03 Intracellular Accumulations

8/12/2019 03 Intracellular Accumulations

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General Pathology(PATH 303)

Lecture # 6

INTRACELLULAR ACCUMULATIONS


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Steatosis (fatty change, lipidosis); it is abnormalaccumulation of neutral fats (triglycerides)

within parenchymal cells. More severe than hydropic

degeneration. Most common in liver, heart, kidney, and skeletal

muscles.


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Causes:

1. hypoxia (Anoxic anoxia)

2. Hepatoxins-bacterial, plant chemical poisons.

3. Metabolic diseases e.g. diabetes, ketosis

4. Deficiency of lipotropic substances e.g. choline.

5. Miscellaneous starvation, obesity.


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Pathogenesis:

Several mechanisms e.g.

Excessive mobilization of fat and entry into the cell.

Decreased fatty acid oxidation as in hypoxia. Decreased synthesis of apoprotiens.

Impaired lipoprotien secretion from liver


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Microscopic appearance:

Early, mild condition- small membrane boundinclusions (liposomes) near ER.

Appear as clear vacuoles which fuse & become largeand displace the nucleus towards periphery.

Special stains Oil red-O and Sudan IV


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Significance:

Reversible change

If injury persist, may cause death of cell

Obesity:excessive accumulation of adipose tissue inthe fat depots. Excessive intake of fat andCarbohydrates.May cause sterility, diabetes andatherosclerosis


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Glycogen:

Abnormal accumulation occurs in liver, musclesand kidney in case of:

1. Diabetes mellitus ( hyperglycemia)2. Corticosteroid therapy

3. Hereditary glycogen storage diseases.

4. Neutrophil leukocytes in inflammatory

conditions.5. Certain neoplasms


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Gross and microscopic appearance:

Affected organ becomes enlarged and pale.

Glycogen appears as clear vacuoles in smooth

endoplasmic reticulum. Special stain - iodine gives reddish brown color

and Bests carmine stains it red.

Tissues should be fixed in absolute alcohol.


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Protein inclusions: Protein inclusions or inclusion bodies have different size,

shape, staining reaction and location in the cell. Identification of inclusions used in diagnosis of several

diseases. Location: may be intracytoplasmic or intranuclear or

both. Shape;may be spherical, globular or homogenous. Staining affinity:may be eosinophilic or basophilic.

Mechanism of inclusion formation:viral infection,toxic injury, absorption of external proteins and secretorystasis.


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Absorption inclusions:

Seen in renal epithelial cells in albumen- uria--endocytic uptake- seen in proximal convoluted

tubules. Protein sequestered in phagolysosomes. Appear as hyaline droplets


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Secretory inclusion:

Secretory synthesis exceeds the capacity forexcretion from the cell.

Commonly seen in liver- composed of albumen andfibrinogen.

Plasma cells develop cytoplasmic condensed globularinclusions.


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Pigment disorders:

Pigments are colored substances, synthesized withinthe body (endogenous) or coming from outside

(exogenous). Endogenous pigments:include melanin,

lipofuscin and derivatives of hemoglobin


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Melanin:A brownish black pigment formed by oxidation oftyrosine to dihydroxyphenylalanine by enzyme tyrosinase

Melanocytes , the cells which produce melanin are ofneuroectodermal origin, present in the basal layer of epidermis.

Black, brown, red color of skin due to amount and distribution of

melanin. Protects against UV rays in sunlight. Microscopic appearance:melanin granules are small, uniform,

dirty brown, round granules.

Foci of melanocytes may be located in intestine, heart, kidney etc

called melanosis usually harmless.


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Hormonal disturbances may causehyperpigmentation acanthosis nigricans observed in dogs due to lesions in adrenal.

Pathological amounts associated with tumors ofmelanocytes, melanomas and melanocarcinomascommon in gray horses.

Nevus is a small accumulation of melanocytes in

the skin.


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Albinism: absence of melanin. Such individualshave melanocytes but are unable to synthesizemelanin due to lack of tyrosinase. These patients are

vulnerable to cancer.

Leukoderma is local loss of pigment observed inareas with rubbing injuries from collar, saddle,harness etc.


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Lipofuscin :it an insoluble brownish yellowpigment also called lipochrome, wear and tearpigment or ageing pigment.

It contains complexes of lipid and protein derivedfrom peroxidation of lipids by free radicals.

It represents indigestible residues of autophagicvacuoles . It gives brown discolorations to tissuesbut is not injurious to the cell.


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Derivatives of hemoglobin: Destruction of old ( senescent) erythrocytes occurs

within mononuclear phagocytic cells of spleen,liver and bone marrow and Hb is released.

Break down of Hb gives rise to globin (protein) andpigment complex heme.

Globin is soluble and is removed by blood andlymph.

Oxidation of heme by heme oxygenase gives rise tobiliverdin, carbon monoxide and iron.


