Indinavir-associated lipodystrophy

Background: Lipodystrophies are rare cutaneous disorders characterized by the symmetrical loss of subcutaneous fat from the body surface. The cause of lipodystrophy is not known, but a possible genetic predisposition is likely and either overt diabetes mellitus or insulin resistance are often associated.

Design and methods: Case study.

Patients: Eight patients who developed either partial or generalized lipodystrophy after protease inhibitor therapy.

Results: In all eight patients lipodystrophy occurred after 2-12 months of starting indinavir and was not preceded by weight loss or inflammatory skin disease. Short-term follow-up after withdrawal of therapy showed no change in the patients' appearance. One patient developed glycosuria as lipodystrophy became manifest. In three cases glucose tolerance test was performed revealing a high level of insulin between the first and third hour of loading.

Conclusions: In our view, lipodystrophy is an unwanted side-effect of protease inhibitor therapy causing noticeable disfigurement.

Introduction

Lipodystrophies are a group of rare cutaneous disorders characterized clinically by the symmetrical loss of sub-cutaneous fat tissue from the body surface. Three main syndromes have been recognised [¹]: (i) partial lipodystrophy with disappearance of subcutaneous fat from the face (Barraquer-Simmons syndrome) and occasionally from only the lower part of the body; (ii) congenital total lipodystrophy (Seip-Berardinelli syndrome); and (iii) acquired total lipodystrophy (Lawrence Seip syndrome). The lipodystrophic syndromes are associated with either diabetes mellitus or insulin resistance, except in some cases of partial lipodystrophy.

Methods

We recently observed eight patients who developed both generalized and partial lipodystrophy after indinavir therapy. In four cases either diabetes or insulin resistance were also disclosed. The following report outlines the observations made in these eight patients.

Results

In a file of 32 HIV patients undergoing triple combination therapy with indinavir for HIV infection, we observed eight cases of pronounced alteration of body composition. Clinical and biological data are summarized in Table 1.

Table 1

In all cases, morphologic changes occurred after 2-12 months of starting indinavir and was not preceded by weight loss or inflammatory skin disease. The overlying skin was normal.

Two patients developed progressive loss of subcutaneous fat from both legs resulting in prominent veins and a muscular appearance (Fig. 1). In contrast, excess fat deposition in the unaffected buttocks and abdomen gave an impression of obesity. In six cases, a cachectic appearance was observed as a result of the loss of buccal, parotid and preauricular fat pads. Sunken eyeballs and prominent zygomata were also evident (Fig. 2). Generalized loss of fatty tissue from the face were seen in two patients.

Fig. 1

Fig. 2

The following laboratory values were either normal or unremarkable. A standard oral glucose tolerance test with simultaneous measurements of insulin and C-peptide was performed in patients 1-3. Serum insulin levels were elevated in patient 2 [baseline, 4 mU/l (normal values, 5-20 mU/l) and at 60 min, 134 mU/l] and in patient 3 (baseline, 16 mU/l, at 60 min, 152 mU/l, and at 120 min, 257 mU/l). Patient 1 had a high basal level of both C-peptide [4.3 mU/l (normal, 0.3-3 mU/l)] and insulin (35 mU/l) without noticeable enhancement after loading. One patient (patient 4) developed glycosuria as morphologic changes became manifest.

Discussion

All our patients exhibited clinical symptoms reminiscent of either partial or generalized lipodystrophies. Recently, atypical accumulations of fatty tissue posterior to the base of the neck were reported in three HIV-infected patients occurring 2-7 months after initiation of protease inhibitor therapy [²]. We also observed such dysmorphic presentation in two cases (patients 1 and 4). Lipodystrophic syndrome occurring after indinavir is a frequent occurrence, and may be underdiagnosed because of frequent wasting during HIV infection.

The aetiology of lipodystrophy is unknown, although patients frequently have hypertriglyceridaemia, overt diabetes mellitus or insulin resistance [¹]. Laboratory findings in our patients disclosed similar abnormalities. These have been previously reported in association with protease inhibitor therapy [^3,4]. There is therefore a strong similarity between classical lipodystrophy and protease inhibitor-induced lipodystrophy, but in both diseases the relationship between insulin resistance and lipodystrophy remains unclear.

Other disorders associated with lipodystrophy include glomerulonephritis, hypocomplementaemia [⁵], pancreatitis [⁶] and coeliac disease [⁷]. In our patients, complement, renal function tests and pancreatic enzymes were normal. Diarrhoea of unknown aetiology was present in three patients. Colonoscopy and duodenal biopsy performed in one patient (patient 2) were normal. In our opinion, lipodystrophy is an unwanted side-effect of protease inhibitor therapy causing noticeable disfigurement. Short-term follow-up after withdrawal of therapy showed no change in the patients' appearance. Further studies are required to determine long-term evolution of these dysmorphic changes.