de novo hATTR Amyloidose nach Domino-Lebertransplantation: Ein Fallbeispiel für den Einsatz von Patisiran

Zusammenfassung

Die hereditäre Transthyretin-Amyloidose (hATTR-Amyloidose) ist eine seltene, schnell fortschreitende und potenziell lebensbedrohliche Krankheit, die durch eine von mehr als 120 Mutationen im Transthyretin (TTR)-Gen verursacht wird. Die Mehrzahl der Patienten entwickelt infolge der daraus resultierenden, kumulierenden Amyloidablagerungen insbesondere in den peripheren Nerven und dem Herzen im Laufe der Jahre eine progrediente, periphere sensomotorische Polyneuropathie und eine biventrikuläre Kardiomyopathie.

Da TTR – und damit auch seine amyloidogenen Varianten – überwiegend in der Leber synthetisiert wird, ist die frühe, orthotope Lebertransplantation (LTx) eine Therapieoption, mit der die Progression der hATTR-Amyloidose potenziell gestoppt werden kann.

Der vorliegende Fall beschreibt einen Patienten mit hepatozellulärem Karzinom, der im Rahmen einer Dominotransplantation das Organ einer Patientin mit hATTR erhalten hatte. Nach etwa 10 Jahren begann der Patient, die charakteristischen Symptome der Stoffwechselkrankheit zu entwickeln, was eine Re-Lebertransplantation erforderlich machte. Aufgrund einer weiteren Progression der Amyloidose wurde anschließend eine Therapie mit dem RNA-Interferenz-Therapeutikum Patisiran eingeleitet, die vorläufig zu einem Stopp der Progression führte.

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, rapidly progressing, and potentially life-threatening disease caused by one of more than 120 mutations in the transthyretin (TTR) gene. As a result of the cumulative amyloid deposits, especially in the peripheral nerves and the heart, the majority of patients develop progressive, peripheral sensorimotor polyneuropathy and biventricular cardiomyopathy over time.

Since TTR – and its amyloidogenic variants too – is predominantly synthesized in the liver, early, orthotopic liver transplantation (LTx) is a treatment option that can be used to potentially stop the progression of hATTR amyloidosis.

The actual case shows a patient with hepatocellular carcinoma who received the organ of a patient with hATTR as part of a domino liver transplantation. After approximately 10 years, the patient started to develop the characteristic symptoms of the metabolic disorder. Because of a further progression of the amyloidosis, therapy with the RNA interference therapeutic patisiran was initiated, which temporarily halted the progression.

Schlüsselwörter

Hereditäre Transthyretin-Amyloidose - kardiale Amyloidose - Kardiomyopathien - Polyneuropathien - Lebertransplantation - Patisiran

Keywords

Hereditary Transthyretin Amyloidosis - Cardiac amyloidosis - Transthyretin - Cardiomyopathies - Polyneuropathies - Orthotopic Liver Transplant - Domino Liver Transplantation - Patisiran