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Body iron occurs in two forms functional (80%)in Hb, myoglobin and iron containing enzymescatalase and cytochrome.The storage pool includes

15-20% of total body iron in the form of ferritinand hemosiderin.

Ferritin:it is a protein iron complex found inliver, spleen, bone marrow and skeletal muscles.

When there is excess of iron , ferritin formshemosiderin.


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A. hemosiderin :it is a golden- yellow, granular pigmentwhich is a storage form of iron. Occurs in localized orsystemic accumulations.

1. localized haemosiderosis :This occurs in local injuries,

haemorrhages, bruises, hematomas etc. Grossly the bruise goes through different changes

indicating formation of different pigments as below:

1-Red blue Hb 2. Greenish blue ( biliverdin green ) 3.Pinkish blue ( bile pigment ) and 4. Golden yellow

hemosiderin, observed in scars.


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Systemic hemosiderosis: In this casehemosiderin is deposited in many organs andtissues, especially in the liver, spleen, lymph node,

bone marrow etc.

It is caused by increased dietary iron, impairedutilization, hemolytic anemia and transfusion


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Gross appearance of hemosiderin: Hemosiderin appear as golden yellow, granular

pigment in the cytoplasm of macrophages. It is seen in renal epithelial cells in intravascular

hemolysis in equine infectious anemia. In the lungs hemosiderin occurs in chronic passive

congestion. RBCs released in the lung alveoli are engulfed by

alveolar macrophages.


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Hemosiderin laden macrophages are known asheart failure cellsand the condition is cell browninduration of lung.

Prussian blue reaction is used for identification ofhaemosiderin. Potassium Ferrocyanidereacts withferric iron and converts it into insoluble blue blackferric ferrocyanide.


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B. Bilirubin :

Bilirubin is the major pigment of bile.

Accumulation of bilirubin in blood (hyperbilirubinemia) causesits deposition in the tissues and the clinical condition is

called jaundice.


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Formation of bilirubin: There are different types of bilirubin and its formation goes through

following stages 1. Hemobilirubin formation 2. Transport to blood. 3. Uptake and

intracellular transport 4. Glucuronidation 5. Secretion into the bilecanaliculi.

Oxidation of heme by heme oxygenase produces biliverdin (greenpigment) CO and iron. Iron is sequestered in ferritin and hemosiderin.

Biliverdin is reduced by biliverdin reductase into yellow pigmentbilirubin inside the macrophages.

Bilirubin is bound with albumen and transported to blood where itcirculates as hemobilirubin or unconjugated bilirubin. It is insoluble inwater and does not pass through the renal filter.


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Hemobilirubin is taken up by the hepatocytes and transported to ERwhere it is conjugated to glucuronide as conjugated bilirubin.

Conjugated bilirubin ( bilirubin diglucuronide ) is soluble in water andis not toxic, excreted into canaliculi.

Conjugated bilirubin reaches intestine where glucuronide is separatedand bilirubin is converted into urobilinogen by bacteria.

Most of urobilinogen is excreted into feces and about 20% isreabsorbed and returned to liver for re-excretion into bile.

A small amount reaches kidneys and is excreted into urine.


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IT IS THE INCREASE OF BILIRUBIN

IN THE BLOOD AND ITS DEPOSITIONIN THE TISSUES LIKE SKIN ANDSCLERA GIVING THEM YELLOW

DISCLOURATION. ACCORDING TOTHE TYPE OF BILIRUBIN AND ITSDISTRIBUTION JAUNDICE MAY BEHEMOLYTIC (PREHEPATIC), TOXIC(INTRAHEPATIC) OR OBSTRUCTIVE

(POSTHEPATIC) TYPES

Jaundice


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1-hemolytic(prehepatic jaundice)

More than 80% serum bilirubin is unconjugated(hemolytic bilirubin). There are three mechanisms

A. overproduction of hemobilirubin due to intravascularhemolysis as in

1. protozoan diseases e.g. babesiosis, anaplasmosis,trypnosomosis,etc

2. Viral infections like equine infectious anemia

3. Bacterial infections due to Clostridium hemolyticumandleptospirosis

4. Isoimmune hemolytic anemia in newborn foals andpiglets.


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B- Reduced hepatic uptake of bilirubin

This has been observed in humnan afteradministration of certain drugs like rifampin, anantitubercular drug


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C-impaired conjugation of bilirubin

Due to the aquired or hereditary deficiency ofgllucuronosyl transferase(GT)

Activity of GT is low at birth and normal levels are

attained at about 2 weeks. Therefore every newborn develops a mild,transient

jaundice called neonatal or physiological jaundice


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2-Toxic or intrahepatic jaundice

Injury to hepatiytes and bile canalculi by infectiousand non infectious agents eg.

