Serdar Balcı

Intracellular Accumulations and Cellular Aging

Serdar BALCI, MD

Intracellular Accumulations


Inadequate removal of a normal substance secondary to defects in mechanisms of packaging and transport

Accumulation of an abnormal endogenous substance

Genetic or acquired defects

Folding, packaging, transport, or secretion


Failure to degrade a metabolite due to inherited enzyme deficiencies

Storage diseases

Deposition and accumulation of an abnormal exogenous substance

Cell cannot degrade or transport

Carbon or silica particles

Fatty Change (Steatosis)

Wheater’s Basic Pathology: A Text, Atlas and Review of Histopathology , Fifth Edition

Cholesterol and Cholesteryl Esters





coal dust

air pollutant

phagocytosed by alveolar macrophages

transported through lymphatic channels to the regional tracheobronchial lymph nodes

pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis)


Coal miners

Lipofuscin “wear-and-tear pigment”

insoluble brownish-yellow granular intracellular material

accumulates in heart, liver and brain

**age or atrophy. **

complexes of lipid and protein, free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes

when present in large amounts an appearance to the tissue that is called brown atrophy

not injurious to the cell but a marker of past free radical injury

By electron microscopy, the pigment appears as perinuclear electron-dense granules


an endogenous, brown-black pigment

synthesized by melanocytes located in the epidermis

screen against harmful ultraviolet radiation

**adjacent basal keratinocytes in the skin accumulate the pigment **

dermal macrophages

Differential Diagnosis in Surgical Pathology Figure 2-65: Blue Nevus


hemoglobin-derived granular pigment

accumulates in tissues when there is a local or systemic excess of iron

Iron is stored within cells with apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of ferritin micelles

readily visualized by light and electron microscopy

Other accumulations


Hyaline change


Usually, the word hyaline is used descriptively to refer to an accumulation of pink, glassy material. Many processes can lead to hyaline change, including: Protein accumulation (Russell bodies and alcoholic hyaline are pink and glassy)

Scarring (fibrous tissue in old scars can look pink and glassy)

Vascular changes in hypertension and diabetes (extravasated plasma proteins and deposition of basement membrane material can give the vessel walls a  pink, glassy appearance)

Mallory body (or Mallory hyaline) in the ballooning hepatocyte in the center of the photo.

Hyaline change in renal arteries

Pigments (colored substances) are sometimes seen in histologic sections. They can be normal or abnormal, and they may be from the outside (exogenous) or made inside the body (endogenous). There are five main pigments seen within tissues. 1. Carbon (coal dust) This is the most common exogenous pigment. It’s seen in urban dwellers, coal miners and smokers. The official name for the blackening of the lungs seen in these patients is anthracosis. 2. Tattoo pigment Tattoo pigments are often composed of metal salts (like iron oxide) but vegetable dyes and plastic-based dyes may be used too. The pigment is phagocytosed by dermal macrophages which retain the pigment for the person’s lifetime. 3. Lipofuscin This pigment, known as the wear-and-tear pigment, is composed of a bunch of lipids and proteins and has a yellow-brown appearance. ** **Here’s the awesome part. The name lipofuscin is derived, in part, from the Latin word fuscus, which means dingy, brown, or dark. That’s probably why “obfuscate” means “to make unclear or obscure.” This is the weird kind of thing that makes me inordinately happy. I have no idea why finding the Latin connection between two seemingly unrelated words should make me happy in such disproportionate measure - or happy at all - but it does. I try sharing this kind of thing with others but they look at me strangely and back away slightly. Happiness aside, lipofuscin accumulates with age, and is of no clinical significance. 

4. Melanin Melanin comes from the Greek word for black (melas). This doesn’t make me as happy as fuscus. I don’t know why. It is a deep brown-black pigment that is seen, not surprisingly, in melanocytes. 5. Hemosiderin This yellow-brown pigment is one of the major storage forms of iron. It is normally seen in macrophages in the bone marrow, spleen and liver (which are actively breaking down red cells). It is also seen when there is a local excess of iron (as in a bruise) or systemic excess of iron (for example, in patients with repeated blood transfusions.


Pathologic Calcification

Abnormal deposition of calcium salts

Together with smaller amounts of iron, magnesium, and other minerals

Dystrophic Calcification

Pathogenesis of dystrophic calcification

initiation (or nucleation) and propagation

may be either intracellular or extracellular

end product is crystalline calcium phosphate

Initiation in extracellular sites

Intracellular calcification

in the mitochondria of dead or dying cells that have lost their ability to regulate intracellular calcium

Propagation of crystal formation

Metastatic calcification

Occur in normal tissues

There is hypercalcemia

Causes of hypercalcemia

Morphology of Calcification


intracellular and/or extracellular basophilic deposits

Heterotopic bone may be formed in the focus of calcification.

Rosai and Ackerman’s Surgical Pathology Figure 18.127

**Peyronie disease. focal dystrophic calcification. **


Why do we age?

Underwood’s Pathology: A Clinical Approach , Sixth Edition

DNA damage

Metabolic insults that accumulate over time

Result in damage to nuclear and mitochondrial DNA

Most DNA damage is repaired by DNA repair enzymes

Some persists and accumulates as cells age

Aging syndromes are associated with defects in DNA repair mechanisms

Life span of experimental animals can be increased if responses to DNA damage are enhanced or proteins that stabilize DNA are introduced

Role of free radicals remains controversial

Decreased cellular replication


short repeated sequences of DNA present at the ends of linear chromosomes

a small section of the telomere is not duplicated, and telomeres become progressively shortened

the ends of chromosomes cannot be protected and are seen as broken DNA

signals cell cycle arrest


Telomere length is maintained by nucleotide addition

a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes

Telomerase activity

Defective protein homeostasis