Diagnosis and treatment of lipodystrophy: a step-by-step approach

Abstract

Aim: Lipodystrophy syndromes are rare heterogeneous disorders characterized by deficiency of adipose tissue, usually a decrease in leptin levels and, frequently, severe metabolic abnormalities including diabetes mellitus and dyslipidemia.

Purpose: To describe the clinical presentation of known types of lipodystrophy, and suggest specific steps to recognize, diagnose and treat lipodystrophy in the clinical setting.

Methods: Based on literature and in our own experience, we propose a stepwise approach for diagnosis of the different subtypes of rare lipodystrophy syndromes, describing its more frequent co-morbidities and establishing the therapeutical approach.

Results: Lipodystrophy is classified as genetic or acquired and by the distribution of fat loss, which can be generalized or partial. Genes associated with many congenital forms of lipodystrophy have been identified that may assist in diagnosis. Because of its rarity and heterogeneity, lipodystrophy may frequently be unrecognized or misdiagnosed, which is concerning because it is progressive and its complications are potentially life threatening. A basic diagnostic algorithm is proposed. Effective management of lipodystrophy includes lifestyle changes and aggressive, evidence-based treatment of comorbidities. Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval in Europe.

Conclusions: Here, we describe the clinical presentation of known types of lipodystrophy, present an algorithm for differential diagnosis of lipodystrophy, and suggest specific steps to recognize and diagnose lipodystrophy in the clinical setting.

Keywords: Diabetes; Dyslipidemia; Insulin resistance; Leptin replacement; Metreleptin.

Fig. 1

A guide to diagnosing different subtypes of lipodystrophy. Diagnosis of lipodystrophy is largely based on physical examination and clinical history. When abnormal fat loss is observed, other diseases (a) causing a negative energy balance should first be excluded (malnutrition, anorexia nervosa, uncontrolled diabetes mellitus, thyrotoxicosis, adrenocortical insufficiency, cancer cachexia, and chronic infections). Recovery of adipose tissue also makes lipodystrophy unlikely. Patients with HIV receiving antiretroviral treatment often develop a syndrome characterized by peripheral lipoatrophy, trunk fat accumulation, and metabolic abnormalities, the pathogenesis of which remains not completely defined. Progeroid syndromes may be associated with lipodystrophy: Aging traits (b), such as short stature, alopecia, graying, sclerodermatous skin changes, skin atrophy, osteoporosis, acro-osteolysis, joint contractures, small mandible, dental crowding, low muscle mass, joint stiffness, or mottled pigmentation of the skin, are highly suggestive of early aging syndromes. Of note, fat loss in the face of children may confer an aging appearance that should not be considered a progeroid trait. Once the above-reported conditions are excluded, the extent of fat loss and the distribution of residual adipose tissue must be defined. Localized lipoatrophy may develop due to subcutaneous injection of certain drugs or as a result of regional panniculitis, in the absence of systemic manifestations. Extensive thinning of the subcutaneous adipose tissue should orientate towards a generalized form, whereas incomplete depletion of the adipose pad associated with fat accumulation in the spared regions indicates partial lipodystrophy. Both in generalized and partial lipodystrophies, occurrence of affected relatives or parental consanguinity indicates an inherited subtype of the disease, which should be confirmed by genetic testing. Fat loss in the lower body with fat accumulation in the face and neck is suggestive of FPLD, whereas lipoatrophy of the face that progresses to the shoulder girdle, upper extremities, and trunk is a sign of APL. Coexisting autoimmune diseases, panniculitis, or inflammatory manifestations (c: see text) at various sites advocate the diagnosis of acquired lipodystrophy that can be partial at early stages and then evolve as a generalized form. A history of total body irradiation, chemotherapy, and allogeneic bone marrow transplant in the context of leukemia treatment in childhood points to a specific subtype resembling FPLD. AGL acquired generalized lipodystrophy, APL acquired partial lipodystrophy, CGL congenital generalized lipodystrophy, FPLD familial partial lipodystrophy

Fig. 2

Physical appearance of patients with different lipodystrophy subtypes. a Congenital subtypes. Congenital generalized lipodystrophy (CGL): anterior view of a 15-year-old Caucasian man with type 2 CGL due to homozygous c.517dupA (p.Thr173AsnfsTer5) in the BSCL2 gene; familial partial lipodystrophy (FPLD): anterior view of a 27-year-old Caucasian woman with type 2 FPLD due to heterozygous c.1444C>T (p.Arg482Trp) in the LMNA gene; Hutchinson-Gilford progeria syndrome (HGPS): lateral view of a 16-year-old Caucasian woman with HGPS due to de novo heterozygous c.1824C>T (p.[=, Val607_Gln656del]) in the LMNA gene; Werner syndrome: anterior view of a 39-year-old Caucasian man with Werner syndrome due to compound heterozygous c.[2886dup]; [1982-5del] (p.[Ile965*]; [Tyr660Ilefs7*]) in the RECQL2 gene; atypical progeria syndrome (PS): anterior view of a 17-year-old Caucasian man with atypical progeroid syndrome due to de novo heterozygous c.29C > T (p.Thr10Ile) in the LMNA gene. b Acquired subtypes. Acquired generalized lipodystrophy (AGL): posterior view of a 35-year-old Caucasian woman with AGL; bone marrow transplant-associated lipodystrophy: anterior view of a 23-year-old Caucasian woman with partial lipodystrophy associated with bone marrow transplant and total body irradiation during childhood as a treatment for acute leukemia; acquired partial lipodystrophy (APL): anterior view of a 9-year-old Caucasian woman with APL