Lipodystrophy

Monique J. Vanaman Wilson

Monica Boen

Mitchel P. Goldman

BACKGROUND

Lipodystrophy is defined as a change in the distribution of subcutaneous adipose tissue due to either congenital or acquired disorders. Redistribution of fat may be seen in only a few parts of the body as in partial lipodystrophy, or the entire body may be involved in a condition called generalized lipodystrophy. Localized lipodystrophy is limited to one area on the body. “Lipoatrophy” and “lipodystrophy” are often used interchangeably, but it is important to note that lipoatrophy is defined specifically as loss of subcutaneous fat, whereas lipodystrophy involves an increase or decrease in the deposition of adipose tissue.¹ There are several causes of lipodystrophy that include rare genetic disorders, medications, and autoimmune conditions. Currently, one of the most prevalent forms of lipodystrophy occurs in patients with human immunodeficiency syndrome (HIV) on antiretroviral therapy (ART).

As adipose tissue plays several crucial roles in the body, including energy storage, glucose homeostasis, and regulation of inflammation, changes in adipose distribution can lead to widespread complications.² A majority of the lipodystrophy disorders have associated metabolic abnormalities such as insulin resistance, hyperlipidemia, and a high metabolic demand. Metabolic complications include nonalcoholic fatty liver disease, diabetes mellitus, and atherosclerosis.³

The lipodystrophy disorders can cause significant psychological distress that negatively affects a patient’s quality of life. For example, HIV-associated lipodystrophy has been shown to have a negative impact on a patient’s self-esteem, social contacts, and daily activites.⁴ The standard treatment of lipodystrophy disorders includes dietary modifications and exercise, as well as medications to control associated diabetes mellitus and hyperlipidemia.⁵,⁶ In recent years injectable fillers have been used to add volume to cosmetically sensitive areas, such as the face and arms, in patients with lipodystrophy. Several fillers are available to address this issue, including autologous fat, hyaluronic acid (HA) fillers,
collagen stimulators, and semipermanent and permanent fillers. Abnormal fat deposition has been treated successfully with liposuction. Management of lipodystrophy requires a multidisciplinary approach and can lead to dramatic improvement in quality of life.

PRESENTATION

Patients with generalized lipoatrophy present with a generalized paucity or absence of adipose tissue during infancy in the congenital form or at any age in the acquired form. Veins are prominent and muscles are well defined, particularly on the extremities. Patients with associated hyperinsulinemia also present with acromegaly, namely, large acra and mandible. Another presenting sign is excessive appetite. Female babies may present at birth with clitoromegaly with or without hirsutism. During puberty, females may present with amenorrhea or polycystic ovary disease.

Those with acquired generalized lipoatrophy may present at any age. Generalized loss of fat is observed. The patients often describe a history of a preceding illness. Many of the similar features seen in the congenital form are present: hyperinsulinemia, diabetes mellitus, acromegaly, prominent veins, acanthosis nigricans, hirsutism, and prominent muscular definition.

DIAGNOSIS

Clinical Diagnosis

The inherited lipodystrophy syndromes can be diagnosed by clinical history and physical examination. Patients should be asked about the age of onset of the lipodystrophy and appetite. The physical examination should evaluate for an increase or decrease in subcutaneous fat, muscular hypertrophy, hepatosplenomegaly, and acanthosis nigricans.¹ Laboratory testing to evaluate for insulin resistance, lipid abnormalities, and adipocytokine levels can be helpful, as well. Furthermore, genetic testing is available for some of these disorders. Imaging studies can be used to objectively measure the extent of lipodystrophy by ultrasonography, computed tomography, or magnetic resonance imaging.⁷ For localized lipodystrophy, a detailed history of prior injectable medications, autoimmune diseases, or repetitive trauma to the affected area can lead to diagnosis.

A diagnosis of HIV/ART-associated lipodystrophy can be made by clinical history, such as exposure to nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs), and physical examination. Patients with HIV-related lipodystrophy on ART should be screened regularly for lipoatrophy and fat accumulation, and blood glucose and lipid levels should be monitored.

TABLE 6.3.1 Carruthers Lipoatrophy Severity Scale

Grade	Clinical Description
1	Mild and localized facial atrophy
2	Deeper central cheek atrophy with muscles beginning to show through
3	Larger, deeper atrophic areas with muscles clearly showing through
4	Lipoatrophy covers a large area (extending up toward orbit) with facial skin lying directly on the underlying muscles
Adapted from James J, Carruthers A, Carruthers J. HIV-associated facial lipoatrophy. Dermatol Surg. 2002;28(11):979-986.

A validated tool for assessing the degree of facial lipoatrophy is the Carruthers Lipoatrophy Severity Scale, whereby the degree of lipoatrophy is graded on a scale of 1 to 4 (Table 6.3.1).⁸ Grade 1 consists of mild and localized facial lipoatrophy that appears almost normal, whereas grade 4 shows widespread facial atrophy with the underlying muscles clearly visible. Grades 3 and 4 are considered abnormal. This assessment tool can help clinicians guide future therapies and monitor treatment response for facial lipoatrophy.

