Selective Pituitary Resistance to Thyroid Hormone: Clinical Hyperthyroidism with High TSH on Levothyroxine Administration in I-131 Ablated “Graves Disease”

Resistance to Thyroid Hormone (RTH) is a rare form of hormone resistance secondary to changes in the genes encoding thyroid hormone receptors. The two subtypes, Pituitary RTH (PRTH) and Generalized RTH (GRTH), cause clinically distinguishable patient presentations. In PRTH, typically only the pituitary gland is resistant to thyroid hormone (TH) while the rest of the body maintains sensitivity. Selective pituitary resistance to thyroid hormone results in dysregulation of thyroid hormone homeostasis with clinical presentation as either euthyroid or hyperthyroidism. PRTH is characterized by elevated thyroid hormone levels with an elevated or inappropriately normal TSH concentration. Herein we describe a case report of a 70-year-old woman who complained of weight loss of over 35 lbs., palpitations, jitters, hair loss, diarrhea, fatigue, muscle weakness, etc. over 6 months, thus, indicating the presence of iatrogenic hyperthyroidism while receiving levothyroxine 175 ug daily prescribed by her primary care provider because of a reported history of “Graves disease” treated by radioactive iodine ablation of the thyroid several years ago. The daily dose of levothyroxine had been increased gradually at an interval of 3 months over a year because of persistent elevation of serum TSH level. Laboratory tests revealed markedly elevated Free T4, Free T3 and TSH levels, along with low concentrations of all lipid fractions, serum creatinine and urea nitrogen levels, indicating TSH induced hyperthyroidism or PRTH. Further testing documented a mutation of thyroid hormone receptor beta gene 2 confirming presence of PRTH. We believe that the initial diagnosis of Graves Disease was erroneous and I-131 ablation further confounded and missed the diagnosis of PRTH. Thus, the purpose of this report is to report a patient with PRTH and describe potential pitfalls in diagnosis and management of this rare disorder.

A new mutation in the thyroid hormone receptor gene of a Chinese family with resistance to thyroid hormone

Background Resistance to thyroid hormone （RTH） is a dominant inherited syndrome of reduced tissue responsiveness to thyroid hormone. It is usually due to mutations located at the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β（TRβ）. We report the clinical and laboratory characteristics and the genetic analysis of a patient with this rare disorder and his family members. Methods The clinical presentations and changes of thyroid function tests （TFTs） including magnetic resonance imaging （MRI） of pituitary and other laboratory tests were analysed. TFTs of his family＇s members were detected as well. Direct DNA sequencing of the TRβ gene was done for those with abnormal TFTs. Results The RTH child had goiter, irritability, aggressiveness, and sudoresis. His TFTs showed high levels of circulating free thyroid hormones （FT4 and FT3） and normal thyroid-stimulating hormone （TSH） concentrations. He felt worse when treated as hyperthyroidism （Grave disease） with thiamazole and his clinical presentations got improved obviously when treated as RTH with bromocriptine without obvious advert effect. We identified a novel missense mutation, A317D, located in exon 9 of the gene of this boy and his mother. His mother had not any clinical presentation, but having abnormal TFTs results. Conclusions This patient reported here was concordant with the criteria of RTH. The feature is dysfunction of hypothalamus-pituitary-thyroid axis. A novel mutation was found in the TRβ, A317D, of this family. This research verified the phenomena that there is a clinical heterogeneity within the same mutation of different RTH patients.

Bariatric surgery in patients with non-alcoholic fatty liver disease-from pathophysiology to clinical effects

Non-alcoholic fatty liver disease(NAFLD) is increasingly recognized as a significant liver disease,and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis(NASH) to fibrosis,subsequent cirrhosis,end-stage liver failure,and liver cancer with a potential need for liver transplantation.NAFLD and NASH are closely related to obesity,metabolic syndrome,and type 2 diabetes(T2 D).The role of gut hormones,especially glucagon-like peptide 1(GLP-1),is important in NAFLD.Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2 D.Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD.Therefore,bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients.In the present review,we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways.We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients.The specific focus was liver histopathology as assessed by the invasive liver biopsy.Additionally,we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.

RET in breast cancer:pathogenic implications and mechanisms of drug resistance

Initiation,progression,outcome and sensibility to therapies in breast cancer(BC),the most frequent cancer in women,are driven by somatic and germline mutations.Although the effectiveness of hormonal therapies is well-founded,it is prescribed for cancers which express steroid hormone receptors,such as estrogen receptor(ER).RET is a proto-oncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands(GDNF,neurturin,artemin or persephin)and one of its coreceptors(Gfrα1-4).Loss-of-function mutations in RET are responsible for Hirschsprung disease,while gain-of-function mutations for multiple endocrine neoplasia type 2.In addition,deregulation of its intracellular signaling,due to mutations,gene rearrangements,overexpression or transcriptional upregulation,can cause several neuroendocrine and epithelial tumors.In BC,amplification of receptor tyrosine kinases,such as ERBB2,EGFR,IGFR and FGFR1,and/or their upregulation contribute to cancer initiation and progression.RET can also have an important role in BC,but only in the subset of ER-positive(ER+)tumors,where it is found overexpressed.Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+BC,improving treatment outcome and preventing tumor-related events.Thus,here,we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

Final results of a 2:1 control-case observational study using interferon beta and interleukin-2,in addition to first-line hormone therapy,in estrogen receptor-positive,endocrine-responsive metastatic breast cancer patients

Aim:We conducted a pilot study that combines immunotherapy(cyclic interleukin-2 interferon-beta sequence)and hormone therapy(HT)to overcome endocrine resistance in metastatic breast cancer.Methods:The final results of a 2:1 control-case retrospective observational study are here shown following 22 additional months of postoperative follow-up and 6 further controls.There were 95 controls and 42 cases in total.The 95 controls were ER+/HER2-metastatic breast cancer patients who underwent first-line HT with aromatase inhibitors(AIs)or fulvestrant.Twenty-eight of them(28.9%)also received biological drugs including cyclin kinase inhibitors(CKIs).The 42 cases were ER+metastatic breast cancer patients who received interferon beta-interleukin-2 immunotherapy in addition to first-line HT.Selective estrogen receptor modulators/down-regulators(SERMs/SERDs)were used for HT in 39(92.9%)of them and AIs in the remaining 3.Results:Median progression-free survival(PFS)and overall survival(OS)were significantly longer in the 42 studied patients who received hormone immunotherapy(HIT)than in the 95 controls(median time 33 vs.18 months,P=0.002,and 81 vs.62 months,P=0.019).In the analysis adjusted for disease-free interval(DFI),hormone receptor,HER2 status,visceral involvement,AIs,and biological therapy,the PFS and OS hazard ratio(HR)further increased in favor of the 42 cases(P=0.004 and P=0.044 respectively).In the same ER+/HER2-metastatic breast cancer patients treated with both AIs and CKIs,a median PFS ranging from 25.3 to 28.18 months and a median OS of 37.5 months were observed.Conclusions:This study strongly suggests multi-center randomized clinical trials should be performed to enter our proposed immunotherapy into clinical practice.