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A. Characteristics navigator

  1. Heterogeneous group of adipose tissue disorders
  2. Selective (but higly variable) loss of adipose tissue
  3. Familial and Acquired (possibly autoimmune) forms
  4. Localized versus generalized lipodystrophies
  5. Generalized lipodystrophies often include other metabolic derangements
    1. Insulin resistance
    2. Hypertriglyceridemia
    3. Early onset diabetes mellitus (due to loss of ß-cells)
    4. Fatty liver
  6. Familial / Genetic Types
    1. Congenital Generalized Lipodystrophy
    2. Familial Partial Lipodystrophies
    3. Miscellaneous Types
  7. Acquired Types
    1. Acquired Generalized Lipodystrophy
    2. Acquired Partial Lipodystrophy
    3. Lipodystrophy Associated with HIV Infection
    4. Localized Lipodystrophies
  8. Localized Lipodystrophies
    1. Drug induced
    2. Pressure induced
    3. Panniculitis
    4. Centrifugal
    5. Idiopathic
  9. PPAR-gamma agonists (glitazones) improve metabolic control in various lipodystrophies [6]

B. Normal Adipocyte Development navigator

  1. Adipocytes derived from multipotent mesenchymal stem cells
  2. These cells then undergo committment to white or brown preadipocytes
    1. Preadipocytes then go on to differentiate to functional adipocytes
    2. White preadipocytes can probably form mechanical or metabolically active adipocytes
  3. Brown Adipose Tissue
    1. Associated with viscera
    2. High mitochondrial content with uncoupled oxidative phosphorylation
    3. Thermoregulatory role - main function is conversion of energy to heat
  4. White Adipose Tissue
    1. Subcutaneous fat
    2. Main function is fat storage
    3. Distribution of white fat in body may determine risk for cardiovascular disease
  5. Adipocyte Energy Metabolism [2]
    1. At rest, >50% of body heat is generated from inefficient conversion of food to ATP
    2. Most of the heat is produced in visceral organs and distributed around the body by blood
    3. When ATP and heat needs have been met, additional food energy converted to fat
  6. Normal Distribution of Body Fat
    1. Body fat is normally distributed mainly in peripheral areas (rather than central)
    2. Peripheral (non-central) obesity appears to be less of a cardiovascular risk factor than central obesity

C. Congenital Generalized Lipodystrophy navigator

  1. Berardinelli-Seip Syndrome
  2. Extremely rare autosomal recessive disorder
    1. Prevalance ~1 per 12 million
    2. Affects all ethnic groups
  3. Physical Development
    1. Nearly complete absence of adipose tissue from birth
    2. Muscular appearance
    3. Accelerated growth and voracious appetite in early childhood
    4. Increased basal metabolic rate and advanced bone age
    5. Normal or slightly increased final height
    6. Enlargement of hands, feet, and mandible (appears acromegaloid)
  4. Other Characteristics
    1. Acanthosis nigricans common, usually by age 8
    2. Umbilical hernia common
    3. Hepatosplenomegaly
    4. Occasional excessive body hair and hyperhidrosis
  5. Metabolic Derangements
    1. Marked insulin resistance is may be present
    2. Severe hyperinsulinemia
    3. Hypertriglyceridemia and chylomicronemia
    4. Eruptive xanthomas may occur
    5. Acute pancreatitis due to triglycerides
    6. Reduced HDL levels
    7. Accellerated atherosclerosis
    8. Low plasma leptin levels
  6. Etiology
    1. Type 1: autosomal recessive, AGPAT2 mutation
    2. AGPAT2 involved in biosyhtesis of triglycerides and phospholipids
    3. Type 2: autosomal recessive, seipin mutations (function unknown)
  7. Diagnostic Criteria
    1. Generalized lack of body fat from birth (required)
    2. Extreme muscularity from birth (required)
    3. Acanthosis nigricans
    4. Acromegaloid features
    5. Umbilical hernia
    6. Clitoromegaly and mild hirsutism in women
    7. Severe fasting or postprandial hyperinsulinemia
    8. Imparied glucose tolerance (or frank diabetes mellitus) in teenage years
    9. Hypertriglyceridemia with reduced HDL
    10. Hepatomegaly
    11. Characteristic body fat distribution on MRI (confirmatory)
  8. Leptin Replacement Therapy [8]
    1. For patients with severely reduced serum leptin levels (<3ng/mL)
    2. Dose of 0.03-0.04mg sc q12 hours given
    3. Reduced glycosylated hemoglobin 1.9%
    4. Allowed reduction or discontinuation of diabetes therapy
    5. Reduced triglyceride levels 60% from elevated baseline
    6. Reduced liver volume by 28%

