Acquired Partial Lipodystrophy 

Updated: Dec 16, 2015
Author: George T Griffing, MD; Chief Editor: George T Griffing, MD 

Overview

Background

Lipodystrophy refers to the loss of adipose tissue. It is classified as either diffuse (generalized) or local (partial) and results from either genetic or acquired etiologies. Ectopic fat in tissues such as liver and muscle may be increased. The cumulative loss of fat leads to a decrease in adipose-derived adiponectin and leptin. Circulating levels of these adipokines are lower in generalized versus partial lipodystrophy as predicted from the loss of fat.[1, 2]

Acquired partial lipodystrophy, also known as Barraquer-Simons syndrome or cephalothoracic lipodystrophy, is one of the rare forms of lipodystrophy. Mitchell initially reported this variety in 1885.[3] Barraquer and Simons further characterized the syndrome at the beginning of the 20th century. Since then, approximately 250 cases have been reported in English literature.

Acquired partial lipodystrophy usually begins in childhood, at a median age of 7 years.[4] It predominantly affects females and often follows an acute febrile illness. Fat loss is usually limited to the face, trunk, and upper extremities. Simultaneously, fat hypertrophy occurs in the lower extremities. These patients may develop nephropathies. Activation of alternate complement pathway has been demonstrated in most patients. The phenotype can be variable and sometimes only affecting the face.[5]

Compared with other types of lipodystrophy, acquired partial lipodystrophy is seldom associated with insulin resistance and its related metabolic derangements.[6] This may be related to the fact that in this syndrome, patients have limited fat loss.

Disorders associated with acquired partial lipodystrophy include the following:

  • Membranoproliferative glomerulonephritis - This condition has been reported in about 20% of cases, and proteinuria, in 45% of cases. However, it is possible that other concomitant diseases (eg, urinary tract infection, diabetes) contribute to the rates of proteinuria.[4] Patients with membranoproliferative glomerulonephritis are more likely to have low C3 levels and the presence of C3 nephritic factor (C3NeF).[7, 8, 9]

  • Autoimmune diseases - Systemic lupus erythematosus is the most common of these[7, 8] ; other reported autoimmune diseases include, but are not limited to, the following:

    • Dermatomyositis

    • Pernicious anemia

    • Celiac disease

    • Dermatitis herpetiformis

    • Rheumatoid arthritis[10]

    • Temporal arteritis

    • Leukocytoclastic vasculitis

  • Propensity to bacterial infections

  • Other - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal component, skin changes) syndrome,[5] mental retardation and retinal disease are among the syndromes that also are associated with acquired partial lipodystrophy.

  • Diabetes and impaired glucose tolerance - In contrast with their occurrence in most other lipodystrophies, diabetes and impaired glucose tolerance are found only rarely in acquired partial lipodystrophy, being reported in 6.7% and 8.9% of patients, respectively.[4]

Pathophysiology

The precise pathophysiology of fat loss is unclear. Activation of an alternate complement pathway, C3 hypocomplementemia with lysis of adipocytes induced by C3NeF, has been implicated.[11, 12] C3 hypocomplementemia likely contributes to the association of this syndrome with autoimmune diseases and with a propensity for patients to acquire bacterial infections.[4] Other proposed mechanisms include an autoimmune process, viral infection,[13] and genetic associations.[14, 15, 16]

Recently novel mutations in the LMNB2 gene have been identified in 4 of 5 acquired partial lipodystrophy patients tested.[14, 17] A related gene, LMNA, has coding mutations associated with another form of lipodystrophy, Dunnigan-type familial partial lipodystrophy.[18, 19]

Another form of lipodystrophy that fits the classification of “acquired partial” not involving the complement pathway is associated with hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma. Five cases were reported but the phenotype resembles Dunnigan-type familial partial lipodystrophy rather than classic acquired partial lipodystrophy.[20]

Epidemiology

Frequency

United States

Approximately 250 cases have been reported since the recognition of this syndrome. It is a rare syndrome with no known prevalence, although it is more common than the generalized form of acquired lipodystrophy (Lawrence syndrome).[4]

International

Several case reports, coming from different parts of the world, have been made. However, the international incidence and prevalence of this disease are not known.

Mortality/Morbidity

Estimating the mortality rate based on the available literature is difficult. Several case reports have revealed an association between acquired partial lipodystrophy and other diseases (see the list of disorders associated with acquired partial lipodystrophy).

