Liver transplantation in transthyretin amyloidosis: Issues and challenges

Abstract

Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non-ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation. Liver Transpl 21:282-292, 2015. V C 2015 AASLD.

Advances in the treatment of hereditary transthyretin amyloidosis: A review

“…In patients with signs, symptoms, or manifestations suggestive of amyloidosis, diagnostic and genetic testing are of utmost importance. Neurologic and cardiac symptoms can be evaluated with numerous tests and procedures, including tissue biopsy, Congo red staining to confirm the presence of amyloid, and mass spectrometry or immunohistochemistry to confirm the type of amyloid (Figure a,b) (Benson et al, ; Carvalho, Rocha, & Lobato, ; Coelho, Maurer, et al, ; Gilbertson et al, ; Linke, Oos, Wiegel, & Nathrath, ; Sperry et al, ). Genetic testing is required to differentiate wtATTR from hATTR and to allow for the detection of specific TTR gene mutations, which may help predict the clinical course of disease (Coelho, Maurer, et al, ).…”

Living donor domino liver transplantation using a maple syrup urine disease donor: A case series of three children – The first report from Japan

“…Therefore, there are few opportunities to receive a whole liver from an age‐matched, similarly sized donor. The possibility of amyloidosis as a late complication of DLT using a FAP donor is also a worrisome issue for pediatric patients . However, for pediatric patients with metabolic liver diseases, such as MSUD, who are undergoing LDLT, DLT is often performed with similarly sized pediatric patients.…”

A review on protein oligomerization process

“…The mechanism by which an oligomer/fiber may form essentially depends on the symmetry of the interfacial association and DS needs not be mandatory to reach this requisite. The formation of the cross-b-spine fibrils intima could follow an end-to-end stacking mechanism, the same followed by non-amyloidogenic proteins, such as hemoglobin-S, 165 or by non-harmful proteins, such as actin 173 or tubulin. 174 Considering that amyloid fibers are technicaly not oligomers as they have high DP, several oligomeric precursors of amyloidogenic proteins are continuously studied, despite their transient nature.…”

“…39 Proteins can become prone to fibrillization because of aging or changes in the environmental conditions, such as crowding, pH or temperature shocks. In addition, point mutations can induce and often speed up fibrilization, such as in TTR V30M or L55P, [160][161][162][163][164][165] for the human prion protein (hPrP), 166 or for the homo-tetrameric p53 tumor suppressor protein. 167,168 Several lethal amyloidoses, e.g.…”