amyloidosis eng (1)

8/7/2019 Amyloidosis Eng (1)

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AMYLOIDOSIS: lecturematerials for students


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Definitions (according to differentsources)

Amyloidosis is a systemic disease, characterizedby deposition of specific fibrillar protein, localizingperireticularly or around the collagen fibers, thatleads to affected organs impairment.Amyloidosis is a disorder of protein metabolism,which may be either acquired or hereditary,characterized by extracellular deposition of abnormal protein fibrils.Amyloidosis is a clinical disorder caused byextracellular deposition of insoluble abnormalfibrils that injure tissue. The fibrils are formedby the aggregation of misfolded, normallysoluble proteins (2006).


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C ommon features of all definitions

presence of systemic proteinmetabolism disorder (acquired or

hereditary)extracellular deposition of abnormalprotein fibrilsimpairment of affected organs dueto amyloid deposition


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W hat is amyloid? (physical

properties)straight, rigid, non-branching, 10 to15nm in diameter; indeterminatelength; regular fibrillar structureconsisting of -pleated sheets

aggregates are insoluble inphysiological solutionsrelatively resistant to proteolysis


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W hat are -pleated sheetsEvery fibril consist of stacks of anti-parallel -pleated sheetsSheets are arranged with the long axesperpendicular to the long axis of the fibrilThis structure resembles the structure of

silk (which is also proteinase resistant)Amyloid structure is visible by x-raydiffraction)


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C hemical properties (maincomponents)

Proteins and their derivatesGlucosaminoglycans

amyloid P componentOther proteins in amyloid deposits: 1-antichymotrypsin, some complement

components, apolipoprotein E, variousextracellular matrix or basementmembrane proteins. Significance of these

findings is unclear


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Main protein precursors (total 22)serum amyloid A protein (SAA)AL proteins (monoclonal light and heavy chains Ig -whole or part of the variable (VL, VH) domains)Transthyretin (TTR) with normal aminoacids sequence

or genetically abnormal TTR2-microglobulin-amyloid protein precursor; abnormal atrial natriuretic

factor; IAPP insular amyloid polypeptide (amylin)C ystatin C ; Gelsolin; Lysozyme; Apolipoproteins AIand AII; Prion protein; ADan and ABri precursor proteins; Lactoferrin; Keratoepithelin; C alcitonin;

Prolactin; Keratin; Medin etc


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Glycosaminoglycans

significance in amyloid is unclear participate in organization of some

normal structural proteins into fibrils;may have fibrillogenic effects oncertain amyloid fibril precursor

proteins.may be ligands to which serumamyloid P component binds.


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amyloid P component and serum

amyloid P componentamyloid deposits in all differentforms of the disease contain the

non-fibrillar glycoprotein amyloid Pcomponent (AP)ins role remains unclear


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Morphology and staining: common

features for all typesAmorphous eosinophilicappearance on light microscopyafter hematoxylin and eosinstaining

Bright green fluorescenceobserved under polarized lightafter C ongo red staining


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C linical syndromes related to

amyloidosisG eneral symptoms and intoxication :weakness, fatigue, sometimes fever and

weight loss (not common)Skin : itching; urticar rash, papules,nodules, and plaques usually on the face

and upper trunk; involvement of dermalblood vessels results in purpuraoccurring either spontaneously or after

minimal trauma


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P eriphreral nervous system:axonal peripheral neuropathy with subsequentdemyelination:

- paresthesiae, numbness, muscular weakness;begin from lower extremities and ascending over time

- feeling constraint in the whole body- painful sensory polyneuropathy (usually

symmetrical, usually affecting lower extremities)with early loss of pain and temperature sensationfollowed later by motor deficitscarpal tunnel syndromeautonomic neuropathy: orthostatic hypotension,impotence, poor bladder emptying andgastrointestinal disturbances may occur alone or

together with the peripheral neuropathy


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C entral nervous system

cerebral blood vessels affectionrecurrent cerebral hemorrhagesintracerebral plaquesprogressive dementia


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G astrointestinal disorders:Tongue: increased, dense, red or purple; so that it

cant go in mouth; tooth imprints, ulcers andfissures; speech is difficult disarthria; difficultiesin swallowing (dysphagia); excessive salivationStomach : early satiety, chronic nausea, vomitingG ut: diarrhea and/or constipation; malabsorption,obstruction or pseudo-obstruction (both due tomucosal deposition); perforation; haemorrhage,infarction (the last one is due to vascular depositsand is mostly localized in descending and sigmoidcolon)M otility disturbances (often secondary toautonomic neuropathy) may affect stomach andgut


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Heart: myocardium

increase of relative cardiac dullness, softheart sounds, systolic murmur at the apexand diastolic at aorta (relative valves

insufficiency in dilated heart);congestive heart failure (with up to 50% of fatal cases); hypotoniarestrictive cardiomyopathy with signs andsymptoms of right ventricular failurecardialgias


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EC G: heart muscle affection

EC G decrease of voltage, plain or inverted T, scars, pseudoinfarction

QS complexes in precordial leads.


