2. Reversible cellular injury 2
Abnormal accumulation of proteins in the cell.
Abnormal accumulation of glycogen in the
cell. Glycogenosis.
Classification of pigment depositions in the
cell.
Hemoglobinogenic pigments. Hemosiderosis.
Deposition of bilirubin. Types of jaundice.
Deposition of non- hemoglobinogenic
/autochthonic/ pigments.
7. Abnormal accumulation of
proteins
Due to excesses proteins presented to
the cells or because the cells synthesize
excessive amounts
“Hyaline” = any “proteinaceous” pink
“glassy” substance
Examples
In the kidney
In nephrotic syndrome (disorders with
heavy protein leakage across the
glomerular filter and increased
reabsorption of the protein
Pinocytic vesicles containing this protein
fuse with lysosomes, resulting in the
histologic appearance of pink, hyaline
cytoplasmic droplets
The process is reversible -if the
proteinuria abates, the protein droplets
are metabolized and disappear.
8. Abnormal accumulation of
proteins
Examples
Russell bodies – rounded, eosinophilic bodies
in some plasma cells
with accumulation of newly synthesized
immunoglobulins in the RER
Mallory bodies or "alcoholic hyalin" -
eosinophilic cytoplasmic inclusion in liver cells
in alcoholic liver disease, due to
accumulations of intracellular proteins
composed of aggregated intermediate filaments
that resist degradation.
The neurofibrillary tangles - in the brain in
Alzheimer disease
aggregated protein inclusion that contains
microtubule-associated proteins and
neurofilaments,
9. Abnormal accumulation of
glycogen
Excessive intracellular deposits of
glycogen due to abnormalities in
the metabolism of either glucose
or glycogen
Water-clear vacuoles
PAS positive
Examples
In poorly controlled diabetes mellitus,
(abnormal glucose metabolism)
Renal proximal tubules – Armani-
Ebstein cells
Liver - cytoplasm, nuclei
Cardiac myocytes
Glycogen storage diseases or
glycogenoses
10. Glycogenosis
A group of autosomal recessive diseases with an inherited
deficiency of any one of the enzymes involved in glycogen
synthesis or degradation
can result in excessive accumulation of glycogen or some abnormal
form of glycogen in various tissues
predominantly in liver or muscles
A dozen forms of glycogenoses have been described on the
basis of specific enzyme deficiencies.
The type of glycogen stored, its intracellular location, and
the tissue distribution of the affected cells vary depending
on the specific enzyme deficiency
Regardless of the tissue or cells affected, the glycogen is most often
stored within the cytoplasm, or sometimes within nuclei
One variant (Pompe disease) is a form of lysosomal storage
11. Glycogenosis
On the basis of pathophysiology- 3 categories
Hepatic type
a deficiency of the hepatic enzymes involved in glycogen
metabolism ⇒ enlargement of the liver due to storage of
glycogen and hypoglycemia due to a failure of glucose
production
Von Gierke disease (type I glycogenosis), resulting from
a lack of glucose-6-phosphatase
Miopatic type
When enzymes that are involved in glycolysis are deficient,
glycogen storage occurs in muscles and there is an associated
muscle weakness due to impaired energy production
McArdle disease (type V glycogenosis), resulting from a
deficiency of muscle phosphorylase
Generalized glycogenosis
Pompe disease (type II)
deficiency of lysosomal acid maltase
associated with deposition of glycogen in virtually every
organ - cardiomegaly is most prominent
12. Classification of pigment depositions
in the cell
Pigments – specifically colored substances found
in the cells and tissues
Diagnostic significance
Classifications of pigments
Exogenous - coming from outside the body
Carbon, tattoo
Endogenous - synthesized within the body itself
Hemoglobinogenic pigments
Hemosiderin, bilirubin
Non- hemoglobinogenic (autochthonic) pigments
melanin, lipofucsin
13. Exogenous pigments
Inorganic chemical substances
Macrophages and parencymal cells –
lysosomes
Examples
Carbon (an example is coal dust), a
ubiquitous air pollutant of urban life.
When inhaled, it is phagocytosed by
alveolar macrophages and transported
through lymphatic channels to the
regional tracheobronchial lymph nodes.
Aggregates of the pigment blacken the
draining lymph nodes and pulmonary
parenchyma (anthracosis).
