Diagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin

Abstract Background Metreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy. Case presentation A 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL. Conclusions Causal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.https://deepblue.lib.umich.edu/bitstream/2027.42/148289/1/40842_2019_Article_76.pd

The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139088/1/jah3374.pd

The complicated clinical course in a case of atypical lipodystrophy after development of neutralizing antibody to metreleptin: treatment with setmelanotide

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients

Cardiac phenotype in familial partial lipodystrophy

ObjectivesLMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations.Study designRetrospective cohort study.MethodsClinical data from 122 patients (age range: 13–77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from a patient with an LMNA variant were studied as proof‐of‐concept for future studies.ResultsSubjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45–9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04–32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34–9.27). Non‐codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41–15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45–127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37–23.76 for conduction disease). LMNA mutant hiPSC‐CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC‐CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure.ConclusionsOur results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC‐CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/1/cen14426_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/2/cen14426-sup-0001-TableS1-4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/3/cen14426.pd

Cardiac phenotype in familial partial lipodystrophy

ObjectivesLMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations.Study designRetrospective cohort study.MethodsClinical data from 122 patients (age range: 13–77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) from a patient with an LMNA variant were studied as proof‐of‐concept for future studies.ResultsSubjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45–9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04–32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34–9.27). Non‐codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41–15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45–127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37–23.76 for conduction disease). LMNA mutant hiPSC‐CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC‐CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure.ConclusionsOur results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC‐CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/1/cen14426_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/2/cen14426-sup-0001-TableS1-4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167817/3/cen14426.pd

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings

Background: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve NASH in more common forms of this heterogeneous condition