Lipodystrophy

At a Glance

The lipodystrophies are a group of rare, genetic or acquired disorders characterized by generalized (nearly the entire body) or partial (limbs only) loss of body fat, with fat hypertrophy in other depots when partial. They are marked by the abnormal degenerative condition of the body’s adipose tissue, which is associated with severe lipid and glucose abnormalities. The condition is also characterized by a lack of circulating leptin, which may lead to osteosclerosis. If the fat loss is significant, patients develop insulin resistance and its complications, such as diabetes, dyslipidemia, hepatic steatosis, acanthosis nigrans, polycystic ovarian syndrome, and hypertension. Thus, the extent of fat loss governs the severity of the metabolic complications.

The two most common types of lipodystrophy are genetic: autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familial partial lipodystrophy (FPL). However, the genetic lipodystrophies are rare and, as of 2011, have only been reported in about 1000 people. Hence, their estimated prevalence is less than 1 in 1,000,000. Affected females are recognized easily and are reported more often than males.

Patients with CGL are usually recognized at birth because of a near-total lack of body fat and prominent muscularity that gives a distinct and severe phenotype. The babies may have an umbilical protrudence or hernia and hepatosplenomegaly. A few patients develop diabetes in infancy, but most become diabetic during adolescence or later. These children usually have a fierce appetite and accelerated growth. In late childhood, acanthosis nigrans develops on large areas of skin. Female patients often become hirsute and may have clitoromegaly, irregular periods, polycystic ovaries, and infertility issues. Other less common clinical features may include mild cognitive deficits and hypertrophic cardiomyopathy.

The most common causes of death are diabetes complications, acute pancreatitis, or cirrhosis. Autosomal recessive mandibuloacral dysplasia-associated lipodystrophy (MAD) is characterized by skeletal abnormalities, such as mandibular and clavicular hypoplasia and acroosteolysis. Other clinical features include cutaneous atrophy with prominent superficial vasculature and mottled hyperpigmentation, thin beaked nose, hair loss, delayed dentition, crowded teeth, and joint stiffness. Metabolic complications are mild but may include diabetes, insulin resistance, glucose intolerance, mild hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol.

The key features of FPL are onset of fat loss from the limbs and other bodily regions during childhood or later, with normal body fat distribution during infancy and early childhood. Diagnosis of men is difficult, as many unaffected men have a muscular physique. Diabetes and metopic complications generally occur in adulthood, with women more severely affected than men. Acanthosis nigricans is present, although usually mild, in the neck, axillae, and groins. A quarter of affected women have hirsutism and irregular periods, possibly reflecting polycystic ovarian syndrome.

The acquired lipodystrophies are mainly autoimmune in origin and display complement abnormalities. Acquired partial lipodystrophy (APL or Barraquer-Simons syndrome) has been reported in only about 250 cases of various ethnicities, with 80% of affected cases being females. Onset of APL usually occurs before 15 years of age. The fat loss is gradual and symmetrical, first affecting the face and spreading downward. Many patients actually accumulate excess fat in the lower half of the body, and metabolic complications are usually absent. However, 20% of APL patients develop membranoproliferative glomerulonephritis, and some of these develop drusen. The fat loss is thought to involve the autoimmune destruction of adipocytes, as most patients have low serum levels of complement 3.

Acquired generalized lipodystrophy (AGL or Lawrence syndrome) has only been reported in about 100 cases, mostly Caucasians and 75% female. Sub-cutaneous fat loss occurs mostly during childhood, with variable pattern and extent, and proceeded by panniculitis in 25% of patients with the most severe fat loss. Most APL patients are likely to go on to develop diabetes and other metabolic complications.

The most prevalent type of acquired generalized and partial lipodystophy occurs in HIV-infected patients after prolonged treatment with protease inhibitor-containing, highly-active antiretroviral therapy and is called LD-HIV (lipodystrophy in HIV-infected patients). It is estimated to affect more than 100,000 patients in the United States and greater numbers elsewhere around the globe. Localized lipodystrophies (fat loss in small, discrete areas) may arise from drug or vaccine injections, pressure, panniculitis, and other unknown reasons.

Lipodystrophies should be suspected in patients presenting with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans, and polycystic ovarian syndrome (PCOS), especially in lean patients with these metabolic disturbances. It is vital to examine the extremities and hips for evidence of fat loss and muscular prominence. An in-depth pedigree analysis to ascertain mode of inheritance is prompted for those suspected of a genetic lipodystrophy.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The diagnosis of lipodystrophy is mainly clinical, but laboratory tests can provide supporting evidence. All patients suspected of generalized or partial lipodystophy should be tested for glucose intolerance, serum lipids, liver function, and hyperuricemia. Analysis of serum complements 3 and 4 and complement 3 nephritic factor and urinalysis for proteinuria should be performed in patients with acquired lipodystrophy. Electro- and echocardiography, stress test, and Holter monitoring are important for those suspected to have cardiomyopathy or coronary heart disease. Deep skin biopsy will confirm a diagnosis of panniculitis, and skeletal surveys may uncover lytic bone lesions in CGL patients and other skeletal defects in MAD patients.

The genetic basis of many rare forms of lipodystrophy has yet to be elucidated, but genes known to be implicated, and for which genetic testing is available, are subsequently described.

Mutations in the genes AGPAT2, CAV1, PTRF, and BSCL2 (most severe phenotype) have been reported to underlie CGL, whereas FPL is caused by genetic mutations in four different genes: LMNA, PPARG, AKT2, and PLIN1. Mutations in LMNA and ZMPSTE24 can cause autosomal recessive mandibuloacral dysplasia-associated lipodystrophy (MAD), whereas an autosomal recessive form of FPL results from a defect in the CIDEC gene. A mutation in PSMB8 has recently been reported to cause autosomal recessive autoinflammatory lipodystrophy syndrome. There is phenotypic heterogeneity between the various types of CGL and FPL in terms of body fat distribution based on which gene is mutated, although the specifics have not been clearly delineated.

Tests Results indicative of the Disorder

Serum concentration of triglycerides can be elevated up to 80 g/L and is sometimes associated with hypercholesterolemia.

Elevated serum concentrations of insulin and C-peptide may occur starting in the first years of life.

Early clinical expression of diabetes is acanthosis nigricans of the groin, neck, and axillae.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

The diagnosis of lipodystrophy is mainly clinical, and laboratory testing is supportive, mainly being utilized to detect associated abnormalities or disease states, such as acanthocytosis, insulin resistance, diabetes, PCOS, and liver disease.

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