Acquired generalized lipodystrophy

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Acquired generalized lipodystrophy
Other namesLawrence-Seip syndrome

Acquired generalized lipodystrophy (AGL), also known as Lawrence syndrome [1] and Lawrence–Seip syndrome, [1] is a rare skin condition that appears during childhood or adolescence, characterized by fat loss affecting large areas of the body, particularly the face, arms, and legs. [2] :496 There are four types of lipodystrophy based on its onset and areas affected: acquired or inherited (congenital or familial), and generalized or partial. Both acquired or inherited lipodystrophy present as loss of adipose tissues, in the absence of nutritional deprivation. The near-total loss of subcutaneous adipose tissue is termed generalized lipodystrophy while the selective loss of adipose tissues is denoted as partial lipodystrophy. [3] Thus, as the name suggests, AGL is a near-total deficiency of adipose tissues in the body that is developed later in life. It is an extremely rare disease with only about 100 cases reported worldwide. [4] [5] There are three main etiologies of AGL suspected: autoimmune, panniculitis-associated, or idiopathic. [6] After its onset, the disease progresses over a few days, weeks, months, or even in years. [6] Clinical presentations of AGL are similar to other lipodystrophies, including metabolic complications and hypoleptinemia. [6] [5] Treatments are also similar and mainly supportive for symptomatic alleviation. Although HIV- or drug-induced lipodystrophy are types of acquired lipodystrophy, their origins are very specific and distinct and hence are usually not discussed with AGL (see HIV-associated lipodystrophy).

Contents

Symptoms

The clinical presentation is similar to people with congenital lipodystrophy: the only difference is that AGL patients are born with normal fat distribution and symptoms develop in childhood and adolescence years and rarely begins after 30 years of age. [6] [7] Females are more often affected than males, with ratio being 3:1. [5] [6] [8] [ page needed ]

The hallmark characteristics are widespread loss of subcutaneous fat, ectopic fat deposition, leptin deficiency, and severe metabolic abnormalities such as insulin resistance. [9] Subcutaneous fat loss in AGL patients are visible in all parts of the body. AGL mostly affects face and the extremities and may look sunken or swollen in the eyes. [6] [8] However, the degree and location of severity may vary by person. [6] [8] Especially, intra-abdominal fat loss is variable. [7] As subcutaneous fat is lost, affected areas show prominent structures of veins and muscle. Those with panniculitis-associated AGL may present erythematous nodules. [10]

Metabolic complications include insulin resistance, high metabolic rate, and uncontrolled lipid levels such as hypertriglyceridemia, low HDL, and high LDL. Patients may develop diabetes mellitus secondary to insulin resistance.

Case reports revealed that lymphoma is present in some patients but its prevalence is not known at this time. [3]

Cause

There is no known cause for this disease; however, three origins of AGL are generally suspected: panniculitis-associated, autoimmune-associated, and idiopathic AGLs. [5] Triggers may include infections that aggravate the panniculitis, or any disease state that can induce autoimmunity. Overlap between panniculitis and autoimmune types also exists. [7] Another theory suggest that AGL is an autoimmune disease itself, as panniculitis can be described as an autoimmune disease, however its triggering factors remains to be unknown. [7] Underlying genetic factors may be implicated; however their existence has neither been confirmed nor rejected. [5]

Panniculitis-associated AGL

About 25% of previously reported AGL is associated with panniculitis. [6] [11] Panniculitis is characterized by inflammatory nodules of the subcutaneous fat, and in this type of AGL, adipose destruction originates locally at the infection or inflammation site and develops into generalized lipodystrophy. [11] [7]

Autoimmune-associated AGL

AGL with autoimmune origin is responsible for about 25% of all AGL reports. [6] [11] Those with autoimmune origin stems from other autoimmune diseases, most commonly with juvenile dermatomyositis and autoimmune hepatitis, but also occurs with rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome. [11]

Idiopathic AGL

Although idiopathic AGL accounts for about 50% of all AGL, it can vary in its origin and it is unclear how it develops. [6] [11] [12]

No known preventive measurement has been reported.

Mechanism

The exact pathophysiologic mechanism is mostly unknown; however, each of three main origins, autoimmune, panniculitis, or idiopathic, may have different mechanisms of pathogenesis. [6] [11]

Normally, adipose tissues contain adipocytes to store fat for energy during fasting period and release leptin to regulate homeostasis of energy and sensitize insulin. In AGL patients, adipose tissues are insufficient and leads to fat deposition in non-adipose tissues, such as muscle or liver, resulting in hypertriglyceridemia. Continuous elevation in triglyceride levels further contributes to metabolic problems including insulin resistance. [12] As the level of leptin in the body is proportional to the amount of adipose tissue present, AGL patients also have a deficiency of leptin which contributes to excessive eating and worsens the metabolic syndrome. [12]

In a few patients with AGL, the presence of antibodies against adipocyte has been identified. [13]

Diagnosis

Diagnosis is made comprehensively, together with visual observation, body fat assessment, a review of lab panels consisting of A1c, glucose, lipid, and patient history.