Nephropathy, in the form of membranoproliferative glomerulonephritis, occurs in approximately 20% of patients.[4]

Usually, patients do not have clinically evident renal disease or abnormalities in renal function until they have had the disease for 8 or more years. Membranoproliferative glomerulonephritis usually presents with asymptomatic proteinuria or hematuria. The disease may gradually progress. About 40-50% of patients develop end-stage renal disease over the course of 10 years. This condition is responsible for most recurrent hospital admissions in patients with acquired partial lipodystrophy.[4]  Rapid progression of renal disease in a pregnant patient was reported.[21]  Recurrent disease in transplanted kidneys is common, although there have been reports of successful transplantations.[22, 23]

Associated autoimmune diseases (eg, systemic lupus erythematosus, thyroiditis) contribute significantly to increased morbidity in these patients compared with the general population. Localized scleroderma has also been reported.[24]

Although uncommon, insulin resistance increases cardiovascular risk.

Susceptibility to bacterial infections probably results from a C3 deficiency (due to complement activation and consumption of C3). Low C3 levels may impair complement-mediated phagocytosis and bacterial killing.

Race

No clear relationship exists between incidence and race in this syndrome; however, most reported patients have been of European descent.

Sex

Women are affected approximately 4 times more often than men.[4]

Age

The median age of onset of lipodystrophy has been reported to be around 7 years; however, onset occurring as late as the 4th or 5th decade of life also has been reported.[4]

The median age at presentation has been about 25 years, and women have been found to present later than men (age 28 y vs 18 y).

 

Presentation

History

The problem usually begins in childhood. In most reports, disease onset occurs when patients are younger than 16 years.

The onset usually follows an acute, febrile viral illness, most commonly measles. Minor surgical procedures and psychological stress have also been reported before the onset of fat loss.

Lipodystrophy progresses slowly and occurs over a period of a few months to 2 years. Seventy-five percent of patients have been found to have significant fat loss when younger than 13 years.

Acquired partial lipodystrophy is characterized by a fat loss that spreads through the cephalocaudal distribution from the face, neck, shoulders, arms, and forearms and that extends to the thoracic region and upper abdomen. Occasionally, fat loss may involve the groin or thighs. The hips and legs are usually spared, as shown in the image below. After puberty, women have a tendency to accumulate fat (lipohypertrophy) disproportionately in the hips and legs.[25]

Fat distribution in acquired partial lipodystrophy Fat distribution in acquired partial lipodystrophy.

The process does not affect patient growth, and children usually experience developmental milestones with no difficulties. No pain is associated, but patients may occasionally complain of muscle weakness.

Patients with acquired partial lipodystrophy do not usually experience the metabolic abnormalities observed in persons with other forms of lipodystrophy. However, inquiring about a history of menstrual irregularities, hirsutism, diabetes mellitus, and dyslipidemia is important, because metabolic abnormalities have been reported in these patients, and therapeutic interventions are available for these diseases. In addition, looking for evidence of renal disease, which occurs in approximately 20% of patients, is essential. Most patients are asymptomatic until the development of advanced renal impairment or acute decompensation.[4]

Hepatomegaly has been reported in over 60% of patients. However, this finding might be due to associated autoimmune diseases.

Patients with acquired partial lipodystrophy may present with a history that is suggestive of autoimmune or rheumatologic disease.

Physical

Patients usually have normal growth and secondary sexual characteristics. No specific bony abnormalities are present.

General inspection may reveal features of one of the associated autoimmune diseases (see the list of disorders associated with acquired partial lipodystrophy). Hepatomegaly might be present. Acanthosis nigricans and increased skin tags are very rare; they indicate the presence of insulin resistance.

Exposing the patient properly for examination is very important; otherwise, the diagnosis can be easily missed. The best exposure during examination is achieved when the patient wears a gown exposing the extremities and trunk.

These patients usually have characteristic body changes, including loss of fat and deposition of fat. Loss of fat occurs in the face (around the cheeks and temples; eg, sunken cheeks), neck, shoulders and upper extremities, and upper abdomen. Breasts may lose fat and consist only of firm glandular tissue. Prominent veins in the arms with a muscular appearance (not associated with heavy exercise or muscle-building routines) are very characteristic of this syndrome. Fat deposits can occur in the hips, lower extremities, breasts (in men and women), or other scattered areas around the body. These patients do not have cushingoid features.

