Amyloidosis Nelson Leung, MD Mayo Clinic Rochester FOURTH - PowerPoint PPT Presentation

Amyloidosis Nelson Leung, MD Mayo Clinic Rochester FOURTH INTERNATIONAL CONGRESS ON IMMUNOINTERVENTION IN NEPHROLOGY Cagliari, 30 April- 3 May 2011

Outline � History � AL � AA � Hereditary amyloidosis

History of Amyloidosis � First described in the 17 Century by Bonet � liver abscess and enormous spleen with white stones (sago spleen) � 1842- Rokitansky � waxy liver with lardaceous degeneration in patients with TB, syphilis and rickets Kyle. Medicine 1975

Amyloid � Schleiden - 1838 � First used the term to describe normal amylaceous constituent of plants � Virchow - 1854 � first to use the term in human pathology � thought it may be starch or cellulose � Budd � later proposed amyloid is albuminous rather than fatty � Friedreich and Kukulé � showed amyloid is albuminoid (protein) � suggested to keep the term amyloid Kyle. Medicine 1975

Primary (Immunoglobulin light chain) AL amyloidosis � Wilks- 1856 � described lardaceous viscera in a 51 yo male with no tuberculosis, osteomyelitis or syphilis � Adams-1872 � described a case of myeloma and amyloidosis � Wild-1886 � Most credit with the first description of AL amyloidosis

Westermark et al. Amyloid 2007

Amyloidogenesis Merlini & Bellotti. NEJM 2003

Systemic Amyloidosis Merlini & Bellotti. NEJM 2003

Amyloidosis Mayo Clinic 1960-2006 n=4,666 Familial 4% (193) Secondary (AA) Senile 4% (206) 3% (148) β 2 M (11) 0.5% Localized 15% (707) Amyloidoma (12) 0.5% Primary (AL) 73% (3,389) CP1102576-5

AL/AH (Primary) Amyloidosis � Plasma cell dyscrasia � Lymphoproliferative disorders � Most common form of amyloidosis in industrialized countries � Most rapidly progressive � Organs involved � Heart / kidney � Nerves � Gastrointestinal/ liver � Lung � Soft tissue � Coagulopathy � endocrinopathies

Age Distribution of AL Patients 40 35 30 25 % 20 15 10 5 0 <40 40-49 50-59 60-69 70-79 >80 Kyle & Gertz. Sem in Hematol 1995

Syndromes at Presentation 30 25 20 % 15 10 5 0 Nephrotic Renal CHF Peripheral Orthostasis GI Carpel Syndrome Insufficiency Neuropathy Tunnel Kyle & Gertz. Sem in Hematol 1995

Melphalan & Prednisone Era C MPC Median survival for melphalan containing groups was 12 � 18 months Hematologic complete response (CR) � rare Organ response - rare Skinner et al. Am J Med 1996 Kyle et al. NEJM 1997

Hematologic Complete Response � 40% Organ response in 66% of patients with Hem CR, 30% in those without Hem CR Ann Intern Med. 2004;140:85-93

Melphalan & Dexamethasone � Treatment � Melphalan 0.22 mg/kg/day � Dexamethasone 40mg/day � Day 1-4 every 28 days � Results � 56 patients � Severe heart involvement � 70% � Hematologic response � 67% � CR � 33% Palladini et al. Blood. 2004

Overall Survival was Superior in the MDex Treated Group Jaccard et al. NEJM 2007

Criticism � 10 patients died in the SCT group prior to receiving SCT � 3 others withdrew � Those who received SCT had a treatment related mortality of 24% Jaccard et al. NEJM 2007

Differences in Survival were due to TRM in the High Risk Group Jaccard et al. NEJM 2007

Renal Response after SCT 60% Responders % Change in Proteinuria 40% Non-responders 20% 0% -20% -40% -60% -80% -100% 0 3 6 9 12 18 24 36 48 60 72 Months Since Stem Cell Transplantation Leung et al. AJKD 2005

Impact of Renal Response on Survival P = 0.01 - Renal Responders - Non-renal responders Leung et al. AJKD 2005

Leung et al. AJKD 2005

Renal Response and Survival p = 0.04 Leung et al. AJKD 2005

AA (Secondary) Amyloidosis � More common in Europe and developing countries � Associated chronic infections and inflammatory diseases

Serum Amyloid A (SAA) protein � Apolipoprotein constituent of HDL � Acute phase reactant � Synthesized in hepatocytes � Controlled by cytokines � 100 � 1000 folds increase � One of the wild type amyloidogenic proteins � B 2 M � IAPP-islet amyloid polypeptide- amylin � Calcitonin � Atrial natriuretic peptide � Abeta � Tau Parmelee et al. Biochem 1982;3298-303 Westermark et al. Amyloid 2007;14:179-83 � Prolactin Simon & van der Meer. Am J Physiol 2007; 292:R86-98