Publication History

Received: 10 February 2021

Accepted after revision: 29 December 2021

Article published online:
09 May 2022

• Literatur

• 1 Ando Y, Coelho T, Berk JL. et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013; 8: 31 DOI: 10.1186/1750-1172-8-31. (PMID: 23425518)
• 2 Accessed July 27, 2020 at: https://ghr.nlm.nih.gov/condition/transthyretin-amyloidosis#inheritance
• 3 Niemietz C. et al. Transthyretin-assoziierte familiäre Amyloidpolyneuropathie. Dtsch Med Wochenschr 2018; 143: 427-430 DOI: 10.1055/s-0043-123681. (PMID: 29544239)
• 4 Kristen AV. Was am Herzen nagt und auf die Nerven geht. Internist 2018; 59: 1208-1213 DOI: 10.1007/s00108-018-0470-x. (PMID: 30039176)
• 5 Coelho T, Adams D, Silva A. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013; 369: 819-829 DOI: 10.1056/NEJMoa1208760. (PMID: 23984729)
• 6 Adams D, Coelho T, Obici L. et al. Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study. Neurology 2015; 85: 675-682 DOI: 10.1212/WNL.0000000000001870. (PMID: 26208957)
• 7 Conceição I, González-Duarte A, Obici L. et al. "Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst 2016; 21: 5-9 DOI: 10.1111/jns.12153. (PMID: 26663427)
• 8 Rapezzi C, Quarta CC, Obici L. et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013; 34: 520-528 DOI: 10.1093/eurheartj/ehs123. (PMID: 22745357)
• 9 Semigran MJ. Transthyretin Amyloidosis: A "Zebra" of Many Stripes. J Am Coll Cardiol 2016; 68: 173-175 DOI: 10.1016/j.jacc.2016.05.020. (PMID: 27386770)
• 10 Holmgren G, Steen L, Ekstedt J. et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 1991; 40: 242-246 DOI: 10.1111/j.1399-0004.1991.tb03085.x. (PMID: 1685359)
• 11 Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord 2013; 6: 129-139 DOI: 10.1177/1756285612470192. (PMID: 23483184)
• 12 Herlenius G, Wilczek HE, Larsson M. et al. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 2004; 77: 64-71 DOI: 10.1097/01.TP.0000092307.98347.CB. (PMID: 14724437)
• 13 Stangou AJ, Heaton ND, Hawkins PN. Transmission of systemic transthyretin amyloidosis by means of domino liver transplantation. N Engl J Med 2005; 352: 2356 DOI: 10.1056/NEJM200506023522219. (PMID: 15930432)
• 14 Goto T, Yamashita T, Ueda M. et al. Iatrogenic amyloid neuropathy in a Japanese patient after sequential liver transplantation. Am J Transplant 2006; 6: 2512-2515 DOI: 10.1111/j.1600-6143.2006.01484.x. (PMID: 16889603)
• 15 Barreiros AP, Geber C, Birklein F. et al. Clinical symptomatic de novo systemic transthyretin amyloidosis 9 years after domino liver transplantation. Liver Transplant 2010; 16: 109 DOI: 10.1002/lt.21928. (PMID: 20035516)
• 16 Ericzon BG, Wilczek HE, Larsson M. et al. Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?. Transplantation 2015; 99: 1847-1854 DOI: 10.1097/TP.0000000000000574. (PMID: 26308415)
• 17 Adams D, Théaudin M, Cauquil C. et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep 2014; 14: 435 DOI: 10.1007/s11910-013-0435-3. (PMID: 24482069)
• 18 Ando Y, Nakamura M, Araki S. Transthyretin-related familial amyloidotic polyneuropathy. Arch Neurol 2005; 62: 1057-1062 DOI: 10.1001/archneur.62.7.1057. (PMID: 16009758)
• 19 Tojo K, Sekijima Y, Machida K. et al. Amyloidogenic transthyretin Val30Met homozygote showing unusually early-onset familial amyloid polyneuropathy. Muscle Nerve 2008; 37: 796-803 DOI: 10.1002/mus.21028. (PMID: 18506713)
• 20 Liepnieks JJ, Zhang LQ, Benson MD. et al. Neurology 2010; 75: 324-327 DOI: 10.1212/WNL.0b013e3181ea15d4. (PMID: 20660862)
• 21 Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid 2007; 14: 277-282 DOI: 10.1080/13506120701614032. (PMID: 17968687)
• 22 Olofosson BO, Backman C, Karp K. et al. Progression of cardiomyopathy after liver transplantation in patients with familial amyloidotic polyneuropathy, Portuguese type. Transplantation 2002; 73: 745-751 DOI: 10.1097/00007890-200203150-00015.
• 23 Hawkins PN, Ando Y, Dispenzeri A. et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015; 47: 625-638 DOI: 10.3109/07853890.2015.1068949. (PMID: 26611723)
• 24 Accessed July 27, 2020 at: https://www.alnylam.com/wp-content/uploads/2020/05/EAN-2020_Pati-Post-OLT.pdf
• 25 Adams D, González-Duarte A, O’Riordan WD. et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med 2018; 379: 11-21 DOI: 10.1056/NEJMoa1716153. (PMID: 29972753)
• 26 Adams D Suhr OB, Dyck PJ. et al. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. N Engl J Med 2017; 17: 181 DOI: 10.1186/s12883-017-0948-5.