Intracellular Accumulation Guide

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Notes on intracellular accumulations… By Dr. Ashish V. Jawarkar
Contact: pathologybasics@gmail.com Facebook: facebook.com/pathologybasics

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OVERVIEW CHART
INTRACELLULAR ACCUMULATIONS

METABOLIC PRODUCTS

PIGMENTS

1. Lipid metabolism disorder products
a. Fatty change
b. Cholesterol metabolism
- Atherosclerosis
- Xanthomas
- Cholesterosis
- Neimann-Pick disease type C

exogenous
endogenous
1. Coal
1.lipofuscin
a. CWP
2.Hemosiderin
b. anthracosis
3.Melanin
4.Homogent
2. Tattooing
isic acid
2. Protein metabolism disorder products
5. Bilirubin
a. Resorption droplets in proximal renal tubules
b. Russel Bodies
c. Alpha 1 antitrypsin deficiency
d. Cytoskeletal proteins
e. Amyloidosis
3. Carbohydrate metabolism disorder products
a. Glycogen storage disorders/Lysosomal storage
disorders
b. Diabetes Mellitus


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* Lipid Metabolism Disorder Products:

1. Fatty change (steatosis)
Normal mechanism of fat metabolism:

Causes of lipid accumulation in liver
1. Excessive entry of free fatty acids in liver
1. starvation
2. Inhibition of catabolism in liver
1. alcohol
2. hypoxia
3. Decreased synthesis of apoproteins
CCl4
1.
2. Protein malnutrition


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Morphology (Liver,Heart)
LIVER
Gross: 1. Enlarged (2-4 times)
2. Cut surface – bright yellow, soft, greasy

Diffuse hepatic steatosis results in pale, yellow parenchyma (as seen here) with greasy cut surfaces due
to lipid accumulation.

Microscopy:
In parenchymal cells
Early – small vacuoles in cytoplasm around the nucleus

Circled area shows early fatty change


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Late – Vacuoles coalesce and create clear spaces that displace nucleus to periphery of cell
Contiguous cells coalesce and produce fatty cysts

Circled area shows late fatty change – fat displacing nucleus to periphery
Special stains for fat demonstration
1. Sudan IV


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2. oil red O

3. PAS stain with diastase – cleared

glycogen

Not cleared with diastase

fat


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Frozen section

Ultrastructure
Early – minute membrane bound inclusions (liposomes) closely applied to ER

EM photos of a Kupffer cell loaded with fat


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HEART
Gross:
Bands of yellow myocardium alternating with unaffected myocardium – tigered
effect

Microscopy


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2. Cholesterol metabolism
A. Atherosclerosis

Plaques
Cholesterol accumulates in intimal layers
of aorta and large arteries
Accumulation is in smooth muscle cells
and macrophages

Cholesterol clefts
Cholesterol esters accumulate in form of
needle shaped crystals

Mechanism


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Atherosclerotic plaque

Atherosclerotic plaque


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Cholesterol clefts
B. Xanthomas
Clusters of foamy cells in subepithelial connective tissue and tendons producing
tumorous masses

Xanthomas


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Achilles tendon xanthoma


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C. Cholesterosis
Focal accumulation of cholesterol laden macrophages in lamina propria of gall bladder

Gall bladder cholesterosis
D. Neimann Pick disease Type C
Lysosomal storage disorder characterized by cholesterol accumulation in multiple organs
Niemann Pick Disease type C (NPC) is an autosomal recessive lipidosis that is
characterized by lysosomal storage of cholesterol and glycosphingolipids. In normal
mammalian cells, low-density lipoprotein (LDL) is bound and internalized by cell surface
receptors and is hydrolyzed in the endocytic compartment. The cholesterol that is
released is transported to the cell surface and endoplasmic reticulum.


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Depiction of the cholesterol transport pathways in normal and NPC cells.
In NPC cells, LDL-derived cholesterol accumulates in lysosomes and endosomes, LDLcholesterol transport from endocytic compartments to other cellular compartments is
delayed


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*Protein metabolism disorder products
A. Resorption droplets in proximal renal tubules
Proteins filtered through glomerulus are reabsorbed by pinocytosis through proximal
tubules
Seen as pink hyaline droplets within cytoplasm of tubular cells in proteinuric states

In proteinuric states, the proximal tubular epithelial cells reabsorbs proteins that has
leaked through the glomerular filter


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B. Russel bodies
In plasma cell myelomas, ER becomes hugely distended with homogenous pink (on HE)
eosinophilic inclusions – Russel bodies
These inclusions basically consist of immunoglobulins

Russel bodies on HE

Russel bodies on MGG


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3. α1 antitrypsin deficiency
Protein folding defect

Build up of partially folded proteins

Aggregate in ER of liver / also results in emphysema

the synthesized protein lacks the ability to migrate from endoplasmic reticulum (ER) to
Golgi zone and thus accumulates inside ER as hyaline globules


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4. Accumulation of cytoskeletal proteins
ALCOHOLIC HYALINE (MALLORY HYALINE)
Eosinophilic globules seen in liver cells, consists predominantly of keratin intermediate
filaments
Seen to be accumulated in alcoholic liver disease

At high magnification can be seen globular red hyaline material within hepatocytes.
NEUROFIBRILLARY TANGLE
Seen in Alzheimers disease

Neurofibrillary Tangles (NFTs) are aggregates of hyperphosphorylated tau protein that
are most commonly known as a primary marker of Alzheimer's Disease.


