Are You Confident of the Diagnosis?
Lipodystrophy is a medical condition of fat metabolism caused by adipose tissue accumulation and lipoatrophy (loss of fat mass). Lipodystrophy can be congenital or acquired
Acquired lipodystrophy is the most common form of lipodystrophy. In partial and generalized acquired lipodystrophy, females are affected more often than males. In partial acquired lipodystrophy fat may accumulate in the legs and hips in women. Partial acquired lipodystrophy is also associated with autoimmune disorders including systemic lupus erythematosus, hypothyroidism and rheumatoid arthritis. Lipodystrophy is also associated with human immunodeficiency virus (HIV) because of long-term treatment with antiretroviral drugs (protease inhibitors and nucleoside reverse transcriptase inhibitors). Fat is lost from the face, arms, legs and buttocks. Fat may accumulate on the neck and upper back.
Acquired lipodystrophy may also appear at steroid injection sites, repeated insulin injection sites or in other injection sites like penicillin, acupuncture, iron, growth hormone and vaccines. Inflammation of subcutaneous fat (panniculitis) and progressive hemifacial atrophy are also called acquired lipodystrophy.
Congenital lipodystrophy can affect all of the body (generalized lipodystrophy) or some parts of the body (partial lipodystrophy). Generalized congenital lipodystrophy is generalized loss of body fat with gene mutations of seipin or AGPAT2 gene. It is characterized by high levels of insulin and high levels of blood fats. Partial congenital lipodystrophy is associated with metabolic syndromes (including hypertension, insulin resistance, diabetes and severe hypertriglyceridemia).
Types of lipodystrophy are summarized in Table I.
|Type||Cause||Features||Key Systemic Associations|
|Acquired Partial Lypodystrophy (Barraquer-Simmonds syndrome, cephalothoracic lipodystrophy)||Associated with autoimmune disease ( lupus, dermatomyositis) and idiopathic cases||Slow, progressive disappearence of subcutaneous fat involving the upper half of the body. Affects children and young adults, women more than men. Fat may accumulate in the legs and hips, especially in women.||Associated with hypocomplementemia (low C3), membranoproliferative glomerulonephritis in 20%, and autoimmune disorders.Presence of C3 nephritic factor. C3 nephritic factor casues activation of the alternative complement path leading to decreased C3 levels.|
|Acquired generalized lipodystrophy(Lawerence syndrome)||Idiopathic 50%, secondary to panniculitis or underlying autoimmune disease in 50% (dermatomyositis, especially the juvenile form||Progressive loss of subcutaneous fat of the face, neck, trunk, and upper and lower extremities.||Associated with hypertriglyceridemia, diabetes, and hepatic cirrhosis in up to 20%|
|Familial partial lipodystrophy (Dunnigan type, congenital partial lipodystrophy)||Heterozygous missense mutations of LMNA||Autosomal dominant disorder, 1 in 15 million. Lack of adipose tissue in the limbs, buttocks and trunk with fat accumulation in the neck and face||Normal childhood fat tissue. After puberty the fat tissue slows, dissipates. Extremities are affected first, and then the trunk. Pateints develop a muscular appearance. Diabetes, hypertriglyceridemia; can lead to pancreatitis. Atherosclerosis.|
|Familial partial lypodystrophy (PPAR type, congenital partial lipodystrophy)||Heterozygous mutations in PPARγ gene||Exceedingly rare.Peripheral fat loss, truncal sparing.||Diabetes, hypertriglyceridemia|
|Congenital generalized lypodystrophy(Beradinelli-Seip syndrome)||Type I AGPAT2 gene mutationsType II Seipin (BSCL2) mutationsType III CAV1 mutationsType IV PTRF mutations||Autosomal recessive, 1 in 10 million||Near complete abscence of fat. Presents at birth. Muscular appearance. Increased risk for hepatic steatotosis/cirrhosis. Increased insulin and triglyceride levels.Type IV associated with myopathy, with increased CPK levels|
|Lipodystrophy secondary to medications||Injections (insulin, vaccines)||Localized depression with loss of fat tissue||None|
|Lipodystrophy secondary to trauma||Nearly any form of trauma including self-induced forms can be causative||Localized depression with loss of fat tissue. In self -induced forms more than one area may be involved.||Self-induced forms may be associated with psychiatric disease.|