Bacteria (salmonella) ---------(infectious caninehepatitis), plant and chemical toxins egphosphorus, CCl4

Both conjugated and unonjugated bilirubinaccumulate in the blood

Swelling and disorganization of hepatocytes maycompress and block canalculi


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3- Obstructive (post hepatic) jaundice

There is obstruction to the excretion of conjugatedbilirubinin the extrahepatic bile dut system (cholestasis)

Obstruction may be caused by

1. Parasites eg cattle and sheep- fasciola hepatica and F.

giganticaPigs- Ascaris lumbricoides

Sheep- tapeworms

2. Gallstones

3.Inflammation of bile duct-cholangitis4.tumours


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Obstructive (post hepatic) jaundice

In case of complete obstruction bile disappearsfrom feces

The feces are of grey colour like wet cement buturine is normal in colour

Bile is necessary for absorption of fats fromintestine Malabsorption of vitamin K predisposes the

animals to haemorrhage

Accumulation of bile pigments in the skin causesitching(pruritis)


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Icterus index

Test for diagnosis of icterus bycomparison of colourof plasma or serum with a standard solution ofpotassium dichromate

For accuracy, standard should be prepared for eachspecies and breed of animals


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Van den Bergh reaction

Ehrlich reagent (diazotized sulphanilic acid) is mixed withplasma or serum

The developing coloured compound (azobilirubin)determines the type of bilirubin involved

Three interpretations are Direct reaction: pink or purple colourdevelops immediately

and reaches maximum density with 1-2 minutes Indirect or delayed reaction: no colour change in first two

minutes. A golden colourdevelops within 10minutes.indicates uncojugated bilirubin i.e. hemolytic

jaundice Biphasic reaction: abrownish redcolour indicates both


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Comparison of three types of jaundice


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Ceroid

It is acid fast, autoflourescent pigment consisting ofpartially oxidized and polymerized unsaturated fattyacids. It is an early form of lipofuscin

Ceroid is associated with Vit. E deficiency. It doesnot stain for iron.


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A. Hepatic ceroidosis

Found in salmon and catfish fed rancid diets.

Hepatocytes contain acid fast, autoflourescentpigment and liver has brown- orange discoloration.


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B. Ceroid- lipofuscinosis disease

There are a group of diseases in sheep, cattle, goatand dogs characterized by accumulation offluorescent lipopigments in neuron and other cells


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Exogenous pigments

Most of these are dust particles in the inhaled air,deposited in the lungs and associated lymph nodes.

The dust particles act as mild irritants and induce

proliferation of fibrous connective tissue( FCT)-(fibrosis) and collection of macrophages.


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The condition is called pneumoconiosis oroccupational hazards

Particles between 1-5 micrometer diameter are

most dangerous Pathogenicity depends upon size, solubility,

cytotoxicity and the amount in the inhaled air

Phagocytosis of dust particles by alveolarmacrophages provides protection


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1- Anthracosis

It is deposition of carbon or coal dust in the lungs inhorses and mules used in coal mines and dogs livingin the smoky areas. Tattooing is a localizedanthracosis

Carbon dust is mildly irritating and causes a slightfibrosis.

It is insoluble and persists in the tissues for life


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2- Silicosis

It is perhaps most prevalent chronic occupationaldisease associated with silicon industries like glassetc

It is a slowly progressive, nodular, fibrosingpneumoconiosis

Silica is a powerful irritant and causes extremefibrosis, predisposing to diseases like tuberculosis


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3-Asbestosis

The condition is associated with asbestos industriesand it is one of the most dangerous pneumoconioses

Asbestos particles cause severe irritation and fibrosis

Asbestos is carcinogenic


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4-Plumbism

It is pigmentation in the tissues resulting from thepresence of lead and hydrogen sulphide.

Lead poisoning may occur from licking of paints orfrom water in lead pipes

Microscopically lead is deposited in the tissues incombination with hydrogen sulphide as a blackpigment


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Continued..

Skin lesions are restricted to hairless and non-pigmented or lightly pigmented areas like teats,udder, ears, eyelids in cows and ears, eyelids, lipsand coronets in sheep


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classification

Photosensitization is classified into three typesaccording to the origin and mechanism ofphotodynamic agent

1. Primary photosensitization

Due to the ingestion of pre-formed photodynamicagents in different plants (fagopyrine) andcertain drugs like phenothiazine, tetracycline,sulphonamide etc. The agent is deposited in thetissues following absorption in the blood. When

such animals are exposed to sunlight,photosensitization occurs.

- ue o a norma porp yr n


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ue o a norma porp yr nmetabolism

Congenital porphyria is a hereditary metabolicdisorder in cattle and cats with excessiveproduction of two porphyrins (derivatives ofhemoglobin):

1-Uroporphyrin and2-Coproporphyrin

Uroporphyrin is deposited in the bones and teethcausing discoloration (pink tooth)

- epa ogenous epa o ox c


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epa ogenous epa o ox cphotosensitization

This occurs in liver diseases in which injuredhepatocytes fail to excrete phylloerythrin.

Phylloerythrin is normal end product of chlorophyllmetabolism and is photodynamic.

This condition is more common in the animalsgrazing on green pastures

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03 Intracellular Accumulations