Acquired Partial Lipodystrophy Associated With Hypocomplementemia

Ceyhun Dizdarer, MD, Sema Kalkan, MD, Tugrul Ozcan, MD, Demet Tumay, MD, Safiye Aktas, MD

Disclosures

Lab Med. 2005;36(9):546-549. 

In This Article

Discussion

Initially reported by Mitchell and later by Barraquer and Simons, acquired partial lipodystrophy occurs before the age of 16 years, with a median age of 8 years.[2] The onset of symptoms is usually preceded by an episode of an acute viral infection. Afterwards there is a symmetrical disappearance of facial fat, extending to involve the neck, shoulders, arms, forearms, thoracic region and upper abdomen, while occasionally extending to the groin or thighs. Usually legs and hips are spared. The face is affected first, and in advanced cases, takes on a characteristic cadaverous look. Ten percent of cases may have hemilipodystrophy involving half of the face or body.[4] Whereas, the Dunnigan variety of the familial type of partial lipodystrophy, commencing at puberty is characterized by loss of subcutaneous fat only from the limbs, with maintenance of fat on face and trunk.[5]

It is well documented that the patients with familial lipodystrophy (partial or generalized) develop insulin-resistant diabetes mellitus, and have high triglycerides and free fatty acids levels. Their plasma leptin concentrations are generally low, consistent with absence of body fat.[6] However, patients with acquired partial lipodystrophy seldom have metabolic abnormalities associated with insulin resistance such as elevated lipid levels, acanthosis nigricans, hirsutism, or menstrual abnormalities.[7] Abnormal glucose tolerance tests and hypertriglyceridemia are inconsistently reported findings.[8] Experiments using lipoatrophic mice, developed by disruption of adipogenesis or inducing adipocyte death, have demonstrated that the metabolic disorder correlates with the amount of fat loss, suggesting that insulin resistance results from the lack of adipose tissue.[9] The lack of white adipose tissue also causes leptin deficiency, which contributes to the insulin resistance. On the other hand, the new classification of human white adipose tissue into metabolically active adipose tissue, which is located in the most subcutaneous areas, intraabdominal and intrathoracic regions, bone marrow, and parathyroid glands, and mechanical adipose tissue, presented in the orbits, crista galli, buccal region, tongue, palms and soles, scalp, perineum, vulva, periarticular regions, epidural area, and pericalyceal regions of the kidney might contribute to the explanation of metabolic derangements in different types of lipodystrophy syndromes. Owing to it, patients with acquired partial lipodystrophy who have well preserved metabolically active adipose tissue seldom have metabolic abnormalities; however, patients with congenital generalized lipodystrophy in whom metabolically active adipose tissue is almost absent develop diabetes, hypertriglyceridemia, low levels of high-density lipoprotein cholesterol, and atherosclerotic vascular disease.[2]

Molecular basis of lipodystrophy syndromes has not been elucidated. Two molecularly distinct forms of congenital generalized lipodystrophy have been defined as type 1 and type 2. Some patients have neither type, so additional genes are most likely involved.[10] The identification of a locus for the Dunnigan variety of familial partial lipodystrophy, on chromosome 1q21-22 led to the identification of a missense mutation in the gene encoding lamins A and C (LMNA). Subsequently, many more missense LMNA mutations have been reported. Recently, a heterozygous missense mutation - Arg397Cys - in the PPAR [gamma] gene was described[3] ( Table 3 ). In contrast, the pathogenesis of an acquired form of lipodystrophy has not been elucidated at the molecular level. Nevertheless, it has been well documented that acquired partial lipodystrophy is associated with autoimmune disorders. Systemic lupus erythematosus has developed in 6 patients, 2 to 28 years after the onset of lipodystrophy. Other autoimmune diseases, such as dermatomyositis, hypothyroidism, pernicious anemia, celiac disease, dermatitis herpetiformis, rheumatoid arthritis, temporal arteritis, and leukocytoclastic vasculitis have also been reported. Several patients had antinuclear and anti-double-stranded DNA antibodies in their serum.[2,6]

Consequently, Reitman and colleagues suggested that adipocyte deficiency can be caused by autoimmune destruction.[1] Moreover, C3 hypocomplementemia, seen in 70% of patients, supports the hypothesis for autoimmunity based on complement activation.[11] Recent studies showed that complement components and proteins identical to factors D and B could be expressed both by the adipose and renal cells. Therefore, the existence of these factors and in particular factor D is the reason for more serious destruction in adipose and renal tissue. In a large number of cases, there may be an associated presence of C3 nephritic factor.[12] A significant number of cases (25% to 90%) may have renal involvement with biopsy showing membranoproliferative glomerulonephritis. Onset of acquired partial lipodystrophy and complement abnormalities antedates the renal disease, sometimes by long periods. Many of these patients may have histologically detectable glomerulonephritis before overt clinical manifestations. The proportion of patients who eventually develop significant renal disease is not known. However, in a reported series of 12 patients with acquired partial lipodystrophy, 4 died of renal failure after onset of lypodystrophic changes.[13]

Presenting this patient, we want to emphasize once again that each lipodystrophy has not only a unique clinical picture but also an unique underlying pathogenic mechanism. Therefore, enlightening of autoimmune base in the etiopathogenesis of acquired partial lipodystrophy may also lead to the discovery of therapeutic approaches to prevent the loss of adipocytes, induce adipogenesis in lipodystrophic regions, and prevent or delay the onset of metabolic complications in patients with lipodystrophy.[14]

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