Diagnostic criteria are as follows:[25]

  • Gradual loss of subcutaneous fat in face, neck, trunk, and upper extremities occurring during childhood or adolescence (essential)

  • Normal or excess subcutaneous fat in the hips and lower extremities

  • Proteinuria or biopsy-proven membranoproliferative glomerulonephritis

  • Low C3 level, reported in about 70% of patients (the C3 level might be normal with an elevated C3 degradation product, C3d)

  • Presence of C3NeF, a polyclonal immunoglobulin G (IgG), able to break down C3 in normal human serum (it is reported to be present in about 80% of patients)

  • Absence of other metabolic derangement

  • Characteristic fat distribution, as measured by skinfold thickness or images from magnetic resonance imaging (MRI) studies[15, 26]

  • Presence of autoimmune disease

Causes

Proposed mechanisms include the activation of an alternate complement pathway, autoimmune diseases, genetic associations, and idiopathic disease.

 

DDx

Diagnostic Considerations

Because of the variable patterns of lipodystrophy in these patients, several other syndromes should be considered in the differential diagnoses of acquired partial lipodystrophy, including the following:

  • Idiopathic localized lipodystrophy

  • Familial partial lipodystrophy

  • Drug-induced lipodystrophy

  • Human immunodeficiency virus 1 (HIV-1) – related lipodystrophy[15, 27]

  • Acute panniculitis

  • SHORT syndrome (short stature, hyperextensibility of joints, ocular depression, Reiger [ocular and dental] anomaly, teething delay)[15]

  • Werner syndrome

  • Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome)

  • Leprechaunism (Donohue syndrome)

  • Mandibuloacral dysplasia

Differential Diagnoses

 

Workup

Laboratory Studies

The diagnosis of the disease is mainly clinical (see the list of diagnostic criteria). The laboratory workup is needed primarily to investigate for the presence of associated disorders (metabolic, autoimmune, and renal diseases).

Every patient should have a fasting blood glucose and lipid profile, creatinine evaluation, and urinalysis for protein content at the first visit, after which he/she should have these tests on a regular basis.

Although uncommon, lipid abnormalities can occur in the form of raised triglyceride levels and low high-density lipoprotein (HDL) cholesterol levels.

Patients usually have decreased serum C3 levels, normal levels of C1 and C4, and high levels of C3NeF (autoantibody), which may indicate the presence of renal involvement. The C3nef is not always present, however.[28, 29]

Antinuclear antibodies (ANA), anti–double-stranded deoxyribonucleic acid (DNA), antiphospholipid, and anticardiolipin antibodies have reportedly been observed in some patients with acquired partial lipodystrophy.[30]

A genetic workup should be performed if the familial form of lipodystrophy is suggested.

Laboratory work for associated diseases includes the following:

  • Metabolic disease - Fasting glucose, glucose tolerance test, lipid profile, and fasting insulin to characterize the insulin resistance state; free testosterone (in women) to look for polycystic ovary syndrome

  • Autoimmune disease - ANA, anti–double-stranded DNA, rheumatoid factor, thyroid antibodies, C3, and C3NeF

Imaging Studies

As a confirmatory test, whole-body MRI usually clearly demonstrates the extent of lipodystrophy. MRI is not recommended on a routine basis.

Procedures

Renal biopsy is the test of choice to help diagnose the type of renal impairment in these patients. A transcutaneous procedure performed under ultrasonographic guidance, it is used to obtain renal tissue using a fine needle. Nephrologists should direct this procedure.

Histologic Findings

Under light microscopy, biopsy specimens of affected areas show a loss of subcutaneous fat; relative adipocyte volume is reduced to 65% of baseline. Lipocytes are usually atrophic or are reduced in number. No infiltrates with lymphocytes have been reported.

 

Treatment

Medical Care

In general, treatment for acquired partial lipodystrophy is limited to cosmetic, dietary, or medical options.

Currently, no effective treatment exists to halt the progression of lipodystrophy.

Thiazolidinediones have been used in the management of various types of lipodystrophies. They bind to peroxisome proliferator-activator receptor gamma (PPAR-gamma), which stimulates the transcription of genes responsible for growth and differentiation of adipocytes.[31] Several case reports have suggested a beneficial effect from treatment with rosiglitazone or pioglitazone on fat distribution in acquired partial lipodystrophy[32, 33] ; however, preferential fat gain was in the lower body.

