pseudo-Cushing's syndrome = HIV visceral fat gains?

[Guest guest]

What is Cushing's syndrome? http://endocrine.niddk.nih.gov/pubs/cushings/cushings.htm

I always wondered why fat accumulation related to HIV lipodystrophy looks so much like Cushing Syndrome, yet cortisol levels are normal when measured in patients with lipodystrophy. I think these papers show 1- how HIV can activate corticoid receptors and 2-higher ratios of urinary cortisol: cortisone metabolites can occur in those with lipodystrophy.

In previous studies, we have seen more fat accumulation in patients who have had the biggest increases in CD4 cells from low baseline values. There is probably a change in cortisol metabolism when viral load is brought down to undetectable levels and CD4 cells expand.

Like a recent email we had in this list, many patients experience this "cortisone-like effect" (increased appetite, increased fat weight, sweating, etc) while going through immune reconstitution. Is a pseudo-Cushing's' syndrome possibly occurring due to the removal of HIV as main activator of the glucocorticoid receptor?

I have had these symptoms after being exposed to corticoids for back pain and "crashing " weeks later after I get hypoadrenal. I get really hungry, no amount of food fills me up, I sweat a lot, get fatugued easily, get bloated, etc. Cortisone is a lot like testosterone and most hormones. If someone gives you a shot or pills, your own body's production of cortisone shuts down and stays depressed after days or weeks.

Sorry for the unclear email. I am just thinking out-loud. Any comments?

J. Exp. Med., Volume 189, Number 1, January 4, 1999 51-62

The HIV-1 Virion-associated Protein Vpr Is a Coactivator of the Human Glucocorticoid Receptor

By Tomoshige Kino,* Gragerov,§ B. Kopp, Roland H. Stauber,§ N. Pavlakis,§ and P. Chrousos*

From the * Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Kidney Disease Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, land 20892; and the § Human Retrovirus Section, ABL Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, land 21702

The HIV-1 virion-associated accessory protein Vpr affects both viral replication and cellular transcription, proliferation, and differentiation. We report that Vpr enhances the activity of glucocorticoids in lymphoid and muscle-derived cell lines by interacting directly with the glucocorticoid receptor and general transcription factors, acting as a coactivator. Vpr contains the signature motif LXXLL also present in cellular nuclear receptor coactivators, such as steroid receptor coactivator 1 and p300/CREB-binding protein, which mediates their interaction with the glucocorticoid and other nuclear hormone receptors. A mutant Vpr molecule with disruption of this coactivator signature motif lost its ability to influence transcription of glucocorticoid-responsive genes and became a dominant-negative inhibitor of Vpr, possibly by retaining its general transcription factor-binding activities. The glucocorticoid coactivator activity of Vpr may contribute to increased tissue glucocorticoid sensitivity in the absence of hypercortisolism and to the pathogenesis of AIDS.

In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue

Auteur(s) / Author(s)

SUTINEN J. (1 2 3) ; KANNISTO K. (4) ; KORSHENINNIKOVA E. (5) ; NYMAN T. (5) ; EHRENBORG E. (4) ; ANDREW R. (6) ; WAKE D. J. (6) ; HAMSTEN A. (4) ; WALKER B. R. (6) ; YKI-JÄRVINEN H. (1 4) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, FINLANDE(2) Division of Infectious Diseases, Department of Medicine, University of Helsinki, Helsinki, FINLANDE(3) Division of Infections Diseases, Department of Medicine, University of Helsinki, Helsinki, FINLANDE(4) King Gustaf V Research Institute, Karolinska Institutet, Stockholm, SUEDE(5) Minerva Research Institute, Helsinki, FINLANDE(6) Endocrinology Unit, University of Edinburgh, Edinburgh, Scotland, ROYAUME-UNI

Résumé / Abstract

Aims/hypothesis. Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing's syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11β-hydroxysteroid dehydrogenase type I (11β-HSD1). Methods. In this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry. Results. Patients with lipodystrophy had significantly higher 11β-HSD1 mRNA concentrations (relative to β2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29±0.20 vs 0.09±0.07, p=0.0004) and higher ratios of urinary cortisol: cortisone metabolites. Adipose tissue 11β-HSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen. Conclusions/interpretation. In adipose tissue of patients with HAART-associated lipodystrophy, 11β-HSD 1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11β-HSD1 may explain the pseudo-Cushing's features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target.