Caliper measurements of skinfold thickness is recommended to quantify fat loss as a supportive information. [7] In this measurement, skinfold thickness of less than 10 millimetres (0.39 in) for men and 22 millimetres (0.87 in) for women at the anterior thigh is suggestive cutoff for the diagnosis of lipodystrophy. [7] Less commonly, biphotonic absorptiometry and magnetic resonance imaging (MRI) can be done for the measurement of body fat. [5]

Other forms of insulin resistance may be assessed for differential diagnosis. [5] Resistance to conventional therapy for hyperglycemia and hypertriglyceridemia serves as an indication for lipodystrophy. Specifically, the diagnosis is strongly considered for those requiring ≥200 units/day of insulin and persistent elevation of ≥250 mg/dl of triglyceride levels. [7]

The use of leptin levels should be carefully approached. [7] While low leptin levels are helpful for making the diagnosis, they are not specific for the lipodystrophy. High leptin levels can help excluding the possible lipodystrophy, but there is no well-established standardized leptin ranges.

Treatment

Initial and general approach for AGL patients are to treat the metabolic complications such as leptin-replacement therapy and/or to control the abnormal levels of lipids or glucose levels. [12] Anti-diabetic medications such as insulin, metformin, or thiazolidinediones are used for insulin-resistance or high glucose levels, or statins or fibrates are used for hyperlipidemia. If symptoms persist, metreleptin can be prescribed.

Metreleptin (MYALEPT) is a recombinant human leptin analog and was approved by FDA in 2014 for generalized lipodystrophy as an adjunct therapy to diet to treat the complication of leptin deficiency. [14] It is the only drug option approved for generalized lipodystrophy-related symptoms and is not intended to use for patients with HIV-related lipodystrophy or complications of partial lipodystrophy. [14] Although it is a recombinant human leptin analog, it is not completely the same as natural leptin as it is produced in e. coli and has added methionine residues at is amino terminus. [14] It works by binding to the human leptin receptor, ObR, and activates the receptor. [14] The receptor belongs to the Class I cytokine family and signals the JAK/STAT pathway. It is available as 11.3 mg powder in a vial for subcutaneous injection upon reconstitution and needs to be protected from the light. For treatment, patients and their doctors need to be enrolled and certified in the Myalept Risk Evaluation and Mitigation Strategy (REMS) Program because people on this treatment has a risk of developing anti-metreleptin antibodies that decrease the effectiveness of metreleptin, and increased risk of lymphoma. [14] Clinical study with GL patients who took metreleptin had increased insulin sensitivity, as indicated by decreased HbA1c and fasting glucose level, and reduced caloric intake as well as fasting triglyceride levels. [12]

Plasmapheresis was previously an option for lowering extremely high triglyceride levels for preventing pancreatitis and painful xanthoma, but its use has been decreased after the approval of metreleptin. [15]

Cosmetic treatments, such as facial reconstruction or implants, can be done to replace adipose tissues.

Lifestyle modifications are also recommended, including changes into less fat diet and exercise.

The prognosis of the disease is unknown as of December 2017. [5]

Research

Much research for the treatment of lipodystrophy focuses on the safety and efficacy of leptin replacement therapy and the outlook is positive in many studies.[ citation needed ]

According to a prospective, open-label clinical study at the NIH, metreleptin decreased the fasting glucose level from 180 mg/dL to 121 mg/dL, HbA1c from 8.4% to 6.4%, total cholesterol from 214 mg/dL to 146 mg/dL, and triglycerides from 467 (200-847)mg/dL to 180 (106-312)mg/dL after 12 months of use (p<0.001). [16] Patients also had decreased use of anti-diabetic medications, lipid-lowering medications, and insulin (p<0.001). [16] In other clinical reports studying 3 patients diagnosed with AGL accompanied by hypoleptinemia, uncontrolled diabetes, and hypertriglyceridemia who were treated with metreleptin for 12–168 weeks, patients had great reduction in HbA1c, from 10.9% to 5.8%, and had normalized serum triglycerides with a mean decline of 90%. Patients reported improved quality of life and reduced need for other medications without significant adverse effects. [9]

One research published in 2017 reported a middle-aged patient developed AGL after treatment and recovery for autoimmune thrombocytopenia that included immunoglobulin therapy and prednisone, [17] which suggests the autoimmune trigger may contribute to the development of AGL.

