Prof.Dr. Sergülen Dervişoğlu

Intracellularaccumulation

Intracellular accumulation

A normal constituent accumulated in excessWater, Lipid, ProteinAn abnormal substance---exogenous ( Mineral, products of infectious agent )Endogenous---products of abnormalmetabolism ( Pigments )

Intracellular accumulation

Overload---under systemic control---reversible accumulationGenetic disorder---genetic storagediseaseUncorrectable metabolic errorProgressive accumulationDeath of the tissue----patient

Complex lipids and carbohydrates

Inborn error of metabolismAbnormal complexes of CH and lipidsaccumulateRES systemMucopolysaccharidoses ( Gaucher’s andTay Sachs, Niemann-Pick diseases )Splenomegaly, hepatomegaly

Fatty change---steatosis

Disturbance of fat metabolismProceeded by cellular swelling or hydropicdegenerationGenerally reversibleWhen severe---death of cell—necrosisParaffin sections---dissolves out---largeclear vacuolesLiver,kidney,heart

Fat metabolism in liver

Excess accumulation of triglyceridesExsessive entry of free fatty acidsEnhanced fatty acid synthesisDecreased fatty acid oxidationIncreased esterification fatty acids totriglycerides alcohol poisoningDecreased apoprotein synthesisCCl4,phosphorus,protein malnutritionImpaired lipoprotein secretion from the liver

Alcohol most common hepatotoxin

Alters mitochondrial functionIncreases free fatty acid synthesisDiminishes trigly. UtilizationDecreases fatty acid oxidationBlocks lipoprotein excretionEnhances lipolysisIncreases delivery and uptake of freefatty acids

Fatty liver --- other causes

Protein malnutritionCertain chronic ilnessesDiabetes mellitusObesityHepatotoxinsToxins of infectious diseasesAcute fatty liver of pregnancy ( Rare, unknown cause)

Fatty liver macroscopy

EnlargedYellow in colorSoft in consistencyMargins are roundedThe cut surface is greasy and bulges fromthe section

Fatty liver microscopyVacuoles in the cytoplasm of the hepatocytesTiny and numerous

LargeReplacing the nucleus

Fatty liver/fatty change

Fat globules in hepatocytes

Fatty kidney

Normal in size Slightly enlargedCut surface is pale and yellowishSoftFriable

Fat accumulation in heart

Patchy or diffusePatchy involvement in severe anemiasSubendocardial region of ventriculesIrregular yellow streaks or lines, alternating withnormal myocardiumTIGROID OR TABBY CATDiffuse involvement---severe infarction or toxicstate, entire myocardium is pale and soft

Adiposity

Fatty ingrowthGeneralized obesityAbnormal accumulation of adipose tissueAdult fat cellsBetween parenchymal cells of an organWithin stromal cells—connective tissue

Cholesterol and esters

Intracellular vacuolesAtherosclerosis --- atheroma plaquesMacrophages in intimaFoamy appearance—foam cellsMacroscopic yellow discolorationExtracellular cholesterol esters distinctivecleftsForeign body reaction

Atheroma plaque

Xanthomas

Intracellular cholesterol accumulationAcquired/hereditary hyperlipidemic statesClusters of foam cellsSubepithelial connective tissueSkin, tendonTumor like masses---Xanthomas

Eruptive xanthoma

Inflammation and necrosis

Foamy macrophagesAt sites of cell injury and inflammationCholesterol from membranes of injuredcellsPhagocytosisCholesterol-laden macrophagesYellow discoloration of inflammation site

Foam cells next to liquefaction necrosis in brain

Cholesterolosis

Gall bladderLamina propria,Foam cell accumulationIn macrophages—foam cellsMechanism of accumulation is unknown

Proteins

Excess of proteinsRounded, eosinophilic dropletsVacuoles, aggregates in the cytoplasmBeyond cellular capacity to rapidmetabolization

Proteins

Reabsorption droplets in proximal renaltubulesProteinuriaReabsorption by pinocytosisProximal tubuleHeavy protein leakageIncreased reabsorption

Proteins

Excessive amount of synthesisNormal secretory proteinPlasma cellsActive synthesis of immunoglobulinsER distanded, large, homogenousEosinophilic bodiesRUSSEL bodies

