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Complement Abnormalities in Acquired Lipodystrophy Revisited

Metabolic Research Laboratories (D.B.S., R.K.S., C.A., S.O.), Institute of Metabolic Science, Department of Medicine (M.R.C., P.A.L., G.J.M.A., A.N.C., K.G.C.S.), Cambridge Institute for Medical Research, and Department of Pathology (S.T.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom; Department of Medical Biochemistry and Immunology (B.P.M.), School of Medicine, Cardiff University, Cardiff CF10 3AT, United Kingdom; Clinical Endocrinology Branch (E.K.C., P.G.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892-2560; Wellcome Trust Clinical Research Facility (P.R.-B., P.R.M.), Addenbrooke’s Hospital, Cambridge CB2 0SP, United Kingdom; Medway Maritime Hospital (I.S.), Gillingham, Kent ME7 5NY, United Kingdom; Department of Haematological Medicine (G.J.M.), Kings College London, London WC2R 2LS, United Kingdom; and Institute of Normal Human Morphology (I.M., S.C.), University of Ancona, I-60131 Ancona, Italy

Address all correspondence and requests for reprints to: Dr. D. B. Savage or Dr. R. K. Semple, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom. E-mail: dbs23{at}medschl.cam.ac.uk, or rks16{at}cam.ac.uk, respectively.

Context: Lipodystrophy is a heterogeneous condition characterized by an inherited or acquired deficiency in the number of adipocytes required for the storage of energy as triglycerides. Acquired lipodystrophy is frequently associated with other autoimmune disorders. One well-studied form is characterized by the selective loss of upper body fat in association with activation of the alternative complement pathway by C3 nephritic factor, low complement factor C3, and mesangiocapillary glomerulonephritis.

Objective: We now describe an immunologically distinct form of acquired generalized lipodystrophy, with evidence of activation of the classical complement pathway (low C4) and autoimmune hepatitis.

Patients and Research Design: Three unrelated patients with acquired lipodystrophy and low complement C4 levels are described. In vitro analysis of the complement pathway was undertaken to determine the reason for the low C4 complement levels. Biopsies were obtained from liver, bone marrow, and adipose tissue for histological analysis.

Results: All three patients manifested near-total lipodystrophy, chronic hepatitis with autoimmune features, and low C4 complement levels. Additional autoimmune diseases, including severe hemolytic anemia, autoimmune thyroid disease, and polyneuropathy, were variably present. Detailed studies of complement pathways suggested constitutive classical pathway activation.

Conclusions: Although the previously described syndrome, which typically results in a cephalad pattern of partial lipodystrophy, results from activation of the alternative complement pathway, this form, in which lipodystrophy is generalized, is associated with activation of the classical pathway. Future therapeutic approaches to these disorders may benefit from being tailored to their distinct immunopathogenesis.