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Baris Akinci Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA
Division of Endocrinology and Metabolism, Dokuz Eylul University, Izmir, Turkey

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Rasimcan Meral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Diana Rus Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Rita Hench Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Adam H Neidert Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Frank DiPaola Division of Pediatric Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA

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Maria Westerhoff Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

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Simeon I Taylor Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA

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Elif A Oral Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Summary

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.

Learning points:

  • A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.

  • Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.

  • The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.

  • Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.

  • Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

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Albert S Kim Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia

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Rashida Hakeem Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

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Azaliya Abdullah Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

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Amanda J Hooper School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia

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Michel C Tchan The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia

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Thushari I Alahakoon The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia

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Christian M Girgis Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
Department of Diabetes and Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Summary

A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered.

Learning points:

  • Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels.

  • Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins.

  • Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia.

  • Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect.

  • Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.

Open access
Aysenur Ozderya Division of Endocrinology and Metabolic Diseases, Kartal Dr Lutfi Kirdar Training and Research Hospital, 34890, Istanbul, Turkey

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Sule Temizkan Division of Endocrinology and Metabolic Diseases, Kartal Dr Lutfi Kirdar Training and Research Hospital, 34890, Istanbul, Turkey

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Kadriye Aydin Tezcan Division of Endocrinology and Metabolic Diseases, Kartal Dr Lutfi Kirdar Training and Research Hospital, 34890, Istanbul, Turkey

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Feyza Yener Ozturk Division of Endocrinology and Metabolic Diseases, Sisli Etfal Training and Research Hospital, Istanbul, Turkey

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Yuksel Altuntas Division of Endocrinology and Metabolic Diseases, Sisli Etfal Training and Research Hospital, Istanbul, Turkey

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Summary

Madelung's disease is a rare fat metabolism disorder characterised by benign multiple symmetric, encapsulated lipomatosis. The exact cause of the disease is unknown; it may be associated with chronic alcoholism and mutations in mitochondrial DNA (A8344G), but there have been cases without these factors reported in the literature. A 29-year-old man with a 6-year history of diabetes mellitus was admitted to our hospital for poorly regulated diabetes and decreased libido. He was not an alcohol consumer. His family history was unremarkable. Physical examination revealed that he had a eunuchoid body shape. There was a symmetric excess fat accumulation in his submandibular, deltoid, nuchal, suprapubic and inguinal areas. He was diagnosed with Madelung's disease, and imaging studies supported the diagnosis. Hormonal evaluation revealed a hypergonadotropic hypogonadism. Karyotype analysis revealed a 47,XXY mutation. Genetic research showed no mitochondrial DNA mutation. Metabolic disorders, such as diabetes mellitus, hyperlipidaemia, hyperuricaemia and liver disease, endocrine gland diseases, such as hypothyroidism, and neurological diseases, such as polyneuropathy and cognitive disorders, may accompany Madelung's disease. The present study represents the first reported case of Madelung's disease accompanied by Klinefelter's syndrome.

Learning points

  • Madelung's disease is a rare fat metabolism disorder characterised by benign multiple symmetric and encapsulated lipid accumulation.

  • The exact cause of the disease is unknown.

  • Metabolic disorders, such as diabetes mellitus, hyperlipidaemia, hyperuricaemia and liver disease, endocrine gland diseases, such as hypothyroidism, and neurological diseases, such as polyneuropathy and cognitive disorders, may accompany Madelung's disease.

Open access