvessels and myxoid alterations. Some of these findings may resemble those of fetal adipose tissue.

TREATMENT Section 6 of 11

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Medical Care: HIV-associated lipodystrophy is a progressive disease that regresses after the withdrawal of protease inhibitor therapy in limited cases. Evidence suggests that switching from stavudine to abacavir or zidovudine causes a slow but continuous increase in the subcutaneous fat mass. Withdrawal of thymidine analogues has shown to be effective for reversing lipoatrophy.

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.

For 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, troglitazone, insulinlike growth factor-1, and DHEA improve glycemic control.

Rosiglitazine has been shown to have positive effects on lipoatrophy, insulin sensitivity, and metabolic indices of HIV-infected patients with lipoatrophy and insulin resistance.

Surgical Care:

Lipohypertrophy: The effects of treatment with liposuction or lipectomy are variable, and recurrence is common.

Lipoatrophy: Free flaps; lipotransfer; or hyaluronic acid, silicone, or other implants are used to replace adipose tissue, especially in facial reconstruction. Polylactic acid has been used as a temporary filler in these patients. Hyaluronic acid provides an efficacious, safe, yet temporary improvement.

Consultations:

Dermatologist - For the evaluation of underlying causes of lipodystrophy

Internal medicine specialist - For the evaluation of underlying causes of lipodystrophy and the management of hyperlipidemia and hyperglycemia

Infectious diseases specialist - For the evaluation of the underlying causes of lipodystrophy and treatment of HIV.

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 diet has been shown to reverse lipohypertrophy or lipoatrophy.

A balanced low-fat low-carbohydrate diet is preferable when hypertriglyceridemia is present.

Activity:

Exercise has been proven to improve insulin sensitivity.

A recent study showed that progressive resistance training with an aerobic component may reduce trunk fat mass.

MEDICATION

Section 7 of 11

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

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.

Referral to a psychiatrist or psychologist may be necessary because of the psychological impact of body shape changes, especially if the discontinuation of HAART is under consideration.

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.

Prognosis:

HIV-associated lipodystrophy progressively worsens as protease inhibitor therapy is continued, and the discontinuation of protease inhibitor 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

Section 9 of 11

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Medical/Legal 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

PICTURES

Section 10 of 11

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Caption: Picture 1. Facial HIV-associated lipodystrophy in a patient receiving highly active antiretroviral therapy.
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Picture Type: Photo

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Lipodystrophy, HIV excerpt