e.x : alpha 1- antitrypsin deficiency - humsc · foam cells: macrophages cells that contain fats...

SCIENTIFIC TEAM 1 –الفريق العلمي

مبسم هللا الرحمن الرحي

Intracellular accumulation :

Accumulation may be transient and reversible or

permanent.

Effect : range from harmless to toxic

Located in : cytoplasm, lysosomes, nucleus

• We have three categories:

1- Accumulation of constituent of normal cell

metabolism : Fat , ptn , carbohydrate

2- Accumulation of abnormal substance of abnormal

cell metabolism : storage diseases, inborn errors

metabolism

3- Accumulation of pigment : exogenous, endogenous

• Mechanism / path ways of accumulation:

1- Abnormal metabolism :

Normal substance produced

Metabolism is inadequate to remove it =accumulation

Lecture 6


E.x :Fatty changes

Metabolism : عن إنتاج مركبات و مكونات عملية يتم من خاللها هي

استهالكها للمركبات أخرى أو طريق استخدامها

هذه العملية بعدالمتفاعلة أو المستهلكة الوضع الطبيعي = نقصان كمية المواد

When we have abnormal metabolism accumulation

will happen

2- Mutated gene =abnormal ptn folding and transport

=inability to degrade abnormal ptn =accumulation in

cytoplasm

e.x : alpha 1- antitrypsin deficiency

Gene mutation : في تسلسل الحمض النووي الذي هي تغير دائم

يتكون من الجين

3- Normal endogenous substance >Enzyme > metabolite

Deficiency of that enzyme = Accumulation

e.x : lysosomal storage enzyme

يؤدي إلى تراكم المواد في ال نقص اإلنزيمات التي تعمل على تكسير أو تحطيم المواد

lysosome

Lysosome: ة عشان تتخلص من موادللمحمسؤولة عن إفراز إنزيمات

. معينة A lysosome is a membrane-bound cell organelle that contains

digestive enzymes

4- Exogenous substance >No enzymatic mmachinery for

its degradation or transport =accumulation


E.x : carbon or silica particles

So, The main pathways of abnormal intracellular

accumulations are inadequate removal and degradation or

excessive production of an endogenous substance, or

deposition of an abnormal exogenous material

: كل مادة بدنا ندرسها هال الزم نعرف عنها

1- Common in + can occur in

2- Causes of it

3- Gross +micro appearance

4- Its stain

5- Its effect

# Lipids:

• Steatosis • Cholesterol and Cholesterol Esters

• Steatosis

Free fatty acid come from :adipose tissue or ingested food are

transported into hepatocytes where there :

1- Esterified to triglycerides

2- Convert to : cholesterol or phospholipid

3- Oxidative to ketone bodies , co2

يتم تحويله للمركبات مختلفة من أجل hypatocyteفي خاليا ال F.Aيعني ال

االستخدام


Transport of triglyceride from hypatocyte requires complixing

with Apoprotein :

Triglyceride+ Apoprotein = lipoprotien (which can move with

the circulation )

fatty changeشو هي مسببات ال الطبيعي، طيب لحد اآلن احنا بنحكي عن الوضع

accumulationأو

1- Alcohol abuse (most common)

2- (starvation) starvation by increase mobilization from

peripheral stores. CCl4 + ptn malnutrition decrease the

synthesis of apoprotein.

3- Obesity

4- Diabetes mellitus

5- Anemia

6- Anoxia by inhibited fatty acid oxidation

7- toxins by decrease apoprotien

8- Ptn malnutrition

So, excess accumulation of triglyceride may result from

defect at any step from fatty acid entry to lipoprotein exit :

1- Over supply

2- Failure of oxidation, due to mitochondrial damage

3- Failure of synthesis of lipoprotein due to damage of

RER

4- Failure of release of lipoprotein, due to cell membrane

damaged


• Fatty changes is intracellular accumulation of fat

(triglyceride) within paranchymal cell

• Common in liver

• Lipid accumulation = accumulation of triglyceride or

accumulation cholesterol and cholesterol esters

• Can occure in :heart , skeletal muscles, kidney

• Fat stains : oil red o = fat appear as red colour

• Fatty change effect : is reversible (we can treat it) but in

severe cases it could be irreversible (poisoning) and

leads to cell death (necrosis).

