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The Pathogenesis, Investigation and Management of Systemic Amyloidosis

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The Pathogenesis, Investigation and Management of Systemic Amyloidosis THE PATHOGENESIS, INVESTIGATION AND MANAGEMENT OF SYSTEMIC AMYLOIDOSIS Prayman Timothy Sattianayagam Doctor of Medicine University College London National Amyloidosis Centre Department of Medicine University College London Medical School (Royal Free Campus) Rowland Hill Street London NW3 2PF 2012 ii I, Prayman Sattianayagam, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. iii ABSTRACT Background: Amyloidosis is a multisystem disorder characterised by abnormal protein folding, in which proteins adopt an abnormal conformation and deposit as insoluble fibrils that disrupt tissue structure and function. Aims and Methods: To characterise the phenotype of the heredo-familial forms of systemic amyloidosis, the role of solid organ transplantation in the different systemic amyloidosis syndromes and to evaluate the gastroenterological and hepatological causes and sequaelae of systemic amyloidosis. These features were sought in patients followed at the UK National Amyloidosis Centre between 1984 and 2011. Results and Conclusions: Familial amyloid polyneuropathy associated with the T60A transthyretin variant has a prominent cardiac phenotype, which negatively impacts upon prognosis. Furthermore this cardiac phenotype has a negative impact upon survival in those who undergo liver transplantation to eliminate variant transthyretin, which is synthesised in the liver, not only by increasing operative risk but also as there is likely ongoing cardiac amyloid deposition associated with wild-type transthyretin from the liver graft. In the face of failing organ function, liver and renal transplantation in hereditary lysozyme amyloidosis (ALys) appears feasible, despite ongoing amyloidogenesis and the risk of recurrent graft amyloid, due to slow turnover of amyloid. Similarly, renal and cardiac transplantation in AL amyloidosis and renal transplantation in AA amyloidosis appear favourable when strategies to suppress amyloidogenic precursor protein production are employed in tandem. Gastrointestinal and hepatic amyloid are recognised in systemic amyloidosis. In ALys both are prevalent; the former is associated with endoscopic abnormalities and the latter may be asymptomatic or present as hepatic rupture. In patients diagnosed with amyloid by liver biopsy after presenting with deranged liver biochemistry, AL iv amyloidosis is the commonest cause and although this presentation has been historically associated with a poor prognosis as there is frequently concomitant extra-hepatic amyloid, in those who achieve a good clonal response to chemotherapeutic regimes in the modern era of treatment a survival advantage is conferred. Primary gastrointestinal disease, such as inflammatory bowel disease, can cause systemic AA amyloidosis. Tight inflammatory control, guided by serial serum amyloid A protein levels, benefits amyloidotic kidneys, as does aggressive treatment of physiological renal stresses, such as sepsis. Systemic AL amyloidosis is commonly associated with malnutrition, especially when there is multisystem amyloid. Malnutrition in this group is associated with a poor quality of life and worse survival and it would appear therefore to be a potential target for intervention studies. v ETHICAL APPROVAL All individuals who participated in the clinical research studies described in this thesis gave full informed consent in a format approved by the Royal Free Hospital Ethics Committee (REC Ref 06/Q0501/42). For the prospective study of malnutrition in systemic AL amyloidosis ethical approval was granted by the Riverside Ethics Committee (REC Ref 09/H0706/27). The dosage and administration of radioactive isotopes were approved by the Administration of Radioactive Substances Advisory Committee of the Department of Health. vi ACKNOWLEDGMENTS I am grateful to Dr. Julian Gillmore and Professor Philip Hawkins for providing the opportunity for me to undertake this M.D. and for their support and supervision. There has also been much appreciated support from all of the clinical staff at the National Amyloidosis Centre. I would also like to thank my family, who have been supportive of all of my educational and academic ventures. Most importantly I would like to thank the referring physicians and the patients themselves who have been enthusiastic about and supportive of the research. vii CONTENTS Page Abstract ....................................................................................................... iii Ethical Approval .......................................................................................... v Acknowledgements ..................................................................................... vi Abbreviations .............................................................................................. xiii List of Figures ............................................................................................. xvii List of Tables ............................................................................................... xix Chapter One INTRODUCTION AMYLOID STRUCTURE ...................................................................................... 1 PATHOGENESIS OF AMYLOIDOSIS .................................................................. 2 AMYLOID DEGRADATION .................................................................................. 3 CLINICAL AMYLOIDOSIS SYNDROMES ........................................................... 6 Systemic AL amyloidosis ...................................................................................... 6 Systemic AA amyloidosis ...................................................................................... 8 Dialysis-associated amyloidosis/β2-microglobulin amyloidosis ............................. 9 Hereditary systemic amyloidosis ........................................................................... 9 Familial amyloid polyneuropathy ........................................................................... 10 Hereditary non-neuropathic systemic amyloidosis ................................................ 10 Senile systemic amyloidosis ................................................................................. 11 Localised amyloidosis ........................................................................................... 11 DIAGNOSIS OF AMYLOIDOSIS .......................................................................... 12 Histology ............................................................................................................... 12 SAP scintigraphy .................................................................................................. 13 Cardiac investigations ........................................................................................... 13 Other investigations .............................................................................................. 14 TREATMENT OF AMYLOIDOSIS ........................................................................ 14 AL amyloidosis ..................................................................................................... 16 viii AA amyloidosis ..................................................................................................... 18 Familial amyloid polyneuropathy ........................................................................... 19 Dialysis-related amyloidosis .................................................................................. 20 FUTURE PROSPECTS IN TREATMENT ............................................................. 20 AIMS AND SCOPE OF THE THESIS ................................................................... 24 Chapter Two MATERIALS AND METHODS DECLARATION .................................................................................................... 26 PATIENTS ............................................................................................................ 27 HISTOLOGY ........................................................................................................ 27 Congo-red staining ............................................................................................... 27 Typing of amyloid by immunohistochemistry ......................................................... 28 Laser microdissection and mass spectrometry based proteomic analysis ............. 29 SAP SCINTIGRAPHY .......................................................................................... 30 CARDIAC ASSESSMENT .................................................................................... 31 RENAL ASSESSMENT ........................................................................................ 33 CRITERIA FOR DIAGNOSIS OF AMYLOID- RELATED MAJOR ORGAN INVOLVEMENT ...................................................... 33 PERFORMANCE STATUS .................................................................................. 36 IMMUNOASSAYS ................................................................................................ 36 C-reactive protein (CRP) ....................................................................................... 36 Serum amyloid A protein (SAA) ............................................................................ 36 Serum free immunoglobulin light chain assay ....................................................... 38 GENE SEQUENCING ........................................................................................... 38 ix STUDY
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