Acquired and Inherited Lipodystrophies
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《新英格兰医药杂志》
To the Editor: The pathogenesis and management of lipodystrophy in patients with human immunodeficiency virus (HIV) infection are discussed in Garg's review article (March 18 issue).1 However, the author should have noted that several lines of evidence point toward nucleoside reverse-transcriptase inhibitors in general, and the mitochondrial toxicity of stavudine in particular, as having a contributory role in this form of fat wasting. Clinical trials have demonstrated that the presence or absence of stavudine in the nucleoside reverse-transcriptase–inhibitor "backbone" of antiretroviral regimens has an influence on the risk of lipoatrophy.2 Nucleoside reverse-transcriptase inhibitors may inhibit gamma-polymerase, the enzyme necessary for the replication of mitochondrial DNA. Consistent with such mitochondrial toxicity, reduced levels of mitochondrial DNA have been linked with the use of stavudine in HIV-infected patients.3 Ultrastructural abnormalities of mitochondria within the adipocytes of subjects with lipoatrophy also point toward mitochondrial toxicity related to nucleoside reverse-transcriptase inhibitors in the pathogenesis of lipoatrophy.4 Finally, it has been demonstrated that lipoatrophy can be improved by switching patients from stavudine to other agents.5 Therefore, this option should be considered for HIV-infected patients with lipodystrophy.
Ulrich A. Walker, M.D.
Medizinische Universit?tsklinik
79106 Freiburg, Germany
ulrich.walker@klinikum.uni-freiburg.de
Editor's note: Dr. Walker reports having received consulting fees, honoraria as a speaker, or both, from Bristol-Myers Squibb (the manufacturer of stavudine) and from companies producing related or competing products, such as Hoffmann–La Roche, GlaxoSmithKline, Boehringer Ingelheim, Gilead, and Pharma Nord.
References
Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004;350:1220-1234.
Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-2454.
Cherry CL, Gahan ME, McArthur JC, Lewin SR, Hoy JF, Wesselingh SL. Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr 2002;30:271-277.
Walker UA, Bickel M, Lütke Volksbeck SI, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002;29:117-121. [ISI][Medline]
Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002;288:207-215.
To the Editor: Garg does not mention the ongoing discussion of alterations of the adrenocortical axis in the context of lipodystrophy. Oral et al. reported normal corticotropin and cortisol levels in patients with severe lipodystrophies.1 In contrast, others have reported alterations of cortisol metabolism in patients with acquired lipodystrophies,2 a finding that accords with our results and other reports of a negative effect of adipocytokines (leptin and tumor necrosis factor ) on adrenocortical steroidogenesis.3,4 Our experience in treating a patient with acquired partial lipodystrophy, in whom we diagnosed partial adrenocortical insufficiency, supports this idea. The cortisol response to corticotropin stimulation (250 μg) was repeatedly diminished (64 to 105 ng per milliliter). An abdominal magnetic resonance image revealed thin adrenal glands embedded in retroperitoneal fat masses (Figure 1). We also found that the serum leptin level was highly elevated (24.1 mg per liter; normal range, 3.7 to 11.1), which is consistent with previous data. In summary, these results indicate that the adrenocortical axis can be diminished in patients with acquired partial lipodystrophy and should therefore be evaluated regularly by means of laboratory testing.
Figure 1. Axial, Fat-Saturated, T1-Weighted Magnetic Resonance Image Showing Excess Fat at the Back, with the Left Adrenal Gland Embedded in Adipose Tissue (Arrow).
Matthias Schott, M.D.
Werner A. Scherbaum, M.D.
Stefan R. Bornstein, M.D.
University of Düsseldorf
40225 Düsseldorf, Germany
schottmt@uni-duesseldorf.de
References
Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002;87:3110-3117.
Yanovski JA, Miller KD, Kino T, et al. Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. J Clin Endocrinol Metab 1999;84:1925-1931.
Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 1997;46:1235-1238.
Mantzoros CS, Moschos S, Avramopoulos I, et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab 1997;82:3408-3413.
