Basic pathology

Dr. Mishaal
Adaptations &
Accumulations
 Objectives
The students should:
- Understand the concept of cells and tissue adaptation to
environmental stress including the meaning & types of
hypertrophy, hyperplasia, aplasia, atrophy, hypoplasia
and metaplasia with their clinical manifestations.
- Understand the causes of and pathologic changes
occurring in intracellular and extracellular
accumulations of materials causing degenerations.
- Understand the causes of and pathologic changes of
exogenous and endogenous pigments (carbon, silica,
iron, melanin, bilirubin and lipofuscin), Amyloidosis
definition & types, Calcification Definition causes and
types (Dystrophic & Metastatic) and differences between
dystrophic and metastatic calcifications.
Intracellular
accumulations
 Cell Injury and accumulations
CELLULAR ACCUMULATIONS :
• Cellular dystrophy is the morphological display of
the broken exchange of materials by cell’s
organelles, accompanied with the change of cell’s
structure.
• Under some circumstances cells may accumulate
abnormal amounts of various substances. Most of
them are manifestations of metabolic derangement
• Accumulation may be transient & reversible or it
may be permanent.
• Effects: range from harmless to toxic
 Intracellular accumulations
• May be found in the :
– cytoplasm
– organelles (typically lysosomes)
– nucleus

• Come to the cell through :

– Synthesis by affected cells
– Produced elsewhere and come to deposit in the affected
cell
Intracellular accumulations mechanisms
Four main mechanisms :
• abnormal metabolism (inadequate metabolic rate),
as in fatty change in the liver
• mutations causing alterations in protein folding
and transport, as in α1-antitrypsin deficiency
• deficiency of critical enzymes involved in
breakdown of substrates that accumulate in
lysosomes, as in lysosomal storage diseases
• inability to degrade or transport these particles, as
in hemosiderosis and carbon pigment
accumulation.
 Mechanisms of
intracellular
accumulations

Fig. 1-35, Pathologic Basis of

Disease, 2005
 Intracellular accumulations
• Types of substances which may accumulate
intracellularly :
1. water
2. Lipids
3. Proteins
4. Glycogen
5. Complex Lipids and Carbohydrates
6. Minerals
7. Pigments, and infectious agents products
 Intracellular accumulations
Lipids accumulate in excess in the cell:
LIPIDS: All major classes of lipids can accumulate in cells:
- Triglycerides e.g. steatosis (fatty change),
considered as a type of reversible cellular injury
- cholesterol/cholesterol esters (accumulation of
cholesterol in the form of intracellular vacuoles can
be seen in atherosclerosis in which there is
accumulation of cholesterol in the smooth muscle
cells and macrophages in the wall of arteries); and
- Phospholipids.
• In addition, abnormal complexes of lipids and
carbohydrates accumulate in the lysosomal storage
diseases.
Accumulations: cholesterol and Cholesteryl Esters
• Pathologic conditions of cholesterol excess:
– lipid laden macrophages : Macrophages in contact
with the lipid debris of necrotic cells or abnormal (e.g.,
oxidized) forms of lipoproteins
– Atherosclerosis : accumulation within macrophages in
intimal layer of large arteries, with associated fibrosis
– Cholesterolosis : accumulation within macrophages of
lamina propria of gallbladder
– Xanthoma : accumulation within macrophages of
dermis or tendons in patients with hypercholesterolemia
– In hereditary and acquired hyperlipidemic syndromes,
macrophages accumulate intracellular cholesterol
– Niemann-Pick disease type C : lysosomal storage disease
 Atherosclerosis:
• These give atherosclerotic plaques their
characteristic yellow color and contribute to the
pathogenesis of the lesion
Accumulations: cholesterol
 Intracellular accumulations
Proteins accumulate in excess in the cell:
• Accumulation of proteins: Intracellular
accumulations of proteins usually appear under the
microscope as rounded, eosinophilic droplets,
vacuoles, or aggregates in the cytoplasm.
• Mechanisms :
- Excesses exceeding capacity of cell to metabolize e.g.
Nephrotic syndrome
- Synthesis and secretion of excessive protein. e.g.
Russel bodies in multiple myeloma
- Defects in protein folding e.g. abnormal α-
1antitrypsin, Malory bodies in alcoholic cirrhosis
Accumulations: proteins
Intracellular accumulations mechanisms
α-1antitrypsin deficiency
 Intracellular accumulations
Glycogens accumulate in excess in the cell:
• Accumulation of Glycogen: Glycogen is a readily
available energy store that is present in the cytoplasm.
• Excessive intracellular deposits of glycogen are seen
in patients with an abnormality in either glucose or
glycogen metabolism.
• Diabetes mellitus is the prime example of a disorder
of glucose metabolism. In this disease, glycogen is
found in the epithelial cells of the distal portions of the
proximal convoluted tubules of kidney, as well as
within liver cells, β cells of the islets of Langerhans,
and heart muscle cells.
 Accumulations: Glycogen
• Glycogen also accumulates within the cells in a group
of closely related genetic disorders, collectively
referred to as the glycogen storage diseases, or
glycogenoses. In these diseases, enzymatic defects in
the synthesis or breakdown of glycogen result in
massive accumulation of glycogen, and cell death.

