The Value of Nerve Biopsy in Transthyretin Amyloidosis with Competing Comorbidities

Up to one-third of individuals over the age of 65 have a diagnosis of diabetes, and a large proportion are undiagnosed.3 Moreover, in a population-based study aimed at determining the prevalence of monoclonal gammopathy of undetermined significance (MGUS), it was found that MGUS increases with age, with a prevalence of 4.7% between the fifth and sixth decades of life, increasing to 11.2% in individuals over the age of 70.4 Further, in a case series of 15 patients with hATTR PN, coincident diabetes mellitus and monoclonal gammopathy occurred in 23% and 7%, respectively.2 Therefore, the traditional nerve biopsy can provide diagnostic clarity in the setting of multiple competing factors, but on the other hand, the guidelines prudently highlight the drawbacks of the nerve biopsy, which include potential risk of infection, sample limitation, and a high proportion of false negatives.1 We are reminded of the value of nerve biopsy by a patient we encountered just weeks prior to the publication of the guidelines – a 74-year-old male of Jamaican ethnicity and a history of poorly controlled insulin-dependent diabetes, dyslipidemia, hypertension, and bilateral carpal tunnel syndrome. [...]EM examination may demonstrate unbranched amyloid fibrils and minute deposits.2 In our study, despite the negative Congo red staining within the tissue portion used for light microscopy histological examination, another tissue portion subject to semi-thin section for EM analysis was able to exhibit endoneurial lobulated deposits of amorphous amyloid material consistent with amyloid fibrils, which prior studies have also demonstrated.2,8 It is important to keep in mind that amyloid fibrils in nerve biopsy specimens analyzed on EM are morphologically heterogenous and differ, not only based on the underlying transthyretin gene variant, but also the patient’s age, whether the patient is from an endemic or non-endemic area, and phase of amyloid fibril formation.10 As such, given the findings from the EM analysis, the patient’s negative bone marrow biopsy for plasma cell dyscrasia and confirmed genetic testing for the Val142Ile variant for hATTR, we felt that a diagnosis of hATTR PN could be made. Given that hATTR is a multisystemic disease that frequently exists with competing diseases that can cause overlapping peripheral nerve pathologies, determining the nature of nerve involvement is important, as it can impact therapeutic decisions and prognosis. [...]our case demonstrates the value