Revue / Journal Title

Diabetologia ISSN 0012-186X

Regards, VergelDirectorProgram for Wellness Restorationpowerusa dot orgLooking for a car that's sporty, fun and fits in your budget? Read reviews on AOL Autos.

[Guest guest]

I should have been clearer

I am talking about fat accumulation, not lipoatrophy

If we give Atripla or any other HAART combo to a person with low baseline CD4 cells, some will gain visceral fat and/or fat around the neck

What I am saying is that in those patients, a pseudo Cushing''s (there is a reason to use the word "pseudo" since it is not Cushings totally) can occur that may be caused by dysfunction of the corticoid receptors induced by immune changes and cytokines. That is what we need to be investigating.

In a message dated 8/14/2008 1:42:16 P.M. Central Daylight Time, pozbod@... writes:

"I always wondered why fat accumulation related to HIV lipodystrophy looks so much like Cushing Syndrome, yet cortisol levels are normal when measured inpatients with lipodystrophy. I think these papers show 1- how HIV can activate corticoid receptors and 2-higher ratios of urinary cortisol: cortisone metabolites can occur in those with lipodystrophy. "

Interesting question, .

Some of the superficial changes of lipodystrophy do resemble some, but not all, of the changes seen with Cushing's syndrome. The big belly and skinny legs, in particular, look much the same.

Facial changes in Cushing's are quite different, though. The neck gets fat, and in everyone, not just in a few. The fat is more of a "moon face" look, distinct from the fat accumulation in HIV pozzers.

Also, thinning of the skin, bleeding issues, etc are not seen in HIV.

I do think there are some components of the "metabolic syndrome" that are found both in HIV lipoatrophy and Cushings. These seem analogous to me, but don't think they have the same cause.....they are just both interfering with glucose metabolism . Truncal obesity itself may lead to some of the analogous problems with lipid metabolism and insulin regulation.

Tellingly, when Cushing's is reversed, the fat changes also revert to normal, which is quite distinct from HIV, which seems, at least after a certain point, irreversible. I still think the main cause of lipoatrophy is mitochondrial toxicity, a change not seen in Cushings.

So, I think that the observation that there are similarities is interesting, but I think this represents partial over-lap, and not shared pathology.

JB

Looking for a car that's sporty, fun and fits in your budget? Read reviews on AOL Autos.

[Guest guest]

"I always wondered why fat accumulation related to HIV lipodystrophy looks so much like Cushing Syndrome, yet cortisol levels are normal when measured inpatients with lipodystrophy. I think these papers show 1- how HIV can activate corticoid receptors and 2-higher ratios of urinary cortisol: cortisone metabolites can occur in those with lipodystrophy. "Interesting question, .Some of the superficial changes of lipodystrophy do resemble some, but not all, of the changes seen with Cushing's syndrome. The big belly and skinny legs, in particular, look much the same.Facial changes in Cushing's are quite different, though. The neck gets fat, and in everyone, not just in a few. The fat is more of a "moon face" look, distinct from the fat accumulation in HIV pozzers. Also, thinning of the skin, bleeding issues, etc are not seen in HIV.I do think there are some components of the "metabolic syndrome" that are found both in HIV lipoatrophy and Cushings. These seem analogous to me, but don't think they have the same cause.....they are just both interfering with glucose metabolism . Truncal obesity itself may lead to some of the analogous problems with lipid metabolism and insulin regulation.Tellingly, when Cushing's is reversed, the fat changes also revert to normal, which is quite distinct from HIV, which seems, at least after a certain point, irreversible. I still think the main cause of lipoatrophy is mitochondrial toxicity, a change not seen in Cushings.So, I think that the observation that there are similarities is interesting, but I think this represents partial over-lap, and not shared pathology.JB

