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Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges
Morie A. Gertz, MD, MACP

Hereditary ATTR Amyloidosis: Burden of Illness and Diagnostic Challenges

Morie A. Gertz, MD, MACP
Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease characterized by deposition of amyloid fibrils in various organs and tissues of the body. There are a wide variety of clinical presentations for this multisystemic disorder, so it is often misdiagnosed or subject to delayed diagnosis. Although the exact prevalence is difficult to determine, existing estimates suggest a worldwide prevalence of 50,000 individuals, with varying phenotypic presentations of disease. Due to the heterogeneous nature of its presentation, incorrect or delayed diagnosis can severely impact quality of life for these patients. hATTR amyloidosis can lead to significant disability and mortality. After an accurate diagnosis of hATTR amyloidosis is established, new patients should undergo appropriate therapy as soon as possible. Current treatment options for hATTR amyloidosis are limited, but orthotopic liver transplant serves as an established option for patients with early-stage disease. Consequently, there is a need for new, effective, and safe therapies.
Am J Manag Care. 2017;23:-S0

Amyloidoses are a heterogeneous group of disorders with a variety of clinical presentations characterized by tissue deposition of insoluble, misassembled fibril proteins (amyloid) that disrupt normal tissue structure and function.1,2 Up to 30 different proteins have been identified as causing amyloidoses, including immunoglobulin light chain and transthyretin (TTR).1-3 Each disorder differs in presentation and prognosis, and presents challenges to diagnosis and treatment due to heterogeneous organ involvement and indistinct, often vague symptoms.3,4

Hereditary transthyretin-mediated (hATTR) amyloidosis, caused by misfolding of the TTR protein, is a progressive, degenerative, multisystemic, life-threatening disease.2,5,6 The best contemporary estimates place the worldwide prevalence at 50,000 individuals, with varying phenotypic presentations.4,5,7 Individuals with symptomatic hATTR amyloidosis experience significant impairment to quality of life, regardless of clinical phenotype, when compared with age-matched controls from the general population.5,8 hATTR amyloidosis represents an unmet medical need. Therefore, the purpose of this review is to highlight the progressive and multisystemic nature of hATTR amyloidosis, diagnostic challenges associated with the disease, the lack of consistently effective treatments, and emerging therapies.

Pathophysiology
The protein TTR is primarily synthesized and secreted by the liver, and it transports thyroxine (T4) and retinol.2,9 Mutations in TTR lead to amino acid substitutions in the TTR protein that render the tertiary structure prone to misfolding into a b-pleated sheet configuration,8 thereby forming insoluble amyloid fibrils.2 This mutation results in an autosomal dominant disorder primarily affecting the nerves and heart.2 Clinical manifestations of hATTR amyloidosis are heterogeneous and influenced by TTR genotype, geographic location, and other genetic and environmental factors.10,11 Thus, the presenting symptomatology, age of onset, and rate of disease progression varies among the patient population.10

More than 120 amyloidogenic TTR mutations have been identified.12 In the United States, the most common mutations, in order from most to least prevalent, are Val122Ile, Thr60Ala, and Val30Met.13 Globally, the most common mutations, in order from most to least, are Val30Met, Val122Ile, and Glu89Gln.8 Val30Met is predominantly found in Portugal, Spain, France, Japan, Sweden, and descendants of these regions.13,14 It is often associated with polyneuropathy,2,5 whereas Val122Ile is frequently found in African Americans presenting late in life with cardiac symptoms.2,15 Other mutations, such as Glu89Gln, have been classically associated with a mixed phenotype.8

Despite associations with particular phenotypes, there is considerable variability among patients.8 The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global, multicenter, longitudinal, observational patient registry, owned by Pfizer Inc, designed to characterize differences in disease presentation, diagnosis, and course among the various geographically dispersed patient populations.8,13 Data from this registry highlight the heterogeneity and multisystemic nature of hATTR amyloidosis.8



 
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