RESUMEN
Autoimmune thyroid diseases (AITD) are the most common group of autoimmune diseases, associated with lymphocyte infiltration and the production of thyroid autoantibodies, like thyroid peroxidase antibodies (TPOAb), in the thyroid gland. Immunoglobulins and cell-surface receptors are glycoproteins with distinctive glycosylation patterns that play a structural role in maintaining and modulating their functions. We investigated associations of total circulating IgG and peripheral blood mononuclear cells glycosylation with AITD and the influence of genetic background in a case-control study with several independent cohorts and over 3,000 individuals in total. The study revealed an inverse association of IgG core fucosylation with TPOAb and AITD, as well as decreased peripheral blood mononuclear cells antennary α1,2 fucosylation in AITD, but no shared genetic variance between AITD and glycosylation. These data suggest that the decreased level of IgG core fucosylation is a risk factor for AITD that promotes antibody-dependent cell-mediated cytotoxicity previously associated with TPOAb levels.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos , Enfermedades Autoinmunes/inmunología , Fucosa/metabolismo , Inmunoglobulina G/metabolismo , Enfermedades de la Tiroides/inmunología , Adulto , Células Sanguíneas/metabolismo , Estudios de Cohortes , Regulación de la Expresión Génica , Glicómica , Glicosilación , Humanos , Inmunoglobulina G/genética , Yoduro Peroxidasa/inmunología , Desequilibrio de Ligamiento/genética , Modelos Biológicos , Polimorfismo de Nucleótido Simple/genética , Polisacáridos/metabolismoRESUMEN
BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune disease characterized by chronic inflammation of thyroid gland. Although HT is the most common cause of hypothyroidism, the pathogenesis of this disease is not fully understood. Glycosylation of serum proteins was examined in HT only to a limited extent. The study was designed to determine the glycosylation pattern of IgG-depleted sera from HT patients. METHODS: Serum N-glycans released by N-glycosidase F (PNGase F) digestion were analyzed by normal-phase high-performance liquid chromatography (NP-HPLC). N-glycan structures in each collected HPLC fraction were determined by liquid chromatography-mass spectrometry (LC-MS) and exoglycosidase digestion. Fucosylation and sialylation was also analyzed by lectin blotting. RESULTS: The results showed an increase of monosialylated tri-antennary structure (A3G3S1) and disialylated diantennary N-glycan with antennary fucose (FA2G2S2). Subsequently, we analyzed the serum N-glycan profile by lectin blotting using lectins specific for fucose and sialic acid. We found a significant decrease of Lens culinaris agglutinin (LCA) staining in HT samples, which resulted from the reduction of α1,6-linked core fucose in HT serum. We also observed an increase of Maackia amurensis II lectin (MAL-II) reaction in HT due to the elevated level of α2,3-sialylation in HT sera. CONCLUSIONS: The detected alterations of serum protein sialylation might be caused by chronic inflammation in HT. The obtained results complete our previous IgG N-glycosylation analysis in autoimmune thyroid patients and show that the altered N-glycosylation of serum proteins is characteristic for autoimmunity process in HT. General Significance Thyroid autoimmunity is accompanied by changes of serum protein sialylation.