• *Fatty changes :

1- Liver:

• Grossly : liver enlarges(3-6 kg) , become increasingly

yellow , soft and greasy. Normal weight =1.5 kg

• Microscopically :

1- Small vacuoles in cytoplasm around the nucleus

2- Vacuoles coalesce (unite together)displacing the

nucleus to periphery

2-heart : occurs ,due to:

A-prolonged moderate hypoxia as (in sever anemia) result in

focal intracellular fat deposits ,characterised as tiger like

pattern .= yellow streaks and lines alternating with unaffected

muscle.


B- sever hypoxia or toxic myocarditis result in diffuse fatty

changes.

• Accumulation of cholesterol and cholesterol esters

Cholesterol: is a waxy, fat-like substance that’s found in all

cells in your body.

In normal conditions cholesterol is metabolized in small

amounts so that it doesn't accumulate بالوضع الطبيعي خاليا ال.

macrophages هي اللي بتخلص من الcholesterol الزائد

Macrophages that are in contact with fats that are in fat

Necrosis may become filled with lipids which then causes foam

cells to occur.

Foam cells: macrophages cells that contain fats type of

macrophages that localized to fatty deposits on blood vessel

walls.

. Cellular cholesterol metabolism is tightly regulated to ensure

normal generation of cell membranes (in which cholesterol is a

key component) without significant intracellular accumulation.

However, phagocytic cells may become overloaded with lipid

(triglycerides, cholesterol, and cholesteryl esters) in several

different pathologic processes, mostly characterized by

increased intake or decreased catabolism of lipids. Of these,

atherosclerosis is the most important.


In atherosclerosis, smooth muscles of the blood vessels

and macrophages are filled with lips vacuoles that is

composed of cholesterol, which give the atherosclerotic plaque

a yellow color.

Deposition of lipids (fat) → leads to accumulation of

atherosclerotic plaques on the wall of blood vessel → leads to

atherosclerosis.

Lipid vacuoles = cholesterol + cholesterol esters


Finally, in hereditary and hyperlipidemic syndrome's,

macrophages accumulate cholesterol in skin and tendons

cause forming masses called xanthomas.

Xanthoma: an irregular yellow nodule on the skin, caused by

deposition of lipids.

effect of fatty changesواللي هو fatty changesوآخر شيء في ال

Effect of fatty changes depend on : cause +severity of the

accumulation

1- Reversible: except ccl4 = inducing free radical

2- Irreversible

#protein accumulation :

Morphologically visible protein accumulations are less common

than lipid accumulations;

1-excesisive exceeding capacity of the cell metabolized

2-synthesis and secretion of excessive protein

3-Defect in ptn folding

Example:

1- In the kidney, trace amounts of albumin filtered through

the glomerulus are normally reabsorbed by pinocytosis

in the proximal convoluted tubules. However, in

disorders with heavy protein leakage across the


glomerular filter (e.g., nephrotic syndrome), much more of

the protein is reabsorbed, and vesicles containing this

protein accumulate.

ترشيح ثم إعادة امتصاص .الكلية بشكل عام =

إلى الجسم إعادة امتصاص = -٢إلى الكلية ترشيح =-١اتجاه المكونات في

عن الكبيبة خالل من ترشيحها يتم التي األلبومين من ضئيلة كميات امتصاص عادة يتم

اعادة بصيرلها األوقات وباغلب .القريبة الملتفة األنابيب في الخاليا كثرة طريق

لكن البول في تخرج البروتينات من قليلة كميات يعني pinocytosis by امتصاص

أي خلل في كمية يكون في كميات قليلة من البروتين urineالوضع الطبيعي أن

يصير لما األمراض بعض يفالبروتين يشير لخلق في وظيفة الكلية .

