Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is an adult-onset multisystemic disease, affecting the sensory-motor and autonomic functions along with other organs, especially the heart, gastrointestinal tract, eyes, and kidney [1]. ATTRv has an autosomal dominant pattern of inheritance, and worldwide, its global prevalence is estimated at up to 38,000 people [2,3]. TTR is a transport protein in the serum and cerebrospinal fluid that carries the thyroid hormone thyroxine and retinol-binding protein bound to retinol. It is encoded by the TTR gene located in the 18th chromosome. The TTR protein forms tetramers constituted by monomers rich in a beta sheet structure [4]. The presence of missense mutations conducts to a less stable tetramer by altering the amino acid sequence, thus favoring its dissociation. The misfolded monomers aggregate, generating amyloid fibrils, which precipitate into tissues [4,5]. The most frequent TTR mutation is V30M with an early onset (50 years) phenotype is prevalent in non-endemic areas [6,7,8]. In peripheral nerves, amyloid fibrils cause a rapidly progressive peripheral sensory-motor polyneuropathy with significant disability, while in the heart, they generate a cardiomyopathy that may influence the progression of the disease and survival of ATTRv patients [9]. Nowadays, several available treatment options are effective in early disease stages of ATTRv [10]. In particular, patisiran, a small interfering RNA acting as a TTR silencer, approved in Italy in 2020, has been shown to stabilize the course of polyneuropathy in ATTRv, but its administration is bound to the presence of neuropathy as a manifestation [11,12]. Consequently, a meticulous assessment of neuropathy is essential. According to the most common scale to assess the overall burden of polyneuropathy [13], ATTRv evolves into three successive stages: in the first, patients have a sensory polyneuropathy leading to difficulty in walking without assistance; in the second phase, there is a significant limitation in ambulation; finally, patients become wheelchair-bound or bedridden. Additionally, in most studies, neuropathy is assessed through nerve conduction studies, Norfolk QOL-DN questionnaires, NIS + 7 scale, and six-minute walking test (6 MWT) [13,14]. Some researchers are involved in the evaluation of serum biomarkers of neuropathy such as light chain neurofilaments [15]. Of interest, muscle strength can be measured through handgrip tools [16]. The handgrip strength (HGS) test evaluates the force that a person is able to produce when grasping an object. Since HGS is performed with just a dynamometer, it is an easy and cost-effective tool that allows one to measure the maximum isometric handgrip strength of the hand and forearm muscles [17]. HGS provides a quantitative measure of distal strength, and several studies have confirmed that HGS can be used as a diagnostic and prognostic tool in several chronic diseases such as sarcopenia [18] we well as acquired neuropathy [19] such as carpal tunnel syndrome (CTS) [20] and hereditary neuropathy such as Charcot–Marie–Tooth [21]. Apart from a progressive sensory-motor neuropathy and cardiomyopathy, accompanying symptoms are reported in ATTRv such as autonomic dysfunction as well as gastrointestinal problems and unexplained weight loss [22]. These self-reported symptoms are difficult to demonstrate and consequently often underestimated [23]. Some questionnaires such as the COMPASS-31 scale and CADT are commonly used in clinical practice, but an instrumental evaluation of dysautonomia through neurophysiological instruments is not systematically performed at most centers [13]. Bioelectrical impedance analysis (BIA) is a very sensitive tool to examine the composition of the body tissues in polyneuropathies and conditions with dysautonomia. Hence, BIA might accurately estimate the body composition in terms of muscle and fat masses as well as water content in ATTRv patients; this might be an indirect measure of dysautonomia and gastrointestinal function. Although BIA has been used to evaluate sarcopenia in diabetic neuropathy and AL amyloidosis [24,25], to our knowledge, there have been no studies to have assessed body composition through bioimpedance analysis in ATTRv patients. Taken together, HGS and BIA might have a potential in the assessment of the severity of the disease and the beneficial effects of treatments. However, clinical trials and real-world studies have demonstrated the effect of patisiran on PND score, NIS scale, and questionnaires [26], but there are no instrumental data on muscle strength, body composition, and gastrointestinal symptoms. Of note, the use of instrumental biomarkers for the evaluation of tissue damage in ATTRv might lead to a higher sensitive and specific approach; moreover, these biomarkers might contribute to detecting the exact clinical onset of the disease in carriers of TTR mutation, giving them the opportunity to be treated early when the polyneuropathy starts. In this study, instrumental data by means of handgrip strength and BIA were systematically collected in ATTRv patients at the baseline and after 9 months of follow-up to evaluate their potential to measure the pathophysiological alterations of ATTRv amyloidosis and the effects of therapy with patisiran.