Heavy accumulations may induce
emphysema or a fibroblastic reaction
that can result in a serious lung disease
called coal workers' pneumoconiosis
Tatoo
Lead poisoning (saturnism)
gums – blue-black strip, “lead edge”
15. Endogenous pigments
Hemoglobinogenic pigments
Hemoglobin
Complex protein
Heme –Fe protoporhhyrin
Globin – 2 α chains and 2β chains
In breakdown of senescent erythrocytes -2 hemoglobinogenic pigments
Hemosiderin
Fe-containing component of heme
Bililubin
From protoporhhyrin component of heme
16. Hemosiderin
A hemoglobin-derived granular pigment
accumulates in tissues when there is a local or
systemic excess of iron
Iron is normally stored within cells in association
with the protein apoferritin, forming ferritin
micelles.
Hemosiderin pigment represents large
aggregates of these ferritin micelles is readily
visualized by light microscopy
golden yellow to brown coloor
the iron can be unambiguously identified by the
Prussian blue histochemical reaction
Hemosiderin accumulation is usually pathologic
small amounts of this pigment are normal in the
mononuclear phagocytes of the bone marrow,
spleen, and liver, where there is extensive red
cell breakdown.
Local excesses of iron, and consequently of
hemosiderin, result from hemorrhage.
A bruise
After lysis of the erythrocytes at the site of
hemorrhage, the red cell debris is phagocytosed by
macrophages; the hemoglobin content is then
catabolized by lysosomes with accumulation of the
heme iron in hemosiderin.
Haemosiderosis pulmonis – alveolar
17. Hemosiderosis
A condition whenever there is systemic overload
of iron and hemosiderin is deposited in many
organs and tissues
It is found at first in the mononuclear phagocytes of
the liver, bone marrow, spleen, and lymph nodes
and in scattered macrophages throughout other
organs.
With progressive accumulation, parenchymal cells
throughout the body (but principally the liver,
pancreas, heart, and endocrine organs) become
"bronzed" with accumulating pigment.
Hemosiderosis occurs in the setting of :
1. increased absorption of dietary iron
2. impaired utilization of iron
3. hemolytic anemias
4. transfusions (the transfused red cells constitute an
exogenous load of iron).
In most instances of systemic hemosiderosis, the
iron pigment does not damage the parenchymal
cells or impair organ function despite an
impressive accumulation
Exception - hereditary hemochromatosis
With more extensive accumulations of iron and tissue
injury including liver fibrosis, heart failure, and
diabetes mellitus.
18. Hereditary hemochromatosis
A genetic disorders characterized by the excessive
accumulation of body iron, most of which is deposited in the
parenchymal organs such as the liver and pancreas.
There are at least four genetic variants of hereditary hemochromatosis
The most common form is an autosomal recessive disease of adult onset
caused by mutations in the HFE gene, located on chromosome 6
regulate the levels of hepcidin, the iron hormone produced by the liver.
hepicidin normally down-regulates the efflux of iron from the intestines and
macrophages into the plasma and inhibits iron absorption. When hepcidin levels
are reduced there is
hepicidin levels are reduced in all currently known genetic forms of
hemochromatosis ⇒ ⇑ iron absorption
Morphology
deposition of hemosiderin - liver, pancreas, myocardium, pituitary, adrenal,
thyroid and parathyroid glands, joints, and skin;
cirrhosis; HCC
cardiomyopathy - arrithmias
pancreatic fibrosis -
skin pigmentation - increased epidermal melanin production, slate-gray.
19. Bilirubin metabolism and elimination.
Bilirubin is the end product of heme degradation
1, Normal bilirubin production (0.2-0.3 gm/day) is derived
primarily from the breakdown of senescent circulating
erythrocytes, with a minor contribution from
degradation of tissue heme-containing proteins.
2, Extrahepatic bilirubin is bound to serum albumin and
delivered to the liver.
3, Hepatocellular uptake, and
4, glucuronidation by glucuronosyltransferase in the
hepatocytes generates bilirubin monoglucuronides
and diglucuronides, which are water soluble and
readily excreted into bile.
5, Gut bacteria deconjugate the bilirubin and degrade it to
colorless urobilinogens. The urobilinogens and the
residue of intact pigments are excreted in the feces,
with some reabsorption and re-excretion into bile
Approximately 20% of the urobilinogens are
reabsorbed in the ileum and colon, returned to the
liver, and promptly re-excreted into bile.
Approximately 20% of the urobilinogens are reabsorbed
in the ileum and colon, returned to the liver, and
promptly re-excreted into bile.
Conjugated and unconjugated bile acids are also
reabsorbed in the ileum and returned to the liver by
enterohepatic circulation.
