Transcript Intracellular accumulations and senescence

Lecture 6
Intracellular accumulations
Aging/Senescence
Associate Professor
Dr. Alexey Podcheko
Spring 2015
Intended Learning Outcomes
To know 4 mechanisms of intracellular accumulations
To know mechanisms of intracellular lipid accumulation
To know examples of diseases associated with
cholesterol accumulation in the tissues
To know examples of diseases associated with protein
intra/extracellular accumulations
To know examples of diseases associated with
excessive accumulation of Hemosiderin, Ca, Melanin
To know diseases associated with premature
senescence
Intracellular Accumulations
As a result of metabolic derangements
cells can accumulate abnormal amounts
of various substances
There are two categories of substances:
1. Normal cellular constituents (lipids,
proteins, carbohydrates)
2. Abnormal substances (deposits of salts,
products of infectious agents, abnormal
metabolites)
First main mechanisms of
intracellular accumulation (out of 4)
1. Normal endogenous
substance is produced
at normal or increased
rate, but the rate of
metabolism is
inadequate to remove
it (hepatic steatosis,
protein droplets in the
plasma cells of
patients with multiple
myeloma)
Second main mechanisms of
intracellular accumulation
2. Product of the
mutated gene
accumulates in the
cell due to defects in
the protein
folding/transport or
cell unable degrade
abnormal protein
(mutated alpha1antytrypsin in the
liver cells,
degenerative
disorders of CNS)
Third main mechanisms of
intracellular accumulation
3. A normal endogenous substance
accumulates due to inherited
defects in enzymes that are
required for metabolism of the
substance
Lysosomal storage diseases
examples:
Tay-Sachs disease aka
Hexosaminidase A deficiency –
gangliosides accumulate in
the nerve cells of the brain
Gaucher's disease
aka lysosomal glucocerebrosidase deficiency accumulation of
glucocerebroside in white blood
cells, macrophages,
oligodendrocytes and Schwann
cells
These enlarged, pale neurons are in a brain
of the child with Tay-Sachs disease
Forth main mechanisms of
intracellular accumulation
4. Exogenous
abnormal
substance
accumulated
because cell does
not have enzymes
to degrade
substance or
transport system
to carry away the
substance
(carbon, silica,
asbestos)
Intracellular Accumulation of Lipids
Types of Lipids accumulating in the
cells:
1. Triglycerides (fatty change in liver
cells)
2. Cholesterol/cholesterol esters
(atherosclerosis, xanthomas)
3. Phospholipids (myelin figures),
complex lipids (Lipid storage disorders –
sphingolipid, glucocerebroside
accumulation)
Steatosis (Fatty change)
Steatosis – abnormal accumulation of triglycerides within
parenchymal cells
Target organs: liver, heart muscle, kidney
Causes: toxins, alcohol, lack of proteins, Diabetes, hypoxia
diabetes, obesity, alcoholism (toxic) are the most common
causes of fatty liver
Normal metabolism of triglycerides
in hepatocytes
Step#1: Free fatty acids
(FFA) transported into
hepatocyte by fatty acids
binding proteins or FFA
synthesize from acetate in
the hepatocytes
Step#2: Esterification into
triglycerides or conversion
into
cholesterol/phospholipids
or oxidization into ketone
bodies.
Step#3: Triglycerides
associate with apoproteins
and form lipoproteins and
released from the cells
Mechanisms of abnormal accumulation of
triglycerides in the hepatocytes induced by alcohol
Alcohol:
1. Shunting of normal substrates away from catabolism toward
lipid biosynthesis due to excessive generation of NADH by
alcohol dehydrogenase and acetaldehyde dehydrogenase
2. Impaired assembly and secretion of lipoproteins
3. Increased peripheral catabolism of fat- more fatty acids
enter into hepatocytes
4. Acetaldehyde induces lipid peroxidation of lipoproteins –
disruption of membranes and cytoskeleton
5. P450 activation produces excess of free radicals
6. Impairment of methionine metabolism leads to reduced
level of glutathione – reduced detoxification activity of liver
cells
7. Increase production of proinflammatory cytokines by
hepatocytes and sinusoidal epithelial cells (TNF-a, IL-6,
TGF-alpha and endothelins)
Hepatic Steatosis
fatty change of the liver. In most cells the well-preserved nucleus is squeezed into
the displaced rim of cytoplasm about the fat vacuole
High fat diet induced hepatic steatosis
Oil red O staining
High fat diet induced
intramyocardial lipid accumulation
Tigered effect of lipid accumulation
Oil red O staining
An autopsy of a 24-year-old medical student who died in
the car accident revealed an enlarged (1800 g) liver with a
yellow cut surface. The microscopic appearance of this
liver is shown in the figure. Before death, the man's total
serum cholesterol and triglyceride levels were normal, but
he had a slightly decreased serum albumin concentration.