Morphology of glycogen accumulation :

• Microscopy : the intracellular deposits of glycogen appear
as clear vacuoles within the cytoplasm.
• Glycogen stains rose pinkish/violet with mucicarmine
stain or the periodic acid schiff (PAS) stain.
 Intracellular accumulations
Pigments accumulate in the cell:

• Accumulation of pigments: Pigments are colored

substances.
• Exogenous pigments: they are not synthesized
within the body itself and are coming from
outside the body.
• Exogenous
– Carbon (coal dust)
– Ink (tattoos)
– Others e.g. argyria (silver poisoning)
 Accumulations: pigments
• Endogenous pigments: synthesized within the
body itself, some of which are normal constituents
of cells (e.g., melanin), whereas others are
abnormal and collect in cells only under special
circumstances.
• Endogenous pigments:
– Lipofuscin
– Melanin
– Iron (hemosiderin)
– Homogentisic acid
– Bilirubin
 Accumulations: pigments
• Exogenous Pigments:
- Anthracosis: the most common exogenous pigment is
carbon pigment or coal dust, which is an air pollutant.
When breathing dirty polluted air, it is picked up by
macrophages in the lung alveoli and also transported to
the neighboring lymph nodes. Accumulation of this
pigment blackens the lungs (anthracosis) and the
draining lymph nodes. Smokers have the most
pronounced anthracosis. The anthracotic pigment looks
bad, but it causes no major organ dysfunction.
- But in the coal mining industry, there is too much carbon
dust in the lung of coal miners, which leads to fibrosis in
the lungs causing a disease known as coal worker's
disease, or pneumoconiosis.
Anthracosis lung
 Endogenous Pigments
Bilirubin is a yellowish pigment found in bile, a fluid
made by the liver.
•Bilirubin is a breakdown product of heme catabolism
(from hemoglobin and myoglobin). Most of the bilirubin
is derived from the break down of hemoglobin.
•High levels of serum bilirubin leads to a condition
called as jaundice.
•Jaundice (also known as icterus) is a yellowish
pigmentation of the skin, the conjunctivae, the sclerae
(whites of the eyes), and other mucous membranes and it
is caused by high blood bilirubin levels. Urine is also
dark in color. It can also cause itching. Jaundice is often
seen in liver disease such as hepatitis or liver cancer or
obstruction of the biliary tract by gallstones or tumors.
 Endogenous Pigments
•Jaundice

