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Patients with partial lipodystrophy frequently show hypocomplementemia but rarely have associated autoimmune diseases. We report here a patient of myasthenia gravis associated with limb lipodystrophy, a variant form of partial lipodystrophy, and hypocomplementemia.
Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.
In an attempt to differentiate the effect of fenfluramine hydrochloride from that of caloric restriction on carbohydrate tolerance in patients with lipodystrophy, parameters of carbohydrate homeostasis were studied in patients with lipodystrophy during periods of fenfluramine treatment and during periods of caloric restriction. Although, carbohydrate tolerance appeared to improve initially in one patient when treated with fenfluramine, this improvement did not permit. No beneficial influence of fenfluramine on carbohydrate tolerance could be identified in the other patients studied. By contrast, all patients demonstrated an improvement in carbohydrate tolerance in response to caloric restriction. These data suggest that caloric restriction improved carbohydrate tolerance in patients with lipodystrophy whereas fenfluramine, in the absence of caloric restriction, has no long-term beneficial effect.
BACKGROUND: The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and cardiovascular risk factors. OBJECTIVE: To compare the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone and metformin for treating HIV lipodystrophy. DESIGN: An open, randomized, 6-month clinical trial. SETTING: University Medical Center, Utrecht, the Netherlands. PATIENTS: 39 HIV-infected men with lipodystrophy. INTERVENTION: Rosiglitazone, 8 g/d, or metformin, 2 g/d [DOSAGE ERROR CORRECTED] MEASUREMENTS: Insulin sensitivity estimated by the oral glucose tolerance test, subcutaneous and visceral abdominal fat measured by single-slice computed tomography, endothelial function measured by flow-mediated vasodilation, and fasting plasma measurements. Two patients in the metformin group withdrew from the study. Complete case analysis was performed. RESULTS: Compared with metformin, rosiglitazone increased subcutaneous abdominal fat (between-treatment change from baseline, 27 cm2 [95% CI, 7 cm2 to 46 cm2]) and visceral abdominal fat (between-treatment change from baseline, 24 cm2 [CI, 6 cm2 to 51 cm2]). The area under the curve for insulin after the oral glucose tolerance test decreased similarly with both agents, but only rosiglitazone increased adiponectin levels. Metformin showed greater benefits on fasting lipid profile than rosiglitazone. Flow-mediated vasodilation statistically significantly increased with metformin (mean change, 1.5% [CI, 0.4% to 3.3%]) and not with rosiglitazone (mean change, 0.7% [CI, -1.1% to 2.7%]). The metformin versus rosiglitazone increases did not statistically differ. Rosiglitazone and metformin did not change C-reactive protein levels. LIMITATIONS: This small trial was not blinded or placebo-controlled and did not measure clinical outcomes. CONCLUSIONS: The findings emphasize the importance of individualized care in HIV-infected patients. Although rosiglitazone may partly correct lipoatrophy, metformin improves visceral fat accumulation, fasting lipid profile, and endothelial function.
Congenital lipodystrophy is an uncommon autosomal recessive disorder that occurs mainly in females and is characterized by loss of subcutaneous fat, insulin-dependent diabetes mellitus, and masculinization due to defective metabolism of fat. Acquired lipodystrophy is now most commonly encountered in patients infected with HIV who take protease inhibitors. We present an illustrative case of lipodystrophy and review the presenting signs allowing for an accurate clinical diagnosis.
Lipodystrophy is the term given to describe a series of changes in body composition [loss of fat in the legs, arms, or face, breast enlargement, central obesity (sometimes called protease paunch), dorsal fat pads (known as buffalo hump, etc.] as well as changes in laboratory markers associated with how the body processes fats and sugars (e.g. cholesterol and triglyceride changes, also called lipids). Several new findings were recently reported a the 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Although these results may help in making decisions about specific therapies, they offer little information on the cause of lipodystrophy syndromes. However, several studies to be presented at the Conference on Retroviruses and Opportunistic Infections in February 2002 may shed more light on the cause and will be reported in the next PI Perspective.
The lipodystrophies are rare disorders characterized by insulin resistance and the absence or loss of body fat. The 4 subtypes of lipodystrophy are characterized by onset and distribution. Partial lipodystrophy is rare, with loss of fat from the extremities and excess fat accumulation in the face and neck; recognizing this phenotype and subsequent referral for endocrinologic care may improve outcome and reduce mortality.
Body composition alterations are common in HIV infection and include AIDS wasting and lipodystrophy. Both are associated with metabolic alterations, including hypertriglyceridemia and reduced high-density lipoprotein cholesterol levels; insulin resistance and elevated low-density lipoprotein cholesterol levels are also associated with lipodystrophy. However, there is no accepted case definition for HIV-associated lipodystrophy, and patients may have one or all aspects at any given time. The inability of cross-sectional studies to capture the dynamic process of these alterations has hindered the search for a case definition. In the meantime, there are several approaches to treatment of the resulting abnormalities. Switching antiretrovirals has been most successful for improving metabolism, with little or not effect on fat distribution. Growth hormone treatment has successfully reduced visceral fat and buffalo humps but is not FDA-approved for this indication. Metformin and rosiglitazone have produced some improvement in fat distribution as well as glucose metabolism. Other methods that have been tried with varying degrees of success (and little published data) include treatment with testosterone and its derivatives, weight reduction through diet and exercise, and plastic surgery.
