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PubMed2001

Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders?

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.

Adult↗
PubMed2005

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

Adolescent↗
PubMed1983

Membranous lipodystrophy-like changes in ischemic necrosis of the legs.

Subcutaneous fat from 3 patients with ischemic necrosis of the legs due to arteriosclerotic obstruction were examined histologically and ultrastructurally. Markedly convoluted membranocystic changes were found in all 3 cases. The light and electron microscopic findings of the membranocystic lesions are very similar to those of fat tissue changes in membranous lipodystrophy. Bone lesions and mental disturbance which suggest membranous lipodystrophy, however, were absent in these cases. It is concluded from these results that the membranocystic changes characteristic of membranous lipodystrophy can be produced by circulatory disturbance and the lesions are one of the non-specific changes of adipose tissue.

Adipose Tissue↗
PubMed1992

Congenital generalized lipodystrophy associated with multiple sclerosis.

We report the case of a 22 year old woman with congenital generalized lipodystrophy who presented a left brachiocrural pyramidal hemisyndrome, bilateral cerebellar signs and a left cranial nerve VI deficit. The clinical pattern had a tendency to regress. MRI brainscan, CSF examination and clinical features led to the diagnosis of "probable demyelinating syndrome". Published data on CNS involvement in patients with congenital generalized lipodystrophy are few and we have found no cases in which a demyelinating syndrome is associated. In the case we report it is tempting to see the disorder of the lipid metabolism underlying the congenital generalized lipodystrophy as underlying the myelin disorder as well.

Adult↗
PubMedDate not supplied

Benefits of the rotating cannula in the treatment of lipodystrophies.

The combination of traditional suction and the use of a cannula which can achieve up to 400 rotations per minute can enable the practitioner to treat lipodystrophies at an angle of 360 degrees. The torque limitation device puts an immediate end to rotations if the cannula meets a resistance, thereby eliminating any risk of lesions to non-fatty tissues. The use of this device over a one year period has proved its efficiency in the treatment of major lipodystrophies and certain areas, which are usually considered difficult because of their density. It is of limited interest, however, in the correction of moderate, classical lipodystrophies.

Adipose Tissue↗
PubMed2000

Mouse models of lipodystrophy.

Lipodystrophies are a group of heterogeneous diseases characterized by the loss of adipose tissue and by abnormalities of carbohydrate and lipid metabolism, including insulin resistance, diabetes, and hyperlipidemia. In this review, we describe several mouse models that recapitulate various aspects of the lipodystrophy syndrome, offering insights into the etiology of this condition and potential therapeutic approaches. Studies on these mice suggest that adipose is the primary tissue affected in lipodystrophy, and that secondary leptin deficiency may be responsible for the associated insulin resistance.

Animals↗
PubMed1992

Generalized lipodystrophy: in vivo evidence for hypermetabolism and insulin-resistant lipid, glucose, and amino acid kinetics.

Stable isotope tracers and indirect calorimetry were used to evaluate whole-body energy, glucose, lipid, and amino acid metabolism in a patient with generalized lipodystrophy during basal conditions and in response to insulin therapy. The results were compared with those obtained in previous studies in normal volunteers. The basal rate of glucose production (33.7 mumol/kg.min) was three times higher than normal. The basal rate of glycerol appearance in blood, an index of lipolysis, was 60% greater than normal when expressed per kilogram body weight (3.82 mumol/kg.min), but was more than 10 times normal when expressed per kilogram body fat mass (123.2 mumol/kg.min) because of the marked decrease in body fat in our patient (3% of total body weight). Leucine rate of appearance, an index of protein breakdown, and nonoxidative leucine disposal, an index of protein synthesis, were also greater than normal. Resting energy expenditure (REE) was 30% greater than normal. The effect of insulin infusion on these metabolic parameters was markedly blunted. These metabolic abnormalities help explain many of the clinical findings such as hyperglycemia, hypertriglyceridemia, fat depletion, hepatomegaly, and steatosis observed in patients with lipodystrophy. Ineffective insulin function in many tissues appears to be an important factor in the pathophysiology of lipodystrophy.

Adult↗
PubMed1979

Hemifacial lipodystrophy. Report of a case.

Lipodystrophy, which may be subdivided into a partial and a total form, is not a commonly reported disorder. One patient is presented in whom the lipodystrophy was not only confined to the face but even to one side. Progressive hemifacial atrophy was excluded by roentgencephalometric analysis and electromyography. It is suggested that the reported entity be considered as a separate group under the name of hemifacial lipodystrophy.

Adult↗
PubMed1986

Serum lipid and lipoprotein levels in premature ageing syndromes: total lipodystrophy and Cockayne syndrome.