Following the online publication of a meta-analysis,[34] the Food and Drug Administration issued an alert on May 21, 2007, to patients and health care professionals warning that rosiglitazone could potentially cause an increased risk of myocardial infarction (MI) and heart-related deaths. A thiazolidinedione derivative, rosiglitazone is an antidiabetic agent that improves glycemic control by improving insulin sensitivity. The drug is highly selective and is a potent agonist for PPAR-gamma. Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large-scale phase III trial (RECORD) has been underway to study the cardiovascular outcomes of rosiglitazone.

As of September 2010, the FDA is requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.

For more information, see the FDA’s Safety Alert on Avandia. Additionally, responses to the controversy, including the following articles, can be viewed at Heartwire news (the heart.org, from WebMD): 1) Rosiglitazone increases MI and CV death in meta-analysis, 2) The rosiglitazone aftermath: Legitimate concerns or hype?, and 3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers.

Direct drug therapy is administered according to the associated condition. Membranoproliferative glomerulonephritis and the presence of renal dysfunction largely determine the prognosis of acquired partial lipodystrophy. Standard guidelines for the management of renal disease should be followed. The course of membranoproliferative glomerulonephritis in acquired partial lipodystrophy has not been significantly altered by treatment with corticosteroids or cytotoxic medications. Recurrent bacterial infections, if severe, might be managed with prophylactic antibiotics.

Metreleptin, a recombinant analogue of human leptin, has recently been approved to treat the metabolic derangements of lipodystrophy. Leptin is an adipocyte-derived hormone, which is decreased in lipodystrophy, leading to insulin resistance, dyslipidemia, and other metabolic problems. Metreleptin replaces this deficiency, thus improving insulin resistance, hyperglycemia, dyslipidemia, and hepatic steatosis. Acquired partial lipodystrophy has relatively higher leptin levels and less metabolic derangements. Therefore, the indications for metreleptin are less than for other forms of lipodystrophy.[35, 36, 37, 38]

Surgical Care

The purpose of surgery is mainly cosmetic. According to guidelines from the American Academy of Dermatology, lipodystrophy is one of the indications for fat transplant.

Several facial reconstruction techniques have been used, with variable success, to restore facial contour. However, surgical intervention cannot restore adipose tissue distribution in other affected areas.

The literature is controversial regarding these procedures. The best approach is to individualize the treatment options based on the patient's condition and requirements. These procedures are not recommended for prepubertal children.

Procedures may include the transposition of facial muscles, adipose tissue transplantation (liposuction), and the insertion of silicone or other implants.

Consultations

Early consultation with a nephrologist or an endocrinologist is very important if renal or metabolic complications are suggested.

Diet

No evidence in the literature favors any specific diets in this group of patients. A low-fat, high-carbohydrate diet can be detrimental with regard to triglyceride levels, and weight gain should be avoided to reduce the risk of worsening metabolic status. However, children with this syndrome should be permitted normal food intake to allow for normal growth.

Activity

Regular exercise should be encouraged to help improve metabolic status.

 

Medication

Medication Summary

Pharmacologic intervention is limited in this syndrome.[32, 34, 31] Biguanides and thiazolidinediones have been used in the treatment of the insulin-resistant state (which includes type 2 diabetes and polycystic ovary disease) and in cases of HIV - related glucose intolerance. Although not studied in this group of patients, these drugs should be the first line of treatment if diabetes occurs. Fibrates are the drug of choice for the treatment of hypertriglyceridemia and low HDL cholesterol syndrome.

Hypoglycemic agents

Class Summary

These medications would be started if the patient has developed diabetes that is not being controlled through diet. Insulin sensitizers (biguanides and thiazolidinediones) can be used to reduce insulin levels in women with polycystic ovarian syndrome and with irregular periods.

Metformin (Glucophage)

Reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in peripheral tissues (muscle and adipocytes). Major drug used in type 2 diabetes and obesity.

Pioglitazone (Actos)

Improves target cell response to insulin without increasing insulin secretion from pancreas. Decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and possibly in liver and adipose tissue.

 

Follow-up

Complications

The most significant complications are disfigurement in severe facial involvement, renal disease, and, rarely, insulin resistance state.

Prognosis

Acquired partial lipodystrophy is a slowly progressive disease. In the absence of associated renal impairment or insulin resistance, the prognosis is excellent.

Patient Education

Educating patients about the disease and its associated complications is very important.

Parents should be notified about facial changes that may occur in their child; they should also be told about the importance of balancing dietary intake in order to avoid metabolic complications and to ensure healthy development.