Lipodystrophies

Article Author:
Kelly Quinn
Article Editor:
Stephen Purcell
Updated:
10/27/2018 12:31:20 PM
PubMed Link:
Lipodystrophies

Introduction

Lipodystrophies are the category of conditions that share the common finding of a reduction in subcutaneous fat. There are multiple subtypes of lipodystrophy, which may be either congenital or acquired and vary in the distribution of fat loss. Although all are relatively rare in incidence, acquired variants have become more common as an adverse effect of certain medications and iatrogenic mechanisms. Regardless of subtype, decreases in overall adipose burden may lead to metabolic complications, with subsequent increases in morbidity and mortality in lipodystrophy patients.

Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy, sometimes referred to as Berardinelli-Seip syndrome, is an uncommon lipodystrophy variant with significant and sometimes near-total fat loss.

Familial Partial Lipodystrophy

Familial partial lipodystrophy is most often an autosomal dominant condition with fat loss primarily involving the extremities, more commonly lower than upper.

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy is an extremely rare condition of widespread subcutaneous fat loss.

Acquired Partial Lipodystrophy

Acquired partial lipodystrophy, or Barraquer-Simons syndrome, is characterized by gradual loss of fat from the upper body and truncal region during childhood.Over the past few decades, however, highly active anti-retroviral therapy induced lipodystrophy has become the most common form of acquired partial lipodystrophy.

Etiology

Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy, sometimes referred to as Berardinelli-Seip syndrome, is an uncommon lipodystrophy variant with significant and sometimes near-total fat loss.  It has autosomal recessive inheritance and patients present with findings at birth or in early infancy. Mutations in four genes coding for the proteins AGPAT2, seipin, caveolin-1, and cavin-1 have been implicated in the different subtypes of congenital generalized lipodystrophy.

Familial Partial Lipodystrophy

Familial partial lipodystrophy is most often an autosomal dominant condition with fat loss primarily involving the extremities, more commonly lower than upper.To date, seven variants of familial partial lipodystrophy have been described. Multiple genetic defects have been reported which can serve to explain the heterogeneity in clinical findings. The best-characterized variant, familial partial lipodystrophy type 2 or Dunnigan’s lipodystrophy, results from defects in the gene encoding lamins A and C.

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy is an extremely rare condition of widespread subcutaneous fat loss. The etiology is poorly understood, but these patients may also have associated autoimmune connective tissue disease.

 Acquired Partial Lipodystrophy

Acquired partial lipodystrophy, or Barraquer-Simons syndrome, is characterized by gradual loss of fat from the upper body and truncal region during childhood.Though no mechanism for the development of acquired partial lipodystrophy has been confirmed, some studies have linked complement induced adipocyte lysis to patients with serum positive for nephritic factor.

Over the past few decades, highly active anti-retroviral therapy induced lipodystrophy has become the most common form of acquired partial lipodystrophy. It is associated with the use of anti-viral agents including the protease inhibitors or nucleoside analogs used to treat human immunodeficiency virus. Although the mechanism is still unclear, it is known that these medications can damage adipocytes.

Epidemiology

Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy is extremely rare with approximately 250 cases reported in the literature. Assuming that a minority of patients with this condition report, it is estimated that the prevalence worldwide ranges from 1 case per 200,000 persons to 1 case per 12 million persons. Patients present at birth or in early infancy.

Familial Partial Lipodystrophy

Familial partial lipodystrophies, including the variants of Dunnigan’s lipodystrophy and Kobberling lipodystrophy, are uncommon. It is thought that the prevalence of the Dunnigan’s variant is less than 1 case in 15 million persons. The mode of transmission is autosomal dominant. The Kobblering variant is less well characterized regarding prevalence and mode of transmission, though some sporadic cases have been reported.

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy has been described in at least 100 patients though this may be under-recognized or reported. Patients most often present in adolescence. Recent proposals seek to further categorize these patients into one of three categories: panniculitis, autoimmune, and idiopathic; patients either have one of these pre-existing conditions before the development of generalized lipodystrophy or have the spontaneous development of generalized lipodystrophy. Women have affected more than men in approximately a 3:1 ratio.

Acquired Partial Lipodystrophy

Acquired partial lipodystrophy is also rare with approximately 250 cases described. The typical age of presentation is after puberty, with one study showing a median age of 25 years. Patients have been identified from multiple ethnic backgrounds, but the largest studies to date involve patients primarily of European descent. Women are again affected more than men with ratios that range from 4:1 to 8:1.

Pathophysiology

The metabolic alterations seen in patients with lipodystrophies result from an overall decrease in adipose tissue burden. Adipose is a metabolically active tissue that has many physiologic functions. Adipose tissue not only provides insulation but also serves to mediate inflammation and secrete many hormones involved in endocrine regulation.In patients with lipodystrophies, a reduction in adipose leads to a deficiency in certain hormones. In particular, a decrease in leptin has been described in many lipodystrophy patients. Leptin is a proinflammatory adipokine secreted by adipose tissue. It is often referred to as the “satiety hormone” because it regulates mediators of appetite and energy expenditure. A decrease in leptin, whether in the setting of intrinsic leptin deficiency or lipodystrophy, leads to the downstream complications of hyperinsulinemia, insulin resistance with possible progression to diabetes, hypertriglyceridemia, and hepatic steatosis.

