Lipodystrophy May Be Related to Cortisol: DHEA Ratio and Serum Alpha-Interferon

     Reported for NATAP by Harvey Bartnof, MD

One of the more interesting posters about lipodystrophy and lipid levels at the Retrovirus Conference was presented by Dr. Nevena Christeff of the Pasteur Institute in Paris, France (abstract 660). Dr. Christeff found that in a prospective study of 31 HIV positive men taking anti-HIV therapy (94% HAART with a PI and NRTI drugs), changes in certain blood markers were associated with worsened, improved or the development of lipodystrophy (LD, fat redistribution). Twenty HIV negative, control men were also included. The men were followed prospectively up to 24 months. At baseline, 20 of those with HIV did not have LD, as determined by CT (computed tomography) scans and physical examination, while the remaining 11 HIV positive men did.

After the follow-up interval, those with LD at baseline were classified as "unchanged" (9 of 20), "aggravated" (worsened, 5 of 20), or "improved" (6 of 20). Those without LD at baseline were classified as "evolution" to LD (2 of 11) or "absence of evolution (9 of 11). Evolution of LD was determined by physical examination by the physician, patient report and "anthropomorphic" measurements including waist-hip ratio and skin-fold thickness.

The major conclusions of the study were that:

• Among men with LD at baseline, worsening of LD was significantly associated with a decrease in blood "DHEA" (dihydroepiandrosterone, steroid hormone precursor), "dramatic increase in cortisol: DHEA ratio," persistently high levels of "interferon alpha," (cytokine, intercellular messenger) and persistently high levels of blood lipids (triglycerides and "VLDL" (very low density lipoprotein cholesterol). (Note cortisol is a natural "stress" hormone released from the adrenal gland on top of each kidney; cortisol measurements were all "fasting" levels).
  
  
• Among men with LD at baseline, LD improvement was significantly associated with an increase in the DHEA levels leading to a normalized cortisol: DHEA ratio, and a normalization of interferon alpha and lipid levels.
  
  
• Among men without LD at baseline, LD development (only 2 patients) was associated with a decrease in DHEA, an increase in the cortisol: DHEA ratio, and increased interferon alpha and lipid levels.
  
  
• Among men without LD at baseline, the absence of developing LD was associated with elevated cortisol, "highly elevated DHEA, leading to a normal cortisol: DHEA ratio," and normal interferon alpha and lipid levels.

The authors concluded, "This study demonstrates that clinical evolution of lipodystrophy and lipid changes associated [with] this syndrome are related to changes in both [the] cortisol: DHEA ratio and interferon-alpha concentrations [and] also confirms our previous observations suggesting that the concomitant action of cortisol, DHEA, particularly the cortisol:DHEA ratio and interferon alpha is one of the mechanisms responsible for lipid perturbations and fat mass distribution in [the] lipodystrophy syndrome.

This study raises more questions than it answers, but might represent the next step in our understanding fat redistribution and lipid alterations in HIV patients taking HAART.* Most of the studies to date about LD are cross-sectional studies; however, this one is prospective. The main question that arises is why did some patients in the current study have or develop abnormal (or normal) levels of cortisol, DHEA and interferon alpha? And, are those abnormal levels a direct cause of fat redistribution or merely a marker that occurs simultaneous to (associated with) LD? The authors reported, "none of the patients tested received any complementary treatment, including glucocorticoids [steroids] or ketoconazole [Nizoral, antifungal drug]." There is an assumption that none were prescribed male sex hormones or growth hormone. But is it possible that some were using illicit steroids outside of the study? Also, DHEA is available as a "dietary supplement" in the US. Were any patients taking supplementary DHEA not known by the study authors? Would taking supplementary DHEA improve or prevent lipodystrophy? Would "stress reduction" interventions that lead to decreased cortisol levels improve or prevent LD? The authors do not address these questions and others that are raised by their findings.

The association with interferon alpha is quite interesting, since this is an approved agent to treat chronic hepatitis C and B and some HIV/HCV co-infected patients have taken it. It is noteworthy that one study at this Conference found a higher rate of LD among HIV/HCV co-infected patients taking HAART than HIV-infected patients taking HAART (see page fill-in). Other potentially confounding factors in the current study include: duration of HAART at study baseline; duration of LD at study baseline; adherence to therapy; CD4 counts and HIV RNA levels (that might correlate with adherence); pre-HAART levels of cortisol, DHEA, interferon alpha and lipids; types of ART in the HAART regimens; types of fat redistribution (lipoatrophy versus fat accumulation); and exercise regimens.

Notwithstanding these limitations and various unanswered questions, the study was rather provocative and certainly will lead to further studies and much discussion.