Intracellular accumulations

- 1 -

Notes on intracellular accumulations… By Dr. Ashish V. Jawarkar Contact: [email protected] Facebook: facebook.com/pathologybasics

- 2 -


OVERVIEW CHART

INTRACELLULAR ACCUMULATIONS

METABOLIC PRODUCTS PIGMENTS

1. Lipid metabolism disorder products a. Fatty change b. Cholesterol metabolism exogenous endogenous

- Atherosclerosis 1. Coal 1.lipofuscin - Xanthomas a. CWP 2.Hemosiderin - Cholesterosis b. anthracosis 3.Melanin - Neimann-Pick disease type C 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

- 3 -


* 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 1. CCl4 2. Protein malnutrition

- 4 -


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

- 5 -


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

- 6 -


2. oil red O

3. PAS stain with diastase – cleared glycogen

Not cleared with diastase fat

- 7 -


Frozen section

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

EM photos of a Kupffer cell loaded with fat

- 8 -


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

Microscopy

- 9 -


2. Cholesterol metabolism A. Atherosclerosis

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

Cholesterol esters accumulate in form of needle shaped crystals

Mechanism

- 10 -


Atherosclerotic plaque

Atherosclerotic plaque

- 11 -


Cholesterol clefts

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

Xanthomas

- 12 -


Achilles tendon xanthoma

- 13 -


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.

- 14 -


Depiction of the cholesterol transport pathways in normal and NPC cells.

In NPC cells, LDL-derived cholesterol accumulates in lysosomes and endosomes, LDL-cholesterol transport from endocytic compartments to other cellular compartments is delayed

- 15 -


*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

- 16 -


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

- 17 -


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

- 18 -


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.

- 19 -


5. Amyloidosis See notes on amyloidosis

- 20 -


* 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

- 21 -


* 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 long-term 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

- 22 -


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

Pigment in dermal macrophages

- 23 -


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

- 24 -


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 Hemochromatosis Due to iron excess due to various reasons Deposition in phagocytes

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.

- 25 -


A Prussian blue iron stain demonstrates the blue granules of hemosiderin in hepatocytes

and Kupffer cells.

- 26 -


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

- 27 -


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

- 28 -


6. Bilirubin Accumulates in jaundice

Intracellular accumulations

Health & Medicine

Transcript of Intracellular accumulations