protein misfolding diseases (current and emerging principles and therapies) || familial and senile...

36FAMILIAL AND SENILEAMYLOIDOSIS CAUSEDBY TRANSTHYRETIN

STEVEN R. ZELDENRUST

Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minnesota

MERRILL D. BENSON

Department of Pathology and Laboratory Medicine, Indiana University

School of Medicine, Indianapolis, Indiana

INTRODUCTION

Transthyretin-associated amyloidosis (ATTR) and senile systemic amyloidosis(SSA) are two different forms of systemic amyloidosis that result in theformation of amyloid deposits derived from the same plasma protein, trans-thyretin (TTR). Despite their common origin, the clinical features of thediseases vary considerably, resulting in markedly different outcomes. Patientswith ATTR typically experience a progressive, fatal form of the disease withextensive morbidity, requiring aggressive treatment approaches. Patientswith SSA have a more benign course, and supportive care is generally thepreferred approach. We will highlight herein the clinical characteristics for eachform of the disease and discuss what is known about the pathogenesis oftransthyretin-derived amyloidosis and the impact of various treatmentapproaches.

Protein Misfolding Diseases: Current and Emerging Principles and Therapies,Edited by Marina Ramirez-Alvarado, Jeffery W. Kelly, and Christopher M. DobsonCopyright r 2010 John Wiley & Sons, Inc.

795

TRANSTHYRETIN-ASSOCIATED AMYLOIDOSIS

Background

To date, over 100 different mutations in the TTR protein have been reported,most in association with ATTR [1]. There are a wide variety of clinicalsyndromes in affected individuals, representing the varied target organs ofamyloid deposition (Table 1). Depending on the predominant organ involved,patients may present with congestive heart failure, peripheral and/or auto-nomic neuropathy, nephrotic-range proteinuria, malabsorption, and evenintracranial bleeding.

Clinical Characteristics

The initial descriptions of ATTR focused on the progressive peripheral sensoryneuropathy present in many cases. The nervous system remains the mostcommonly affected organ, with up to 90% of affected persons developingperipheral nerve involvement at some point in the disease course [2]. Affectedpersons typically present with a progressive peripheral parasthesia, in a stock-ing-glove pattern of distribution. Pain and temperature impairment is alsocommon, with many experiencing painful dysesthesias. Bilateral carpal tunnelsyndrome is seen in nearly half of patients with ATTR. More advancedinvolvement leads to motor weakness and gait instability. Autonomic involve-ment is less common, affecting a little over a third of patients [3]. Patients maypresent with dyshidrosis, impotence, orthostatic hypotension, or urinaryretention. Alternating diarrhea and constipation are also frequently indicativeof autonomic failure. More rarely, intestinal pseudo-obstruction develops,resulting in persistent nausea, vomiting, and malnutrition.

More recently, reports of central nervous system (CNS) involvement inATTR have been published [4–7]. These people may exhibit cerebral infarctionand hemorrhage, ataxia, seizures, and even dementia. Of note, although TTRhas been implicated in Alzheimer disease, a form of CNS amyloid, noparenchymal amyloid deposits have been reported in ATTR [8,9]. The relation-ship between leptomeningeal amyloid deposits and the clinical symptoms seen inthese patients remains unclear. It has been suggested that aberrant metabolismof TTR produced locally by the choroid plexus, rather than circulating plasmaprotein, is responsible for the CNS deposits [10]. This theory has beensubstantiated by the finding of new leptomeningeal deposits in recipients oforthotopic liver transplantation, in which the circulating variant form of theprotein is undetectable and only wild-type protein is synthesized by the liver [11].

Cardiac deposits occur less frequently, with only a fourth having evidence ofcardiomyopathy at diagnosis [2]. As with nerve deposition, clinically apparentheart involvement becomes more common during the course of the disease,with nearly two-thirds ultimately developing cardiac amyloid. Deposition ofamyloid within the myocardium is not always uniform, but classic features are

796 FAMILIAL AND SENILE AMYLOIDOSIS CAUSED BY TRANSTHYRETIN

TABLE 1 Transthyretin Amyloidosis

Mutation Codon Change Clinical Featuresa Geographic Kindreds

Cys10Arg TGT–CGT Heart, eye, PN United States (PA)

