1. Reversible
cellular injury
Part 1
Cellular swelling- vacuolar and hydropic
degeneration
Intracellular accumulation of lipids -atherosclerosis.
Lipidoses.

2. Reversible cellular injury 1
 Disorders in the cellular water balance.
 Lipid accumulation within the parenchymal
cells /lipid degeneration/.
 Lipid accumulation within the mesenchymal
cells. Lipid phagocytosis.
 Lysosomal storage diseases /
tesaurismoses/.
 Abnormal accumulation of complex lipids in
the cell - lipidosis.

3. CELLULAR RESPONSES TO
STRESS AND PATHOGENIC
FACTORS
hypertrophy,
hyperplasia,
atrophy
metaplasia

4. REVERSIBLE CELL
INJURY
 Morphologic changes in early stages or
mild forms of injury
 reversible if the damaging stimulus is removed
 Some injuries can lead to death if prolonged
and or severe enough
 In the past
 Degeneration (degenerare – changing)
 Dystrophia (dys+trophe –abnormal feeding)

5. REVERSIBLE CELL
INJURY
 Two groups morphologic changes
 Disorders in the cellular water balance

Cellular swelling
 Abnormal intracellular accumulations

Lipids

Glycogen, mucopolysacharides

Proteins

Pigments

6. Disorders in the cellular water
balance
Cellular swelling
 The first manifestation of almost all forms
of injury to cells – hypoxia, infections,
poisons
 Increased cellular water content
 Due to failure of energy-dependent ion pumps
in the plasma membrane, leading to an
inability to maintain ionic and fluid
homeostasis.

7. Disorders in the cellular water
balance
Cellular swelling
 It is difficult to appreciate with the light
microscope
 It may be more apparent at the level of the whole
organ-macroscopy
 it causes some pallor, increased turgor, and increase
in weight of the organ.
 Site of localization
 Renal tubular cells
 Hepatocytes
 Myocardial cells

8. Disorders in the cellular water balance
Cellular swelling
 Microscopic examination

Cells are swollen, deformed,
pale

hydropic change or
vacuolar degeneration –the
presense of small, clear
vacuoles within the cytoplasm
 they represent distended and
pinched-off segments of the
ER.
 Swelling of cells is reversible.

9. Degeneratio parenchymatosa renis
The epithelial cell of the proximal convoluted tubules are swollen and
deformed, with pale and dull cytoplasm

10. Abnormal intracellular accumulations
 Under some circumstances cells may
accumulate abnormal amounts of
various substances
 They may be harmless or associated with
varying degrees of injury.
 may be located in the cytoplasm, within
organelles (lysosomes), or in the nucleus

11. Abnormal intracellular accumulations
3 main pathways of intracellular accumulations
 A normal substance is produced at a normal or an
increased rate, but the metabolic rate is
inadequate to remove it.
 fatty change in the liver
 A normal or an abnormal endogenous substance
accumulates because of genetic or acquired
defects in its folding, packaging, transport, or secretion.
 accumulation of proteins - α1-antitrypsin deficiency
 defect in an enzyme results to failure to degrade a
metabolite – storage diseases
 An abnormal exogenous substance is deposited and
accumulates because the cells has no enzymatic
machinery to degrade the substance nor the ability
to transport it to other sites
 Accumulations of carbon or silica particles

12. Intracellular accumulations
 Lipids
 Neutral Fat
 Cholesterol
 Proteins
 “Hyaline” = any “proteinaceous” pink “glassy”
substance
 Glycogen
 Pigments
 Endogenous
 exogenous

13. Intracellular lipid accumulations
 Sites of localization
 within the parenchymal cells -lipid
degeneration
 within the fat cells – obesitas, lipomatosis
 within the macrophages -lipid
phagocytosis.

14. Lipid accumulation within the parenchymal cells
Lipid degeneration
 = Fatty Change (Steatosis)
 refers to any abnormal accumulation of
triglycerides within parenchymal cells.
 It is most often seen in the liver, since this is
the major organ involved in fat metabolism
 It may also occur in heart, skeletal muscle,
kidney, and other organs.
 Steatosis may be caused by toxins, protein
malnutrition, diabetes mellitus, obesity, and
anoxia.

