Cell injury

Pathology : is the science that deal with the study of disease & its effect on the body . It has many branches include :
1- Histopathology & Cytology : which study the structural changes of the tissue by necked eye inspection ,light & even electron microscope .
2- Biochemistry : study the abnormalities of body fluid especially the blood .
3- Hematology : study the abnormalities of blood cells & clotting mechanism .
4- Microbiology : Study the Microorganism (m.o) responsible for diseases such as bacteria , virus , fungus , & protozoa .
5- Immunology : study the abnormalities in the immune mechanism which is responsible for defense mechanism .

Biopsy:

is a piece of tissue taken from living body during live . it is of many types ;
* Incisonal biopsy in which part of the lesion is removed .
* Exisonal biopsy in which the whole lesion is removed .
* Fine needle aspirate : in which few cells from the lesion is removed .

Autopsy : A peice of tissue taken from a living body after death .

Pathology include the gross & microscopic appearance .

Pathogenesis : The sequence of event in the disease development from the onset till termination including any influencing agent .


Causes of diseases :
1-Genetically determine : due to abnormalities in the base sequence of the DNA & this abnormalities is either inherited from parent or occur by mutation .
2- Acquired : include :
a- nutrional abnormality : either due to deficiency as in malabsorption , anaemia or due to excess diet as in obesity .
b- Chemical agent as poison drugs & air pollution .
c- Physical agents : trauma , extreme of temperature ,radiation , & electric shock .
d- Infectious agent : virus ,bacteria , fungi .
e- Immunological causes : Autoimmune diseases
f-Psychological : anxiety & stress can cause disease but the mechanism is unknown .
g-Iatrogenic: due to medical or surgical intervention it may be predictable or unpredictable
H- Idiopathic.

Cell injury

Normally the cell preserve their immediate environment to maintain normal homeostasis .
If the cell encounter physiological stress or pathological stimuli then it can undergo adaptation by which the cell achieve a new steady state to preserve the viability .
Adaptation include atrophy, hypertrophy, hyperplasia and metaplasia.

1-hyperplasia:- increase in size of organ due to increase in no. of cell usually associated with hypertrophy.could be physiological or pathological.

Physiological ( hormonal as in breast enlarge during pregnancy

( compensatory: hyperplasia of the cell when part of the tissue is removed e.g. when part of the liver is resected.


pathological due to excess hormone or growth factor stimulation
e.g. endometrial hyperplasia after menstrual cycle.

2-hypertrophy:- increase in size of organ due to increase in size of cell.

* physiological : due to functional demand or due to hormone stimuli.
e.g. as enlargement of uterus during pregnancy and enlargement of skeletal muscle in lifter.
* Pathological as in the wall of intestine proximal to site of obstruction .

3-Atrophy:- which decrease in the size of cell lead to diminish in the size of organ.

*physiological : atrophy of thymus after puberty
*nutritional generalize atrophy at starvation
*disuse paralyzed limb
*neuropathic: in nerve cutting
*pressure atrophy: in benign tumor
*endocrine: damage to pituitary gland cause reduction in trophic hormone ( atrophy of thyroid or adrenal gland.

4-metaplasia:- reversible change in which one adult type of tissue is replace by other adult type of tissue , it could epithelial or mesenchymal.

Epithelial metaplasia in the bronchus in which the columnar cell is replaced by squamous cell , usually occur due to chronic irritation of bronchus by smoking .
Although the viability of the cell is maintain but it loss its specialized protective function & in long standing ( neoplasia
mesenchymal metaplasia is rare. e.g bone may form at site of injury


If the adaptation capacity is exceeded or if the cell cannot undergo adaptation the cell injury will occur &up to certain limit these changes are reversible and then cell can return to normal if the causative agent is remove however if the stress is severe or persistent this lead to irreversible cell injury & cell death which is of tow type:
1-necrosis 2- apoptosis

