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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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Joanna Prokop Departments of Endocrinology, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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João Estorninho Departments of Endocrinology, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Sara Marote Departments of Internal Medicine, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Teresa Sabino Departments of Endocrinology, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Aida Botelho de Sousa Departments of Hemato-Oncology, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Eduardo Silva Departments of Internal Medicine, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Ana Agapito Departments of Endocrinology, Centro Hospitalar Universitário Lisboa Central, Lisbon, Portugal

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Summary

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes) is a rare multisystemic disease. Clinical presentation is variable, the only mandatory criteria being polyneuropathy and monoclonal gammapathy in association with one major and one minor criterion. Primary adrenal insufficiency is rarely reported. We describe a case of a 33-year-old patient, in whom the presenting symptoms were mandibular mass, chronic sensory-motor peripheral polyneuropathy and adrenal insufficiency. The laboratory evaluation revealed thrombocytosis, severe hyperkalemia with normal renal function, normal protein electrophoresis and negative serum immunofixation for monoclonal protein. Endocrinologic laboratory work-up confirmed Addison’s disease and revealed subclinical primary hypothyroidism. Thoracic abdominal CT showed hepatosplenomegaly, multiple sclerotic lesions in thoracic vertebra and ribs. The histopathologic examination of the mandibular mass was nondiagnostic. Bone marrow biopsy revealed plasma cell dyscrasia and confirmed POEMS syndrome. Axillary lymphadenopathy biopsy: Castleman’s disease. Gluco-mineralocorticoid substitution and levothyroxine therapy were started with clinical improvement. Autologous hematopoietic cell transplantation (HCT) was planned, cyclophosphamide induction was started. Meanwhile the patient suffered two ischemic strokes which resulted in aphasia and hemiparesis. Cerebral angiography revealed vascular lesions compatible with vasculitis and stenosis of two cerebral arteries. The patient deceased 14 months after the diagnosis. The young age at presentation, multiplicity of manifestations and difficulties in investigation along with the absence of serum monoclonal protein made the diagnosis challenging. We report this case to highlight the need to consider POEMS syndrome in differential diagnosis of peripheral neuropathy in association with endocrine abnormalities even in young patients.

Learning points:

  • POEMS syndrome is considered a ‘low tumor burden disease’ and the monoclonal protein in 15% of cases is not found by immunofixation.

  • Neuropathy is the dominant characteristic of POEMS syndrome and it is peripheral, ascending, symmetric and affecting both sensation and motor function.

  • Endocrinopathies are a frequent feature of POEMS syndrome, but the cause is unknown.

  • The most common endocrinopathies are hypogonadism, primary hypothyroidism and abnormalities in glucose metabolism.

  • There is no standard therapy; however, patients with disseminated bone marrow involvement are treated with chemotherapy with or without HCT.

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Ana Coelho Gomes Endocrinology, Diabetes and Metabolism Department, Hospital de Santa Maria, Lisbon, Portugal

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José Maria Aragüés Endocrinology Department, Hospital Beatriz Ângelo, Lisbon, Portugal

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Sílvia Guerra Endocrinology Department, Hospital Beatriz Ângelo, Lisbon, Portugal

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Joana Fernandes Infectious Diseases Department, Hospital de Santa Maria, Lisbon, Portugal

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Mário Rui Mascarenhas Endocrinology, Diabetes and Metabolism Department, Hospital de Santa Maria, Lisbon, Portugal

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Summary

Hypogonadotropic hypogonadism (HH) is common and occurs prematurely in HIV-infected men. However, HH with very low testosterone has not been described. Three men with normal pubertal development and HIV1 diagnosis at the ages of 22, 34 and 35 years. All complained of decreased libido, anejaculation and erectile dysfunction thirteen years, six months and one year after HIV diagnosis, respectively. Two had depressive syndrome and two were treated with antiretroviral therapy. Laboratory tests revealed isolated HH in all. Sellar and head CT scans were normal and all had normal CD4 count. They started testosterone replacement therapy, with symptoms improvement. Causes of HH in HIV-infected men include undernutrition, severe illness, drugs, pituitary dysfunction and comorbidities. Despite having none of these conditions (except two that were treated with low-dose psychotropics), our patients had HH with uncommonly low testosterone. This suggests that a different mechanism contributes to severe HH in HIV-infected men.