Leaking of protein across the kidney glomerular filter to the

urine

ب بتمر اللي البروتينات انه بصير اللي proteinuria اسمها حالة في بصير هون

filter glomerular كل مش لهيك يستوعبها ممكن اللي الكميات من اكبر للفلترة

فبصير بالبول تطلع وبتبلش من الكلية امتصاص اعادة بصيرلها الكميات هاي

hypoprotien or hypoalbumin ومع الكلية بتخرجه اللي البروتين نوع حسب

edema . When the level of protein in theقلة البروتين في المريض بصير عنده blood is low, water may leave the blood vessels and collect in the tissues. Water

in the tissues is called "edema" .

هذا على المحتوية الحويصالت ملتبدأ تتراك األيام بمرور الحالة ازدياد ومع

مظهرورديpinocyt األنسجة يعطي مما البروتين،

So, Nephrotic syndrome is a collection of symptoms due to

kidney damage. This includes protein in the urine, low blood


albumin levels, and significant swelling. Other symptoms

may include weight gain ,feeling tired and foamy urine

• Microscopy : giving the histologic appearance of pink,

hyaline cytoplasmic droplets.

• Effect: The process is reversible: if the proteinuria

abates, the protein droplets are metabolized and

disappear.

2- the marked accumulation of newly synthesized

immunoglobulins that may occur in the RER of some

plasma cells, forming rounded, eosinophilic Russell

bodies.

Immunoglobulin ينتجه الجسم ويستخدم من قبل مضاد(بروتين)هو عبارة عن

جهاز المناعة

3- alcoholic hyalinein the liver or Mallory bodies

Is an inclusion found in the cytoplasm of liver cells.

Mallory bodies are damaged intermediate filaments within

the hypatocytes. And we know that intermediate filaments

are composed of a variety of proteins.

ن ع ارة وهي عب السيتوبالزم داخل (الكبد الكحوليد )هاي الحالة بتكون في خاليا الكب

intermediate filaments بعض متضررة تحاول مقاومة التحلل بتتجمع مع

highly eosinophilic and thus appearMallory bodies are

pink on H&E Stain We see

• Mallory bodies in acute military disease in liver and

acute hepatitis


# Glycogen : caused by abnormalities in the metabolism of

glucose or glycogen.

Examples:

1-In diabetes mellitus, glycogen accumulates

a. renal tubular epithelium

b. heart

c. β cells of the islets of Langerhans Within the pancreas

• Type 1 diabetes is an autoimmune disease. The immune system attacks and

destroys cells in the pancreas, where insulin is made. Insulin deficiency

• Type 2 diabetes occurs when your body becomes resistant to insulin, and

sugar builds up in your blood.

.نو الغاليكوجيفبتراكم الغلوكوز بستخدمهبس الجسم ما االنسولينهو النوع الموجود فيه

can't effectively use the insulin

•2-Glycogen also accumulates in glycogen storage

disease(glycogenoses)

A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is

a metabolic disorder caused by enzyme deficiencies affecting

either glycogen synthesis, glycogen breakdown or glycolysis (glucose

breakdown), typically in muscles and/or liver cells.

https://www.healthline.com/health/type-1-diabetes-causes-symtoms-treatmentshttps://www.healthline.com/health/autoimmune-disordershttps://www.healthline.com/human-body-maps/pancreashttps://www.healthline.com/health/type-2-diabeteshttps://www.healthline.com/health/type-2-diabetes/insulinhttps://en.m.wikipedia.org/wiki/Metabolic_disorderhttps://en.m.wikipedia.org/wiki/Enzymehttps://en.m.wikipedia.org/wiki/Deficiency_(medicine)https://en.m.wikipedia.org/wiki/Glycogenhttps://en.m.wikipedia.org/wiki/Glycolysishttps://en.m.wikipedia.org/wiki/Musclehttps://en.m.wikipedia.org/wiki/Liver


• Effect :glycogen accumulation may lead to liver fibrosis and liver

cirrhosis and this depend on the severity of the disease and

how much there is defect in enzyme.

# pigment : colored substances that are either :

1. Exogenous: from outside the body, such as carbon.

2. Endogenous :synthesized inside the body, such as

lipofuscin, melanin, and certain derivatives of hemoglobin.

• Carbon:

×This air pollutant is the most common exogenous

×When it inhaled ,

1-it phagocytosed by alveolar macrophages

2-Transported through lymphatic channels to lymph

node

3-It aggregates and appear grossly blacken the draining

LN and pulmonary parenchymal (atheracosis)

Pneumoconiosis: a severe fibroblastic reaction caused by

heavy

accumulation of coal dust in lungs.