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Heart: coronary arteries

secondary coronary syndrome andmyocardial infarction.

more marked affection of intramyocardial arteries;angiographic changes may not be

revealed


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Rhythm and conductivity disorders

conductivity disorders in sinus node, AV node and left bundle branch with

dizziness, syncopes, bradycardia,SA block and lower automaticitycenters activation

predisposition to cardiac arrest(especially ATTR)sensitivity to digoxin also may cause

fatal arrhythmias


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Pericardium and endocardium

affectionPericardium deposits constrictivepericarditis

Valves affection (amyloid deposits invalves): mild stenosis due to valverings infiltration

Endomyocardial thrombi withembolisms


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Echo

The most common: thickening of the intraventricular septum(usually 15 mm and more; normalvalues being


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WHO staging system for cardiacamyloid

1 no symptomatic or occult cardiac amyloidby biopsy or non-invasive testing

2 asymptomatic cardiac involvement bybiopsy or non-invasive testing eg wall thickness> 1.1 cm in the absence of prior hypertension or valvular disease, unexplained low voltage of EC G3 compensated symptomatic cardiacinvolvement

4 uncompensated cardiomyopathy


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Vessels

capillaries in the subcutaneous fatdermal capillars

coronary and brain arteries (coronarysyndrome, recurrent strokes)aorta

rare pulmonary artery


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L iver and spleenHepatomegaly; usually elevation of alkaline phosphatase is revealed with near normal levels of transaminases andbilirubinJaundice due to cholestasis

SplenomegalyRarely - portal hypertension; liver failure


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K idneys : symptoms

Proteinuria (usually with nephrotic

syndrome)C hronic renal failureAcute renal failure due to tubules affection


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Kidneys: staging systemStage Phase Course

Initial Proteinuric Slowly progressing

Clinicalmanifestations

-Nephrotic-Oedematic-

proteinuric-Hypertensive (rare)

Rapidly progressing

Terminal Chronic renal failure Relapsing


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J oints affection

usually occurs in association withmyelomamimic acute polyarticular rheumatoidarthritis affecting large jointsasymmetrical arthritis affecting the hip or shoulder.

infiltration of the glenohumeral articulationoccasionally with characteristic shoulder pad sign.


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Blood

Acquired bleeding diathesis:- deficiency of factor X and sometimes

factor IX, or increased fibrinolysis: (AL)

- in all variants may be serious bleeding inthe absence of any identifiable factor deficiency.

lymphadenopathybone marrow affection

splenomegaly


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tracheobronchial

associated with focal clonal immunocytedyscrasia

nodular or diffuse infiltrativemanifested by dyspnea, coughOccasionally - haemopthysis; distal

athelectasis with recurrent pneumonias


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parenchymal nodular associated with focal clonal immunocytedyscrasiasolitary (amyloidoma) or multiple nodules inlung parenchyma; usually peripheral or subpleural, more frequently in lower lobes; maybe bilateral; diameter ranges from 0.4 to 15sm;grow slowly

frequently cavitate or calcifylarger nodules can occasionally produce spaceoccupying effects


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diffuse al v eolar septal

usually is a manifestation of systemic ALamyloidosis associated with low grademonoclonal gammopathy, myeloma;

ATTR, AA-variants etcrestrictive respiratory symptomsrestrictive functional tests changes andimpared gas exchangeradiological changes may be absent


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intrathoracic lymphadenopathy

usually manifestation of systemic ALamyloidosis (hilar or meduastinalamyloidosis)is uni- or bilateralmay be asymptomatic

may calcifymay cause tracheal compression or venacaval obstruction.


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Eye

visible or palpable periocular mass or tissue infiltrationptosisperiocular discomfort or painproptosis or globe displacementlimitations in ocular motilityrecurrent periocular subcutaneoushemorrhagesdiplopia


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Endocrine and exocrine glands

adrenal gland infiltration(hypoadrenalism)thyroid infiltration (hypothyroidism)IAAP progressive loss of insular productioncorpora amylacea of the prostate ( 2-

microglobulin)seminal vesiclessalivary glands


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C lassifications: before 1993

AA (inflammatory)AL (light chains related)AF (familial)AS (senile)

AD (dermal)AH (haemodyalysis-related)


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W HO (1993): biochemical structure-basedclassification. Systemic variants

AA (ApoSAA): chronic inflammatory diseases;periodical fever; Muckle- W alesAL (Systemically produced monoclonal lightchains Ig: A ( VI); A ( III): primary (idiopathic)or associated with gammapathiesATTR

- normal TT R : senile systemic amyloidosis withgradual heart involvement

- M et30: Family amyloid polyneuropathy- M et111: Family amyloid cardiopathy

A 2 M ( 2-microglobulin): haemodialysis-associated systemic amyloidosis


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W HO (1993): local variants

AL (L ocally produced monoclonal Ig):local urogenital; skin, eyes, respiratoryA ( -amyloid protein precursor):cerebral; cerebrovascular; Alzgeimer-associatedAANF (abnormal atrial natriuretic

factor): local atrialAIAPP (IAPP insular amyloidpolypeptide): Langerhans insuliamyloidosis in II type of diabetes mellitus


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From 1993 to nowadays newprecursors and new variants were

found (2006 22 precursors).So, new approaches tobiochemistry-based classificationbecame necessary .


