唾液中差异性蛋白在2型糖尿病早期诊断中的临床研究

目的：探讨唾液中的胱抑素C（Cys‐C）、α2‐巨球蛋白（α2‐MG）、α1‐抗胰蛋白酶（A1AT）及转甲状腺素蛋白（TTR）在2型糖尿病早期诊断中的临床意义及运用。方法选取体检正常人群38例（正常组）,空腹血糖升高患者23例（IFG组）,糖耐量患者31例（IGT组）及2型糖尿病患者86例（2‐DM组）,通过免疫印迹检测4组人群唾液中Cys‐C、α2‐MG、A1AT 及TTR蛋白的表达并进行半定量分析。同时通过ELISA方法对唾液及血液中Cys‐C、α2‐MG、A1AT及TTR进行定量分析后研究其相关性。同时,根据 ELISA 定量结果对Cys‐C、α2‐MG、A1AT 及TTR绘制ROC曲线,确定各指标检测的特异性和灵敏度。结果免疫印迹条带进行半定量及ELISA定量检测均表明2‐DM 组患者唾液中 Cys‐C、α2‐MG、A1AT 明显上调,而 TTR蛋白无明显变化。唾液及血液中 Cys‐C、α2‐MG、A1AT及 TTR呈正相关,且唾液中Cys‐C、α2‐MG与血液中血糖浓度呈正相关。ROC曲线表明唾液中Cys‐C、α2‐MG可作为2‐DM早期诊断标志物。结论通过唾液中Cys‐C、α2‐MG的检测,可在2‐DM 早期进行筛查,并在糖尿病早期予以干预治疗,具有潜在的临床运用价值。     

Transthyretin deposition in the eye in the era of effective therapy for hereditary ATTRV30M amyloidosis

Background: Ocular abnormalities have been known to occur in hereditary amyloidotic polyneuropathy since the 1950s. While vitreous opacities and scalloped pupils were described early it has become evident that every component of the eye from the conjunctiva to the retinal vasculature can be involved. Reports from the major centres in Japan, Portugal and Sweden, which primarily treat patients with ATTRV30M, have indicated that with the increased longevity seen in patients treated with liver transplantation the frequency of the more severe eye findings, notably vitreous opacities and subsequent glaucoma, are being detected more frequently.

Methods: In an attempt to confirm that the experience was similar in a broader range of locales we performed a survey of ten treatment centres in eight countries to determine the frequency of severe ocular abnormalities (vitreous opacities and glaucoma) in 804 patients with V30M disease and whether there was any relationship to treatment with liver transplantation or the transthyretin stabilizer tafamidis.

Results: The data indicate that the frequency of these abnormalities increases with increasing duration of disease. In patients broadly matched for duration of disease the frequency was higher in subjects who had undergone liver transplantation than in those who were untreated.

Conclusions: Retrospective surveys are subject to a number of potential biases. In this case, the major potential confounders were defining the time of disease onset and physician bias in choice of therapy, particularly regarding the choice of patients and the time in their course when they should undergo liver transplantation, and when and whether they should receive tafamidis. Nonetheless it appears that the incidence of severe ocular abnormalities in V30M subjects from centres around the world is similar to those found in centres in the areas endemic for this variant protein. The incidence increased with duration of disease regardless of therapy with the highest frequencies seen in patients more than ten years after diagnosis who had undergone liver transplantation.     

Three patients of transthyretin amyloidosis in a Japanese family with amyloidogenic transthyretin Thr49Ser (p.Thr69Ser) variant

Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance.The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, ^99mTechnetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart.The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention.     