Dr. Garg replies: In response to Schott and colleagues: the hypothalamo–pituitary–adrenocortical axis is usually normal in patients with various types of acquired and genetic lipodystrophies. In HIV-infected patients with lipodystrophy, detailed investigations showed that only a few patients had increased serum or 24-hour urinary free cortisol concentrations, but they all had preservation of the circadian rhythm of serum cortisol and normal serum cortisol responses to oral dexamethasone — findings that essentially rule out overt hypercortisolism.1 The patient with acquired partial lipodystrophy who is described by Schott et al. is likely to have autoimmune partial adrenal insufficiency. However, among 35 of our patients and 220 previously described patients with acquired partial lipodystrophy, none were found to have adrenal insufficiency.2 Therefore, I do not support the recommendation of regular testing for adrenal insufficiency in patients with acquired partial lipodystrophy.
Walker suggests that nucleoside reverse-transcriptase inhibitors, particularly stavudine, have a contributory role in inducing lipodystrophy in HIV-infected patients. In contrast, some investigators report no difference in the prevalence of lipodystrophy between patients receiving stavudine and those receiving zidovudine.3 Lactic acidosis and hepatic dysfunction have been attributed to mitochondrial dysfunction caused by nucleoside reverse-transcriptase inhibitors, but whether this leads to a syndrome of lipodystrophy characterized by selective loss of adipose tissue and manifestations of insulin resistance, such as hypertriglyceridemia or hyperinsulinemia, remains unclear. Patients with familial multiple symmetric lipomatosis due to mitochondrial DNA mutations have cervical lipomas, but loss of fat from the extremities and face has not been reported.1 HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors alone who were considered to have lipodystrophy did not have marked hypertriglyceridemia or hyperinsulinemia.1 Similarly, a gain of subcutaneous fat in the extremities on switching from stavudine or zidovudine to abacavir does not improve serum lipids or insulin or C-peptide levels.4 Furthermore, currently available data on the substitution of nucleoside reverse-transcriptase inhibitors come from observational or other trials that appear to be prone to bias and subjective assessment.1,4,5 Only well-designed, rigorous, long-term, prospective, double-blind, placebo-controlled clinical trials — in which different nucleoside reverse-transcriptase inhibitors are used in previously untreated HIV-infected patients and objective methods, instead of subjective assessment, are used to evaluate lipodystrophy — can provide irrefutable evidence of the effects of these drugs on body fat and metabolic variables.
Abhimanyu Garg, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9052
abhimanyu.garg@utsouthwestern.edu
References
Chen D, Misra A, Garg A. Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 2002;87:4845-4856.
Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore) 2004;83:18-34.
Bogner JR, Vielhauer V, Beckmann RA, et al. Stavudine versus zidovudine and the development of lipodystrophy. J Acquir Immune Defic Syndr 2001;27:237-244.
Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipodystrophy: a randomized trial. JAMA 2002;288:207-215.
Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-2454.
Ulrich A. Walker, M.D.
Medizinische Universit?tsklinik
79106 Freiburg, Germany
ulrich.walker@klinikum.uni-freiburg.de
Editor's note: Dr. Walker reports having received consulting fees, honoraria as a speaker, or both, from Bristol-Myers Squibb (the manufacturer of stavudine) and from companies producing related or competing products, such as Hoffmann–La Roche, GlaxoSmithKline, Boehringer Ingelheim, Gilead, and Pharma Nord.
References
Garg A. Acquired and inherited lipodystrophies. N Engl J Med 2004;350:1220-1234.
Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-2454.
Cherry CL, Gahan ME, McArthur JC, Lewin SR, Hoy JF, Wesselingh SL. Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr 2002;30:271-277.
Walker UA, Bickel M, Lütke Volksbeck SI, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr 2002;29:117-121. [ISI][Medline]
Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002;288:207-215.
To the Editor: Garg does not mention the ongoing discussion of alterations of the adrenocortical axis in the context of lipodystrophy. Oral et al. reported normal corticotropin and cortisol levels in patients with severe lipodystrophies.1 In contrast, others have reported alterations of cortisol metabolism in patients with acquired lipodystrophies,2 a finding that accords with our results and other reports of a negative effect of adipocytokines (leptin and tumor necrosis factor ) on adrenocortical steroidogenesis.3,4 Our experience in treating a patient with acquired partial lipodystrophy, in whom we diagnosed partial adrenocortical insufficiency, supports this idea. The cortisol response to corticotropin stimulation (250 μg) was repeatedly diminished (64 to 105 ng per milliliter). An abdominal magnetic resonance image revealed thin adrenal glands embedded in retroperitoneal fat masses (Figure 1). We also found that the serum leptin level was highly elevated (24.1 mg per liter; normal range, 3.7 to 11.1), which is consistent with previous data. In summary, these results indicate that the adrenocortical axis can be diminished in patients with acquired partial lipodystrophy and should therefore be evaluated regularly by means of laboratory testing.