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Principles related to cell injury:
*-Cellular response to injurious stimuli depend on type of injury , its duration & its severity .
*- Consequences of an injurious depend on type , status & genetic make up of the cell.
*- Four intracellular systems are vulnerable to injury include : ATP , Protein synthesis , integrity of genetic apparatus & cell membrane.
*- Structural & biochemical component of the cell are closely connected regardless of initial locus of injury, multiple secondary effects occur later
* cellular function is lost before cell death & morphological changes of cell injury i.e cellular dysfunction occur before them.

causes of cell injury

hypoxia: is the main cause of the cell injury & either due to ischemia that is say reduction of blood supply or due to poor oxygenation of blood as pneumonia or decrease in oxygen carrying capacity of blood as in anemia.
Any chemical agent even if innocuous substance as glucose can cause disease if it is concentrated. Other chemical agent such as (poison, air pollutant and drug)
Physical agent such as trauma, extreme of temp radiation and electric shock.
Infectious agent such as virus, bacteria, fungi and protozoa.
Immunology mechanism: it is a defense mechanism in the body, it may harmful as in auto immune disease.
6-Aging .
7-Genetic ,


Mechanism of cell injury
ATP depletion: ATP is necessary for all process in the cell so decrease in it can lead to rapid shut down of all homeostatic process.
2-O2 deprivation and generation of active O2 species (free radical) can cause cell injury .free radical is any chemical substance with single electron in the outer orbit such as super oxide O2, H2O2 , OH , No , these substance are unstable so it react with any organic or inorganic substances to be stable .

Free radicals generated within the cell by:

1-Reduction oxidation reaction occur during respiration .
2-Nitric oxide can form in different cells.
3-Radiation ( x-ray & UV light ) can hydrolyze water into hydroxyl group & hydrogen free radical .
4- enzymatic metabolism of certain exogenous substance e.g carbon tetrachloride

Free radical cause cell injury by:

( DNA fragmentation which lead to cell death & neoplasia
( Peroxidation of lipid membrane
( cross link of protein which enhance Loss of enzyme activity or Cause fragmentation of protein.

The body can defense itself against free radical by either:

*anti oxidant ( enzyme-s aSOD(super oxide dismutase)-catalase & glutathion peroxidase zymes
*scavenger (Vitamin A;C;E 7 B carotene) .

loss Calcium ion homeostasis

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Injury (ischemia or toxin) stimulate the influx of Ca+2 inside the cell which stimulate the release of Ca+2 from intracellular store which cause increase in cytosolic calcium which affect many enzyme as mentioned in the figure above .

4-defect in plasma membrane : Plasma membrane may be damaged directly by certain bacterial toxin ,viral protein , complement , ATP depletion & by calcium activation of phospholipase .
Defect of plasma membrane barrier lead to break down of the concentration gradient of metabolite necessary for normal metabolic activity .

5-Mitochondria damage : Increase in cytosolic calcium ,oxidative stress & lipid breakdown ,all lead to the formation of high conductive channel in the inner mitochondrial membrane ,this pore allow the proton (H) ion to dissipate & prevent ATP generation ,In addition cytochrome also leak lead to apoptosis .

Reversible cell injury :

It is a common type of cell injury usually due to ischemia which lead to hypoxia & reduction in oxidation phosphorelation lead to reduction in ATP , this reduction cause :
Decrease in sodium pump ,so it will accumulate inside the cell , this stimulate influx of water & calcium lead to cellular swelling .
It stimulate anaerobic glycolysis lead to reduction in glycogen with lactic acid accumulation causing reduction in PH which cause chromatin clumping .
Detachment of the ribosome & conversion of polysome into monosome ,this cause reduction in protein synthesis .

If hypoxia is stopped i.e re-oxygenation of tissue take place the cell will return to normal but if hypoxia continue then irreversible cell injury take place ending into cell death .