Leu12Pro CTG–CCG LM UK

Asp18Glu GAT–GAA PN South America, United States

Asp18Gly GAT–GGT LM Hungary

Asp18Asn GAT–AAT Heart United States

Val20Ile GTC–ATC Heart, CTS Germany, United States

Ser23Asn AGT–AAT Heart, PN, eye United States

Pro24Ser CCT–TCT Heart, CTS, PN United States

Ala25Ser GCC–TCC Heart, CTS, PN United States

Ala25Thr GCC–ACC LM, PN Japan

Val28Met GTG–ATG PN, AN Portugal

Val30Met GTG–ATG PN, AN, eye, LM Portugal, Japan, Sweden,

United States (FAP I)

Val30Ala GTG–GCG Heart, AN United States

Val30Leu GTG–CTG PN, heart Japan

Val30Gly GTG–GGG LM, eye United States

Val32Ala GTG–GCG PN Israel

Phe33Ile TTC–ATC PN, eye Israel

Phe33Leu TTC–CTC PN, heart United States

Phe33Val TTC–GTC PN UK, Japan, China

Phe33Cys TTC–TGC CTS, heart, eye, kidney United States

Arg34Thr AGA–ACA PN, heart Italy

Arg34Gly AGA–GGA Eye UK

Lys35Asn AAG–AAC PN, AN, heart France

Lys35Thr AAG–ACG Eye United States

Ala36Pro GCT–CCT Eye, CTS United States

Asp38Ala GAT–GCT PN, heart Japan

Trp41Leu TGG–TTG Eye, PN United States

Glu42Gly GAG–GGG PN, AN, heart Japan, United States,

Russia

Glu42Asp GAG–GAT Heart France

Phe44Ser TTT–TCT PN, AN, heart United States

Ala45Thr GCC–ACC Heart United States

Ala45Asp GCC–GAC Heart, PN United States

Ala45Ser GCC–TCC Heart Sweden

Gly47Arg GGG–CGG/

AGG

PN, AN Japan

Gly47Ala GGG–GCG Heart, AN Italy, France

Gly47Val GGG–GTG CTS, PN, AN, heart Sri Lanka

Gly47Glu GGG–GAG Heart, PN, AN Turkey, United

States, Germany

Thr49Ala ACC–GCC Heart, CTS France, Italy

Thr49Ile ACC–ATC PN, heart Japan, Spain

Thr49Pro ACC–CCC Heart, PN United States

(Continued)

TRANSTHYRETIN-ASSOCIATED AMYLOIDOSIS 797

TABLE 1 (Continued)


Ser50Arg AGT–AGG AN, PN Japan, France/Italy,

United States

Ser50Ile AGT–ATT Heart, PN, AN Japan

Glu51Gly GAG–GGG Heart United States

Ser52Pro TCT–CCT PN, AN, heart, kidney UK

Gly53Glu GGA–GAA LM, heart Basque, Sweden

Glu54Gly GAG–GGG PN, AN, eye UK

Glu54Lys GAG–AAG PN, AN, heart, eye Japan

Glu54Leu GAG – CTG UK

Leu55Pro CTG–CCG Heart, AN, eye United States, Taiwan

Leu55Arg CTG–CGG LM Germany

Leu55Gln CTG–CAG Eye, PN United States

Leu55Glu CTG–CAG Heart, PN, AN Sweden

His56Arg CAT–CGT Heart United States

Gly57Arg GGG–AGG Heart Sweden

Leu58His CTC–CAC CTS, heart United States (MD) (FAP II)

Leu58Arg CTC–CGC CTS, AN, eye Japan

Thr59Lys ACA–AAA Heart, PN, AN Italy, United States (Chinese)

Thr60Ala ACT–GCT Heart, CTS United States (Appalachian)

Glu61Lys GAG–AAG PN Japan

Glu61Gly GAG–GGG Heart, PN United States

Phe64Leu TTT–CTT/

TTG

PN, CTS, heart United States, Italy

Phe64Ser TTT–TCT LM, PN, eye Canada, UK

Ile68Leu ATA–TTA Heart Germany

Tyr69His TAC–CAC Eye, LM Canada, United States

Tyr69Ile TAC–ATCb Heart, CTS, AN Japan

Lys70Asn AAA–AAC Eye, CTS, PN United States

Val71Ala GTG–GCG PN, eye, CTS France, Spain

Ile73Val ATA–GTA PN, AN Bangladesh

Ser77Tyr TCT–TAT Kidney United States (IL, TX), France

Ser77Phe TCT–TTT PN, AN, heart France

Tyr78Phe TAC–TTC PN, CTS, skin France

Ala81Thr GCA–ACA Heart United States

Ala81Val GCA–GTA Heart UK

Ile84Ser ATC–AGC Heart, CTS, eye United States (IN),

Hungary (FAP II)

