Improvement of acquired partial lipodystrophy with rosiglitazone despite ongoing complement activation

U. A. Walker, M. Kirschfink1 and H. H. Peter

Albert-Ludwigs University Medical School, Department of Rheumatology and Clinical Immunology, Freiburg and
1 Institute for Immunology, Heidelberg, Germany

SIR, Acquired partial lipodystrophy is characterized by a regional loss of subcutaneous adipose tissue which usually starts in the face, extends downward to the waist, but spares the legs. The disease is often associated with the presence of an IgG autoantibody called C3 nephritic factor (C3Nef) which binds to and stabilizes C3bBb, the C3 convertase of the alternative complement pathway (Fig. 1Go) [1]. We here present a patient with acquired partial lipodystrophy in whom nephritis was absent despite persistent complement activation due to C3Nef. We show that this condition may be cosmetically improved with rosiglitazone, an agonist of the peroxisome proliferator-activated receptor (PPAR)-gamma, which promotes adipocyte differentiation.



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FIG. 1. Model of the adipocyte destruction in partial lipodystrophy. Sera containing C3Nef prevent the alternative complement C3-convertase C3bBb from degradation. Adipocytes synthesize C3, factor D and factor B. Complement is activated at the adipocyte surface and mediates adipocyte lysis.

 
A 20-yr-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. Her mother reported that the adipose tissue started to vanish in the face at 5 yr of age and that the fat loss had rapidly progressed to involve the upper part of the body. At presentation the condition had not changed for years. The patient history was otherwise uneventful, as was the family history. The anthropometric and complement measurements (CH50, C3, C3d) at baseline and at follow-up are detailed in Table 1Go. Although C3 was not consistently reduced and CH50 only at the lower limit of normal, the marked and persistent elevation of C3d (a stable C3 degradation product) indicated C3 turnover. C3Nef was positive [2], and C4 was always within normal limits. Erythrocyte sedimentation rate, C-reactive protein, serum creatinine, urine analysis, antinuclear antibodies, antineutrophil cytoplasmic antibodies, HbA1c, fasting lipids, insulin, c-peptide and glucose determinations were normal.


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TABLE 1. Anthropometric characteristics and complement measurements at baseline and during therapy*

 
After 8 months of follow-up without therapy during which no apparent change of the clinical phenotype was noted, treatment was begun with rosiglitazone. The initial daily dose of 4 mg was increased to 8 mg after 3 months. After 7 months her body weight had increased without a change in lifestyle. Notably, the subcutaneous fat of the abdomen, as well as the buccal fat, also participated in the gain of adipose tissue. However, the fat increased more pronouncedly in areas of intact body fat, especially in the hip region. Bioelectric impedance analysis confirmed that weight gain was almost entirely due to an increase of body fat, whereas the lean body mass remained unchanged.

In vitro experiments demonstrated that adipocytes are lysed by complement in the presence of C3Nef [3]. Adipocytes synthesize C3, factor B and factor D (adipsin), which allows C3bBb to be formed locally, but which usually does not result in the activation of the terminal lytic part of the complement pathway (C5–9). C3NeF prevents C3bBb from inactivation resulting in adipocyte lysis [1, 3]. Adipocytes synthesize factor D, the limiting component of the alternative complement pathway, which cleaves C3-bound factor B to its active enzymatic form [3]. Factor D is thought to be expressed to a higher extent in the fat cells of the upper half of the body than in the lower half and it is possibly this regional difference which accounts for the restriction of the fat loss to the head, arms and trunk [4].

C3Nef is also associated with type II, dense-deposit membranoproliferative glomerulonephritis in which subendothelial deposits of immunoglobulin and of C3 are probably due to a deregulated alternative complement pathway [4]. In our patient, the clinical course was not complicated by glomerulonephritis, indicating that the presence of C3Nef and systemic complement activation alone is not sufficient to cause glomerulonephritis. This is also supported by the description of a baby born to a mother with membranoproliferative glomerulonephritis. The baby had acquired C3Nef transplacentally but did not develop glomerulonephritis [5]. Although C3 and factor B are expressed in the kidney, this organ may be locally spared because of a lack of factor D production [4]. Alternatively, higher degrees of systemic C3 activation may be necessary for the manifestation of renal disease.

Only a minority of individuals with detectable C3Nef, ongoing systemic complement activation and frank glomerulonephritis presents with lipodystrophy. It has been speculated that interindividual variation in factor D expression may account for the variability of disease manifestation [4, 6] or that infections with subsequent cytokine release and complement up-regulation are important triggers for this acute-onset lipoatrophy [4, 7].

PPAR-gamma ligands promote adipocyte differentiation and seem to be beneficial in causally heterogeneous forms of lipodystrophy [8]. The patients' clinical course suggests that some regenerative capacity is retained in the areas of fat loss despite years of disease activity with ongoing complement activation. There may therefore be a balance between adipocyte destruction and adipocyte regeneration and the PPAR-gamma agonist may shift the equilibrium towards regeneration.

In summary, 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.

Notes

Correspondence to: U. A. Walker, Albert-Ludwigs University Medical School, Department of Rheumatology and Clinical Immunology, Hugstetterstr. 55, D-79106 Freiburg, Germany. E-mail: walkerrul{at}uni-freiburg.de Back

References

  1. Mathieson PW, Würzner R, Oliveria DB, Lachmann PJ, Peters DK. Complement-mediated adipocyte lysis by nephritic factor sera. J Exp Med 1993;177:1827–31.[Abstract]
  2. Rother U. A new screening test for C3 nephritis factor based on a stable cell bound convertase on sheep erythrocytes. J Immunol Methods 1982;51:101–7.[CrossRef][ISI][Medline]
  3. Choy LN, Rosen BS, Spiegelman BM. Adipsin and an endogenous pathway of complement from adipose cells. J Biol Chem 1992;267:12736–41.[Abstract/Free Full Text]
  4. Mathieson PW, Peters DK. Lipodystrophy in MCGN type II: the clue to links between the adipocyte and the complement system. Nephrol Dial Transplant 1997;12:1804–6.[Free Full Text]
  5. Weiss L, Rougier N, Blouin J, Kazatchkine MD, Lhotta K, Konig P. Hypocomplementaemia in a newborn caused by transplacental passage of maternal autoantibody with C3 nephritic factor (C3 NeF) activity. Nephrol Dial Transplant 1995;10:2374.
  6. Skattum L, Martensson U, Sjoholm AG. Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti-C1q autoantibodies. J Intern Med 1997;242:455–64.[ISI][Medline]
  7. Gewurz AT, Imherr SM, Strauss S, Gewurz H, Mold C. C3 nephritic factor and hypocomplementaemia in a clinically healthy individual. Clin Exp Immunol 1983;54:253–8.[ISI][Medline]
  8. Arioglu E, Duncan-Morin J, Sebring N, Rother KI, Gottlieb N, Lieberman J et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med 2000;133:263–74.[Abstract/Free Full Text]
Accepted 15 July 2002





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