Characteristics of Patients with AA � Organs involved � Kidney � 97% � Liver � Hepatomegaly � 9% � SAP scintigraphy � 23% � Cardiac � 1 � CHF � 2 � Echocardiography � Neuropathy � Symptomatic � none � Adrenal deposit by SAP � 41% � Median time from Sx to Dx - 17 years Lachmann et al. NEJM 2007;356:2361-71

Incidence of AA � In the US: � AL:AA = 17-22: 1 � 1 in 2,125,000 to 2,750,000/yr � In Europe: � AL:AA = 2:1 � 1 in 125,000 - 250,000/yr Verine et al. Hum Path 2007 Kyle et al. Sem Hem 1995 Kyle et al. Best Prac & Res Clin Hem 2007

Most Common Causes � Chronic inflammatory arthritis � Rheumatoid arthritis � Ankylosing spondylitis � Chronic infections � Bronchiectasis � Osteomyelitis � Tuberculosis � Chronic inflamatory conditions � Castleman � s disease � Crohn � s disease � Neoplasia � Periodic fever syndromes Lachmann et al. NEJM 2007;356:2361-71 Verine et al. Hum Path 2007;38-1798-1809

Case 35 yo female referred for amyloidosis. � Long history of fever, abdominal pain, and myalgia since puberty � No history of chronic infection/arthritis/back pain � Was found to have 4.5 g/d of proteinuria after her first pregnancy � She was taking large amount of ibuprofen for muscle pain � This was stopped and proteinuria decreased to 200 mg/d. � Proteinuria increased to 5 g/d after second child � Renal biopsy showed amyloidosis with no predominate light chain

Family History � Mother � had always been sick with � undulant fevers � � developed ESRD secondary to unknown etiology � underwent a cadaveric kidney transplantation � Died during surgery for bowel perforation � Incidentally, pathology showed amyloidosis. � Sister and nephew have recurrent fevers, abdominal pain. � Father side is Irish, Mother is English, French, and German

Additional History � At one point, patient was felt to have Familial Mediterranean Fever (FMF). Was placed on colchicine for several years with no benefit. � ESR > 100 � CRP � 17.8 mg/L � Denies rash � Denies hearing deficits � No carpel tunnel � No M-proteins on multiple occasions

Renal Biopsies First biopsy- IF Repeat Biopsy � IF IgG � 2+ albumin � 1+ C3 � 4+ Rest were negative IgM � 1+ Amyloid Battery IgA � 1+ SAA (+) κ - 1+ SAP (+) λ - 1+ λ / κ - negative Fibrinogen, alb and C1q prealbumin - negative negative

Hereditary Periodic Fever Syndromes Simon & van der Meer. Am J Physiol 2007; 292:R86-98

Familial Mediterranean Fever (FMF) � Most common of the hereditary autoinflammatory syndromes � People of the Mediterranean basin � Armenians, Sephardic Jews, Arabs, Turks � Symptoms � Fever, severe abdominal pain, serositis, arthritis � Erysipeloid erythema confined to the legs � Mode of inheritance � Autosomal recessive � Mutation � MEFV (Mediterranean Fever gene) on chromosome 16p � Pyrin Role in fever genesis is unknown � (? survival advantage in heterozygotes) � Co-localizes with microtubules � Church et al. Springer Semin Immun 2006 Simon & van der Meer. Am J Physiol 2007;292:R86-98

Hyper IgD Syndrome � High prevalence in Netherlands � Symptoms � Lymphadenopathy and splenomegaly � Triggered by vaccinations � High levels of IgD and sometimes IgA � Headaches � Symptoms may improve with age � Mode of inheritance � Autosomal recessive � Mutation � Mevalonate kinase (MVK) Isoprenoid pathway � cholesterol biosynthesis � Mevalonic aciduria (mental retardation, ataxia, myopathy, failure to thrive, � early death) The build up of mevalonate increases urinary excretion of mevalonate � Simon et al. Clin Pharmacol Ther 2004

Muckle-Wells Syndrome � Cryopyrinopathies (MWS, FCAS, NOMID/CINCA) � Symptoms � Cold provocation � Urticaria � Sensorineural deafness � Anterior uveitis � Mode of inheritance � Most are autosomal dominant � Mutation � CIAS1 (cold induced autoinflammatory syndrome) � Cryopyrin � Inflammasome � Caspase-1 mediated IL-1 β activation Aksentijevich et al. Arthritis & Rheum 2007

TNF receptor type 1 (TRAPS) � Most common autosomal dominant HFS � 2% N American & Irish, 9% African � Symptoms � Migratory myalgia, conjunctivitis, periorbital edema, rash, testicular pain and inguinal hernia � Mode of inheritance � Autosomal dominant � Mutation � TNFRSF1A � type 1 TNF receptor � > 40 mutations identified, mostly involving CRDs (cysteine rich domains) � Decreased shedding � Mutant TNFR1 aggregates resulting in ligand independent activation or enhanced unfolded protein response � activation of IL-1 β � CRD mutations are associated with more AA

TNF � Pathway Simon & van der Meer. Am J Physiol 2007; 292:R86-98