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Systemic

Ig light chains (plasma cell disorders)Transthyretin (Familial amyloidosis,

senile cardiac amyloidosis)A amyloidosis (Inflammation,Mediterranean fever

Beta2 microglobulin (Dialysis-associated)Ig heavy chains (Systemic amyloidosis)


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Hereditary(Familial systemic amyloidosis, sometimes

called Familial Renal)Fibrinogen alpha chain

Apolipoprotein AI

Apolipoprotein AII

L ysozyme


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Ocular

G elsolin (Familial amyloidosis;Finnish type)

L actoferrin (Familial cornealamyloidosis)

K eratoepithelin (Familial cornealdystrophies)


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LocalizedCalcitonin (Medullary thyroid carcinoma)IAAP= Amylin (Insulinoma, type 2diabetes)Atrial natriuretic factor (Isolated atrialamyloidosis)P rolactin (Pituitary amyloid)K eratin (C utaneous amyloidosis)M edin (Aortic amyloidosis in elderly)


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Inflammatory amyloidosis

Amyloid A (AA) amyloidosis is the mostcommon form of systemic amyloidosisworldwide. It is characterized byextracellular tissue deposition of fibrils thatare composed of fragments of serumamyloid A (SAA) protein, a major acute-

phase reactant protein, producedpredominantly by hepatocytes


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AA protein is a single non-glycosylatedpolypeptide of mass 8000 Da containing 76residues corresponding to the N -terminal portionof the 104 residue serum amyloid A protein(SAA)SAA is an apolipoprotein of high densitylipoprotein particles and is the polymorphicproduct of a set of genes located on the shortarm of chromosome 11. SAA is a major acutephase proteinP roduced : mostly - by hepatocytes ;

transcriptional regulation by cytokines,especially interleukin 1(I L -1), interleukin 6 (I L -6), and TNF , acting via nuclear factor B-likeand possibly other transcription factors.


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The circulating concentration can risefrom normal levels (3mg/l) to over 1000mg/;l within 24 to 48h of an acutestimulus; in presence of chronicinflammation the level may remain very

high .SAA as an exquisitely sensitive acutephase protein (more sensitive than C RP)AA protein is derived from circulating SAAby proteolytic cleavage by macrophagesand by a variety of proteinases


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PathogenesisInflammationM

acrophages activation: IL-1, 6IL -1,6:- Increased hepatic transcription of the messenger

ribonucleic acid (mR N A) for SAA (up to1000-times)

- High SAA level in serum- macrophages: SAA proteolytic cleavage

AA-peptide in blood

In presence of amyloid synthesis acceleratingfactor:- macrophages surface: amyloid fibrils synthesis

(membrane-binding enzymes)

Amyloid synthesis


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C auses

chronic inflammatory disorderschronic inflammation due to bacterial

infectionsmalignant neoplasms; proliferativediseases of blood system

subcutaneous drug abuse


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C hronic inflammatory disordersV ery often:rheumatoid arthritis and juvenile rheumatoidarthritis in 10% of arthrites casesBecchet diseaseankylosing spondylitisPsoriatic arthritis

C rohn's diseaseM

ore rare:- systemic lupus erythematosus- ulcerative colitis


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C hronic bacterial infections

tuberculosis; leprosychronic osteomyelitis

bronchiectasischronic abscess (different localizations)chronically infected burnschronic ulcers of lower extremitiesother chronic bacterial infections


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Malignant neoplasms; proliferativediseases of blood system

M ost frequent:diseases, causing fever, other systemicsymptoms, and a major acute phase response(SAA protein) or increased IL-6 production- Hodgkin's disease- renal carcinoma

Occasionally: atrial myxomas, renal cellcarcinomas, Hodgkin disease, hairy cellsleukemia, carcinomas of the lung and stomach


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Subcutaneous drug abuse

Development of AA amyloidosis wasreported in subcutaneous drug

abusers in some cities in the UnitedStates.Pathogenesis of this is not clear (drug

related or chronic inflammation due tosome contaminating substance)


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C linical symptomsR elating to the main diseaseG eneral: weakness, weight lossK idneys affection (up to renal failure)G I symptoms: dyspepsia (nausea, episodesof vomiting, loss of appetite); diarrhea, which isnot related with any infectionL iver and spleen affection(hepatosplenomegalia)Thyroid enlargementInvolvement of the heart: Echo-signs in

10% ; doesnt cause severe impairment .