Morphology of reversible cell injury:

It is of two types :
* Cellular swelling : It is the first manifestation seen in all form of cell injury & it is happen when the cell fail to maintain water & ion homeostasis . it is difficult to be shown by light microscope & it is more apparent when the whole organ is involved in that case the organ become pale & increase in weight .
Microscopically : At the beginning the cytoplasm show many vacuoles & this is called (vacuolar changes) , if the vacuoles combine with each other the cell appear as balloon & in that case the condition is called (hydropic changes )

* Fatty changes : It is less universal & seen only in cell participate in lipid metabolism It is abnormal deposition of triglyceride in paranchymal cells as liver ,kidney .Although fatty changes is an indicator for reversible cell injury however it may be seen adjacent to area of necrosis .

Causes :

toxin as alcohol .
hypoxia .
protein malnutrition .
diabetes mellitus .
obesity

Normally fatty acid derived to the liver from two sources mainly ,the G.I.T the adipose tissue & small amount is formed in the liver from acetate . The majority of fatty acid by the action of alpha glycerol phosphate is converted into triglyceride & small amount of fatty acid is converted into phospholipids & keton . Then triglyceride join apoprotein forming lipoprotein which diffuse outside the liver .

Pathogenesis ( mechanism of fatty changes ) :

increase the amount of fatty acid entering the liver .
increase in the conversion of acetate to fatty acid .
increase in alpha glycerol phosphate .
decrease in the conversion of fatty acid into phospolipid & keton .
reduction in apoprotein .
block in the excretion of lipoprotein to the circulation .


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Grossly : the liver enlarge , soft & greasy .

Microscopically : small fat globules appear in the cytoplasm , later they join form one big vacuole that push the nucleus to one side of the cell form signet ring appearance ,occasionally adjacent cells may rupture form fatty cyst . by H&E stain fat vacuole appear as empty space , however fat can be demonstrated by special stain ( oil red ) which should be used on frozen section & the fat appear as red or orange .

Irreversible cell injury:

necrosis
apoptosis

Necrosis:- sequence of morphological change that follow cell death in a living tissue.

The morphological changes in necrosis result from two processes :-
1 : enzymatic digestion of the cell either by its own enzyme (autolysis) or the cell digest by proteolytic enzyme secreted from inflammatory cell infiltrate & this is called (heterolysis)
2 : denaturation of protein.

The morphological change of necrosis usually required (4-12)h to bee seen by light microscope , although ultra structural change can be demonstrate within 20-40 m while the enzyme released from damage cell can be detected within 2hrs in the serum such as (CPK- creatinin phosphokinase ) which is secreted in myocardial infarction .

Morphology ( microscopic feature of necrosis ) :

* changes in cytoplasm include :
increase eosinphilia: due to increase binding of eosin to denature protein and decrease in basophilia of ribosome.
It show more glassy appearance than viable cell .
calcification may occur


* nuclear change (path gnomonic ) :
pyknosis: nuclear shrinkage & increase basophilic appearance of nucleus
karyorrhexis: pyknotic cell fragment in 1-2 day & the nucleus completely disappear.
karyolysis: fading of basophilia of the chromatin .

types (gross appearance) of necrosis

It depend on the mechanism of necrosis , if enzymatic digestion dominate liquifactive necrosis occur, if denaturation of protein dominate coagulative necrosis happen however other type of necrosis can occur.
coagulation necrosis
liquifactive necrosis
fat necrosis
caseous necrosis
fibrinoid necrosis
gangrene

coagulative necrosis:

1. commonest 2. Occur Any where in the body except C.N.S 3. usually due to hypoxia 4. the Outline of tissue is preserved because denaturation of protein involve the enzyme of the cell .e.g. myocardial infraction ,the cardiac muscle become pale, swollen, firm and microscopically the cell become more eosinophilic , loss of striation, absence of nucleus & the outline is preserved .