Serum lipids and lipoproteins were investigated in two girls who suffered from total lipodystrophy, in their family members, and in two brothers suffering from Cockayne syndrome. Hyperlipoproteinemia type IIb (Fredrickson) was detected in one case with total lipodystrophy. Very low levels of serum high density lipoprotein cholesterol (HDL-Ch) were observed in both of total lipodystrophic cases, in most of their first degree relatives, and in one of patients with Cockayne syndrome. Because total lipodystrophy and the Cockayne syndrome belong to ageing syndromes they can serve as a useful model of premature arteriosclerosis and the defect lipid metabolism.

Adult↗
PubMed1988

A case of membranous lipodystrophy complicated by Fanconi's syndrome.

A case of membranous lipodystrophy complicated by Fanconi's syndrome is described. A 40-year old man complaining of pain in his legs was admitted to our hospital. Roentgenograms showed cystic changes in the long bones. Biopsy of the affected lesion of the femur revealed a peculiar membranocystic structure in the marrow that is typical of membranous lipodystrophy. He had a neuropsychiatric disorder which is often associated with this disease. Laboratory studies were remarkable for renal proximal tubular dysfunction, i.e., Fanconi's syndrome. Membranous lipodystrophy is a rare, hereditary disease that has been reported mainly from Japan and Finland. This is the first case of this disease complicated by Fanconi's syndrome. The possible relationship between these disorders is discussed.

Adult↗
PubMed2005

Lipodystrophy and quality of life in HIV: symptom management issues.

The purpose of this study was to examine the incidence and prevalence of lipodystrophy-related symptoms in persons with HIV ( n = 165) and to determine the impact of these symptoms on health-related quality of life. Since the introduction of highly active antiretroviral therapy in HIV, the quality of life of persons is affected across the spectrum of the disease. The sample was composed of 165 persons from three national outpatient HIV settings (clinics and community-based organizations) in Boston, MA, Fresno, CA, and Victoria, TX. The descriptive, cross-sectional study included self-report instruments measuring lipodystrophy-associated symptom presence, intensity, and quality of life. The sample was primarily male (75.8%), with ethnicity represented across several groups including African American (30.9%), Hispanic/Latino (26.7%), White/Anglo (38.8%), Native American/Indian (1.8%), and other (1.8%). On quality-of-life measures, only 7.9% of the sample indicated excellent health, 28.5% indicated very good health, 22.4% indicated good health, and more than 40% indicated fair or poor health. Most of the participants indicated that aspects of their quality of life have equally good and bad parts (37.6%). Quality of life was significantly correlated with adequacy of income ( r = .241, p = .002), most recent CD4 count ( r = -.276, p = .012), and most recent viral load value ( r = .379, p = .019). In addition, bodily pain was significantly correlated with most recent CD4 count ( r = -.312, p = .004) and with lowest CD4 count ( r = -.191, p = .050). The results of the study indicate that quality of life is affected by HIV symptoms and that lipodystrophy-related symptoms may negatively affect quality of life.

Adult↗
PubMed2004

Lipodystrophies: rare disorders causing metabolic syndrome.

Recent advances in the understanding of the molecular basis of genetic lipodystrophies have promoted understanding of how adipose tissue disorders can cause the metabolic syndrome and its complications. These discoveries hold promise for elucidating pathways and mechanisms by which common disorders of obesity cause metabolic complications. Novel therapeutic approaches for patients with lipodystrophies also may have implications for treatment of the metabolic syndrome in patients with regional adiposity. This article reviews these recent advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or other bases of various types of lipodystrophies.

Humans↗
PubMed2004

Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy.

Leptin, an adipocyte hormone, when replaced in patients with lipodystrophy, improves insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Changes in body composition accompany this metabolic improvement. We studied 14 patients (3 men and 11 women); 12 of who had generalized lipodystrophy (7 congenital, 5 acquired), and 2 patients had partial lipodystrophy. Body composition and related parameters were evaluated at baseline and after 4 and 12 months of leptin therapy. Baseline body mass index (BMI) was 21.7 +/- 0.8 kg/m(2), the percent body fat was 9.5% +/- 1.6%, and the serum leptin level was 1.7 +/- 0.3 ng/mL. On treatment, serum leptin levels increased by 10-fold. All patients reported a decrease in appetite on therapy. After 4 months, both daily caloric intake and resting energy expenditure (REE) decreased. The liver volume decreased (baseline = 3,055 +/- 281 cm(3); 4 months = 2,433 +/- 243 cm(3), P =.006). Dual energy x-ray absorptiometry (DEXA) demonstrated significant decreases in fat mass (5.4 +/- 0.8 kg to 5.0 +/- 0.8 kg; P =.003) and lean body mass (51.2 +/- 3.2 kg to 48.3 +/- 3.4 kg; P =.003) at 4 months on therapy. There was no impact of leptin therapy on bone mineral content, mineral density, and metabolism. Changes in body composition occurred during the first 4 months of leptin therapy, but then stabilized and were sustained thereafter.