Histopathology

Skin biopsy specimens of lipodystrophy may show evidence of a lobular panniculitis with an inflammatory infiltrate consisting of histiocytes, foamy histiocytes and multinucleated histiocytes, neutrophils, and eosinophils. Necrotic lipocytes and microcysts containing necrotic debris may be evident. In late-stage or complete lipoatrophy, a complete loss of subcutaneous fat is noted, with dermis abutting the muscular fascia.⁹

Subtypes

Lipodystrophy disorders are categorized as inherited and acquired. The 2 main types of rare inherited lipodystrophy syndromes are congenital generalized lipodystrophy, also called Berardinelli-Seip syndrome, and familial partial
lipodystrophy, including the Dunnigan and Kobberling varieties.¹⁰ The other main subtypes are acquired generalized lipodystrophy and acquired localized lipodystrophy, drug-induced, autoimmune-associated, pressure-induced, and HIV-associated lipodystrophy.

Inherited Subtypes

Congenital Generalized Lipodystrophy. Berardinelli-Seip syndrome is an autosomal recessive disorder characterized by a generalized lack of subcutaneous fat at birth or in the first year of life and prominent muscular appearance.¹¹ Patients have a severe leptin deficiency resulting in voracious appetite. These patients develop diabetes by adolescence, acanthosis nigricans, and hepatic steatosis. Genetic analysis has revealed that the most common mutations are 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), which regulates triglyceride biosynthesis, and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), a gene that helps with adipocyte differentiation.³

Familial Partial Lipodystrophy. Familial partial lipodystrophy is inherited in an autosomal dominant manner and presents with a progressive and symmetric loss in adipose tissue starting in puberty, predominantly located on the upper and lower extremities.¹ Some patients with this disorder develop fat accumulation in the head and neck, especially in the dorsocervical area, causing a buffalo-hump appearance.¹¹,¹² There are fewer metabolic complications in this disorder when compared with congenital generalized lipodystrophy; however, hypertriglyceridemia is common and patients can have cardiac abnormalities.¹¹ The most common subtype of the familial partial lipodystrophy syndromes is the Dunnigan variant, which is caused by a missense mutation in lamin A and C, structural proteins in the nuclear lamina.³

Acquired Subtypes

Acquired Generalized Lipodystrophy. In acquired generalized lipodystrophy, also known as Lawrence syndrome, patients have a normal fat distribution at birth but gradually begin to lose adipose tissue on the face and body during childhood or adolescence. There are associated metabolic complications and decreased leptin levels.¹¹ The etiology of this disorder is unknown. On the other hand, acquired partial lipodystrophy, or Barraquer-Simons syndrome, is characterized by loss of fat in the face, trunk, and upper extremities. It may be associated with autoimmune diseases, and an antibody to complement 3 nephritic factor is often present, which can predispose to membranoproliferative glomerulonephritis, and lamin B2 mutations.¹¹,¹³

Acquired Localized Lipodystrophy. Localized lipodystrophy has several etiologies and presents with adipose tissue loss in one or multiple areas.

Drug-Induced Lipodystrophy

Drug-induced localized lipodystrophy is most commonly caused by corticosteroid and insulin injections.¹ Of note, lipohypertrophy can also occur as a result of insulin injections.

Autoimmune-Associated Lipodystrophy

Autoimmune diseases, such as lupus or dermatomyositis, can cause panniculitis in the upper or lower extremities.

Pressure-Induced Lipodystrophy

Lipoatrophia semicircularis is a symmetric and asymptomatic bandlike lipoatrophy on the thighs primarily in young women, caused by pressure from leaning against a desk or wearing tight-fitting clothes.¹

HIV-Associated Lipodystrophy

One of the most common lipodystrophy disorders is found in patients with HIV on ART. Over 50% of patients with HIV on ART develop lipodystrophy both on the face and other parts of the body.¹⁴,¹⁵ Lipodystrophy has been associated with the use of NRTIs, such as stavudine and zidovudine, and PIs after 6 to 12 months of therapy but has also been shown to occur in treatment-naive patients.¹⁶ Risk factors for the development of HIV/ART-associated lipodystrophy include older age, CD4 counts of less than 200/µL, and longer duration of therapy with NRTIs or PIs.¹ PIs may cause lipodystrophy by interfering with prelamin A production due to inhibition of zinc metalloproteases, and NRTIs are thought to cause mitochondrial toxicity in adipose tissue.¹⁷,¹⁸ Adiponectin and leptin levels are also decreased, similar to the congenital lipodystrophy syndromes.¹⁹

Classic HIV-associated lipodystrophy presents with a loss of the buccal and temporal fat pads in the face resulting in a cachectic appearance, as well as lipoatrophy of the extremities and buttocks.¹ There can be an increase in visceral fat and fat accumulation in the
dorsocervical region and breasts. Metabolic abnormalities such as hyperlipidemia, insulin resistance, and problems with bone homeostasis are common.

There is significant psychological distress associated with the lipodystrophies, as the loss of fat causes a more aged appearance, and accumulation of fat in abnormal areas, such as the upper back, can be disfiguring. Fortunately, there are multiple treatment options for patients with lipodystrophy, ranging from cosmetic fillers to liposuction, to help restore patients’ confidence in their appearance.

PATHOGENESIS

Adipose tissue serves a variety of functions in the body, many of which were coincidentally discovered in the study of lipodystrophy syndromes. Several hormones and inflammatory markers that play a key role in metabolic hemostasis, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, leptin, and adiponectin, are secreted by adipose tissue.¹ Thus, dysfunction in adipose tissue leads to the metabolic abnormalities seen in the lipodystrophy disorders.

The adipocytokines, leptin and adiponectin, regulate energy metabolism and are usually decreased in the lipodystrophy syndromes.¹¹ Leptin inhibits appetite, stimulates energy expenditure, and decreases glucose and body weight.²⁰ Similarly, adiponectin promotes insulin sensitivity and energy expenditure and decreases hepatic gluconeogenesis.²¹

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