|Semicircular and annular lipoatrophy||Felt to be casued by repetitive trauma||Semicircular linear depression along the anterior thigh.Annular depressed linear bands around arms and lower leg.||Annular lipoatrophy may be associated with arthritis.|
|HIV-associated lipodystrophy||Felt to be caused by protease inhibitors and/or reverse transcriptase inhibitors. Starts within 6 months of initiation of medications.||Acral lipoatrpohy and truncal fat deposition, “Buffalo Hump.” Lipomatosis also seen. Muscular appearance is seen. Severe facial lipoatrophy.||HIV infection|
|Centrifigual abdominal lipodystrophy (lipodystrophia centrifugalis abdominalis)||Unknown||Rare, mostly seen in Asian children. Spontaneously resolves in 50%.||None|
|Mandibuloacral dysplasia lipodystrophy||Possibly caused by mutations in the LMNA gene||Autosomal recessiveType A – Arm and leg fat lossType B – Generalized fat loss||Mandible and clavicular hypoplasia, alopecia, skin atrophy, and dental abnormalities|
Characteristic findings on physical examination
-Temporal wasting and loss of buccal fat pad
-Peripheral fat wasting (from face, arms, shoulders, thighs and buttocks)
-Neck fat pad (dorsocervical fat pad) hypertrophy (seen also in Cushing’s syndrome)
-The circumference of the neck expands
-Abdominal visceral fat accumulation results with central truncal adiposity
-Pubic lipomas occur in some patients
Who is at Risk for Developing this Disease?
The risk for developing one of the forms of lipodystrophy is dependent on the subtype. The congenital generalized and partial forms are inherited in an autosomal recessive fashion and are exceedingly rare (estimated at 1 in 10 to 15 million).
The acquired forms of lipodystrophy are more common in patients with the following characteristics:
-Patients with metabolic syndromes
-Women: abdominal and breast fat increases, men: arms and legs fat increases
-Whites are at higher risk.
-Length and severity of HIV infection
-People with higher body mass indices
What is the Cause of the Disease?
Evidence suggest that lipodystrophy is associated with taking nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) at the same time. Cortisol level is elevated but not elevated so high as in Cushing’s syndrome. HIV causes insulin resistance, which interferes with glucose metabolism. Lipodystrophy may be a complication of living with a long-term HIV infection.
Although the precise mechanisms underlying this syndrome are not well recognized, several hypotheses based on in vitro and human studies may explain the pathogenesis of the changes:
-Inhibition of mitochondrial DNA polymerase gamma.
-Inhibition of lipid metabolism
-Prevention of the development of adipocytes.
-Decreased insulin sensitivity and beta cell dysfunction in patients with HIV associated lipodystrophy
-Circulating levels of hormones secreted by the adipose tissue such as leptin and adiponectin (reduced in patients with lipodystrophy)
Systemic Implications and Complications
-Pancreatitis caused by hypertriglyceridemia
-Prothrombotic state with potential increased risks: Increased risk of cardiovascular disease, stroke.
-Hepatic disease including cirrhosis
-Autoimmune diseases seem to have a higher incidence of lipodystrophy, especially juvenile dermatomyositis.
-Glomerulonephritis in 20% of patients with acquired partial lipodystrophy. This is associated with increased C3 nephritic factor levels, which is responsible for decreased C3 levels.
-Gastrointestinal hemorrhage due to esophageal varices is also important for the patients with acquired partial lipodystrophy. It is a common cause of death in these patients, especially in middle age.
-Hyperinsulinemia and insulin resistance characterize generalized lipodystrophy. Hyperlipemia usually precedes the diabetes.
-A novel Berardinelli-Seip congenital lipodystrophy type 2 gene mutation, E189X, has been described in a Chinese family with a child with congenital generalized lipodystrophy and early-onset diabetus mellitus.
-Acanthosis nigricans (AN) in varying degrees probably is a constant finding in acquired and congenital forms.
-Osteopenia of the lumbar spine results from increased visceral fat accumulation, and neck pain results from dorsocervical fat pad accumulation, especially in HIV lipodistophy
The treatment depends on the cause of the lipodystrophy.
