ىفطصم يداهلا دبع حلاص دهش · #Cholesterol & Cholesteryl Esters Normally, cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis

شهد صالح

عبد الهادي مصطفى

SCIENTIFIC TEAM 1 –الفريق العلمي

مبسم الله الرحمن الرحي

Intracellular Accumulation

#Under some circumstances, cells may accumulateabnormal

amounts of various substances.

* Substance may be harmless or may cause injury

* Substance may locate either within organelles (typically

lysosomes), in the cytoplasm, or in the nucleus .

* Substance may be endogenous synthesized by the affected

cells, or may be exogenous , produced elsewhere.

#General pathways by which cells can accumulate abnormal

intracellular material are illustrated in

1- Abnormal metabolism : as in fatty change in the liver.

It will lead to accumulation of triglyceride in the liver causing

fatty changes

2- Protein mutation causing alteration in protein folding &

transport, with defective protein accumulation in the

cytoplasm . (e.g. alpha 1- antitrypsin deficiency).

When there's alpha 1 antitrypsin deficiency it will lead to the

accumulation of alpha 1 anti globular inside the parenchymal

cells in the liver.

Intracellular Accumulation

Lecture #6

Date : 27/10/2020

السلايدالأسود: ✓

كلام الدكتور الأزرق: ✓

الأخضر: شرح أو توضيح خارجي ✓


3- Lack of enzyme responsible for breaking down certain

compounds causing substrates to accumulate in

lysosomes, as in e.g. lysosomal storage diseases

The reason is : the cycle of these compounds in the body need

certain enzymes , some thing there us deficiency if this enzyme

lead to accumulation of those substances in the organelle, one ov

them is the lysosomal starch disease

4- Ingestion of indigestible materials e.g. accumulations of

carbon or silica particles.

Such as patient working in factories ( rubber or plastic

factories)lead to the accumulation of the carbon or silica or the

minor that people who work in coal mines this will lead to the

inhibition or ingestion of carbon particles that will engulf by the

macrophage and then it will accumulate in the tissue in the body

like the lung

# Fatty change = Steatosis

Normally, free fatty acids from adipose tissue or ingested

food are transported into hepatocytes where they are…

a. Esterified to triglycerides

b. Converted into cholesterol or phospholipids or

c. Oxidized to ketone bodies

Transport of the triglycerides from the hepatocytes

requires complexity with Apoproteins to form lipoproteins,

which then traverse the circulation.

Excess accumulation of triglycerides may result from

defects at any step from fatty acid entry to lipoprotein exit .

Steatosis is an abnormal accumulation of triglycerides within


parenchymal cells.

Steatosis mostly seen in the liver , the major organ involved

in fat metabolism , it may also occur in heart , skeletal

muscle, kidney & other organs.

Triglyceride إلا إذا ارتبط ب لا يمكن نقلهApoproteins

Patient during starvation, when there is deficiency in the ptn, it

will lead go the fatty changes of the liver ,because the

triglyceride will accumulate in the liver because there is no ptn

to complex with the triglyceride to be transformed into the

circulation so it accumulates .

شديد لشخص في جوع fatty changesيصبح عنده نفس الشرح بالنسبة للشخص الذي

# The mechanisms leading to accumulation of triglycerides in fatty

liver. Defects in any of the steps of uptake,catabolism, or secretion can

lead to Steatosis. B, Microscopically, the fat vacuole in the cytoplasm

displace & squeeze the nucleus to the periphery of the cell.

▪ Any defect in any step can cause accumulation for triglyceride

in the liver which appears as fat globular, that pushing the

nucleus to the side

▪ When we stain this liver with the oil red o or the sodium black to

stain the fat, fatty globular filled with fat .

#These are the most common causes of the fatty changes in

the liver :

1‐ Alcohol abuse is the most common cause of fatty change in the liver

in industrialized nations .

▪ 2-Protein malnutrition ,obesity, diabetes mellitus, anemia,

anoxia,& toxins are other causes of fatty change . Specially in

industrialized nations because they consume large amount of it


2-CCL4 & protein malnutrition decrease the synthesis of apoproteins

Anoxia inhibits fatty acid oxidation .