Which of the following activities most likely
led to these findings?
(A) Injecting heroin
(B) Playing basketball
(C) Drinking beer
(D) Smoking cigarettes
(E) Ingesting aspirin
Intracellular accumulation of Cholesterol
and Cholesterol Esters
•
•
Most of the cells do not
deposit cholesterol but use it
immediately
Pathologic cholesterol
accumulations manifest by
appearance of intracellular
vacuoles
Diseases associated with
cholesterol accumulation:
1. Atherosclerosis - cholesterol
accumulation in the smooth
muscle cells and
macrophages
Morphological features:
a. Foam cells
b. Atheromas
c. Cholesterol Clefts- crystals of
cholesterol
Diseases associated with cholesterol
accumulation
2. Xanthomas: Tumor like clusters of foamy cells in the
subepithelial connective tissue of the skin and tendons
Morphological features: similar to atherosclerosis (foam
cells+clefts)
Diseases associated with cholesterol
accumulation
3. Cholesterolosis (strawberry gallbladder ): Focal accumulation of cholesterollaiden macrophages in the lamina propria of the gallbladder
Diseases associated with cholesterol
accumulation
4. Neimann-Pick Disease, Type C :
Lysosomal storage autosomal
recessive disease caused by mutation
affecting an enzyme involved in
cholesterol trafficking and
accumulation of cholesterol in multiple
organs
Features:
1. mutations
in NPC1 and NPC2 genes (transporter
in the endosomal-lysosomal system,
which moves large waterinsoluble molecules through the cell)
2. The disruption of this transport
system results in the accumulation of
cholesterol and glycolipids in
lysosomes
Intracellular accumulations of proteins
•Usually appear as rounded eosinophilic droplets, vacuoles
or aggregates
•Sometimes deposited in extracellular spaces
Pathology associated with
protein accumulation:
1. Reabsorbtion droplets in
proximal renal tubules –Lipid
Nephrosis( aka Minimal
Change Disease)
Features:
Pink hyaline droplets within
the cytoplasm of tubular cells
Normal proximal tubules
Intracellular accumulations of proteins
Pathology associated with
protein accumulation:
2. Russel Bodies –
accumulation of
immunoglobulins in plasma
cells
Features:
ER is highly distended and
looks like pink aggregate
within the cell
Russel bodies (Myeloma)
Intracellular accumulations of proteins
Pathology associated
with protein
accumulation:
3. Alcoholic Hyaline –
accumulation of keratin
intermediate filaments in
the hepatocytes during
alcoholic hepatitis
Features:
Favorite USMLE picture of
alcoholic hepatitis – fatty
changes+ pink condensed
ropy material inside of the
cells
Mallory bodies
Extracellular accumulations of proteins
Amyloid
Hyaline arteriolosclerosis
Hyaline membrane disease of the
newborn
Amyloidosis group of diseases characterized by
deposition of amyloid
Amyloid is a pathologic proteinaceous substance, deposited in the extracellular
space in various tissues and organs of the body in a wide variety of clinical settings.
Main Features:
1. No distinct chemical
structure
2. Congo red stain provide
apple-green birefringence
in the polarized light due to
beta-sheet conformation of
fibrills proteins
3. More than 20 biochemically
distinct forms, most
frequently tested ALight
(plasma cell tumors),
serumAA (chronic
inflammation), ABeta
(Alzheimer )
Hyaline arteriolosclerosis
Hyaline is any deposition of protein in the extracellular
space that gives a homogeneous, glassy pink
appearance on H&E staining
Hyaline arteriolosclerosis is the deposition of proteins in
the arterioles
Mechanism:
1. plasma protein leakage across the endothelium due to
increased hydrostatic pressure and
2. increased production of cell matrix by smooth muscle
cells in vessel wall
3. Dysfunction of endothelial cells induced by
hyperglycemia
Hyaline arteriolosclerosis is a small vessel
arteriosclerosis that is commonly found in
diabetics and hypertensive patients.