Quantitative sudomotor test helps differentiate transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy

ObjectiveTransthyretin familial amyloid polyneuropathy (TTR-FAP) is an aggressive hereditary neuropathy characterized by sensory and autonomic dysfunction. There are numerous reports of TTR-FAP misdiagnosed and treated as chronic inflammatory demyelinating polyneuropathy (CIDP), leading to delayed diagnosis, risk of iatrogenic adverse events and increased socio-economic costs. Quantitative sudomotor function measured by electrochemical skin conductance (ESC) appears to be a sensitive test in TTR-FAP. We aimed to evaluate the performance of ESC in differentiating TTR-FAP from CIDP.MethodsThirty-eight patients with genetically confirmed hereditary TTR amyloidosis and 26 with definite CIDP according to the EFNS/PNS guidelines and negative TTR-FAP genetic testing were involved in this study. We compared the ESC for feet and hands measured by Sudoscan for each patient.ResultsESC (µS) was significantly lower in TTR-FAP for both hands (72 vs 45, p < 0.0001) and feet (77 vs 35, p < 0.0001). Feet ESC < 64 µS had a 89% sensitivity and a 96% specificity to differentiate between CIDP and TTR-FAP.ConclusionSudoscan is a fast, non-invasive and easy to perform test, able to distinguish CIDP and TTR-FAP patients with good sensitivity and specificity.SignificanceSudoscan can be helpful in distinguishing between CIDP and TTR-FAP.     

转甲状腺素蛋白淀粉样变性多发性神经病的疾病负担研究进展

目的 系统梳理全球转甲状腺素蛋白淀粉样变性多发性神经病（transthyretin amyloid polyneuropathy,ATTR-PN）疾病负担研究进展。方法 检索ISI Web of Knowledge、PubMed、Embase、Cochrane Library、中国学术文献网络出版总库、维普数据库、中国生物医学文献数据库和万方等数据库,查找关于转甲状腺素蛋白淀粉样变性多发性神经病的疾病负担研究的文献,按照纳入排除标准筛选文献、提取资料后,概括全球ATTR-PN的流行病学和疾病负担特点。结果 ATTR-PN的疾病负担主要表现为低发病率、低患病率、低生存率、患者地区分布不均、患者及照顾者生活质量较差和家庭、社会的经济负担重等特点。结论 国内外关于ATTR-PN疾病负担的研究较少且分散,未来应加强相应的研究和患者登记工作。     

Potential treatment of transthyretin-type amyloidoses by sulfite

Familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis (SSA) are characterized by systemic extracellular deposition of insoluble transthyretin (TTR) fibrils. While only normal TTR is found in fibrils from SSA patients who predominantly suffer from cardiomyopathy, autosomal dominant FAP preferentially affects peripheral nerves and heart and is associated with so-called amyloidogenic mutations of this protein, giving rise to TTR forms of decreased stability. Using isoelectric focusing in urea gradients we were able to demonstrate a stabilizing effect of sulfite on TTR monomers and tetramers, as well as an increase in the tetramer/monomer ratio. We demonstrate that this ratio, which is decreased in FAP patients, can be increased to beyond normal levels. We show that doses of sulfite which are tolerable in vivo produce a significant increase in the tetramer/monomer ratio and postulate that sulfite may be a potent drug for delaying the onset and progress of FAP and SSA. Received: July 20, 1999 / Accepted: July 26, 1999 · Published online: September 27, 1999     

The presence of transthyretin in rat ependymal cells is due to endocytosis and not synthesis

The presence and synthesis of transthyretin, a major carrier protein of thyroxine in rat cerebrospinal fluid, was investigated in choroid plexus epithelial cells and ependymal cells by immunocytochemistry, in situ hybridization, and analysis by Northern and Western blot using a specific oligonucleotide probe and a specific polyclonal antibody to transthyretin. Choroid plexus epithelial cells expressed transthyretin at high levels in developing rat cerebral hemispheres and in cultured cells. These cells secreted transthyretin into the cerebrospinal fluid. In the developing rat brain transthyretin was present in the cytoplasm of ependymal cells, in vesicles in contact with the apical membrane and in cilia. In ependymal cell cultures this protein was particularly abundant in the cilia of these cells. In contrast, ependymal cells did not synthesize transthyretin. It is postulated that transthyretin is transported to ependymal cells from the cerebrospinal fluid by endocytosis.     

French practical guidelines for the diagnosis and management of AA amyloidosis

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.