Pigments

Colored substanceNormal constituents of cellsAbnormal accumulation under abnormalcircumstancesExogenous/endogenous

Exogenous pigments

Carbon---coal dustPollutant urban lifeInhalationPicked up in the alveoli by macrophagesLymphatic drainageRegional lymph nodesBlacken the tissue ( Anthracosis)

Exogenous pigments

Entrance by inspirationIngestionInoculation into the skinArgyria---silver poisoningPlumbism---lead poisoningCarotenemia---plant pigments

Heavy exposuresCoal miners, heavy pollutionInduce fibroblastic reactionEmphysemaCoal workers pneumoconiosis

Other exogenous pigments

TatooingLocalized pigmentation in skinFor decorative purposesDermal macrophagesUsually no inflammatory reactionPlumbismArgyria

Endogenous pigments

Lipofuscinİnsoluble pigmentLipochromeWear and tear pigmentAging pigmentBrown in colorDerives from lipid peroxidation

Lipofuscin

Not injurious to cellNo dysfunctionSign of free radical injuryFuscus=brownFinely granular, yellow/brownPerinuclearSlow regressive changes=BROWN ATROPHY

Lipofuscin

Liver and heart of aging peopleSevere malnutritionCancer cachexiaElectron dense perinuclear accumulationIndigestible residue of autophagic vacuoles

Lipofuscin/liver

Melanin

Derived from greek term=Melas=blackEndogenousNon-hemoglobin derivedBrown/black pigmentOnly endogenous brown-black pigmentOther is alcaptonuria=homogentisic acid--ochronosis

Melanin

Exposure to sunlightAmount of melanin increasesPrecursor of the pigment is tyrosineAlbinism---lack of tyrosinase enzymeMSH ( melanocyte stimulating hormone)Increased pigmentation in Addison’sdisease and pregnancy

Hemosiderin

Hemoglobin derivedGolden yellow/brownGranular-crystalline pigmentIron storageNormally iron is carried by transferritinIn cells it is distored as apoferritinLocal or systemic excess of Fe ferritinforms hemosiderin granules

Hemosiderin

Pigment represents aggregates of ferritinmicellesNormally small amounts in mononuclearphagocytes of RESActive red cell breakdown sites

Excess hemosiderin

Local excess---Gross hemorrhageCommon bruiseSevere vascular congestion—minutehemorrhages

Common bruise

Local hemorrhageRed/blueLysis of erythrocytesHb undergoes to transformation tohemosiderinRed cell debris phagocyte engulfingLysosomal enzymes---hemosiderinGreen/blue biliverdin

Systemic overload of iron

HemosiderosisIncreased absorption of dietary ironImpaired use of ironHemolytic anemiasRepeated transfusions exogenous redcell/iron load

Heart failure cells/alveolar macrophages

Hemosiderosis

Coarse, granular pigmentPigmentation RES cellsRed cell breakdownLiver,bone marrow,spleen,lymph nodesProgressive accumulation---parenchymalcells pigmentedPrussian blue reaction

Renal hemosiderosis prussian blue RX

Hemochromatosis

Systemic hemosiderosis—no harm to functionHemochromatosis—extreme accumulation in parenchymal cellsImpaired functionLiver, pancreas damageFibrosis,Diabetes mellitus,bronz diabetesExcessive absorption from normal diet-idiopatic

Hemochromatosis/liver

Biluribine

Normal major pigment of bileBreakdown of hemoglobin---RESContains no ironNormal formation and excretion is vital tohealthJaundice is clinical disease in excess

Bile production

Biluribine formationTransport in the bloodUptake and intracellular transportGlucuronidationExcretion into the canaliculusConjugation is important step to makenontoxic form

Unconjugated biluribine

Toxic to tissuesNot soluble in the aqueous solutionTightly complexed to albumineIt cannot be excreted in the urine

Conjugated biluribine

Water-solubleNon-toxicLoosely bound to albumineExcreted in the urine ( Biluribinuria)

Jaundice/Icterus

Yellow pigmentation of the skin and skleraHyperbiluribinemiaSerum level exceeds 2mg/ltClinically evident after this pointHemolyticHepatocellularCholestatic

Liver cholestasis/bile plugs in the bile canaliculi

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)