3-Starvation increase fatty acid mobilization from peripheral Stores.

Effects of fatty change depend on the cause & the severity of

accumulation. When mild, it may have no effect on the cellular

function. More sever fatty change may transiently impair cellular

function specially in liver , but unless some vital intracellular process is

irreversibly impaired (e.g., in CCL4 poisoning) , fatty change is

reversible. In a severe form, fatty change may precede cell death .

تصبح لكن عندما mildلما تكون reversibleهي fatty change بشكل عام ال ▪

sever تعتبرirreversible لأنها تسببnecrosis

▪ Figure 89: the shape of liver become greasy soft

#Cholesterol & Cholesteryl Esters

Normally, cellular cholesterol metabolism is tightly regulated to ensure

normal cell membrane synthesis without significant intracellular

accumulation. Phagocytic macrophages in contact with the lipid debris

of necrotic cells may become stuffed with lipid, imparting a foam

appearance to their cytoplasm, called foam cells .In atherosclerosis ,

smooth muscle cells & macrophages are filled with lipid vacuoles

composed of cholesterol & cholesterol esters; these give

atherosclerotic plaques their characteristic yellow color .In hereditary &

acquired hyperlipidemic syndromes , macrophages accumulates

intracellular cholesterol in the skinor in tendons, forming masses called

Xanthomas .

▪ Foam cell : phagocytic macrophages stuffed with lipid

(cholesterol) in atherosclerosis it leads into accumulation of fat

in the wall of the blood vessel many accumulation of fat


(cholesterol and cholesterol easter) in smooth muscles and

macrophages precipitated on the walls blood cells causing

damage to the endothelial of the blood vessels which will lead

that when blood component like platelets contact with damage

in the endothelial cells ,it will cause accumulation of these

substances which might cause thrombus which might lead to

occluding of the blood vessel subsequently cause ischemic,

because of narrowing of blood vessels (lumen of the blood

vessels) and decrease of blood supply to the tissue and organs

. If there is complete occlusion of the blood vessels,it might lead

to infarction بسرعة لمنع الجلطة لذا يعتبر تصلب الشرايين خطيرا و يجب علاجه

القلبية أو نقص التروية .

Sometimes there is gene that runs in the family that leads to

hyperlipidaemia in young age group ,because the macrophage

stuffed with their lipid accumulate in the skin or tendon which

form masses called xanthomas.

#

▪ Figure 91: This is atherosclerotic in the aorta

وقد يكبر مع thrombusوقد يسبب مرور الدم سيؤدي لتصلب الشرايين ونقص التروية هذا التجمع عند م

blood vesselل غلق اوقد يسبب plaqueال

=necrosis

▪ Figure93:1- this is the patient with registry hyperlipidaemia

2-we see accumulation of cholesterol fold

3-In microscopical examination we will see that

macrophage filled with the lipid ( cholesterol)

4- it called foam cells in the skin and subcutaneous tissue


▪ Figure 94: Nodular lesion in the skin and subcutaneous of

the hand of a patient with hypercholesterolemia , its mainly

consisting of foam cells ,macrophage stuffed with

cholesterol

#protiens slide :

1-Explain the first point :

In this syndrome the patient has ptn urea , has generalized edema

,preorpital edema ,sometimes has hyperlipidemia and hypoalbanemia .

These group of disorder affect the glomeruli. Most of the minimal

changes like the glomerulonephritis which mostly occurs in children , in

membranous glomerulonephritis and other types of glomerulonephritis

which cause neurotic syndrome .In those cases the patient presented

with the puffiness of the face , adema (pre orbital)and when we

examine the urine it will show ptn urea, in addition we see the pink

hyaline cytoplasmic droplet in the hyaline in renal tubules.