Histopathology

When obtaining a biopsy from patients with suspected lipodystrophy, it is important to consider the depth of pathology. An ideal specimen would extend to at least include epidermis, dermis, and subcutaneous fat. There may be a benefit to increasing the depth of the biopsy to include fascia to allow visualization of the full subcutis. The histopathological findings of the lipodystrophy syndromes are somewhat nonspecific. The background is typically pauci-inflammatory, and individual adipocytes become shrunken and separated. In certain circumstances with localized involvement, a perivascular lymphocytic inflammatory infiltrates may be seen.

History and Physical

Congenital Generalized Lipodystrophy

The extent of fat loss results in a striking clinical appearance. Patients not only have a widespread fat loss but also have skeletal muscle hypertrophy due to excess adipose deposition within the musculature. As is common to many lipodystrophies, metabolic anomalies including hyperinsulinemia, insulin resistance, and hypertriglyceridemia often occur. Due to the early onset of this condition, these findings occur before adulthood. The life expectancy of patients with congenital generalized lipodystrophy is reduced due to complications of diabetes or from liver or heart disease.

Familial Partial Lipodystrophy

Patient demonstrates fat loss primarily involving the extremities, more commonly lower than upper. Patients appear normal at birth and throughout childhood regarding fat distribution but develop clinically apparent changes near puberty. In contrast to the fat loss involving the extremities, patients demonstrate a fat gain in the face, neck, and abdomen.

These patients show clinical findings consistent with that described above and additionally may have hypertriglyceridemia severe enough to induce pancreatitis. Insulin resistance, adverse cardiac events, and hepatic steatosis may also be present and sometimes severe.

Acquired Generalized Lipodystrophy

At birth fat distribution is normal but as time progresses fat loss develops. The face, arms, and legs are most commonly affected. The absence of mature adipocytes inhibits the ability to synthesize adipocytokines that are important for normal metabolism.This loss leads to leptin deficiency and severe metabolic derangements. Fat deposition in the liver may lead to cirrhosis. Diabetes mellitus and hypertriglyceridemia are often also present. One-quarter of patients will develop an inflammatory panniculitis at the time the fat loss begins, though this is not specific to acquired generalized lipodystrophy.

Acquired Partial Lipodystrophy

Acquired partial lipodystrophy is characterized by gradual loss of fat from the upper body and truncal region during childhood. This condition is progressive, and patients may demonstrate compensatory fat deposition in the hips and legs. The metabolic complications seen in the other lipodystrophies do not seem to be as common in patients with acquired partial lipodystrophy. However, these patients may be more susceptible to kidney disease. Most patients with acquired partial lipodystrophy have circulating levels of the nephritic factor.

Highly active anti-retroviral therapy induced lipodystrophy has become the most common form of acquired partial lipodystrophy. The resultant lipodystrophy is well-documented and has a typical clinical presentation. Patients demonstrate subcutaneous fat loss of the extremities and the face and an increase in adiposity of the trunk. Due to this classic clinical picture, the appearance became stigmatized as an association with HIV.

Evaluation

As described above, in patients who present with findings suspicious for a lipodystrophy syndrome, a metabolic work up must be pursued. Patients should have a complete metabolic panel checked for hyperglycemia and any alterations of hepatic enzymes. A cholesterol panel should also be checked to rule out hypertriglyceridemia. Leptin levels can be obtained and, if low, may predict responsiveness to replacement treatment. Genetic testing is not routine at this time but for certain subtypes of lipodystrophy may be performed in clinical laboratories. There are ongoing clinical trials which can be reviewed at www.clinicaltrials.gov.

Treatment / Management

Management of lipodystrophies is dependent upon the specific subtype and the extent of associated metabolic abnormalities. For patients with severe metabolic derangement, it is important to implement the use of lipid-lowering agents and diabetic medications. With a goal of increasing insulin sensitivity, pioglitazone has been shown to be more efficacious than metformin in this patient population. Severe cases may require insulin. Leptin analogs, particularly metreleptin, have shown efficacy in maintaining normal metabolism in patients who cannot effectively synthesize leptin naturally. Metreleptin is recombinant human leptin and the only FDA-approved replacement therapy for certain patients with lipodystrophy. Hypertriglyceridemia may respond to troglitazone, though interventions may not be very effective in fixing dyslipidemias in these patients. Furthermore, patients with lipodystrophy in cosmetically sensitive areas may be treated with fillers such as poly-L lactic acid and calcium hydroxyapatite. More research needs to be done in the field of lipodystrophies to establish diagnostic and management guidelines. As we learn more about the intricacies of metabolic regulation, it is anticipated that more treatment options will emerge for this patient population.