Background
Lipodystrophy refers to the loss of adipose tissue. It is classified as either diffuse (generalized) or local (partial) and results from either genetic or acquired etiologies. Ectopic fat in tissues such as liver and muscle may be increased. The cumulative loss of fat leads to a decrease in adipose-derived adiponectin and leptin. Circulating levels of these adipokines are lower in generalized versus partial lipodystrophy as predicted from the loss of fat. [1, 2]
Acquired partial lipodystrophy (APL) also known as Barraquer-Simons syndrome or cephalothoracic lipodystrophy, is one of the rare forms of lipodystrophy. This syndrome was initially reported in 1885 and further characterized by Barraquer and Simmons early in the 20th century. Since then, approximately 250 cases have been reported in English literature. [3]
Acquired partial lipodystrophy usually begins in childhood, at a median age of 7 years. [4] It predominantly affects females and often follows an acute, febrile viral illness, most commonly measles. [3] Fat loss is usually limited to the face, trunk, and upper extremities. Simultaneously, fat hypertrophy occurs in the lower extremities. These patients may develop nephropathies. Activation of alternate complement pathway has been demonstrated in most patients. The phenotype can be variable and sometimes only affecting the face. [5]
In contrast with their occurrence in other types of lipodystrophy, diabetes and impaired glucose tolerance are found only rarely in APL, being reported in 6.7% and 8.9% of patients, respectively. [4] This may be related to the fact that in this syndrome, patients have limited fat loss.
Associated Disorders
Disorders associated with acquired partial lipodystrophy include the following:
Membranoproliferative glomerulonephritis (MPGN) - This condition has been reported in about 20% of cases, and proteinuria, in 45% of cases. However, it is possible that other concomitant diseases (eg, urinary tract infection, diabetes) contribute to the rates of proteinuria. [4] Patients with MPGN are more likely to have low C3 levels and the presence of C3 nephritic factor (C3NeF). [6, 7, 8]
Autoimmune diseases - Systemic lupus erythematosus is the most common of these [6, 7] ; other reported autoimmune diseases include, but are not limited to, the following:
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Pernicious anemia
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Celiac disease
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Dermatitis herpetiformis
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Temporal arteritis
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Leukocytoclastic vasculitis
Propensity to bacterial infections
Other - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal component, skin changes) syndrome, [5] mental retardation and retinal disease are among the syndromes that also are associated with acquired partial lipodystrophy.
Patient Education
Educating patients about the disease and its associated complications is very important. Parents should be notified about facial changes that may occur in their child; they should also be told about the importance of balancing dietary intake in order to avoid metabolic complications and to ensure healthy development.
Pathophysiology and Etiology
The precise pathophysiology of fat loss in acquired partial lipodystrophy (APL) is unclear. Activation of an alternate complement pathway, C3 hypocomplementemia with lysis of adipocytes induced by C3NeF, has been implicated. [10, 11, 12] C3 hypocomplementemia likely contributes to the association of this syndrome with autoimmune diseases and with a propensity for patients to acquire bacterial infections. [4] Other proposed mechanisms include an autoimmune process, viral infection, [13] and genetic associations. [14, 15, 16, 17] A related gene, LMNA, has coding mutations associated with another form of lipodystrophy, Dunnigan-type familial partial lipodystrophy. [18, 19]
Another form of lipodystrophy that fits the classification of “acquired partial” not involving the complement pathway is associated with hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma. Five cases were reported but the phenotype resembles Dunnigan-type familial partial lipodystrophy rather than classic APL. [20] Hosokawa et al reported two cases of APL associated with HSCT in children who manifested graft-versus-host disease (GVHD) following treatment for leukemia. They suggest a connection between GVHD; evaluations of fat distribution and metabolic disease may be indicated in the long-term follow-up of these patients. [21]
Epidemiology
Approximately 250 cases have been reported since the recognition of this syndrome. Women are affected approximately 4 times more often than men. [4] The majority of cases have been of European descent. The median age of onset of lipodystrophy has been reported to be around 7 years; however, onset occurring as late as the 4th or 5th decade of life also has been reported. [4]
Prognosis
There is no cure and therapeutic approaches for acquired partial lipodystrophy (APL) consist of improving appearance with plastic surgery and managing comorbid systemic disorders. The main goal of cosmetic procedures is to minimize psychological distress and improve quality of life. Metabolic complications are rare but should be treated when present. Following diagnosis, guidelines recommend all patients be screened for diabetes, dyslipidemia, liver disease, and cardiovascular and reproductive dysfunction. Clinical judgment should guide follow-up screening. A hypolipidic diet plan and regular exercise are also advised. [22]
APL is a slowly progressive disease. In the absence of associated renal impairment or insulin resistance, the prognosis is excellent. The most significant complications are disfigurement in severe facial involvement, renal disease, and, rarely, insulin resistance. Estimating the mortality rate based on the available literature is difficult. Several case reports have revealed an association between APL and other diseases (see Background).
Nephropathy, in the form of membranoproliferative glomerulonephritis (MPGN), occurs in approximately 20% of patients. [4] Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years. MPGN usually presents with asymptomatic proteinuria or hematuria. The disease may gradually progress. About 40-50% of patients develop end-stage renal disease over the course of 10 years. This condition is responsible for most recurrent hospital admissions in patients with APL. [4] Rapid progression of renal disease in a pregnant patient was reported. [23] Recurrent disease in transplanted kidneys is common, although there have been reports of successful transplantations. [24, 25]
Associated autoimmune diseases (eg, systemic lupus erythematosus, thyroiditis) contribute significantly to increased morbidity in these patients compared with the general population. Localized scleroderma has also been reported. [26]
Although uncommon, insulin resistance increases cardiovascular risk.
Susceptibility to bacterial infections probably results from a C3 deficiency (due to complement activation and consumption of C3). Low C3 levels may impair complement-mediated phagocytosis and bacterial killing.
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Fat distribution in acquired partial lipodystrophy.
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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.
