[Hereditary transthyretin amyloidosis - from symptomatic to curative treatment?] / Ärftlig transtyretinamyloidos ­ från lindring till potentiell bot.

Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multi-systemic disease with clustering areas in, for example, northern Sweden. Until the 1990s, only symptomatic treatments were available but liver transplantation has, in selected patients, been a good therapeutic option since. The first disease-modifying drug for ATTRv amyloidosis was approved in 2011 and since then, the development of new therapeutic drugs has been rapid and successful. Two gene silencing therapies were approved for the disease in 2018, both showing a robust reduction in serum transthyretin levels and a satisfactory safety profile. Recently, CRISPR-Cas9 gene editing has also shown promising results in patients with ATTRv amyloidosis. The recent developments have had a paramount effect on the management of these patients, and will probably also have a significant positive effect on their life expectancy. However, treatment costs have skyrocketed, which implies future challenges.

Amyloid fibril composition type is consistent over time in patients with Val30Met (p.Val50Met) transthyretin amyloidosis.

BACKGROUND: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses. MATERIAL AND METHODS: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients´ initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot. RESULTS: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies. DISCUSSION: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

Epidemiology of hereditary transthyretin amyloidosis in the northernmost region of Sweden: a retrospective cohort study.

INTRODUCTION: Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse. METHODS: We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs). RESULTS: Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84-2.47) cases in 2006-2009 to 4.92 (95%CI, 3.46-6.78) cases in 2016-2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006-2018 (95%CI, 1.78-3.77). However, there were indications of lower SMRs over time (2006-2012, 2.96 [95%CI, 1.73-4.74]; 2013-2018, 2.32 [95%CI, 1.23-3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87-5.13]; yes, 2.09 [95%CI, 1.08-3.64]). CONCLUSION: The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis - with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.