Lipodystrophy, Partial, Acquired, With Low Complement Component C3, With Or Without Glomerulonephritis

Description

Acquired partial lipodystrophy (APLD) is characterized clinically by the gradual onset of bilaterally symmetrical loss of subcutaneous fat from the face, neck, upper extremities, thorax, and abdomen, in the 'cephalocaudal' sequence, sparing the lower extremities. A large group of patients (83%) with acquired partial lipodystrophy have low serum levels of complement component C3 due to the presence of C3 nephritic factor, an IgG antibody that causes continuous activation of the alternative complement pathway and consumption of serum C3. About 22% of patients with this acquired complement defect develop membranoproliferative glomerulonephritis. Some individuals may also show an increased risk of infection (Misra et al., 2004).

Acquired partial lipodystrophy is not inherited in a classic mendelian pattern; it rather represents a phenotype with a complex etiology. Affected individuals may have genetic susceptibility factors that require the additional presence of environmental factors or acquired disorders to be expressed (summary by Hegele et al., 2006). Most cases are sporadic, family history is negative, and females are more often affected than males (ratio, 4:1) (summary by Misra et al., 2004).

See 608709 for a subtype of APLD not associated with low complement C3 or renal disease.

Clinical Features

Alper et al. (1973) reported a 30-year-old woman with a lifelong history of recurrent bacterial infections who was found to have low serum C3 due to presence in the serum of an activator of C3, which the authors termed hypercatabolism. Since age 4 years, she had progressive loss of subcutaneous fat from the upper part of the body. There was no family history of a similar disorder. Although renal disease was not specifically mentioned, she did have protein and granular casts in the urine on at least 1 occasion. Alper et al. (1973) noted the association between partial lipodystrophy, low C3, and a circulating factor that activated the alternative complement pathway, and suggested that the increased risk of infection was due to continuous depletion of C3.

Sissons et al. (1976) reported 21 unrelated patients with partial lipodystrophy. Laboratory studies showed that 17 had low serum C3, accompanied in 14 by C3 nephritic factor, suggesting activation of the alternative complement pathway. These abnormalities occurred in 10 patients without clinically overt renal disease. However, 7 patients had overt membranoproliferative nephritis. Lipodystrophy preceded the nephritis in all patients. Sissons et al. (1976) concluded that the majority of patients with partial lipodystrophy have hypocomplementemia. Although nephritis may not invariably develop, the high rate of mesangiocapillary nephritis in these patients suggested that complement activation via the alternative pathway predisposes to the development of glomerular disease.

A patient with acquired partial lipodystrophy reported by Kraai and van Son (1983) was the only member of her family to show features. Since the age of 5 years, she had ascetic facial features with loss of facial fat ('facies Voltarien'). At age 20 years, she developed nephrotic syndrome after a throat infection. Kidney biopsy showed membranoproliferative glomerulonephritis, and laboratory values showed decreased serum C3 and C4, as well as proteinuria, hematuria, and leukocyturia.

Misra et al. (2004) reported 35 cases of acquired partial lipodystrophy and reviewed 220 cases reported in the literature. The median age at onset of lipodystrophy was 7 years, and the female to male ratio was 4:1. Approximately 83% of patients had low serum C3 with the presence of the C3 nephritic factor autoantibody. Approximately 22% of patients developed membranoproliferative glomerulonephritis about 8 years after the onset of lipodystrophy. Diabetes mellitus and impaired glucose tolerance were seen in 6.7% and 8.9%, respectively. Activation of the alternative complement pathway was implicated in the cooccurrence of these features.

Inheritance

Acquired partial lipodystrophy is not an inherited disorder in the classic mendelian sense; it rather represents a phenotype with a complex etiology (summary by Hegele et al., 2006).

Reichel et al. (1976) reported identical twins who were discordant for partial lipodystrophy. A 7-year-old girl developed acute glomerulonephritis with proteinuria, hematuria, and lymphocytosis, without edema. Following a tonsillectomy, the patient developed sunken facial features which progressed to loss of subcutaneous fat from the trunk and upper limbs by age 18 years. Proteinuria and erythrocyturia were found, and kidney biopsy showed membranoproliferative glomerulonephritis with focal crescents and complement component C3 deposits along glomerular basement membranes. Serum C3 was approximately one-third of normal values, while C4 was normal. Reichel et al. (1976) noted that the patient had a susceptibility to infection, with a history of pneumonia, meningitis, encephalitis, and viral hepatitis. As her identical twin sister had no symptoms, the authors concluded that the disorder was acquired.

Bier et al. (1978) also reported discordance for cephalothoracic lipodystrophy with hypocomplementemic renal disease in identical twin sisters. Following a tonsillectomy at the age of 5 years, the affected sister was noted to have loss of facial fat with progression to the upper limbs and upper chest. Laboratory findings showed proteinuria, hematuria, and decreased serum C3. Her twin sister had normal clinical features and laboratory findings.

Power et al. (1990) described a family in which 3 members had partial lipodystrophy. Two of the 3, a mother and a son, also had C3 nephritic factor and membranoproliferative glomerulonephritis. Both the mother and the son had end-stage renal disease. Power et al. (1990) stated that the occurrence of these features is usually sporadic, but their family report suggested that the pathogenesis of these conditions may be linked and that genetically determined factors may, in some circumstances, contribute to disease susceptibility.

Pathogenesis

The loss of fat from the waist upward with sparing of the legs in partial lipodystrophy was a mystery until it was discovered that adipose cells are the main source of factor D (134350), which completes the formation of the C3 convertase enzyme (C3bBb) by cleaving factor B bound to C3b (White et al., 1992). There is a gradient in the concentration of factor D in the fat cells of the body; more is present in the upper than in the lower half of the body, which may explain the distribution of the fat loss. It is likely that in patients with partial lipodystrophy with C3 nephritic factor, the antibody stabilizes the C3bBb C3 convertase that forms in the immediate vicinity of adipocytes. The abnormally stabilized enzyme may then cleave enough C3 to allow assembly of the membrane-attack complex, which lyses adipocytes. These reactions and others involved in complement activation were diagrammed by Walport (2001).