"Jaundice" by Sab3el3eish - Own work. Licensed under CC BY 3.0 via Commons -

https://commons.wikimedia.org/wiki/File:Jaundice.jpg#/media/File:Jaundice.jpg
Endogenous Pigments
 Intra &Extra-cellular
accumulation and depositions
• Some substances can accumulate
intracellularly and extracellularly
simultaneously.
• Examples:
- Pathologic calcification:
 Pathologic Calcification
• Definition: abnormal deposition of calcium salts,
often with associated Mg or Fe salts.
• Must be distinguished from physiologic
calcification, as in normal bone.
• Two forms of pathologic calcification
– Dystrophic calcification : local deposition of calcium
salts in nonviable (dead or damaged) or degenerating
tissue in living organism, despite normal serum calcium
level
– Metastatic calcification : deposition of calcium salts in
normal, viable tissues in living organism secondary to
hypercalcemia
 Dystrophic calcification
• Morphology :
• Gross : calcium salts are grossly seen as fine white
granules or clumps, often felt as gritty deposits.
• Sometimes a tuberculous lymph node with
dystrophic calcification is essentially converted to
radio-opaque stone.
• Microscopy: calcification appears as intracellular
and/or extracellular basophilic amorphous granular
deposits. Progressive deposition on outer layers
may create lamellated configurations, called
psammoma bodies (eg. In papillary cancers of
thyroid, ovary, kidney and in brain meningeoma).
Dystrophic calcification of the aortic valves
Pathologic Calcification
 Psammoma bodies
• Psammoma body is a special type of
dystrophic calcification made up of
concentric lamellated calcified
structures, seen in papillary cancers in
the body (e.g. thyroid, ovary, kidney)
and in the meningioma of the brain.
 Metastatic calcification
• May occur in normal tissues whenever
hypercalcemia is present. Most common sites are
kidney, lung, stomach, blood vessels and cornea.
• Major causes of hypercalcemia:
– Increased PTH (most common cause) : in primary
hyperparathyroidism due to parathyroid adenoma or
hyperplasia; or malignant neoplasm making PTH-
related protein
– Destruction of bone : primary bone tumors,
metastatic cancer to bone, or Paget’s disease
– Vitamin D disorders : vitamin D toxicity, sarcoidosis
– Renal failure : renal failure, in which phosphate
retention leads to secondary hyperparathyroidism.
 Metastatic calcification
• Morphology: Metastatic calcification can occur
widely throughout the body but principally affects
the interstitial tissues of the vasculature, kidneys,
lungs, and gastric mucosa. The calcium deposits
morphologically resemble those described in
dystrophic calcification.
• Extensive calcifications in the lungs and breast
may produce remarkable radiographs and clinical
manifestations

• Massive deposits in the kidney (nephrocalcinosis)

can cause renal damage.
 Metastatic calcification
Metastatic calcification" in the lung of a patient with a very
high serum calcium level
 Extracellular accumulation and depositions
• Types of substances which may accumulate in
extra-cellular matrix:
1. water
2. Lipids
3. Carbohydrates (Glycogen)
4. Complex Lipids and Carbohydrates
5. Proteins
6. Nucleic acid products
7. Minerals
8. Pigments, and infectious agents products
 Extracellular accumulation and
depositions
• water : may accumulate extracellularly causing
pathologies such as oedema, ascites, pleural
effusion.
 Extracellular accumulation and depositions
Amyloid
• Amyloid : Term amyloid first coined by Virchow
in mid 19th century (meaning similar to starch or
cellulose).
• Fibrillar nature and beta pleated sheet
configuration was described by electron
microscopy in 1959.
 Amyloid
Amyloidosis is an extracellular deposition of
fibrillary amyloid protein in various organs (kidney,
liver, blood vessels, heart etc.) leading to organ
damage.
It is associated with a number of inherited and
inflammatory disorders.
Amyloid protein has
a disorder of protein
mis-folding. Amyloid
is composed of non-
branching fibrils of β-
pleated sheets. Light microscopy H&E stain
Pathpedia.com
Figure 6-53 Structure of an amyloid fibril, depicting the β-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified
from Glenner GG: Amyloid deposit and amyloidosis. The β-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
 Amyloidosis
• Amyloidosis is not a single disease; rather it is a
group of diseases having in common the
deposition of similar-appearing abnormal
proteins.
• There are three major and several minor
biochemical forms of amyloid.
 Chemical Nature of Amyloid
- Approximately 95% of the amyloid material
consists of fibril proteins,
- the remaining 5% is P component and other
glycoproteins.