Liquifactive necrosis: The second most common type of necrosis

usually occur in association with bacterial infection and sometime with fungal infection and in CNS due to hypoxia which may be due to high content of lipid in CNS.
Here enzyme digestion & autolysis is predominate so the area become
soft ( cystic
Microscopically : complete loss of tissue architecture , the cyst contain necrotic debris & macrophage, while the wall show capillary, inflammatory cell + proliferating glial cell(brain) or fibroblast (any where in the body).


caseous necrosis: it is a special form of necrosis usually see n in tuberculosis grossly : it has white cheesy appearance
Microscopically : the necrotic area has structurless granular and amorphous material surround by multiple granulommata ,which consist of collection of epitheloid cells which is large flat cells with eosinophilic cytoplasm & ill define cell membrane & langhan,s giant cell in which the nucleus arrange at the periphery of the cell or it has horse shoe appearance .the granuloma surround by collar of lymphocyte & fibrosis ,

Fat necrosis:

1- enzymatic fat necrosis: which usually follow acute pancreatitis due to release of pancreatic enzyme ( necrosis of pancreatic tissue & release of free fatty acid, the later combine with calcium form fat saponification

2- traumatic fat necrosis: occur in the breast after trauma which caused release of fatty acid from cell this stimulate macrophage infiltration which engulf fat ( foamy macrophages (lipid laden macrophage) and giant cell infiltrate with massive fibrosis so the lesion grossly become hard mimic carcinoma

fibrinoid necrosis: characterized by deposition of fibrin like material in the tissue as in :
* immune complex vasculatis (auto immune disease) &-arthus reaction
* wall of peptic ulcer
* hypertensive change of arteriole

Microscopically bright eosinophilic material seen in the wall of b.vessel or in the luminal surface of peptic ulcer.

Gangrene

It is a form of necrosis of a tissue with superadded putrefaction , the type of necrosis is usually coagulative due to ischemia . There are 3 types of gangrene dry , wet & gas gangrene .

Dry gangrene :

It occur in the distal part of the limb due to arterial occlusion as in old patient due to arteriosclerosis , other causes are Rayanaud,s disease , thromboangitis obliterans , trauma & ergot poisoning .
The gangrene spread slowly upward until it reaches a point where the blood supply is adequate so a line of separation is formed between the viable & gangrenous tissue .
X : the affected part is dry , shrunken with black discoloration due to the formation of iron sulfide .
RBC--------- Hb + H2S( produced by bacteria)--------- Iron sulfide .



Wet gangrene :
It occur in moist tissue such as mouth , bowel , lung , diabetic foot is other cause of wet gangrene due to high sugar content .
Wet gangrene is usually occur due to venous block & less commonly due to arterial block (due to thrombosis or embolism) as in strangulated hernia & volvolus . The absorbed toxic product cause features of septicemia .
X : the affected part is soft moist swollen & dark with lack of line of demarcation .

Gas gangrene :

Caused by gas forming bacteria (Clostridia) which is gram positive anaerobic bacteria which enter the tissue through an open contaminated wound or as a complication of operations on the colon which normally contain clostridia .
Clostridia produce various toxin which produce local necrosis & oedema in-addition to the features of septicemia .
X : the affected part is swollen , oedematous, painful with crepitation due to accumulation of gas bubbles within the tissue , subsequently the affected tissue become dark black with foul smelling .

fate necrosis:

it cause acute inflammation with acute inflammatory cell infiltrate in the surrounding tissue follow by macrophage infiltration which tried to removed the dead tissue then healing can occur which is either by the same type of cell (regeneration) or by fibrosis (organization).

Calcification :deposition of calcium seen in necrotic tissue as in caseous necrosis or in fat necrosis.
Gangrene

Effect of necrosis: it is variable depending on the type of the cell involve, extent of necrosis (small, large), the involve organ and the proliferation capacity of the cell involved .
Extensive necrosis in spleen which lead to autospleenctomy as in sickle cell anemia is capable for normal life.
While ischemic necrosis involved few cells in the brain can lead to the paralysis.

Apoptosis: it is another type of cell death in which the cell shed after it reach the end of its life span and this is called programmed cell death.

