In this study, we clearly found that two-thirds of patients with clinically undiagnosed sporadic ATTR CA exhibited cholecystic involvement. This result is consistent with a previous autopsy-based study (3/4 cases, 75%)15. The prevalence of sporadic ATTR deposition among patients ≥ 80 years old has been reported as approximately 9–12% in Japan8,15,19 and 20–25% in Western countries20–22. Therefore, it is estimated that sporadic ATTR deposition is present in approximately 6–8% and 13–17% of cholecystectomy materials obtained from patients older than 80 years in Japan and Western countries, respectively. Thus, it should be noted that cholecystic ATTR deposition may not be rare in elderly patients, and most instances of deposition might have been overlooked.
This study clearly demonstrated that the severity of ATTR deposition in the gallbladder is correlated with that in the heart. Therefore, we considered that the severity of ATTR deposition in the heart could be predicted from the amount of deposition in the organs other than the heart. In particular, the presence of cholecystic ID was indicative of severe cardiac involvement. Of note, most patients with cholecystic ID exhibited obstructive VD that was easily identified in HE-stained specimens. In addition, in the gallbladder, ATTR deposits were mainly observed on the vessels. Thus, to ensure that latent cholecystic ATTR deposition is not overlooked, careful observation of the vessels appears important9.
Conversely, we could not identify most instances of non-obstructive VD using HE-stained specimens. This may be related to the fact that gallbladder specimens are prone to degeneration because of autolysis and inflammation, which make it difficult to observe the tissue architecture. In addition, histopathological diagnoses in the gallbladder are generally made using only HE staining unless cancer or another specific disease is clinically suspected. Thus, latent ATTR deposition could be easily missed. This may one reason why cholecystic involvement in systemic amyloidosis is considered rare9–14. Although the severity of cardiac involvement in patients with only non-obstructive VD is considered mild to moderate, the presence of sporadic ATTR deposition in the heart, regardless of its amount, might be a risk factor for sudden cardiac death8. Thus, we recommend CR staining to evaluate the presence or absence of amyloid deposition in cholecystectomy specimens obtained from patients aged 80 years or older, especially those with signs of sporadic ATTR amyloidosis including edema, heart failure, arrhythmia (especially atrial fibrillation), and carpal tunnel syndrome (CTS)1,2,23,24. Moreover, we should assess whether cholecystic ATTR deposition is associated with the increased postoperative mortality after cholecystectomy.
According to the aforementioned correlation in the severity of deposition between the gallbladder and heart, patients with only non-obstructive VD are considered to have early-stage CA. Recently, the efficacy of tafamidis against cardiac ATTR amyloidosis was confirmed, making the disease treatable4. This drug is expected to have greater benefit when administered early in the disease course. Therefore, these patients are considered good candidates for treatment with tafamidis because their physical condition and cardiac function were considered sufficient to permit cholecystectomy4. However, tafamidis is one of the most expensive cardiovascular drugs to reach the market, and it may be impractical to provide this treatment to all patients with cardiac ATTR amyloidosis25,26. Therefore, we should discuss the future management of ATTR amyloidosis that is incidentally detected in surgical specimens including samples from cholecystectomy.
The prevalence of amyloid deposition in several organs in this study was consistent with previous findings15,27,28. The prevalence of cholecystic involvement was comparable with that in the GI tract, perhaps because both have similar tissue architecture. Contrarily, renal involvement was rare, and no glomerular and interstitial involvement was identified. Therefore, although Sekijima et al. reported that renal dysfunction is a common clinical finding in patients with ATTRwt amyloidosis in a nationwide survey in Japan29, direct deposition of ATTR fibrils in the kidneys might not be the major cause of symptoms. Meanwhile, no amyloid deposition was identified in the BM stroma. Taken together with previous findings28, the presence of amyloid deposition in the BM stroma may be a diagnostic clue for immunoglobulin light chain amyloidosis.
Ligament involvement is extremely common in ATTRwt amyloidosis23,24,30,31. In particular, CTS has been reported as the most common initial symptom, and patients may present with symptoms of CTS 5–15 years prior to cardiac impairment23. However, only one-third of patients with ATTR CA exhibited ligament involvement in this study. There are two possibilities for this discrepancy. First, some ligaments are more prone to ATTR amyloid deposition, similarly as the susceptibility to deposition varies by organ18,32. The second possibility is that ATTR deposition is affected by the presence or absence of degeneration and inflammation. Because previous reports evaluated surgical materials obtained from symptomatic sites, degeneration and inflammation should be present24,30,31. Conversely, we evaluated the ligaments with no observed inflammation and degeneration, and thus, amyloid deposition might have been missed.
In addition to a certain level of bias in our study population, this study was also limited by the lack of clinical information for some patients including the presence or absence of CTS or spinal stenosis, mainly because of the lack of severe clinical symptoms. Moreover, we could not perform TTR gene testing and prevent the inclusion of patients with elderly-onset hereditary ATTR amyloidosis6. Therefore, we described the cases as sporadic ATTR amyloidosis. Furthermore, because cholecystic specimens obtained at autopsy are degenerated in almost all cases and these specimens are often of no macroscopic pathological significance, they are not regularly sampled in our department, and we could evaluate them in 15 of 50 patients.
In summary, we demonstrated that sporadic ATTR amyloidosis frequently involves the gallbladder, and the severity of cholecystic amyloid deposition is correlated with that of the heart. Because ATTR deposition in the gallbladder is often indefinite in HE-stained specimens, we recommend CR staining for cholecystectomy specimen obtained from elderly patients, especially those aged 80 years or older with signs of CA. Because ATTR amyloidosis has become a treatable disease, clinicians and pathologists must recognize the importance of accurate diagnosis, especially in the early stage. Pathologists should be aware that sporadic ATTR amyloidosis is not a rare disease and evidence of its involvement that may be present within routine pathological specimens.