Ile84Asn ATC–AAC Heart, eye United States

Ile84Thr ATC–ACC Heart, PN Germany, UK

His88Arg CAT–CGT Heart Sweden

Glu89Gln GAG–CAG PN, heart Italy

Glu89Lys GAG–AAG PN, heart United States

His90Asp CAT–GAT Heart UK

Ala91Ser GCA–TCA PN, CTS, heart France

Glu92Lys GAG–AAG Heart Japan

(Continued)


symmetric thickening of the intraventricular septum and posterior ventricularwall. The electrocardiogram may show typical low-voltage changes or thepseudoinfarction pattern due to loss of anterolateral or inferior forces. Theechocardiogram remains the gold standard, showing concentric hypertrophyand diastolic dysfunction as the classic features. A granular, sparkling patternof the myocardium is often observed. Systolic function, measured by ejectionfraction, is typically intact until late in the course of the disease. Cardiacbiomarkers such as troponin I (TnI) and brain natriuretic peptide (BNP) havebeen shown to be highly sensitive and predictive of survival in light-chainamyloidosis (AL) [12]. No such studies have been reported in familial forms ofthe disease to date. More advanced imaging methods include cardiac magneticresonance imaging to detect delayed gadolinium enhancement, which has beenshown to be informative in three-fourths of patients with cardiac amyloidosis[13]. Scintigraphy using 99mTc-labeled phosphonates has also been reported tohave a high sensitivity and specificity for cardiac involvement and may behelpful in distinguishing the different forms of amyloid [14]. Retention of thesecompounds in the myocardium noted during a routine bone scan is occasion-ally the first evidence of TTR amyloidosis with cardiac involvement (Fig. 1).

Patients with cardiac amyloid involvement typically present with dyspnea onexertion or orthopnea, reflecting the diastolic dysfunction seen early in thedisease. More advanced cardiac involvement leads to systolic failure andconduction system disruption. Conduction delay can result in isolated bundle

TABLE 1 (Continued)


Val94Ala GTA–GCA Heart, PN, AN, kidney Germany, United States

Ala97Gly GCC–GGC Heart, PN Japan

Ala97Ser GCC–TCC PN, heart Taiwan, United States

Ile107Val ATT–GTT Heart, CTS, PN United States

Ile107Met ATT–ATG PN, heart Germany

Ile107Phe ATT–TTT PN, AN UK

Ala109Ser GCC–TCC PN, AN Japan

Leu111Met CTG–ATG Heart Denmark

Ser112Ile AGC–ATC PN, heart Italy

Tyr114Cys TAC–TGC PN, AN, eye, LM Japan, United States

Tyy114His TAC–CAC CTS, skin Japan

Tyr116Ser TAT–TCT PN, CTS, AN France

Ala120Ser GCT–TCT Heart Afro-Caribbean

Val122Ile GTC–ATC Heart United States

DVal122 GTC–DDD Heart, PN United States

(Ecuadoran), Spain

Val122Ala GTC–GCC Heart, eye, PN United States

aAN, autonomic neuropathy; CTS, carpal tunnel syndrome; eye, vitreous deposits; LM, leptome-

ningeal; PN, peripheral neuropathy.bDouble nucleotide substitution.


branch block, atrioventricular nodal block, tachyarrhythmias, or atrial fibrilla-tion. Sudden death remains a common cause of mortality. More rarely, patientsmay present with classical anginal symptoms probably due to subendocardialischemia resulting from vascular amyloid deposition.

Of particular note in regard to cardiac involvement in ATTR is the V122Imutation found in a significant number of African-Americans. Carriers ofthis mutation have a high incidence of symptomatic cardiac amyloidosis. Thehigh allele frequency makes this one of the most common pathologic geneticmutations in the United States and may explain the increased incidence ofcardiovascular disease in elderly blacks. Unfortunately, recognition of thedisease is frequently poor, leading to decreased reporting and appropriatetreatment in many cases.