Hyaline membrane disease of newborn
•Deficiency of pulmonary surfactant due to
mutations or insufficient level of
glucocorticoids
•Hyaline composed of fibrin mixed with cell
debris
Other Cellular Alterations During Injury
Exogenous pigments
Anthracotic pigmentation of lungs
Tattoos
Other Cellular Alterations During Injury
•Pigments are colored substances which
accumulate under special circumstances, can
be endogenous and exogenous
Endogenous pigments
1. Lipofuscin
2. Melanin
3. Hemosiderin
LIPOFUCIN
Wear and tear pigment
Product of lipid peroxidation and aging
Perinuclear yellow-brown pigment
Preferred locations: Liver and Heart
Pathology: Excessive accumulation of Lipofuscin
in the heart is associated with atrophy of heartbrown atrophy
Melanin
Black-brown pigment
Found in melanocytes and substantia nigra
malignant melanoma
Hemosiderin
Golden-yellow-brown granules
Areas of hemorrhage or bruises
Systemic Iron overload
(Hemosiderosis/Hemochromatosis)
Prussian Blue Stain to detect iron
HEREDITARY HEMOCHROMATOSIS
Mutations of genes encoding HFE, transferrin receptor 2 (TfR2), or hepcidin
Prussian Blue Stain to detect iron
Prussian blue reaction of the liver
Pathologic forms of Calcification
Dystrophic calcification: precipitation of
Ca3(PO4)2 in dying or necrotic tissues
(saponification)
Metastatic calcification: precipitation of
Ca3(PO4)2 in normal tissues due to
hypercalciemia
Dystrophic calcification examples
Fat Necrosis and saponification
Psammoma bodies –laminated calcification
(papillary cancer of thyroid, ovaries serous
cystadenocarcinoma , meningiomas)
Monckeberg’s medial calcific sclerosis
Atherosclerotic plaques
Oligodendrocytoma and craniopharyngioma
associated with calcification of brain tissue
Psammoma bodies:
Psammomatous meningioma
Also may be found in:
Papillary renal cell carcinoma
Ovarian papillary serous cystadenocarcinoma
Endometrial adenocarcinomas
Peritoneal and Pleural Mesothelioma
Prolactinoma of the pituitary
Thyroid Papillary Carcinoma
Metastatic calcification examples
Hyperparathyroidism (primary)
Parathyroid adenomas
Renal failure (due to accumulation of phosphates!)
Paraneoplastic syndrome
Vit D intoxication
Milk-alkali syndrome
Sarcoidosis
Paget Disease
Multiple Myeloma to the bone
Metastatic cancer to the bone
Metastatic Calcification (examples)
Lung
Coronary Artery
A 70-year-old man died suddenly. At autopsy, multiple
tissue sites were sampled for microscopic analysis.
Examination of the tissues showed noncrystalline
amorphous deposits of calcium salts in gastric
mucosa, renal interstitium, and
alveolar walls of lungs. Which of the following
conditions would most likely explain these findings?
(A) Chronic hepatitis
(B) Disseminated tuberculosis
(C) Renal failure due to chronic glomerulonephritis
(D) Generalized atherosclerosis
(E) Normal aging process
Cellular Aging and Senescence
Result of progressive decline in cellular function and viability
caused by genetic abnormalities and the accumulation of cellular
and molecular damage
Decreased cellular proliferation
Terminal growth arrest- senescence
Mechanisms of Senescence:
1. Incomplete replication of telomeres
2. Increased levels of cell cycle inhibitors
(p16, p21)
3. Accumulation of genetic errors
Cellular Aging and Senescence
Cellular Aging and Senescence
Role of Telomeres in replicative senescence
Consequences of caloric restriction on cell metabolism and survival pathways.
