Identification and management of gastrointestinal manifestations of hereditary transthyretin amyloidosis: Recommendations from an Italian group of experts

Published: May 24, 2024

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Reference Materials

Key Information

Source

ScienceDirect

Year

2024

summary/abstract

Gastrointestinal manifestations are common across all hereditary transthyretin amyloidosisexternal link, opens in a new tab (ATTRv) genotypes. However, they are poorly specific, and their recognition as part of ATTRv is difficult, resulting in misdiagnosis with more common conditions. Moreover, delays in diagnosis occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv management, and the scarce involvement of gastroenterologists in multidisciplinary teams. A group of Italian gastroenterologists with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists through an online survey and providing education about practical aspects of ATTRv management. Survey results reported low participation, and very few patients with ATTRv were cared for by gastroenterologists. This highlights the need for greater attention to rare diseasesexternal link, opens in a new tab in gastroenterologyexternal link, opens in a new tab and emphasizes increasing awareness of ATTRv and diagnostic suspicion. Based on the experts' recommendations, a diagnosis of ATTRv should be suspected when at least one of the 'red flags' is detected. Subsequently, it is suggested to promptly ask for genetic testing and exclude a serum and urinaryexternal link, opens in a new tab monoclonal protein, even before the detection of amyloid in biopsy samplesexternal link, opens in a new tab, particularly in non-endemic areas.

1. Introduction

Hereditary transthyretin amyloidosis (ATTRv, variant) is a rare, rapidly progressive and fatal disease caused by pathogenic variants in the TTR gene, which are transmitted in an autosomal dominant manner [1,2]. ATTRv is characterized by the accumulation of amyloid fibrils in the extracellular milieu of different organs, mainly peripheral nerves, heart, kidney, eye and gastrointestinal (GI) tract, which progressively undergo impairment of functionality [3,4]. ATTRv has been increasingly reported worldwide, with a cumulative estimated number of patients of 10,186 (range: 5526-38,468) updated in 2018 [5]. The prevalence of ATTRv in Europe is 0.052 per 10,000, with an incidence of 0.003 cases per 10,000/year [6]. Italy represents a non-endemic area for ATTRv with a prevalence of 4.3 per million, with quite variable regional differences [7,8]. The mean age of ATTRv onset in Italy is relatively high (59 years), with only 20 % of patients showing an early onset [7].

Although ATTRv has long been defined as an untreatable disease, in recent years, the therapeutic scenario has changed significantly due to the availability of drugs able to target key molecular events in the process of amyloidogenesis [9], [10], [11], [12], [13]. In light of these developments, the correct and timely diagnosis of ATTRv plays a central role in setting up effective therapy, increasing the patient's survival and quality of life, and offering adequate genetic counseling to family members at risk [14,15].

Phenotypes associated with ATTRv can be extremely heterogeneous since the presentation can be predominantly neurologic, predominantly cardiac, or a mix of both depending on the TTR variant and other, yet unknown, factors [16]. In most cases, the involvement is often multisystemic [17], [18], [19], [20]. In this context, GI manifestations are quite common across all ATTRv genotypes and are most common in patients with neuropathic amyloidosis, in particular those with Val30Met, Glu89Gln, Glu54Gln and Gly47Glu TTR mutations [6,21]. In a cross-sectional study from the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry, between 56 and 69 % of patients reported GI disturbances, depending on TTR mutation [22]. More recently, results from one single-center Italian study involving patients with ATTRv reported that the prevalence of GI symptoms was 82 % [23].

GI disturbances can present even before the onset of polyneuropathy and are associated with significantly reducing the quality of life [22]. The GI disease course is highly variable, and clinical signs and symptoms are not necessarily related to genotypes and geographic area of origin [24,25].

GI manifestations are poorly specific, and their recognition as part of ATTRv may be difficult, resulting in misdiagnosis with more common conditions with higher epidemiological relevance, such as irritable bowel syndrome (IBS) and functional dyspepsia [26,27]. Moreover, delays in diagnosis may occur because of fragmented knowledge, a shortage of centers of excellence and specialists dedicated to ATTRv disease management, and the scarce involvement of gastroenterologists in multidisciplinary teams [28].

Identification of systemic red flags along with GI disturbances might alert the gastroenterologist to start a diagnostic work-up to confirm or rule out ATTRv. Consequently, promoting awareness among gastroenterologists represents an unmet need to improve patient management, especially in non-endemic areas.

To address these issues, a group of Italian gastroenterologists coordinated by two clinicians with experience in the management of ATTRv took part in a project aimed at assessing the awareness of ATTRv among the community of Italian gastroenterologists and providing education about practical aspects of ATTRv management. This paper discusses the results of this activity, providing practical recommendations on the correct pathway for patient identification, diagnosis and management of GI involvement to improve clinical practice from the gastroenterologist perspective.

Authors

Maria Cappello, Giovanni Barbara, Massimo Bellini, Danilo Consalvo, Antonio Di Sabatino , Giovanni Marasco, Mariabeatrice Principi h, Edoardo Vincenzo Savarino, Annalisa Tortora k, Laura Obici