Ocular involvement, although not a fatal consequence, remains a significantsource of morbidity in ATTR patients [15]. TTR is known to be synthesizedlocally by the pigmented retinal epithelium [16]. Vitreous amyloid accumula-tion leads to vision loss and frequently requires vitrectomy, which is helpful inrestoring vision. Most patients will develop recurrent deposits and requireadditional procedures. Secondary glaucoma may result, requiring more

FIG. 1 Cardiac uptake of 99mTc PYP seen on a bone scan of a patient with TTR

cardiac amyloidosis. This finding in nearly always associated with TTR-associated

amyloidosis.


aggressive surgical treatment [17]. The scalloped pupil deformity seen in bothJapanese and Swedish patients with ATTR is another ocular manifestation,probably related to ciliary nerve involvement [18].

Renal involvement, while common in AL, is less frequent in ATTR patientswith up to one-third of patients showing evidence of significant proteinuria atsome stage of the disease [19]. Patients may develop glomerular deposition withresulting nephrotic-range proteinuria, leading to significant hypoalbuminemiaand edema. More rarely, vascular deposits have been observed, resulting in adecrease in glomerular filtration and eventual end-stage renal disease requiringdialysis.

Direct involvement of the gastrointestinal tract is a frequent finding in somekindreds, but frank malabsorption is rare [20]. More often, gastrointestinalsymptoms are the result of significant autonomic neuropathy, as describedabove. Mucosal friability due to amyloid infiltration can lead to gastrointest-inal bleeding in rare cases [2]. Given the prevalence of gastrointestinalsymptoms, endoscopy with biopsy of the stomach, colon, or small bowel isoften the initial diagnostic procedure.

The wide variety and variable severity of clinical manifestations of ATTRoften results in a substantial delay in accurate diagnosis. Peripheral neuropathyand renal injury are frequently attributed to diabetes and cardiomyopathy toischemic injury. A positive family history is often obtained only after thediagnosis has been established. In one series, the time from initial onset ofsymptoms to the histologic diagnosis of amyloidosis ranged from 2 to 100months, with a median of nearly three years [2]. Even when the diagnosis ofamyloidosis is established, patients can be misclassified as AL or AA andtreated inappropriately with cytotoxic chemotherapy. In a retrospective ana-lysis of 350 patients diagnosed with AL at a major amyloid treatment center inthe UK, nearly 4% were found to have ATTR [21].

Survival in ATTR is difficult to predict in individual cases, due to theconsiderable clinical heterogeneity seen in different kindreds. As a group,patients with ATTR fare considerably better than those with AL. Themedian survival in ATTR is between 5 and 15 years, depending on thepopulation being studied, compared to a median of 20 months for AL [2,3].The site of predominant clinical involvement is critical, with the presence ofcardiomyopathy conferring a median survival of 3.4 years [2,3]. Once again,this compares favorably to AL patients with cardiomyopathy, who have amedian survival of less than one year. This suggests that the rate of amyloiddeposition and/or toxic effects of fibrils derived from TTR are less than thatof light-chain-derived amyloid. Age, gender (male), and the presence ofperipheral or autonomic neuropathy and carpal tunnel syndrome have alsobeen shown to affect survival. Death typically results from progressive heartfailure, inanition related to progressive neuropathy, wasting from malab-sorption, and infection. Sudden cardiac death is not uncommon. End-stagerenal failure and resulting complications related to hemodialysis are alsoreported.


Pathogenesis

Although a great deal has been discovered about the underlying cause of ATTRin the last 25 years, including the genetic lesions responsible and resultingchanges in the TTR protein, the mechanism by which amyloid fibrils of anytype exert their toxic effects is not known. It has been clearly shown that intactTTR amyloid fibrils themselves are nontoxic in vitro, but the formation offibrils from a soluble precursor results in apoptosis [22]. These data suggest thatit is an intermediate formed during the conversion of TTR from its normalsoluble state into the mature fibril that is the toxic species. The exact nature ofthis intermediate remains elusive, but studies have implicated monomeric anddimeric forms of TTR, as well as soluble oligomers and nonfibrillar aggregates,as potential candidates [23–25]. A similar phenomenon has been observed inthe toxicity of the Ab protein in Alzheimer disease, in which oligomeric orprotofibrillar species have been identified as potent toxins [26,27]. Thus, itappears that the mature amyloid deposits seen at the time of biopsy mayrepresent a final endpoint on the path of toxicity, with the damage being donemuch earlier in the course of fibril formation.