-Different treatment procedures have been utilized such as liposuction as an invasive method, and mechanical massage, mesotherapy, carboxytherapy, laser or radiofrequency and infrared light techniques, manual lymphatic drainage and connective massage manipulation as noninvasive or minimally invasive methods. These techniques have been employed with little evidence that any of these therapies are effective, especially in localized lipodystrophy.
-Low-fat diet and exercise
-Managing diabetes and high cholesterol
-Changes in anti-HIV medications
-Patient education about the disease and its associated complications
Optimal Therapeutic Approach for this Disease
It depends on the cause and type of the lipodystrophy.
Leptin, an adipocyte-secreted hormone, has been used in severe lipodystrophy and has significantly improved metabolic abnormalities.
Metreleptin treatment has been well tolerated but is not yet approved in clinical use.
Thiazolidinediones have been used in the various types of lipodystrophy.
If the fat gain was in the lower body, a single report has suggested a beneficial effect from the treatment of rosiglitazone on fat distribution in acquired lipodystrophy. However, rosiglitazone could potentially cause an increased risk of myocardial infarction and health-related deaths according to the meta-analysis. The Food and Drug Administration (FDA) is requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy in 2010. Also if there was a problem, standard treatment procedures for the management of renal disase should be followed, especially in acquired lipodystrophy.
The FDA has approved tesamorelin (synthetic analogue of growth hormone-relasing factor) acetate injection as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy. (Treatment with tesamorelin is contraindicated in patients with disruption of the hypothalamic–pituitary axis resulting from hypophysectomy, hypopituitarism, or pituitary tumor/surgery; active malignancy; or pregnancy and in patients with known hypersensitivity to tesamorelin and/or mannitol.)
In acquired partial lipodystrophy, biguanides and thiazolidinediones have been used in the treatment of the insulin-resistant state and in cases of HIV-related glucose intolerance.
Leptin-analog metreleptin lowers blood glucose levels and triglycerides.
Tesamorelin was recently approved for reduction of visceral adipose tissue in HIV-associated lipodistrophy
Surgery can be a treatment option, but the main purpose of the surgery is cosmetic.
Low fat and high carbohydrate diet (according to the triglyceride levels). Regular exercise, especially aerobic exercises, should be advised to help improve metabolic status.
-Patients have to take care of their diet, exercise and proper medications
-Preparation of poly-L-lactic acid particles that are injected into the superficial subdermis, where a fibrous response is elicited in HIV-associated lipodystrophy
-HIV-associated lipodystrophy patients should be followed every 3 to 6 months, and laboratory assessments should be performed if necessary.
-In progressive lipodystrophy, patients should be followed for evidence of glomerulonephritis and systemic lupus erythematosus.
Unusual Clinical Scenarios to Consider in Patient Management
There are many genetic diseases that are unusual but that need mentioning. Such patients require a multidisciplinary team of geneticists, endocrinologists and pediatricians/family physicians/internists.
Leprachaunism (Donohue syndrome): Rare autosomal recessive disorder, mutations in the insulin receptor gene, intrauterine and postnatal growth restrictions, lipoatrophy, facial features, acanthosis nigricans, abnormal glucose homeostasis, severe insulin resistance.
Keppen-Lubinsky syndrome: growth retardation, generalized lipodystrophy, facial skin tightly adherent to underlying muscle and bone.
Werner syndrome: Autosomal recessive disorder, prematurely aged appearance, cataract, diabetes mellitus, hypogonadism, atherosclerosis, beak-shaped nose, hoarseness of the voice, graying of hair, thickening of the skin.
SHORT syndrome: Rare congenital disease, sensorineural hair loss, lipodystrophy, growth retardation, inguinal hernia, teething delay, triangular face, Rieger anomaly, ocular depression.
AREDYLD syndrome: Rare disease, lipoathrophic diabetes, ectodermal dysplasia, abnormalities of the extremities, teeth-hair-nail and kidney, absent breast, scoliosis.
Mandibuloacral dysplasia: Rare autosomal recessive syndrome, postnatal growth retardation, lipodystrophy, mandibular hypoplasia, delayed cranial suture closure, dysplastic clavicles, beak-shaped nose, atrophy of the extremity skin, acroosteolysis, premature loss of teeth, craniofacial anomalies, mottled cutaneous pigmentation, joint contractures.
Cockayne syndrome: Rare auotosomal recessive disorder characterized by growth failure, onset during second year of life, lipodystrophy, ocular abnormalities, microcephaly, photosensitivity, hearing loss, mental retardation, premature aging.