15. Pathogenesis of fatty liver
 Fat metabolism
 Free fatty acids from adipose tissue or ingested
food are normally transported into hepatocytes
 they are esterified to triglycerides, converted into
cholesterol or phospholipids, or oxidized to
ketone bodies
 Some fatty acids are synthesized from acetate
within the hepatocytes as well.
 Secretion of the triglycerides from the
hepatocytes requires the formation of complexes
with apoproteins to form lipoproteins, which are
able to enter the circulation
 Excess accumulation of triglycerides may result
from defects at any step from fatty
acid entry to lipoprotein exit, thus accounting
for the occurrence of fatty liver after diverse
hepatic insults.
 Overfeeding, obesitas, diabetes mellitus - ↑ FFA
income
 Starvation- ↑ fatty acid mobilization from
peripheral stores.
 Hypoxia and Hepatotoxins (e.g., alcohol) - ↓fatty
acid oxidation (alter mitochondrial, SER function)
 CCl4 and protein malnutrition - ↓ synthesis of
apoproteins

16. Morphology of fatty changes
 In any site, fatty accumulation appears
as clear vacuoles within parenchymal
cells.
 Special staining techniques are
required to distinguish fat from
intracellular water or glycogen, which
can also produce clear vacuoles but
have a different significance.
 To identify fat microscopically, tissues
must be processed for sectioning
without the organic solvents typically
used in sample preparation - frozen
sections, by staining with Sudan IV or
oil red O (stain fat orange-red).
 Glycogen may be identified by staining
for polysaccharides using the periodic
acid-Schiff stain (stains glycogen red-
violet).
 If vacuoles do not stain for either fat or
glycogen, they are presumed to be
composed mostly of water.

17. LIPID LAW
 ALL Lipids are
YELLOW grossly and
WASHED out
(CLEAR)

18. FATTY LIVER
 Gross appearance
 Mild fatty change in the
liver may not affect the
gross appearance.
 With increasing
accumulation, the organ
enlarges and becomes
progressively yellow

it may weigh 3 to 6 kg
(1.5-3 times the normal
weight)
 bright yellow, soft, and
greasy.

19. FATTY LIVER
 Microscopic features
 Microvesicular
steatosis
 Macrovesicular
steatosis
 mixed

20. Degeneratio Adiposa Hepatis
(HE, Sudan III)

21. Lipid degeneration of myocardium
 In the heart, lipid is found in the form of
small droplets, occurring in one of two
patterns
 In prolonged moderate hypoxia (anemia)- focal
intracellular fat deposits (papillary muscles)

creating grossly apparent bands of yellowed myocardium
alternating with bands of darker, red-brown, uninvolved
heart ("tigered effect").
 In more profound hypoxia or by some forms of
toxic injury (e.g., diphtheria) – diffuse pattern of
fatty change

uniformly affected myocytes.

22. Lipid degeneration of the ren
 In the ren, lipid is found in the form of
small droplets, occurring in the epithelial
cells of convoluted tubules
 In severe hypoxia
 In nephrotic syndrome

Increases reabsorption of lipoproteins

23. FATTY CHANGES
 The significance of fatty change depends on
the cause and severity of the accumulation.
 When mild it may have no effect on cellular
function.
 More severe fatty change may transiently impair
cellular function - fatty change is reversible.
 In the severe form, fatty change may precede cell
death, and may be an early lesion in a serious liver
disease called nonalcoholic steatohepatitis

24. Lipid accumulations within the fat
cells
 General obesitas
 within the fat cells of adipose
tissue
 Lipomatosis (local
obesitas)
 within the fat cells of
connective tissue of different
organs, no functional
disturbances

Heart – subepicardium of right
chamber

Pancreas – interlobular
connective tissue

25. Lipid accumulations within the
macrophages
Lipid phagocytosis.
 Phagocytic cells may become overloaded with lipid (triglycerides,
cholesterol, and cholesterol esters) in several different pathologic
processes.
 Macrophages in contact with the lipid debris of necrotic cells or abnormal
(e.g., oxidized) forms of lipoproteins may become stuffed with phagocytosed
lipid.

foam cells - macrophages filled with minute, membrane-bound vacuoles of lipid,
imparting a foamy appearance to their cytoplasm.
 In atherosclerosis - smooth muscle cells and macrophages are filled with lipid
vacuoles composed of cholesterol and cholesteryl esters

these give atherosclerotic plaques their characteristic yellow color and contribute to
the pathogenesis of the lesion
 Xantomas – fibromas (benign tumors, where tumor cells accumulate
cholesterol esters)

xanthos – yellow,
 Xantelasmas

clusters of these foamy macrophages present in the subepithelial connective tissue
of skin
 In hereditary hyperlipidemic syndromes macrophages accumulate intracellular
cholesterol - lipidoses