It is clear, however, that amyloid deposits do result in direct effects on end-organ function. This is particularly evident in the effects of amyloid on theheart. Early deposition results primarily in diastolic dysfunction, resulting fromimpaired relaxation [28]. The thickening of the myocardium as a result ofinterstitial amyloid buildup results in significant mass effect on the heart, withan increase in size from 350 g to over 1000 g in many cases. Contractility, asmeasured by systolic ejection fraction, is maintained until the wall thicknessreaches a critical threshold. Early systolic impairment can be seen through theuse of more sensitive methods of detection, such as strain rate Doppler analysisechocardiography [29]. This effect presumably represents a direct physicaleffect of the amyloid deposits rather than a toxic effect of the fibrils orintermediates on the cardiac myocytes themselves.

Deposition of amyloid within the vitreous of the eye is clearly a direct effectin which the fibrils interrupt the path of light to the retina. This results indecreased visual acuity. Removal of the deposits by vitrectomy immediatelyrestores vision, confirming the lack of a deleterious effect on the retina itself.Vitreous deposits ultimately recur and diminished vision develops, resulting inthe need for repeat extraction, in most cases.

Gastrointestinal involvement can result inmalabsorption through a variety ofmeans. Dysmotility from autonomic neuropathy can cause gastric dumping andaltered digestion of crucial nutrients. Extensive submucosal deposits can alsohave direct effects by interfering with the transit of fatty acids and amino acidsacross the intestinal epithelium. This results in steatorrhea and high-volumediarrhea. This disruptionof the normal functionof the gastrointestinal tract is yetanother example of direct effects of amyloid deposits themselves.

The presence of amyloid deposits in peripheral nerves results in axonaldegeneration and demyelination [30]. Fibers near amyloid deposits demonstrate


distortion of the myelin sheath, segmental demyelination, and Walleriandegeneration [31]. Due to the proximity of these effects to the depositsthemselves, direct compression of the nerve as a result of amyloid depositionhas been postulated to play a role in the development of peripheral neuropathy[32]. In addition, the presence of amyloid within endoneurial blood vesselssuggests that ischemia is another mechanism of direct neurotoxicity of thedeposits. In support of this theory, interstitial edema of the endoneuriumadjacent to deposits of amyloid in the sciatic nerves and brachial plexuses ofFAP patients have been reported [33]. Altered permeability resulting fromvascular amyloid involvement may produce severe endoneurial edema, leadingdirectly to ischemic injury of peripheral nerves.

Leptomeningeal amyloidosis is yet another example of vascular involvementleading directly to tissue injury. Patients with specific TTR variants associatedwith leptomeningeal deposits exhibit cerebral hemorrhage, dementia, ataxia,cerebral infarction, and seizures [5,34–36]. Pathologic examination in thesepatients reveals extensive leptomeningeal and vascular wall involvement withno discernible parenchymal deposits. Symptoms in these patients have beenlinked to direct impairment of cortical blood flow resulting from the amyloiditself. Cerebral hemorrhage results from breakdown of vascular integrity, also adirect effect of the amyloid deposits themselves. Hydrocephalus has beenreported in some cases, requiring ventriculoperitoneal shunt placement [37].It is possible that the presence of amyloid within the leptomeninges results in achronic basal arachnoiditis, a well-known cause of hydrocephalus, representingyet another direct effect of the deposits.

A second mystery is why so many different mutations within the TTR generesult in the same tendency to form amyloid. It has been shown thatamyloidogenic mutations destabilize the native structure of TTR, leading toconformational changes that favor reassembly into fibrils [38,39]. A widevariety of altered conditions can induce dissociation of TTR into alternativemonomeric intermediates, including temperature, ionic strength, pH, andprotein concentration, promoting the formation of soluble aggregates [40,41].A correlation between the thermodynamic stability of TTR variants and theirability to unfold and form aggregates has been demonstrated [42,43]. Wild-typeTTR has been shown to undergo similar conformational changes at increasedtemperatures at physiologic pH and under hydrostatic pressure, resulting inincreased fibrillogenesis [44,45].

The means through which the toxic form of TTR exerts its effect on the cellremains equally obscured. Multiple pathways have been implicated in studies ofTTR toxicity, including activation of the receptor for advanced glycation endproducts (RAGE), mitogen-activated protein kinases (MAPK), endoplasmicreticulum stress, oxidative stress, and calcium homeostasis [24,46–50].The activation of RAGE is an attractive hypothesis, as it has been shown tobe involved in many pathways of cellular toxicity, such as the regulation ofnuclear factor k-B, MAPK, and Jun-N terminal kinase signaling. A greater


understanding of the toxicity of amyloid deposits is clearly needed, sincetreatment for these patients is less effective than desired in many cases.

