Are ‘buffalo hump’ syndrome, Madelung's disease and multiple symmetrical lipomatosis variants of the same dysmetabolism?

Abstract

A typical dorsocervical fat pad known as the ‘buffalo hump’ syndrome has been described in HIV patients under treatment with protease inhibitors [1,2]. Recently, a case of diabetes mellitus with symmetrical lipomatosis (Madelung's collar) has been reported in a patient referred for alcohol abuse and presenting with a pattern of metabolic alterations similar to those caused by protease inhibitors [3]. The cause of Madelung's disease has not been determined, and it has been hypothetically related to mitochondrial disorders. As in Madelung's disease, multiple symmetrical lipomatosis is characterized by the presence of lipomas located in the subcutaneous tissue of the cervical, deltoid, thoracic, abdominal and lumbar areas [4]. Multiple symmetrical lipomatosis is also associated with alcohol consumption, dyslipidaemia and impaired glucose tolerance. Interestingly, insulin resistance, triggered by alcohol-induced hypertriglyceridaemia, is present in patients with multiple symmetrical lipomatosis [5–7]. HIV patients treated with protease inhibitors exhibit the lipodystrophy syndrome, which is characterized by central adiposity and peripheral fat wasting, dyslipidaemia, impaired glucose tolerance, and insulin resistance [8]. Indeed, hypertriglyceridaemia occurs in more than 50% of the patients treated with protease inhibitors after one year of therapy [9]. It is also noteworthy that nucleoside reverse transcriptase inhibitors block mitochondrial γ-DNA polymerase, with the consequent failure of oxidative phosphorylation, which could lead to metabolic disturbances such as those found in multiple symmetrical lipomatosis [10]. On the basis of data reported in the medical literature, it is possible to hypothesize that fat storage in the neck and neighbouring subcutaneous tissues could result from the same pathogenesis in different clinical conditions such as ‘buffalo hump’ syndrome, multiple symmetrical lipomatosis and Madelung's disease. In fact adipocytes of subcutaneous fat tissue in the neck and interscapular area could originate from brown adipose tissue. Decreased lipolysis can be related to metabolic disorders in the mitochondria of brown adipose tissue [11]. Fat tissue plays an important role in mammalian energy balance, not only as a lipid dissipator (white adipose tissue), but also as an energy dissipator (brown adipose tissue). As a result of the presence of a mitochondrial protein, the uncoupling protein, brown adipocytes can produce heat. The uncoupling protein appears in the last 3 months of pregnancy in fat cells along the cervical axis, between the shoulder blades and around the kidneys. Brown adipose tissue and uncoupling protein rapidly decrease at birth with a total regression in adulthood [11–13]. Adipocytes of multiple symmetrical lipomatosis, smaller than the adipocytes of white adipose tissue, are not monovacuolar and are similar to the largest adipocytes found in human brown adipose tissue. Some morphological features found in the adipocyte precursors of multiple symmetrical lipomatosis are found more in brown than in white adipocytes [14,15]. We suggest that two different types of fat tissue play a different role in the lipodystrophy syndrome. One type of fat tissue is involved in triglyceride accumulation, and the other type of fat tissue is involved in lipid mobilization. Drugs and alcohol-induced hypertriglyceridaemia could activate fat storage in ‘brown memory’ adipocytes inhibiting white adipocytes. The biochemical activity of subcutaneous fat tissue lying around the neck and between the shoulders, both in the ‘buffalo hump’ syndrome and in multiple symmetrical lipomatosis, could be transformed in brown-like adipose tissue by metabolic triggers and drugs, e.g: alcohol, protease inhibitors, and steroid hormones as in Cushing's syndrome. Alternatively, it has been suggested that the masses of multiple symmetrical lipomatosis are not functional brown adipose tissue because of the failure to detect brown adipose tissue uncoupling protein messenger RNA in Madelung's disease [16,17]. In conclusion, the ‘buffalo hump’ syndrome, which is a clinical aspect of the lipodystrophy syndrome during HIV infection, should be considered to be a special variant of multiple symmetrical lipomatosis, also known as Madelung's disease. Studies focusing on a histopathological and ultrastructural examination of fat tissue lying around the neck and between the shoulders are needed to investigate this important clinical event further. Rocco Urso Marco Gentile