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Prof Dr Sergülen Dervişoğlu
AmyloidosisCalcification andstones
Amyloidosis
Pathologic proteinaceous substanceDeposited between cellsWide variety of clinical settingsInsidious depositionImmunological mechanism is probablyresponsible
Amyloidosis
Standart tissue stainsAmorphousEosinophilicHyaline extracellular substanceProgressive accumulationPressure on adjacent cell---atrophy
Amyloidosis
Differentiate from other hyaline pinkdepositsCollagen, fibrinMethyl violet--- metachromatic stainingreaction---deep purpleCongo red --- orange redPolarized microscopy--- greenbirefringance
Amyloidosis
Not chemically distinctSeveral different pathogenetic mechanismNot be considered as a single diseaseThree major and several minor biochemicalforms
Physical nature
Non branching fibril proteins95%P componentGlycoproteinNonproteineous substances derived fromconnective tissue in which amyloiddeposited
Chemical nature
Amyloid proteinsAL--- amyloid light chain---derived from plasmacellsAA---amyloid associated---nonimmunoglobulinprotein synthesized by liverDistinct clinicopathologic settingsAbeta---amyloid found in cerebral lesions of Alzheimer patients
Amyloidosis
AL type--- immunoglobulin secreting cellsMonoclonal B cell proliferationAA type--- secondary amyloidosisTransthyretin (TTR) mutant form---familial amyloid polyneuropathiesBeta 2 microglobulin---longtermhemodialysisBeta amyloid protein---Alzheimer disease
Amyloid clasification
Based on its constituent chemical fibrilsAA, AL, ATTRIt can be both systemic or localizedClinically---Primary—Immunocytedyscrasias---Monoclonal gammopathySecondary---AA---reactive systemicamyloidosis---underlying chronic disease
Systemic generalized primaryamyloidosis
Immunocyte dyscrasiasSystemicAL typePlasma cell dyscrasiasMultiple myelomaMonoclonal gammopathyAbnormal protein
Systemic generalized secondaryamyloidosis
Underlyig chronic disease---AA typeReactiveTbc, Ulcerative colitis,Chr. OMBronchiectasisRA, AS, İnflammatory bowel diseaseHodgkin diseaseRenal cell carcinoma
Hereditary familial systemicamyloidosis
Familial, rareGeographic limitationFMF---AA proteinsReccurent bouts of inflammationFamilial amyloiditic polyneuropathyMutant transthyretin
Localized amyloidosis
Single organ, tissueNodular massesTumor forming amyloid accumulationLung, larynx, skin, urinary bladder, tongue, eyeAL typePeripheral plasmacytes
Endocrine amyloid
Microscopic deposits of localized amyloidEndocrine tumorsMedullary carcinoma of thyroidIslet cell tumor of pancreasPheochromocytomaUnique proteinsPolypeptide hormones
Hemodialysis associatedamyloidosis
Longterm hemodialysis for renal failureDeposition of beta2 microglobulineCan not be filtered through dialysismembranesAmyloid deposition in the synovium,joints, tendon sheath60-80% of patients
Senile amyloidosis---Amyloid of aging
Elderly patients ( 70-80)Dominant involvement in the heartDysfunctionSenile cardiac amyloidosisRestrictive cardiomyopathyArrhythmiasNormal or mutant form of transthyretinSystemic—lungs, pancreas, spleen
Pathogenesis
Stimulus----soluble precursor---Insoluble fibersUnknown ( Carcinogen?)---Monoclonal B cellproliferation---plasma cells---Ig Light chain---limited proteolysis---P component---AL amyloidChronic inflammation---Macrophage activation---IL1,6 secretion---Liver cells---SAA---Limitedproteolysis---P component--- AA amyloidGenetically determined alteration---abnormalTTR---ATTR amyloid
Organ findings in amyloidosis
No distinct or consistent pattern of distributionSecondary form tend to be severe systemic involvement---kidneys, liver, spleen, lymph nodes, adrenal glands, thyroidImmunocyte associated---heart,kidney,gastrointestinal tract, peripheral nerves,skin, tongue
Macroscopic apperarance
Enlarged, firmWaxy appearanceSufficiently large deposit---iodinepainting of cut surface---yellow colorturns to blue violet—after application of sulfuric acid
Microscopy
Staining with specific dyesCongo redCresyl violetElectron microscopic confirmationPolarized microscopySpecific immunohistochemistry forsubtypes AA, AL, ATTR
Kidney amyloidosis
Most commonMost seriousRenal amyloidosis is the major cause of deathNormal in size and color or enlargedIn advanced case shrunken/contracted---vascular narrowing---due to depositionof amyloid in arteriolar wall
Kidney amyloidosis microscopy
Glomerular accumulation/ Mesangial matrixInterstitial peritubular tissueArteries, arteriolesWidening of glomreular capillaries basalmembraneDistortion of vascular tuftGlomeruli turn into confluent masses of amyloid
Amyloidosis of the spleen
Splenomegaly moderate to markedTwo patterns of depositionDeposition limited to splenic follicles—white pulp---tapioca like granules---SAGO spleenAmyloid depoistion in sinusoidal walls andconnective tissue framework---red pulp---maplike---LARDECEOUS spleen
Amyloidosis of liver
Moderate to marked hepatomegalyAmyloid deposition in Disse spaceProgressive pressure atrophy of adjacenthepatocyteTotal replacement of liver parenchymaVascular involvement, Kupffer celldepositionNormal liver function is usually preserved
Amyloidosis of heart