Absorptiometry, Photon↗
PubMed2005

Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity.

The lipodystrophy syndrome and associated metabolic alterations are the most prevalent adverse effects in HIV-infected patients taking highly active anti-retroviral therapy (HAART). This syndrome involves profound disturbances in adipose tissue. The toxic effect of nucleoside reverse transcriptase inhibitors on mitochondrial function is a major contributor to the lipodystrophy syndrome. Although adipocytes were not expected to be preferential targets of mitochondrial toxicity, recent re-evaluation of the role of mitochondria in white adipocytes helps to explain the molecular basis of HAART-associated lipodystrophy. Adipocytes are a source of paracrine and endocrine signals that influence adipocyte biology and systemic metabolism. Mitochondrial disturbances elicited by HAART result in an abnormal perception of the bioenergetic status by adipocytes, thus leading to enhancement of catalytic pathways and apoptosis in peripheral adipose tissue, alterations in the differentiation of brown versus white adipocytes, and the release of hormonal signals that lead to systemic metabolic disturbances.

Adipocytes↗
PubMed1999

Protease inhibitor-induced lipodystrophy.

The development of lipodystrophy as evidenced by central obesity, "moon facies," and a "buffalo hump" is a classical feature of Cushing's disease. Recently an association of "lipodystrophy" with the use of protease inhibitors has been reported. We describe a patient with lipodystrophy secondary to protease inhibitor therapy for HIV infection.

Female↗
PubMedDate not supplied

Iatrogenic lipodystrophy in HIV patients - the need for very-low-fat diets.

In HIV patients, chronic treatment with protease inhibitors often precipitates a peripheral lipodystrophy associated with insulin resistance syndrome and premature coronary disease. In vitro studies demonstrate that these drugs can compromise the ability of adipocytes to store triglycerides; in vivo, peripheral subcutaneous adipocytes appear to be most affected, such that body fat often redistributes to visceral or truncal adipose stores. Dysfunction of peripheral subcutaneous adipocytes - ordinarily quite efficient for storing fat - can be expected to give rise to an excessive flux of free fatty acids (FFAs) following fatty meals; chronic overexposure of tissues to FFAs is a likely explanation for the insulin resistance syndrome associated with lipodystrophy. These considerations suggest that a very-low-fat diet - less than 15% fat calories - may ameliorate the cardiovascular risk associated with lipodystrophy; such diets are known to have a favorable effect on the insulin sensitivity of healthy subjects. Very-low-fat whole-food vegan diets are particularly recommendable in this context, as they may help to shrink visceral fat depots while markedly reducing LDL cholesterol. Appropriate adjunctive measures may include aerobic exercise training - beneficial both for insulin sensitivity and weight control - as well as administration of statins or policosanol, and of fibrates or fish oil, to decrease LDL and triglycerides, respectively. Despite perceptions to the contrary, very-low-fat diets can meet with good compliance in well-motivated subjects given appropriate instruction.

Adipocytes↗
PubMed2003

A search for candidate genes for lipodystrophy, obesity and diabetes via gene expression analysis of A-ZIP/F-1 mice.

Genome scans for diabetes have identified many regions of the human genome that correlate with the disease state. To identify candidate genes for type 2 diabetes, we examined the transgenic A-ZIP/F-1 mouse. This mouse model has no white fat, resulting in abnormal levels of glucose, insulin, and leptin, making the A-ZIP/F-1 mice a good model for lipodystrophy and insulin resistance. We used cDNA-based microarrays to find differentially expressed genes in four tissues of these mice. We examined these results in the context of human linkage scans for lipodystrophy, obesity, and type 2 diabetes. We combined 199 known human orthologs of the misregulated mouse genes with 33 published human genome scans on a genome map. Integrating expression data with human linkage results permitted us to suggest and prioritize candidate genes for lipodystrophy and related disorders. These genes include a cluster of 3 S100A genes on chromosome 1 and SLPI1 on chromosome 20.

Animals↗
PubMed2000

Barraquer-Simons lipodystrophy, Raynaud's phenomenon and cutaneous vasculitis.

We report a 32-year-old man who presented with a 2-year history of unexplained weight loss and symptoms of Raynaud's phenomenon. Clinical examination and investigations were consistent with a diagnosis of acquired partial lipodystrophy (Barraquer-Simons disease). This patient also exhibited an associated cutaneous vasculitis and peripheral perniotic changes. He had normal renal function and glucose tolerance and no immunological abnormality has been detected in his serum to date. The absence of C3-nephritic factor in the presence of overt lipodystrophy suggests that there may be another factor or immunological mediator responsible for the subcutaneous changes seen in patients with lipodystrophy.

Adult↗