Usually involve single cell however it may involve group of cell, is either due to physiological causes as in shedding of gastro-intestinal epithelium or due to hormone dependant involution of the tissue which occur in the endometrial during menstrual cycle. Or pathological as in the malignant tumor, radiation , steroid and cytotoxic therapy.
Apoptosis is usually active process that is to say need energy or ATP and not associated with acute inflammation.


Microscopically: apoptosis appear in hematoxylen eosin stain section as around or oval mass with intense eosinophilic cytoplasm and condense chromatin. The chromatin is broken into regular fashion by endnuclease enzyme and at the same time transglutaminase convert the cell into rigid shrinkage shell show intense eosinophilic staining then the dead cell break down into many fragment some of them are shaded from free surface of the cell or taking by adjacent cell or by macrophage.
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Mechanism of apoptosis: Include 4 steps:

Signaling: apoptosis will be initiated by different signal some of them are intrinsic as ( embryogenesis signal), or extrinsic as( injury ,radiation, toxin and free radical) or due to withdrawal of growth factor or also due to receptor legend interaction such as (TNF) and TNF receptor or by cytotoxic T cell due to release granzyme enzyme secreted from T cell .
Control and interaction: which is caused by certain type of protein that carry the signal death to the execution capses, this signal is carried either directly to the execution capses by specific adaptor protein or indirectly due to the interaction with mitochondria which release the cytochrome c this substance combine with protein and activate it and then carry the information to the execution capses.

the execution capses: characterized by formation /or activation of a no. of catabolic enzyme which is responsible for morphological changes of apoptosis This include endonuclease which cause fragmentation of DNA and transglutaminaze which convert the cytosolic protein into condense shell .

removable of death cell: the apoptotic body has cell marker on their surface facilitate their uptake by the adjacent cell or macrophage.

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Intra cellular accumulation :
Excess storage of substances inside the cells ,can be seen in many conditions include :
Upset of normal metabolism by toxin or some drugs result in accumulation of normal substance e.g fatty changes .
Genetic defect in the enzyme lead to accumulation of its substrate ( abnormal) as in storage disease .
Some materials are incapable for digestion or transport to other place so it will accumulate as a pigment which is either exogenous or endogenous .

Fatty changes :

.


Pigmentation :
There are two types : exogenous & endogenous

Exogenous pigmentation :

Carbon ( as coal dust ) is a common air pollutant in an urban area which when reach the alveoli it is taken by the macrophage to the regional lymph node which when contain excess amount of coal it appear black & this condition is called anthracosis . however if there is excess deposition of carbon in the lung it may lead to emphysema & it may cause extensive fibrosis & the condition is called pneumoconiosis .
Tattooing : harmless , taken by injection .

Endogenous pigmentation : include :

Lipofuscin : yellow brown pigment seen inside the cell of the liver , heart & brain ,seen in old ages & it is a marker of damage by free radical .
Melanin : Intracellular brown pigment seen in the melanocyte inside the epidermis ,produce from tyrosin by the action of tyrosinase , it is a screen mechanism against the harmful effect of ultra violet radiation .
* Generalized hyperpigmentation :
As in addison disease ( generalize hyperpigmentation especially in exposed part & buccal mucosa ) & chloasma (hyperpigmentation of face , nipple & genitalia during pregnancy ) .
* Focal hyperpigmentation :
As in Caf-au lait spot , melanosis coli ( pigmentation of the colon ) & melanocytic tumors as pigmented naevi & Peutz-Jegher syndrome( focal oral pigmentation).
* generalized hypopigmentation as in albinism
* Localize hypopigmentation: as in leucoderma ( partial albinism ) & vitiligo .