Figure 1. Axial, Fat-Saturated, T1-Weighted Magnetic Resonance Image Showing Excess Fat at the Back, with the Left Adrenal Gland Embedded in Adipose Tissue (Arrow).
Matthias Schott, M.D.
Werner A. Scherbaum, M.D.
Stefan R. Bornstein, M.D.
University of Düsseldorf
40225 Düsseldorf, Germany
schottmt@uni-duesseldorf.de
References
Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002;87:3110-3117.
Yanovski JA, Miller KD, Kino T, et al. Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. J Clin Endocrinol Metab 1999;84:1925-1931.
Bornstein SR, Uhlmann K, Haidan A, Ehrhart-Bornstein M, Scherbaum WA. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes 1997;46:1235-1238.
Mantzoros CS, Moschos S, Avramopoulos I, et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab 1997;82:3408-3413.
Dr. Garg replies: In response to Schott and colleagues: the hypothalamo–pituitary–adrenocortical axis is usually normal in patients with various types of acquired and genetic lipodystrophies. In HIV-infected patients with lipodystrophy, detailed investigations showed that only a few patients had increased serum or 24-hour urinary free cortisol concentrations, but they all had preservation of the circadian rhythm of serum cortisol and normal serum cortisol responses to oral dexamethasone — findings that essentially rule out overt hypercortisolism.1 The patient with acquired partial lipodystrophy who is described by Schott et al. is likely to have autoimmune partial adrenal insufficiency. However, among 35 of our patients and 220 previously described patients with acquired partial lipodystrophy, none were found to have adrenal insufficiency.2 Therefore, I do not support the recommendation of regular testing for adrenal insufficiency in patients with acquired partial lipodystrophy.
Walker suggests that nucleoside reverse-transcriptase inhibitors, particularly stavudine, have a contributory role in inducing lipodystrophy in HIV-infected patients. In contrast, some investigators report no difference in the prevalence of lipodystrophy between patients receiving stavudine and those receiving zidovudine.3 Lactic acidosis and hepatic dysfunction have been attributed to mitochondrial dysfunction caused by nucleoside reverse-transcriptase inhibitors, but whether this leads to a syndrome of lipodystrophy characterized by selective loss of adipose tissue and manifestations of insulin resistance, such as hypertriglyceridemia or hyperinsulinemia, remains unclear. Patients with familial multiple symmetric lipomatosis due to mitochondrial DNA mutations have cervical lipomas, but loss of fat from the extremities and face has not been reported.1 HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors alone who were considered to have lipodystrophy did not have marked hypertriglyceridemia or hyperinsulinemia.1 Similarly, a gain of subcutaneous fat in the extremities on switching from stavudine or zidovudine to abacavir does not improve serum lipids or insulin or C-peptide levels.4 Furthermore, currently available data on the substitution of nucleoside reverse-transcriptase inhibitors come from observational or other trials that appear to be prone to bias and subjective assessment.1,4,5 Only well-designed, rigorous, long-term, prospective, double-blind, placebo-controlled clinical trials — in which different nucleoside reverse-transcriptase inhibitors are used in previously untreated HIV-infected patients and objective methods, instead of subjective assessment, are used to evaluate lipodystrophy — can provide irrefutable evidence of the effects of these drugs on body fat and metabolic variables.
Abhimanyu Garg, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9052
abhimanyu.garg@utsouthwestern.edu
References
Chen D, Misra A, Garg A. Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 2002;87:4845-4856.
Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Baltimore) 2004;83:18-34.
Bogner JR, Vielhauer V, Beckmann RA, et al. Stavudine versus zidovudine and the development of lipodystrophy. J Acquir Immune Defic Syndr 2001;27:237-244.
Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipodystrophy: a randomized trial. JAMA 2002;288:207-215.
Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS 2002;16:2447-2454.