Untangling the Heterogeneity of Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy (AGL) is characterized by extensive adipose tissue loss, subsequent development of metabolic disease with severe insulin resistance and hypertriglyceridemia and a varying spectrum of autoimmune or immune-dysregulatory features. We recently evaluated twelve patients (8 females, 4 males; age range: 14 - 54 years). The reported onset of fat loss varies from age 2 to 31 years of age but most patients presenting between age 3 and 19 years. The age of diagnosis varies from 4 to 53 years. Clinical panniculitis was reported in 4 patients. Although adipose tissue loss occurred in a generalized fashion, several patients had measured body fat as high as 35 percent on DEXA scans with leptinemia also covering a spectrum from undetectable levels to as high as 6.2 ng/ml. All patients had insulin resistance. Eight patients had diabetes (4 had type 1 diabetes). Dyslipidemia was diagnosed in 11 patients. Hepatic steatosis and/or elevated liver function tests were detected in all subjects. The liver disease was varied and had distinctive characteristics of episodic increases in liver tests in 4 with development of portal hypertension and splenomegaly. These patients had periportal lymphocytic and eosinophilic infiltration on liver biopsies when undertaken during transaminitis and developed portal hypertension, splenomegaly and biliary obstruction while preserving synthetic liver function over time, suggesting that their clinical course may be consistent with nodular regenerative hyperplasia (NRH). Patients also developed a wide range of immune-dysregulatory features including IgA deficiency, common variable immunodeficiency, autoimmune hives, angioedema, eczematous dermatitis, autoimmune hypothyroidism, Graves’ disease, atrophic gastritis, juvenile dermatomyositis, rheumatoid arthritis, polyarthritis, immune thrombocytopenia, cutaneous morphea, lentigo, peripheral T cell lymphoma, graft versus host disease, hemophagocytic syndrome, interstitial lung disease, autoimmune hemolytic anemia, autoimmune colitis, Crohn disease, and periodic fevers. Low complement 4 levels were detected in 5 patients, and 3 had low complement 3 levels. Genetic workup revealed CTLA-4 haploinsufficiency in one case and variants of uncertain significance in P4HA3, TTN, TNFRSF13B, and NLRP3 genes in several others. One distinctive patient was heterozygous for a pathogenic LRBA variant. The exact etiology of AGL is unknown and heterogeneity creates a diagnostic challenge. While panniculitis is a distinct initial presentation in some cases, immune dysregulation affecting multiple organs with accompanying NRH may constitute a new subgroup of AGL. Immune check-point perturbation via gremlin mutation may also lead to AGL. Collective review of cases with predetermined clinical and laboratory evaluation criteria may be helpful to describe subgroups of AGL.