×Effect : Normally, small amount of this is harmless but

excess amount involved in the tissue will cause

inflammatory reaction . Heavy accumulation induce a


fibroblastic reaction that can result serious lung disease

called Pneumoconiosis.

• Lipofuscin :

• • Fuscus = brown

• • Inclusions of lipid peroxides, phosphates, proteins

• • Not harmful

• • Accumulates in liver, heart from normal “wear and tear”

• • Sign of free radical damage

• • Pigment accumulates near nucleus

• • Indicative of age, oxidative damage

• • Does not stain blue with Prussian blue or Perl’s iron

من المنتجة والدهون البروتينات من معقدات عن عبارة الصبغة

peroxidationالجذور بتحفزها العملية وهاي غريالمشبعة الدهون من

ROSل على نشاطتدلخلية بس لب أذى تسبهي ما ب ROSالحرة

• Melanin

• • Melas = black

• • found in epidermis

• • Blocks UV radiation

• Hemosidren :


• is a hemoglobin-derived golden yellow to brown

pigment

• Accumulates because local or systemic excess of iron.

• Local excess of iron, and consequently of hemosidren

result from hemorrhage, e.g in the skin = bruise

• • Accumulation of hemosiderin is hemosiderosis

• • Hemosiderin is normally found in marrow, spleen,

liver/ نقطة إضافية

• Hemosiderosis:

• is a condition characterized by systemic overload of

iron.

• First in the mononuclear phagocyte of the liver , bone

marrow ,spleen heart, and pancreas , lymph node,


but later in : parenchymal cell principally in liver,

heart, pancreas.

• Occurs in the setting of :

(1)Increased absorption of dietary iron, a disease called

hereditary hemochromatosis, one of the most common

inborn errors of metabolism, in which excessive

absorption of iron from the intestine lead extensive

accumulations of iron in tissue, causing liver cirrhosis,

heart failure& diabetes mellitus .

وهي hemochromatosis بسموها وهون جيني مرض سببها تكون ممكن

اجا اذا هون hemochromatosis hereditary جين في نقص نع ناتجة

المعادن من الحديد طبعا) جدا عالي الحديد انه والحظنا فحوصات وعمل مريض

والعين بالكبد يترسب رح بالتالي (بسهولة الجسم من بتطلع ما اللي جدا الثقيلة

اذا جدا كبير التجمع وكونهتفاعل بيعطي كبيرة بكميات يترسب ولما والبنكرياس

وهاي fibrosis يعمل رح بالكبد:* مثال للجسم يكون مؤذي رح reaction ال

cirrhosis ل بتتطور

المريض مع سكري يصير رح بالبنكرياس*

(2) Hemolytic anemias:

deposition of ironد المرض وتكسر و تؤدي إلى هابخاليا الدم الحمراء

وتعطي اللون البني المريض بهذه الحالة بحاجة لنقل وبالتالي تتراكم في الجسم

الدم

(3)Frequent Blood transfusions, in which the transfused

red cells constitute an exogenous load of iron.

Thalassemia =abnormal hemoglobin =destruction if

RBCs =hemodialysis

فيزيد الحديد وبترسب بالجسم مرضى الثالثينيات بحاجة لعمليات نقل متكررة

و يصبر النسيج ، الحل : أخذ أدوية تمتص الحديدبكميات


(4) Localized hemosiderosis : occurs at sites of trauma

,commonly seen in hands ,feet, trunk or face as dark red

patches due to local hemorrhage its color gradually

changes into brownish , bluish , yellowish then

disappears

وهاد اصفر وبعدين بنفسجي بعدين باألول زرقا بتصير ب اليد ينطخ حدا لما

leaking from RBCs صارله اللي الهيموغلوبين بسبب

# Pathological CALCIFICATION: Is the abnormal deposition of

calcium salts in tissue

•1-Dystrophic Calcification: occurs in areas of necrosis and

atherosclerosis.

• Associated aging or damaged heart valves

• Precipitated calcium salts look white

• Basophilic when stained with H&E

• Blue granular crystals

*can be seen in :

(1) TB caseous necrosis .