3- Hemosidrin : a golden yellow to brown pigment occur any where I in the body which has excess iron store .
in side the cell iron combines with apoferritin to form ferretin which if accumulate in excess amount it will form hemosidrin which can be demonstrated by Prussian blue reaction .
Excess iron accumulate either :
* Locally : which is seen in hemorrhage as in bruses , here the extravasated red blood cell hemolysed & the released hemoglobin is digested into hemosidrin .
* Systemic iron over load : which could be :
a-Primary as in idiopathic hemochromatosis which is an autosomal dominant disease characterized by excess absorption of iron from the gut . here the deposition hemosidrin usually in the parenchyma cells as in the liver cause ( fibrosis & cirrhosis ) , in the heart cause (heart failure & arrhythmia ) in the pancreas cause ( diabetes mellitus ) & in the skin form bronze pigmentation so it is sometime called bronze diabetes .
b-Secondary :as in
1- Increase absorption of dietary iron .
2- Ineffective erythropoiesis (thalassemia).
d-parental iron overload :as in repeated blood transfusion as in aplastic anemia .
3- Excessive intake of dietary iron ( Bantu,s disease) .
4- Chronic liver diseases as alcoholism .


4-Bilirubin pigment : Yellow brown pigment . it is usually less than 1 mg / 100 ml in the serum . If the level of bilirubin exceed
this level it will lead to a clinical condition called jaundice which characterized by yellow discoloration of skin & mucous membrane. .
Types( causes ) of jaundice :
Pre hepatic jaundice : due to increase in red blood hemolysis .
Hepatic jaundice : due to failure in bilirubin conjugation as in liver disease .
Post hepatic jaundice : due to obstruction in the excretion of bilirubin & the site of obstruction is either intra hepatic or post hepatic .

Tests used for the diagnosis of jaundice :

Total serum bilirubin . If the direct fraction increase mainly then it is due to obstruction . If the indirect fraction increase mainly then it is due to failure of conjugation .
SGPT ( serum glutamate pyruvate transaminase) increase due to failure of conjugation .
Serum alkaline phosphates : increase in case of obstruction .

Heterotrophic ( pathological) calcification :

Abnormal deposition of calcium any where in the body except in the bone & the teeth , & it is of two types :
Dystrophic calcification : Deposition of calcium occur in dead or degenerated tissue such as caseous necrosis ,fat necrosis , chronic abscess , thrombi , infarction ,dead parasite & atherosclerosis . The condition is usually associated with normal calcium metabolism & normal calcium level .
Pathogenesis : is not well known , it could be due to one of the followings :
Increase in the PH of the tissue i.e become alkaline .
Release of alkaline phosphates which stimulate the deposition of calcium .
The presence of cellular product which act as a nucleus that stimulate the deposition of calcium around it .

Metastatic calcification : Abnormal deposition of calcium in a normal tissue associated with abnormal calcium metabolism & high calcium level .
Causes :
excess absorption of calcium from intestine as in patient taken excess milk which is used previously in the treatment of peptic ulcer .
excess mobilization of calcium from the bone as in hyperparathyroidism , prolong immobilization ,& destructive disease of the bone such as multiple myeloma & secondary deposit in the bone


Here the calcium is usually deposit in the kidney either in the renal tubules cause nephrocalcinosis or in the renal pelvis form stone .
Calcium may also deposit in the lung , blood vessel & the cornea .

Amyloidosis:

It is clinical syndrome characterized by abnormal deposition of protein called amyloid usually between cells and adjacent to cell mucus membrane . or in the wall of small blood vessels .

Physical nature of Amyloidosis :

95% of Amyloidosis is formed from non branching fibril it is about 7.5-10 nm in diameter and it has B-pleated configuration that is to say the polypeptide is arrange in sheets at right angle to the axis of filament , remaining 5% include non fibril pentagonal glycoprotein which is also called p- protein .