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Course:

Initially, disease is manifesting only bytransient proteinuria, increasing in casesof main disease exacerbations.C ourse is progressive and is terminated bychronic renal failure developmentC ourse is determined by the efficacy of themain disease treatment


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O utcomes and complications:

Main outcome is chronic renal failure (end-stage- 5-10 years from 1st symptoms); the firstproteinuric period is the longest 2-4 years;marked clinical manifestations period lasts about1 year, then chronic renal failure develops).Renal vessels thrombosis may develop as acomplication, which makes prognosis moreunfavorableFibrinous-purulent peritonitis, accompanying bypain and ascitis, is a rare complication.


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P rognosisDepends on the course of the main diseaseSurvival: 50% of patients die within 5 yearsof the amyloid being diagnosed.Availability of chronic hemodialysis andtransplantation prevents early death fromuraemia

Renal vessels thrombosis makes prognosismore unfavorable

Familiar M editerranean fever


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Familiar M editerranean fever (recurrent polyserositis)

and AA-amyloidosisEpidemiology:Incidence: in families with healthy parents:18%; with one affected parent 36%Nationality: most often in non-Ashkenazi Jews,

Armenians, Anatolian Turks, and Levantine Arabs; prevalence doesnt depend on place of

settlement of these nationalitiesrepresentatives.Inheritance: autosomal recessiveSex: M:F 1.7:1


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M orphologyserosa: non-specific inflammation;hyperaemia and cellular infiltrate(neutrophils, lymphocytes, monocytes,sometimes, plasma cells and eosinophils)synovia: pannus formation and extensiveintra-articular damage is possiblevascular changes - thickening of the

basement membrane; reduplication of thebasement membrane is possibly due torepeated episodes of cell death andregeneration.


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P athogenesisgenetic natureimmunological disturbances (higher incidence of autoimmune diseases and allergyin patients with Mediterrhanian fever; highserum Ig and circulating immune complexeslevels)involvement of vascular system

C5a-inhibitor deficiency in joint and peritonealfluids may have a role in the pathogenesis of the attacks (result in severe inflammatoryattacks following the accidental release of C 5a).


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2 F


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2. Fever:

may be even asymptomatic (afebrilemild attacks)abdominal pain attacks with fever up to38-40 C with tachycardia, and (in 25%) chills; temperature returns to normalafter 12hours - 3days.in arthritis high fever peak lasts for 1-3days


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3. J oints affection:

from arthralgia to arthritis (24-84%,mean 55%)symptoms increase during the first 24-48h; may last about a week.course: accompanied by fever with highpeaks lasting 1-3 days; in 5% acuteattack fails to resolve and the symptoms

may persist several weeks or evenmonths before they abate with noresidual damage.

A most common:


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A. most common:asymmetric, non-destructive mono- or

oligoarthritis affecting the large joints ;knees and ankles (3 times more often thanhips, shoulders, feet, wrists; involvement of small joints is very rare).

joints are painful and swollen withoutmarked local redness and heat.1-2 large joints are affected at a time;in frequent attacks involvement of one jointmay start before previous joint improves, soimpression of migratory arthritis is present


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B . Rarely (2%):

chronic destructive mono- or oligoarthritisaffecting most frequently the hip or the knee.permanent organic damage results from oneprotracted attack or from repeated shortattacks.C. Also had been described:- sacroiliitis, frequently asymptomatic


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InvestigationsSynovial fluid

- usually turbid; forms a good mucin clot- white count ranges between 15000 and

30000 polymorphonuclears per mm3- is always sterile.

R adiographic changes:

- loss of cortical definition- sclerosis with or without bone erosion- fusion of the joints.


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4. Chest (pleurisy) pain morethan 50%

sharp and stabbing, localized in the lower part, mostly on the right side; radiating toabdomen and shoulders; patients splint their respiratory excursionssuppression of breath sounds over theaffected side is usual but pleural friction isexceptionalsmall effusion may be in the costophrenicangle.


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5. Abdominal pain - almost in all patientsattacks originate in one area, spread over wholeabdomen within few hours; patients flex their thighs and lie motionless to relieve the pain;intensity of pain vary from mild discomfort to that insevere generalized peritonitisconstipation and vomiting are frequentsymptoms of acute peritonitis - exquisiteabdominal tenderness, involuntary rigidity, rebound

tenderness, and diminished peristalsis.attack usually reaches its peak in 12h; resolvesspontaneously and is usually over within 24 to 48h;then pain subsides gradually.

