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
SCIENTIFIC TEAM 2 –الفريق العلمي
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
SCIENTIFIC TEAM 3 –الفريق العلمي
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
SCIENTIFIC TEAM 4 –الفريق العلمي
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
SCIENTIFIC TEAM 5 –الفريق العلمي
• 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.
SCIENTIFIC TEAM 6 –الفريق العلمي
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.
SCIENTIFIC TEAM 7 –الفريق العلمي
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
SCIENTIFIC TEAM 8 –الفريق العلمي
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
SCIENTIFIC TEAM 9 –الفريق العلمي
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
SCIENTIFIC TEAM 10 –الفريق العلمي
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
SCIENTIFIC TEAM 11 –الفريق العلمي
# 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
SCIENTIFIC TEAM 12 –الفريق العلمي
• 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
SCIENTIFIC TEAM 13 –الفريق العلمي
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 :
SCIENTIFIC TEAM 14 –الفريق العلمي
• 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,
SCIENTIFIC TEAM 15 –الفريق العلمي
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
SCIENTIFIC TEAM 16 –الفريق العلمي
(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 .
SCIENTIFIC TEAM 17 –الفريق العلمي
(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
SCIENTIFIC TEAM 18 –الفريق العلمي
(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 .
SCIENTIFIC TEAM 19 –الفريق العلمي
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
.
SCIENTIFIC TEAM 20 –الفريق العلمي
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.
SCIENTIFIC TEAM 21 –الفريق العلمي
××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 22 –الفريق العلمي
❖ Scientific Team
▪ Scientific Team
▪ Scientific Team
بالتوفيق ..
بسم الله الرحمن الرحيمIntracellular accumulation :