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Lipodystrophy, lactic acidosis/acidemia and mitochondrial toxicity issues
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Written by Cecilia Shikuma, MD, University of Hawaii and ACTG lipodystrophy researcher
Abstracts presented at this conference extended our understanding of the mechanisms inducing lipodystrophy and related metabolic abnormalities. Unfortunately, no new break throughs were reported in therapeutic interventions for lipoatrophy.
TOPICS:
Leptin as a potential replacement therapy for lipoatrophy
Pathophysiologic Mechanisms: in cell, muscles and tissue
Mitochondrial dysfunction in the liver
Modalities for the assessment of lipodystrophy
Genetic polymorphisms and lipoatrophy
Switch Therapy for lipoatrophy
Mitochondrial DNA analysis in blood specimens: using blood vs tissue samples
Longitudinal assessment of body composition over time: ACTG 384 results
Clinical management of lipodystrophy
Reconstructive surgery options for facial lipoatrophy
Leptin as a potential replacement therapy for lipoatrophy
The Monday sessions started with a Keynote Lecture on "Leptin, lipodystrophy and insulin resistance" given by Jeffrey Friedman and a Plenary Lecture by Philip Gorden on "Treatment of non-HIV lipodystrophy with thiazolidinediones and leptin". Leptin is a hormone produced by adipose tissue which acts as a satiety signal to the brain and regulates appetite. Decreased levels are seen as a response to starvation. In non-HIV infected individuals with congenital and acquired forms of lipodystrophy, leptin has been noted to reverse insulin resistance and decrease the elevated serum triglycerides and free fatty acids associated with severe fat lipoatrophy. Leptin may therefore have some efficacy in countering the diabetic tendencies and hyperlipidemia associated with fat loss in HIV patients on HAART. While much of leptin's effect seems to be secondary to a central effect on the hypothalamus, direct effects have been demonstrated on peripheral tissues including T cells. The precise mechanism of action of leptin on fat is unknown. Increased leptin may act to decrease levels of stearoyl-CoA desaturase (SCD1). The decrease in SCD1 may not only block the production of free fatty acids and triglycerides but also lead to increased metabolic disposition of fat by indirectly increasing the activity of CPT1, the enzyme that catalyzes the entry of saturated fatty acyl CoA into the mitochondria for b oxidation.
Pathophysiologic Mechanisms
In tissue culture (test tube testing), adipocyte (fat cells)dysfunction following indinavir may be related to impaired lamin A/C maturation, and disruption of nuclear architecture [Abs 1]. Inhibitory effect on adipocyte differentiation may involve inhibition of glycerol-3-phosphate dehydrogenase activity due to increased levels of TNF-a and IL-6 [Abs 3]. In cultured adipocytes, d4T and ddI did not alter cell differentiation although they moderately impaired lipid accumulation and promoted apoptosis. Cell loss was further increased when stavudine was used in combination with indinavir. However d4T and ddI partly reversed the indinavir-induced alterations of cell differentiation and insulin resistance, possibly by restoring the intra-nuclear penetration of SREBP-1 [Abs 9]. Interpretation of anti-retroviral medication effects in cell culture is difficult as results are dependent on such variables as type of cell culture, and on the timing, concentration and duration of administration of drugs. It appears clear however that both NRTIs and PIs appear to have effects on adipocyte metabolism and that various agents in each class may have unique and different effects.
Lipoprotein lipase (LPL) mRNA expression is reduced in thigh subcutaneous tissue from HIV-1 infected subjects with subcutaneous lipoatrophy [Abs 4], suggesting a defect in triglyceride uptake by adipocytes in these individuals.
An interesting modality for possibly assessing reduced oxidative enzyme function by assessing the body's ability to extract O2 for its use was presented by WT Cade, SouthWest Texas State University [Abs 16]. Utilizing a breathing apparatus, a maximal exercise threadmill test to exhaustion and calculations based on a rearrangement of the indirect Fick equation (oxygen consumption = cardiac output x difference between Arterial to Venous O2 level) the authors noted that the peak oxygen extraction was diminished in subjects infected with HIV taking HAART compared with HIV-infected subjects not taking HAART and non-infected controls, raising the intriguing question as to whether this was due to decreases in mitochondrial function.
Using positron emission tomography (PET) [Abs 17], b-oxidation was studied in skeletal muscle. No evidence of impaired b-oxidation was found in individuals with lipodystrophy and it was suggested that the high free fatty acids in the blood was the result of increased release of fatty acids rather than the failure of skeletal muscle to metabolize and utilize this energy source.
Two abstracts [Abs 32, 33] addressed the potential role of adiponectin in lipodystrophy and associated metabolic dysfunction. Adiponectin is a newly discovered hormone secreted by fat cells that appear to reverse the effects of insulin resistance in non-HIV models of diabetes. O Tong et al [Abs 32] reported that concentrations of this hormone were significantly reduced in HIV infected subjects with lipodystrophy and was strongly correlated with adipose tissue redistribution, hyperinsulinemia, insulin resistance and dyslipidemia. They speculated that reduction in adiponectin might contribute to the metabolic abnormalities in lipodystrophic individuals and that replacement might be used as a therapeutic strategy.