2-Explain the Second point :

This happened in certain disease like multiple myeloma. Its seen in the plasma

cell disorders or a new plasma like multiple myeloma

3-Explain the third point :Seen in alcoholic liver disease

▪ Figure96: normally glomeruli shouldn’t allow the ptn

passing through it, but when there is any disease affecting

the glomeruli such as in the nephritic syndrome ,minimal

changes glomerulonephritis (membrane or fosal

segmental) or any other disease affecting the kidney and

cause passing of the ptn to the glomeruli into the renal

tubule which appeared in the picture as hyaline pink

granule the renal tubule cell .


▪ Figure 97:

1-This is a patient with multiple myeloma

2-The plasma cells appeared larger than lymphocytes, with

eccentric nucleus (it’s slightly pushing into the side of the

cell) which is characteristic feature of the plasma cell and

plasma cell synthesis immunoglobulin which is synthesized

in the endoplasmic reticulum in this cell it's called Russel

body appeared as red colored dots .

▪ Figure 98:

It shows the accumulation of intermediate filaments in liver

cell

#Glycogen

Excessive intracellular deposits of glycogen are associated with

abnormalities in the metabolism of either glucose or glycogen.

(1) In poorly controlled diabetes mellitus : glycogen accumulates in

renal tubular epithelium, cardiac myocytes, & beta cells of the

islets of Langerhans.

In diabetes there’s abnormal metabolism of glucose , sometimes due

to deficiency of insulin which is produced by beta cells of langerhans or

sometimes there’s increase in peripheral resistance that to say the

patient has normal insulin but there is peripheral resistance to insulin

especially those patient which are obese , some times polycystic

ovary, all of these have peripheral resistance to insulin .

(2) In a group of related genetic disorders collectively referred to as

glycogen storage diseases, or glycogenoses, glycogen

accumulates within cells.In these diseases, enzymatic defects in


the synthesis or breakdown of glycogen result in massive

accumulation of glycogen with secondary Injury & cell death.

Glycogen accumulation happens because of the deficiency in

certain enzyme that are responsible for some steps are included

in the steps of the metabolism of these substances

• Figure100: these hepatocytes shaped like cord of cell

radiating from the centra vein to the portal truck

• Fig101: if we compare this microscopical picture with the

previous one, we see this is advanced of the fibers collagen

that exchange btw the tubules ,so this patient in addition to

the clear cell or the accumulation of glycogen which appear

the cell as clear because of accumulation of the glycogen

this induce the fibrosis of liver

Are colored substances can be either :Endogenous pigments i.e.

synthesized within the body itself, or exogenous pigments coming from

outside the body

I- Exogenous pigments :The most common exogenous pigment

is carbon (e.g. coal dust), a universal air pollutant. When

inhaled, carbon is phagocytosed by alveolar macrophages &

transported through lymphatic channels to the regional lymph

nodes (LN).Aggregates of the carbon pigment grossly blacken

the draining LN & the pulmonary parenchyma

(anthracosis).Heavy accumulations may induce a fibroblastic

reaction that can result in a serious lung disease called coal

dust worker pneumoconiosis .

II- Endogenous pigments

include lipofuscin , melanin & derivatives of hemoglobin .


III- (1) Lipofuscin : or “wear-&- tear pigment” seen due to aging , is

an insoluble, brownish-yellow granular intracellular material that

accumulates in a variety of tissues (particularly the heart , liver,

& brain) . It causes a brownish color of the tissue e.g. thebrown

atrophy of the heart .

(2) Melanin : is an endogenous, brown-black pigment.It is

synthesized exclusively by melanocytes , specific cells

characteristically found in the epidermis of skin & acts as an

endogenous screen against harmful ultraviolet radiation.