Asunto(s)
Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/metabolismo , Inmunoglobulina G/metabolismo , Adulto , Cromatografía Líquida de Alta Presión/métodos , Femenino , Fucosa/metabolismo , Glicosilación , Enfermedad de Hashimoto/sangre , Humanos , Inflamación/metabolismo , Lectinas/metabolismo , Espectrometría de Masas/métodos , Persona de Mediana Edad , Ácido N-Acetilneuramínico/metabolismo , Péptido-N4-(N-acetil-beta-glucosaminil) Asparagina Amidasa/metabolismo , Polonia , Polisacáridos/análisis , Polisacáridos/sangre , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Glándula Tiroides/metabolismo , Tiroiditis/metabolismoRESUMEN
CONTEXT: Aggressive pituitary tumours causing Cushing's Disease are very rare, difficult to treat, and usually resistant to conventional therapy. There is growing evidence for the use of temozolomide (TZM), an alkylating chemotherapeutic agent, as first line chemotherapy in tumours resistant to repeated neurosurgery, radiotherapy and adrenalectomy. OBJECTIVE: To present the response to TMZ in a rare case of an aggressive pituitary tumour in the course of Cushing's Disease and to review the literature referring to similar cases. PATIENT: In this report, we present the case of a 61 year old male patient who was diagnosed with Cushing's Disease in the course of a pituitary invasive macroadenoma in 2011. The patient underwent 4 transphenoidal non-radical neurosurgeries (2012,2013) with rapid tumour progression, repeated non-radical bilateral adrenalectomy (2012, 2013) and stereotactic radiotherapy, and gamma knife surgery (2013, 2015). Histopathological examination revealed macroadenoma with high cell polymorphism and the presence of Crooke's cells, Ki- < 2%. Since 2015 the patient has been treated with 6 cycles of TMZ (320 mg per day for 5 consecutive days, 28-day cycle) with clinical and biochemical improvement and stabilized tumour size and no side effects. TMZ was continued for up to 9 cycles with a stable serum level of cortisol and ACTH being observed. However, clinical symptoms like headaches, visual field impairment, and finally hearing loss started to progress from the eighth cycle. After the ninth cycle of TMZ, there was a sudden increase in the size of the tumour, impairment of the cortisol and ACTH level, marked deterioration of the clinical status with the recurrence of severe headaches, narrowing of the visual field and hearing loss. At the beginning of 2016, a sudden clinical status and sight deterioration, strong headaches, drop of the right eyelid with widening of the pupil were observed. The patient died in February 2016. LESSONS: The case of our patient suggests that the response to the TMZ treatment monotherapy in aggressive pituitary tumour causing Cushing's Disease could be partial and restricted to 7-8 cycles followed by rapid progression of the tumor mass. Therefore, further research should be carried out with regard to new methods to extend the responsiveness and duration of TMZ treatment and to investigate predictors of responsiveness. < p > < /p >.
Asunto(s)
Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Dacarbazina/análogos & derivados , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/etiología , Adenoma Hipofisario Secretor de ACTH/complicaciones , Adenoma Hipofisario Secretor de ACTH/cirugía , Adenoma/complicaciones , Adenoma/cirugía , Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , TemozolomidaRESUMEN
RATIONALE: Traumatic thoracic injuries in adolescents are rare but could be connected with traumatic brain injuries (TBI) and development of chronic hypopituitarism. Early recognition of these endocrine problems is a significant challenge to clinicians. We present difficulties in diagnosis of hypothalamic-pituitary insufficiency following traumatic thoracic injury in adolescence. We also review the literature of similar cases. PATIENT CONCERNS: We present a case of a 24-years-old male. In 2007, at the age of 15 he underwent a severe traffic accident followed by thoracic injury with concussion, hemothorax and dissection of the aorta requiring aortic stent-graft implantation. DIAGNOSES: During the post-traumatic period, transient polydipsia and polyuria symptoms were observed. The patient had no medical history of any serious disease before the accident, his growth and pubertal development was normal. After the accident the patient did not undergo any routine medical check-ups. In 2013 gonadal axis deficiency was diagnosed during investigation of libido problems. Following the diagnosis testosterone replacement therapy was initiated. INTERVENTIONS: Further endocrinological investigation was carried out in 2016. The patient's main complaints were decreased mood and poor physical fitness. BMI was 27.34âkg/m, with a tendency to abdominal fat distribution. The patient's height is 160âcm, while Mid Parental Height (MPH) is 173.5âcm. Decreased bone density was found in DEXA examination. Serum growth hormone level (GH) was normal while insulin-like growth factor-1 (IGF-1) level was below normal. Insulin tolerance test (ITT) and low levels of IGF-1 confirmed somatotropic axis deficiency. Nuclear magnetic resonance (NMR) of the hypothalamo-pituitary region showed no abnormalities. PROP 1 and other common genetic mutations associated with GH deficits were excluded. Testosterone treatment was continued. The patient increased physical activity and implemented diet. OUTCOMES: The patient has lost weight, improved physical activity performance and is feeling better. The procedure to start GH supplementation is now in process. LESSONS: Based on our case and available literature we suggest that adolescent patients after traumatic brain injuries may require precise investigation and strict monitoring due to the possibility of unrecognized hypopituitarism.