Learning points:

  • The pathogenesis of hypogonadotropic hypogonadism in HIV-infected men is multifactorial and androgen deficiency is more often a consequence of secondary hypogonadism than primary hypogonadism.

  • Causes of hypogonadotropic hypogonadism in HIV-infected men include undernutrition, severe illness, drugs (psychotropics, opiates, megestrol acetate or steroids), pituitary dysfunction (tumor, hyperprolactinemia), an AIDS-related lesion (very rarely) and comorbid conditions, such as antibody to hepatitis C virus seropositivity and injection drug use.

  • Highly active antiretroviral therapy (HAART), particularly protease inhibitor therapy has been associated with sexual dysfunction in men, but the causal nature of this relation has not been clearly established.

  • Hypogonadotropic hypogonadism with uncommonly low testosterone levels are not usually associated with the conditions referred and this suggests that a different mechanism could contribute to severe hypogonadotropic hypogonadism in HIV-infected men.

  • Screening for hypogonadism in all HIV-infected men might help to understand its etiology.

Open access
Etienne Larger Department of Diabetology, Hôpital Bichat and University Paris Denis Diderot, Paris, France

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Nicolai J Wewer Albrechtsen Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Lars H Hansen Department of Molecular Signaling, Hagedorn Research Institute, Gentofte, Denmark

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Richard W Gelling Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

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Jacqueline Capeau Inserm UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France

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Carolyn F Deacon Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Ole D Madsen Global Research External Affairs, Novo Nordisk A/S, 2760 Måløv, Denmark

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Fumiatsu Yakushiji Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan
Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan

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Pierre De Meyts Global Research External Affairs, Novo Nordisk A/S, 2760 Måløv, Denmark

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Jens J Holst Department of Biomedical Sciences
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Erica Nishimura Metabolic Disease Research, Novo Nordisk A/S, Måløv, Denmark

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Summary

Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.

Learning points:

  • Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.

  • Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.

  • A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.

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Motoyuki Igata Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Kaku Tsuruzoe Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Junji Kawashima Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Daisuke Kukidome Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Tatsuya Kondo Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Hiroyuki Motoshima Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Seiya Shimoda Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Noboru Furukawa Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Takeshi Nishikawa Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Nobuhiro Miyamura Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Eiichi Araki Faculty of Life Sciences, Department of Metabolic Medicine, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan

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Summary

Resistance to thyroid hormone (RTH) is a syndrome of reduced tissue responsiveness to thyroid hormones. RTH is majorly caused by mutations in the thyroid hormone receptor beta (THRB) gene. Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear. Here, we report a rare case of RTH with a papillary thyroid carcinoma (PTC). A 26-year-old woman was referred to our hospital due to a thyroid tumor and hormonal abnormality. She had elevated serum thyroid hormones and non-suppressed TSH levels. Genetic analysis of THRB identified a missense mutation, P452L, leading to a diagnosis of RTH. Ultrasound-guided fine-needle aspiration biopsy of the tumor and lymph nodes enabled the cytological diagnosis of PTC with lymph node metastases. Total thyroidectomy and neck lymph nodes dissection were performed. Following surgery, thyroxine replacement (≥500 μg) was necessary to avoid the symptoms of hypothyroidism and to maintain her TSH levels within the same range as before the operation. During the follow-up, basal thyroglobulin (Tg) levels were around 6 ng/ml and TSH-stimulated Tg levels were between 12 and 20 ng/ml. Up to present, the patient has had no recurrence of PTC. This indicates that these Tg values are consistent with a biochemical incomplete response or an indeterminate response. There is no consensus regarding the management of thyroid carcinoma in patients with RTH, but aggressive treatments such as total thyroidectomy followed by radioiodine (RAI) and TSH suppression therapy are recommended.

Learning points

  • There are only a few cases reporting the coexistence of RTH and thyroid carcinoma. Moreover, our case would be the first case presenting one with lymph node metastases.

  • Recent studies indicated a close association of THRB mutations with human cancers, but the role of THRB mutation in carcinogenesis is still unclear.

  • When total thyroidectomy is performed in patients with RTH, a large amount of thyroxine is needed to maintain their thyroid function.

  • There is no consensus regarding the management of thyroid carcinoma in patient with RTH, but effective treatments such as total thyroidectomy followed by RAI and TSH suppression therapy are recommended.

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