(3) Hemosiderin : Is a hemoglobin-derived granular pigment that is

golden-yellow to brown & accumulates in tissues when there is a local

or systemic excess of iron.Local excess of iron, & consequently of

hemosiderin, result from hemorrhage, e.g., in the skin, where it called

bruiseThe iron ions of hemoglobin are accumulated as golden yellow

hemosiderin .

you can understand this pigment when we have a trauma in the arm or

when you hit by something in the arm ,you can see that the bruise at

the site of the trauma within few days it appears as a bluish in color ,

while then the color is changed into the yellow soap and this because

of the hemorrhage in skin and subcutaneous tissue , so the iron of the

hemoglobin is accumulated as golden yellow hemoglobin

▪ Fig 104: it’s more seen in the Scandinavian countries and

USA ,because of the dark exposure tithe UV light and

becomes of their very white complexion in skin

#Hemosiderosis : is a condition characterized by systemicoverload of

iron, with hemosiderin deposited: first in the mononuclear phagocytes

of the liver, bone marrow, spleen, & lymph nodes, but, later, in the


parenchymal cells of the body, principally in the liver, heart, &

pancreas.Hemosiderosis 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 .

The patient should be diagnosed early in order to avoid development

of liver cirrhosis , heart failure and diabetes because of the

accumulation iron in the tissue and cause damage of the tissue or

organ

(2) Hemolytic anemias it will also lead to hemocidrosis

3)Frequent Blood transfusions, in which the transfused red cells

constitute an exogenous load of iron.

(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 .

#Pathologic Calcification

• In this form calcium salts are deposited in necrotic tissue with normal

calcium level in blood .

• Dystrophic calcification 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 .

This calcification can be important sign to go further investigation to the

female breast ,because this one might be beyond more aggressive

process in the breast ,maybe there is necrosis ,maybe malignant

tumorbecause it's seen in carcinoma of the breast.

• Grossly :

• the calcium salts are seen as fine, white granules or clumps, often

• felt as gritty deposits, or stony hard white nodules .

# Metastatic calcification :

It is characterized by deposition of calcium salts in normaltissues due

to increased calcium level in blood :

Causes of hypercalcemia are :

1- Increased secretion of parathyroid hormone ,such as in parathyroid

adenoma or parathyroid hyperplasia which lead to increased

parathyroid hormone because it cause immobilization of calcium form

the bone into the blood

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

tumors as in in multiple myloma, leukemia, or diffuse skeletal

metastases.

(3) Vitamin D-related disorders .

(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 .

This also because denial failure causes phosphate retention which

leads to secondary hyper par

Why it is secondary ?

Because it’s not caused by primary disease of the parathyroid .

*Primary hyperparathyroidism it's due to the hyperplasia of parathyroid

or due to the parathyroid adenoma or carcinoma

*secondary that means increase in the secretion of the parathyroid

from parathyroid gland , but the close is not deep in the hormone para

thyroid itself .it’s due to the other cause ,might be due to the renal

failure

*fig 108: any type of tissue can be affected with this

#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 ensuring the

complete replication of chromosome ends & 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 .

Telomeres consist of hundreds or thousand of repeat if the same short

of DNA sequences which vary btw the organism , but these repeats


gradually make up telomeres eating away slowly over time with each

division

#Telomere length is maintained by nucleotide addition mediated by

enzyme called Telomerase which is a specialized RNA-protein

complex that uses its own RNA as a template for adding nucleotides to

the end of chromosomes .Telomerase activity is present at germ cells ,

less in stem cells & absent in most somatic cells .In cancer cells,

telomerase is often reactivated.

Some cells have the ability to reverse telomere shortening be

expressing telomerase

#Defective protein Homeostasis:

Overtime the cells cannot maintain normal protein homeostasis ,

because of increased turnover & decreased synthesis.Abnormal

protein homeostasis can have many effects on cell survival , replication

& function , as well accumulated misfolded proteins , which trigger

apoptosis .Other factors : progressive accumulation of metabolic

damage ; possible roles of growth factors that promote aging in simple

mode organisms

يصبح هناك توازن بناء الخلايا الجديدة حتى يصل إلى عمر معين عند الأطفال يكون الجسم في حالة

البناء . الهدم ويقلبناء و الهدم ثم يتحول إلى في ال

الزهايمر والعديد من الأمراض المزمنة هو التخلص في الخلايا أحد أسباب

بالتوفيق ..


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ىفطصم يداهلا دبع حلاص دهش · #Cholesterol & Cholesteryl Esters Normally, cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis