Generalized Lipodystrophy (GL): Triglyceride Levels

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Generalized lipodystrophy (GL): triglyceride levels

Background GL is a rare, complex, and clinically heterogeneous disorder characterized by the widespread lack or loss of subcutaneous adipose tissue in most or all parts of the body leading to relative leptin deficiency and associated metabolic abnormalities.1,2 In normal physiology, leptin acts in the brain and periphery to regulate energy homeostasis and metabolic function in the body.2,3 There are 2 types of GL: congenital generalized lipodystrophy (CGL), also known as Berardinelli- Seip syndrome, and acquired generalized lipodystrophy (AGL), also known as Lawrence syndrome. CGL is an autosomal recessive disorder characterized by a generalized lack of adipose tissue at birth or shortly thereafter (within the first year of life) and is accompanied by prominent muscularity and subcutaneous veins.1 In contrast to patients with CGL, patients with AGL are born with normal fat distribution but lose fat in a generalized fashion over time, typically starting in childhood or adolescence. Approximately 50% of patients with AGL present with panniculitis or juvenile dermatomyositis during or prior to fat loss.1,4

Triglyceride levels Categories for triglyceride ranges in children and adults are defined in the table below.5,6

Triglyceride category Triglyceride concentration (mg/dL)

In children 0-9 years In children 10-19 years In adults

Normal <75 <90 <150

Borderline-high 75-99 90-129 150-199

High ≥100 ≥130 ≥200

Very high levels that put people at risk >500 >500 >1000 for pancreatitis

Although many patients with GL have very high triglycerides (>500 mg/dL), some patients with GL have triglyceride values within the normal range or slightly above the normal range.7 Therefore, when making a clinical diagnosis of GL, triglyceride values should be assessed in conjunction with other clinical characteristics that are supportive of GL. The table below shows the variable nature of triglyceride values in patients with GL receiving fibrates.7

Type of GL AGL CGL AGL CGL CGL CGL CGL AGL CGL CGL AGL CGL CGL CGL

Age/sex 17/F 17/F 27/F 17/F 16/F 36/F 40/F 13/F 12/F 47/F 29/F 23/F 14/F 17/M

Triglyceride 7420 523 450 322 944 731 471 2984 261 1543 438 702 3385 433 value (mg/dL) GL requires a clinical diagnosis The American Association of Clinical Endocrinologists (AACE) task force recommends considering a group of clinical characteristics that are supportive of GL. Identifying key clinical characteristics may lead to early detection of GL.1

Core clinical characteristic for GL1

• Loss or absence of subcutaneous body fat in a generalized fashion

Supportive clinical characteristics for GL1

• Presence of diabetes with evidence of severe insulin resistance ––Diabetes mellitus with requirement for high doses of insulin (eg, requiring ≥200 U/day, ≥2 U/kg/day, or currently taking U-500 insulin) ––Ketosis-resistant diabetes • Other evidence of severe insulin resistance ––Acanthosis nigricans ––PCOS or PCOS-like symptoms (hyperandrogenism, oligomenorrhea, and/or polycystic ovaries) • Presence of hypertriglyceridemia ––Severe hypertriglyceridemia (≥500 mg/dL) ––Triglyceride levels that are nonresponsive to therapy and/or modifications to diet ≥( 250 mg/dL) ––History of pancreatitis associated with hypertriglyceridemia • Evidence of hepatic steatosis or steatohepatitis ––Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease (eg, viral hepatitis) may be consistent with nonalcoholic fatty liver disease ––Radiographic evidence of hepatic steatosis (eg, on ultrasound or computed tomography) • Family history of similar physical appearance and/or history of fat loss • Prominent muscularity and phlebomegaly (enlarged veins) in the extremities • Disproportionate hyperphagia (cannot stop eating, waking up to eat, fighting for food) • Secondary hypogonadism in a male or primary/secondary amenorrhea in a female patient

Abbreviation: PCOS, polycystic ovary syndrome.

Not all patients with the clinical characteristics listed in the table above will have GL.

References: 1. Handelsman Y, Oral EA, Bloomgarden ZT, et al. The clinical approach to the detection of lipodystrophy – an AACE consensus statement. Endocr Pract. 2013;19(1):107-116. 2. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. doi:10.1210/jc.2004- 0395. 3. Mantzoros CS, Magkos F, Brinkoetter M, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011;301(4):e567-e584. doi:10.1152/ajpendo.00315.2011. 4. Garg A. Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96(11):3313-3325. 5. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128(suppl 5):S213-S256. doi:10.1542/peds.2009-2107C. 6. Jellinger PS, Smith DA, Mehta AE, et al. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(suppl 1):1-78. 7. Javor ED, Cochran EK, Musso C, Young JR, DePaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(7):1994-2002.