1.

3 Intracellular Accumulations
Settings in which Substances Accumulate inside Cells:
An intracellular accumulation refers to the abnormal deposition of a substance inside a cell, whether in the cytoplasm, nucleus, or in the lysosomes. The settings in which this abnormal deposition occurs are: 1. Excess of Substance: there is excess amount of a normal substance inside the cell. 2. Abnormal Metabolism: there is a defective enzyme, resulting in the accumulation of its substrate. 3. Pigments: pigments (whether exogenous or endogenous) can accumulate inside cells, and the cell will have no idea of how to handle or get rid of it. Now we have examples for each type.

1. Excess of Substance
Fatty Change
Fatty change (or steatosis) is the

2. Protein

malnutrition will

(e.g. cause

in a

kwashiorkor)

deficiency of the apoproteins that are required for the export of triglycerides from the liver in the form of VLDL. 3. In diabetes mellitus there is

accumulation of triglycerides inside cells. Organs most commonly affected are the liver (since it is a central organ in metabolizing all kinds of things) and the heart (because it uses lipids a lot for energy). Triglycerides are made up of a glycerol backbone and three fatty acids. Therefore, excess production or decreased metabolism/transport of any of these two components can lead to fatty change. Some scenarios are: 1. Alcohol is the most common cause of fatty liver. It causes it mainly by increasing the level of NADH, which increases the production of glycerol-3-phosphate and of fatty acids, thus increasing the production of triglycerides.

increased lipolysis due to the reduced level of insulin (and this is helpful since you cannot make good use of your glucose). This results in a larger amount of fatty acids reaching the liver. 4. Anoxia causes mitochondrial

damage (which also alcohol does), thus slowing down the oxidation of fatty acids, and this leads to their accumulation. Under the microscope, fat appears as clear vacuoles (since it is removed in routine preparations) in the cytoplasm, often pushing the nucleus to the periphery. To see it, you can stain it orange-red with Sudan IV or oil red O.
1

Cholesterol and Cholesteryl Esters

Cholesterol stores are tightly regulated in body cells and are kept only as needed (e.g. for membrane synthesis.) Excess cholesterol can accumulate inside cells in a number of conditions: 1. In atherosclerotic plaques,

4. In

type

of

Niemann-Pick

3. If there is alcoholic liver damage, some of the cytoskeletal elements of the injured hepatocytes will accumulate as a pink material called Mallory hyaline (alcoholic hyalin). 4. Accumulation of proteins of

disease there is a problem in getting cholesterol out of late endosomes and lysosomes, leading to their accumulation in these organelles.

macrophages and smooth muscle cells accumulate cholesterol in their cytoplasm (thus they are called foam cells), giving an overall yellow color to the plaque. 2. Xanthomas collections of are tumor-like

Protein Accumulations
Normal or damaged proteins can pile up inside cells in a number of conditions: 1. Albumin can accumulate in the renal tubular cells in nephrotic syndrome (since a large amount of proteins are being filtered from the glomerulus and they are reabsorbed into the tubular cells.) 2. If plasma cells make too many immunoglobulins (as they do in some plasma cell tumors, like plasmacytomas), they will pile up in the RER, where they are called Russell bodies.

microtubules in the brain will form the neurofibrillary tangles seen in Alzheimer disease.

2. Abnormal Metabolism
When there is a defect in a particular enzyme of a certain metabolic pathway, there will be a buildup of the substrate of that enzyme in all the tissues that use it. A number of such genetic diseaess are: 1. Glycogen storage diseases (or glycogenoses): including Pompe disease, McArdle disease, von Gierke disease, etc. Note that a more common cause of glycogen accumulation is diabetes (it will be

cholesterol-laden

macrophages in the connective tissue of skin and tendons. It occurs in some hyperlipidemic states (whether hereditary or acquired). 3. In cholesterolosis of galbladder (strawberry gallbladder) there are cholesterol-laden macrophages in the lamina propria.

in the renal tubular cells, cardiac myocytes, and beta islet cells). 2. Lysosomal storage diseases: these include diseases like Tay-Sachs, Nieman-Pick, Gaucher, Hurler,

brown material (hence called brown atrophy). They are also responsible for the brown color of age spots (lentigo).

protect

the skin When

from harmful this

UV

radiation.

melanin

accumulates in keratinocytes and dermal macrophages, it can give rise to freckles.

Carbon
Carbon is present in many sources,

Hunter, etc. [See the presentation.] 3. Other enzyme defects like including coal dust. When this carbon is inhaled, alveolar it. macrophages Some of will these phagocytose

Hemosiderosis
Hemosidern refers to the aggregation of clumps of iron and apoferritin. Accumulation of this pigment occurs whenever there is an excess of iron. This occurs either from increased red cell breakdown (as occurs in a bruise) or when there is systemic excess of iron from blood transfusion, or increased iron absorption from the gut (as in primary hemochromatosis). Hemosiderin will give a yellow-brown color. It mainly accumulates in the liver, heart, and pancreas. Only when there is severe accumulation will it lead to injury

galactosemia, phenylketonuria, etc.

macrophages will then travel to the local

3. Pigments
Lipofuscin
This is the wear-and-tear pigment that appears with age due to free radical injury. When free radicals damage subcellular membranes, those parts of the membranes that are not degraded (by enzymes) will become lipofuscin. Lipofuscin is thus a marker of past free radical injury, but is not harmful by itself. It appears in the heart, liver, and brain in the form of a granular yellow-

lymphatics. The accumulation of these carbon-filled macrophages in the lungs and the lymph nodes will impart a black color to the area (anthracosis). Although benign in its mild form, severe accumulation can induce a fibroblastic response and lead to a serious disease called coal workers pneumoconiosis.

Melanin
Melanocytes are the exclusive factories of melanin production, which serves to

and

organ

damage,

including heart

liver failure

fibrosis,

diabetes,

and

(remember that iron can make free radicals by the Fenton reaction).

Pathologic Calcification
Deposition of calcium can occur on injured or dead cells (called dystrophic calcification) or it can even occur in normal tissues when (called there is hypercalcemia calcification). Calcium is grossly seen as white chalky material (since chalk is made of calcium carbonate), whereas microscopically it appears basophilic. When there is accumulation of large amount of calcium deposits, it is referred to as psammoma bodies (seen in a number of cancers, like papillary carcinoma of thyroid). Metastatic calcification, as stated above, occurs on normal tissues and results from hypercalcemia. Causes of hypercalcemia include: 1. Increased parathyroid renal failure, etc) production hormone of (e.g. metastatic

2. Increased bone destruction (e.g. Paget disease, multiple myeloma, metastatic bone tumors like leukemia, etc) 3. Vitamin D excess

parathyroid tumors, renal tumors,