(2) Calcification in atheromas of advanced atherosclerosis , is

extremely common .

(3) Calcific aortic valve in the elderly .


(4) Carcinoma of the breast .

2- Metastatic Calcification: occurs in normal

tissues when there is hypercalcemia.

××Causes of hypercalcemia are :

1- Increased secretion of parathyroid hormone.

2- Destruction of bone : due to immobilization, or bone

involvement by tumors as in in multiple myloma, leukemia, or

diffuse skeletal metastases. بصير حركة بدون طويلة فترة يضل العظم لما

deposition دم ال الى العظم من للكالسيوم


(3) Vitamin D-related disorders . V.D increase the absorption

of Ca in intestine

(4 ) Renal failure in which phosphate retention leads

tosecondary hyperthyroidism .Metastatic calcification resemble

dystrophic calcification.It can occur widely throughout the body

but principally affects the interstitial tissues of the blood

vessels , , kidneys, lungs & gastric mucosa

الغدة بافرازات مرتبط والكالسيوم hyperthyroidism الى يؤدي الكلوي الفشل

.يزيد رح زادت ما كل ف الدرقية

#cellular aging :

Aging is one of the strongest independent risk factor for

chronic diseases like cancer , Alzheimer disease& ischemic

heart diseases .

تتمو الخلية وانه تنقسم وتبطل وظيفتها تفقد انه لمرحلة وتصل الخلية تكبر××

. للسرطان المضادةالدوية وا السرطان بتطور بدخل××

Aging is regulated by limited:

1- number of genes and

2-signaling pathways that are evolutionary conserved from

yeasts to mammals .

Cellular aging is the result of a progressive decline in the life

span and functional capacity of cells .


Several mechanisms are responsible for cellular aging ,

including :

1-DNA damage :

A variety of metabolic insults that accumulate overtime may

result in damage to nuclear & mitochondrial DNA . Although

most DNA damage is repaired by DNA repair enzymes ,some

persists and accumulates as cells age .

Some aging syndromes are associated with defects in DNA

repair mechanisms & the life span of cellstaken from

experimental animals can be increased if responses to DNA

damage are enhanced or proteins that stabilize DNA are

introduced .

Damage of the cell = يتضرر الDNA = ه تموت ألنالزم بهذه الحالة الخلية

المواد جينيا غير طبيعية هذا يؤدي إلنتاج السرطان إذا صار في تجمع

. Pre mature aging : التي يحدث فيها نقص في ال مثل بعض المتالزمات

DNA

2-Decreased cellular replication :

All normal cells have a limited capacity for replication .and after

a fixed number of divisions cells become arrested in a

terminally non dividing state , known as replicative senescence

Aging is associated with progressive replicative senescence

.


Cells from patients with Werner syndrome , a rare disease

characterized by premature aging , have a markedly reduced

in vitro cellular life span ( tissue culture ) , as compared to cells

taken from healthy children which have the capacity to undergo

more rounds of replications & longer life span .Also seen in

Progeria syndrome .

In human cells , the mechanism of replicative senescence

involves progressive shortening of telomeres , which

ultimately results in cell cycle arrest .

Telomeres are short repeated sequence of DNA present at the

ends of linear chromosomes ,that are important for

1-ensuring the complete replication of chromosome ends

2-for protecting the ends from fusion & degradation .When

somatic cells replicate a small fraction of the telomere is not

duplicated and telomeres become progressively shorter, & as a

consequence for its shortening the DNA may break & its ends

cannot be protected .

tolemere بقصر الخاليا اإلنسان لما يصير في انقسام

Telomere length is maintained by nucleotide addition

mediated by an enzyme called telomerase.


××where it is presented ?

Telomerase activity is present at germ cells ,

less in stem cells & absent in most somatic

cells .

In cancer cells, telomerase is often

reactivated.


❖ Scientific Team

▪ Scientific Team

▪ Scientific Team

بالتوفيق ..

بسم الله الرحمن الرحيمIntracellular accumulation :

e.x : alpha 1- antitrypsin deficiency - humsc · foam cells: macrophages cells that contain fats...

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