Enlarged, firmNo significant macroscopic changeFocal subendocardial accumulationBetween muscle fibersConduction system may be damagedPressure atrophy of fibersIntractable heart failure
Amyloidosis of other organs
Adrenals, pitutary glands, thyroidAdrenals first site is zona glomerulosaReplacement of parenchymaGIS---early lesions blood vessel walls—BxdiagNodular deposition in the tongueRespiratory tractAlzheimer---brain
Clinical correlation
No clinical findingsIt may cause deathMagnitude of depositsParticular organ or sites affectedNonspesific general symptomsWeight loss, weakness,syncope
Clinical findings of amyloidosis
Renal involvement---proteinuriaNephrotic syndromeRenal failure---uremiaCardiac amyloidosis---insidious congestiveheart failureConduction disturbancesGastrointestinal amyloidosis---asymptomatic---malabsorption, diarrhea
Prognosis
Generalized amyloidosis poor prognosisImmunocyte derived form---2 yearsmedian survivalMyeloma associate ones---poorerprognosisDepends on the control of underlyingcause
Pathologic calcification
Abnormal deposition of calcium saltsTogether with small amounts of othermineral saltsCa phosphateCa carbonateOther salts
Calcification
Dystrophic calcificationNonviable/dying tissueMetastatic calcificationVital tissues
Dystrophic calcification
Areas of necrosisCoagulative, liquefactive typeEnzymatic fat necrosisWhenever the necrotic tissue persist forlong period of time
Dystrophic calcification
Not dependent on an increase in thecalcium content of the bloodInfluenced by local relative alkalinity of the damaged tissueAbnormal amount of phosphateaccumulating in necrotic tissue may favorthe deposition of Ca salts
Dystrophic calcification
Atheroma plaques in advancedatherosclerosisAging or damaged heart valvesCalcific aortic stenosisDead fetus intrauterinLithopedion
Macroscopy
Fine, white granulesClumpsGritty depositsStone like appearance in lymph nodes ( Tbc)In fat necrosis---Ca and released fattyacids---SOAPS
Microscopy
Hematoxylen/eosin stains---basophilic, amorphous, granular, clumpedIntracellularExtracellularBoth locationIn the course of time---heterotopic bone formation in the focus of calcification
Single necrotic cell
Progressive acquesition of outer layers bymineral depositsLamellated configurationPsammoma bodiesResemblance to grains od sand---Psammom=sand---Greek word
Psammoma bodies
Papillary carcinoma of thyroidPapillary carcinoma of ovaryMeningiomaIn asbestosis---calcium iron salts---longslender spicules---exotic dumbbell forms
Pathogenesis
Formation of crystalline calcium phosphatemineral---apatite form ( resemblinghydroxyapatite of bone)InitiationPropagationIntracellular calcification---in the mitochondriaof dead or dying cellExtracellular calcification---phospholipids in membrane bound vesicles
Metastatic calcification
Calcification in previously undamagedtissueInterstitial tissue of blood vesselsKidneysLungsGastric mucosaMorphology is similar with dystrophiccalcification
Hypercalcemia
HyperparathyroidismVit D intoxicationSystemic sarcoidosisMilk-alkali syndromeHyperthyroidismIdiopathic hypercalcemia of infancyAddison’s disaeseIncreased bone catabolism
No clinical dysfunctionMassive involvement of lungs---X-ray changes-respiratory difficultiesIn the kidney---nephrocalcinosis---in time---renal damage
Increased bone catabolism
Disseminated bone tumorsMultiple myelomaMetastatic cancer leukemia
Pathologic ossification
Preceeded by calcificationTransformed fibroblasts---osteoblastsHeterotopic bone formationBone marrowReactive, metaplasticMyozitis ossificans---localized aftertrauma to a muscle
Stones or calculi
In urinary tract---by precipitation of chemicalsalts in urineInfectionStasisIncreased urinary concentration of crystalloidsChanges of a physical and chemical nature of urine or urinary tract that favor theprecipitation
Types of urinary tract stones
White stones---mixtures of uric acid, Caoxalate and phosphatesCertain constituents predominateUric acid and cystine---precipitate in an acid urinePhosphate---associated with alkaline urinesOxalate stones---any pH
Renal calculi
Obstruction of outflow of urineStasis---Promote infectionPyelonephritisRenal colic painDilatation of ureter or renal pelvisHydroneprosis
Gall stones
Normal constituents of bileCholesterolCalcium biluribinateCalcium carbonateMain substances
Pure gallstones
Excess of the stone forming substance in bileDisturbance of liver function ormetabolismCholesterol stone mostlyPigment stones ( Ca biluribinate)
Mixed gallstones
Most common form ( 80%)Exact mechanism of their formation is uncertainMultipleHuge numbers
Combined gall stones
Solitary stoneCholesterol nucleusOuter shell similar to a mixed gallstone
References and further reading
Robbins Pathologic Basis of Disease, Cotran, Kumar 2004Pathology Illustrated, Macfarlane, Reid,Callande 2000Sandritters Color Atlas and Textbook of Macropathology, Thomas, Kirstn, 1984Basic Pathology, 6th ed, Kumar, Kotran, RobbinsPathology Rubin, Farber, 1999Mohan Harsh Textbook of Pathology, 2005Cerrahpaşa Pathology archievesInternet (various medical web sites)
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