20. Jaundice and Cholestasis
Jaundice - occurs when systemic retention of bilirubin leads to
elevated serum levels above 2.0 mg/dL (the normal in the adult
is <1.2 mg/dL)
may reach 30-40 mg/dL in severe liver disease
a yellow discoloration of skin and sclerae (icterus)
Liver
ren
Cholestasis - systemic retention of not only bilirubin but also
other solutes eliminated in bile (particularly bile salts and
cholesterol)
↑ Alkaline phosphatase
↓ absorption of the fat-soluble vitamins A, D, and K.
Pruritus
Skin xantomas
22. Jaundice
Jaundice occurs when the
equilibrium between bilirubin
production and clearance is
disturbed by one or more of the
following mechanisms:
1. excessive production of
bilirubin,
2. reduced hepatic uptake,
3. impaired conjugation,
4. decreased hepatocellular
excretion,
5. impaired bile flow (both
intrahepatic and
extrahepatic).
The 1-st, 2-nd and 3-th
mechanisms
unconjugated
hyperbilirubinemia
The 4-th and 5-th
mechanisms
predominantly conjugated
hyperbilirubinemia.
More than one
mechanism may operate
to produce jaundice
one mechanism
predominates
23. Main Causes of Jaundice
Predominantly Unconjugated
Hyperbilirubinemia
Excess production of bilirubin
Hemolytic anemias
Resorption of blood from internal
hemorrhage (e.g., alimentary tract
bleeding, hematomas)
Ineffective erythropoiesis
syndromes (e.g., pernicious anemia,
thalassemia)
Reduced hepatic uptake
Drug interference with membrane
carrier systems
Diffuse hepatocellular disease (e.g.,
viral or drug-induced hepatitis,
cirrhosis)
Impaired bilirubin conjugation
Physiologic jaundice of the newborn
Predominantly Conjugated
Hyperbilirubinemia
Decreased hepatocellular excretion
Deficiency in canalicular membrane
transporters
Drug-induced canalicular
membrane dysfunction (e.g., oral
contraceptives, cycloporine)
Hepatocellular damage or toxicity
(e.g., viral or drug-induced
hepatitis, total parenteral nutrition,
systemic infection)
Impaired intra- or extra-hepatic bile
flow
Inflammatory destruction of
intrahepatic bile ducts (e.g.,
primary biliary cirrhosis, primary
sclerosing cholangitis, graft-versus-
host disease, liver transplantation)
25. Jaundice
May also result from inborn errors of metabolisms
Gilbert syndrome - a relatively common, benign, heterogeneous
inherited condition
due to decreased hepatic levels of glucuronosyltransferase
presenting as mild, fluctuating unconjugated hyperbilirubinemia
may go undiscovered for years and does not have associated
morbidity.
Dubin-Johnson syndrome - autosomal recessive defect
in the transport protein responsible for hepatocellular excretion of
bilirubin glucuronides across the canalicular membrane
asymptomatic conjugated hyperbilirubinemia
having a darkly pigmented liver and hepatomegaly, otherwise without
functional problems.
Rotor syndrome – multiple defects in uptake and excretion of
bilirubin
asymptomatic conjugated hyperbilirubinemia
Liver – not pigmented
26. Non- hemoglobinogenic pigments
Melanin
Melanin is an endogenous, brown-black
pigment produced in melanocytes
following the tyrosinase-catalyzed oxidation of
tyrosine to dihydroxyphenylalanine.
It is synthesized exclusively by melanocytes
located in the epidermis and acts as a screen
against harmful ultraviolet radiation.
Although melanocytes are the only source of
melanin, adjacent basal keratinocytes in the
skin can accumulate the pigment (e.g., in
freckles), as can dermal macrophages.
Increased melanin deposition-examples
Pigmented naevus
Addison’s disease
Melanoma
Decreased melanin
albinism –a leck of enzyme tirosinase
vitiligo –a local defficiency of melanin in the
dermis
28. Non- hemoglobinogenic pigments
Lipofuscin
Lipofuscin represents complexes of
lipid and protein that derive from the
free radical-catalyzed peroxidation of
polyunsaturated lipids of subcellular
membranes
"wear-and-tear pigment"
Lipofuscin is an insoluble brownish-
yellow granular intracellular material
accumulates in a variety of tissues
-particularly the heart, liver, and brain
as a function of age or atrophy.
The brown pigment when present in
large amounts, imparts an appearance
to the tissue that is called brown
atrophy.
By EM - the pigment appears as
perinuclear electron-dense granules
It is not injurious to the cell but is
important as a marker of past free-
radical injury.