D. Familial Partial Lipodystrophynavigator

  1. Four Distinct Variants
    1. Dunnigan Variety
    2. Kobberling Variety
    3. Mandibuloacral Dysplasia Variety
    4. PPARgamma Mutation Variety [1]
  2. Dunnigan Variety
    1. Most common form; ~100 patients, all caucasian, reported worldwide
    2. Prevalence estimates <1 in 15 million
    3. Autosomal dominant due to mutations in Lamins A and C genes (LMNA)
    4. Missense mutations in exon 1 of LMNA gene found in two families with Dunnigan [11]
    5. Mutations in LMNA or zinc metalloproteinase gene ZMPSTE24 associated with mandibuloacral dysplasia variety
    6. LMNA mutations also found in dilated cardiomyopathy and limb-girdle muscular dystrophies
  3. Dunnigan Characteristics
    1. Marked absence of subcutaneous fat from extremities and trunk
    2. Prominent veins and muscularture
    3. Excessive fat deposition in face, chin, neck, labia majora
    4. Intra-abdominal and intrathoracic fat is not reduced
    5. Bone marrow fat and mechanical adipose tissue present in normal amounts
  4. Diagnostic Criteria for Dunnigan Variety
    1. Normal appearance at birth with fat loss commencing at puberty
    2. Lack of subcutaneous fat and extreme muscularity in all extremities
    3. Excessive or normal adipose tissue in face and neck
    4. Acanthosis nigricans
    5. Mild to moderate fasting or postprandial hyperinsulinemia
    6. Onset of impaired glucose tolerance or diabetes after age 20
    7. Hypertriglyceridemia with reduced HDL
    8. Characteristic body fat distribution on MRI (confirmatory)
  5. Kobberling Variety
    1. Loss of adipose tissue restricted to extremities
    2. Very few patients, mainly women, have been described
    3. Hypertriglyceridemia and diabetes mellitus
  6. Mandibuloacral Dysplasia Variety
    1. Autosomal recessive condition
    2. Mandibular and clavicular hypoplasia with dental abnormalities
    3. Short stature and high pitched voice
    4. Acro-osteolysis and stiff joints
    5. Skin atrophy, alopecia and nail dysplasia may occur

E. Acquired Generalized Lipodystrophynavigator

  1. Lawrence Syndrome
  2. About 50 cases have been reported
  3. About 3:1 females to males
  4. Loss of fat begins in childhood to early adolescence
  5. Believed to have an autoimmune etiology
  6. Diagnostic Criteria
    1. Generalized lack of body fat from childhood or later (required)
    2. Extreme muscularity from childhood or later (required)
    3. Loss of subcutaneous fat from palms or toes
    4. Subcutaneous nodular swelling (panniculitis) preceding onset of lipodystrophy
    5. Severe fasting or postprandial hyperinsulinemia
    6. Imparied glucose tolerance (or diabetes)
    7. Hypertriglyceridemia with reduced HDL
    8. Characteristic body fat distribution on MRI (confirmatory)
    9. Presence of other autoimmune disorders