6 Skin rash 10 20%


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6. Skin rash 10-20%typical is erysipelas; skin becomes bright-red, hot,swollen, and painful; rash is usually unilateral and itsborder may or may not be sharply definedlocalization - over extensor surfaces of the legs belowhe knees, over the ankle joints, or the dorsum of thefoot.

symptoms intensify rapidly and then disappear within2-3 days without any therapy.on biopsy: mild acanthosis and hyperkeratosis,dermis contains an inflammatory exudate consisting of polymorpho-nuclear cells, lymphocytes, and somehistiocytes concentrated mainly around the bloodvessels.nodular rashes, Schonlein-Henoch purpura, andurticaria are also reported.


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7 . O ther organs affectionattacks of pericarditis (occasionally)severe headache may occur during attackstransient E C G signs of myopericarditis and non-specific EEG abnormalities during paroxysms.

severe myalgia; muscle atrophy at affected joints

numerous attacks in children may lead togrowth retardation.colloid bodies are often found in the eyegroundsspleen is palpable in more than 33% of

patients.


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8. K idneys: AA-amyloidosis

at the late stagesthe first sign is massive albuminuria;

within several years - nephroticsyndromeprogresses to chronic renal failure


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Clinical variants

with abdominal; thoracic, joint andfever syndromes dominating

may vary in different life periodsof the individual


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Course

at childhood first symptoms are usually sudden onsetof asymptomatic fever, arthralgia, chest andabdominal pain.symptoms last for days or weeks and then relieve by

themselves with no objective symptoms revealed.attacks recur, usually at irregular periods of severaldays to several months; spontaneous remissions maylast years.further progression includes recurrent episodes withincreasing frequency and shortening of theasymptomatic periods.


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Factors influencing exacerbations

physical exertionstresswalking and standingpregnancy.


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O utcomes

end-stage chronic renal failure anddeath.

adequate treatment can delay (butnot stop) the disease developmentrapid progression is observed after

the first signs of asotemia


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Immunoglobulin-relatedamyloidosis (AL)

Immunoglobulin-related amyloidosis is amonoclonal plasma cell disorder in which thesecreted monoclonal immunoglobulin proteinforms insoluble fibrillar deposits in 1 or more

organsMostly related to light chains (AL-amyloidosis)In few reported patients amyloid depositscontained immunoglobulin heavy (H) chainsamyloid H-chain type (AH).Light chains consist of the whole or part of thevariable (VL) domain, more commonly derivedfrom chains than from chainsassociated with gammapathies


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C onditions causing AL-amyloidosis

Multiple myelomaW aldenstrom diseaseMonoclonal gammapathy of undetermined

significance (MGUS)


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PathogenesisIn L chains certain amino acid and glycosylationcharacteristics predispose to amyloid formation (why -remains unknown).probably these changes promote aggregation andinsolubilization

amyloidogenicity of particular monoclonal light chainswas confirmed in an in vivo model (injection of isolatedBence Jones proteins into mice, who developedtypical amyloid deposits)I n some patients with monoclonal gammapathy monoclonal proteins accumulate in v arious organs, but the deposits do not form fibrils . P atients with this formare described as ha v ing nonamyloid monoclonal immunoglobulin deposition disease (MIDD).


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EpidemiologyIncidence: annually, 1-5 cases per 100,000people occur (may be higher basing onmyeloma incidence underdiagnosis?)

R ace: probably not related (no comparativeinvestigations)Sex: M:F 2:1

Age: It is revealed usually in aged (in UK 66% were between 50 and 70 years old atdiagnosis; 4% - less than 40 years. Median age

64 years old (Mayo clinic)


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SymptomsMajor systemic amyloidosis with affectionof most organs described (except CN S)M ost common initial symptoms :peripheral edema, hepatomegaly, purpura,orthostatic hypotension, peripheralneuropathy (10-20%), carpal tunnelsyndrome (20%), and macroglossia (10%)

Hepatosplenomegaly is revealed in 25%Heart is affected in about 90%Kidneys in 33-40%


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L ocalized amyloid L -chain type

most commonly in respiratory tractoften remains localizedmay involve ureter or urinary bladder (hematuria)Amyloidomas may be also in soft tissues,including the mediastinum and the

retroperitoneumSkin involvement can manifest as plaques andnodulesIsolated heart affection (not common in AL)


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C omplications

congestive heart failure, arrhythmias,or both (cause of death more than 50%)renal failurebleedings


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C ourse and prognosis

In the absence of chemotherapy alwaysprogressive courseRapid development of heart or renal failureTreatment of heart and renal failure is usually

ineffective.Survival: 18 months-10 years; mean 18-20months; 1-year survival rate is 51%, 5 16%;10 4.7%Heart affection is the most unfavorable sign(mean survival after symptoms appearance 6months).


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ATT R amyloidosisTTR is a serum protein that transports thyroxine andretinol-binding protein.It circulates as a tetramer of 4 identical subunits of 127amino acids each.TTR formerly was called prealbumin because itmigrates anodally to albumin on serum proteinelectrophoresis, but this name was misleadingbecause TTR is not a precursor of albumin.