26. Arteriosclerosis
 Endothelial cell damage of muscular and elastic arteries
 Abdominal aorta
 coronary artery,
 popliteal artery
 Internal carotid artery
 Causes of endothelial cell injury
 Hypertension, smoking, LDL
 Cell response to endothelial injury
 Macrophages and platelets adhere to damaged
endothelium.
 Released cytokines cause hyperplasia of medial smooth
muscle cells.
 Smooth muscle cells migrate to the tunica intima.
 Cholesterol enters smooth muscle cells and macrophages
(foam cells).
 Smooth muscle cells release cytokines that produce
extracellular matrix.

collagen, proteoglycans, and elastin
 Development of fibrous cap (plaque)

Smooth muscle, foam cells, inflammatory cells,
extracellular matrix

Fibrous cap overlies a necrotic center.
 Cellular debris, cholesterol crystals (slit-like spaces),
foam cells

Disrupted plaques may extrude underlying necrotic material
leading to vessel thrombosis

Fibrous plaque becomes dystrophically calcified and ulcerated.

27. Arteriosclerosis
 Complications of atherosclerosis
 Vessel weakness (e.g., abdominal
aortic aneurysm)
 Vessel thrombosis

acute MI (coronary artery),

Stroke (internal carotid artery, middle
cerebral artery),

Small bowel infarction (superior
mesenteric artery),
 Hypertension

Renal artery atherosclerosis may
activate the renin-angiotensin-
aldosterone system.
 Peripheral vascular disease
 Increased risk of gangrene

Pain in the buttocks and when walking
(claudication)
 Cerebral atrophy

circle of Willis vessels or internal carotid artery

28. Atheromatosis Aortae
(HE, SUDANIII)

29. Atheromatosis Aortae
The slit-like spaces are cholesterol clefts, a
classic feature of atherosclerosis

30. Tesaurismoses
Lysosomal Storage Diseases
 There is an inherited lack of a lysosomal
enzyme, catabolism of its substrate remains
incomplete, leading to accumulation of the
partially degraded insoluble metabolites within
the lysosomes
 Lysosomes, contain a variety of hydrolytic enzymes
that are involved in the breakdown of complex
substrates into soluble end products.
 Approximately 40 lysosomal storage
diseases, divided into broad categories based
on the biochemical nature of the substrates
and the accumulated metabolites
 Lipidosis
 Glycogenosis
 Mucopolysaccharidoses

Within each group are several entities, each resulting
from the deficiency of a specific enzyme.

Despite this complexity, certain features are common to
most diseases in this group

31. LIPIDOSIS
 Autosomal recessive transmission of
enzyme defects for lipid metabolism,
leading to accumulation of undegraded
lipid metabolites in the cells of different
organs
 Gaucher Disease
 Tay-Sachs disease
 Niemann-Pick Disease, Types A and B

32. LIPIDOSIS
Gaucher Disease
 The disease results from mutation in the gene
that encodes glucosylceramidase
(glucocerebrosidosis)
 an accumulation of glucosylceramide in the
mononuclear phagocytic cells (liver, lien, bone
marrow) and their transformation into so-called
Gaucher cells

derived from the breakdown of senescent blood
cells, particularly erythrocytes
 Gaucher cells
 enlarged, (100 μm), because of the
accumulation of distended lysosomes,
 a pathognomonic cytoplasmic appearance
characterized as "wrinkled tissue paper“
 EM –lysosomes with tubular structures and
fibrils
 Clinical features
 hepatosplenomegaly
 Bones-osteopenia
 ± neurologic disorders

33. LIPIDOSIS
Tay-Sachs disease
 Characterized by a mutation in
and consequent deficiency of the
α subunit of the enzyme
hexosaminidase A, involving in
the degradaytion of gangliosides
 CNS –neurons, ganglia, retina

Neurologic disturbances, amaurosis
 Affected cells - swollen, possibly
foamy
 EM- a whorled configuration within
lysosomes

34. LIPIDOSIS
Niemann-Pick Disease
 A primary deficiency of acid
sphingomyelinase and the resultant
accumulation of sphingomyelin
 Affected cells and organs
 phagocytic cells of spleen, liver, bone
marrow, lymph nodes, lungs

stuffed with droplets or particles of the
complex lipid, imparting a fine vacuolation or
foaminess to the cytoplasm
 Neurons of CNS

enlarged and vacuolated as a result of the
storage of lipids.
 2 types
 Type A –manifests itself in infancy with
massive visceromegaly and severe
neurologic deterioration
 Type B – no neurologic disorders