F. Acquired Partial Lipodystrophy [12]navigator

  1. Barraquer-Simons Syndrome
  2. Women 3:1 over men
  3. Onset usually around 8 years, always before age 16
  4. About 33% of patients develop mesangiocapillary glomerulonephritis
  5. Diagnostic Criteria
    1. Gradual onset loss of subcutaneous fat from face, neck, trunk, upper extremities
    2. Fat loss begins during childhood or adolescence (required)
    3. Normal or excess subcutaneous fat in hips and lower extremitites
    4. Proteinuria or biopsy-proven glomerulonephritis
    5. Low serum complement C3 levels (with normal C4)
    6. Absence of insulin resistance and metabolic complications
    7. Presence of other autoimmune diseases
    8. May be ANA+ and/or rheumatoid factor (RF) positive
  6. Etiology
    1. Likely autoimmune
    2. About 90% of patients have serum IgG called C3 nephritic factor
    3. Levels of serum C3 are low, but other complement proteins are normal
    4. C3 nephritic factor (C3NeF) is an IgG autoantibody that stabilizes complement components
    5. C3NeF binds to C3bBb complex leading to prolonged activation of alternative complement
    6. This complex binds to kidneys and mediates complement dependent damage
    7. C3NeF also appears to mediate lysis of adipocytes
    8. C3NeF is also associated with mesangiocapillary glomerulonephritis Typ II
    9. Arthritis may be similar to rheumatoid and/or systemic lupus type
  7. Arthritis may improve on hydroxychloroquin

G. Lipodystrophy in HIV Infection [3,7,8] navigator

  1. Characteristics of the Syndrome
    1. Wasting of peripheral fat
    2. Accumulation of in dorsocervical area ("buffalo hump")
    3. Accumulation of fat in breasts and inside the abdominal cavity
    4. Hyperlipidemia and insulin resistance occur
    5. Protease inhibitors (PI) and other antiretrovirals implicated
    6. Development of lipodystrophy is multifactorial [8]
    7. Specific case definition has now been proposed includes clinical and lab markers [3]
  2. Overview of Mechanisms
    1. PI bind HIV in protease region that has homology to CRABP1 and to LRP
    2. PI and other antiretrovirals alter peripheral adipocyte differentiation
    3. Sterol regulatory element binding protein I (SREBP1) dysregulation implicated [10]
    4. SREBP1 is critical in normal adipocyte differentiation
    5. Tumor necrosis factor alpha (TNFa) elevated and leptin reduced in peripheral fat [10]
  3. Cytosolic Retinoic Acid Binding Protein 1 (CRABP1)
    1. CRABP1 binds to all retinoic acids (RA)
    2. Complex of CRABP1-RA interacts with cytochrome P450 system
    3. Protease binding to CRABP1 could prevent conversion of RA by P450 3A as well
    4. RA is converted to active cis-9-retinoic acid (C9RA) form
    5. C9RA binds to Retinoid X Receptor (RXR) and activates it
    6. RXR-RA binds to and stimulates PPAR gamma (PPARg)
    7. PPARg is responsible for stimulation of peripheral adipocytes and uptake of lipids
    8. PPARg levels are substantially reduced in patients with lipodystrophy [10]
  4. Role of Nucleoside Reverse Transcriptase Inhibitors [4]
    1. Likely that RTI's contribute to development of lipodystrophy in HIV infected persons
    2. Inhibition of mitochondrial DNA polymerase gamma contributes to lipodistrophy
    3. Mitochondrial dysfunction plays a role in lipodystrophy, myopathy, and neuropathy
    4. Therefore, HIV associated lipodystrophy likely has multiple contributing etiologies
  5. Low Density Lipoprotein (LDL) Related Protein (LRP)
    1. LRP is coexpressed on capillary epithelium with lipoprotein lipase (LPL)
    2. LRP-LPL complex cleaves fatty acids from circulating triglycerides
    3. This allows fatty acids to be stored in adipocytes
    4. Protease binding to this complex could prevent lipolysis and increase triglycerides
    5. LRP also clears many endogenous proteases including tissue plasminogen activator
    6. Blocking TPA clearance could increase bleeding risk
  6. Effect on Cytochrome P450 System
    1. Many protease inhibitors inhibit cytochrome P450 3A (CYP 3A)
    2. CYP 3A converts retinoic acid to
    3. Ritonovir, which causes the greatest lipodystrophy, is a potent inhibitor of CYP 3A
    4. C9RA (and not RA itself) binds to RXR (above) and activates PPARg pathways
  7. Proposed Pathophysiology of Syndrome
    1. Experiments evaluating the above possibilities have not been reported
    2. Likely, however, that protease inhibitor effects modulate fat metabolism as follows:
    3. Inhibiting C9RA formation leads to peripheral adipocyte apoptosis and lipodystrophy
    4. Reduced peripheral fat uptake of triglycerides leads to hyperlipidemia
    5. Hyperlipidemia appears to increase insulin resistance
    6. Central obesity occurs apparently as a compensatory mechanism after hyperlipidemia
  8. Clinical Characteristics [3,5]
    1. PI's may cause hyperglycemia and frank diabetes occurs in ~5%
    2. PI's are associated with lipodistrophy, hyperlipidemia and diabetes
    3. Lipodystrophy (atrophy of fat) occurs in up to 83% of patients treated with PI's
    4. Central adiposity also occurs and is likely related to insulin resistance
  9. Metabolic Derangements [7]
    1. Hypertriglyceridemia
    2. Hypercholesterolemia
    3. Insulin resistance (hyperinsulinemia, elevated C-peptide)
    4. Type 2 Diabetes Mellitus
  10. Diagnosis [3]
    1. Diagnosis can be made by observation and measurement of various laboratory markers
    2. Demonstration of glucose intolerance with oral glucose loading can also be done
    3. Glucose intolerance is not required to meet case definition
  11. Treatment
    1. Rosiglitazone (Avandia®) 4mg po bid x 48 weeks had no benefit in HIV-1 lipodystrophy [13]
    2. Both rosiglitazone and metformin were beneficial in HIV lipodystrophy; metformin appeared superior for abomdinal fat reduction, lipid improvement, endothelial function [14]
    3. Growth hormone releasing hormone (GHRH) 1mg sc bid x 12 weeks increased IGF-1 and increased lean body mass while reducing abdominal visceral fat [15]