Treatment of ATTR

The goal of treatment for all forms of systemic amyloidosis is to reduce orremove the supply of the precursor protein, thereby preventing further amyloiddeposition. Since the synthesis of circulating TTR is almost exclusively hepatic,orthotopic liver transplantation (OLT) has been offered as a potentiallycurative treatment for ATTR since 1990 [51]. This approach has been widelyadopted, and data from the Familial Amyloidotic Polyneuropathy WorldTransplant Registry (FAPWTR) documents over 1300 OLTs performedworldwide as of 2006 (unpublished data). Given the normal synthetic functionof the liver in ATTR, surgical outcomes are excellent in ATTR patients, leadingto decreased surgical mortality, shorter hospital stays, and decreased need forblood products. The overall survival of transplanted ATTR patients is alsogood, at 77% at five years [52].

The benefit of OLT in this patient population is predominantly subjectiveimprovement in neurologic symptoms. Of the 149 evaluable patients, 42%reported an improvement in their sensory neuropathy. Patients with durationof symptoms for less than two years and relatively mild impairment prior totransplantation were more likely to result in improvement after OLT. Theseverity of the neurologic deficit prior to transplant was shown to be similarlypredictive of outcome in a report of 25 French patients [53]. In this study, noimprovement was noted in any patient, and 40% showed progression of theirneurologic deficit following OLT. Similar results of stable peripheral neuro-pathy with lack of objective improvement has been reported in a series ofpatients from the UK [54]. In a series of 15 patients treated with OLT in theUnited States, only 35% showed stable or improved peripheral neuropathysymptoms following transplant [55]. Overall, despite encouraging results fromsome centers, the benefit of OLT appears to be greatest in patients with shorterduration and milder presenting peripheral neuropathy.

Autonomic neuropathy is reported by the FAPWTR to improve in up tohalf of patients following OLT, as determined by improvement in gastrointest-inal symptoms [52]. Improvement in autonomic neuropathy was noted to be theearliest sign of improvement following OLT in a series of nine patients fromthe United States, with most showing an improvement in gastrointestinalsymptoms, orthostasis, and anhidrosis [56]. Other series have shown a lack ofimprovement in symptoms such as orthostatic hypotension, but recoveryof nutritional status has been reported in patients who were malnourisheddue to significant autonomic neuropathy prior to OLT [57].

The benefit of OLT for ATTR patients with cardiac involvement is less clear.A high rate of death due to cardiovascular causes occurs following OLT, oftenwithin 90 days of surgery [52]. Despite early reports of stable or improvement incardiac status of ATTR patients undergoing OLT, subsequent studies have


shown that it is common for cardiac involvement by echocardiographicfindings to progress in some patients [55,58–60]. Similarly, cardiac conductionabnormalities become more frequent and can even be life-threatening followingOLT [61]. Progressive cardiac amyloidosis following OLT is not limited tothose with preoperative cardiomyopathy or specific TTR mutations.

It has been noted that some patients appear to show a parodoxical increasein the rate of amyloid deposition following OLT [60]. Since the sourceof variant TTR production leading to amyloid fibril is removed at thetime of OLT, the accumulation of new amyloid deposits is completelyunexpected. Subsequent evaluation of the amyloid deposits has shown thatwild-type TTR is present in increased amounts in the heart following OLT[62,63]. Thus, it appears that wild-type TTR can continue to form amyloiddeposits, particularly in the heart, in patients with ATTR following OLT. Thismay also explain why patients with nerve involvement show progressivesymptoms following OLT, as wild-type TTR has also been shown tocontribute to peripheral nerve amyloid deposits [64].

Progressive vitreous amyloid deposits have similarly been reported to occurfollowing OLT [65]. Since TTR is known to be synthesized by the pigmentedretinal epithelium, it is likely that continued production of variant TTR isresponsible for ongoing amyloid formation in these cases. Similar results of denovo leptomeningeal amyloid deposition have been reported in two Japanesepatients following OLT, further documenting that variant TTR produced bythe choroid plexus can form progressive amyloid [11].

Since the synthetic function of the liver is intact in ATTR patients, it hasbecome common practice to perform a domino transplant, in which the liverharvested from the ATTR patient is subsequently transplanted into anotherperson [66–68]. A total of 532 domino transplantations are reported from 47centers in 16 counties by the FAPWTR.The recipients of theATTR livers tendedto be somewhat older than most liver transplant candidates and most often hadeither primary or metastatic malignancy as the indication for transplant.Survival does not appear adversely affected, although tumor recurrence andinfection remain frequent causes of death. Interestingly, reports of amyloiddeveloping in the peripheral nerves and gastric mucosa of recipients of ATTRlivers have now surfaced after extended periods [69,70]. This has necessitated asecond liver transplant in at least one case [69].