SIRT1Sirtuin1 –
histone
deacetylase
Caloric restriction (CR) promotes cellular resistance to stress, inhibits apoptosis,
promotes DNA repair and increases cellular production of antioxi-dants. CR
lowers blood insulin-like growth factor-l (IGF-I) and insulin levels, increases Sirt1
leves and DNA repair
Diseases of Premature Aging
1. Hutchinson-Guilford
progeria - the process of aging,
including features such as malepattern baldness, cataracts and
coronary artery disease, life
expectancy is less than 10 years
-Cause: mutation in the LMNA
gene encoding nuclear protein
lamin A ( abnormal protein
accumulates in the nucleus and
affect mitotic activity)
Diseases of Premature Aging
2. Werner syndrome (adult progeria) - early cataracts, hair
loss, atrophy of the skin, osteoporosis, atherosclerosis,
increased risk for the development of a variety cancers.
Patients typically die in the fifth decade. from either cancer or
cardiovascular disease. Life expectancy app. 50 years
Cause: loss of function of the Werner (WRN) gene, which codes
for a protein with multiple DNA-dependent enzymatic activities,
including ATPase, helicase, exonuclease and strand annealing
Diseases of Premature Aging
3. Cockayne syndrome easily sunburns, premature
aging, microcephaly,
neurodevelopment delay,
short stature (height <5th
percentile), contractures,
unsteady gait, spasticity,
rounded back, deep set eyes,
small slender straight nose,
dental caries, retinopathy
and/or cataracts, hearing loss,
life expectancy app. 12 years
Cause: mutations in the genes
that participate in
transcription-coupled DNA
repair, CSA and CSB, lead to
cells accumulating DNA
damage, causing defects in
transcription and eventuating
in cell death.
Age 12
Objectives Review:
Name the three most common causes of
fatty liver:
1. Diabetes
2. Obesity
3. Alcoholism
Objectives Review:
To know 2 morphological signs of alcoholic
hepatitis
1. fatty changes
2. Alcoholic hyaline - pink condensed ropy material
inside of the cells
Objectives Review:
Be able to name 2 diseases associated with
hyaline changes
1. Hyaline arteriosclerosis (Essential
Hypertension)
2. Hyaline membrane disease of the newborn(Neonatal Respiratory Distress Syndrome )
Objectives Review:
To know main causes of anthracotic
pigmentation of lungs
1. Smoking
2. Inhalation of carbon dust in big cities or occupational
hazard
Objectives Review:
List at least one tissue where is possible to find
deposition of Lipofuscin, Melanin and
Hemosiderin
1. Lipofuscin – Liver, Heart
2. Melanin – Melanoma
3. Hemosiderin – Liver, Lymph nodes.
Objectives Review:
List 3 types of tumors morphologically
associated with psammoma bodies
Papillary Thyroid Cancer
Papillary Ovarian Cancer
Meningioma
Objectives Review:
Name at least 2 diseases associated with
metastatic calcification
1 hyperparathyroidism (parathyroid gland tumors, renal
failure)
2 diffuse skeletal metastasis (multiple myeloma)
3 vitamin D intoxication
4 renal failure
Please, take your pen and answer
on the following questions
You have 80 seconds to answer
each question
Q1: A 69-year-old woman has had transient ischemic
attacks for the past 3 months. On physical
examination, she has an audible bruit on auscultation
of the neck. A right carotid endarterectomy is
performed. The curetted atheromatous plaque has a
grossly yellow-tan, firm appearance. Microscopically,
which of the following materials can be found in
abundance in the form of crystals that produce long,
cleft-like spaces?
(A) Glycogen
(B) Lipofuscin
(C) Hemosiderin
(D) Immunoglobulin
(E) Cholesterol
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End
Q2. An experiment analyzes cells for enzyme
activity associated with sustained cellular
proliferation. Which of the following
cells is most likely to have the highest telomerase
activity?
(A) Endothelial cells
(B) Germ cells
(C) Neurons
(D) Neutrophils
(E) Erythrocytes
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End
Q3: A 22-year-old woman has a congenital
anemia that has required multiple transfusions of
RBCs for many years. On physical examination,
she now has no significant findings; however,
liver function tests show reduced serum albumin
and high level of iron. Which of the following
findings would most likely appear in a liver biopsy
specimen?
(A) Steatosis in hepatocytes
(B) Bilirubin in canaliculi
(C) Glycogen in hepatocytes
(D) Amyloid in portal triads
(E) Hemosiderin in hepatocytes
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