H. Management [1]navigator

  1. Cosmetic appearance - weight loss and adipose transplantation have been used
  2. Dyslipidemia
    1. Advise extremely low fat diet (<15% of total enerergy from fat)
    2. Glycemic control reduces hypertriglyceridemia
    3. Regular exercise
    4. Fibrates and n-3 polyunsaturated fat supplements
  3. Hyperglycemia
    1. Oral hypoglycemic drugs or insulin (or combinations)
    2. Metformin (Glucophage®) is first line
    3. Insulin is generally second or third line
    4. Glitazones may also be used, particularly in PPAR gamma mutation syndromes
  4. Recombinant leptin may be effective in hypoleptinemic states (see above)

References navigator

  1. Garg A. 2004. NEJM. 350(12):1220 abstract
  2. Mackowiak PA. 1998. Arch Intern Med. 158(17):1870 abstract
  3. HIV Lipodystrophy Case Definition Study Group. 2003. Lancet. 361(9359):726 abstract
  4. Brinkman K, Smeitink JA, Romijn JA, Reiss P. 1999. Lancet. 354(9184):1112 abstract
  5. Carr A, Samaras K, Thorisdottir A, et al. 1999. Lancet. 353(9170):2093 abstract
  6. Arioglu E, Duncan-Morin J, Nebring N, et al. 2000. Ann Intern Med. 133(4):263 abstract
  7. Carr A and Cooper DA. 2000. Lancet. 356(9239):1423 abstract
  8. Martinez E, Mocroft A, Garcia-Viejo MA, et al. 2001. Lancet. 357(9256):592 abstract
  9. Oral EA, Simha V, Ruiz E, et al. 2002. NEJM. 346(8):570 abstract
  10. Bastard JP, Caron M, Vidal H, et al. 2002. Lancet. 359(9311):1026 abstract
  11. Garg A, Speckman RA, Bowcock AM. 2002. Am J Med. 112(7):549 abstract
  12. Dalbeth N and Callan M. 2002. Lancet. 360(9342):1300 (Case Report) abstract
  13. Carr A, Workman C, Carey D, et al. 2004. Lancet. 363(9407):429 abstract
  14. Van Wijk JPH, de Koning EJP, Cabezas MC, et al. 2005. Ann Intern Med. 143(5):337
  15. Koutkia P, Canavan B, Breu J, et al. 2004. JAMA. 292(2):210 abstract