Other researches focus on genetics of lipodystrophy; however its relevance to acquired generalized lipodystrophy has not been confirmed so far. One clinical report published in July 2017 stated two brothers with juvenile-onset generalized lipodystrophy was due to lamin C-specific mutation but it is unknown at this point if this will fall into acquired or familial lipodystrophy. [18]

There have been many published case reports. Meta-analysis of published case reports published within the decade will be very helpful in establishing patient demographic, etiologies, and prognosis of the diagnosis.[ opinion ]

See also

Related Research Articles

<span class="mw-page-title-main">Metabolic syndrome</span> Medical condition

Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).

<span class="mw-page-title-main">Leptin</span> Hormone that inhibits hunger

Leptin is a protein hormone predominantly made by adipocytes and its primary role is likely to regulate long-term energy balance.

Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy, is used when describing the loss of fat from one area. This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Adipose tissue</span> Loose connective tissue composed mostly by adipocytes

Adipose tissue is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines. In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

<span class="mw-page-title-main">Adipocyte</span> Cells that primarily compose adipose tissue, specialized in storing energy as fat

Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.

<span class="mw-page-title-main">Hypertriglyceridemia</span> High triglyceride blood levels

Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.

<span class="mw-page-title-main">Panniculitis</span> Medical condition

Panniculitis is a group of diseases whose hallmark is inflammation of subcutaneous adipose tissue. Symptoms include tender skin nodules, and systemic signs such as weight loss and fatigue.

<span class="mw-page-title-main">Adiponectin</span> Mammalian protein found in Homo sapiens

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone used for the treatment of multiple sclerosis. In the latter case, an injection may produce a small dent at the injection site. Lipoatrophy occurs in HIV-associated lipodystrophy, one cause of which is an adverse drug reaction that is associated with some antiretroviral medications.

Barraquer–Simons syndrome is a rare form of lipodystrophy, which usually first affects the head, and then spreads to the thorax. It is named for Luis Barraquer Roviralta (1855–1928), a Spanish physician, and Arthur Simons (1879–1942), a German physician. Some evidence links it to LMNB2.

Congenital generalized lipodystrophy is an extremely rare autosomal recessive condition, characterized by an extreme scarcity of fat in the subcutaneous tissues. It is a type of lipodystrophy disorder where the magnitude of fat loss determines the severity of metabolic complications. Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide.

Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat.

<span class="mw-page-title-main">Familial hypertriglyceridemia</span> Medical condition

Familial hypertriglyceridemia is a genetic disorder characterized by the liver overproducing very-low-density lipoproteins (VLDL). As a result, an affected individual will have an excessive number of VLDL and triglycerides on a lipid profile. This genetic disorder usually follows an autosomal dominant inheritance pattern. The disorder presents clinically in patients with mild to moderate elevations in triglyceride levels. Familial hypertriglyceridemia is typically associated with other co-morbid conditions such as hypertension, obesity, and hyperglycemia. Individuals with the disorder are mostly heterozygous in an inactivating mutation of the gene encoding for lipoprotein lipase (LPL). This sole mutation can markedly elevate serum triglyceride levels. However, when combined with other medications or pathologies it can further elevate serum triglyceride levels to pathologic levels. Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of acute pancreatitis.

<span class="mw-page-title-main">Lipotoxicity</span> Metabolic syndrome

Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.

<span class="mw-page-title-main">MDP syndrome</span> Medical condition

MDP syndrome, also known as mandibular dysplasia with deafness and progeroid features, is an extremely rare metabolic disorder that prevents fatty tissue from being stored underneath the skin. It is only known to affect a very small number of people worldwide. Recent research has suggested that it may be caused by an abnormality of the POLD1 gene on chromosome 19, which causes an enzyme crucial to DNA replication to be defective.

Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia. It has been approved in Japan for metabolic disorders including lipodystrophy and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.

The Metabolic Score for Insulin Resistance (METS-IR) is a metabolic index developed with the aim to quantify peripheral insulin sensitivity in humans; it was first described under the name METS-IR by Bello-Chavolla et al. in 2018. It was developed by the Metabolic Research Disease Unit at the Instituto Nacional de Ciencias Médicas Salvador Zubirán and validated against the euglycemic hyperinsulinemic clamp and the frequently-sampled intravenous glucose tolerance test in Mexican population. It is a non-insulin-based alternative to insulin-based methods to quantify peripheral insulin sensitivity and an alternative to the Homeostatic Model Assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). METS-IR is currently validated for its use to assess cardio-metabolic risk in Latino population.

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