New insights into the clinical evaluation of hereditary transthyretin amyloidosis patients: a single center's experience

Abstract

Over the last decade, new medical treatment modalities have emerged based on increased insights into amyloid formation. With the increased possibilities for treatment of amyloidosis caused by transthyretin (TTR) amyloid deposits comes the need for diagnostic procedures for early diagnosis and better tools to follow disease progression. This is of particular importance in clinical trials evaluating the efficacy of new treatments. Until recently, the treatment of TTR amyloidosis (ATTR) was based solely on liver transplantation, a procedure that has halted disease progression in many patients. Liver transplantation has been especially effective in patients under the age of 50 years carrying the TTR V30M mutation, whereas the outcome of the procedure has been variable for others, particularly elderly male patients and those carrying a non-V30M mutation. This review concentrates on new insights derived from our center's experience with liver transplantation, how to implement this experience in evaluation of new treatment modalities for ATTR, and how to facilitate early diagnosis of neuropathy with easily available diagnostic tools. Attention has focused on manifestations of the disease that involve the heart and the peripheral nervous system; change in peripheral nerve function has been the primary endpoint in two controlled clinical trials, one finished and one ongoing. New insights into the amyloid formation process and the lessons learned from liver transplantation give the opportunity to design potentially effective treatment modalities for ATTR. It appears reasonable to suspect that a combination of different treatment modalities may be required to treat the disease, and that different treatment regimes will be designed according to the phenotype of the disease. For the patients and their relatives there is now a solid foundation for optimism, with prospects of several effective medical treatment possibilities within the coming decade.

Keywords: amyloid; cardiomyopathy; diagnostic tools; neuropathy; new treatment modalities.

Figure 1

Box plots of thermal thresholds in a group of transthyretin V30M amyloidosis patients with no sign of electrophysiological abnormalities (familial amyloid polyneuropathy [FAP]; n = 23) and a reference group (controls; n = 43), at the dorsum of the foot (DF), medial (ML) and lateral (LL) parts of the lower leg, and ventral part of the thigh (VT). Thermal thresholds are expressed as change in degrees Celsius (absolute values) from an adapted starting temperature of 32°C. Notes: Boxes show median, 25th, and 75th percentiles, and circles show outliers below/above the 10/90 percentiles. Note the increased thermal thresholds in FAP patients, most prominent at distal test sites. *, **,***. Figure reproduced from Heldestad and Nordh, with permission from the publisher. Abbreviations: CT, cold threshold; NS, not significant; WT, warm threshold. *P < 0.05; **P < 0.01; ***P < 0.001

Figure 2

Recordings of heart rate (HR) variability patterns in three transthyretin amyloidosis patients during spontaneous and deep breathing, where the recordings were performed in the supine position. Patient A showed the normal response in HR during deep breathing, whereas patients B and C presented marked increases in HR variability because of cardiac arrhythmia during the test.

Figure 3

Typical patterns found in echocardiographic examinations in transthyretin amyloidosis patients. Notes: Left panel: two-dimensional echocardiogram showing increased sparkling echoes or highly refractile echoes (detected at points indicated by red arrows) within the ventricular septum (indicated by red oval). Right panel: M-mode examination showing low septal and posterior wall thickening between diastole (yellow) and systole (red). In this case the wall is not thickening during systole but is being dragged into the left ventricular cavity by tethering from other segments.