Given the variable benefit of OLT in ATTR and the fact that many patientsare either too old or too ill to be considered candidates for a major surgery atthe time of diagnosis, alternative forms of treatment have been explored. Thesestudies have focused on alternative means of suppressing variant TTRproduction by the liver and stabilization of the TTR tetramer.

Efforts to prevent or diminish the formation of amyloid fibrils through theuse of small molecules that stabilize the TTR tetramer have been pursued basedon several lines of evidence. The first was the finding that Portuguese patientscarrying both an amyloidogenic V30M-mutated TTR gene and a nonpatho-genic T119M allele had a milder clinical course than those with the V30M


mutation alone [71]. It was subsequently shown that hybrid tetramers contain-ing both the V30M and T119M variants showed reduced amyloid-formingpotential than that off tetramers containing only V30M [72]. This decrease inamyloidogenicity was linked to increased stabilization of the tetramer, decreas-ing the pool of free monomer able to undergo conformational shifts leading toamyloid formation.

Further work in this area has demonstrated that small molecules that bind tothe thyroxine-binding site of the tetramer can have a similar stabilizing effect,resulting in a decreased rate of tetramer dissociation [73]. One of thesecompounds is the commercially available anti-inflammatory drug diflunisal.Although not the most potent stabilizer of TTR, the safety and tolerability ofdiflunisal make it an attractive choice for testing in clinical trials in humans.Testing performed in vivo have demonstrated that orally administered diflunisalprovides sufficient serum levels to stabilize TTR tetramers against dissociation[74]. This work has led to a first-in-class randomized international phase IIIclinical trial of diflunisal for the prevention of ATTR in patients with peripheralneuropathy that is currently under way at multiple centers. An additional novelcompound with much more potent tetramer stabilizing activity is also currentlybeing tested in a phase II clinical trial. The results of these trials are eagerlyawaited as proof of concept that stabilization of the TTR tetramer will result inclinical benefits.

The finding that TTR knockout mice, which produce absolutely nodetectable TTR, have no phenotypic consequences, has led to the investigationof additional treatment approaches designed to diminish or abolish variantTTR production without the need for liver transplantation. Recently publisheddata using antisense oligonucleotides in mice transgenic for the I84S humanTTR gene have shown that hepatic TTR synthesis can be effectively suppressedfor substantial periods [75]. Other groups have shown that suppression of TTRsynthesis by ribozymes may be a feasible approach for treatment [76]. Inaddition, gene therapy in the form of targeted conversion of the variant allelehas been demonstrated to be possible both in vitro and in vivo [77]. Althoughthese approaches have not yet been tested in clinical trials, they offer hope forpatients that are either not candidates for liver transplantation or those whodevelop progressive disease after liver transplantation.

SENILE SYSTEMIC AMYLOIDOSIS

Background

Senile systemic amyloidosis (SSA) is the most common form of systemicamyloidosis. In autopsy series, up to 28% of persons over 80 years old werefound to have cardiac amyloid deposits composed of TTR [78,79]. Earlystudies identified TTR as the main component of the amyloid fibrils is thesepatients [80]. Subsequent sequencing of the TTR protein extracted from


patients with SSA showed only wild-type protein, confirming the lack of aninherited mutation as seen in ATTR [81]. Sequencing of the cDNA from apatient with SSA confirmed the lack of a mutation within the TTR gene andaltered transcription as a potential contributor [82]. Some overlap in theclinical picture and age of onset in people with the V122I mutation led toinitial confusion whether all patients with SSA had an inherited form of thedisease [83]. It is now recognized that although there is distinct similarity inthe phenotype of V122I ATTR and SSA, wild-type TTR is solely responsiblefor the amyloid in SSA.

Clinical Characteristics

The clinical picture of SSA is much different from that in ATTR. Cardiacinvolvement is seen in virtually all cases, and congestive heart failure is thedominating presenting symptom, which led to the initial use of the term senilecardiac amyloidosis for this disease [84]. More detailed examination hasrevealed that deposits are not limited to the heart, but frequently involve theaorta, lung, gastrointestinal tract, liver, and kidney, prompting the adoption ofsenile systemic amyloidosis (SSA) as being more accurate [78]. Men are affectedfar more often than women, for unclear reasons. Despite the widespreadappearance of amyloid deposits, patients rarely present with any symptomsattributable to disease outside the heart. Carpal tunnel syndrome may be anexception, as it is not uncommon to see localized amyloid deposits at the timeof surgical release [85,86]. Patients may have hepatomegaly, but this is almostalways secondary to severe congestive heart failure. Renal failure is uncommon,but may be significant in some cases.