In a retrospective cohort study and analysis of 137 repository plasma samples, pretreatment leptin levels, but not BMI, predicted risk of lipoatrophy [Abs 78].
Mitochondrial dysfunction in the liver
Bernard Fromenty gave a plenary lecture on "Mitochondrial dysfunction in the liver: from drugs to NASH." b oxidation is a process whereby fatty acids are metabolized. Effective mitochondrial b oxidation require the availability of Coenzyme A and L carnitine, the ability to reoxidize NADH, and functional integrity of the mitochondria. Drugs that inhibit b oxidation can be classified as those that have a direct toxic effect on b oxidation with enzymatic inhibition and/or sequestration of coenzyme A or carnitine, those that accumulate in the mitochondria and interact and affect the OXPHOS components of the mitochondria and those that have its effect on inhibition of mtDNA. The fatty liver seen in the context of NRTI therapy may belong to this last category. Interestingly excessive alcohol intake can affect b oxidation by all three mechanisms. (editorial note: fatty liver, also called steatosis, is a condition among some patients with HCV where fat accumulates in the liver perhaps due to impaired liver function and may contribute to accelerated liver disease. In HIV, elevated fats like cholesterol and triglycerides may also contribute to fatty liver and HCV/HIV coinfected patients may be more prone to fat accumulation and glucose abnormalities in the liver due to liver impairment and elevated lipids).
Inability to metabolize fat by b oxidation leads to accumulation of fat within cells. When examined at a cellular level, accumulation of fat can be categorized as "macrovesicular" (the accumulation of fat in large droplet form) or as "microvesicular" (in smaller droplet form). Macrovesicular fat accumulation is considered a benign type of fatty liver that does not progress. Microvesicular fat accumulation, on the other hand, is associated with ATP depletion and fatty acid toxicity with risk to eventual liver inflammation followed by cirrhosis and liver failure. A significant component of this process may be secondary to the production of cytokines such as TNF alpha which are produced when damaging effects of the byproducts of fat (lipid peroxidation products) interact with reactive oxygen species (ROS) produced in excess by a dysfunctional mitochondrial energy system. (editorial note: it has been suggested that TNF alpha abnormalities may be associated with body composition changes: see below).
Modalities for the assessment of lipodystrophy
Investigators from Washington University [Abs 29] found that MRI measurements of abdomen and thigh fat area correlated well with DEXA measurements of trunk and leg fat content in 56 HIV seropositive subjects and 18 controls. During the question and answer period, it was commented that other researchers have not had similar experiences in regards to truncal fat. Whether truncal fat by DEXA (which measures both visceral and subcutaneous fat in the trunk) could be used to estimate visceral fat specifically as can be done by MRI or CT, probably remains to be demonstrated in larger cohort studies.
Genetic polymorphisms and lipoatrophy
In yet another indication of the strong influence that genetics could play in the development of various human disorders, D Nolan from Perth, Australia [Abs 26], reported that having a tumor necrosis factor alpha gene -238G/A promoter polymorphism (found in 11.4% of their cohort all of white racial origin), was a risk factor for the development of lipoatrophy. The risk was modest and was independent of the usual well-recognized risks for the development of lipoatrophy such as age and time on NRTI therapy.
Switch Therapy for lipoatrophy
Tyler Lonergan [Abs 21] presented the 48 wk data from the TARHEEL study reporting continued beneficial effect and lack of recurrence of asymptomatic and symptomatic hyperlactatemia when stavudine (d4T) is replaced by either abacavir (ABC) or zidovudine (ZDV). A sustained normalization of lactate levels and a decrease in liver function values were seen. Improvement in lipoatrophy was also seen. At week 48 in the group as a whole, there was a median increase of 35% (249g) of fat in the arms, 18% (949) median increase of fat in the trunk and 12% (288g) in the legs. Interestingly, single slice CT scan through L4 at baseline and at week 48 demonstrated a tendency for visceral fat to decrease following switch while abdominal subcutaneous fat increased. HIV-1 viral load remained well suppressed in these individuals. These results indicating favorable response past 48 weeks are encouraging and support the view that d4T substitution with either abacavir or zidovudine may be a viable option for some individuals with lipoatrophy and/or hyperlactatemia.