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5. Amyloidosis
See notes on amyloidosis


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* Carbohydrate metabolism disorder products
Glycogen
Glycgoen accumulates in renal tubular epithelial cells, liver cells and islets of langerhans,
heart cells in diabetes mellitus and glycogen storage disorders.
It is cleared by diastase unlike fat.
PAS gives it a rose violet color.

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of
defects in the processing of glycogen synthesis or breakdown within muscles, liver, and
other cell types


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* PIGMENTS
EXOGENOUS PIGMENTS
1. Carbon
Gets deposited in Coal worker’s pneumoconiosis and anthracosis.
Coal workers' pneumoconiosis (CWP), colloquially referred to as black lung disease, is
caused by long exposure to coal dust. It is a common affliction of coal miners and others
who work with coal, similar to both silicosis from inhaling silica dust, and to the longterm effects of tobacco smoking[citation needed]. Inhaled coal dust progressively builds up in
the lungs and is unable to be removed by the body; that leads to inflammation, fibrosis,
and in worse cases, necrosis.
Coal workers' pneumoconiosis, severe state, develops after the initial, milder form of the
disease known as anthracosis (anthrac — coal, carbon). This is often asymptomatic and
is found to at least some extent in all urban dwellers[1] due to air pollution.

Coal workers pneumoconiosis


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2. Tattooing
Pigments injected reside in dermal macrophages
No inflammatory response

Pigment in dermal macrophages


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ENDOGENOUS PIGMENTS
1. Lipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules
composed of lipid-containing residues of lysosomal digestion. It is considered to be one
of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retina,
adrenals, nerve cells, and ganglion cells. It is specifically arranged around the nucleus,
and is a type of lipochrome.

Neuronal lipofuscin


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2. Hemosiderin
Normally hemosiderin is seen in mononuclear phagocytes of bone marrow, spleen and
liver engaged in red cell break down.
Local deposition of hemosiderin can be seen in bruises
Systemic excess of iron as in increased dietry iron, hemolytic anemias and blood
transfusion leads to deposition in 1. Initially in phagocytes of spleen, liver, bone marrow and lymphnodes
(hemosiderosis)
2. Then in parenchymal cells of liver, pancreas (bronze diabetes), heart and
endocrine organs
It is a golden brown pigment on HE
Prussian blue stain is used to stain hemosiderin
Hemosiderosis
Due to iron excess due to various reasons
Deposition in phagocytes

Hemochromatosis
Due to inherited defect in iron transporter
Deposition in parenchymal cells

The hepatocytes and Kupffer cells here are full of granular brown deposits of
hemosiderin from accumulation of excess iron in the liver.


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A Prussian blue iron stain demonstrates the blue granules of hemosiderin in hepatocytes
and Kupffer cells.


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3. Melanin
Melanin is a derivative of the amino acid tyrosine, however it is not itself made of amino
acids and is not a protein. The pigment is produced in a specialized group of cells known
as melanocytes.
In humans, melanin is the primary determinant of skin color. It is also found in hair, the
pigmented tissue underlying the iris of the eye, and the stria vascularis of the inner ear. In
the brain, tissues with melanin include the medulla and pigment-bearing neurons within
areas of the brainstem, such as the locus coeruleus and the substantia nigra. It also occurs
in the zona reticularis of the adrenal gland.
Melanin is brown, non-refractile, and finely granular with individual granules having a
diameter of less than 800 nanometers. This differentiates melanin from common blood
breakdown pigments, which are larger, chunky, and refractile, and range in color from
green to yellow or red-brown. In heavily pigmented lesions, dense aggregates of melanin
can obscure histologic detail. A dilute solution of potassium permanganate is an effective
melanin bleach.

Pigmented melanoma


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4. Homogentisic acid
Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder of
phenylalanine and tyrosine metabolism.
This is an autosomal recessive condition that is due to a defect in the enzyme
homogentisate 1,2-dioxygenase which participates in the degradation of tyrosine.
As a result, homogentisic acid and its oxide, called alkapton, accumulate in the blood and
are excreted in urine in large amounts (hence -uria).
Excessive homogentisic acid causes damage to cartilage (ochronosis, leading to
osteoarthritis) and heart valves as well as precipitating as kidney stones


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6. Bilirubin
Accumulates in jaundice


Intracellular Accumulation Guide

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