• There are 15 biochemically distinct forms of

amyloid proteins that have been identified.
 Classification of Amyloidosis
• Amyloid may be classified based on its constituent
chemical fibrils into categories such as AL, AA, and ATTR.
• Amyloid may be classified based on distribution or range
of affected parts into :systemic (generalized), or localized.
• The systemic (generalized) pattern is subclassified based on
aetiology into:
a) Primary amyloidosis: is associated with B-cell dyscrasias
such as plasma cell abnormality e.g. multiple myeloma.
In it the “AL” type amyloid is deposited.
b) Secondary amyloidosis: it is secondary to tissue
destructive process such as chronic inflammatory or
autoimmune diseases (osteomyelitis, tuberculosis,
rheumatoid arthritis etc). In it “AA” type (amyloid
associated protein) amyloid is deposited.
- Hereditary or familial amyloidosis constitutes a separate
group.
 Most common biochemical Forms of
amyloid

(1) AL (amyloid light chain) is derived from plasma

cells and contains immunoglobulin light chains
(2) AA (amyloid-associated) is a unique
nonimmunoglobulin protein synthesized by the
liver
 Other biochemical forms of Amyloid
• Transthyretin (TTR): is deposited familial
amyloid polyneuropathies and in the heart of aged
individuals (senile systemic amyloidosis).

• β2-microglobulin: seen in amyloidosis that occurs

in patients on long-term hemodialysis.

• β-amyloid protein (Aβ), found in Alzheimer

disease.The Aβ protein is derived from a
glycoprotein, called amyloid precursor protein.
 Amyloidosis
Pathogenesis
• The proteins that form amyloid fall into two
general categories:
(1) normal proteins that have an inherent tendency
to fold improperly and form fibrils, and do so
when they are produced in increased amounts.
(2) mutant proteins that are structurally unstable and
prone to misfolding and then form fibrils.
 Amyloidosis
Morphology
• Histologic diagnosis of amyloid is based on its
characteristic staining with dye Congo red,
which under ordinary light gives a pink or red
color to amyloid deposits. Under polarized light,
the Congo red-stained amyloid shows a green
birefringence.
• Under electron microscopy the fibrillar structure
is identified
Morphology of
amyloid
Light Light microscopy H&E stain
microscopy: Pathpedia.com

- With H&E it is
pink eosinophilic
material.
- With Congo red
stain: it appears
bright orange. CONGO RED STAIN
- And when the
congo red stained
tissue is exposed
to polarized light
it produces an
apple-green
birefringence. POLARIZED LIGHT
Briggs JH, Singleton WG, Burke MM, Hart LA, Parker RJ - Cases J (2009)
 Amyloid
Morphology of amyloid:
Electron microscopy (very rarely used): amyloid
deposits are composed of non-branching fibrils, 7.5 to 10
nanomicron in diameter. The fibers have characteristic
cross-β-pleated sheets and are responsible for the
distinctive staining and birefringence of Congo red-
stained amyloid
 Amyloidosis
Clinical Correlation
• Amyloidosis may be found incidentally with no
clinical manifestations, or it may cause severe
disease leading to death.
• The symptoms depend on the magnitude of the
deposits and on the organs affected. At first
nonspecific symptoms such as weakness, weight
loss, light-headedness, or syncope. Specific
findings appear later and most often relate to renal,
cardiac, and gastrointestinal involvement.
 Amyloidosis
Clinical Correlation
1) Renal involvement: proteinuria, can cause the
nephrotic syndrome. Progressive obliteration of
glomeruli in advanced cases leads to renal
failure and uremia
2) Cardiac amyloidosis: insidious congestive heart
failure. The most serious complications are
conduction disturbances and arrhythmias, which
may prove fatal.
 Amyloidosis
Clinical Correlation
3) Gastrointestinal amyloidosis: may be
asymptomatic. Amyloidosis of the tongue may
cause enlargement and hamper speech and
swallowing. Depositions in the stomach and
intestine may lead to malabsorption, diarrhea,
and disturbances in digestion.
 Amyloidosis
Prognosis
• The prognosis for patients with generalized
amyloidosis is poor especially those with
immunocyte-derived amyloidosis or with
myeloma-associated amyloidosis.
• Patients with reactive systemic amyloidosis have a
better prognosis and it depends to some extent on
the control of the underlying condition.
• Resorption of amyloid after treatment of the
associated condition is rare.
• New therapeutic strategies aimed at correcting
protein misfolding and inhibiting fibrillogenesis
are being developed.
•THANKS