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THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease.

ABSTRACT: Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients' nutritional status and health-related quality of life (HRQoL).The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL.Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty-three percent of those with the hereditary form and 15% of those with the wild-type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p?

SUBMITTER: Wixner J

PROVIDER: S-EPMC4005902 | biostudies-other | 2014 Apr

REPOSITORIES: biostudies-other

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THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease.

Wixner Jonas J Mundayat Rajiv R Karayal Onur N ON Anan Intissar I Karling Pontus P Suhr Ole B OB

Orphanet journal of rare diseases 20140427

<h4>Background</h4>Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transt ...[more]

PMID: 24767411

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Project description:BackgroundHereditary and wild-type transthyretin-mediated (ATTRv and ATTRwt) amyloidoses result from the misfolding of transthyretin and aggregation of amyloid plaques in multiple organ systems. Diagnosis of ATTR amyloidosis is often delayed due to its heterogenous and non-specific presentation. This review investigates the association of musculoskeletal (MSK) manifestations with ATTR amyloidosis and the delay from the onset of these manifestations to the diagnosis of ATTR amyloidosis.MethodsThis systematic review utilized Medline and EMBASE databases. Search criteria were outlined using a pre-specified patient, intervention, comparator, outcome, time, study (PICOTS) criteria and included: amyloidosis, ATTR, and MSK manifestations. Publication quality was assessed utilizing Joanna Briggs Institute (JBI) critical appraisal checklists. The search initially identified 7,139 publications, 164 of which were included. PICOTS criteria led to the inclusion of epidemiology, clinical burden and practice, pathophysiology, and temporality of MSK manifestations associated with ATTR amyloidosis. 163 publications reported on ATTR amyloidosis and MSK manifestations, and 13 publications reported on the delay in ATTR amyloidosis diagnosis following the onset of MSK manifestations.ResultsThe MSK manifestation most frequently associated with ATTR amyloidosis was carpal tunnel syndrome (CTS); spinal stenosis (SS) and osteoarthritis (OA), among others, were also identified. The exact prevalence of different MSK manifestations in patients with ATTR amyloidosis remains unclear, as a broad range of prevalence estimates were reported. Moreover, the reported prevalence of MSK manifestations showed no clear trend or distinction in association between ATTRv and ATTRwt amyloidosis. MSK manifestations precede the diagnosis of ATTR amyloidosis by years, and there was substantial variation in the reported delay to ATTR amyloidosis diagnosis. Reports do suggest a longer diagnostic delay in patients with ATTRv amyloidosis, with 2 to 12 years delay in ATTRv versus 1.3 to 1.9 years delay in ATTRwt amyloidosis.ConclusionThese findings suggest that orthopedic surgeons may play a role in the early diagnosis of and treatment referrals for ATTR amyloidosis. Detection of MSK manifestations may enable earlier diagnosis and administration of effective treatments before disease progression occurs.

Project description:AimsCardiac transthyretin amyloidosis (ATTR-CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow-up and whether it maintains its prognostic value throughout the disease course.Methods and resultsWe performed a retrospective study of 945 patients with wild-type ATTR-CM (wtATTR-CM) or hereditary ATTR-CM associated with the V122I variant (V122I-hATTR-CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease-modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan-Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow-up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR-CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95-2.67; P < 0.001; Stage III vs. II, HRs 1.64-2.25; P < 0.001-0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow-up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58-3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86-4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I-hATTR-CM than in wtATTR-CM (43% vs. 27% at 12 months of follow-up; P = 0.003).ConclusionsNational Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR-CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow-up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I-hATTR-CM than in wtATTR-CM.

Project description:AimTo identify and analyze the genotype of the patients with special ocular manifestations of familial vitreous amyloidosis (FVA) in a Chinese Han family.MethodsPars plana vitrectomy (PPV) surgery was performed on a 52-year-old Chinese woman presented with vitreous amyloidosis and progressive visual impairment, without evidence of cardiac, renal, gastrointestinal, central nervous system or peripheral nervous system dysfunction. During the surgery, the patient presented with a gray-white dense and thick cotton wool-like change in the vitreous body, accompanied by complete retinal detachment. Additionally, hard, free and movable yellow-white deposits were observed in the posterior pole and surrounding retina, the vitreous and subretinal deposits were examined by Congo red staining and immunohistochemical pathological examination, and whole exome sequencing was performed on blood samples from the patient and her cousin.ResultsDuring the operation, it was discovered that there was a complete detachment of the retina and a significant amount of hard, free-floating yellow-white deposits were observed beneath the posterior pole and surrounding retina. This is an exceedingly rare ocular manifestation. Pathological examination of the vitreous and subretinal deposit specimens revealed positive Congo red staining, as well as elevated vascular endothelial growth factor (VEGF) expression in vascular endothelial cells within the sediment specimens upon immunohistochemical examination. The patient and her cousin both exhibited a heterozygous mutation in Glyl03Arg within the transthyretin (TTR) gene, resulting in a substitution of glycine (Gly) at position 103 with arginine (Arg).ConclusionFVA may present with various ocular manifestations, but panretinal detachment is a rare occurrence. In cases where retinal detachment persists for an extended period of time, amyloid deposits may form under the retina through retinal tears, leading to subretinal deposits that can impede retinal reattachment and negatively impact visual prognosis. Elevated levels of VEGF in the eyes of FVA patients may indicate an overexpression state, necessitating careful postoperative follow-up. The heterozygous mutation Gly103Arg may represent a unique pathogenic site in Chinese individuals.

Dataset Information

THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease.

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THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease.

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