Congenital muscular dystrophy: autosomal recessive disease present at birth, muscle weakness, joint deformities.
And many others
What is the Evidence?
Sattler, FR. “Perspective pathogenesis and treatment of lipodystrophy: What clinicians need to know”. Top HIV Med. vol. 16. 2008. pp. 127-33. (This article summarizes a presentation on lipodystrophy made by Fred R. Sattler, MD, at an International AIDS Society–USA Continuing Medical Education course in Washington, DC, in May 2008.)
Camacho, D, Pielasinski, U, Revelles, JM, Gonzales, M, Haro, R, Martin, L. ” Diffuse lower limb lipoatrophy”. J Cutan Pathol. vol. 38. 2011. pp. 270-4. (A 76-year-old female who developed diffuse and symmetric lipoatrophy of lower limbs after an extensive inflammatory process affecting both extremities from thighs to ankles. Histopathologic assessment revealed a lobular panniculitis with a lymphohistiocytic infiltrate, foamy macrophages and lipophagic granuloma formation. The most striking feature in this patient was the clinical presentation as a symmetrical diffuse inflammatory process resulting in lipoatrophy of the lower limbs.)
Bayrakci Tunay, V, Akbayrak, T, Bakar, Y, Kayihan, H, Ergun, N. “Effects of mechanical massage, manual lymphatic drainage and connective tissue manipulation techniques on fat mass in women with cellulite”. JEADV. vol. 24. 2009. pp. 138-42. (The objectives of this study were to evaluate and compare the effectiveness of three different noninvasive treatment techniques on fat mass and regional fat thickness of the patients with cellulites. Sixty subjects were randomized into three groups. Group 1 (n= 20) treated with mechanical massage (MM), group 2 (n= 20) treated with manual lymphatic drainage (MLD) and group 3 (n=20) treated with connective tissue manipulation (CTM) techniques. All the treatment techniques are effective in decreasing the regional fat values of the patients with cellulites.)
Milani, GB, Filho A’Dayr, N, Joao, SMA. “Correlation between lumbar lordosis angle and degree of gynoid lipodystrophy (cellulite) in asymptomatic women”. Clinics. vol. 64. 2008. pp. 503-8. (The objective of this study was to correlate the degree of cellulite with the angle of lumbar lordosis in asymptomatic women. The analysis suggests that there is no correlation between the degree of cellulite and the angle of lumbar lordosis as measured using Cobb's method.)
Rossi, ABR, Vergnanini, AL. “Cellulite: A review”. JEADV.. vol. 14. 2000. pp. 251-62. (Gynoid lipodystrophy (cellulite) is an extremely controversial topic. A lack of knowledge regarding specific etiopathogenic factors, as well as the opportunism of some professionals and the media, has fueled debate regarding the scientific basis of this condition. This article reviews the clinical, epidemiologic, histopathologic and therapeutic aspects of cellulite.)
Troll, JG. “Approach to dyslipidemia, lipodystrophy, and cardiovascular risk in patients with HIV infection”. Curr Atheroscler Rep. vol. 13. 2010. pp. 51-6. (This review focuses on HIV and HIV treatment–associated metabolic and cardiovascular concerns, including dyslipidemias, lipodystrophy syndromes, endothelial dysfunctions, and associated metabolic events such as insulin resistance.)
Pirmohamed, M. “Clinical management of HIV associated lipodystrophy”. Curr Open Lipidol. vol. 20. 2009. pp. 309-14. (This article provides an update on the latest findings of the different clinical management strategies that have been utilized in patients with lipodystrophy.)
Fiorenza, CG, Chou, SH, Mantzoros, CS. “Lipodystrophy: Pathophysiology and advances in treatment”. Nat Rev Endocrinol. vol. 7. 2011. pp. 137-50. (Circulating levels of hormones secreted by the adipose tissue, such as leptin and adiponectin, are greatly reduced in distinct subpopulations of patients with lipodystrophy.)
Cao, H, Hegele, RA. “Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan type familial partial lipodystrophy”. Hum Mol Genet. vol. 9. 2000. pp. 109-12. (This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.)
