Progressive Lipodystrophy

Updated: Jul 14, 2017
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD  more...
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Overview

Background

Lipodystrophy syndromes represent a group of rare, heterogeneous disorders characterized by progressive loss of fat tissue, mainly from the subcutaneous compartment and occasionally from visceral fat. [1] Subcutaneous loss of fat can occur as generalized or partial lipodystrophy; the latter is more common. Progressive lipodystrophy is the most common type of partial lipodystrophy.

The other types, such as the Kobberling-Dunnigan variety or the familial mandibuloacral dysplasia syndrome, may be familial and tend to be associated with metabolic anomalies such as glucose intolerance and hypertriglyceridemia. Nakajo-Nishimura syndrome is an inherited inflammatory disease that usually begins in early infancy with a perniolike rash, periodic high fever, and nodular erythemalike eruptions, with gradually progressive partial lipoatrophy of the upper body, mainly the face and the upper extremities. [2] Acquired partial lipodystrophy is a rare condition of unknown etiology characterized by progressive loss of fat of the face, neck, trunk, and upper extremities beginning during childhood and is more common in girls. [3]

Progressive lipodystrophy is a rare condition that typically affects children and young adults. The first case was described by Mitchell in 1886, [4] and later cases were described by Barraquer in 1907 and Simons in 1911. The onset is usually insidious with the slow, progressive disappearance of subcutaneous fat involving the upper half of the body. The predictive progression of the disease from the face to the neck, upper extremities, and trunk (sparing the buttocks and lower limbs) is characteristic. Associated hypocomplementemia, glomerulonephritis, and autoimmune disorders are frequently present in some patients. However, some forms of partial lipodystrophy in children do not seem to fit the diagnostic criteria for any of the established lipodystrophy subset. [5]

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Pathophysiology

The etiology of this condition is obscure. Lipodystrophy is often associated with glomerulonephritis, low C3 serum complement levels, and the presence of a C3 nephritic factor. C3 nephritic factor is a serum immunoglobulin G that interacts with the C3bBb alternative pathway convertase to activate C3.

C3 nephritic factor induces the lysis of adipocytes that secrete adipsin, a product identical to complement factor D. The distribution of the lipoatrophy is postulated to be dictated by the variable amounts of adipsin secreted by the adipocytes at different locations.

Human PTRF mutations may cause secondary deficiency of caveolins, resulting in generalized lipodystrophy in association with in muscular dystrophy. [6]

Dunnigan-type familial partial lipodystrophy was linked with heterozygous R482W mutation in the LMNA gene in an analysis of 3 women from one family. [7, 8]

Berardinelli-Seip congenital lipodystrophy type 2, the severest form of human lipodystrophy with an almost complete loss of adipose tissue, is due to loss-of-function mutations in the BSCL2/SEIPIN gene. [9]

See the model below.

Model of the adipocyte destruction in acquired par Model of the adipocyte destruction in acquired partial lipodystrophy showing complement activation at the adipocyte surface resulting in adipocyte lysis. 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).The IgG antibody, C3Nef, prevents the alternative complement C3-convertase C3Bb from dissociative inactivation, resulting in adipocyte lysis. Adipocytes synthesize factor D, the limiting component of the alternative complement pathway, which cleaves C3-bound factor B to its active enzymatic form. Factor D is expressed to a higher extent in the fat cells of the upper half of the body compared with the lower half, and it is possibly this regional difference that accounts for the restriction of fat loss to the head, arms, and trunk. C3Nef is also associated with type II, dense-deposit membranoproliferative glomerulonephritis in which subendothelial deposits of immunoglobulin and C3 are probably due to a deregulated alternative complement pathway.
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Epidemiology

Frequency

Progressive lipodystrophy is rare, with fewer than 200 cases reported in the world literature since the first case was reported in 1885. [10]

Race

No racial predilection is reported for progressive lipodystrophy.

Sex

Progressive lipodystrophy is 4-5 times more common in women than in men. Of patients with progressive lipodystrophy, 80% are females. The accumulation of fat in the buttocks and lower limbs occurs almost exclusively in females. Males who are affected usually have lipoatrophy without lower body hypertrophy.

Age

Progressive lipodystrophy typically starts in individuals aged 0-20 years, with most cases starting before individuals are aged 15 years. Progressive lipodystrophy tends to develop earlier in most male patients compared with female patients.

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Prognosis

The prognosis for progressive lipodystrophy is correlated with the renal complications and the onset of renal failure. Acquired progressive lipodystrophy is a nonfatal condition, but it is frequently associated with mesangiocapillary glomerulonephritis, which can lead to renal insufficiency. In pregnancy, more severe renal disease is associated with a risk of intrauterine growth retardation, prematurity, and fetal death. [11] Associated autoimmune disorders are also present in some patients, including systemic lupus erythematosus and dermatomyositis.

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