TTR monomer contains 8 antiparallel beta pleatedsheet domains.TTR is synthesized primarily in the liver, as well as inthe choroid plexus and retina. Its gene is located onchromosome 18 and contains 4 exons.


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N ormal-sequence TTR

senile cardiac amyloidosis (S C A).microscopic deposits are also found inmany other organs - senile systemicamyloidosis (SSA)


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C linical manifestations; SSAin 25% of old patients clinically silentmicroscopic, systemic deposits of transthyretin (TTR) amyloid involving theheart and blood vessel walls, smooth andstriated muscle, fat tissue, renal papillae, and

alveolar walls are revealed.spleen and renal glomeruli are rarely affectedbrain is not involved.occasionally more extensive deposits in the

heart, affecting ventricles and atria andsituated in the interstitium and vessel walls,cause significant impairment of cardiacfunction and may be fatal.


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C linical manifestations; S C A

may be silent or accompanied bysignificant impairment of cardiac

function


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TT R mutationsaccelerate the process of TTR amyloidformationmutations destabilize TTR monomers or

tetramers and allow molecule to more easilyattain amyloidogenic intermediateconformation

more than 85 amyloidogenic TT R variantscause systemic familial amyloidosis.M ostly autosomal dominant inheritance

V ri nts of TT R s stemic f mili l


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V ariants of TT R systemic familialamyloidosis

FA P (family amyloid polyneuropathy) V al30 M et(V alin to M etionin in 30 position)Cardiac amyloidosis ( L eu111 M et, Dutch)Cardiac amyloidosis V 122I (late-onset (after age 60)cardiac amyloidosis, most common)late-onset systemic amyloidosis T60A with cardiac,and sometimes neuropathic, involvement (northwestIreland)

amyloidosis of carpal ligament and nerves of theupper extremities L 58 H (Germany, MidAtlanticregion)In total, 100 variants of TTR, about 98 areamyloidogenic

Epidemiology


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EpidemiologyIncidence:

- cardiac ATTR with normal sequence 15% of allthe autopsies after 80 years old

- for mutant TTR - depends on the type (V122I in USA- 2%-3.9%)R ace and region : types of mutations are region-relatedSex: all TT R variants encoded on chromosome 18,so M=F; for unknown reasons, penetrance is more

and age of onset earlier in males.Age : depending on the mutation and region (age of onset in V30M in Portugal, Brazil, and Japan is 32,in Sweden 56); normal TT R after 60; rapid

increase after 80 .


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C linical manifestationsG

eneral - cachexiaSkin: purpura (vascular fragility dueto subendothelial deposits)H eart: heart failure, arrhythmias(blocks, PV C , VT, posturalhypotension (subendothelial depositsin peripheral vessels)G

I gastric symptoms, diarrheaand/or constipationL iver: hepatomegaly

N europathy: axonal degeneration of


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small nerve fibers due to deposits

sensorimotor impairment (V30M - lower limbneuropathy; I84S, L58H - primarily upper limb neuropathy).

hyperalgesia; altered temperature sensationcarpal tunnel syndrome most typical for L58H, may be in normal TTR

autonomic dysfunction (sexual or urinary common for V30M)cranial neuropathy

eye: deposits in corpus vitreum

FA P (family amyloid polyneuropathy) V30M


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FA P (family amyloid polyneuropathy) V30Mmajor foci - Portugal, Japan, Sweden; age 20-70

Clinical manifestations include :progressive peripheral and autonomic neuropathy;vitreous and cornea of the eye affection;V arying degrees of visceral involvement : kidneys,

thyroid, adrenalsG eneral symptoms: weight loss etcH eart affection is not typical, but predisposition tosudden heart stoppage exists

Course and prognosis: progression; disorder is fatal.Death results from the effects and complications of peripheral and/or autonomic neuropathy, or fromcardiac or renal failure.


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P th i


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PathogenesisBeta-2-microglobulin is a component of beta chain of HLA class I molecule and ispresent on the surface of most of the cellsIn normally functioning kidney, beta-2-microglobulin is filtrated by glomerulusIn renal failure , impaired renal catabolismcauses an increase in beta-2-

microglobulin synthesis leads to 10- to 60-times increase of its levelRole of IL-6 stimulation by dialysis is

discussed


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Epidemiology

1st symptoms 4-8 years after haemodialysis onset (in 20%)10 years after in 70% of cases15 years after in 95% of cases20 years after in 100% of cases

Race, age and sex: no differences


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C linical manifestations

1. Neurological syndromes:carpal tunnel syndrome most common(deposits in hands ligaments compress thenerves)

- bilateral and progressive- numbness, paresthesias, pain, swelling in

the region of the distal median nerve- worse during dialysis and at night- progresses to contraction of the hand and

atrophy of the muscles

J i d b ff i


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J oints and bones affection

Flexor tenosynovitisScapulohumeral arthropathy - shoulder painworse in supine position