[Guest guest]

"I am talking about fat accumulation, not lipoatrophyIf we give Atripla or any other HAART combo to a person with low baseline CD4 cells, many will gain visceral fat and some may gain fat around the neck What I am saying is that in those patients, a pseudo Cushing''s (there is a reason to use the word "pseudo" since it is not Cushings totally) can occur that may be caused by dysfunction of the corticoid receptors induced by immune changes and cytokines. That is what we need to be investigating"Again, I think this is interesting, but there isn't much evidence to suggest that this is the issue, and it has been looked at. Current thinking seems to suggest that there is no real, separate "fat accumulation" syndrome. There is destruction of peripheral fat cells, due to some combination of HIV related inflammation, drug-related mitochondrial dysfunction, and PPAR dysregulation. This leads to wasting.There are still calories in your diet, and if they are to be stored, they are deposited in other fat compartments, which for reasons that are not well understood, are less susceptible to the insults that kill off fat cells elswhere. Therefore, when someone with lipoatrophy gains fat, it is developed in the visceral compartment, cheeks, neck, or shoulders, wherever fat cells remain. This is the cause of fat accumulation, there's just nowhere else to go.JB

[Guest guest]

Visceral Fat accumulation can and does occur in the absence of lipoatrophy and in people who have never taken zerit or azt

In a message dated 8/15/2008 2:05:22 P.M. Central Daylight Time, pozbod@... writes:

Current thinking seems to suggest that there is no real, separate "fat accumulation" syndrome. There is destruction of peripheral fat cells, due to some combination of HIV related inflammation, drug-related mitochondrial dysfunction, and PPAR dysregulation. This leads to wasting.Looking for a car that's sporty, fun and fits in your budget? Read reviews on AOL Autos.

[Guest guest]

Visceral Fat accumulation can and does occur in the absence of lipoatrophy and in people who have never taken zerit or azt

In a message dated 8/15/2008 2:05:22 P.M. Central Daylight Time, pozbod@... writes:

Current thinking seems to suggest that there is no real, separate "fat accumulation" syndrome. There is destruction of peripheral fat cells, due to some combination of HIV related inflammation, drug-related mitochondrial dysfunction, and PPAR dysregulation. This leads to wasting.Looking for a car that's sporty, fun and fits in your budget? Read reviews on AOL Autos.

[Guest guest]

"Visceral Fat accumulation can and does occur in the absence of lipoatrophy and in people who have never taken zerit or azt"It also happens in men who don't have HIV or take medications, too.There are some interesting similarities that could be linked to components of metabolic syndrome, but I think the question of Cushing's and corticosteroid issues was put to rest ages ago.It isn't a bad question, and I would not say that some link is impossible......... It isn't where I would spend time and effort, though.JB

[Guest guest]

"Visceral Fat accumulation can and does occur in the absence of lipoatrophy and in people who have never taken zerit or azt"It also happens in men who don't have HIV or take medications, too.There are some interesting similarities that could be linked to components of metabolic syndrome, but I think the question of Cushing's and corticosteroid issues was put to rest ages ago.It isn't a bad question, and I would not say that some link is impossible......... It isn't where I would spend time and effort, though.JB

[Guest guest]

"It isn't a bad question, and I would not say that some link is impossible......... It isn't where I would spend time and effort, though."Just wanted to re-enforce that-- I some of the physical findings of lipoatrophy/lipodystrophy do bear at least a superficial resemblance to some component parts of Cushing's syndrome. It would not surprise me if there were some relationship, having more to do with shared components of metabolic syndrome and insulin insensitivity, than to a causal relationship to cortisol sensitivity.It is not a bad question, it just doesn't ring true, at this point. Can't say it's wrong, thoughJB