Mitochondrial DNA analysis in blood specimens
Much interest has been generated in assessing the mitochondrial DNA levels of peripheral blood mononuclear cells (PBMCs) in individuals at risk of or suffering from hyperlactatemia, lipoatrophy and other mitochondrial side effects of NRTIs. Several abstracts were presented on the relevance and technical aspects of such mitochondrial DNA assays in PBMCs. Investigators from the International Antiviral Therapy Evaluation Center (ITEC) and Primagen in the Netherlands serially assessed PBMC mtDNA and mtRNA levels using the single tube duplex real-time NASBA method [Abs 25] in a subset of 36 subjects within the EASIER trial. Individuals in this trial were randomized to receive either RTV/IND + EFV with or without d4T. They reported that inclusion of d4T in the regimen was associated with a delayed 24% increase (rather than a decrease) in mtDNA after 24 weeks. A Cossarizza from Milan, Italy [Abs 23] presented data stressing the importance of platelet elimination before assaying PBMCs for mtDNA. Platelets contain mtDNA but no nuclear DNA; therefore contamination can lead to falsely elevated mtDNA levels. S. Lopez from Barcelona, Spain [Abs 24] presented information on doing functional studies on mitochondria from PBMCs (by assessing the enzyme activity of the mitochondria's energy generating system (OXPHOS) and determining oxygen consumption) in addition to mtDNA analysis. They found that functional assays were often normal even when mtDNA levels were not. They urged caution in focusing too much relevance on mtDNA levels. During the panel discussion that followed, several key points were made: First that increases in mtDNA levels, such as seen in the EASIER trial, may be seen as a response to mitochondrial injury and could not be interpreted as lack of mitochondrial toxicity. Secondly, mitochondrial toxicity is extremely tissue specific; therefore, lack of toxicity in blood lymphocytes do not mean that no toxicity is occurring in the tissue of interest whether it is fat or skeletal muscle. For clinical care, the relevance and role of mtDNA levels in blood lymphocytes is not clear at the moment; therefore, similar to the situation in plasma lactates, routine assessment of PBMC mtDNA levels cannot be recommended at this time.
Longitudinal assessment of body composition over time
Longitudinal results of body composition from 2 reasonably large cohort trials were reported. M. Dube of Indiana University [Abs 27] presented the preliminary DEXA results in a cohort of 156 subjects up to week 80 in A5005s, a metabolic substudy of ACTG 384. ACTG 384 was a large anti-retroviral trial in ARV naive subjects. Subjects received a backbone of either ZDV +3TC or d4T + ddI. NFV and/or EFV were added to this backbone. Anti-retroviral naive subjects randomized to d4T + ddI lost a greater proportion of limb fat than those receiving ZDV + 3TC at weeks 48 - 80. Subjects randomized to nelfinavir lost a greater proportion of limb fat at week 80 than with efavirenz. Although trunk fat increased across all group, regimen specific differences in trunk fat changes were not detected. D. Nolan of Perth, Australia [Abs 28] presented longitudinal DEXA study in 53 subjects in the Western Australian HIV Cohort Study who had at least 2 sequential DEXA scans while undergoing a first HAART triple therapy regimen containing either stavudine or zidovudine. A new non-linear mixed effects model was proposed to assess fat wasting as a continuous time-dependent variable rather than as a dichotomous subjective outcome. The investigators reported that both stavudine and zidovudine groups averaged approximately 22% leg fat at the time they first began HAART. This percentage dropped exponentially to approximately 13% after 2 years in patients on stavudine. In contrast, the zidovudine treated group leveled off after 2 years to approximately 19% leg fat. Interestingly, whether these individuals had started HAART as completely anti-retroviral naive or whether they had had 30 months of prior ZDV, subjects on each NRTI group after 2 years drifted down and leveled off to these same levels.
Clinical management of lipodystrophy
Several speakers gave an overview of the state of the art in the clinical management of lipodystrophy. Treatment for metabolic abnormalities should include therapy modalities commonly given to non-HIV infected individuals including diet, exercise regimens and statins, fibrates and oral antidiabetic agents as required. Treatment options for lipodystrophy are limited. Judith Currier, UCLA, noted clinical trials of various agents including anabolic agents such as growth hormone or anabolic steroids such as testosterone, and insulin-sensitizing drugs such as thiazolidinediones and metformin. Substitution or avoidance of certain NRTIs may be appropriate in some individuals. Trials of possible preventive strategies to delay or eliminate the onset of lipodystrophy may be in order.
Reconstructive surgery options for facial lipoatrophy
Derek Jones, UCLA, presented a review of reconstructive surgery options for facial lipoatrophy. Non-permanent reconstructive options such as injections of fat or collagen suffer from gradual resorption of the injected material. Currently, more permanent reconstructive surgery options for facial soft tissue molding are limited particularly for residents in the United States. Medical grade liquid injectible silicone is legally marketed in the U.S. as an FDA-approved medical device although not explicitly approved for building soft tissue. Other products are available in Europe but not FDA approved for use in the United States. Clinical trials of these products are needed. Satisfactory results are often dependent on the skill and experience of the technician. The costs of many of these products are high. Difficulties are often encountered in seeking medical reimbursement for these procedures and the point of view that these procedures cannot be considered as simple "cosmetic surgery" was presented. (editorial note: my take on Jones talk was there is potential small risk with all these procedures. Many of the benefits that result can fade after 6 or 12 months and procedures may have to be repeated}.
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