Spondyloarthropathy (more cervical)Bone cysts (thin-walled; in carpal bone,femoral heads, humerus, acetabulum,

spine), cause stiffness and/or pain.Pathological fractures (femoral neck mostlycommon)

Systemic manifestations


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Systemic manifestationsafter 10-15 years, usually asymptomaticG I: macroglossia, dysphagia, small bowelischemia, malabsorption, andpseudoobstruction

Cardiovascular: Myocardium, pericardium,valves; small pulmonary arteries and veinsK idneys: renal and bladder calculicontaining beta-2-microglobulin deposits

R eproductive: prostate and the femalereproductive tractSpleen deposits

Familial Systemic (Familial Renal -


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y (FRA)

Syndrome of familial systemic amyloidosiswith predominant nephropathyFirst described in 1932 by Ostertag,

former name - N on-neuropathic systemicamyloidosis, Ostertag typeAutosomal dominantAge from first decade to old age butmost typically in mid adult life


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A myloid precursors

L ysozymeApolypoprotein I

A polipoprotein A II F ibrinogen A alpha-chain

L ysozyme Ile56Thr Asp67His


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L ysozyme Ile56Thr, Asp67His,Try64Arg

Renal: P roteinuria and renal failureG I tract - B leeding and perforation

L i v er and spleen - Organomegaly and hepatic hemorrhageSali v ary glands Sicca syndromePetechial rashes may occur

Apolypoprotein I


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Apolypoprotein IP roteinuria and renal failure almost in allP eptic ulcers (Gly26 A rg )P rogressive neuropathy (Gly26 A rg )L iver and spleen varying from organomegaly toliver failure ( T rp50 A rg ; deletions 60-71 )H eart failure (L eu90 P ro; A rg173 P ro etc); aggressiveearly IHD ( deletion L ys107)R etina - C entral scotoma ( deletion 70-72 )

Skin: Infiltrated yellowish plaques (L

eu90 P

ro);acanthosis nigricans-like plaques ( A rg173 P ro)L arynx dysphonia ( A rg173 P ro )M ales reproductive: infertility ( A la175 P ro )

A polipoprotein A I with normal


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polipoprotein with normalsequence

C auses amyloid deposits in human

aortic atherosclerotic plaquesFound in 20-30% of elderlyindividuals at autopsy


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A polipoprotein A II

Proteinuria and renal failure


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F ibrinogen A alpha-chain

Proteinuria and renal failure

In Glu526Val varianthepatosplenomegaly and liver

failure may occur (late sign)


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CN S amyloidosisBeta protein precursor (Alzheimer syndrome,Down syndrome, hereditary cerebral hemorrhagewith amyloidosis - Dutch type)P rion protein (C reutzfeldt-Jakob disease,

Gerstmann-Strussler-Scheinker disease, fatalfamilial insomnia)Cystatin C (hereditary cerebral hemorrhage withamyloidosis - Icelandic type)ABri precursor protein (Familial dementia Britishtype)ADan precursor protein (Familial dementia

Danish type)

H ereditary cerebral haemorrhage withamyloidosis; hereditary cerebral amyloid


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amyloidosis; hereditary cerebral amyloidangiopathy

Icelandic typeautosomal dominant; symptoms early adultlife.

cerebrovascular deposits (cystatin C )recurrent major cerebral haemorrhagesappreciable but clinically silent amyloiddeposits are present in the spleen, lymphnodes, and skin.no extravascular amyloid in the brain.multi-infarct dementia is common

Dutch type


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Dutch type

autosomal dominant; starts at middle age-protein depositsrecurrent normotensive cerebral

hemorrhagesMulti-infarct dementia; some patientsbecome demented in the absence of

stroke.Amyloid outside the brain has not beenreported

f l d


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Diagnosis of amyloidosis

1. P resence of amyloid: c ongo red staining2. Type of amyloid: immunohistochemistry

3. M utation type: amino acid sequenceanalysis

i f bi


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Tissues for biopsy

subcutaneous fat aspiration (providesenough material for all investigations) 60%rectal biopsy 80-85%

cheek biopsy 60%organ biopsy: if subcutaneous fat investigationdidnt not provide enough information for

diagnosisAnyway, kidney biopsy is usually performed todetermine the cause of nephrotic syndrome(informativity is 100%)

AA


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AA

SAA precursor level in bloodSerum immunoglobulins (to exclude AL;in

AA amyloidosis usually polyclonalhypergammaglobulinemia is presentdue tounderlying inflammation)Kidney function (urine analysis, daily

proteinuria, GFR)

Instrumental methods


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Instrumental methodsAvoid I V pyelography if amyloidosis issuspected (more frequent renal failure)Ultrasonography: kidneys size (non-specific)CT scanning : with technetium which binds to

soft-tissue amyloid deposits (to monitor progression)R adiolabeled P -component gammascanning: total body burden of amyloid and itsdisappearance after successful treatment of theprimary disease. most useful in AA amyloidosisbecause the major sites of deposition areaccessible to the imaging agent


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Bi h i


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Biochemistry

concentration of normal Ig is oftendecreasedamyloid A type is mostly associated with

hypergammaglobulinemia due topersistent inflammation and interleukin 6production .