Membranous lipodystrophy is known as Nasu-Hakola disease. The main symptoms of membranous lipodystrophy are those of a progressive presenile dementia due to sclerosing leukoencephalopathy with skeletal polycystic lesions. There is no report detailing long-term follow-up of patients with membranous lipodystrophy. We present a 56-year-old woman with this disease who has not manifested any typical neuropsychiatric symptoms during the 16-year follow-up, and thus has had an unusually benign clinical course. The patient underwent curettage and bone grafts. Periodic examinations have been continued for 16 years from discharge. No recurrence of lesions or occurrence of new cystic lesions has been noted. Computerized tomography and magnetic resonance imaging of the brain revealed none of the abnormal change which are reported in this disease. Our findings suggest that some patients with this disease may be fortunate enough to follow a relatively benign clinical course.
HIV infection is associated with a number of metabolic abnormalities, including lipodystrophy, a difficult-to-define disorder whose characteristics include hyperlipidemia, insulin resistance, and fat redistribution. Current data suggest that lipodystrophy is caused by multiple factors. Dual-nucleoside reverse transcriptase inhibitor therapy combined with protease inhibitor therapy has been shown to increase the risk of metabolic abnormalities, but susceptibility independent of drug effects has also been shown. While many of the treatments for the broad range of signs and symptoms of lipodystrophy bring about improvements in patient status, none have been demonstrated to bring about a return to baseline levels.
To determine the prevalence and clinical characteristics of lipodystrophy in HIV-infected Thai patients, a cross-sectional study was performed on 278 HIV-infected patients at Bamrasnaradura Infectious Disease Institute. Laboratory data related to lipid and glucose metabolism were obtained from both patients who self reported fat maldistribution or diagnosed by a physician. The history of antiretroviral treatment and HIV infection were recorded. Prevalence of lipodystrophy found in the present study was 17%. Lipodystrophy was reported mostly on the face, buttock, legs, arms, and abdomen respectively. Two-thirds of these patients had mixed syndromes of fat accumulation and fat wasting and the others had only fat wasting. Ninety-three percent of lipodystrophic patients had at least 1 abnormality in either lipid or glucose metabolism. Eighty-eight percent had dyslipidemia, 21% had impaired glucose tolerance, 30% had insulin resistance and 27% had diabetes mellitus. Lipodystrophic patients have a high rate of lipid and glucose metabolism abnormalities which are the major risk factors for cardiovascular events.
In patients with lipodystrophies a post binding defect in insulin action has been described involving phosphorylation of the beta subunit of the insulin receptor, suggesting the presence of a genetically determined defect in insulin action; the receptor gene has been mapped to the distal short arm of chromosome 19 close to the break-point of a specific chromosome translocation frequently found in pre-B Acute Lymphoblastic Leukemia (ALL). We report on a 13 years old female patient with partial lipodystrophy, acanthosis nigricans and insulin resistance who developed a pre-B ALL. Since lipodystrophy and pre-B ALL are rare disorders, a possible causal relationship between the two diseases is suggested possibly mediated by a mutation in the insulin receptor gene.
Renal involvement is found in 20 to 50% of cases of Partial lipodystrophy (PLD). We report 8 cases of PLD of which 6 had a glomerular nephropathy and 2 had no renal disease but all had persistent hypocomplementemia and 5 had circulating nephritic factor (C3NeF). The analysis of these cases and of all the cases reported in the literature shows the specificity of the glomerular involvement. Membranoproliferative glomerulonephritis (MPGN) with dense intramembranous deposits is a constant finding in PLD with renal involvement. This variety of MPGN is well known for being associated with persistent hypocomplementemia. However, the presence of hypocomplementemia and C3NeF in patients with PLD but without nephritis raises the question of the interrelationship between alternative pathway complement activation and the development of MPGN with or without lipodystrophy. There is no valid explanation in the present state of knowledge for the association of partial lipodystrophy hypocomplementemia, and MPGN. From the answer to this problem should emerge a better understanding of the role of complement in renal disease and in particular in the unusual form of glomerular injury seen in MPGN.
INTRODUCTION: Membranous lipodystrophy represents a peculiar dermatopathologic type of cystic forming adipose tissue necrosis. In skin pathology two distinct entities are currently known: a primary idiopathic type and a secondary type found in association with various cutaneous or systemic diseases (lupus erythematosus, scleroderma, dermatomyositis, venous disorders, trauma, diabetes mellitus...). This secondary type is more common. CASE REPORT: We report the case of a female patient treated with cytostatic regimen for metastatic adenocarcinoma of the breast. She was seen with cyclic painful attacks of hypodermitis of lower limbs following drug infusions. Attacks finally vanished after treatment withdrawal. Membranous lipodystrophy was observed microscopically. DISCUSSION: This is, to the best of our knowledge, the first case of membranous lipodystrophy occurring during cytostatic treatment. The origin of such a phenomenon remains nuclear but cystic formation occurs after adipocyte necrosis and membranes are thought to be formed from dead cells plasma membrane remnants. Primary cell injury could be due to ischemia to which adipose tissue is especially susceptible. In our case, role of circulatory troubles or cytostatic chemotherapy could be equally discussed. However cyclic attack of painful hypodermatitis following drug administration was strongly in favour of treatment responsibility. Moreover clearing of lesions after treatment discontinuation brought more arguments for this last hypothesis.