Cardiac involvement is often extensive at the time of diagnosis of SSA. Theseverity of symptoms is typically less than one would expect for a patient witha similar amount of AL deposits. Patients with SSA have significantly greaterseptal and ventricular wall thickness at diagnosis then to patients with AL[87]. This may be due to less impairment of the conduction system, althoughatrial fibrillation is commonly seen due to atrial enlargement. Low voltage onelectrocardiogram, a classic finding in AL patients with cardiac involvement,is seen in only about a third of SSA patients [87]. However, conductionabnormalities, including complete heart block, can be seen in a significantnumber of patients. Rarely, septal thickening can lead to left ventricular tractoutflow obstruction, as seen more commonly in hypertrophic obstructivecardiomyopathy [88]. Thickening of the cardiac valves is occasionally seen,due to direct infiltration of the valve leaflets by amyloid (Fig. 2). The impacton cardiac function is predominantly a restrictive cardiomyopathy withresulting diastolic dysfunction. Survival for SSA is vastly superior to thatof patients with AL cardiac involvement, with a median of 60 to 75 monthsversus 6 to 11 months [87,89]. Progressive heart failure is the most commoncause of death.

SENILE SYSTEMIC AMYLOIDOSIS 807

Treatment of SSA

Unlike ATTR, in which aggressive therapy is warranted immediately upondiagnosis of symptomatic disease, the treatment of SSA focuses on supportivecare. Since the amyloidogenic protein in SSA is not altered in any detectablefashion, liver transplantation does not have a role in the management of thisdisease. Diuretics are the mainstay of treatment, but careful attention must bepaid to fluid status and daily weight to prevent a significant loss of fillingpressure. Calcium channel blockers have been reported to cause clinicalworsening in amyloid heart disease, presumably due to their negative inotropiceffects [90]. Beta-adrenergic receptor blockers are avoided for similar concerns.Implantation of a permanent pacemaker is helpful in symptom relief ifindicated clinically, but has not shown a survival benefit [91].

Although the mean age at presentation is over 70 years, rare patients maypresent earlier. Of 18 patients diagnosed with SSA at the Mayo Clinic between1984 and 1992, three were younger than 70 [89]. In these younger patients withsignificant symptoms, consideration should be given to orthotopic heart

FIG. 2 Two-dimensional echocardiogram for an 80-year-old man with senile cardiac

amyloidosis. Classic features of amyloid cardiomyopathy are thickened intraventricular

septum (IVS), thickened left ventricular posterior wall (LVPW), and enlarged left atrium

(LA). Right ventricle (RV) and aorta (Ao) are also labeled. This long-axis view is

displayed in midsystole to demonstrate thickening of aortic valve leaflets, which may

occur but is relatively uncommon.


transplantation, which has been successful in restoring quality of life in somecases [92].

Based on the accumulating data on TTR tetramer stabilization, it is reason-able to consider SSA patients for clinical trials of compounds designed toprevent dissociation of TTR into the monomeric or oligomeric intermediates.Indeed, the wild-type TTR protein has been shown to undergo conformationalchanges and resulting fibril formation similar to amyloidogenic variants underdenaturing conditions [38]. Studies of wild-type TTR undergoing heat dena-turation have shown that several key changes occur during the process that arenot completely reversed on renaturation, leading to the hypothesis that thesepermanent conformational events may promote subsequent fibril formation[44]. Kinetic stabilization by small molecules has been shown to stabilize thewild-type TTR tetramer and prevent or slow the formation of amyloid fibrils invitro [93]. Thus, these compounds have significant promise in preventing theprogression of SSA, in which patients are generally far older than ATTRpatients. Methods of suppression of TTR synthesis, such as antisense oligonu-cleotides, hold similar hope.

In summary, significant advances have been made in understanding themolecular and pathologic consequences of genetic alterations in the TTRprotein leading to systemic amyloidosis. With greater understanding, newtherapeutic methods are being employed to prevent the inevitable fatalprogression of these diseases. It is an exciting time in the study of thesedevastating diseases, and we look forward to the future, where a cure seemspossible for the first time.

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