Clinical, pathological, and proteomic characteristics of newly diagnosed amyloidosis patients: Experience from a single referral center in Japan

Abstract

Novel therapies have recently been used for different amyloidoses including hereditary transthyretin (ATTR, ATTRv) amyloidosis, wild‐type ATTR (ATTRwt) amyloidosis, immunoglobulin light chain (AL)amyloidosis, and amyloid A (AA) amyloidosis. Early, accurate diagnosis is important for improved prognosis and cure. However, early intervention with early diagnosis is often difficult, because these diseases are frequently difficult to identify given their phenotypic heterogeneity. This study aimed to analyze characteristics of patients with amyloidosis that was diagnosed at the Amyloidosis Medical Practice Center, Kumamoto University Hospital, which, as an amyloidosis center in Japan, conducts histopathological, proteomic, and genetic analyses of amyloidosis. We analyzed diagnostic results and disease manifestations of patients diagnosed during April 2012 and March 2019. This study reviewed 1937 consecutive consultations that provided clinical information. The patients’ average age was 65.9 (median 69) years. Of all patients, 66.6% were male. Diagnoses included ATTRv: 13.4%, ATTRwt: 14.3%, ATTR (no genetic analysis consultation requested): 4.6%, ALλ: 19.7%, ALκ: 8.8%, AA: 3.0%, β2‐microglobulin (dialysis‐related): 0.8%, and others: 1.9%, no TTR gene mutation (no histopathological analysis consultation requested): 23.2% (including duplicate consultations). ATTRv amyloidosis cases included V30M in endemic areas: 7.4%, V30M in non‐endemic areas: 51.2%, and non‐V30M: 41.4%. Sixty‐six cases required laser microdissection and liquid chromatography‐tandem mass spectrometry. Initial manifestations included polyneuropathy: 13.2%, carpal tunnel syndrome: 5.6%, autonomic dysfunction: 2.7%, heart failure: 28.4%, cardiac hypertrophy: 2.2%, arrhythmia: 5.0%, renal impairment: 11.1%, and stroke: 1.8%. Amyloidosis types and manifestations were diverse. For early diagnosis and appropriate interventions, improved diagnostic systems are needed.

Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review

“…The included publications were highly heterogenous in terms of how the possible association of ATTR amyloidosis with MSK manifestations was demonstrated (Tables 2 , 3 , 4 , 5 , 6 and 7 ). Biopsy followed by tissue staining of MSK or other specified tissues [ 14 , 16 , 18 , 21 , 22 , 25 , 27 , 30 , 33 – 37 , 44 , 51 , 61 , 63 , 66 , 68 , 74 , 75 , 81 , 91 , 92 , 94 – 96 , 99 , 101 , 102 , 104 , 106 – 115 , 117 – 119 , 121 , 124 – 131 , 134 , 139 , 148 – 150 , 152 – 160 , 171 , 173 , 175 , 177 , 183 ] were common. However, detecting amyloid in MSK tissues alone does not necessarily mean a patient is or will be diagnosed with ATTR amyloidosis.…”

“…Tc-99 m PYP/DPD scintigraphy [ 19 , 20 , 24 , 29 , 37 , 39 , 41 , 42 , 45 , 51 , 58 , 60 , 63 , 64 , 66 , 68 , 69 , 73 , 77 , 78 , 80 , 95 , 96 , 109 , 110 , 118 , 120 , 122 , 132 , 137 – 139 , 148 , 152 , 165 , 166 ], a non-invasive diagnostic method which has been more commonly used during last several years to make a diagnosis of cardiac amyloidosis [ 3 ], was also used to confirm the disease in 30% of the publications included in this review (Table 2 ). Additionally, methods such as mass spectrometry were utilized to confirm that amyloid was caused by TTR [ 14 , 16 , 18 , 108 , 112 , 114 , 115 , 131 , 149 , 152 , 165 ]. Another significant limitation is that, although an association between MSK manifestations and ATTR amyloidosis is shown in the literature, it does not necessarily demonstrate causation in all cases.…”

Practice of Hereditary ATTR Amyloidosis in Non-endemic Areas of Japan

“…The most common abnormal transthyretin (TTR) mutation in ATTRv amyloidosis is V30M (p.V50M). In addition, various other TTR mutations, such as S50R (p.S70R), E61K (p.E81K), and Y114C (p.Y134C), have also been reported ( 3 ). In contrast, in non-endemic areas, the onset tends to be relatively old, the family history is unclear, and autonomic dysfunction is unnoticeable ( 4 ).…”