Background: Cases of lipodystrophy syndrome and metabolic disorders have been described since the onset of highly active antiretroviral therapy in HIV-infected patients. The aim of our study was to estimate the prevalence of lipodystrophy (LD) and to define the associated lipid profile of these patients. Methods: The following were determined for each patient: lipid profile (cholesterol and its subfractions, atherogenicity ratios, and triglycerides), blood glucose, and immunovirological markers (CD4(+) cell count and plasma viral load). Patients were classified into two groups on the basis of whether or not they presented with clinical signs of LD. Results: Among 233 HIV-infected patients included in the study, 61 cases (26.1%) of lipodystrophy (LD) were noted. Compared with non-LD patients (NLD), LD patients were older men (P<10(-4)) with a lower CD4(+) lymphocyte cell count (P<0.007) and more often at the AIDS stage (P<10(-3)) (OR=3.2 (95% CI: 1.47-6.2)). Multivariate analysis showed a correlation between LD cases and age (10 years older) (OR=1.78 (95% CI: 1.23-2.57), P<0.002) and the decrease in CD4(+) cell count (100 CD4(+)/mm(3) lower) (OR=1.31 (95% CI: 1.09-1.58), P<0.004). An analysis of lipid subfractions and atherogenicity ratios clearly indicated a proatherogenic lipid profile for the LD patients. Conclusions: The underlying physiopathological mechanism of LD is still unknown. However, the lipid profile of HIV-1-infected patients with a LD syndrome appears to place these patients at an increased risk of progression of atherosclerosis.
BACKGROUND: Familial partial lipodystrophy (FPLD) is a monogenic form of diabetes characterised by a dominantly inherited disorder of adipose tissue associated with the loss of subcutaneous fat from the limbs and trunk, with excess fat deposited around the face and neck. The lipodystrophy causes severe insulin resistance, resulting in acanthosis nigricans, diabetes, dyslipidaemia, and increased risk of cardiovascular disease. Preliminary results from animals and man suggest that increasing subcutaneous fat by treatment with thiazolidinediones should improve insulin resistance and the associated features of this syndrome. CASE REPORT: We report a 24-year-old patient with FPLD caused by a mutation in the LMNA gene (R482W) treated with 12 months of rosiglitazone. Subcutaneous fat increased following rosiglitazone treatment as demonstrated by a 29% generalised increase in skin-fold thickness. Leptin levels increased from 5.8 to 11.2 ng/ml. Compared with treatment on Metformin, there was an increase in insulin sensitivity (HOMA S% 17.2-31.6) but no change in glycaemic control. The lipid profile worsened during the follow-up period. CONCLUSION: This initial case suggests that, for modification of cardiovascular risk factors, there are no clear advantages in treating patients with FPLD with rosiglitazone despite increases in subcutaneous adipose tissue. Larger series will be needed to identify moderate beneficial effects and treatment may be more effective in patients with generalised forms of lipodystrophy.
One hundred forty-eight children, aged 11.9 +/- 3.7 years, who had insulin-dependent diabetes mellitus (IDDM) for 4.5 +/- 3.7 years and glycosylated Hb values (HbA1) of 10.5% +/- 4.5%, were examined for limited joint mobility (LJM) and lipodystrophy. In all diabetics, human biosynthetic insulin was used. Six hundred forty-eight pupils, aged 11.8 +/- 2.5 years, served as controls. LJM was found in 28.4% of the diabetics and in 7.5% of the controls (p < 0.001). The presence and severity of LJM was positively correlated with the duration of diabetes and negatively with height. There was no correlation between the presence of LJM and sex, chronological age, age of diabetes onset, HbA1 values, or retinopathy. Lipodystrophy at insulin injection sites was found in 37.1% of the diabetics. Hypertrophic lesions predominated. Our findings and those of the literature lead to the following conclusions: the prevalence of LJM in IDDM subjects of comparable age using Rosenbloom's criteria is almost uniform in all published studies (28%); the correlation, however, of prevalence and severity to different parameters presents discrepancies which cannot be interpreted at present. Human biosynthetic insulin does not protect from lipodystrophy and alterations of insulin injections still remain the only currently available preventive and therapeutic measure.
We describe the clinical findings and natural history of an autosomal dominant form of partial lipodystrophy found in four affected individuals from three generations in the same family. The lipodystrophy was present from infancy/early childhood, involved primarily the face and local areas on the buttocks, and was nonprogressive. Affected individuals also had the Rieger anomaly, midface hypoplasia, short stature, retarded bone age, and hypotrichosis. An affected woman developed insulinopenic diabetes mellitus at 39 yr and another had glucose intolerance at 55 yr.