Chemical nature of amyloidosis :

It has about 15 subtype ,the most common 3 types are :
1- AL amyloid (amyloid light chain protein ) : compose of the whole light chain of immunoglobulin or the NH2 terminal fragment of the light chain . It is usually form from plasma cell & deposition is seen in B cell monoclonal proliferation .
2- AA amyloid( Amyloid associated protein ) : It is non immunoglobulin protein compose of 76 amino acid residue , form in the liver from precursor called SAA (serum associated amyloid ) & deposition occur in chronic inflammatory state .
3-AB amyloid : less common seen in Alzheimer disease .

Classification of amyloidosis : depend on clinico-chemical state :

1- Localized amyloidosis : here the amyloid is deposited in local area of tissue form a mass seen in the larynx , skin , tongue ,eye , lung & urinary bladder .sometime it is also seen in malignant condition as in basal cell carcinoma of skin & medullary carcinoma of the thyroid .
2- Systemic amyloidosis : includes :
a- primary amyloidosis ( AL amyloidosis ) : usually seen in elderly patient of unknown causes , however it may associated with multiple myeloma or with monoclonal gammopathy in which malignant B lymphocyte synthesize abnormal amount of single immunoglobulin producing M band in serum protein electrophoresis , plasma cells may also form kappa or lambda light chain that secrete in urine as Bence jones protein . The disease affect the heart , GIT , nerve , tongue ,skin & sometime affect solid abdominal organs.
clinically the patient may have diarrhea , malabsorption syndrome or purpra . death usually occur due to heart failure or renal failure .

B- secondary amyloidosis :usually associated with chronic inflammatory state which is either due to:
1- ch inflammation of unknown cause as in rheumatoid arthritis.
2-chron suppurative disease with pus forming as in tuberculosis and chronic osteomylitis .
3- It may occur with certain malignant condition such as Hodgkin's disease & renal cell carcinoma .
4- Chronic non suppurativ disease such as leprosy & syphilis .
It usually affect solid abdominal viscera such as liver ,pancreas , spleen , kidney , adrenal & thyroid gland. .


3- Hereditary ( familial ) Amyloidosis :
Seen in certain familial condition such as familial Mediterranean fever which is a rare disease Occur in limited area , transmitted as autosomal recessive & it is of AA type .characterized by fever of unknown origin with inflammation of serosal surfaces.

Pathogenesis of Amyloidosis :

Primary type : Usually of unknown cause , or due to certain carcinogen , this stimulate B- lymphocyte monoclonal proliferation which is differentiated into plasma cell that form light chain immunoglobulin --

Unknown cause,carcinogen



B- lymphocyte proliferation

& differentiation

Plasma cell

 Light chain


Deffect in proteolysis
AL protein

Secondary type :

Chronic inflammation cause macrophage activation which secrete interleukin 1&6 , they stimulate liver cell to form amyloid precurssor (SAA) , normaly this substance is degraded by certain proteolytic enzyme ,diffecency of this enzyme lead to deposition of amyloid A protein .


Chronic inflammation


Macrophage activation



secretion of Interleukin 1&6

liver cell


SAA

defect in proteolytic enzyme

AA protein

Effect ( clinical correlation ) of Amyloidosis :
It is variable depend on the site & extension of deposition :
it is either remain silent ( undetected ) .
or it may cause serious effect in the form of renal involvement (as nephritic syndrome which may lead to chronic renal failure) ,
hepatosplenomegaly.
Cardiac involvement in the form of arrhythmia or cardiomyopathy which lead to heart failure .


Microscopic features :
In H&E stain section Amyloid appear as eosinophilic refractile extra cellular material which should differentiate from hyaline changes by special stains include :
1- Lugols iodine : used for gross specimen only , tissue contain Amyloid stain deep brown while normal tissue stain light brown .
2- Congo red : Amyloid appear red under light microscope & yellow green under polarized microscope .
3- Electron microscope : it appear as amorphous thin fibril .
4- Immunohistochemical stain : used to differentiate the subtype of Amyloid .

Diagnosis of Amyloidosis :

1- Clinical signs & symptoms .
2- Biopsy ( rectal gingival or renal .
3- Serum & urine protein electrophoresis .