2. OBJECTIVES
The objectives of this talk are to review:
Lipodystrophy Syndromes
Classification/Clinical Features of Lipodystrophy Syndromes
Focus on HIV Related Lipodystrophy
Management of Metabolic Complications
Novel Treatment Options
3. WHAT IS LIPODYSTROPHY?
Definition:
Heterogeneous group of rare acquired and inherited disorders
characterized by selective loss of adipose tissue (lipoatrophy)
In some cases, there is accumulation of fat (lipohypertrophy) in other regions of the
Generalized vs Localized vs Partial
5. WHAT ARE THE
COMPLICATIONS?
• The extent of lipoatrophy correlates with the severity of metabolic
abnormalities.
• The strong bond between fat loss and metabolic abnormalities
demonstrates the significance of adipose tissue as
dynamic endocrine organ.
6. ADIPOSE TISSUE
Highly active metabolic endocrine organ
Mainly composed of adipocytes, but also is an intricate network of connective
tissue, nerve cells, stromovascular cells and immune cells
Adipose tissue is extremely responsive to hormonal signals and to the demands of
the CNS
Secretes sex steroids and glucocorticoids
Insulin and steroids induce transcription factors to prompt the pre-adipocyte to
being differentiation into a standard adipocyte
Once there is excess substrate (“food”) available, lipids droplets form within the adipocyte and
subsequently differentiate the adipocytes level of maturity
7. ADIPOSE TISSUE
Lipid droplets are small organelles
that store triglycerides intracellularly
They form as vesicles within the
endoplasmic reticulum that fuse and
accumulate
As these droplet grow in size and
bulk, the adipocyte increases in bulk,
and this process is essentially
reversed in periods of
fasting/starvation
Normal adipose tissue protects again
lipo- and glucotoxicity (via adipocyte
differentiation)
8. MECHANISM OF DISEASE
Adipocytes provide a place to store lipids; when these cells are absent, lipid
will accumulate in the muscle, liver and other areas of the body
This accumulation of triglycerides is thought to cause metabolic instability,
including insulin resistance, hepatosteatosis, and often cirrhosis
10. CONGENITAL GENERALIZED
LIPODYSTROPHY
Metabolic Abnormalities
Insulin resistance is typically seen in an early age
DM usually develops in teens, ketosis is rare
DM usually refractory to insulin
Hypertriglyceridemia
Pancreatitis
Serum leptin are low
Consistent with near total absence of body fat
12. ASSOCIATED METABOLIC
ABNORMALITIES
Dyslipidemia
See increased LDL and TGs; decreased HDL
Certain PIs may increase TG synthesis, but variability between individual agents
In addition, the increase in visceral fat and reduction in lower body subcutaneous
fat independently are associated with dyslipidemia
13. ASSOCIATED METABOLIC
ABNORMALITIES
Diabetes / Insulin Resistance
Risk is increased in HAART-treated HIV infected patients compared to
HIV-uninfected controls
Thought to be multifactorial in etiology with contributions from:
HIV itself
Patient related factors (genetics, weight, lifestyle)
Antiretroviral therapy
15. TREATMENT
CONSIDERATIONS
Stopping or Switching HAART
AIDS 2000
Design: Prospective study of 26 Causasian men with HIV-1 viral loads under 500
copies/ml while on HAART
Intervention: interruption of HAART for 7 weeks (median)
Measure: lipids, glucose, insulin levels, 24-hr urinary free cortisol
Conclusion: relatively brief interruption of HAART resulted in significant
improvements in total cholesterol, LDL cholesterol, and TG levels. No change
observed in insulin.
16. TREATMENT
CONSIDERATIONS
Switching HAART
Switching has been extensively evaluated in their effect on reversing body
composition and metabolic abnormalities
Abacavir or tenofovir are “less toxic” than stavudine or zidovudine
May require collaboration between HIV specialists, endocrinologists, and
pharmacists
17. TREATMENT
CONSIDERATIONS
Lipoatrophy
TZDs (rosi) has shown efficacy for increasing subcutaneous fat in non-HIV
lipoatrophy
Mixed results for HIV-infected patients
RCT with pioglitazone (48 weeks) showed significant improvement in limb circumference, skin fold
thickness; but change in fat was not perceptible to patients
Statins
Small RCT, pravastatin treated patients for 16 weeks showed increase in limb fat compared to placebo
Uridine
May prevent/reverse mitochondrial toxicity in patients treated with stravudine
Surgery
Facial fillers, reconstruction by plastic surgeons = improvement in QoL, decrease anxiety/depression
Autologous fat transplantation
18. TREATMENT
CONSIDERATIONS
Lipohypertrophy = very difficult to treat
Lifestyle
Only modest improvements have been seen with resistance training, aerobic exercise
Metformin
Decreases visceral fat in HIV-infected patients; variable results
Metformin + exercise appears to have use treating lipohypertrophy
GH Axis
HIV infected patients with body composition changes also show reduced GH mean pulse amplitude, and
may be correlated to central fat accumulation
Surgery
Liposuction can be successful (particularily for dorsocervical fat pad accumulation)
Recurrence is a problem
19. TREATMENT
CONSIDERATIONS
Dyslipidemia
Recommended to use the CCS Lipid Guidelines
Preferred agent: statins
Need to consider risk of pharmacologic interactions
Pravastatin and fluvastatin are safe with ritonavir
Simavastatin and lovastatin are contraindicated
20. TREATMENT
CONSIDERATIONS
Diabetes / Insulin Resistance
Continue to use the CDA guidelines
Insulin sensitizers may be have a role
Reports shown that HbA1c may be inappropriately low in patients with HIV, thereby,
underestimated glycemia
? Due to chronic low-level hemolytic state from viral infection or HAART
Editor's Notes
Type 1 and 2 are responsbiel for 95% of reported cases.
