Conjunctival lymphangiectasia and retinal angiopathy in hereditary transthyretin amyloidosis

Background Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare condition where a mutation in the transthyretin gene leads to systemic deposition of amyloid. The manifestations and prognosis of ATTR amyloidosis depends on the specific ATTR mutation, with over 100 mutations reported in the literature. The manifestations of many rare forms of ATTR amyloidosis have not been well described, particularly the late-onset ophthalmic findings. Case presentation We present the case of a 43-year-old Caucasian male with a diagnosis of ATTRD18E amyloidosis confirmed by fat pad biopsy. He had diffuse systemic involvement, including cardiovascular, pulmonary, and gastrointestinal symptoms. He also had significant ocular involvement including vitreous opacities, retinal angiopathy, and conjunctival lymphangiectasia. These ocular findings modestly progressed at 2-year follow-up. Discussion The ATTRD18E mutation is a rare variant, with few described cases. To our knowledge, this is the first documented case of ATTRD18E amyloidosis with significant ocular involvement. These ocular findings may serve as a relevant biomarker for severe disease prognosis in ATTRD18E amyloidosis. With improving treatments addressing the systemic symptoms of ATTR amyloidosis, a better understanding of the late-onset ocular symptoms is becoming increasingly relevant.

Long-Term Survival With Tafamidis in Patients With Transthyretin Amyloid Cardiomyopathy

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P <0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33–0.99]; P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Phenotypic heterogeneity and diagnostic features of transthyretin amyloidosis with polyneuropathy

Transthyretin amyloidosis (ATTR-amyloidosis) is a systemic progressive fatal disease, for which a modifying therapy has recently been proposed that delays the progression of the disease and improves the patient’s quality of life. The delay in the diagnosis of ATTR-amyloidosis is associated with the heterogeneity of the manifestations of the disease, as well as insufficient awareness of doctors of different specialties about the disease. A review of recent studies on the symptomatology, diagnosis, molecular genetic characteristics of ATTR-amyloidosis and the most common forms of the disease with the predominant involvement of peripheral nerves and the heart, as well as the kidneys, gastrointestinal tract, and eyes is presented. The international consensus recommendations for the diagnosis of suspected ATTR-amyloidosis using modern methods that facilitate early and accurate diagnosis are discussed. The reasons and the most frequent misdiagnoses of ATTR-amyloidosis, which also lead to a delay in the timely appointment of therapy, are considered. Molecular genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy and cardiomyopathy. A diagnostic algorithm based on the initial symptoms and manifestations of the cardiovascular and nervous systems facilitates the identification of a patient with clinical suspicion of ATTR-amyloidosis by the general practitioner. Early diagnosis is critically important for patients with ATTR polyneuropathy, since the early prescription of Vindakel (tafamidis), registered in the Russian Federation in 2017, allows a significant clinical effect to be obtained. Timely administration of Vindakel significantly slows down the progression of the disease, improves the prognosis and quali ty of life in patients with ATTR polyneuropathy.

Machine learning quantification of amyloid deposits in histological images of ligamentum flavum

ABSTRACTBackgroundWild-type transthyretin amyloidosis (ATTRwt) is an underdiagnosed and potentially fatal disease. Interestingly, ATTRwt deposits have been found to deposit in the ligamentum flavum (LF) of patients with lumbar spinal stenosis prior to the development of systemic and cardiac amyloidosis. In order to study this phenomenon and its possible relationship with LF thickening and systemic amyloidosis, a precise method of quantifying amyloid deposits in histological slides of LF is critical. However, such a method is currently unavailable. Here, we present a machine learning quantification method with Trainable Weka Segmentation (TWS) to assess amyloid deposition in histological slides of LF.MethodsImages of ligamentum flavum specimens stained with Congo red are obtained from spinal stenosis patients undergoing laminectomies and confirmed to be positive for ATTRwt. Amyloid deposits in these specimens are classified and quantified by TWS through training the algorithm via user-directed annotations on images of LF. TWS can also be automated through exposure to a set of training images with user-directed annotations, and then application to a set of new images without additional annotations. Additional methods of color thresholding and manual segmentation are also used on these images for comparison to TWS.ResultsWe develop the use of TWS in images of LF and demonstrate its potential for automated quantification. TWS is strongly correlated with manual segmentation in the training set of images with user-directed annotations (R = 0.98; p = 0.0033) as well as in the application set of images where TWS was automated (R = 0.94; p = 0.016). Color thresholding was weakly correlated with manual segmentation in the training set of images (R = 0.78; p = 0.12) and in the application set of images (R = 0.65; p = 0.23).ConclusionTWS machine learning closely correlates with the gold standard comparator of manual segmentation and outperforms the color thresholding method. This novel machine learning method to quantify amyloid deposition in histological slides of ligamentum flavum is a precise, objective, accessible, high throughput, and powerful tool that will hopefully pave the way towards future research and clinical applications.

Cardiac Transthyretin Amyloidosis: Hidden in Plain Sight

Amyloidosis is an underappreciated medical condition with symptoms camouflaging as common medical comorbidities leading to its underdiagnosis due to its systemic involvement. Despite common misconceptions, amyloidosis and its systemic comorbidities are more prevalent and treatable than previously acknowledged by the medical community. There are two major forms of amyloidosis: amyloid light-chain and transthyretin amyloidosis. Each of these have a distinct pathophysiology, diagnostic work-up, treatment, and prognosis. The patient described in this study was diagnosed with transthyretin cardiac amyloidosis months after presenting with heart failure of unknown etiology. Usually, clinicians presume that heart failure results from common comorbidities such as hypertension, diabetes, and hyperlipidemia. Here, the correct etiology was transthyretin cardiac amyloidosis. The patient had five admissions for heart failure symptoms prior to a physician identifying the etiology as cardiac transthyretin amyloidosis. After initiating the transthyretin stabilizer tafamidis, the patient did not experience another heart failure exacerbation. This vignette provides an example of the clinical presentation, diagnostic work-up, and treatment of a patient with cardiac transthyretin amyloidosis. The review of the literature focuses on the epidemiology, and clinical symptoms that should prompt an evaluation for cardiac amyloidosis as well as the diagnostic and therapeutic options are available. Transthyretin cardiac amyloidosis is a rare and underdiagnosed disease, while heart failure is a highly prevalent condition. This clinical vignette seeks to provide education and awareness to an overlooked medical disorder.