Shastry, S, Delgado, MR, Dirik, E, Turkmen, M, Agarwal, AK, Garg, A. “Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations”. Am J Med Genet . vol. 152. 2010. pp. 2245-53. (Excellent review and discussion on congenital lipodystrophy. Discusses in depth the cases that they discovered with the PTRF mutations. Reviews the basic genetic defects of the subtypes of congenital generalized lipodystrophy.)
Herranz, P, de Lucas, R, Pérez-España, L, Mayor, M. “Lipodystrophy syndromes”. Dermatol Clin. vol. 26. 2008. pp. 569-78. (The best overall review of the lipodystrophy syndromes. Touches on all the main and most of the minor types. Current and well organized.)
Jin, J, Cao, L, Zhao, Z, Shen, S, Kiess, W, Zhi, D. “Novel BSCL2 gene mutation E189X in Chinese congenital generalized lipodystrophy child with early onset diabetes mellitus”. Eur J Endocrinol. vol. 157. 2007. pp. 783-7. (The objective of this study was to analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family. E189X is a novel BSCL2 gene mutation that contributes to CGL formation in a family of Chinese origin.)
Miehle, K, Stumvoll, M, Fasshauer, M. “[Lipodystrophy : Mechanisms, clinical presentation, therapy.]”. Internist (Berl). vol. 52. 2011. pp. 362-73. (In Germany, leptin treatment for lipodystrophic patients with severe metabolic abnormalities is offered free of charge by the University Medicine Leipzig within a compassionate use program.)
Chong, AY, Lupsa, BC, Cochran, EK, Gorden, P. “Efficacy of leptin therapy in the different forms of human lipodystrophy”. Diabetologia. vol. 53. 2009. pp. 27-35. (The aims of this study were to determine whether leptin replacement in lipodystrophy patients ameliorates their metabolic abnormalities over an extended period of time and whether leptin therapy is effective in the different forms of lipodystrophy. Leptin replacement in lipodystrophy patients leads to significant and sustained improvements in glycemic control and dyslipidemia. Leptin is effective in the various forms of lipodystrophy, whether they are acquired or inherited, generalized or partial.)
Guettier, JM, Park, JY, Cochran, EK, Poitou, C, Basdevant, A, Meier, M. “Leptin therapy for partial lipodystrophy linked to a PPAR-gamma mutation”. Clin Endocrinol (Oxf). vol. 68. 2008. pp. 547-54. (A 36-year-old woman with PL associated with a heterozygous PPARG mutation complicated by poorly controlled diabetes and severe refractory hypertriglyceridemia was enrolled in a National Institutes of Health (NIH) protocol to evaluate the role of r-metHu leptin in lipodystrophy. r-MetHu leptin is effective in treating metabolic complications associated with PL due to PPARG mutations. In the context of previously published work, our findings suggest that the response to r-MetHu leptin is independent of the etiology in lipodystrophy.)
Walker, UA, Kirschfink, M, Peter, HH. “Improvement of acquired partial lipodystrophy with rosiglitazone despite ongoing complement activation”. Rheumatology (Oxford). vol. 42. 2003. pp. 393-4. (A 20-year-old female patient presented with virtually absent subcutaneous adipose tissue at the cheeks, the trunk and the upper extremities, whereas fat distribution was normal at the hips and the lower extremities. This case illustrates that acquired partial lipodystrophy with detectable C3Nef and complement activation can occur without concomitant glomerulonephritis and metabolic derangements. Lipoatrophy can be treated cosmetically with PPAR-gamma agonists despite ongoing complement activation, demonstrating some regenerative capacity of adipose tissue in this condition.)
Nissen, SE, Wolski, K. “Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes”. N Engl J Med. vol. 356. 2007. pp. 2457-71. (They conducted searches of the published literature, the Web site of the Food and Drug Administration, and a clinical-trials registry maintained by the drug manufacturer (GlaxoSmithKline). Criteria for inclusion in our meta-analysis included a study duration of more than 24 weeks, the use of a randomized control group not receiving rosiglitazone, and the availability of outcome data for myocardial infarction and death from cardiovascular causes. Of 116 potentially relevant studies, 42 trials met the inclusion criteria. Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance. This study was limited by a lack of access to original source data, which would have enabled time-to-event analysis. Despite these limitations, patients and providers should consider the potential for serious adverse cardiovascular effects of treatment with rosiglitazone for type 2 diabetes.)
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