Functional systems tests


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Functional systems tests

clotting system abnormalitieskidney function tests

liver function tests

Instrumental


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InstrumentalEchocardiographyRadiolabeled P component scanningBone imaging: plasma cell infiltration

C hest radiography: pulmonarydeposits

ATTR


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ATTR

subcutaneous fat aspirationsural nerve biopsyrectum, stomach, myocardium biopsy

C ongo red; antiserum against TTR

I t t l


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Instrumental

EchocardiographyN erve conduction studies to monitor course of disease and assess response totreatmentGenetic studies ( TT R variant)

F ili l t i ( l)


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Familial systemic (renal)

Biopsy: amyloid confirmationAffection of organsRadiolabeled P component scanningDN A analysis obligatory in all patients withsystemic amyloidosis who cannot beconfirmed absolutely to have the AA or ALtype.

b t 2 i gl b li


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beta-2-microglobulin

reference range of serum beta-2-microglobulin concentration of is 1.5-3mg/L; can be elevated to values of 50-100

mg/L.Beta-2-microglobulin levels correlate withelevated serum creatinine levels and are

inversely related to the glomerular filtrationrate

Radiologic:


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g

joint erosions (usually large joints)lytic and cystic bone lesions (typically

juxta-articular)pathological fracturesspondyloarthropathiesvertebral compression fracturesMay precede the pain appearance

C T


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C T

amyloid deposits: intermediate attenuation.identification pseudotumors andpseudocystic areas in the juxta-articular bone.best method for detecting small areas of osteolysis in cortical bone or osseouserosionsmay be used in the assessment of thedistribution and extent of destructivechanges.

MRI


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MRI

differentiating destructivespondyloarthropathies from inflammatoryprocesses and infections.

Ultrasound


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Ultrasound

tendon thickness.rotator cuff thickness greater than 8 mm,thickening of joint capsules (especially of the hip and knee) may be presentretention of synovial fluid may be present

Scintigraphy


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Scintigraphy

radiolabeled P-component scans

Biopsy with C ongo red staining and


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with immunostainingcentrifuged synovial fluid sedimentscystic bone lesions biopsysynovia biopsymost common site for biopsies:sternoclavicular joint.rectal biopsy and subcutaneous fataspiration are of little value.antisera to beta-2-microglobulin

Treatment: AA


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Treatment: AAprimary inflammatory disease treatmenttumor necrosis factor-a inhibitors andinterleukin-1 inhibitors (arthritis, FMF)C olchicine FMF

N ew approachesAntiIL-6R therapy (clinical studies)anionic sulphonates (clinical studies)

NC -503: interfers fibril formation and depositionof amyloid by inhibiting interaction of SAA withglycosaminoglycans (at study)palindromic compound ( C PHP C ) triggers:dimerization of human SAP molecules (vivo pre-clinical studies)

AL


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AL:

melphalan plus prednisonemelphalan, prednisone, and colchicineOther chemotherapeutic regimens used

for multiple myeloma (vincristine,carmustine, melphalan,cyclophosphamide, prednisone schemeetc)

Pharmacologic therapy to solubilize


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amyloid fibrilsanthracycline analogue of

doxorubicin, 4-iododoxorubicin(Idox) : in vivo and clinical studies(solubilize amyloid L-chaintype deposits) in combination withcytotoxic chemotherapy

Treatment of localized amyloid L-


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chain typehas not been studied systematicallychemotherapy is not indicatedLocalized radiation therapy aimed at destroyingthe local collection of plasma cells producingthe amyloid L-chain type can be administeredwhen a plasma cell collection can be identifiedL ocal collections of amyloid L -chain type inthe genitourinary tract, even in the absence of an identified clonal plasma cell collection, cancause hematuria. In these patients, surgicalresection of amyloidomas may be required tocontrol the bleeding.

TTR


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TTR

Digoxin and calcium channel blockers arecontraindicatedLiver transplantationpatients with cardiac, leptomeningeal,gastrointestinal, or ocular involvement oftenprogress despite transplantationCombined heart and liver or liver and kidneytransplantation has been reported in a veryfew patients, with variable success

no pharmacologic therapy is available for ATTR. A number of small molecules that may have thepotential to inhibit or reverse TTR amyloidformation are under preclinical study



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no adequate treatment (symptomatic)Improvement of dialysis membranesOnline hemodiafiltration

Familial systemic (familial renal)


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Familial systemic (familial renal)

Transplantation: liver (in case of liver failure), kidney, heart

amyloidosis eng (1)

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